COVID-19 Vaccines

fjara Copy-editor: R. Camp

Updated on 18 September 2021

We have changed the presentation of the scientific data. Please find below a continously updated bibliography, with commented articles previously presented in our daily top papers.

The original textbook chapter (last update: 23 May 2021) is still available at https://covidreference.com/Vaccines_May2021.


The latest:

17 September 2021

FDA 20210917. Vaccines and Related Biological Products Advisory Committee Meeting. FDA 2021, published 17 September. Full text: https://www.fda.gov/media/152161/download

A panel of advisers to the Food and Drug Administration voted not to recommend BioNTech/Pfizer booster shots for most Americans. They

  • voted 18-0 in support of a booster shot of the BioNTech/Pfizer vaccine for people 65 and older or at high risk of severe COVID-19;
  • voted 16-2 against approval of a booster dose of the vaccine for all people 16 years and older.

The panel also unanimously supported authorization of a booster dose for health care workers or others at high risk of occupational SARS-CoV-2 exposure.

Find more about booster injections here.

 

17 September 2021

Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions — United States, March–August 2021. MMWR Morb Mortal Wkly Rep. ePub: 17 September 2021. Full text: http://dx.doi.org/10.15585/mmwr.mm7038e1

In this analysis of 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals during March 11–August 15, 2021 vaccine effectiveness (VE) against COVID-19 hospitalization as higher for the Moderna vaccine (93%) than the BioNTech/Pfizer vaccine (88%) and the Janssen vaccine (71%). Protection for the BioNTech/Pfizer vaccine declined 4 months after vaccination. Differences in VE between the two mRNA vaccines might be due to 1) higher mRNA content in the Moderna vaccine, 2) differences in timing between doses (3 weeks for Pfizer-BioNTech versus 4 weeks for Moderna), or possible differences between groups that were not accounted for in the analysis.

 

15 September 2021

Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021 Sep 15. PubMed: https://pubmed.gov/34525275. Full text: https://doi.org/10.1056/NEJMoa2114255

A booster dose of the BioNTech/Pfizer vaccine may reduce the rates of both confirmed infection and severe Covid-19 illness. In this large Israeli population of people 60 years of age or older (n = 1,137,804, fully vaccinated at least 5 months earlier), the rates of 1) confirmed infection and 2) severe illness were lower in the booster group than in the nonbooster group by a factor of 11.3 and 19.5, respectively.


Vaccines: Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective and will help ending or at least slowing down the pandemic in the immediate future.

Breakthrough infections, either asymptomatic or symptomatic, may occur in fully vaccinated people. Symptoms are generally mild. The risk of severe COVID-19 and death is around 10 times lower than for unvaccinated individuals.

If infected, vaccinated people can transmit SARS-CoV-2 (although the window of transmissibility is probably shorter than in unvaccinated individuals). In places with high community transmission, vaccinated people should continue to adopt measures of social distancing.

Vaccine-mediated immunity wanes over time. Early booster injections might benefit elderly and immunosuppressed people. The usefulness of booster injections in other population groups is currently being discussed.

Updated vaccines which target new SARS-CoV-2 variants, especially the Delta variant, are under development.

 

Approved Vaccines

BioNTech/Pfizer vaccine

Moderna vaccine

AstraZeneca vaccine

Johnson & Johnson vaccine

Gamaleya vaccine

Sinovac vaccine

Sinopharm vaccine

Bharat vaccine

Novavax vaccine

Efficacy

General efficacy

Antibody response and protection

Hybrid immunity

Breakthrough infections and SARS-CoV-2 transmission

Booster vaccination

Heterologous vaccine schedules

Timing of the second vaccine dose

Vax vs. No-vax

Adverse Events

Thromboses and thrombocytopenia (VITT)

Anaphylaxis and allergic reactions

Myocarditis

Facial paralysis

Other

Special Populations

Elderly people

Pregnant women

Children and adolescents

Oncology and hematology

Neurology

HIV

Chronic inflammatory diseases

Autoimmune diseases

Special Topics

Global inequality

Impact on local epidemics

Interventional vaccinology

Differential diagnosis

COVID vaccines: History and development

Future

Pan-coronavirus vaccines

Aerosolized vaccines

Past futures


Approved Vaccines

As of 28 August 2021, four COVID-19 vaccines have been approved or authorized for emergency use in the EU or the US:

  • The BioNTech/Pfizer vaccine. Trade name: Comirnaty™ (tozinameran, formerly known as BNT162b2)
  • The Moderna vaccine. Trade name: Spikevax™ (elasomeran, formerly known as mRNA-1273)
  • The AstraZeneca/University of Oxford vaccine. Trade name: Vaxzevria™/Covishield™ (formerly known as ChAdOx1 nCoV-19, AZD1222)
  • The Johnson & Johnson (Janssen) vaccine, also known as Ad26.COV2.S

Outside the EU and the US, other vaccines have been approved, for example:

  • The Gamaleya vaccine (Sputnik-V), first approved in Russia, 28 December 2020
  • The Sinovac vaccine (CoronaVac), first approved in China
  • The Bharat vaccine (Covaxin), first approved in India on 3 January 2021

Vaccines that might be approved soon include:

  • The Novavax Vaccine

BioNTech/Pfizer vaccine

In November 2020, the German company BioNTech and the New York-based Pfizer made history by presenting data which indicated that their vaccine tozinameran (formerly BNT162b2; trade name: Comirnaty™) had an extraordinary efficacy of over 90% (Polack 2020).

Four months later, these results were reproduced in a spectacular real-life analysis of almost 1.2 million people in Israel (Dagan 2021).

Recent work suggests that vaccine efficacy wanes with time. In some countries, a third booster dose vaccination is currently under way or is being considered.

In August 2021, The BioNTech/Pfizer vaccine was the first COVID-19 vaccine to gain full approval by the FDA (FDA 20210823).

 

15 September 2021

Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021 Sep 15. PubMed: https://pubmed.gov/34525275. Full text: https://doi.org/10.1056/NEJMoa2114255

A booster dose of the BioNTech/Pfizer vaccine may reduce the rates of both confirmed infection and severe Covid-19 illness. In this large Israeli population of people 60 years of age or older (n = 1,137,804, fully vaccinated at least 5 months earlier), the rates of 1) confirmed infection and 2) severe illness were lower in the booster group than in the nonbooster group by a factor of 11.3 and 19.5, respectively.

 

28 August

Barda N, Dagan N, Ben-Shlomo Y, et al. Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. N Engl J Med. 2021 Aug 25. PubMed: https://pubmed.gov/34432976. Full text: https://doi.org/10.1056/NEJMoa2110475

This observational data set involving more than 2.4 million vaccinated persons from Israel identified an excess risk of lymphadenopathy (78.4 events per 100,000 persons), herpes zoster infection (15.8 events), appendicitis (5.0 events), and myocarditis (2.7 events). Compared to the risk of adverse events associated with SARS-CoV-2 infection, this is almost meaningless.

 

21 July 2021

Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021 Jul 21. PubMed: https://pubmed.gov/34289274. Full-text: https://doi.org/10.1056/NEJMoa2108891

Effectiveness after one dose of the BioNTech/Pfizer or AstraZeneca was lower among individuals infected with the Delta variant (B.1.671.2, “India”) than with the Alpha variant (B.1.1.7, “England”): Delta, 30.7% – Alpha, 48.7% (there was no difference between the two vaccines). After two doses, differences in vaccine effectiveness with the two variants were modest, but the BioNTech/Pfizer vaccine was superior to the AstraZeneca vaccine (BioNTech/Pfizer: Delta, 88.0% – Alpha, 93.7%; AstraZeneca: Delta, 67.0%; Alpha, 74.5%).

 

30 June 2021

Thompson MG, Burgess JL, Naleway AL, et al. Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines. N Engl J Med. 2021 Jul 22;385(4):320-329. PubMed: https://pubmed.gov/34192428. Full text: https://doi.org/10.1056/NEJMoa2107058

This prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers shows that mRNA vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination.

 

7 June 2021

Chodick G, Tene L, Patalon T, et al. Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization. JAMA Netw Open. 2021 Jun 1;4(6):e2115985. PubMed: https://pubmed.gov/34097044. Full text: https://doi.org/10.1001/jamanetworkopen.2021.15985

In this study of 503,875 individuals from Israel who received 1 dose of the BNT162b2 vaccine, the first dose was associated with an approximately 54% reduction in the risk of symptomatic SARS-CoV-2 infections at 13 to 24 days after immunization compared to 1 to 12 days after vaccination.

 

17 May 2021

Chodick G, Tene L, Rotem RS, et al. The effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world data. Clinical Infectious Diseases May 17, 2021, ciab438, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab438/6276888

Real life data from Israel. Incidence rate of a SARS-CoV-2 infection between 7 to 27 days after the second dose (the protection period) was compared to days 1 to 7 after the first dose, where no protection by the vaccine is assumed (the reference period). In 1.1 million vaccinated persons, vaccine effectiveness in preventing infection was 90% and 94% against COVID-19. Look at the beautiful Figure 1.

 

14 May 2021

Pilishvili T, Fleming-Dutra KE, Farrar JL, et al. Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel — 33 U.S. Sites, January–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 14 May 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7020e2.htm

This large US multisite test-negative design vaccine effectiveness study among HCP found a single dose of Pfizer-BioNTech or Moderna vaccines to be 82% effective against symptomatic COVID-19 and 2 doses to be 94% effective.

 

13 May

Bernal JL, Andrews N, Gower C, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ May 13, 2021; 373. https://www.bmj.com/content/373/bmj.n1088

Early real-life data in older people (older than 70 years) from England: with BNT162b2, vaccine effectiveness reached 61% from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards.

 

8 May 2021

Hall VJ, Foulkes S, Saei A, et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021 May 8;397(10286):1725-1735. PubMed: https://pubmed.gov/33901423. Full text: https://doi.org/10.1016/S0140-6736(21)00790-X

These data from the SIREN (Sarscov2 Immunity and REinfection EvaluatioN) study suggest that the Pfizer-BioNTech vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults. (The SIREN study is a prospective cohort study among staff working in publicly funded hospitals.) The vaccine was 72% effective (95% CI 58-86) 21 days after first dose and 86% effective (95% CI 76-97) seven days after two doses in the antibody negative cohort (Hall 2021).

 

6 May 2021

Angel Y, Spitzer A, Henig O, et al. Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers. JAMA. 2021 Jun 22;325(24):2457-2465. PubMed: https://pubmed.gov/33956048. Full text: https://doi.org/10.1001/jama.2021.7152

Among 6710 health care workers in Tel Aviv, 757 (11.3%) were not vaccinated. Symptomatic SARS-CoV-2 infection occurred in 8 fully vaccinated and 38 unvaccinated health care workers (adjusted IRR, 0.03). The corresponding numbers for asymptomatic SARS-CoV-2 infections were 19 and 17, respectively (adjusted IRR, 0.14). Results were qualitatively unchanged by the propensity score sensitivity analysis.

 

5 May 2021

Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet. 2021 May 15;397(10287):1819-1829. PubMed: https://pubmed.gov/33964222. Full text: https://doi.org/10.1016/S0140-6736(21)00947-8

 

By April 3, 2021, 4.7 M people aged 16 years and older were fully vaccinated with two doses of BNT162b2 in Israel. Vaccine effectiveness at 7 days or longer after the second dose was 95% against SARS-CoV-2 infection, 97% against symptomatic COVID-19, 97% against hospitalization, and 98% against severe or critical disease. In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 outcomes declined. Estimated prevalence of the B.1.1.7 variant was 95%.

 

5 May 2021

Abu-Raddad LJ, Chemaitelly H, Butt AA; National Study Group for COVID-19 Vaccination. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. N Engl J Med. 2021 Jul 8;385(2):187-189. PubMed: https://pubmed.gov/33951357. Full text: https://doi.org/10.1056/NEJMc2104974

Following a mass immunization campaign with BNT162b2 in Qatar, as of March 31, 2021, a total of 385,853 persons had received at least one vaccine dose and 265,410 had completed both doses. The estimated effectiveness against any documented infection with the B.1.1.7 variant was 89.5% at 14 days or more after the second dose. The effectiveness against any documented infection with the B.1.351 variant was 75%. Of note, effectiveness against severe, critical, or fatal disease (with the B.1.1.7 and B.1.351 variants being predominant in Qatar) was very high, at 97%.

 

23 April

Vasileiou E, Simpson CR, Shi T, et al. Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. Lancet. 2021 May 1;397(10285):1646-1657. PubMed: https://pubmed.gov/33901420. Full text: https://doi.org/10.1016/S0140-6736(21)00677-2

Paper of the day! Between Dec 8, 2020, and Feb 22, 2021, a total of 1,331,993 people were vaccinated in Scotland. The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85–94) for reduced COVID-19 hospital admission at 28–34 days post-vaccination. Vaccine effect for the ChAdOx1 vaccine was 88% (95% CI: 75–94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar the analysis was restricted to those aged 80 years and older (83%, 95% CI: 72–89).

 

15 April 2021

Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021 Apr 15;384(15):1412-1423. PubMed: https://pubmed.gov/33626250. Full text: https://doi.org/10.1056/NEJMoa2101765

No doubt, paper of the day! Encouraging real-life data from Israel: Estimated vaccine effectiveness (> 1 M people vaccinated) during the follow-up period starting 7 days after the second dose was 92% for documented infection, 94% for symptomatic COVID-19, 87% for hospitalization, and 92% for severe COVID-19. Estimated effectiveness days 14 through 20 (after one dose) and days 21 through 27 (gradual shifting between the first and second vaccine doses) was 46% and 60% for documented infection, 57% and 66% for symptomatic COVID-19, 74% and 78% for hospitalization, 62% and 80% for severe COVID-19, and 72% and 84% for COVID-19–related death, respectively.

 

29 March 2021

Thompson MG, Burgess JL, Naleway AL, et al. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers – Eight U.S. Locations, December 2020-March 2021. MMWR Morb Mortal Wkly Rep. 2021 Apr 2;70(13):495-500. PubMed: https://pubmed.gov/33793460. Full text: https://doi.org/10.15585/mmwr.mm7013e3

In this prospective cohort of 3950 health care personnel, first responders, and other essential and frontline workers who completed weekly SARS-CoV-2 testing for 13 consecutive weeks, mRNA vaccine effectiveness of full immunization (≥ 14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥ 14 days after first dose but before second dose) was 80%.

 

18 February

Amit S, Regev-Yochay G, Afek A, Kreiss Y, Leshem E. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. Lancet. 2021 Mar 6;397(10277):875-877. PubMed: https://pubmed.gov/33610193. Full text: https://doi.org/10.1016/S0140-6736(21)00448-7

Good news from Israel, showing substantial early reductions in SARS-CoV-2 infection and symptomatic COVID-19 rates following first mRNA vaccine dose administration. Using a retrospective cohort of 9109 vaccine-eligible HCWs, Sharon Amit and colleagues estimate adjusted rate reductions of SARS-CoV-2 infections of 30% and 75% for days 1–14 and days 15–28 after the first dose, respectively.

 

1 February 2021

Vogel AB, Kanevsky I, Che Y, et al. Immunogenic BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature. 2021 Feb 1. PubMed: https://pubmed.gov/33524990. Full-text: https://doi.org/10.1038/s41586-021-03275-y

The people from BioNTech talk about the beginnings of the vaccine developed now in cooperation with Pfizer. This Nature paper reports the first antigen-specific immune responses in… mice and rhesus macaques.

 

29 January 2021

Muik A, Wallisch AK, Sänger B, et al. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera. Science. 2021 Mar 12;371(6534):1152-1153. PubMed: https://pubmed.gov/33514629. Full text: https://doi.org/10.1126/science.abg6105

The authors tested SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 40 participants who were vaccinated in a previously reported trial with the Pfizer-BioNTech mRNA-based vaccine Comirnaty. The immune sera had slightly reduced but overall largely preserved neutralizing titers against the B.1.1.7 lineage pseudovirus. These data indicate that the B.1.1.7 lineage will not escape BNT162b2-mediated protection.

 

23 December 2020

EMA 20201221. Comirnaty. European Medicines Agency 2020, published 23 December. Full-text: https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty

Find the 32-page product information of the EMA.

 

13 December 2020

Oliver SE, Gargano JW, Marin M, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine – United States, December 2020. MMWR Morb Mortal Wkly Rep. 2020 Dec 18;69(50):1922-1924. PubMed: https://pubmed.gov/33332292. Full text: https://doi.org/10.15585/mmwr.mm6950e2

On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of the Pfizer-BioNTech COVID-19 vaccine in persons aged ≥ 16 years for the prevention of COVID-19. Mass vaccinations in the US started two days later.

 

10 December

Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. PubMed: https://pubmed.gov/33301246. Full text: https://doi.org/10.1056/NEJMoa2034577

The first data from a phase 2/3 trial evaluating the safety, immunogenicity, and efficacy of 30 μg of the Pfizer/BioNTech vaccine candidate BNT162b2. A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Reactogenicity was generally mild or moderate, and reactions were less common and milder in older adults than in younger adults. A must-read.

Moderna vaccine

Like the Pfizer vaccine, the Moderna vaccine had more than 90% efficacy at preventing COVID-19 illness, including severe disease (Baden 2021). (This study is the equivalent of the Polack study for the BioNTech/Pfizer vaccine.)

Antibodies elicited by the vaccine have been shown to persist through 6 months after the second dose (Doria-Rose 2021) – and will probably persist much longer.

 

17 September 2021

Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions — United States, March–August 2021. MMWR Morb Mortal Wkly Rep. ePub: 17 September 2021. Full text: http://dx.doi.org/10.15585/mmwr.mm7038e1

In this analysis of 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals during March 11–August 15, 2021 vaccine effectiveness (VE) against COVID-19 hospitalization as higher for the Moderna vaccine (93%) than the BioNTech/Pfizer vaccine (88%) and the Janssen vaccine (71%). Protection for the BioNTech/Pfizer vaccine declined 4 months after vaccination. Differences in VE between the two mRNA vaccines might be due to 1) higher mRNA content in the Moderna vaccine, 2) differences in timing between doses (3 weeks for Pfizer-BioNTech versus 4 weeks for Moderna), or possible differences between groups that were not accounted for in the analysis.

 

1 September 2021

Steensels D, Pierlet N, Penders J, et al. Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273. JAMA August 30, 2021. https://jamanetwork.com/journals/jama/fullarticle/2783797

This large prospective cohort study in Belgian HCWs demonstrated a significantly higher humoral immunogenicity of the mRNA-1273 vaccine (Moderna) compared with the BNT162b2 vaccine (Pfizer-BioNTech), in infected as well as in uninfected participants, and across age categories. According to the authors, the higher mRNA content in mRNA-1273 compared with BNT162b2 and the longer interval between priming (4 weeks vs 3 weeks for BNT162b2) might explain this difference.

 

12 August 2021

Pegu A, O’Connell S, Schmidt SD, et al. Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants. Science 2021, published 12 August. PubMed: https://pubmed.gov/34031659. Full text: https://doi.org/10.1126/science.abj4176

Most individuals vaccinated with the Moderna vaccine maintained binding and functional antibodies against SARS-CoV-2 variants for 6 months, including Alpha, Beta, Gamma, B.1.429, and B.1.526. Neutralizing responses were rare after a single Moderna dose, but at the peak of response to the second dose, all individuals had robust responses to all variants. The study included the results from 8 volunteers in each of three age groups: 18-55, 55-70, and 71+ years of age.

 

29 July 2021

Corbett KS, Nason MC, Flach B, et al. Immune Correlates of Protection by mRNA-1273 Immunization against SARS-CoV-2 Infection in Nonhuman Primates. Science 2021, published 29 July. PubMed: https://pubmed.gov/33907752. Full text: https://science.sciencemag.org/content/early/2021/07/29/science.abj0299

In Rhesus macaques, viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs following a SARS-CoV-2 challenge in vaccinated animals and strongly correlated with levels of anti-S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway.

 

16 June 2021

Gupta K, O’Brian WJ, Bellino P, et al. Incidence of SARS-CoV-2 Infection in Health Care Workers After a Single Dose of mRNA-1273 Vaccine. JAMA Netw Open June 16, 2021;4(6):e2116416. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781173

This study demonstrated an association between receipt of the mRNA-1273 vaccine and a reduction in SARS-CoV-2 infection in HCWs beginning 8 days after dose 1. Vaccine clinical effectiveness was 50.3% for the entire 42-day period of follow-up, 77.5% for days 8 through 42, and 95.0% for days 15 through 42.

 

21 May 2021

Chu L, McPhee R, Huang W, et al. A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine. Vaccine. 2021 May 12;39(20):2791-2799. PubMed: https://pubmed.gov/33707061. Full text: https://doi.org/10.1016/j.vaccine.2021.02.007

Half-doses (50 μg) of Moderna’s mRNA-1273 vaccine might be as good as full doses (100 ug) at eliciting robust immune responses.

 

14 May 2021

Pilishvili T, Fleming-Dutra KE, Farrar JL, et al. Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel — 33 U.S. Sites, January–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 14 May 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7020e2.htm

This large US multisite test-negative design vaccine effectiveness study among HCP found a single dose of Pfizer-BioNTech or Moderna vaccines to be 82% effective against symptomatic COVID-19 and 2 doses to be 94% effective.

 

6 April 2021

Doria-Rose N, Suthar MS, Makowski M, et al. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19. N Engl J Med. 2021 Apr 6. PubMed: https://pubmed.gov/33822494. https://www.nejm.org/doi/10.1056/NEJMc2103916

In 33 healthy adult participants in an ongoing Phase I trial, antibodies that were elicited by mRNA-1273 (Moderna) persisted through 6 months after the second dose, as detected by three distinct serologic assays.

 

29 March 2021

Thompson MG, Burgess JL, Naleway AL, et al. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 29 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm

In this prospective cohort of 3950 health care personnel, first responders, and other essential and frontline workers who completed weekly SARS-CoV-2 testing for 13 consecutive weeks, mRNA vaccine effectiveness of full immunization (≥ 14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥ 14 days after first dose but before second dose) was 80%.

 

3 March 2021

Kimberly G. Blumenthal KG, Freeman EE, Saff RR. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. NEJM, March 3, 2021. DOI: 10.1056/NEJMc2102131. https://www.nejm.org/doi/full/10.1056/NEJMc2102131

Case series of 12 delayed large but varying local reactions to the mRNA-1273 vaccine, with a median onset on day 8 after the first dose. After the second shot, 6 had no recurrence, 3 had similar and 3 had recurrent reactions that were of a lower grade than those after the initial dose.

 

6 January 2021

EMA 20210106. COVID-19 Vaccine Moderna. European Medicines Agency 2021, published 6 January. Full-text: https://www.ema.europa.eu/en/medicines/human/summaries-opinion/covid-19-vaccine-moderna

Find the product information as approved by the CHMP on 6 January 2021, pending endorsement by the European Commission.

 

1 January 2021

Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2021 Feb 4;384(5):403-416. PubMed: https://pubmed.gov/33378609. Full text: https://doi.org/10.1056/NEJMoa2035389

Finally – after press releases, an emergency use authorization and the start of mass vaccinations – the scientific paper by Lindsey Baden et al.! Nothing new: the mRNA-1273 vaccine developed by Moderna and the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID), within the National Institutes of Health (NIH), has more than 90% efficacy at preventing COVID-19 illness, including severe disease. Moderate-to-severe systemic side effects, such as fatigue, myalgia, arthralgia, and headache, were noted in about 50% of participants in the mRNA-1273 group after the second dose. These side effects were transient, starting about 15 hours after vaccination and resolving in most participants by day 2, without sequelae. The incidence of serious adverse events reported throughout the entire trial was similar for mRNA-1273 and placebo. Importantly, mRNA-1273 did not show evidence in the short term of enhanced respiratory disease after infection, a concern that had emerged from animal models used in evaluating SARS and Middle East Respiratory Syndrome (MERS) vaccine constructs. The authors rightly conclude that the safety of the mRNA-1273 vaccine regimen seems to be reassuring.

 

1 January 2021

Oliver SE, Gargano JW, Marin M, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Moderna COVID-19 Vaccine – United States, December 2020. MMWR Morb Mortal Wkly Rep. 2021 Jan 1;69(5152):1653-1656. PubMed: https://pubmed.gov/33382675. Full text: https://doi.org/10.15585/mmwr.mm695152e1

The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Moderna COVID-19 (mRNA-1273) vaccine. Adverse events that occur in a recipient after receipt of COVID-19 vaccine should be reported to the Vaccine Adverse Events Reporting System (VAERS). FDA requires that vaccination providers report vaccination administration errors, serious adverse events, cases of multisystem inflammatory syndrome, and cases of COVID-19 that result in hospitalization or death after administration of the COVID-19 vaccine under an EUA. Information on how to submit a report to VAERS is available at https://vaers.hhs.gov/index.html.

 

17 December 2020

Anderson EJ, Rouphael NG, Widge AT, et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N Engl J Med, December 17 2020; 383:2427-2438. Full-text: https://doi.org/10.1056/NEJMoa2028436

Phase I, dose-escalation, open label trial in 40 older adults. Serum neutralizing activity was detected in all the participants by multiple methods after the second immunization. Solicited adverse events were dose-dependent and predominantly mild or moderate in severity.

 

3 December 2020

Widge AT, Rouphael NG, Jackson LA. Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination. N Engl J Med 2020, published 3 December. Full-text: Full-text: https://doi.org/10.1056/NEJMc2032195

The correlates of protection against SARS-CoV-2 infection are not yet established. In this short letter, Alicia Widge et al. report the results of immunogenicity studies 3 months after the second vaccination with mRNA-1273. (The 57 days results were published by Jackson et al. in July and Anderson et al. in September.) The data shows that mRNA-1273 produced high levels of binding and neutralizing antibodies that declined slightly over time but they remained elevated in all participants 3 months after the booster vaccination. The authors conclude that mRNA-1273 has the potential to provide durable humoral immunity. Studies of vaccine-induced B cells are ongoing.

 

12 August 2020

Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020, published 12 August. Full-text: https://doi.org/10.1038/s41586-020-2639-4

Mark Mulligan, Kirsten Lyke, Nicholas Kitchin, Judith Absalon and colleagues report the safety, tolerability, and immunogenicity data from an ongoing study among 45 healthy adults, randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1. BNT162b1, developed by BioNTech and Pfizer, is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD). A clear dose-level response in elicited neutralizing titers was observed after doses 1 and 2 with a particularly steep dose response between the 10 μg and 30 μg dose levels. Geometric mean neutralizing titers reached 1.9- to 4.6-fold that of a panel of COVID-19 convalescent human sera at least 14 days after a positive SARS-CoV-2 PCR. The clinical testing of BNT162b1 is taking place in the context of a broader, ongoing COVID-19 vaccine development program by both companies. That program includes the clinical testing of three additional vaccine candidates, including candidates encoding the full-length spike.

 

5 August 2020

Corbett KS, Edwards DK, Leist SR et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 2020, published 5 August. Full-text: https://doi.org/10.1038/s41586-020-2622-0

Barney Graham, Andrea Carfi and colleagues show that mRNA-1273, a vaccine currently tested in Phase 3 trials, protects mice against SARS-CoV-2 infection in the lungs and noses without evidence of immunopathology. The vaccine induced both potent neutralizing antibody responses to wild-type (D614) and D614G mutant2 SARS-CoV-2 and CD8 T cell responses. The authors are prolific – a week ago, they evaluated the same vaccine in non-human primates and published their paper in the N Engl J Med. Read also the last paragraph of this week’s paper where Corbett et al. describe a new paradigm for rapid vaccine development.

 

29 July 2020

Corbett KS, Flynn B, Foulds KE, et al. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med 2020, published 28 July. Full-text: https://doi.org/10.1056/NEJMoa2024671

Vaccination of non-human primates with mRNA-1273 induces robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. For this important vaccine trial, Barney S. Graham, Robert A. Seder and colleagues divided 12 female and 12 male Indian-origin rhesus macaques into groups of three and vaccinated them intramuscularly at week 0 and at week 4 with either 10 or 100 μg of mRNA-1273 or placebo. At week 8 (4 weeks after the second vaccination), all animals were challenged with SARS-CoV-2. mRNA-1273 induced antibody levels exceeding those found in human convalescent phase serum. Vaccination also induced type 1 helper T cell (Th1)–biased CD4 T cell responses and low or undetectable Th2 or CD8 T cell responses.

No viral replication was detectable in the nose of any of the eight animals in the 100 μg dose group by day 2 after challenge (8 weeks after the first vaccination). The ability to limit viral replication in both the lower and the upper airways will have important implications for vaccine-induced prevention of both SARS-CoV-2 disease and transmission.

 

16 July 2020

Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 – Preliminary Report. N Engl J Med. 2020 Jul 14. PubMed: https://pubmed.gov/32663912. Full-text: https://doi.org/10.1056/NEJMoa2022483

This study conducted in Washington and Atlanta evaluated the candidate vaccine mRNA-1273 that encodes the stabilized prefusion SARS-CoV-2 spike protein. In a Phase I open label trial, 45 healthy adults received two vaccinations, 28 days apart, at three different doses. Antibody responses were higher with a higher dose and further increased after the second vaccination, leading to serum-neutralizing activity in all participants. Values were similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in > 50% included fatigue, chills, headache, myalgia, and pain at the injection site.

AstraZeneca vaccine

A company press release about a 32,000-person study in the US, Peru and Chile (AstraZeneca 20210325) suggested a 76% efficacy of the AstraZeneca vaccine (Vaxzevria™, formerly AZD1222, ChAdOx1 nCoV-19) against symptomatic SARS-CoV-2 infection.

Preliminary data suggest that long-time efficacy could be comparable to that of the Pfizer and Moderna vaccines.

The development of the AstraZeneca has been plagued by turbid data, supply shortfalls and difficult negotiations with EU.

The AstraZeneca vaccine has been linked to rare, but life-threatening thromboses together with thrombocytopenia (VITT: vaccine-induced immune thrombotic thrombocytopenia).

 

24 August – Preprint!

Pouwels KB, Pritchard E, Matthews PC, et al. Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. medRxiv 2021, posted 24 August. Full text: https://doi.org/10.1101/2021.08.18.21262237

The authors found that vaccination with two doses of the BioNTech/Pfizer (BNT162b2 ) or the AstraZeneca vaccine (ChAdOx1) still significantly reduced the risk of new PCR-positive SARS-CoV-2 infections. However, benefits from two AstraZeneca doses were reduced with Delta more than from two BioNTech/Pfizer doses.

 

16 August 2021

Hillus D, Schwarz T, Tober-Lau P, et al. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study. Lancet Respir Dis 2021, published 12 August. Full text: https://doi.org/10.1016/S2213-2600(21)00357-X

A new prospective vaccine mixing study comparing “AstraZeneca (AZ) + BioNTech/Pfizer (BP)” with 2 x AZ and 2 x BP. The authors show “AZ first, BP second” elicited a stronger immune response than two doses of either vaccine. Could these data spur a renaissance for the AstraZeneca vaccine? Not sure. The difference might be explained by the longer (and possibly more effective) immunization interval of AZ+BP compared to the typical 3-week interval of the two BP injections.

 

21 July 2021

Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021 Jul 21. PubMed: https://pubmed.gov/34289274. Full-text: https://doi.org/10.1056/NEJMoa2108891

Effectiveness after one dose of the BioNTech/Pfizer or AstraZeneca was lower among individuals infected with the Delta variant (B.1.671.2, “India”) than with the Alpha variant (B.1.1.7, “England”): Delta, 30.7% – Alpha, 48.7% (there was no difference between the two vaccines). After two doses, differences in vaccine effectiveness with the two variants were modest, but the BioNTech/Pfizer vaccine was superior to the AstraZeneca vaccine (BioNTech/Pfizer: Delta, 88.0% – Alpha, 93.7%; AstraZeneca: Delta, 67.0%; Alpha, 74.5%).

 

17 July 2021

Normark J, Vikström L, Gwon YD, et al. Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination. NEJM July 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2110716

This relatively small cohort suggests that the mRNA-1273 vaccine (MODERNA) boost may provide better protection against the B.1.351 variant than a ChAdOx1 nCoV-19 boost. However, the mRNA-1273 boost led to more frequent reports of fever, headache, chills, and muscle aches than the ChAdOx1 nCoV-19 boost.

 

13 May

Bernal JL, Andrews N, Gower C, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ May 13, 2021; 373. https://www.bmj.com/content/373/bmj.n1088

Early real-life data in older people (older than 70 years) from England: with BNT162b2, vaccine effectiveness reached 61% from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards.

 

6 March 2021

Voysey M, Costa Clemens SA, Madhi SA, et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet. 2021 Mar 6;397(10277):881-891. PubMed: https://pubmed.gov/33617777. Full text: https://doi.org/10.1016/S0140-6736(21)00432-3

In the case of the ChAdOx1 nCoV-19 (AZD1222) vaccine, it may be better to wait with the second shot. This pre-specified pooled analysis of AstraZeneca’s vaccine trials suggests that a 3-month dose interval might have advantages over a program with a shorter dosing interval. In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81% at ≥ 12 weeks) than in those with a short interval (vaccine efficacy 55% at < 6 weeks).

 

23 April

Vasileiou E, Simpson CR, Shi T, et al. Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. Lancet. 2021 May 1;397(10285):1646-1657. PubMed: https://pubmed.gov/33901420. Full text: https://doi.org/10.1016/S0140-6736(21)00677-2

Paper of the day! Between Dec 8, 2020, and Feb 22, 2021, a total of 1,331,993 people were vaccinated in Scotland. The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85–94) for reduced COVID-19 hospital admission at 28–34 days post-vaccination. Vaccine effect for the ChAdOx1 vaccine was 88% (95% CI: 75–94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar the analysis was restricted to those aged 80 years and older (83%, 95% CI: 72–89).

 

10 April

Emary KRW, Golubchik T, Aley PK, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021 Apr 10;397(10282):1351-1362. PubMed: https://pubmed.gov/33798499. Full text: https://doi.org/10.1016/S0140-6736(21)00628-0

This study by Andrew Pollard, Katherine Emary and colleagues reports that among participants in Phase II/III ChAdOx1 studies who had been infected with B117, vaccine efficacy against symptomatic SARS-CoV-2 infection was similar for B117 and non-B117 lineages (74,6% [95% CI: 41,6-88,9] and 84% [95% CI: 70,7-91,4], respectively). Importantly, virus neutralization activity by vaccine-induced antibodies was 9-fold lower against B117 than against a canonical non-B117 lineage.

 

14 February 2021

McKie R. Life savers: the amazing story of the Oxford/AstraZeneca Covid vaccine. The Guardian 2021, published 14 February. Full-text: https://www.theguardian.com/world/2021/feb/14/life-savers-story-oxford-astrazeneca-coronavirus-vaccine-scientists

A year ago, Sarah Gilbert and Andrew Pollard began work on the response to a new virus. Now, as their vaccine is being given to millions, they tell of their incredible 12 months.

 

7 February 2021

University of Oxford 20210207. ChAdOx1 nCov-19 provides minimal protection against mild-moderate COVID-19 infection from B.1.351 coronavirus variant in young South African adults. University of Oxford 2021, published 7 Febuary. Full-text: https://www.ox.ac.uk/news/2021-02-07-chadox1-ncov-19-provides-minimal-protection-against-mild-moderate-covid-19-infection

In an analysis, submitted as a pre-print prior to peer-review publication, a two-dose regimen of the ChAdOx1 nCoV-19 vaccine provides minimal protection against mild-to-moderate COVID-19 infection from the B1351 coronavirus variant first identified in South Africa.

 

12 January

Mahase E. How the Oxford-AstraZeneca covid-19 vaccine was made. BMJ. 2021 Jan 12;372:n86. PubMed: https://pubmed.gov/33436419. Full text: https://doi.org/10.1136/bmj.n86

Andrew Pollard has been leading the Oxford vaccine clinical trials in the UK, Brazil, and South Africa. He tells how the Oxford vaccine came to be, how dosing was worked out, and whether it will stand up to the new variants.

 

30 December 2020

GOV.UK 20201230. Regulatory approval of COVID-19 Vaccine AstraZeneca. https://www.gov.uk 2020, published 30 December. Full-texts: https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca

On December 30, UK regulatory authorities approved the Oxford University/AstraZeneca vaccine. ChAdOx1 nCoV-19 (AZD1222) needs only normal refrigeration at 2-8°C and is far cheaper than the previously approved vaccines Comirnaty (BioNTech/Pfizer) and mRNA-1273 (Moderna).

 

30 December 2020

Joint Committee on Vaccination and Immunisation. JCVI issues advice on the AstraZeneca COVID-19 vaccine. JCVI 2020, published 30 December 2020. Full-text: https://www.gov.uk/government/news/jcvi-issues-advice-on-the-astrazeneca-covid-19-vaccine

The Joint Committee on Vaccination and Immunisation (JCVI) recommends that both the AstraZeneca (ChAdOx1) and the BioNTech/Pfizer (Comirnaty) vaccines are safe and provide high-levels of protection against COVID-19, including severe COVID-19. As protection is obtained around 2 weeks after the first vaccine dose, the committee recommends that vaccinating more people with the first dose is prioritized above offering others their second dose. This would provide the greatest public health benefits in the short term and save more lives. For the BioNTech/Pfizer vaccine, the second vaccine dose can be offered between 3 to 12 weeks after the first dose. (Pfizer is not amused.) For the AstraZeneca vaccine, the second dose can be offered 4 to 12 weeks after the first dose.

 

8 December 2020

Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021 Jan 9;397(10269):99-111. PubMed: https://pubmed.gov/33306989. Full text: https://doi.org/10.1016/S0140-6736(20)32661-1

60-70% protection: this is what we can probably expect from inactivated vaccines. This important paper describes the first interim safety and efficacy data for a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222, developed at Oxford University), evaluated in four trials across three continents. Between April 23 and Nov 4, 2020, 23,848 participants were recruited and vaccinated: 1077 in COV001 (UK), 10.673 in COV002 (UK), 10.002 in COV003 (Brazil), and 2096 in COV005 (South Africa). The vaccine showed significant vaccine efficacy of 70.4% after two doses and protection of 64.1% after at least one standard dose, against symptomatic disease. Across all four studies, the vaccine had a good safety profile with serious adverse events and adverse events of special interest balanced across the study arms. The efficacy of 90.0% seen in those who received a low dose as prime in the UK by error (COV002, read how this dosing error happened and about the implications) was intriguingly high compared with the other findings in the study. However, this has to be confirmed. Moreover, pre-specified sub-group analyses (elderly, those with comorbidities) were not included in this report. Of note, the ChAdOx1 vaccine can be easily administered in existing healthcare systems (in contrast to mRNA vaccines), stored at ‘fridge temperature’ (2-8 °C) and distributed via existing logistics.

 

18 November 2020

Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 2020, published 18 November. Full-text: https://doi.org/10.1016/S0140-6736(20)32466-1

Phase II results of a single-blind, randomized, controlled trial that describe the safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine in a wide range of participants, including adults aged 70 years and older. The results are encouraging: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose.

 

9 September 2020

Phillips N, Cyranoski D, Mallapathy S. A leading coronavirus vaccine trial is on hold: scientists react. Nature News September 9, 2020. Full-text: https://www.nature.com/articles/d41586-020-02594-w

This article summarizes what is known about the news of the day: AstraZeneca has reported a case of a transverse myelitis in a person who received AZD1222, an adenoviral-vector vaccine that harnesses a cold-causing ‘adenovirus’ isolated from chimpanzees. The Phase III trial was “voluntarily paused”. However, details of the adverse event, including how serious it was and when it happened, have not been reported. It is still unclear whether the person received the vaccine or placebo. Let’s wait for the details.

 

30 July 2020

van Doremalen N, Lambe T, Spencer A, et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 2020, published 30 July. Full-text: https://doi.org/10.1038/s41586-020-2608-y

The good news first or the bad news first? OK, the good news: Vincent Munster, Sarah Gilbert and colleagues showed that vaccination with the adenovirus-vectored ChAdOx1 vaccine induced a balanced Th1/Th2 humoral and cellular immune response in rhesus macaques. The authors observed a significantly reduced viral load in bronchoalveolar lavage fluid and lower respiratory tract tissue, and no pneumonia was observed in vaccinated animals. The bad news (for prevention policies in general and for anti-vaxxers in particular): there was no difference in nasal shedding between vaccinated and control animals. Back to the good news: there was no evidence of immune-enhanced disease following viral challenge in vaccinated animals.

 

28 July 2020

Graham SP, McLean RK, Spencer AJ et al. Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19. npj Vaccines 5, 69 (2020). Full-text: https://doi.org/10.1038/s41541-020-00221-3

Simon P. Graham, Teresa Lambe and colleagues compare the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cell responses, a booster immunization enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralizing titers.

 

20 July 2020

Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet, 20 July 2020. Full-text: https://www.thelancet.com/lancet/article/s0140-6736(20)31604-4

Andrew Pollard and colleagues report their Phase 1/2 randomized trial of a chimpanzee adenovirus-vector vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein. Study participants received either ChAdOx1 nCoV-19 (n = 543) or a meningococcal conjugate vaccine (MenACWY) as control (n = 534). In ChAdOx1 vaccinees, T cell responses peaked on day 14, anti-spike IgG responses rose by day 28, and neutralizing antibody responses against SARS-CoV-2 were detected in > 90% (find more details in the paper, especially about results after a booster dose). Adverse events such as fatigue, headache, and local tenderness commonly occurred. There were no serious adverse events.

Johnson & Johnson vaccine

In a Phase III trial, the Johnson & Johnson (J&J) vaccine Ad26.COV2.S protected 66% of recipients against moderate to severe–critical COVID-19 and 85% against severe–critical COVID-19 one month after vaccination (Sadoff 2021b, FDA 20210226, EMA 20210311).

As the AstraZeneca vaccine, the J&J vaccine has been rarely linked to vaccine-induced immune thrombotic thrombocytopenia (VITT). Reporting rates were 7.0 cases per million doses administered to women aged 18−49 years and 0.9 per million to women aged ≥ 50 years (MacNeil 2021).

 

5 August 2021

Takuva S, Takalani A, Garrett N, et al. Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study. N Engl J Med. 2021 Aug 5;385(6):570-571. PubMed: https://pubmed.gov/34077639. Full text: https://doi.org/10.1056/NEJMc2107920

Interim safety data from the first 288,368 participants who were vaccinated with Ad26.COV2.S (Johnson & Johnson) in the Sisonke study — an open-label, Phase IIIb implementation study. The rate of adverse events with vaccination is low, and thromboembolic events occur mainly in persons with risk factors for thromboembolism.

 

14 July 2021

Barouch DH, Stephenson KE, Sadoff J, et al. Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination. N Engl J Med. 2021 Jul 14:NEJMc2108829. PubMed: https://pubmed.gov/34260834. Full text: https://doi.org/10.1056/NEJMc2108829

This small study indicates that the Ad26.COV2.S vaccine (J&J) elicited durable humoral and cellular immune responses with minimal decreases for at least 8 months. Moreover, there was an expansion of neutralizing antibody breadth associated with improved coverage of SARS-CoV-2 variants over time, including increased neutralizing antibody titers against Delta.

 

28 April 2021

Solforosi L, Kuipers H, Jongeneelen M, et al. Immunogenicity and efficacy of one and two doses of Ad26.COV2.S COVID vaccine in adult and aged NHP. J Exp Med April 28 2021. https://rupress.org/jem/article/218/7/e20202756/212032/Immunogenicity-and-efficacy-of-one-and-two-doses

In rhesus macaques, spike protein–specific immune responses were better with two-doses of the Ad26.COV2.S vaccine. In humans, a two-dose regimen is currently evaluated in a Phase 3 study (ENSEMBLE 2).

 

27 April 2021

MacNeil JR, Su JR, Broder KR, et al. Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients — United States, April 2021. MMWR Morb Mortal Wkly Rep. ePub: 27 April 2021. DOI: https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e4.htm?s_cid=mm7017e4_w

On April 23, the Advisory Committee on Immunization Practices concluded that the benefits of resuming Janssen’s vaccination in persons aged ≥ 18 years outweigh the risks. Up to now, there are 15 cases of cerebral venous sinus thrombosis (CVST), mostly among women aged 18−49 years. Two occurred among women aged ≥ 50 years; no cases post-authorization were reported among men. Reporting rates were 7.0 cases per million doses administered to women aged 18−49 years and 0.9 per million to women aged ≥ 50 years.

 

22 April 2021

Sadoff J, Gray G, Vandebosch A, et al. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med. 2021 Jun 10;384(23):2187-2201. PubMed: https://pubmed.gov/33882225. Full text: https://doi.org/10.1056/NEJMoa2101544

In this large Phase III study, Johnson & Johnson’s Ad26.COV2.S vaccine protected 67% (66%) against moderate to severe/critical COVID-19 with onset at least 14 (28) days after administration. Vaccine efficacy was higher against severe/critical disease (85% for onset at ≥ 28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 82% against severe/critical COVID-19 with onset at least 28 days after administration.

 

11 March 2021

Stephenson KE, Le Gars M, Sadoff J, et al. Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19. JAMA March 11, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777598

The COVID-19 vaccine from Janssen (Johnson & Johnson) is the fourth vaccine recommended in the EU for preventing COVID-19. Ad26.COV2.S is a recombinant, replication-incompetent Ad26 vector encoding the full length and stabilized SARS-CoV-2 S protein derived from the first Wuhan strain. This phase I study (in 25 recipients from Boston) shows that a single immunization induced rapid binding and neutralization antibody responses as well as cellular immune responses, including induction of RBD-specific binding antibodies in 90% of vaccine recipients by day 8.

 

2 March 2021

Oliver SE, Gargano JW, Scobie H, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Janssen COVID-19 Vaccine — United States, February 2021. MMWR Morb Mortal Wkly Rep. ePub: 2 March 2021. DOI: https://www.cdc.gov/mmwr/volumes/70/wr/mm7009e4.htm

The Janssen COVID-19 vaccine is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector vaccine, encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2. On February 27, 2021, the FDA issued an Emergency Use Authorization (EUA). This is an interim recommendation for use in persons aged ≥ 18 years for the prevention of COVID-19, discussing the available data and the question who to vaccinate and when. Answer: everybody, ASAP. Of note, the Janssen vaccine seems to work in the B.1.351 lineage from South Africa as well in the P.2 lineage from Brazil.

 

26 February 2021

FDA 20210226. Vaccines and Related Biological Products Advisory Committee February 26, 2021 Meeting Announcement. FDA 2021, published 26 February. Documents: https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-february-26-2021-meeting-announcement#event-materials

Find here the documents that will lead to the approval of vaccine #4 – the one-shot adenovirus vector vaccine by Johnson & Johnson. The best news of the day: the vaccine had only a slightly reduced overall efficacy rate in South Africa (64% vs 72% in the US). Most importantly, the J&J vaccine showed 86% and 82% efficacy against severe disease of COVID-19 in the US and South Africa, respectively.

 

13 January 2021

Sadoff J, Le Gars M, Shukarev G, et al. Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine. N Engl J Med 2021, published 13 January. Full-text: https://doi.org/10.1056/NEJMoa2034201

Hanneke Schuitemaker, Jerald Sadoff and colleagues describe the safety and immunogenicity profiles of Ad26.COV2.S. As with other SARS-CoV-2 vaccines, the most frequent adverse events were fatigue, headache, myalgia, and injection site pain. Systemic adverse events were less common in people 65 years or older than in those 18 to 55 years of age. Neutralizing-antibody titers against wild type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488), regardless of vaccine dose or age group. Ad26.COV2.S, developed by Janssen Pharmaceutical Companies of Johnson & Johnson, is a recombinant replication-incompetent adenovirus type 26 (Ad26) vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen.

 

28 September 2020

Bos R, Rutten L, van der Lubbe JEM, et al. Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses. npj Vaccines 5, 91 (2020). Full-text: https://doi.org/10.1038/s41541-020-00243-x

Hanneke Schuitemaker, Rinke Bos and colleagues report more details about Ad26.COV2.S which is currently being evaluated in a clinical trial (ClinicalTrials.gov: NCT04436276). Vaccines based on transgenes delivered by recombinant replication-incompetent adenovirus type 26 vectors (Ad26) have previously been shown to have an acceptable safety profile in humans and are able to induce neutralizing and binding antibodies, CD4 and CD8 T cell responses and a Th1-biased immune response in animals and humans.

 

30 August 2020

Mercado NB, Zahn R, Wegmann F et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 2020, published 30 July. Full-text: https://doi.org/10.1038/s41586-020-2607-z

For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Hanneke Schuitemaker, Dan Barouch and colleagues developed a series of adenovirus serotype 26 (Ad26) vectors encoding different variants of the SARS-CoV-2 spike (S) protein and showed the immunogenicity and protective efficacy of a single dose of Ad26 vector-based vaccines in 52 rhesus macaques. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs following SARS-CoV-2 challenge.

Gamaleya vaccine

The Sputnik V vaccine is a combination of two genetically modified and replication-incompetent human common cold virus adenoviruses, Ad26 and Ad5.

In February 2021, an interim analysis of the Phase III Gam-COVID-Vac trial (n=14,964 in the vaccine group and 4902 in the placebo group) reported an efficacy of 91.6% from 21 days after the first dose of the vaccine (Logunov 2021; see also the comment by Jones 2021).

The hair-raising presidential approval in August 2020 before Phase III clinical trials had even begun, gave the vaccine a long-lasting credibility blow. Another exercise in ridicule, claiming Sputnik to be ‘The first registered COVID-19 vaccine’, is equally embarassing.

 

26 July 2021

Ikegame S, Siddiquey M, Hung CT, et al. Neutralizing activity of Sputnik V vaccine sera against SARS-CoV-2 variants. Res Sq. 2021. PubMed: https://pubmed.gov/33851150. Full-text: https://www.nature.com/articles/s41467-021-24909-9

In Argentina, sera from Sputnik vaccine recipients had a median 6.1-fold and 2.8-fold reduction in GMT against B.1.351 and the E484K mutant spike, respectively. “When extrapolated to full serum strength, half of the sera samples failed to achieve an IC80 and only 1 out 12 achieved an IC90 against B.1.351.” The authors conclude that “control of some emergent SARS-CoV-2 variants may benefit from updated vaccines.”

 

13 July 2021

Rossi AH, Ojeda DS, Varese A, et al. Sputnik V Vaccine Elicits Seroconversion and Neutralizing Capacity to SARS CoV-2 after a Single Dose. Cell Rep Med July 13, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00208-1

Of 227 seronegative healthcare workers in Argentina, 94% developed spike-specific IgG antibodies at day 21 after the first dose. A single Sputnik V dose elicited higher antibody levels and virus neutralizing capacity in 67 previously infected individuals than in naïve ones receiving the full two-dose schedule.

 

20 February 2021

Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet. 2021 Feb 20;397(10275):671-681. PubMed: https://pubmed.gov/33545094. Full text: https://doi.org/10.1016/S0140-6736(21)00234-8

A new entry in the COVID-19 Vaccine Club (CVC): Denis Logunov and colleagues report on the interim clinical efficacy results of the Russian Sputnik V vaccine (rAd26 and rAd5). From 21 days after the first dose of vaccine, 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6–95·2).

 

21 September 2020

Bucci E, Andreev, Björkman A, et al. Safety and efficacy of the Russian COVID-19 vaccine: more information needed. Lancet September 21, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31960-7

A few days later, the study received these notes of serious concerns. Dozens of authors raised doubts about the reliability of the data. The main issue (among many others): there were several data patterns which appeared repeatedly for the reported experiments. A Photoshop fake? Enrico Bucci and colleagues conclude that “in lack of the original numerical data, no conclusions can be definitively drawn on the reliability of the data presented, especially regarding the apparent duplications detected”. For more details see also https://cattiviscienziati.com/2020/09/07/note-of-concern/

Logunov DY, Dolzhikova IV, Tukhvatullin AI. Safety and efficacy of the Russian COVID-19 vaccine: more information needed – Authors’ reply. Lancet September 21, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)31970-X

The author’s reply. They “confirm that individual participant data will be made available on request to DYL and that after approval of a proposal, data can be shared through a secure online platform”. Shall we hold our breath?

 

3 September 2020

Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020 Sep 3:S0140-6736(20)31866-3. PubMed: https://pubmed.gov/32896291. Full-text: https://doi.org/10.1016/S0140-6736(20)31866-3

On September 5, we commented that it was high time to see some data on an “approved” vaccine, consisting of two recombinant adenovirus vectors carrying the spike glycoprotein (Sputnik V, presented as the world’s “premiere”, like planting a tiny flag in the sea bed two and a half miles beneath the North Pole in 2007).

Sinovac vaccine

CoronaVac™ (formerly PiCoVacc) is an inactivated virus vaccine developed by Sinovac Biotech, a private Chinese company. In Brazil, CoronaVac is being developed in partnership with the Butantan Institute.

In real-world studies, the estimated effectiveness was 51% (Brazil, de Faria 2021) to 67% (Chile, Vergara 2021).

In a small study from Hong Kong, health-care workers who received the BioNTech-Pfizer vaccine had higher antibody concentrations and higher PRNT50 (plaque reduction neutralization test) titers than those who received the Sinovac vaccine (Lim WW 2021).

 

2 September 2021

Jara A, Undurraga EA, González C, et al. Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. N Engl J Med. 2021 Sep 2;385(10):875-884. PubMed: https://pubmed.gov/34233097. Full text: https://doi.org/10.1056/NEJMoa2107715

In this prospective national cohort study of the Sinovac vaccine (Chile, n = 10.2 million), the adjusted vaccine effectiveness was 65.9% for the prevention of COVID-19 and 87.5% for the prevention of hospitalization, 90.3 for the prevention of ICU admission, and 86.3% for the prevention of Covid-19–related death. As expected, the vaccine effectiveness as assessed 14 days after one dose of vaccine was considerably lower: 37.4% against hospitalization, 44.7% against ICU admission, and 45.7% against Covid-19–related death. See also the comment by Wilder-Smith A, Mulholland K. Effectiveness of an Inactivated SARS-CoV-2 Vaccine. N Engl J Med. 2021 Sep 2;385(10):946-948. PubMed: https://pubmed.gov/34469651. Full text: https://doi.org/10.1056/NEJMe2111165

 

20 August 2021

Ranzani OT, Hitchings MD, Durion M, et al. Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study. BMJ August 20, 2021; 374. doi: https://doi.org/10.1136/bmj.n2015

Moderate results with the inactivated whole virus vaccine CoronaVac (from Sinovac Biotech) in older people (> 70 years) in a setting with extensive transmission of the gamma variant: adjusted vaccine effectiveness against symptomatic COVID-19 was 24.7% at 0-13 days and 46.8% at ≥ 14 days after the second dose. Adjusted vaccine effectiveness against hospital admissions was 55.5% (death 61.2%) at ≥ 14 days after the second dose, declining with increasing age.

 

30 July 2021

Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, et al. Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial. Nat Med (2021). https://doi.org/10.1038/s41591-021-01469-5

In 910 adults with autoimmune rheumatic diseases (ARD) vaccinated with the Chinese CoronaVac vaccine, all had lower IgG seroconversion rates, and lower neutralizing antibody titers were lower than in 182 age- and sex-matched healthy adults.

 

20 July 2021

Lim WW, Mak L, Leung GM, Cowling BJ, Peiris M. Comparative immunogenicity of mRNA and inactivated vaccines against COVID-19. Lancet Microbe 2021, published 15 July. Full text: https://doi.org/10.1016/S2666-5247(21)00177-4

Preliminary data from a study by Malik Peiris et al., one of the central figures of the 2002/2003 SARS-CoV-1 epidemic. Health-care workers in Hong Kong who received the BioNTech-Pfizer vaccine (n = 63) had higher antibody concentrations and higher PRNT50 (plaque reduction neutralization test) titers than those who received the Sinovac vaccine (n = 30). The authors conclude that “the difference in concentrations of neutralizing antibodies identified in our study could translate into substantial differences in vaccine effectiveness”.

 

15 July 2021

Lim WW, Mak L, Leung GM, Cowling BJ, Peiris M. Comparative immunogenicity of mRNA and inactivated vaccines against COVID-19. Lancet Microbe 2021, published 15 July. Full text: https://doi.org/10.1016/S2666-5247(21)00177-4

Preliminary data from a study by Malik Peiris et al., one of the central figures of the 2002/2003 SARS-CoV-1 epidemic. Health-care workers in Hong Kong who received the BioNTech-Pfizer vaccine (n = 63) had higher antibody concentrations and higher PRNT50 (plaque reduction neutralization test) titers than those who received the Sinovac vaccine (n = 30). The authors conclude that “the difference in concentrations of neutralizing antibodies identified in our study could translate into substantial differences in vaccine effectiveness”.

 

3 February

Wu Z, Hu Y, Xu M, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021, published 3 February. Full-text: https://doi.org/10.1016/S1473-3099(20)30987-7

Weidong Yin, Yuliang Zhao, Zhiwei Wu and colleagues report the results of Sinovac’s CoronaVac safety and immunogenicity data in adults aged 60 years or older (previous publications: Zhang Y 2020,
Gao 2020). Reminder: CoronaVac™ is an inactivated virus vaccine. On 12 January, the government of São Paulo, Brazil, announced the overall effectiveness of the Sinovac vaccine to be 50,38%. The data was obtained with tests carried out on 12.508 volunteers in the country, all health professionals. According to a report of The New York Times (7 January), Sinovac has sold more than 300 million doses, mostly to low- and middle-income countries, accounting for about half of the total production of Sinovac.

 

17 November 2020

Zhang Y, Zeng G, Pan H. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18–59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet November 17, 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30843-4

Phase I/II study of an inactivated vaccine candidate against COVID-19. In total, 743 participants at the Suining County of Jiangsu province, China, received at least one dose (n = 143 for Phase 1 and n = 600 for Phase 2; safety population). At day 28 after the days 0 and 28 vaccination schedule, seroconversion of neutralising antibodies was seen for 109 (92%) of 118 participants in the 3 μg group which is the suggested dose for efficacy assessment in future Phase III trials. Adverse events such as mild injection-site pain, occurred in 81 (17%) of 480 vaccine recipients.

Sinopharm vaccine

BBIBP-CorV is an inactivated virus vaccine developed by Sinopharm and the Beijing Institute of Biological Products, China. On 30 December 2020, the company announced that the vaccine had an efficacy of 79%. A day later, China’s health authorities approved the vaccine for general use (Davidson 2020, Wee SL 2021).

 

6 August 2021

Zhang H, Liu Y, Liu D, et al. Time of day influences immune response to an inactivated vaccine against SARS-CoV-2. Cell Res. 2021 Aug 2. PubMed: https://pubmed.gov/34341489. Full text: https://doi.org/10.1038/s41422-021-00541-6

Should you better go early in the morning to get your vaccine shot? The authors analyzed 63 health care workers who received the inactivated BBIBP-CorV vaccine (Sinopharm) either between 9 and 11 o’clock in the morning or between 3 and 5 o’clock in the afternoon. Strikingly, participants vaccinated in the morning showed significantly higher level of NAbs in the sera, 34.70 vs 19.35. Early birds also had stronger B cell and Tfh responses. Interesting path to follow.

 

15 October 2020

Xia S, Zhang Y, Wang Y, e al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2020, published 15 October. Full-text: https://doi.org/10.1016/S1473-3099(20)30831-8

A Chinese candidate vaccine, BBIBP-CorV (Beijing Institute of Biological Products), based on inactivated coronavirus, seems to be safe and elicits an antibody response. This is the first study of an inactivated SARS-CoV-2 vaccine to include participants older than 60 years. In these participants, antibodies took up to 42 days to be detected, compared with 28 days for participants aged 18 to 59. As expected, antibody levels were lower in those aged 60 to 80 years. Two-dose immunization with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralizing antibody titers than the single 8 μg dose or 4 μg dose on days 0 and 14. A Phase III trial of BBIBP-CorV is currently underway in Abu Dhabi and the United Arab Emirates. See also the comment by Isakova-Sivak I, Rudenko L. A promising inactivated whole-virion SARS-CoV-2 vaccine. Lancet Infect Dis 2020, published 15 October. Full-text: https://doi.org/10.1016/S1473-3099(20)30832-X

Bharat vaccine

The Bharat vaccine Covaxin™ (formerly known as BBV152) is a whole virion inactivated SARS-CoV-2 vaccine, adjuvanted with Algel-IMDG (an imidazoquinoline molecule which is a toll-like receptor (TLR) 7/8 agonist, chemisorbed on alum [Algel]) (Ganneru 2021).

In Syrian hamsters, Covaxin induced a potent humoral immune response, led to early clearance from the lower respiratory tract and protected the animals from pneumonia (Mohandas 2021). In rhesus macaques, too, the vaccine induced a strong immune response and protected the monkeys from pneumonia after infection with SARS-CoV-2, with complete viral clearance in nasal swab specimens 7 days post-infection (Yadav 2021).

 

8 March 2021

Ella R, Reddy S, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial. Lancet March 08, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00070-0/fulltext

Inactivated vaccines have the advantage of being easily stored and shipped. BBV152 (COVAXIN) is a whole-virion inactivated SARS-CoV-2 vaccine adjuvanted with Algel-IMDG. An imidazoquinoline molecule (IMDG), a TLR7/8 agonist, is added to augment cell-mediated responses. According to the Phase I/II data from India presented here, BBV152 has shown the potential to provide durable humoral and cell-mediated immune responses (even against variants of concern). The Algel-IMDG formulation was selected for the ongoing Phase III efficacy trial, which involves 25,800 volunteers. BBV152 has received emergency use authorisation in India.

 

21 January 2021

Ella E, Vadreva KM, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis January 21, 2021. Full-text: https://doi.org/10.1016/S1473-3099(20)30942-7

In this double-blind, multi-center, randomized Phase I trial from India, the inactivated vaccine BBV152 led to tolerable safety outcomes and enhanced immune responses. Different adjuvants were also evaluated (chemosorbed imidazoquinoline onto the aluminum hydroxide gel or not). In 375 participants who were assigned to receive two doses separated by 2 weeks of BBV152 3 μg with Algel-IMDG (n = 100), 6 μg with Algel-IMDG (n = 100), or 6 μg with Algel (n = 100), or an Algel-only control (n = 75), 80% of patients in each vaccine group seroconverted, with at least a four-fold increase in binding antibody titers. Seroconversion occurred by microneutralization in 88% and 92% of the 3 and 6 μg Algel-IMDG groups but also in 8% of the control group, suggesting SARS-CoV-2 infections occurred in some participants.

Novavax vaccine

The Novavax vaccine ‘NVX-CoV2373’ is a recombinant “nanoparticle” vaccine (rSARS-CoV-2; sometimes also called a ‘protein[1] subunit vaccine’) composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. The vaccine is produced by creating insect-infecting baculoviruses containing a gene for a modified SARS-CoV-2 spike protein which infects moth cells (the fall armyworm, Spodoptera frugiperda) in 2000 liter bioreactors (Wadman 2020).

In a Phase III trial from the pre-Delta era (15,000 adult participants, with 27% percent being older than 65), a two-dose regimen showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant (Heath 2021).

 

30 June 2021

Heath PT, Galiza EP, Baxter DN, et al. Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine. N Engl J Med. 2021 Jun 30:NEJMoa2107659. PubMed: https://pubmed.gov/34192426. Full text: https://doi.org/10.1056/NEJMoa2107659

Paper of the day. The next vaccine! Large RCT of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant. Among 14039 participants, the two-dose regimen conferred 89.7% protection. A post hoc analysis showed an efficacy of 86.3% against the B.1.1.7 (or alpha) variant and 96.4% against non-B.1.1.7 variants.

 

5 May 2021

Shiinde V, Bhikha S, Hoosain Z, et al. Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant. NEJM May 5, 2021, https://www.nejm.org/doi/full/10.1056/NEJMoa2103055

Early findings on the efficacy of a randomized, placebo-controlled, Phase IIa/b trial of Novavax’ nanoparticle vaccine NVX-CoV2373. The trial was conducted in 4347 predominantly young and healthy people in South Africa during a period of predominant circulation of the B.1.351 variant. Vaccine efficacy among HIV-negative participants was 60% (B.1.351: 51%). Severe COVID-19 was rare. Of note, previous infection with wild type viruses did not appear to reduce the risk of COVID-19 due to subsequent infection with B.1.351 variants among placebo recipients during the first 2 months of follow-up.

 

14 January 2021

Tian JH, Patel N, Haupt R, et al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nat Commun. 2021 Jan 14;12(1):372. PubMed: https://pubmed.gov/33446655. Full text: https://doi.org/10.1038/s41467-020-20653-8

In mice and baboons, low-dose levels of NVX-CoV2373 with Matrix-M was highly immunogenic. NVX-CoV2373, developed by Novavax, is a recombinant nanoparticle vaccine (rSARS-CoV-2) composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant.

 

10 December 2020

Keech C, Albert G, Cho I, et al. Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N Engl J Med. 2020 Dec 10;383(24):2320-2332. PubMed: https://pubmed.gov/32877576. Full text: https://doi.org/10.1056/NEJMoa2026920

The first Phase I-II results of NVX-CoV2373 (Novavax), a recombinant nanoparticle vaccine. Cheryl Keech et al. evaluated the safety and immunogenicity of the vaccine in 131 adults using 5-μg and 25-μg doses, with or without Matrix-M1 adjuvant. Reactogenicity was absent or mild in the majority of participants and more common with adjuvant. The addition of adjuvant resulted in enhanced immune responses, was antigen dose–sparing, and induced CD4+ T cell responses that were biased toward a Th1 phenotype. The two-dose 5-μg adjuvant regimen induced geometric mean anti-spike IgG (63,160 ELISA units) and neutralization (3906) responses that exceeded geometric mean responses in convalescent serum from mostly symptomatic COVID-19 patients (8344 and 983, respectively). NVX-CoV2373 is composed of trimeric full-length SARS-CoV-2 spike glycoproteins and a Matrix-M1 adjuvant.

Efficacy

Most SARS-CoV-2 efficacy studies are from the pre-Delta era. More recent analyses from countries where the Delta variant was already dominant during the study period suggest that vaccines offer less protection against reinfection. In some cases, the time since vaccination (>6 months) may also contribute to waning immunity.

Evaluation of vaccine effectiveness

5 July 2021

Patel MK, Bergeri I, Bresee JS, et al. Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization. Vaccine. 2021 Jul 5;39(30):4013-4024. PubMed: https://pubmed.gov/34119350. Full text: https://doi.org/10.1016/j.vaccine.2021.05.099

Guidance on how to conduct and evaluate post-introduction vaccine effectiveness studies.

General efficacy

Most vaccine efficacy data are from the pre-Delta era and can only partially be transposed to today’s situation where the Delta variant is the dominant SARS-CoV-2 strain in many countries. The following paragraph is divided into Delta era and pre-Delta era.

Delta era

2 September 2021

Seppälä E, Veneti L, Starrfelt J, et al. Vaccine effectiveness against infection with the Delta (B.1.617.2) variant, Norway, April to August 2021. Euro Surveill September 2, 2021;26(35):pii=2100793. https://doi.org/10.2807/1560-7917.ES.2021.26.35.2100793

The adjusted VE against infection with the Delta variant was 22% among those partly vaccinated and 65% among those fully vaccinated, compared with 55% and 84%, respectively, against the Alpha variant.

 

24 August 2021

Fowlkes A, Gaglani M, Groover K, et al. Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance — Eight U.S. Locations, December 2020–August 2021. MMWR Morb Mortal Wkly Rep. ePub: 24 August 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e4.htm?s_cid=mm7034e4_x

In this cohort of 4217 frontline workers (mainly HCW), the vaccine effectiveness (VE) declined from 91% to 66% when the SARS-CoV-2 Delta variant became predominant. However, this trend should be interpreted with caution (increasing time since vaccination, low numbers).

 

24 August 2021 – Preprint!

Pouwels KB, Pritchard E, Matthews PC, et al. Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. medRxiv 2021, posted 24 August. Full text: https://doi.org/10.1101/2021.08.18.21262237

The authors found that vaccination with two doses of the BioNTech/Pfizer (BNT162b2 ) or the AstraZeneca vaccine (ChAdOx1) still significantly reduced the risk of new PCR-positive SARS-CoV-2 infections. However, benefits from two AstraZeneca doses were reduced with Delta more than two BioNTech/Pfizer doses.

 

20 August 2021

Chung H, He S, Nasreen S, et al. Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study. BMJ August 20, 2021; 374. doi: https://doi.org/10.1136/bmj.n1943

Two doses of mRNA COVID-19 vaccines were observed to be highly effective against symptomatic infection and severe outcomes. Vaccine effectiveness of one dose was observed to be lower, particularly for older adults shortly after the first dose. Of note, a higher effectiveness was seen after one dose of mRNA-1273 (MODERNA) than after one dose of BNT162b2 (BioNTech/Pfizer).

 

19 August 2021

Nanduri S, Pilishvili T, Derado G, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant — National Healthcare Safety Network, March 1–August 1, 2021. MMWR Morb Mortal Wkly Rep. ePub: 18 August 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7034e3

“Two doses of mRNA vaccines were 74.7% effective against infection among nursing home residents early in the vaccination program (March–May 2021). During June–July 2021, when B.1.617.2 (Delta) variant circulation predominated, effectiveness declined significantly to 53.1%.”

 

21 July 2021

Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021 Jul 21. PubMed: https://pubmed.gov/34289274. Full-text: https://doi.org/10.1056/NEJMoa2108891

Effectiveness after one dose of the BioNTech/Pfizer or AstraZeneca was lower among individuals infected with the Delta variant (B.1.671.2, “India”) than with the Alpha variant (B.1.1.7, “England”): Delta, 30.7% – Alpha, 48.7% (there was no difference between the two vaccines). After two doses, differences in vaccine effectiveness with the two variants were modest, but the BioNTech/Pfizer vaccine was superior to the AstraZeneca vaccine (BioNTech/Pfizer: Delta, 88.0% – Alpha, 93.7%; AstraZeneca: Delta, 67.0%; Alpha, 74.5%).

Pre-Delta era

17 September 2021

Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions — United States, March–August 2021. MMWR Morb Mortal Wkly Rep. ePub: 17 September 2021. Full text: http://dx.doi.org/10.15585/mmwr.mm7038e1

In this analysis of 3,689 adults aged ≥18 years who were hospitalized at 21 U.S. hospitals during March 11–August 15, 2021 vaccine effectiveness (VE) against COVID-19 hospitalization as higher for the Moderna vaccine (93%) than the BioNTech/Pfizer vaccine (88%) and the Janssen vaccine (71%). Protection for the BioNTech/Pfizer vaccine declined 4 months after vaccination. Differences in VE between the two mRNA vaccines might be due to 1) higher mRNA content in the Moderna vaccine, 2) differences in timing between doses (3 weeks for Pfizer-BioNTech versus 4 weeks for Moderna), or possible differences between groups that were not accounted for in the analysis.

 

2 September 2021

Jara A, Undurraga EA, González C, et al. Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. N Engl J Med. 2021 Sep 2;385(10):875-884. PubMed: https://pubmed.gov/34233097. Full text: https://doi.org/10.1056/NEJMoa2107715

In this prospective national cohort study of the Sinovac vaccine (Chile, n = 10.2 million), the adjusted vaccine effectiveness was 65.9% for the prevention of COVID-19 and 87.5% for the prevention of hospitalization, 90.3 for the prevention of ICU admission, and 86.3% for the prevention of Covid-19–related death. As expected, the vaccine effectiveness as assessed 14 days after one dose of vaccine was considerably lower: 37.4% against hospitalization, 44.7% against ICU admission, and 45.7% against Covid-19–related death. See also the comment by Wilder-Smith A, Mulholland K. Effectiveness of an Inactivated SARS-CoV-2 Vaccine. N Engl J Med. 2021 Sep 2;385(10):946-948. PubMed: https://pubmed.gov/34469651. Full text: https://doi.org/10.1056/NEJMe2111165

 

1 September 2021

Steensels D, Pierlet N, Penders J, Mesotten D, Heylen L. Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273. JAMA. 2021 Aug 30. PubMed: https://pubmed.gov/34459863. Full text: https://doi.org/10.1001/jama.2021.15125

This large prospective cohort study in Belgian HCWs demonstrated a significantly higher humoral immunogenicity of the mRNA-1273 vaccine (Moderna) compared with the BNT162b2 vaccine (Pfizer-BioNTech), in infected as well as in uninfected participants, and across age categories. According to the authors, the higher mRNA content in mRNA-1273 compared with BNT162b2 and the longer interval between priming (4 weeks vs 3 weeks for BNT162b2) might explain this difference.

 

19 August 2021

Baltas I, Boshier FAT, Williams CA, et al. Post-vaccination COVID-19: A case-control study and genomic analysis of 119 breakthrough infections in partially vaccinated individuals. Clin Infect Dis. 2021 Aug 19:ciab714. PubMed: https://pubmed.gov/34410361. Full text: https://doi.org/10.1093/cid/ciab714

This matched control study from the UK describes a cohort of BioNTech/Pfizer or AstraZeneca vaccinated multimorbid patients developing COVID-19 predominantly from the B.1.1.7 lineage post first vaccination. One life was saved every four to five vaccinations. As mortality benefit from vaccination occurred immediately after COVID-19 infection, these data indirectly question whether pauci-symptomatic/asymptomatic patients should be offered vaccination.

 

13 August 2021

Moline HL, Whitaker M, Deng L, et al. Effectiveness of COVID-19 Vaccines in Preventing Hospitalization Among Adults Aged ≥65 Years – COVID-NET, 13 States, February-April 2021. MMWR Morb Mortal Wkly Rep. 2021 Aug 13;70(32):1088-1093. PubMed: https://pubmed.gov/34383730. Full text: https://doi.org/10.15585/mmwr.mm7032e3

Among adults aged ≥ 65, the effectiveness of full vaccination for preventing hospitalization was 96% for the BioNTech/Pfizer and Moderna vaccines (exception: 91% for the BioNTech/Pfizer vaccine in age ≥ 75 years) and 84% for the Janssen vaccine. Note that these data are from the pre-Delta era.

 

4 August 2021

Elliott P, Haw D, Wang H, et al. REACT-1 round 13 final report: exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant in England during May to July 2021. Imperial College London 2021, published 4 August. https://spiral.imperial.ac.uk/handle/10044/1/90800

First, the good news: fully vaccinated people have lower viral loads (median Ct: 27.6) than unvaccinated or partially vaccinated people (23.1), so vaccines are likely to decrease the potential for the transmission of the Delta variant. Now, the bad news: between 24 June and 12 July 2021, with the Delta variant already firmly established in the UK, 44% of infections occurred in fully vaccinated individuals. The authors estimate vaccine effectiveness against infection to be 49%. Sex, ethnicity, household size and local levels of economy also jointly contributed to the risk of higher prevalence. The authors anticipate that increased mixing during the autumn in the presence of the Delta variant may lead to a new wave of the pandemic, even at high levels of vaccination. [Note that men had higher odds of infection than women, a finding not seen in a previous analysis (20 May and 7 June). The reason? Increased social mixing during England’s progression in the Euro 2020 football competition during June and July 2021…]

 

20 July 2021

Butt AA, Omer SB, Yan P, Shaikh OS, Mayr FB. SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting. Ann Intern Med 2021, published 20 July. Full text: https://doi.org/10.7326/M21-1577

In this large US veteran cohort (> 108,000), the overall vaccine effectiveness was 97% seven or more days after the second dose of the mRNA vaccine.

 

30 June 2021

Thompson MG, Burgess JL, Naleway AL, et al. Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines. NEJM June 30, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2107058?query=featured_home

This prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers shows that mRNA vaccines attenuated the viral RNA load, risk of febrile symptoms, and duration of illness among those who had breakthrough infection despite vaccination.

 

16 June 2021

Gupta K, O’Brian WJ, Bellino P, et al. Incidence of SARS-CoV-2 Infection in Health Care Workers After a Single Dose of mRNA-1273 Vaccine. JAMA Netw Open June 16, 2021;4(6):e2116416. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781173

This study demonstrated an association between receipt of the mRNA-1273 vaccine and a reduction in SARS-CoV-2 infection in HCWs beginning 8 days after dose 1. Vaccine clinical effectiveness was 50.3% for the entire 42-day period of follow-up, 77.5% for days 8 through 42, and 95.0% for days 15 through 42.

 

7 June 2021

Chodick G, Tene K, Patalon T, et al. Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization. JAMA Netw Open June 7, 2021; 4(6):e2115985. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780700

In this study of 503,875 individuals from Israel who received 1 dose of the BNT162b2 vaccine, the first dose was associated with an approximately 54% reduction in the risk of symptomatic SARS-CoV-2 infections at 13 to 24 days after immunization compared to 1 to 12 days after vaccination.

 

17 May 2021

Chodick G, Tene L, Rotem RS, et al. The effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world data. Clinical Infectious Diseases May 17, 2021, ciab438, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab438/6276888

Real life data from Israel. Incidence rate of a SARS-CoV-2 infection between 7 to 27 days after the second dose (the protection period) was compared to days 1 to 7 after the first dose, where no protection by the vaccine is assumed (the reference period). In 1.1 million vaccinated persons, vaccine effectiveness in preventing infection was 90% and 94% against COVID-19. Look at the beautiful Figure 1.

 

14 May 2021

Pilishvili T, Fleming-Dutra KE, Farrar JL, et al. Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel — 33 U.S. Sites, January–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 14 May 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7020e2.htm

This large US multisite test-negative design vaccine effectiveness study among HCP found a single dose of Pfizer-BioNTech or Moderna vaccines to be 82% effective against symptomatic COVID-19 and 2 doses to be 94% effective.

 

13 May

Bernal JL, Andrews N, Gower C, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ May 13, 2021; 373. https://www.bmj.com/content/373/bmj.n1088

Early real-life data in older people (older than 70 years) from England: with BNT162b2, vaccine effectiveness reached 61% from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards.

 

12 May 2021

Liu Y, Liu J, Xia H, et al. BNT162b2-Elicited Neutralization against New SARS-CoV-2 Spike Variants. NEJM May 12, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2106083

The newly emerged B.1.526, B.1.429, and B.1.1.7+E484K variants remained susceptible to BNT162b2-elicited immune effector (neutralizing antibody).

 

8 May 2021

Hall VJ, Foulkes S, Saei A, et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021 May 8;397(10286):1725-1735. PubMed: https://pubmed.gov/33901423. Full text: https://doi.org/10.1016/S0140-6736(21)00790-X

These data from the SIREN (Sarscov2 Immunity and REinfection EvaluatioN) study suggest that the Pfizer-BioNTech vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults. (The SIREN study is a prospective cohort study among staff working in publicly funded hospitals.) The vaccine was 72% effective (95% CI 58-86) 21 days after first dose and 86% effective (95% CI 76-97) seven days after two doses in the antibody negative cohort (Hall 2021).

 

6 May 2021

Angel Y, Spitzer A, Henig O, et al. Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers. JAMA May 6, 2021. https://jamanetwork.com/journals/jama/fullarticle/2779853

Among 6710 health care workers in Tel Aviv, 757 (11.3%) were not vaccinated. Symptomatic SARS-CoV-2 infection occurred in 8 fully vaccinated and 38 unvaccinated health care workers (adjusted IRR, 0.03). The corresponding numbers for asymptomatic SARS-CoV-2 infections were 19 and 17, respectively (adjusted IRR, 0.14). Results were qualitatively unchanged by the propensity score sensitivity analysis.

 

5 May 2021

Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. The Lancet May 05, 2021. DOI:https://doi.org/10.1016/S0140-6736(21)00947-8

By April 3, 2021, 4.7 M people aged 16 years and older were fully vaccinated with two doses of BNT162b2 in Israel. Vaccine effectiveness at 7 days or longer after the second dose was 95% against SARS-CoV-2 infection, 97% against symptomatic COVID-19, 97% against hospitalization, and 98% against severe or critical disease. In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 outcomes declined. Estimated prevalence of the B.1.1.7 variant was 95%.

 

5 May 2021

Abu-Raddad LJ, Chemaitelly H, Butt AA. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. NEJM May 5, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2104974

Following a mass immunization campaign with BNT162b2 in Qatar, as of March 31, 2021, a total of 385,853 persons had received at least one vaccine dose and 265,410 had completed both doses. The estimated effectiveness against any documented infection with the B.1.1.7 variant was 89.5% at 14 days or more after the second dose. The effectiveness against any documented infection with the B.1.351 variant was 75%. Of note, effectiveness against severe, critical, or fatal disease (with the B.1.1.7 and B.1.351 variants being predominant in Qatar) was very high, at 97%.

 

3 May 2021

Fabiani M, Ramigni M, Gobbetto V, et al. Effectiveness of the Comirnaty (BNT162b2, BioNTech/Pfizer) vaccine in preventing SARS-CoV-2 infection among healthcare workers, Treviso province, Veneto region, Italy, 27 December 2020 to 24 March 2021. Eurosurveillance May 3, 2021. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.17.2100420

In this study on 6423 HCW from northern Italy, vaccine effectiveness (VE) was high. VE in preventing symptomatic infections during the time intervals 1–14 days and 15–28 days from administration of the first dose were 40% (95% CI: 9–60) and 86% (95% CI: 33–97), respectively.

 

23 April

Vasileiou E, Simpson CR, Shi T, et al. Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. Lancet. 2021 May 1;397(10285):1646-1657. PubMed: https://pubmed.gov/33901420. Full text: https://doi.org/10.1016/S0140-6736(21)00677-2

Paper of the day! Between Dec 8, 2020, and Feb 22, 2021, a total of 1,331,993 people were vaccinated in Scotland. The first dose of the BNT162b2 mRNA vaccine was associated with a vaccine effect of 91% (95% CI 85–94) for reduced COVID-19 hospital admission at 28–34 days post-vaccination. Vaccine effect for the ChAdOx1 vaccine was 88% (95% CI: 75–94). Results of combined vaccine effects against hospital admission due to COVID-19 were similar the analysis was restricted to those aged 80 years and older (83%, 95% CI: 72–89).

 

10 April

Emary KRW, Golubchik T, Aley PK, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021 Apr 10;397(10282):1351-1362. PubMed: https://pubmed.gov/33798499. Full text: https://doi.org/10.1016/S0140-6736(21)00628-0

This study by Andrew Pollard, Katherine Emary and colleagues reports that among participants in Phase II/III ChAdOx1 studies who had been infected with B117, vaccine efficacy against symptomatic SARS-CoV-2 infection was similar for B117 and non-B117 lineages (74,6% [95% CI: 41,6-88,9] and 84% [95% CI: 70,7-91,4], respectively). Importantly, virus neutralization activity by vaccine-induced antibodies was 9-fold lower against B117 than against a canonical non-B117 lineage.

 

29 March 2021

Thompson MG, Burgess JL, Naleway AL, et al. Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 29 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7013e3.htm

In this prospective cohort of 3950 health care personnel, first responders, and other essential and frontline workers who completed weekly SARS-CoV-2 testing for 13 consecutive weeks, mRNA vaccine effectiveness of full immunization (≥ 14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status; vaccine effectiveness of partial immunization (≥ 14 days after first dose but before second dose) was 80%.

 

16 March

Mahdi SA, Baillie C, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. NEJM, March 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2102214

No protection from mild-to-moderate COVID-19 with AstraZeneca in this large RCT on young (median age 30 years), HIV-negative patients in South Africa. Infections were seen in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% CI, −49.9 to 59.8). Main caveat: as there were no cases of hospitalization in the study, it remains unclear whether ChAdOx1 nCov-19 may protect against severe infection with the B.1.351 variant.

 

18 February

Amit S, Regev-Yochay G, Afek A, Kreiss Y, Leshem E. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. Lancet. 2021 Mar 6;397(10277):875-877. PubMed: https://pubmed.gov/33610193. Full text: https://doi.org/10.1016/S0140-6736(21)00448-7

Good news from Israel, showing substantial early reductions in SARS-CoV-2 infection and symptomatic COVID-19 rates following first mRNA vaccine dose administration. Using a retrospective cohort of 9109 vaccine-eligible HCWs, Sharon Amit and colleagues estimate adjusted rate reductions of SARS-CoV-2 infections of 30% and 75% for days 1–14 and days 15–28 after the first dose, respectively.

Antibody response and protection

16 August 2021

Schmitz AJ, Turner JS, Liu Z, et al. A vaccine-induced public antibody protects against SARS-CoV-2 and emerging variants. Immunity 2021, published 16 August. Full text: https://doi.org/10.1016/j.immuni.2021.08.013

The authors describe an antibody, dubbed 2C08 (a SARS-CoV-2 vaccine-induced mAb cloned from a germinal center B cell isolated from a draining axillary lymph node sampled from a healthy adult after receiving their second dose of an mRNA-based vaccine) which potently neutralizes the Delta, Gamma and Alpha strains and reduces lung viral load and morbidity in hamsters challenged with Delta and Gamma. Clonal analysis identified 2C08-like public clonotypes among B cells responding to SARS-CoV-2 infection or vaccination in 41 out of 181 individuals. Ergo: SARS-CoV-2 vaccines mitigate resistance by circulating variants of concern. Tell your friends to get vaccinated.

 

6 August 2021

Boekel L, Steenhuis M, Hooijberg F, et al. Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies. Lancet Rheumatology 2021, published 6 August. Full text: https://doi.org/10.1016/S2665-9913(21)00222-8

Two prospective studies of 3682 patients with rheumatic diseases, 546 patients with multiple sclerosis, and 1147 healthy controls. Seroconversion after first vaccination was significantly lower in patients than in controls, but after the second vaccination, seroconversion exceeded 80% in all patient treatment subgroups, except among those treated with anti-CD20 therapies (three [43%] of seven patients). We all know the final message: don’t delay the second shot in patients receiving immunosuppressive drugs.

 

5 August 2021 – Preprint!

Israel A, Merzon E, Schäffer AA, et al. Elapsed time since BNT162b2 vaccine and risk of SARS-CoV-2 infection in a large cohort. medRxiv. 2021 Aug 5:2021.08.03.21261496. PubMed: https://pubmed.gov/34401882. Full text: https://doi.org/10.1101/2021.08.03.21261496

A retrospective study from Israel describing 33,993 fully vaccinated adults tried to answer one of the bigger questions these days: is the amount of time since the second injection of the BioNTech/Pfizer vaccine significantly associated with a risk of post-vaccination COVID-19 infection? Yes, it is. Those who received their second dose of vaccine at least 146 days before a new RT-PCR test (Group 1) had a higher risk of infection that those who received their vaccine less than 146 days before (Group 2). The absolute numbers are somewhat less scary: among people older than 60, 182/7021 (2.6%) tested positive in Group 1 and 19/2164 (0.9%) in Group 2.

 

21 July 2021

Wei J, Stoesser N, Matthews PC, et al. Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom. Nat Microbiol. 2021 Jul 21. PubMed: https://pubmed.gov/34290390. Full-text: https://doi.org/10.1038/s41564-021-00947-3

In this UK cohort of 45,965 adults, seroconversion rates and antibody levels after a single vaccine dose were lower in older individuals, especially in those aged > 60 years. Low responders were more common among people taking immunosuppressants or corticosteroids, as well as in patients with rheumatoid arthritis, chronic liver disease, cancer, type 2 diabetes, obesity, and asthma.

 

2 July 2021

Lustig Y, Sapir E, Regev-Yochay G, et al. BNT162b2 COVID-19 vaccine and correlates of humoral immune responses and dynamics: a prospective, single-centre, longitudinal cohort study in health-care workers. Lancet Resp Med Jul 2, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00220-4/fulltext

A lot of data from Israel. A high correlation (r=0.92) was seen between IgG against the receptor-binding domain and neutralizing antibody titers. First-dose induced IgG response was significantly lower in individuals aged 66 years and older and immunosuppressed individuals. Of note, this disparity was partly abrogated following the second dose.

 

17 May 2021

Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med May 17, 2021. https://www.nature.com/articles/s41591-021-01377-8

Using data from several large vaccine trials (because of the different assays used, neutralization titers were normalized to the mean convalescent titer using the same assay in the same study), the authors estimate the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20% of the mean convalescent level. The estimated neutralization level required for 50% protection from severe infection was significantly lower (3%). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained.

 

6 April 2021

Doria-Rose N, Suthar MS, Makowski M, et al. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19. N Engl J Med. 2021 Apr 6. PubMed: https://pubmed.gov/33822494. https://www.nejm.org/doi/10.1056/NEJMc2103916

In 33 healthy adult participants in an ongoing Phase I trial, antibodies that were elicited by mRNA-1273 (Moderna) persisted through 6 months after the second dose, as detected by three distinct serologic assays.

Hybrid immunity

Hybrid immunity (Crotty 2021), a prior SARS-CoV-2 infection plus one dose of vaccine, seems to be better than any two-dose vaccine schedule. “Natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity (Gazit 2021).”

 

25 August 2021 – Preprint!

Gazit S, Shlezinger R, Perez G, et al. Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthrough infections. medRxiv 2021, posted 25 August. Full text: doi: https://doi.org/10.1101/2021.08.24.21262415

The authors compare natural immunity, gained through previous SARS-CoV-2 infection, to immunity induced by the BioNTech/Pfizer vaccine in more than 100,000 people. During the follow-up period, 257 cases of SARS-CoV-2 infection were recorded, of which 238 occurred in the vaccinated group (breakthrough infections) and 19 in the previously infected group (reinfections). The authors conclude that “natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalization caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity.”

 

28 July 2021 – Preprint!

Keeton R, Richardson SI, Moyo-Gwete T, et al. Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner. medRxiv 2021, posted 28 July. Full text: https://www.medrxiv.org/content/10.1101/2021.07.24.21261037v1

Therefore, vaccination with the J&J vaccine following previous infection, even > 6 months previously, may result in substantially enhanced protection against COVID-19. The authors conclude that this finding may be of particular relevance in settings of high SARS-CoV-2 seroprevalence.

 

Crotty S. Hybrid immunity. Science 2021, published 25 June. Full text: https://www.science.org/lookup/doi/10.1126/science.abj2258

When natural immunity is combined with vaccine-generated immunity, the result is a “25 to 100 times higher antibody response, driven by memory B celles and CD4+ T celles and broader cross-protection from variants.”

 

15 April 2021

Blain H, Tuaillon E, Gamon L, et al. Spike Antibody Levels of Nursing Home Residents With or Without Prior COVID-19 3 Weeks After a Single BNT162b2 Vaccine Dose. JAMA. 2021 Apr 15;325(18):1898-9. PubMed: https://pubmed.gov/33856406. Full text: https://doi.org/10.1001/jama.2021.6042

One shot may be enough in people with previous COVID-19. What had already been described in HCW (https://jamanetwork.com/journals/jama/fullarticle/2777171) may also be true for nursing home residents: all 36 residents (100%) with prior COVID-19 were seropositive for S protein IgG after one mRNA vaccine dose vs only 29 of 60 residents (49.2%) without prior COVID-19.

 

14 April 2021

Anichini G, Terrosi C Gandolfo C, et al. SARS-CoV-2 Antibody Response in Persons with Past Natural Infection. NEJM April 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2103825

This study indicates a significantly lower neutralizing antibody titer after administration of a second dose of vaccine in previously uninfected patients than the titer after only a single dose of vaccine in previously infected participants.

 

25 March 2021

Stamatatos L, Czartoski J, Wan YH, et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 2021, published 25 March. Full text: https://science.sciencemag.org/content/early/2021/03/24/science.abg9175

The preprint we presented on 10 February now published in Science. The study highlights the importance of vaccinating both uninfected and previously infected persons to elicit cross-variant neutralizing antibodies.

 

25 Februrary 2021

Prendecki M, Clarke C, Brown J, et al. Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine. Lancet February 25, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00502-X/fulltext

Early evidence for vaccine responses following previous natural infection. Maria Prendecki and colleagues looked at 72 HCWs from Imperial College Healthcare NHS Trust in London who were vaccinated, among them 21 (29%) participants with evidence of previous SARS-CoV-2 infection. Immune responses were analyzed 21-25 days after the first shot. In almost all individuals with previous SARS-CoV-2 infection, strong humoral and cellular responses to one dose of BNT162b2 vaccine, with evidence of high titers of virus neutralization were seen. In contrast, most infection-naive individuals generated only weak T cell responses and low titers of neutralizing antibodies.

 

25 Februrary 2021

Manisty C, Otter AD, Treibel TA, et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet February 25, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00501-8/fulltext

Same direction: in this nested case-control analysis of 51 participants of COVIDsortium (24 seropositive) seronegative individuals had anti-S titers after one dose of vaccine comparable to peak anti-S titers in individuals with a previous natural infection who had not yet been vaccinated. Among those with a previous SARS-CoV-2 infection, vaccination increased anti-S titers more than 140-fold from peak pre-vaccine levels. This increase appears to be at least one order of magnitude greater than reported after a conventional prime-boost vaccine strategy in previously uninfected individuals.

Breakthrough infections and SARS-CoV-2 transmission

Vaccinated people can become infected with SARS-CoV-2 and transmit the virus. Transmission rates can be astonishingly high. In one case, 346 of 469 individuals (74%) infected during large public gatherings were vaccinated (Brown 2021).

For Delta variant infections, the viral load cycle threshold (Ct) has been described as being similar for unvaccinated individuals (17.8) and those with a full vaccination schedule (18.0) (Public Health England 202100806). However, vaccinated people are thought to shed infectious virus for less time than unvaccinated individuals.

Vaccination continues to be superior to non-vaccination. In one study, those who were not vaccinated had a 2.34 times higher risk of reinfection than those who were fully vaccinated (Cavanaugh 2021).

 

2 September 2021

Feder KA, Patel A, Vepachedu VR, et al. Association of E484K spike protein mutation with SARS-CoV-2 infection in vaccinated persons—Maryland, January – May 2021, Clin Inf Dis September 2, 2021, ciab762, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab762/6362726

Among 9048 cases, SARS-CoV-2 viruses carrying the spike protein mutation E484K were disproportionately prevalent among persons infected after full vaccination (adjusted OR 1.96).

 

10 August 2021

Van Vinh Chau N, Ngoc NM. Transmission of SARS-CoV-2 Delta Variant Among Vaccinated Healthcare Workers, Vietnam. Lancet Preprints 2021, posted 10 August. Full text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3897733

In this study of 62 healthcare workers, breakthrough infections with the Delta variant were associated with high viral loads (251 times higher than in people infected with historical strains), prolonged PCR positivity (8–33 days; median: 21), and low levels of vaccine-induced neutralizing antibodies. The authors conclude that physical distancing measures will be critical to reduce the transmission of the Delta variant.

 

6 August 2021

Cavanaugh AM, Spicer KB, Thoroughman D, Glick C, Winter K. Reduced Risk of Reinfection with SARS-CoV-2 After COVID-19 Vaccination — Kentucky, May–June 2021. MMWR Morb Mortal Wkly Rep. ePub: 6 August 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7032e1

The immunological response elicited by vaccines might be better than the response elicited by natural SARS-CoV-2 infection. In Kentucky residents infected by COVID in 2020, those who were not vaccinated had a 2.34 times higher risk of reinfection than those who were fully vaccinated.

 

6 August 2021

Public Health England 202100806. SARS-CoV-2 variants of concern and variants under investigation in England | Technical briefing 20. UK Government 2021, 6 August. https://www.gov.uk/government/publications/investigation-of-novel-sars-cov-2-variant-variant-of-concern-20201201 | PDF: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1009243/Technical_Briefing_20.pdf

Again, for Delta variant infections, the viral load cycle threshold (Ct) is described as being similar for unvaccinated individuals (17.8) and those with a full vaccination schedule (18.0). The authors conclude that “similar Ct values (…) suggest limited difference in infectiousness.” Note that there is still the possibility that vaccinated people shed the virus for a shorter period of time. Vaccination may also reduce an individual’s overall risk of becoming infected. In any case, vaccination should be expected to reduce SARS-CoV-2 transmission, even of the Delta variant. Interesting discussions ahead.

 

30 July 2021

Brown CM, Vostok J, Johnson H, et al. Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings — Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. ePub: 30 July 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7031e2

Bad news from Barnstable County, Massachusetts. In July 2021, following multiple summer events and large public gatherings, 469 COVID-19 cases were identified among Massachusetts residents who had traveled to the town during July 3–17. Intriguingly, 346 (74%) occurred in fully vaccinated persons. Even more intriguingly: cycle threshold values were similar among specimens from patients who were fully vaccinated and those who were not. The driving force behind the outbreak: the Delta variant.

 

28 July

Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med. 2021 Jul 28. PubMed: https://pubmed.gov/34320281. Full-text: https://doi.org/10.1056/NEJMoa2109072

Long COVID after breakthrough infections? Most breakthrough infections during the 4-month period after the second vaccine dose (39/1497, 0.4%) were mild or asymptomatic; however, 7 patients (19%) had persistent symptoms (> 6 weeks), including headaches, muscle pain, loss of taste and smell and fatigue), indicating that Long COVID may occur among people who experience breakthrough infections. Note that the study is from the pre-Delta world (20 January through 28 April; 85% of the samples yielded the Alpha strain [B.1.1.7]). Expect the data to be less favorable in settings where Delta (B.1.617.2) is the dominant strain. It may be wise to follow the new CDC guidelines and wear masks indoors in risky situations (see the next paragraph, “Prevention”).

 

7 July 2021

Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully-vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect. 2021 Jul 7:S1198-743X(21)00367-0. PubMed: https://pubmed.gov/34245907. Full-text: https://doi.org/10.1016/j.cmi.2021.06.036

Retrospective study of 152 individuals who developed COVID-19 more than 7 days after the second BioNTech/Pfizer vaccine dose and required hospitalization. High rate of existing co-morbidities: hypertension (71%), diabetes (48%), congestive heart failure (27%), lung diseases (24%), chronic kidney (24%), dementia (19%) and cancer (24%). Importantly, 60 (40%) patients were immunocompromised. Thirty-four (22%) patients died.

 

14 June 2021

Kustin T, Harel N, Finkel U, et al. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Nat Med June 14, 2021. https://www.nature.com/articles/s41591-021-01413-7

Analyzing 813 viral genome sequences, the authors showed that vaccinees who tested positive at least 7 days after the second dose were disproportionally infected with B.1.351, compared with controls. Those who tested positive between 2 weeks after the first dose and 6 days after the second dose were disproportionally infected by B.1.1.7.

 

12 June 2021

Pollett SD, Richard SA, Fries AC, et al. The SARS-CoV-2 mRNA vaccine breakthrough infection phenotype includes significant symptoms, live virus shedding, and viral genetic diversity. Clin Inf Dis June 12, 2021, ciab543. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab543/6297424

A total of 24 “VBI” (vaccine breakthrough infections) in predominantly young healthy persons. While none required hospitalization, a proportion experienced severe symptoms and shed live virus as high as 4.130 PFU/mL. Though of relatively low magnitude, the presence of infectious virus which may indicate a transmission risk of VBI. Infecting genotypes included both variants and wild type.

 

25 May 2021

CDC COVID-19 Vaccine Breakthrough Case Investigations Team. COVID-19 Vaccine Breakthrough Infections Reported to CDC — United States, January 1–April 30, 2021. MMWR Morb Mortal Wkly Rep. ePub: 25 May 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7021e3.htm?s_cid=mm7021e3_w

As of April 30, 2021, approximately 101 million persons in the US had been fully vaccinated against COVID-19. A total of 10,262 SARS-CoV-2 vaccine breakthrough infections had been reported, among them 6446 (63%) in females. In total, 995 (10%) patients were known to be hospitalized, and 160 (2%) patients died. Sequence data were available from 555 (5%) reported cases, 356 (64%) of which were identified as SARS-CoV-2 variants of concern, including B.1.1.7 (199; 56%), B.1.429 (88; 25%), B.1.427 (28; 8%), P.1 (28; 8%), and B.1.351 (13; 4%).

 

16 May 2021

Bailly B, Guilpain L, Bouiller K, et al. BNT162b2 mRNA vaccination did not prevent an outbreak of SARS COV-2 variant 501Y.V2 in an elderly nursing home but reduced transmission and disease severity. Clinical Infectious Diseases, 16 May 2021. ciab446, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab446/6276392

An outbreak of SARS-CoV-2 1.351 (the South African variant) in a nursing home in Jura, in eastern France. 5/5 non-vaccinated residents versus 13/26 of those vaccinated with BNT162b2 were infected. Two of 13 vaccinated versus 4 of 5 non-vaccinated residents presented severe disease.

 

21 April

Cavanaugh AM, Fortier S, Lewis P, et al. COVID-19 Outbreak Associated with a SARS-CoV-2 R.1 Lineage Variant in a Skilled Nursing Facility After Vaccination Program — Kentucky, March 2021. MMWR Morb Mortal Wkly Rep. ePub: 21 April 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e2.htm?s_cid=mm7017e2_w#suggestedcitation

In a COVID-19 outbreak at a Kentucky skilled nursing facility involving a newly introduced variant (characterized by E484K and other mutations within the spike protein) to the region, 26/83 residents (18/75 fully vaccinated with BioNTech) and 20/116 HCP (4/61 vaccinated) became infected. Vaccine was 86.5% protective against symptomatic illness among residents and 87.1% protective among HCP. Three residents died, two of whom were unvaccinated (vaccine effectiveness 94%).

 

21 April 2021

Teran RA, Walblay KA, Shane EL, et al. Postvaccination SARS-CoV-2 Infections Among Skilled Nursing Facility Residents and Staff Members — Chicago, Illinois, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. ePub: 21 April 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7017e1.htm

During the investigation period, an estimated 7931 skilled nursing facility residents and 6834 staff members received two doses of the COVID-19 vaccine. Among 12 possible breakthrough SARS-CoV-2 infections among fully vaccinated residents ≥ 14 days after their second dose of COVID-19 vaccine, 8 were asymptomatic.

 

21 April 2021

Hacisuleyman E, Hale H, Saito Y, et al. Vaccine Breakthrough Infections with SARS-CoV-2 Variants. NEJM April 21, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2105000

Two breakthrough cases. Despite evidence of vaccine efficacy in both women, symptoms of COVID-19 developed, and they tested PCR positive 19 and 36 days after the second Moderna shot. Rapid identification of sequence variants by targeted PCR amplification showed that neither sequence precisely fit any known clade.

 

23 March 2021

Keehner J, Pfeffer MA, Longhurst CA, et al. SARS-CoV-2 Infection after Vaccination in Health Care Workers in California. N Engl J Med 2021, 2021, published 23 March. https://www.nejm.org/doi/full/10.1056/NEJMc2101927

COVID-19 infection after complete vaccination? Possible, but rare. At the University of California, San Diego (UCSD) and the University of California, Los Angeles (UCLA) health systems, 379 persons (/36,659 who received the first dose, and /28,184 of whom received the second dose) tested positive for SARS-CoV-2 at least 1 day after vaccination, the majority (71%) of whom tested positive within the first 2 weeks after the first dose. After receiving both vaccinations, 37 health care workers tested positive; of these workers, 22 had positive test results 1 to 7 days after the second dose. Only 8 health care workers tested positive 8 to 14 days after the second vaccination, and 7 tested positive 15 or more days after the second vaccination.

Booster vaccination

17 September 2021

FDA 20210917. Vaccines and Related Biological Products Advisory Committee Meeting. FDA 2021, published 17 September. Full text: https://www.fda.gov/media/152161/download

A panel of advisers to the Food and Drug Administration voted not to recommend BioNTech/Pfizer booster shots for most Americans. They

  • voted 18-0 in support of a booster shot of the BioNTech/Pfizer vaccine for people 65 and older or at high risk of severe COVID-19;
  • voted 16-2 against approval of a booster dose of the vaccine for all people 16 years and older.

The panel also unanimously supported authorization of a booster dose for health care workers or others at high risk of occupational SARS-CoV-2 exposure.

 

15 September 2021

Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med. 2021 Sep 15. PubMed: https://pubmed.gov/34525275. Full text: https://doi.org/10.1056/NEJMoa2114255

A booster dose of the BioNTech/Pfizer vaccine may reduce the rates of both confirmed infection and severe Covid-19 illness. In this large Israeli population of people 60 years of age or older (n = 1,137,804, fully vaccinated at least 5 months earlier), the rates of 1) confirmed infection and 2) severe illness were lower in the booster group than in the nonbooster group by a factor of 11.3 and 19.5, respectively.

 

13 September 2021

Krause PR, Fleing TR, Peto R, et al. Considerations in boosting COVID-19 vaccine immune responses. Lancet 2021, published 13 September. Full text: https://doi.org/10.1016/S0140-6736(21)02046-8

The authors warn that “current evidence does not appear to show a need for boosting in the general population, in which efficacy against severe disease remains high” and that the benefits of boosting, “will not outweigh the benefits of providing initial protection to the unvaccinated”.

 

12 July 2021

Arunachalam PS, Scott MKD, Hagan T, et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature. 2021 Jul 12. PubMed: https://pubmed.gov/34252919. Full-text: https://doi.org/10.1038/s41586-021-03791-x

Booster injections of mRNA vaccines might stimulate a “strikingly enhanced innate immune response” compared to the primary injection.

Heterologous vaccine schedules

17 August 2021

Behrens GM, Cossmann A, Stankov MV, et al. SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination. Lancet August 17, 2021. https://doi.org/10.1016/S0140-6736(21)01891-2

Robust inhibition of variants including Delta by the switch vaccination of AstraZeneca then BioNTech/Pfizer.

 

12 August 2021

Hillus D, Schwarz T, Tober-Lau P, et al. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study. Lancet Respir Dis 2021, published 12 August. Full text: https://doi.org/10.1016/S2213-2600(21)00357-X

A new prospective vaccine mixing study comparing “AstraZeneca (AZ) + BioNTech/Pfizer (BP)” with 2 x AZ and 2 x BP. The authors show “AZ first, BP second” elicited a stronger immune response than two doses of either vaccine. Could these data spur a renaissance for the AstraZeneca vaccine? Not sure. The difference might be explained by the longer (and possibly more effective) immunization interval of AZ+BP compared to the typical 3-week interval of the two BP injections.

 

6 August 2021

Liu X, Shaw RH, Stuart ASV, et al. Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial. Lancet. 2021 Aug 6:S0140-6736(21)01694-9. PubMed: https://pubmed.gov/34370971. Full text: https://doi.org/10.1016/S0140-6736(21)01694-9

BioNTech/Pfizer vs AstraZeneca ­– the first immunogenicity comparison of heterologous vaccine schedules. After measuring the SARS-CoV-2 anti-spike IgG concentrations (measured by ELISA) at 28 days after the vaccine boost, the authors find the following values for homologs and heterologs schedules (BNT: BioNTech/Pfizer; AZ: AstraZeneca):

  • BNT/BNT: 14,080 ELU/mL
  • AZ/BNT: 12,906 ELU/mL
  • BNT/AZ: 7133 ELU/mL
  • AZ/AZ: 1392 ELU/mL

 

14 July 2021

Normark J, Vikström L, Gwon YD, et al. Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination. N Engl J Med. 2021 Jul 14:NEJMc2110716. PubMed: https://pubmed.gov/34260850. Full text: https://doi.org/10.1056/NEJMc2110716

This relatively small cohort suggests that the mRNA-1273 vaccine (MODERNA) boost may provide better protection against the B.1.351 variant than a ChAdOx1 nCoV-19 boost. However, the mRNA-1273 boost led to more frequent reports of fever, headache, chills, and muscle aches than the ChAdOx1 nCoV-19 boost.

 

July 2021

Powell AA, Power L, Westrop S, et al. Real-world data shows increased reactogenicity in adults after heterologous compared to homologous prime-boost COVID-19 vaccination, March-June 2021, England. Euro Surveill. 2021 Jul;26(28):2100634. PubMed: https://pubmed.gov/34269172. Full text: https://doi.org/10.2807/1560-7917.ES.2021.26.28.2100634

Same direction. After the second vaccine dose, previously uninfected adults in both heterologous vaccination groups had significantly higher reactogenicity than their homologous counterparts, with similar rates among those receiving ChAd/BNT (54.4%) and BNT/ChAd (55.2%) compared with ChAd/ChAd (33.5%) or BNT/BNT (33.3%). Severe reactogenicity was 2.4 times (27.8% vs. 11.6%) more likely with heterologous regimens, including increased requirement for medical attention. These findings were irrespective of the reason for receiving a heterologous schedule.

 

14 July 2021

Barros-Martins J, Hammerschmidt SI, Cossmann A, et al. Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Nat Med Jul 14, 2021. https://www.nature.com/articles/s41591-021-01449-9

ChAdOx1 (AstraZeneca/Oxford)-primed immune responses before and 3 weeks after booster with ChAd (n = 32) or BioNTech/Pfizer’s BNT162b2 (n = 55): although both vaccines boosted prime-induced immunity, BNT162b2 induced significantly higher frequencies of spike-specific CD4+ and CD8+ T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and P.1 variants.

Timing of the second vaccine dose

1 September 2021

Flaxman A, Marchevsky NG, Jenkin D, et al. Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002). Lancet September 01, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01699-8/fulltext

Sub-study of two trials in which the timing of the second dose varied and allowed for comparisons of immunogenicity between the recommended vaccination schedule and a longer interval. Results: the extended interval between the first two doses (44–45 weeks) resulted in higher antibody titers after the second dose than with a shortened interval. A third dose given 28–38 weeks after the second dose increased the antibody titers to above those after the primary (1-2) series.

 

1 September 2021

McQuade ET, Breskin A. Longer intervals and extra doses of ChAdOx1 nCoV-19 vaccine. Lancet September 01, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01817-1/fulltext

But what do these data tell us? In their comment, Elizabeth Rogawski McQuade and Alexander Breskin point out that “the total public health impact of the extended prime-boost interval is unclear given the trade-off between a longer period at the lower level of protection afforded by a single dose and the higher level of protection obtained after a delayed second dose”. However, data may assuage concerns about the potential for impaired responses after repeated use of a replication deficient simian adenoviral vector and suggest that a third dose of the AZ/Oxford vaccine could be successful if necessary.

 

Vax vs. No-vax

24 August 2021

Griffin JB, Haddix M, Danza P, et al. SARS-CoV-2 Infections and Hospitalizations Among Persons Aged =16 Years, by Vaccination Status — Los Angeles County, California, May 1–July 25, 2021. MMWR Morb Mortal Wkly Rep. ePub: 24 August 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7034e5.htm?s_cid=mm7034e5_w

From May 1–July 25, 2021, among 43,127 SARS-CoV-2 infections in residents of Los Angeles County, 25.3% were in fully vaccinated persons, 3.3% were in partially vaccinated persons, and 71.4% were in unvaccinated persons. On July 25, infection and hospitalization rates among unvaccinated persons were 4.9 and 29.2 times, respectively, those of fully vaccinated persons. Of note, in July, when Delta was predominant, cycle threshold values were similar for unvaccinated and vaccinated persons.

Adverse Events

3 September

Klein NP, Lewis N, Goddard K, et al. Surveillance for Adverse Events After COVID-19 mRNA Vaccination. JAMA September 3, 2021. https://jamanetwork.com/journals/jama/fullarticle/2784015

COVID-19 vaccines are safe. In this interim analysis of surveillance monitoring of more than 11.8 million doses of 2 mRNA vaccines in diverse populations and weekly analyses from December 14, 2020, to June 26, 2021, no vaccine-outcome association met the prespecified threshold for a signal.

 

27 April 2021

Menni C, Klaser K, May A, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Inf Dis April 27, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00224-3/fulltext

Between Dec 8, and March 10, 2021, 627,383 individuals reported being vaccinated: 282,103 received one dose of BNT162b2, of whom 28,207 received a second dose, and 345,280 received one dose of ChAdOx1 nCoV-19. Systemic side effects were reported by 13.5%, 22.0%, and by 33.7%, respectively. Local side effects were reported by 71.9%, 68.5% and 58.7%. Systemic side effects were more common (1.6 times after the first dose of ChAdOx1 nCoV-19 and 2.9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection.

Thromboses and thrombocytopenia (VITT)

Until the end of April 2021, several hundred cases of unusual thrombosis in veins in the brain (cerebral sinus vein thromboses, CSVT[2]), the abdomen (splanchnic vein thrombosis) and in arteries were reported after the first injection of the AstraZeneca vaccine.

The first symptoms appeared as early as five days and as late as a month after vaccination. Cases of the new syndrome – vaccine-induced immune thrombotic thrombocytopenia (VITT) or thrombosis-thrombocytopenia syndrome (TTS) – have been reported from several countries, including Germany and Austria (Greinacher 2021), Norway (Schultz 2021), France (ANSM 20210416), and the UK (MHRA 20210401, Scully 2021).

The risk for vaccine-induced immune thrombotic thrombocytopenia (VITT) has been estimated to be around one case in 70,000 vaccinated.

VITT has also been described after injection of the Johnson & Johnson vaccine. The risk appears to be 10 times lower than for the AstraZeneca vaccine.

 

27 August 2021

Hippisley-Cox J, Patone M, Mei XW, et al. Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study. BMJ August 27, 2021; 374 doi: https://doi.org/10.1136/bmj.n1931

This patient level data obtained for approximately 30 million people vaccinated in England shows that the slightly increased risks of severe hematological and vascular events after the first doses of the AstraZeneca and BioNTech/Pfizer vaccines were minimal vs the substantially higher and more prolonged events after SARS-CoV-2 infection in the same population.

 

25 August 2021

Uzun G, Althaus K, Bakchoul T. No Correlation between Anti-PF4 and Anti–SARS-CoV-2 Antibodies after ChAdOx1 nCoV-19 Vaccination. NEJM August 25, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2111305

This study does not support the hypothesis that the immune response against SARS-CoV-2 proteins leads to the formation of anti-platelet factor 4 antibodies in patients with vaccine-induced immune thrombotic thrombocytopenia.

 

6 August 2021

Perry RJ, Tamborska A, Bhagteshwar S, et al. Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study. Lancet 2021, published 6 August. Full text: https://doi.org/10.1016/S0140-6736(21)01608-1

An analysis of 95 patients from more than 40 hospitals across the UK. Seventy patients had vaccine-induced immune thrombotic thrombocytopenia (VITT) and 25 did not. Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed than non-VITT patients; they also more frequently had extracranial thrombosis. Death or dependency occurred in 47% of patients with VITT-associated cerebral venous thrombosis. Non-heparin anticoagulants and immunoglobulin treatment might improve VITT outcome.

 

5 August 2021

Takuva S, Takalani A, Garrett N, et al. Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study. N Engl J Med. 2021 Aug 5;385(6):570-571. PubMed: https://pubmed.gov/34077639. Full text: https://doi.org/10.1056/NEJMc2107920

Interim safety data from the first 288,368 participants who were vaccinated with Ad26.COV2.S (Johnson & Johnson) in the Sisonke study — an open-label, Phase IIIb implementation study. The rate of adverse events with vaccination is low, and thromboembolic events occur mainly in persons with risk factors for thromboembolism.

 

2 July 2021

Sánchez van Kammen M, Brodard J, Scutelnic A, et al. Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic. JAMA July 2, 2021. https://jamanetwork.com/journals/jama/fullarticle/2781791?resultClick=1

In 865 patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon (8.4%), and heparin-induced thrombocytopenia (0.1%) and platelet factor 4/heparin antibodies were rare.

 

1 July 2021

Ropper AH, Klein JP. Cerebral Venous Thrombosis. N Engl J Med. 2021 Jul 1;385(1):59-64. PubMed: https://pubmed.gov/34192432. Full text: https://doi.org/10.1056/NEJMra2106545

Nice review. Allan H. Ropper and Joshua P. Klein summarize current knowledge on how to diagnose and how to treat cerebral venous thrombosis.

 

5 May 2021

Pottegård A, Lund LC, Karlstad Ø, et al. Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study. BMJ May 5, 2021; 373. https://www.bmj.com/content/373/bmj.n1114

Among 281,264 people who received ChAdOx1-S, 11 and 2.5 excess events per 100,000 vaccinations were seen for venous thromboembolic events and cerebral venous thrombosis, respectively.

 

30 April 2021

See I, Su JR, Lale A, et al. US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021. JAMA April 30, 2021. https://jamanetwork.com/journals/jama/fullarticle/2779731

Twelve US cases of cerebral venous sinus thrombosis (CVST) with thrombocytopenia following vaccination with Ad26.COV2.S, the COVID-19 vaccine produced by Janssen/J&J. All were women, younger than 60 years, and had symptom onset ranging from 6 to 15 days after vaccination that required hospitalization.

 

16 April 2021

Sadoff J, Davis K, Douoguih M. Thrombocytopenia after Ad26.COV2.S Vaccination — Response from the Manufacturer. NEJM April 16, 2021, https://www.nejm.org/doi/full/10.1056/NEJMc2106075

Response from Janssen: Their ongoing safety surveillance received reports of six cases of CVST with thrombocytopenia occurring 7 to 14 days after vaccination, including the above case. These cases were reported among more than 7.2 million persons who had been vaccinated with Ad26.COV2.S globally as of April 14. Janssen argues (and surely hopes) that their numbers are lower, due to substantial vector and spike differences between their vaccine and Astra Zeneca’s. Their vaccine uses a human Ad26–based vector (vs the chimpanzee one for ChAdOx1 nCoV-19) with different host cell receptors and is likely to have different phylogenetic and biologic characteristics. Let’s hope.

 

16 April 2021

Ledford H. COVID vaccines and blood clots: five key questions. Nature News April 16, 2021. https://www.nature.com/articles/d41586-021-00998-w

Heidi Ledford summarizes the key questions (but has no definite answers): What could the connection be between blood clots and vaccines? Are other COVID-19 vaccines linked to blood clotting disorders? How rare are they and are certain groups of people more at risk? What impact will fears over potential side effects have on global vaccination efforts? Answers needed.

 

16 April 2021

Scully M, Sing D, Lown R, et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19. NEJM April 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2105385

This case series of 23 patients from London who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). All patients had D-dimer levels at presentation much higher than what would be expected in patients with acute venous thromboembolism.

 

14 April 2021

Muir KL, Kallam A, Koepsell SA, et al. Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination. NEJM April 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2105869

First case seen with the Ad26.COV2.S vaccine from Johnson & Johnson. A 48-year-old White woman presenting with extensive thrombosis associated with severe thrombocytopenia and disseminated intravascular coagulation. The patient remained critically ill at the time of this report.

 

9 April 2021

Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. NEJM April 9, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2104840?query=featured_home

A case series of 11 patients (9 women) from Germany and Austria in whom thrombosis or thrombocytopenia developed after vaccination with ChAdOx1 nCov-19. All had moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites beginning 5-16 days after first vaccination. All had platelet-activating antibodies directed against platelet factor 4 (PF4)–heparin.

 

9 April 2021

Schultz NH, Sørvoll ICH, Michelsen AE, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. NEJM April 9, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2104882

Another five patients (four women) from Norway. Same findings.

 

Anaphylaxis and allergic reactions

The incidence of anaphylaxis associated with the BioNTech/Pfizer vaccine appears to be approximately 10 times as high (1 in 100,000) as the incidence reported with all previous vaccines (Castells 2020, Shimabukuro 2021).

The CDC recommends that appropriate medical treatment for severe allergic reactions be immediately available in the event that an acute anaphylactic reaction occurs following administration of an mRNA COVID-19 vaccine (CDC 20201231, CDC 20210303).

 

31 August 2021

Shavit R, Maoz-Segal R, Iancovici-Kidon M, et al. Prevalence of Allergic Reactions After Pfizer-BioNTech COVID-19 Vaccination Among Adults With High Allergy Risk. JAMA Netw Open August 31, 2021; 4(8):e2122255. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2783626

In this cohort study of 8102 individuals with a history of allergies, an algorithm was used to define 429 (5%) as “highly allergic”; this group was referred to receive immunization under medical supervision. A total of 98% of the highly allergic individuals had no allergic reaction, 6 (1%) had mild allergic responses, and 3 (0.7%) had anaphylactic reactions.

 

26 July 2021

Krantz MS, Kwah JH, Stone CA Jr, et al. Safety Evaluation of the Second Dose of Messenger RNA COVID-19 Vaccines in Patients With Immediate Reactions to the First Dose. JAMA Intern Med. 2021 Jul 26. PubMed: https://pubmed.gov/34309623. Full text: https://doi.org/10.1001/jamainternmed.2021.3779

All 159 patients with an immediate allergic reaction to the first dose of the Pfizer/BioNTech or Moderna vaccine, including 19 individuals with first-dose anaphylaxis, tolerated the second dose. (Antihistamine pre-medication had been given to 47 patients [30%] before the second dose). Thirty-two patients (20%) reported immediate and potentially allergic symptoms that were associated with the second dose that were self-limiting, mild, and/or resolved with antihistamines alone.

 

8 March 2021

Blumenthal KG, Robinson LB, Camargo Jr CA, et al. Acute Allergic Reactions to mRNA COVID-19 Vaccines. JAMA March 8, 2021; https://jamanetwork.com/journals/jama/fullarticle/2777417

Of 64,900 vaccine recipients in Massachusetts, anaphylaxis was confirmed in 16 (0.025%). Of note, 15/16 were female, 10 had a prior history of allergies and 5 had a history of anaphylaxis. Mean time to anaphylaxis onset was 17 minutes (range, 1-120). All recovered.

 

28 February 2021

Shimabukuro T. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine – United States, December 14-23, 2020. Am J Transplant. 2021 Mar;21(3):1332-1337. PubMed: https://pubmed.gov/33641264. Full text: https://doi.org/10.1111/ajt.16516

One case of anaphylaxis in 100.000 vaccine recipients of the BioNTech/Pfizer vaccine Comirnaty. That is the result of the 10 days of monitoring (14-23 December) by the Vaccine Adverse Event Reporting System which detected 21 cases of anaphylaxis after administration of a reported 1.893.360 first doses of the vaccine (11,1 cases per million doses). Note that 71% of these occurred within 15 minutes of vaccination. Screen recipients for contraindications and precautions; have the necessary supplies available to manage anaphylaxis; implement the recommended post-vaccination observation periods; and immediately treat suspected cases of anaphylaxis with intramuscular injection of epinephrine! For detailed insight, check also Castells MC, Phillips EJ. Maintaining Safety with SARS-CoV-2 Vaccines. N Engl J Med 2020, published 30 December. Full-text: https://doi.org/10.1056/NEJMra2035343

 

12 February 2021

Shimabukuro TT, Cole M, Su JR. Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US-December 14, 2020-January 18, 2021. JAMA. 2021 Feb 12. PubMed: https://pubmed.gov/33576785. Full-text: https://doi.org/10.1001/jama.2021.1967

During December 14, 2020 through January 18, 2021, a total of 9 943 247 doses of the Pfizer-BioNTech vaccine and 7 581 429 doses of the Moderna vaccine were reported administered in the US. CDC identified 66 case reports that met Brighton Collaboration case definition criteria for anaphylaxis (levels 1, 2 or 3): 47 following Pfizer-BioNTech vaccine, for a reporting rate of 4.7 cases/million doses administered, and 19 following Moderna vaccine, for a reporting rate of 2.5 cases/million doses administered.

 

29 January 2021

CDC COVID-19 Response Team; Food and Drug Administration. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine – United States, December 21, 2020-January 10, 2021. MMWR Morb Mortal Wkly Rep. 2021 Jan 29;70(4):125-129. PubMed: https://pubmed.gov/33507892. Full text: https://doi.org/10.15585/mmwr.mm7004e1

Two in a Million: from December 21, 2020 to January 10, 2021, CDC detected 10 cases of anaphylaxis after administration of a reported 4.041.396 first doses of the Moderna COVID-19 vaccine (2.5 cases per million doses administered). No anaphylaxis-related deaths were reported. Nine events occurred in persons with a documented history of allergies or allergic reactions, five of whom had a previous history of anaphylaxis. The median interval from vaccine receipt to symptom onset was 7.5 minutes. Nine patients had onset within 15 minutes, and one had onset after 30 minutes.

 

31 December 2020

CDC 20201231. Interim considerations: preparing for the potential management of anaphylaxis after COVID-19 vaccination. Vaccines & Immunizations 2020, last reviewed: December 31, 2020. Full-text: https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/anaphylaxis-management.html

Anaphylaxis has been reported following COVID-19 vaccination. The incidence of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines, at approximately 1 in 100,000, as compared 1 in 1,000,000 (Castells 2020). The CDC recommends that appropriate medical treatment for severe allergic reactions must be immediately available in the event that an acute anaphylactic reaction occurs following administration of an mRNA COVID-19 vaccine. In particular, persons without contraindications to vaccination who receive an mRNA COVID-19 vaccine be observed after vaccination for the following time periods:

  • 30 minutes: Persons with a history of an immediate allergic reaction of any severity to a vaccine or injectable therapy and persons with a history of anaphylaxis due to any cause.
  • 15 minutes: All other persons

 

30 December 2020

Castells MC, Phillips EJ. Maintaining Safety with SARS-CoV-2 Vaccines. N Engl J Med 2020, published 30 December. Full-text: https://doi.org/10.1056/NEJMra2035343

On December 8, 2020, within 24 hours after the start of the U.K. mass vaccination program for health care workers and elderly adults, the program reported probable cases of anaphylaxis in two women, 40 and 49 years of age, who had known food and drug allergies and were carrying auto-injectable epinephrine. One week later, a 32-year-old female health care worker in Alaska who had no known allergies presented with an anaphylactic reaction within 10 minutes after receiving the first dose of the vaccine. Since then, several more cases of anaphylaxis associated with the Pfizer mRNA vaccine have been reported in the United States after vaccination of almost 2 million health care workers, and the incidence of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines, at approximately 1 in 100,000, as compared 1 in 1,000,000. Mariana Castells and Elizabeth Phillips explain what is at stake: “It is critical that we focus on safe and efficient approaches to implementing mass vaccination. In the future, these new vaccines may mark the beginning of an era of personalized vaccinology in which we can tailor the safest and most effective vaccine on an individual and a population level.” Happy New Year!

Myocarditis

“Two distinct self-limited syndromes, myocarditis and pericarditis, were observed after COVID-19 vaccination. Myocarditis developed rapidly in younger patients, mostly after the second vaccination. Pericarditis affected older patients later, after either the first or second dose.” (Diaz 2021)

 

17 August 2021

Diaz GA, Parsons GT, Gering SK, Meier AR, Hutchinson IV, Robicsek A. Myocarditis and Pericarditis After Vaccination for COVID-19. JAMA. 2021 Aug 4. PubMed: https://pubmed.gov/34347001. Full text: https://doi.org/10.1001/jama.2021.13443

Among 2,000,287 individuals receiving at least 1 COVID-19 vaccination (BioNTech/Pfizer: 52.6%, Moderna: 44.1%, Johnson & Johnson: 3.1%), 20 individuals had vaccine-related myocarditis (1 per 100,000) and 37 had pericarditis (1.8 per 100,000). Myocarditis occurred a median of 3.5 days after vaccination. Fifteen individuals (75%) were male. Four persons (20%) developed symptoms after the first vaccination and 16 (80%) after the second one. Nineteen patients (95%) were admitted to the hospital. All were discharged after a median of 2 days. There were no readmissions or deaths. Find more details about pericarditis in the article.

 

30 July

Pepe S, Gregory AT, Denniss AR. Myocarditis, Pericarditis and Cardiomyopathy After COVID-19 Vaccination. Heart Lung Circ. 2021 Jul 30:S1443-9506(21)01156-2. PubMed: https://pubmed.gov/34340927. Full text: https://doi.org/10.1016/j.hlc.2021.07.011

Among 2,000,287 individuals receiving at least one dose of vaccine, 20 had vaccine-related myocarditis (1.0/100,000; median age: 36) and 37 had pericarditis (1.8/100,000; median age: 59). Myocarditis occurred a median of 3.5 days after vaccination, pericarditis developed after a median of 20 days. All patients were discharged after a median of 1 to 2 days. No one died.

 

1 June 2021

Vogel G, Couzin-Frankel J. Israel reports link between rare cases of heart inflammation and COVID-19 vaccination in young men. Nature NEWS June 1, 2021. https://www.sciencemag.org/news/2021/06/israel-reports-link-between-rare-cases-heart-inflammation-and-covid-19-vaccination

Brief summary of current knowledge: in Israel, between one in 3000 and one in 6000 men ages 16 to 24 who received the BioNTech vaccine developed myocarditis. Most cases were mild and resolved within a few weeks. It is speculated that very high antibody levels generated in young people may also, in rare cases, lead to a sort of immune overreaction that inflames the heart.

Facial paralysis

16 August 2021

Wan EY, Chui CD, Lai FT, et al. Bell’s palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study. Lancet Inf Dis August 16, 2021. DOI: https://doi.org/10.1016/S1473-3099(21)00451-5

An additional 4.8 cases of this generally self-limiting adverse event per 100,000 people vaccinated with CoronaVac and 2.0 cases per 100,000 people vaccinated with BNT162b2.

 

24 February 2021

Ozonoff A, Nanishi E, Levy O. Bell’s palsy and SARS-CoV-2 vaccines. The Lancet Infectious Diseases, February 24, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00076-1/fulltext

Bell’s palsy is a type of facial paralysis that results in a temporary inability to control the facial muscles on the affected side of the face. Al Ozonoff and colleagues say that observed incidence of Bell’s palsy following mRNA vaccination is 3-7 times higher than would be expected in the general population. According to their comment, this signals a potential safety phenomenon and suggests inaccurate reporting to the public. However, it is also noted that Bell’s palsy usually self-resolves and that the mRNA vaccines offer a substantial net benefit to public health.

Other

In this paragraph, find more about SARS-CoV-2 vaccines related or not related to episodes of anxiety, capillary leak syndrome, facial pustular eruption, hearing loss, and adult multisystem inflammatory syndrome. There was no significant decrease in sperm parameters (repeat: no significant decreases).

Anxiety

30 April 2021

Hause AM, Gee J, Johnson T, et al. Anxiety-Related Adverse Event Clusters After Janssen COVID-19 Vaccination — Five U.S. Mass Vaccination Sites, April 2021. MMWR Morb Mortal Wkly Rep. ePub: 30 April 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7018e3.htm

Anxiety-related events, including fainting, can occur immediately after vaccination with any vaccine and might be caused by anxiety about receiving an injection. The stress of an ongoing pandemic might increase anxiety: Reports of syncope (fainting) are approximately 164 times more common after the Janssen COVID-19 vaccination (8.2 per 100,000) than after influenza vaccination (0.05 per 100,000).

Capillary leak syndrome

June 15 2021

Matheney M, Maleque N, Channell N, et al. Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series. Ann Int Med June 15, 2021. https://doi.org/10.7326/L21-0250

Three patients who had severe flares of SCLS immediately after receiving standard doses of the COVID-19 vaccines (AstraZeneca, BioNTech and Moderna). The authors recommend that patients with a diagnosis or suspected diagnosis of SCLS should receive IVIG prophylaxis before vaccination.

Facial pustular eruption

28 Juli 2021

Merrill ED, Kashem SW, Amerson EH, et al. Association of Facial Pustular Neutrophilic Eruption With Messenger RNA-1273 SARS-CoV-2 Vaccine. JAMA Dermatol. 2021 Jul 28. PubMed: https://pubmed.gov/34319363. Full text: https://doi.org/10.1001/jamadermatol.2021.2474

The authors report a facial eruption that developed within 24 hours after receiving the Moderna vaccine in 2 patients without a history of known allergies, rosacea, facial/dental fillers, or prior SARS-CoV-2 infection.

Hearing loss

20 May 2021

Formeister EJ, Chien W, Agrawal Y, et al. Preliminary Analysis of Association Between COVID-19 Vaccination and Sudden Hearing Loss Using US Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System Data. JAMA Otolaryngology–Head & Neck Surgery, May 20, 2021. https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2780288

No association exists between mRNA vaccines and sudden hearing loss.

Sperm parameters

20 July 2021

Gonzalez DC, Nassau DE, Khodamoradi K, et al. Sperm Parameters Before and After COVID-19 mRNA Vaccination. JAMA. 2021 Jul 20;326(3):273-274. PubMed: https://pubmed.gov/34137808. Full text: https://doi.org/10.1001/jama.2021.9976

No significant decreases (repeat: no significant decreases).

Multisystem inflammatory syndrome

26 May 2021

Salzman MB, Huang C-W, O’Brien CM, Castillo RD. Multisystem inflammatory syndrome after SARS-CoV-2 infection and COVID-19 vaccination. Emerg Infect Dis May 26, 2021. https://wwwnc.cdc.gov/eid/article/27/7/21-0594_article

Three patients from California are described, who experienced multisystem inflammatory syndrome (MIS) after immunization and SARS-CoV-2 infection.

Special Populations

Elderly people

13 August 2021

Moline HL, Whitaker M, Deng L, et al. Effectiveness of COVID-19 Vaccines in Preventing Hospitalization Among Adults Aged ≥65 Years – COVID-NET, 13 States, February-April 2021. MMWR Morb Mortal Wkly Rep. 2021 Aug 13;70(32):1088-1093. PubMed: https://pubmed.gov/34383730. Full text: https://doi.org/10.15585/mmwr.mm7032e3

Among adults aged ≥ 65, the effectiveness of full vaccination for preventing hospitalization was 96% for the BioNTech/Pfizer and Moderna vaccines (exception: 91% for the BioNTech/Pfizer vaccine in age ≥ 75 years) and 84% for the Janssen vaccine. Note that these data are from the pre-Delta era.

 

26 June 2021

Mazagatos C, Monge S, Olmedo C, et al. Effectiveness of mRNA COVID-19 vaccines in preventing SARS-CoV-2 infections and COVID-19 hospitalisations and deaths in elderly long-term care facility residents, Spain, weeks 53 2020 to 13 2021. Euro Surveill. 2021 Jun;26(24):2100452. PubMed: https://pubmed.gov/34142647. Full-text: https://doi.org/10.2807/1560-7917.ES.2021.26.24.2100452

Elderly residents (aged 65 years and older) in long-term care facilities: partial vaccine effectiveness (VE) of 50% with the first dose of the BioNTech/Pfizer and the Moderna vaccine. After the second dose, VE was 71% against SARS-CoV-2 infection, 88% and 97% against COVID-19 hospitalizations and deaths, respectively.

 

23 June 2021

Shroti M, Krutikov M, Palmer T, et al. Vaccine effectiveness of the first dose of ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of long-term care facilities in England (VIVALDI): a prospective cohort study. Lancet Inf Dis June 23, 2021. https://doi.org/10.1016/S1473-3099(21)00289-9

Among 10,412 care home residents aged 65 years and older, adjusted hazard ratios (HRs) for PCR-positive infection relative to unvaccinated residents declined from 28 days after the first vaccine dose to 0.44 (95% CI 0.24–0.81) at 28–34 days and 0.38 (0.19–0.77) at 35–48 days. Similar effect sizes were seen for ChAdOx1 and BNT162b2 vaccines at 35–48 days.

 

23 June 2021

Hyams C, Marlow R, Maseko Z. Effectiveness of BNT162b2 and ChAdOx1 nCoV-19 COVID-19 vaccination at preventing hospitalisations in people aged at least 80 years: a test-negative, case-control study. Lancet Inf Dis June 23, 2021. https://doi.org/10.1016/S1473-3099(21)00330-3

Same direction. One dose of either BNT162b2 or ChAdOx1 nCoV-19 resulted in substantial risk reductions of COVID-19-related hospitalisation in people aged at least 80 years. The adjusted vaccine effectiveness was 80.4% (95% CI 36.4–94.5).

 

23 June 2021

Prendecki M, Willicombe M. Single-dose SARS-CoV-2 vaccination efficacy in the elderly. Lancet Inf Dis 2021, June 23. https://doi.org/10.1016/S1473-3099(21)00354-6

In their comment on the two studies above, Maria Prendecki and Michelle Willicombe argue that both studies give cause for optimism; despite older individuals developing decreased humoural responses to vaccines, including SARS-CoV-2, vaccine efficacy is high, and second doses will probably increase efficacy further. The results also highlight some of the difficulties in trying to make comparisons between vaccines in real-world studies.

 

20 May

Madhi SA, Baillie V, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med. 2021 May 20;384(20):1885-1898. PubMed: https://pubmed.gov/33725432. Full text: https://doi.org/10.1056/NEJMoa2102214

Shabir Madhi et al. report a ChAdOx1-nCoV19 (AstraZeneca) trial in HIV-uninfected people in South Africa. 23/717 (3.2%) placebo and 19/750 (2.5%) vaccine recipients developed mild-moderate Covid-19. Of the primary endpoint cases, 39/42 (92.9%) were the B.1.351 variant – against which vaccine efficacy was 10.4%. The authors conclude that a two-dose regimen of ChAdOx1-nCoV19 did not show protection against mild-moderate Covid-19 due to B.1.351 variant.

 

13 May 2021

Bernal JL, Andrews N, Gower C, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ May 13, 2021; 373. https://www.bmj.com/content/373/bmj.n1088

Early real-life data in older people (older than 70 years) from England: with BNT162b2, vaccine effectiveness reached 61% from 28 to 34 days after vaccination, then plateaued. With ChAdOx1-S, effects were seen from 14 to 20 days after vaccination, reaching an effectiveness of 60% from 28 to 34 days, increasing to 73% (27% to 90%) from day 35 onwards.

 

28 April 2021

Tenforde MW, Olson SM, Self WH. Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years — United States, January–March 2021. MMWR April 28. https://www.cdc.gov/mmwr/volumes/70/wr/mm7018e1.htm 

In a multi-state network of US hospitals during January–March 2021, receipt of Pfizer/BioNTech or Moderna COVID-19 vaccines was 94% effective against COVID-19 hospitalization among fully vaccinated adults and 64% effective among partially vaccinated adults aged ≥ 65 years. There was no significant effect for receiving the first dose of a 2-dose COVID-19 vaccine series within 14 days prior to illness onset.

 

7 April 2021

Van Praet JT, Vandecasteele S, de Roo A, et al. Humoral and cellular immunogenicity of the BNT162b2 mRNA Covid-19 Vaccine in nursing home residents. Clin Inf Dis, ciab300, April 7, 2021. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab300/6213866?searchresult=1

Four weeks after the first dose, the humoral and cellular immunogenicity of the BNT162b2 mRNA vaccine (BioNTech/Pfizer) was suboptimal in COVID-19-naïve nursing home residents in comparison to COVID-19-naïve healthcare workers.

Pregnant women

18 June 2021

Razzaghi H, Meghani M, Pingali C, et al. COVID-19 Vaccination Coverage Among Pregnant Women During Pregnancy – Eight Integrated Health Care Organizations, United States, December 14, 2020-May 8, 2021. MMWR Morb Mortal Wkly Rep. 2021 Jun 18;70(24):895-899. PubMed: https://pubmed.gov/34138834. Full text: https://doi.org/10.15585/mmwr.mm7024e2

As of May 8, 2021, 16.3% of pregnant women identified in the CDC Datalink had received ≥ 1 dose of a COVID-19 vaccine during pregnancy in the US. Vaccination was lowest among Hispanic (11.9%) and non-Hispanic Black women (6.0%) and women aged 18–24 years (5.5%) and highest among non-Hispanic Asian women (24.7%) and women aged 35–49 years (22.7%).

 

15 June 2021

Collier AY, McMahan K, Yu J, et al. Immunogenicity of COVID-19 mRNA Vaccines in Pregnant and Lactating Women. JAMA. 2021 Jun 15;325(23):2370-2380. PubMed: https://pubmed.gov/33983379. Full text: https://doi.org/10.1001/jama.2021.7563

In this study of 103 pregnant and lactating women, mRNA vaccines were immunogenic in and induced immune responses against SARS-CoV-2 variants.

 

22 April

Shimabukuro TT, Kim SY, Myers TR. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. NEJM April 22, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2104983?query=featured_home

Data on more than 35,000 pregnant women receiving mRNA vaccines (BioNTech or Moderna) indicate no safety signals. However, as this was a participant-reported surveillance system, more data is needed.

 

3 April

Rottenstreich A, Zarbiv G, Oiknine-Dijan E, et al. Efficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination. Clinical Infectious Diseases 03 April 2021, ciab266. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab266/6209876

In 20 pregnant women, two doses of BNT162b2 mRNA vaccine (median time between the second dose until delivery was 11 days) induced an adequate maternal serologic response that had the potential to provide neonatal protection through transplacental transfer of vaccine-stimulated maternally-derived antibodies.

Children and adolescents

11 August 2021

Ali K, Berman G, Zhou H, et al. Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents. N Engl J Med. 2021 Aug 11. PubMed: https://pubmed.gov/34379915. Full text: https://doi.org/10.1056/NEJMoa2109522

Nothing truly new: the Moderna vaccine had an acceptable safety profile in adolescents, the immune response was similar to that in young adults, and the vaccine prevented COVID-19. Interestingly, in the placebo group, after the first and second injections, study participants experienced injection-site pain (in 34.8% and 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). It’s fascinating how just the thought of getting a vaccine that might give you headache or fatigue is sufficient to give you… headache fatigue. In this trial, about half of all mild adverse events were probably the product of human imagination.

 

30 July 2021

Hause AM, Gee J, Baggs J, et al. COVID-19 Vaccine Safety in Adolescents Aged 12–17 Years — United States, December 14, 2020–July 16, 2021. MMWR Morb Mortal Wkly Rep. ePub: 30 July 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7031e1

As of July 16, 2021, almost 9 million US adolescents aged 12–17 years had received the BioNTech/Pfizer vaccine. The Vaccine Adverse Event Reporting System (VAERS) received 9246 reports, 90.7% of which were for non-serious adverse events while 9.3% were for serious adverse events, including around 400 cases of myocarditis (4.3%; about 1:25,000 vaccinees; see also https://www.cdc.gov/mmwr/volumes/70/wr/mm7027e2.htm). Systemic reactions were more common after the second dose.

 

27 May 2021

Frenck RW, Klein NP, Kitchin N, et al. Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. NEJM May 27, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2107456

In 1131 adolescents (12 to 15 years old), the BNT162b2 vaccine had a favorable safety profile. The immune response was non-inferior to that observed in the cohort of 16-to-25-year-old young adults.

 

14 May

Wallace M, Woodworth KR, Gargano JW, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine in Adolescents Aged 12–15 Years — United States, May 2021. MMWR Morb Mortal Wkly Rep. ePub: 14 May 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7020e1.htm?s_cid=mm7020e1_w#suggestedcitation

On May 10, 2021, the Food and Drug Administration expanded Emergency Use Authorization for the Pfizer-BioNTech COVID-19 vaccine to include adolescents aged 12–15 years. Read why here.

Oncology and hematology

Oncology, general

11 August 2021

Eliakim-Raz N, Massarweh A, Stemmer A, Stemmer SM. Durability of Response to SARS-CoV-2 BNT162b2 Vaccination in Patients on Active Anticancer Treatment. JAMA Oncol. 2021 Aug 11:e214390. PubMed: https://pubmed.gov/34379092. Full text: https://doi.org/10.1001/jamaoncol.2021.4390

Anti-spike (anti-S) IgG antibody response to the BioNTech/Pfizer vaccine in 95 patients with solid tumors on active anti-cancer treatment after a median of 4 months from the second vaccination. Eighty-three patients (87%) were seropositive for anti-S IgG antibodies. The median titer levels in patients with cancer was significantly lower than those in the control group. There was a 3.6-fold range in median titer values across tumor types and a wider range (8.8-fold) across treatment types. The only variable significantly associated with lower IgG titers was treatment with chemotherapy plus immunotherapy and immunotherapy plus biological therapy.

 

8 July 2021

Goshen-Lago T, Waldhorn I, Holland R, et al. Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer. JAMA Oncol July 8, 2021. https://jamanetwork.com/journals/jamaoncology/fullarticle/2781608

This cohort study compared serologic status and safety of the BNT162b2 vaccine in 232 patients receiving active treatment for cancer and 261 health care workers who served as controls. After the first dose of the vaccine, only 29% of the patients were seropositive compared with 84% of the controls; after the second dose, the seropositive rate of the patients reached 86%, and reported adverse events resembled those of healthy individuals.

 

18 June 2021

Addeo A, Shah PK, Bordry N, et al. Immunogenicity of SARS-CoV-2 messenger RNA Vaccines in Patients with Cancer. Cancer Cell June 18, 2021. https://doi.org/10.1016/j.ccell.2021.06.009

None of the patients with a history of anti-CD20 antibody in the 6 months prior to vaccination developed an antibody response. None of the four patients with a history of anti-CD20 antibody in the 6 months prior to vaccination developed an antibody response.

 

5 June 2021

Thakkar A, Gonzalez-Lugo JD, Goradia N, et al. Seroconversion rates following COVID-19 vaccination amongst patients with cancer. Cancer Cell June 05, 2021. https://www.sciencedirect.com/science/article/pii/S1535610821002853

A high seroconversion rate (94%) in 200 vaccinated patients with cancer. Seroconversion was lower in recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%) but not immune checkpoint inhibitor therapy (97%). IgG titers were lower following vaccination with the adenoviral than with the mRNA-based vaccines.

Hematology, general

11 August 2021

Ollila TA, Lu S, Masel R, et al. Antibody Response to COVID-19 Vaccination in Adults With Hematologic Malignant Disease. JAMA Oncol. 2021 Aug 11:e214381. PubMed: https://pubmed.gov/34379085. Full text: https://doi.org/10.1001/jamaoncol.2021.4381

Retrospective study of 160 adults with hematologic malignant disease who were vaccinated with a COVID-19 vaccine. (One hundred and five (66%) patients received a B cell–depleting monoclonal antibody, most commonly rituximab (n = 85)). Sixty-three patients (39%) demonstrated seroconversion. Longer time (greater than or less than 12 months) from last chemotherapy administration to vaccination was associated with increased rates of seroconversion. The quantitative antibody response was also lower among patients with exposure to B cell/plasma cell–depleting antibodies and those with active malignant disease.

 

10 August 2021

Malard F, Gaugler B, Gozlan J, et al. Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies. Blood Cancer J. 2021 Aug 10;11(8):142. PubMed: https://pubmed.gov/34376633. Full text: https://doi.org/10.1038/s41408-021-00534-z

In patients with hematological malignancies, vaccination with two doses of the BioNTech/Pfizer vaccine translates into a significant increase in humoral response, allowing almost half of the patients to achieve immune protection against COVID-19 (retrospective study, n = 237). The use of B cell targeting treatment within the previous 12 months before vaccination, and a low CD19+ B cell level predicted failure in achieving immune protection.

 

2 July 2021

Maneikis K, Šablauskas K, Ringelevičiūtė U, et al. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Hematology July 02, 2021. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(21)00169-1/fulltext

According to this large cohort, patients actively treated with BTKIs, ruxolitinib, venetoclax, or anti-CD20 antibody therapies seem to be the most negatively affected and unprotected from SARS-CoV-2 infection.

Chronic lymphocytic leukemia (CLL)

30 July 2021

Parry H, McIlroy G, Bruton R, et al. Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J. 2021 Jul 30;11(7):136. PubMed: https://pubmed.gov/34330895. Full text: https://doi.org/10.1038/s41408-021-00528-x

In 267 patients with B cell chronic lymphocytic leukemia (CLL), one dose of vaccine generated detectable spike-specific antibody responses in 34% of patients with CLL compared to 94% of healthy donors. After the second dose of vaccine, antibody responses increased to 75% (n = 55), but titers remained lower than in controls. Current treatment with Bruton’s tyrosine kinase (BTK) inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine.

 

13 May 2021

Roeker LE, Knorr DA, Thompson MC. et al. COVID-19 vaccine efficacy in patients with chronic lymphocytic leukemia. Leukemia May 13, 2021. https://www.nature.com/articles/s41375-021-01270-w

Only half of fully vaccinated patients (two doses of mRNA vaccines) with CLL develop detectable anti-SARS-CoV-2 S1/S2 antibodies. There was a significant difference between rates of detectable anti-SARS-CoV-2 S1/S2 antibodies between treatment-naïve patients (17/18, 94%) and those who had received CLL directed therapy (6/26, 23%).

 

16 April 2021

Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia. Blood April 16, 2021. https://ashpublications.org/blood/article/doi/10.1182/blood.2021011568/475742/Efficacy-of-the-BNT162b2-mRNA-COVID-19-Vaccine-in?searchresult=1

Antibody response to BNT162b2 mRNA COVID-19 vaccine in CLL patients is markedly impaired and affected by disease activity and treatment. In a total of 167 patients with CLL who received two doses, the antibody response rate was only 39.5%. In patients treated with either Bruton’s tyrosine kinase inhibitors or venetoclax ± anti-CD20 antibody, responses were particularly low (16% and 14%).

Multiple myeloma

29 July 2021

Stampfer SD, Goldwater MS, Jew S, et al. Response to mRNA vaccination for COVID-19 among patients with multiple myeloma. Leukemia. 2021 Jul 29:1-8. PubMed: https://pubmed.gov/34326466. Full text: https://doi.org/10.1038/s41375-021-01354-7

Study of 103 multiple myeloma (MM) patients (96 patients with active MM and 7 with smoldering (asymptomatic) disease). Smoldering MM patients responded better than those with active disease. Only 45% of active MM patients developed an adequate response, while 22% had a partial response. Lower spike antibody levels were associated with older age, impaired renal function, low lymphocyte counts, reduced uninvolved immunoglobulin levels, > second line of treatment, and among those not in complete remission.

Solid Organ Transplant

11 August 2021

Hall VG, Ferreira VH, Ku T, et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. N Engl J Med. 2021 Aug 11. PubMed: https://pubmed.gov/34379917. Full text: https://doi.org/10.1056/NEJMc2111462

A double-blind, randomized, controlled trial of a third-dose booster of the Moderna vaccine in 120 organ-transplant recipients (median time from transplantation to the third dose was 3.16 years). After four months, an anti–receptor-binding domain (RBD) antibody level of at least 100 U per milliliter was present in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group. The median percent virus neutralization was 71% in the Moderna group and 13% in the placebo group. The trial was not powered to detect differences in clinical outcomes.

 

23 July 2021

Stumpf J, Siepmann T, Lindner T, et al. Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine. Lancet Reg Health Eur. 2021 Jul 23:100178. PubMed: https://pubmed.gov/34318288. Full text: https://doi.org/10.1016/j.lanepe.2021.100178

A prospective study exploring the eight-week time course of specific cellular or/and humoral immune responses after two doses of vaccine. Seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in 368 kidney transplant recipients (42%).

 

23 July 2021

Benotmane I, Gautier G, Perrin P, et al. Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses. JAMA. 2021 Jul 23. PubMed: https://pubmed.gov/34297036. Full-text: https://doi.org/10.1001/jama.2021.12339

Important study from Strasbourg, France. In kidney transplant recipients (n = 159), a third dose of the Moderna vaccine induced a serologic response in 49% of patients who did not respond after 2 doses. Patients taking tacrolimus, mycophenolate, and steroids were less likely to develop anti–SARS-CoV-2 antibodies than those treated with other regimens (35% vs 63%).

 

22 July 2021

Massa F, Cremoni M. Safety and Cross-Variant Immunogenicity of a Three-Dose COVID-19 mRNA Vaccine Regimen in Kidney Transplant Recipients. Lancet Preprints 2021, posted 22 July. Full text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3890865

Same message as above, now from Nice, France. In kidney transplant recipients (n = 61), a three-dose BioNTech/Pfizer vaccine regimen led to an increase in spike-specific IgG levels, neutralizing activity and number of IFN-γ-secreting cells. However, neutralizing antibody titers remained low even after three doses, especially against new variants. The authors recommend continuation of barrier measures and vaccination of relatives.

 

15 June 2021

Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Ann Int Med 15 June, 2021. https://www.acpjournals.org/doi/10.7326/L21-0282

A booster may work. In 30 patients, antibody titers increased after the third dose in one third of patients who had negative antibody titers and in all patients who had low-positive antibody titers. Vaccine reactions seem to be acceptable.

 

5 May 2021

Boyarsky NJ, Werbel WA, Avery RK, et al. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA May 5, 2021. https://jamanetwork.com/journals/jama/fullarticle/2779852?resultClick=1

At a median of 29 days after dose 2, antibody was detectable in 357/658 organ recipients (54%). Poor humoral response was persistently associated with use of anti-metabolite immunosuppression.

 

15 March

Boyarsky BJ, Werbel WA, Avery RK, et al. Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients. JAMA March 15, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777685

In this multicenter study on 436 solid organ transplant recipients taking different immunosuppressive agents, only 76 (17%) had detectable antibodies (anti-S1 or anti–receptor-binding domain) at a median of 20 days after the first dose of vaccine. These results contrast with the robust early immunogenicity observed in mRNA vaccine trials.

Neurology

Ben David SSS, Potasman I, Rahamim-Cohen D. Rate of Recurrent Guillain-Barré Syndrome After mRNA COVID-19 Vaccine BNT162b2. JAMA Neurol September 1, 2021; https://jamanetwork.com/journals/jamaneurology/fullarticle/2783708?resultClick=1

In this cohort study of 702 patients, only 1 person needed short medical care for relapse of their previous syndrome, representing a minimal risk

 

HIV

17 August 2021

Madhi SA, Koen AL, Izu A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in people living with and without HIV in South Africa: an interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial. Lancet 2021, published 17 August. Full text: https://doi.org/10.1016/S2352-3018(21)00157-0

A double-blind, placebo-controlled, Phase 1B/2A study of the AstraZeneca vaccine in 104 people with HIV and 70 HIV-negative controls. The authors found similar full-length spike (FLS)-binding and receptor-binding domain (RBD)-binding IgG and SARS-CoV-2 neutralizing response patterns in people with HIV and HIV-negative SARS-CoV-2-naive participants.

 

18 June 2021

Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV, June 18, 2021. https://doi.org/10.1016/S2352-3018(21)00103-X

In this study of 53 people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic. There was no correlation between the magnitude of the anti-spike IgG response at day 56 and CD4 cell count or age.

Chronic inflammatory diseases

31 August 2021

Deepak P, Kim W, Paley MA. Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2. Annals Int Med August 31, 2021. https://www.acpjournals.org/doi/10.7326/M21-1757

This study shows that compared with non-users, patients with chronic inflammatory disease treated with glucocorticoids and B cell depletion therapy seem to have lower SARS-CoV-2 vaccine-induced antibody responses.

Autoimmune diseases

30 July 2021

Medeiros-Ribeiro AC, Aikawa NE, Saad CGS, et al. Immunogenicity and safety of the CoronaVac inactivated vaccine in patients with autoimmune rheumatic diseases: a phase 4 trial. Nat Med (2021). https://doi.org/10.1038/s41591-021-01469-5

In 910 adults with autoimmune rheumatic diseases (ARD) vaccinated with the Chinese CoronaVac vaccine, all had lower IgG seroconversion rates, and lower neutralizing antibody titers were lower than in 182 age- and sex-matched healthy adults.

Special Topics

Global inequality

Kupferschmidt K. Unprotected African health workers die as rich countries buy up COVID-19 vaccines. Science 2021, published 17 February. Full-text: https://www.sciencemag.org/news/2021/02/unprotected-african-health-workers-die-rich-countries-buy-covid-19-vaccines

While we are discussing how soon we can immunize everyone in the EU or the US, health workers continue to die in countries with zero doses administered so far.

Impact on local epidemics

19 April 2021

Rossman H, Shilo S, Meir T, et al. COVID-19 dynamics after a national immunization program in Israel. Nat Med April 19, 2021. https://www.nature.com/articles/s41591-021-01337-2

By no doubt the paper of the day, analyzing the early effect of the national vaccination campaign in Israel on the pandemic dynamics. A little over 2 months after the initiation of the campaign, with 85% of individuals older than 60 years already vaccinated with two doses (24 February 2021), there was an approximately 77% drop in cases, a 45% drop in positive test percentage, and a 68% drop in hospitalizations compared to peak values. Larger and earlier decrease in COVID-19 cases and hospitalization was observed in individuals older than 60 years, followed by younger age groups, by the order of vaccination prioritization. This pattern was not observed in the previous lockdown and was more pronounced in early-vaccinated cities.

Interventional vaccinology

24 July 2021

Paetzold J, Krammer F, van Laer D, et al. The effects of rapid mass vaccination against SARS-CoV-2 and its Variants-of-Concern: Evidence from an early VoCs hotspot. Research Square 2021, posted 24 July. Full text: https://doi.org/10.21203/rs.3.rs-741944/v1

Following a large outbreak of the Beta (B.1.351, “South Africa”) and Alpha variants (B.1.1.7/E484K, “England”) in the district of Schwaz, Austria, more than 70% of the adult population of the district received their first Pfizer/BioNTech vaccine dose within 6 days (11 and 16 March). Result: a 60% reduction in new SARS-CoV-2 infections relative to people residing just outside of the vaccinated district.

Differential diagnosis

22 July 2021

Robinson KA, Maimone S, Gococo-Benore DA, Li Z, Advani PP, Chumsri S. Incidence of Axillary Adenopathy in Breast Imaging After COVID-19 Vaccination. JAMA Oncol. 2021 Jul 22. PubMed: https://pubmed.gov/34292295. Full-text: https://doi.org/10.1001/jamaoncol.2021.3127

In this retrospective analysis (n = 750), 23 (3%) patients had axillary adenopathy on mammography. This incidence is higher than axillary adenopathy in otherwise normal mammography (0.02% – 0.04%). The incidence of adenopathy decreased over time with no adenopathy seen in patients who received the vaccine more than 28 days previously. When possible, consider scheduling screening breast imaging 4 to 6 weeks after the second COVID-19 vaccination dose (National Comprehensive Cancer Network, 15 June 2021, Recommendations of the NCCN COVID-19 Vaccination Advisory: https://www.nccn.org/docs/default-source/covid-19/2021_covid-19_vaccination_guidance_v3-0.pdf

 

4 March 2021

Nawwar AA, Searle J, Singh R, Lyburn ID. Oxford-AstraZeneca COVID-19 vaccination induced lymphadenopathy on [18F]Choline PET/CT-not only an FDG finding. Eur J Nucl Med Mol Imaging. 2021 Mar 4:1-2. PubMed: https://pubmed.gov/33661328. Full-text: https://doi.org/10.1007/s00259-021-05279-2

Lymphadenopathy is seen in some people after vaccination. In this case report of a cancer patient who underwent PET/CT 3 days after vaccination, nodal uptake was reactive in the axilla.

COVID vaccines: History and development

10 August 2021

Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021 Aug 10:1-17. PubMed: https://pubmed.gov/34394960. Full text: https://doi.org/10.1038/s41578-021-00358-0

The authors discuss the physiological barriers and possible administration routes for lipid nanoparticle–mRNA systems and highlight preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer and genetic disorders.

 

3 August 2021

Bok K, Sitar S, Graham BS, Mascola JR. Accelerated COVID-19 vaccine development: milestones, lessons, and prospects. Immunity. 2021 Aug 3:S1074-7613(21)00303-4. PubMed: https://pubmed.gov/34348117. Full text: https://doi.org/10.1016/j.immuni.2021.07.017

SARS-CoV-2 vaccines have been developed and approved in time frames never before seen, a feat that bodes well for future advancements in medicine, not only in infectious diseases. The authors review the milestones, methods and outcomes of this effort and provide a perspective for how partnership and preparedness can be better utilized in response to future public-health pandemic emergencies.

 

25 March 2021

Desmond A, Offit PA. On the Shoulders of Giants – From Jenner’s Cowpox to mRNA Covid Vaccines. N Engl J Med. 2021 Mar 25;384(12):1081-1083. PubMed: https://pubmed.gov/33764709. Full text: https://doi.org/10.1056/NEJMp2034334

mRNA vaccines will change the course of the COVID-19 pandemic and the impact of other infectious diseases. Their development goes back to 2008 when Katalin Karikó, Drew Weissman, and colleagues modified messenger RNA (mRNA) using nucleoside analogues. These modifications stabilized the molecule and eliminated its capacity for inducing innate immunity, thereby making mRNA a vaccination tool (Karikó K 2008). A short vaccine history for the weekend.

 

19 January 2021

Connors M, Graham BS, Lane HC, Fauci AS. SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn. Ann Intern Med. 2021 Jan 19. PubMed: https://pubmed.gov/33460347. Full-text: https://doi.org/10.7326/M21-0111

Progress toward effective vaccines for SARS-CoV-2 has proceeded at an unprecedented pace and it is highly likely that vaccination and its subsequent ability to prevent disease will provide critical and life-saving benefit in the coming months and may be one of our surest ways to emerge from this pandemic to a more normal society. However, acknowledging that there is still much to learn while strongly encouraging vaccination is a critical challenge facing health care today.

 

12 January 2021

Dolgin E. How COVID unlocked the power of RNA vaccines. Nature 2021, published 12 January. Full-text: https://www.nature.com/articles/d41586-021-00019-w

The technology could revolutionize efforts to immunize against HIV, malaria, influenza and more.

 

9 November 2020

Callaway E. What Pfizer’s landmark COVID vaccine results mean for the pandemic. Nature NEWS 09 November 2020. Full-text: https://www.nature.com/articles/d41586-020-03166-8

Yesterday, Pfizer and BioNTech announced that their mRNA-based vaccine candidate, BNT162b2, demonstrated “evidence of efficacy“, based on the first interim efficacy and safety analysis conducted on November 8, 2020 by an external, independent Data Monitoring Committee from the Phase III clinical study.

  • BNT162b2 was found to be “more than 90% effective” in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection
  • Analysis evaluated 94 confirmed cases of COVID-19 in trial participants
  • Study enrolled 43,538 participants, with 42% having diverse backgrounds, and no serious safety concerns have been observed
  • Clinical trial to continue through to final analysis at 164 confirmed cases in order to collect further data and characterize the vaccine candidate’s performance against other study endpoints

That’s what we know. Read how scientists welcome the first compelling evidence that a vaccine can prevent COVID-19. But many questions remain about how much protection it offers, to whom and for how long.

 

27 October

Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020 Oct;586(7830):516-527. PubMed: https://pubmed.gov/32967006. Full-text: https://doi.org/10.1038/s41586-020-2798-3

Brilliant review of SARS-CoV-2 vaccines: vaccine platforms, results from studies on non-human primates and results from Phase I/II trials in humans. Read the review this evening and read it again next week.

 

26 August 2020

Slaoui M, Hepburn M. Developing Safe and Effective Covid Vaccines — Operation Warp Speed’s Strategy and Approach. N Engl J Med 2020, published 26 August. Full-text: https://doi.org/10.1056/NEJMp2027405

What is OWS and what does it do? Moncef Slaoui and Matthew Hepburn from Operation Warp Speed explain the forces behind a national vaccine strategy. The players: Pfizer and BioNTech, AstraZeneca and Oxford University, Janssen, Moderna, Janssen, Novavax, Sanofi/GSK. Will they succeed in this unprecedented endeavor?

 

10 August 2020

Dagotto G, Yu J, Barouch DH. Approaches and Challenges in SARS-CoV-2 Vaccine Development. Cell Host Microbe 2020, published 10 August. Full-text: https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(20)30455-8

Progress in SARS-CoV-2 vaccine development to date has been faster than for any other pathogen in history. In this perspective, Dan Barouch, Gabriel Dagotto and Jingyou Yu discuss three topics that are critical for SARS-CoV-2 vaccine development:

  1. Antigen selection and engineering
  2. Pre-clinical challenge studies in non-human primate models
  3. Immune correlates of protection

 

20 July 2020

Bar-Zeev N, Moss WJ. Encouraging results from phase 1/2 COVID-19 vaccine trials. Lancet, 20 July 2020. Full-text: https://www.thelancet.com/lancet/article/s0140-6736(20)31611-1

A comment on the two papers above as well as a list of questions to be addressed by the coming Phase 3 trials:

  • Will a single dose be sufficient in older adults, or is a booster dose required?
  • Does longevity of response or rates of waning differ with a two-dose regimen, and does longevity of clinical protection require cell-mediated responses?
  • Are there host-specific differences in immunogenicity by age, sex, or ethnicity?
  • Do T cell responses correlate with protection irrespective of humoral titers?
  • Are there specific adverse events in pregnant women?

Future

Pan-coronavirus vaccines

18 August 2021

Tan CW, Chia WN, Young BE, et al. Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors. N Engl J Med. 2021 Aug 18. PubMed: https://pubmed.gov/34407341. Full text: https://doi.org/10.1056/NEJMoa2108453

If you had survived SARS-CoV-1 in 2002-2004, the BioNTech/Pfizer vaccine would today give you potent cross-clade pan-sarbecovirus neutralizing antibodies. This study (n = 8) is another proof of concept that a pan-coronavirus vaccine is possible. Such a vaccine might cover not only SARS-CoV-2 and its current and future variants but also other coronaviruses with known potential to cause severe human diseases.

 

28 June 2020

Dai L, Zheng T, Xu K, et al. A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS. Cell June 28, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.06.035

The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. The authors identified a dimeric form of MERS-CoV RBD that overcomes this limitation and significantly increased the immunogenicity. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. This can be a generalizable strategy for beta-CoV vaccine design.

Aerosolized vaccines

26 July 2021

Wu S, Huang J, Zhang Z, et al. Safety, tolerability, and immunogenicity of an aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in adults: preliminary report of an open-label and randomised phase 1 clinical trial. Lancet Resp Med 2021, published 26 July. Full text: https://doi.org/10.1016/S1473-3099(21)00396-0

Two doses of an aerosolized adenovirus type-5 vector-based COVID-19 vaccine – equivalent to a fifth or two-fifths of an intramuscular dose – were well-tolerated and did not produce serious side effects in healthy adults. They elicited strong IgG and neutralizing antibody responses similar to one dose of an intramuscular injection.

 

23 July 2021

Lund FE, Randall TD. Scent of a vaccine. Science 2021, published 23 July. Full text: https://science.sciencemag.org/content/373/6553/397

About the advantages of intranasal vaccines: needle-free administration, on-site delivery and mucosal immunity.

Past futures

11 April 2020

Le TT, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nature reviews drug discovery. 09 April 2020. Full-text: https://www.nature.com/articles/d41573-020-00073-5

Brief data-driven overview by seven experts. The conclusion is that efforts are unprecedented in terms of scale and speed and that there is an indication that a vaccine could be available by early 2021. As of 8 April 2020, the global vaccine landscape includes 115 candidates, of which the 5 most advanced candidates have already moved into clinical development, including mRNA-1273 from Moderna, Ad5-nCoV from CanSino Biologicals, INO-4800 from Inovio, LV-SMENP-DC and pathogen-specific aAPC from Shenzhen Geno-Immune Medical Institute. The race is on!

 

31 March 2020

Lurie N, Saville M, Hatchett R, Halton J. Developing Covid-19 Vaccines at Pandemic Speed. NEJM March 30, 2020. Full-text: https://doi.org/10.1056/NEJMp2005630

Excellent review on vaccine development. Outlook on new platforms for RNA and DNA vaccines that can be made quickly because they require no culture or fermentation, instead using synthetic processes. Hope and despair.

 

 

[1] Licensed protein-based vaccines include the hepatitis B vaccine licensed in 1986, a flu vaccine approved in 2013 and the human papillomavirus vaccine for the prevention of of cervical cancer.

[2] Cerebral sinus vein thromboses are a rare health condition (Capecchi 2018) with a published background incidence of 0.2 to 1.57 per 100,000 person-years.