This page will be updated on 28 February. In the meantime, check new papers at https://covidreference.com/top10.
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.
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.
Krammer F, Srivastava K, the PARIS team, Simon V. Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. MedRxiv 2021, posted 1 February. Full-text: https://doi.org/10.1101/2021.01.29.21250653
Should individuals who already had SARS-CoV-2 infection receive one or two shots of the currently authorized mRNA vaccines? Florian Krammer et al. remind us that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naïve individuals after the second dose. They conclude that giving only one dose of vaccine would not negatively impact on antibody titers and free up many urgently needed vaccine doses.
Wahl A, Gralinski LE, Johnson CE, et al. SARS-CoV-2 infection is effectively treated and prevented by EIDD-2801. Nature (2021). Full-text: https://doi.org/10.1038/s41586-021-03312-w
Victor Garcia, Angela Wahl and colleagues show that therapeutic and prophylactic administration of EIDD-2801 (Molnupiravir, MKK-4482), an oral broad spectrum antiviral currently in Phase II–III clinical trials, dramatically inhibits SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.
(Another) Paper of the Day
Madhi A, Baillie VL, Cutland CL, et al. Safety and efficacy of the ChAdOx1 nCoV-19 (AZD1222) Covid-19 vaccine against the B.1.351 variant in South Africa. medRxiv 2021, posted 12 February. Full-text: https://www.medrxiv.org/content/10.1101/2021.02.10.21251247v1
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.
Petter E, Mor O, Zuckermann N, et al. Initial real world evidence for lower viral load of individuals who have been vaccinated by BNT162b2. GitHub 2021, posted 7 February. Full-text: http://bit.ly/3aPIetS
Vaccination with Pfizer-BioNTech’s Comirnaty could reduce the viral load by 1.6x to 20x in individuals who are positive for SARS-CoV-2. This estimate might improve after more individuals receive the second dose. Yaniv Erlich, Ella Petter and colleagues conclude that their findings indicate vaccination is not only important for an individual’s protection but can also reduce transmission.
Stamatatos L, Czartoski J, Wan YH, et al. Antibodies elicited by SARS-CoV-2 infection and boosted by vaccination neutralize an emerging variant and SARS-CoV-1. MedRxiv 2021, posted 8 February. Full-text: https://www.medrxiv.org/content/10.1101/2021.02.05.21251182v1
Andrew McGuire, Leonidas Stamatatos and colleagues found that a single shot of the Pfizer or Moderna mRNA vaccines boosts the neutralizing antibody response in people who were previously infected. Importantly, these antibodies also had neutralizing activity against the B1351 variant first detected in South Africa. The authors point to the importance of vaccination of both uninfected and of previously infected subjects. Read also Burton DR, Topo EJ. Toward superhuman SARS-CoV-2 immunity? Nat Med 27, 5–6 (2021). Full-text: https://doi.org/10.1038/s41591-020-01180-x
Burton DR, Topol EJ. Variant-proof vaccines — invest now for the next pandemic. Nature 2021, published 8 February. Full-text: https://www.nature.com/articles/d41586-021-00340-4
The rapid development and delivery of highly effective COVID-19 vaccines less than a year after the emergence of the disease is a huge success story. This was possible, in part, because of certain properties of the coronavirus SARS-CoV-2 that favor vaccine design — in particular, the spike protein on the viral surface. However, the next pathogen to emerge might be less accommodating. Eric Topol and Dennis Burton underline the importance of rational vaccine design based on broadly neutralizing antibodies.
Gadoth A, Halbrook M, Martin-Blais R, et al. Cross-sectional Assessment of COVID-19 Vaccine Acceptance Among Health Care Workers in Los Angeles. Ann Intern Med. 2021 Feb 9. PubMed: https://pubmed.gov/33556267. Full-text: https://doi.org/10.7326/M20-7580
In the context of a highly publicized coronavirus vaccine rollout, initial uptake by health care workers (HCWs) is critical for safety, health system functioning, and public opinion. In this survey, participants overwhelmingly acknowledged the importance and utility of general vaccination to a public health practice; however, they were widely hesitant about partaking in COVID-19 vaccination in either a trial or post-marketing settings and expressed uncertainties about the regulatory approval and protective capabilities of novel SARS-CoV-2 vaccines.
Paper of the Day
Levine-Tiefenbrun M, Yelin I, Katz R, et al. Decreased SARS-CoV-2 viral load following vaccination. MedRxiv 2021, posted 8 February. Full-text: https://www.medrxiv.org/content/10.1101/2021.02.06.21251283v1
Roy Kishony, Matan Levine-Tiefenbrun and colleagues analyzed positive SARS-CoV-2 test results following the first shot of the Pfizer-BioNTech vaccine. They found that the viral load is reduced 4-fold for infections occurring 12-28 days after the first dose of vaccine. These reduced viral loads might hint to lower infectiousness, further contributing to vaccine impact on virus spread.
Xie X, Liu Y, Liu J, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med 2021, published 8 February. Full-text: https://www.nature.com/articles/s41591-021-01270-4
In this in vitro study, the neutralization GMT of the serum panel against a virus with three mutations from the variant first detected in South Africa (E484K + N501Y + D614G) was slightly lower than the neutralization GMTs against a N501Y virus or a virus with three mutations from the UK variant (Δ69/70 + N501Y + D614G). The authors tested a panel of human sera from 20 participants in the Pfizer-BioNTech vaccine trial, drawn 2 or 4 weeks after immunization with two 30-μg doses of Comirnaty spaced 3 weeks apart.
News from Oxford
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.
Paper of the Day
Aran D. Estimating real-world COVID-19 vaccine effectiveness in Israel. GitHub 2021, posted 4 February. Full-text: https://github.com/dviraran/covid_analyses/blob/master/Aran_letter.pdf
This unpublished non-peer reviewed study suggests that the Pfizer-BioNTech vaccine might be between 66%-83% effective at preventing infection in individuals 60 years and older, 76-85% in those younger than 60 years, and 87-96% effective in preventing severe cases.
Emary KRW, Golubchik T, Aley PK, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) Vaccine Against SARS-CoV-2 VOC 202012/01 (B.1.1.7). Lancet Preprints 2021, posted 4 February. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3779160
This unpublished non-peer reviewed 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.
Rossman H, Shilo S, Meir T, Gorfine M, Shalit U, Segal E. Patterns of covid-19 pandemic dynamics following deployment of a broad national immunization program. GitHub 2021, posted 3 February. Full-text: http://bit.ly/36KhjOU
SARS-CoV-2 vaccines work under real-world conditions. Eran Segal, Hagai Rossman and colleagues show that there was a 41% drop in COVID-19 infections in people aged 60 or older from mid-January to early February. During the same period, there was also a 31% drop in hospitalizations (Rossmann 2021, Figure 11). In people aged 59 and younger who received the vaccine later, cases dropped by only 12% and hospitalizations by 5%.
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. Lancet Preprints 2021, posted 1 February. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777268
Andrew Pollard, Sarah Gilbert, Merryn Voysey and colleagues present data from Phase III efficacy trials of ChAdOx1 nCoV-19 in the United Kingdom and Brazil, and Phase I/II clinical trials in the UK and South Africa. They report that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 post vaccination was 76% (59%, 86%), and that protection did not wane during this initial 3-month period. The authors conclude that vaccination programs aimed at vaccinating a large proportion of the population with a single dose, with a second dose given after a 3 month period is an effective strategy for reducing disease, and may be optimal for rollout of a pandemic vaccine when supplies are limited.
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. See also COVID Reference Vaccines.
Gerberding JL, Haynes BF. Vaccine Innovations — Past and Future. N Engl J Med 2021; 384:393-396. Full-text: Full-text: https://doi.org/10.1056/NEJMp2029466
A 4-page overview by Julie Gerberding and Barton Haynes. The authors anticipate that the future holds great promise for vaccine-mediated control of global pathogens but providing affordable access to effective vaccines for everyone who could benefit from them remains an important challenge. Difficulties facing vaccinologists now include
- predicting the type and timing of the next pandemic;
- developing vaccines to combat rapidly changing pathogens such as HIV-1, influenza, and multidrug-resistant bacteria;
- and establishing rapid-response strategies to control emerging and reemerging infectious diseases.
Saadat S, Rikhtegaran-Tehrani Z, Logue J, et al. Single Dose Vaccination in Healthcare Workers Previously Infected with SARS-CoV-2. medRxiv 2021, posted 1 February. Full-text: https://doi.org/10.1101/2021.01.30.21250843
The same direction: Healthcare workers (HCW) with prior COVID-19 showed clear secondary antibody responses to vaccination with IgG spike binding titers rapidly increasing by 7 days and peaking by days 10 and 14 post-vaccination. The authors’ conclusion: in times of vaccine shortage 1) a single dose of vaccine for patients already having had laboratory-confirmed COVID-19; and 2) patients who have had laboratory-confirmed COVID-19 can be placed lower on the vaccination priority list.
Paper of the Day
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, published 2 February. Full-text: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00234-8/fulltext
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). The vaccine will help to diversify the world SARS-CoV-2 vaccine pipeline. Welcome to the CVC, Sputnik V!
See also Jones I, Roy P. Sputnik V COVID-19 vaccine candidate appears safe and effective. Lancet 2021, published 2 February. Full-text: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00191-4/fulltext
Krammer F, Srivastava K, PARIS team, Simon V. Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. medRxiv 2021, posted 1 February. Full-text: https://doi.org/10.1101/2021.01.29.21250653
Individuals with pre-existing immunity against SARS-CoV-2 need only one dose of vaccine. Consequence: we could spare the second for other people. This is the result of a study by Florian Krammer and colleagues who provide evidence that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naive individuals after the second dose. They also show that the reactogenicity is significantly higher in individuals who were previously infected with SARS-CoV-2. See also Willyard C. Had Covid? You May Need Only One Dose of Vaccine, Study Suggests. The New York Times 2021, published 1 February. Full-text: https://www.nytimes.com/2021/02/01/health/have-you-had-covid-19-coronavirus.html
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.
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, published 29 January. 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.
Richmond P, Hatchuel L, Dong M, et al. Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomised, double-blind, placebo-controlled trial. Lancet 2021, published 29 January. Full-text: https://doi.org/10.1016/S0140-6736(21)00241-5
Ralf Clemens, Peter Richmond and colleagues show that the Clover Biopharmaceuticals SCB-2019 vaccine (comprising S-Trimer protein formulated with either AS03 [GSK] or CpG/Alum adjuvants), elicited robust humoral and cellular immune responses against SARS-CoV-2, with high viral neutralizing activity. See also comment by Blakney AK, McKay PF. Next-generation COVID-19 vaccines: here come the proteins. Lancet 2021, published 29 January. Full-text: https://doi.org/10.1016/S0140-6736(21)00258-0
Callaway E, Mallapaty S. Novavax offers first evidence that COVID vaccines protect people against variants. Nature 2021, published 29 January. Full-text: https://www.nature.com/articles/d41586-021-00268-9
Novavax’s experimental shot is highly effective against the variant identified in Britain — but saw a worrying drop in efficacy against a lineage detected in South Africa.
Wang P, Lihong L, Iketani S, et al. Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization. bioRxiv 2021, posted 26 January. Full-text: https://doi.org/10.1101/2021.01.25.428137
E484K is the bad boy on the block. David Ho, Pengfai Wang and colleagues at Columbia University produced retroviruses with spike proteins incorporating each of B1351’s mutations separately, as well as all at once. E484K accounted for much of the effect. The serum of 12 people vaccinated with Moderna’s vaccine and 10 people vaccinated with the Pfizer-BioNTech vaccine was six to nine times less potent against B.1.351. Serum from 20 previously infected people was 11 to 33 times less potent.
Kupferschmidt 20210126. Vaccine 2.0: Moderna and other companies plan tweaks that would protect against new coronavirus mutations. Science 2021, published 26 January. Full-text: https://www.sciencemag.org/news/2021/01/vaccine-20-moderna-and-other-companies-plan-tweaks-would-protect-against-new
Antibodies triggered by the vaccine may be a little less potent against the new variant B.1.351, first described in South Africa, vs the one the vaccine was developed for. So, researchers were perhaps relieved to hear the company will start development of booster shots tailored to B.1.351 and other variants.
Brunning A. How are RNA vaccines made? Periodic Graphics 2021, published 3 January. Link: https://cen.acs.org/pharmaceuticals/vaccines/Periodic-Graphics-RNA-vaccines-made/99/i1
RNA vaccines produced by Pfizer-BioNTech and Moderna have become the first COVID-19 vaccines. How are these vaccines made?
Brouwer JM, Brinkkemper M, Maisonnasse P, et al. Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection. Cell 2021, published 25 January. Full-text: https://www.cell.com/cell/fulltext/S0092-8674(21)00078-7
Rogier Sanders, Philip Brouwer and colleagues present a two-component protein-based nanoparticle vaccine that displays twenty copies of pre-fusion SARS-CoV-2 S protein, capable of inducing potent neutralizing antibody responses in 400 in mice, rabbits and cynomolgus macaques. The vaccine-induced immunity protected macaques against a high dose challenge, resulting in strongly reduced viral infection and replication in upper and lower airways.
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. bioRxiv 2021, posted 19 January. Full-text: https://doi.org/10.1101/2021.01.18.426984
Good news from the variants vaccine front. Ugur Sahin, Alexander Muik and colleagues report that after analyzing immune sera from individuals vaccinated with the Pfizer-BioNTech vaccine (Comirnaty™), it seems unlikely that the (“UK”) B.1.1.7 variant will escape vaccine-mediated protection. The authors investigated SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with the sera of 16 participants in a previously reported trial with the mRNA-based COVID-19 vaccine Comirnaty™. The immune sera had equivalent neutralizing titers to both variants.
Wu K, Werner AP, Moliva JI, et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv 2021, published 25 January. Full-text: https://doi.org/10.1101/2021.01.25.427948
Good news from another variants vaccine front. Kai Wu et al. demonstrate that people aged 18-55 years who received two 100 µg doses of the mRNA-1273 vaccine, “maintained activity against all circulating strain variants tested to date”, and only the B.1.351 variant showed reduced neutralizing titers. Viral escape was not detected from any sample and neutralizing titers remained above those previously found to be protective in NHP challenge studies. (Editor’s Note: All circulating strain variants? The paper doesn’t seem to mention the P.1 variant from Brazil.) See also the Moderna press release at https://investors.modernatx.com/news-releases/news-release-details/moderna-covid-19-vaccine-retains-neutralizing-activity-against
Cele S, Gazy I, Jackson L, et al. Escape of SARS-CoV-2 501Y.V2 variants from neutralization by convalescent plasma. medRxiv 2021, published 26 January. Full-text: https://doi.org/10.1101/2021.01.26.21250224
Bad news from the variants antibody front. Mutations in the B.1.351 variant (alias 501Y.V2) may cause the virus to lose much of its sensitivity to antibodies. That is the result of a pre-print paper by Tulio de Oliveira, Alex Sigal, Sandile Cele and colleagues. After examining the neutralizing effect of convalescent plasma collected from six adults hospitalized with COVID-19, the authors observed that neutralization of the B.1.351 variant was strongly attenuated, with IC50 6 to 200-fold higher relative to the first wave virus. Reduced protection against re-infection? Let’s live on and see!
Wang Z, Schmidt F, Weisblum Y, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. bioRxiv 2021, published 19 January. Full-text: https://doi.org/10.1101/2021.01.15.426911
And, finally, good news again: Michel Nussenzweig and colleagues tested samples from 14 and 6 people who had received the Moderna and the Pfizer-BioNTech vaccine, respectively. They saw a slight decrease in antibody activity against engineered viruses with three key mutations of the B.1.351 variant first discovered in South Africa.
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. ePub: 22 January 2021. Full-text: http://dx.doi.org/10.15585/mmwr.mm7004e1external icon.
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.
Bubar KM, Reinholt K, Kissler SM, et al. Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science 21 Jan 2021:eabe6959. DOI: 10.1126/science.abe6959
Mathematical models comparing five age-stratified prioritization strategies: a highly effective transmission-blocking vaccine prioritized to adults ages 20-49 years minimized cumulative incidence, but mortality and years of life lost were minimized in most scenarios when the vaccine was prioritized to adults over 60 years old. Use of individual-level serological tests to redirect doses to seronegative individuals improved the marginal impact of each dose while potentially reducing existing inequities in COVID-19 impact.
Fitzpatrick MC, Galvani AP. Optimizing age-specific vaccination. Science 21 Jan 2021: eabg2334. DOI: 10.1126/science.abg2334
Vaccination strategies are not one size fits all. In their perspective, Meagan C. Fitzpatrick and Alison P. Galvani looked at vaccination of different age groups. Although vaccination of younger adults is projected to avert the greatest incidence, vaccinating older adults will most effectively reduce mortality.
Callaway E. Fast-spreading COVID variant can elude immune responses. Nature News 21 January 2021. Full-text: https://www.nature.com/articles/d41586-021-00121-z
Ewen Callaway discusses the growing evidence that the SARS-CoV-2 variant identified in South Africa might compromise immunity sparks concerns about vaccine effectiveness.
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.
Rostad CA, Anderson EJ. Optimism and caution for an inactivated COVID-19 vaccine. Lancet Inf Dis January 21, 2021. Full-text: https://doi.org/10.1016/S1473-3099(20)30988-9
Christina Rostad and Evan Anderson see an inactivated vaccine as a welcome addition to the COVID-19 vaccine landscape. However, they discuss the open questions and concerns regarding inactivated vaccines (i.e. antibody-dependent enhancement of infection and vaccine-associated enhanced respiratory disease). Until then, they “will wait with cautious optimism on this vaccine candidate poised to bolster worldwide equitable access to COVID-19 prevention”. Ok, let’s wait. But for how long?
Siegel CA, Melmed GY, McGovern DP, et al. SARS-CoV-2 vaccination for patients with inflammatory bowel diseases: recommendations from an international consensus meeting. Gut. 2021 Jan 20:gutjnl-2020-324000. PubMed: https://pubmed.gov/33472895. Full-text: https://doi.org/10.1136/gutjnl-2020-324000
The panel recommends vaccinating all patients with IBD as soon as they are able to receive the vaccine, regardless of immune-modifying therapies. The exception is for any live-attenuated virus vaccines or replication-competent viral vector vaccines that come to market.
Klass P, Ratner AJ. Vaccinating Children against Covid-19 — The Lessons of Measles. NEJM January 20, 2021. Full-text: https://doi.org/10.1056/NEJMp2034765
Perri Klass and Adam Ratner argue that we need to consider lessons from recent measles epidemics — not only about the power of legislative mandates, but also about their potential for sowing distrust if delivered without careful, sensitive, accurate public health messaging. Communication, people!
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.
Kim JH, Marks F, Clemens JD. Looking beyond COVID-19 vaccine phase 3 trials. Nat Med (2021). Full-text: https://doi.org/10.1038/s41591-021-01230-y
After Phase III vaccine trials, a comprehensive program of prevention, continued work on vaccine optimization, new vaccines, correlates, long-term safety and continued surveillance will be needed simultaneously with the steady implementation of vaccination.
Glover RE, Urquhart R, Lukawska J, Blumenthal KG. Vaccinating against covid-19 in people who report allergies. BMJ. 2021 Jan 18;372:n120. PubMed: https://pubmed.gov/33461962. Full-text: https://doi.org/10.1136/bmj.n120
A history of severe allergy does not preclude vaccination unless that allergy is to the vaccine or its components. Discover the key facts and reassure your patients.
Topol EJ. Messenger RNA vaccines against SARS-CoV-2. Cell 2021, published 16 January. Access: https://www.cell.com/cell/fulltext/S0092-8674(20)31761-X
The first two vaccines proven to be effective for inhibiting COVID-19 illness were both mRNA, achieving 95% efficacy (and safety) among 74.000 participants (half receiving placebo) after intramuscular delivery of two shots, 3–4 weeks apart. A one-page summary by Eric Topol.
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 12, 372 (2021). 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. Find more information about NVX-CoV2373 at https://covidreference.com/vaccines.
Ledford H. How can countries stretch COVID vaccine supplies? Scientists are divided over dosing strategies. Nature 2021, published 11 January. Full-text: https://www.nature.com/articles/d41586-021-00001-6
On 30 December, the United Kingdom announced that it would allow doses of two coronavirus vaccines to be administered as many as 12 weeks apart, even though, in clinical trials, the two doses of the vaccine made by Pfizer of New York City and BioNTech of Mainz, Germany, were given to participants about three weeks apart. Not everyone agrees.
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.
Efrati I. Israel to Share Vaccination Data With Pfizer as Part of Secret Deal. Haaretz 2021, published 10 January. Full-text: https://www.haaretz.com/israel-news/.premium-israel-to-share-covid-vaccine-data-with-pfizer-but-agreement-remains-secret-1.9438504
The Israeli newspaper reports a deal between Israel and Pfizer: Pfizer will receive anonymized data about consequences of the inoculations, side effects, efficacy, and the amount of time it takes to develop antibodies, according to different types of population, age, gender, pre-existing conditions, and other factors.
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.
Mahase E. How the Oxford-AstraZeneca covid-19 vaccine was made. BMJ 2021; 372. 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.
Marjot T, Webb GJ, Barritt AS. SARS-CoV-2 vaccination in patients with liver disease: responding to the next big question. Lancet Gastroenterol Hepatol 2021, published 11 January. Full-text: https://doi.org/10.1016/S2468-1253(21)00008-X
Patients with advanced liver disease have well recognized deficiencies in innate and humoral immunity, termed cirrhosis-associated immune dysfunction (CAID). Nonetheless, given the high COVID-19-related mortality in patients with decompensated cirrhosis, it remains of utmost importance to prioritize vaccinations in this sub-group. Eleanor Barne, Thomas Marjot and colleagues express their belief that patients with advanced liver disease should be prioritized for vaccination, with the likely benefits far outweighing any potential risks. Until it is established whether patients with liver disease and transplantation achieve optimal protection after immunization, clinicians should remain vigilant for post-vaccination COVID-19 in these cohorts.
Bordon, Y. Immune readouts from the Oxford COVID-19 vaccine. Nat Rev Immunol 2021, published 11 January. Full-text: https://doi.org/10.1038/s41577-021-00503-4
Yvonne Bordon comments on two recent reports from the Oxford COVID-19 vaccine team which detail the immune outcomes observed in a Phase I/II trial of their ChAdOx1 nCoV-19 vaccine. In one of the papers we presented on 21 December, the authors give a detailed description of the immune response after administration of one dose of ChAdOx1 nCoV-19 in 88 adults (ages 18-55 years) (Ewer 2020). They define the isotypes, subclasses and antibody avidity induced after vaccination. They also performed multiplex cytokine profiling and intracellular cytokine staining analysis, demonstrating that ChAdOx1 nCoV-19 vaccination induces a predominantly Th1-type response (that appears to be good). See also Barrett JR, Belij-Rammerstorfer S, Dold C, et al. Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses. Nat Med. 2020 Dec 17. PubMed: https://pubmed.gov/33335322. Full-text: https://doi.org/10.1038/s41591-020-01179-4
Xie X, Zou J, Fonte-Garfias CR, et al. Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera. bioRxiv 2021, posted 7 January. Full-text: https://doi.org/10.1101/2021.01.07.425740
Recent SARS-CoV-2 variants in the United Kingdom and South Africa have multiple mutations in their S glycoproteins, which are key targets of viral neutralizing antibodies. These rapidly spreading variants share the spike N501Y substitution. Pei-Yong Shi, Philip R. Dormitzer and Xuping Xie generated isogenic N501 and Y501 SARS-CoV-2. Sera of participants in a previously reported trial of the mRNA-based COVID-19 vaccine BNT162b2 had equivalent neutralizing titers to the N501 and Y501 viruses.
Wood S, Schulman K. Beyond Politics — Promoting Covid-19 Vaccination in the United States. N Engl J Med 2021, published 6 January. Full-text: https://doi.org/10.1056/NEJMms2033790
In France, some 60% of the population is skeptic about getting vaccinated. In search of inspiration, French authorities should take a look at this paper by Stacy Wood & Kevin Schulman. They should be ready to revise their marketing skills. Communication needs to become more a part of regular science.
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.
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.
Garde D. ‘I haven’t even told my wife’. Stat 2020. Full-text: https://www.statnews.com/2020/12/15/inside-the-frantic-and-secretive-sprint-to-name-the-covid-19-vaccines/
Naming a vaccine is almost always a matter of threading semantic needles, branding experts said, where the goal is to evoke positive vibes without irking the world’s more conservative regulatory bodies. And it takes time.
Callaway E. Could new COVID variants undermine vaccines? Labs scramble to find out. Nature 2021, published 8 January. Full-text: https://www.nature.com/articles/d41586-021-00031-0
Researchers race to determine why variants identified in Britain and South Africa spread so quickly and whether they’ll compromise vaccines.
CDC 20210106. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020. MMWR Morb Mortal Wkly Rep. ePub: 6 January 2021. DOI: http://dx.doi.org/10.15585/mmwr.mm7002e1
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 which we presented on 1 January.
Iacobucci G, Mahase E. Covid-19 vaccination: What’s the evidence for extending the dosing interval? BMJ 2021, published 6 January. Full-text: https://doi.org/10.1136/bmj.n18
On 30 December the four UK chief medical officers announced that the second doses of the COVID vaccines should be given towards the end of 12 weeks rather than in the previously recommended 3-4 weeks. German authorities will issue a similar recommendation soon. Gareth Iacobucci and Elisabeth Mahase look at the questions this has raised.
De Vrieze J. Suspicions grow that nanoparticles in Pfizer’s COVID-19 vaccine trigger rare allergic reactions. Science 2020, published 21 December (sorry for being late!). Full-text: https://www.sciencemag.org/news/2020/12/suspicions-grow-nanoparticles-pfizer-s-covid-19-vaccine-trigger-rare-allergic-reactions
Severe allergy-like reactions in at least eight people who received the COVID-19 vaccine produced by Pfizer and BioNTech over the past 2 weeks may be due to a compound in the packaging of the messenger RNA (mRNA) that forms the vaccine’s main ingredient, scientists say. A similar mRNA vaccine developed by Moderna, which was authorized for emergency use in the United States on Friday, also contains the compound, polyethylene glycol (PEG).
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
Emergency Use Authorizations for two mRNA COVID-19 vaccines represent a turning point in the pandemic. They also herald a new era for vaccinology – an era where vaccines are designed on computers, iteratively optimized in discovery and manufactured on demand — all without expensive and finicky cell culture.
Oliver S, Gargano J, 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;69:1653-1656. Full-text: http://dx.doi.org/10.15585/mmwr.mm695152e1
Use of all COVID-19 vaccines authorized under an EUA should be implemented in conjunction with ACIP’s interim recommendations for allocating initial supplies of COVID-19 vaccines. Before vaccination, the EUA Fact Sheet should be provided to recipients and caregivers. Providers should counsel Moderna COVID-19 vaccine recipients about expected local and systemic reactogenicity.
Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2020, published 30 December. 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.
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!
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).
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.
Our World in Data. COVID-19 vaccination doses administered per 100 people. 30 December 2020. Link: https://ourworldindata.org/grapher/covid-vaccination-doses-per-capita
The Pfizer–BioNTech COVID-19 vaccine, codenamed BNT162b2, is now being sold under the brand name Comirnaty™ (INN: Tozinameran). Find here a summary of the product characteristics and the package leaflet if you want to be able to answer the questions of your patients: https://www.ema.europa.eu/en/documents/product-information/comirnaty-epar-product-information_en.pdf
Burki T. Equitable distribution of COVID-19 vaccines. Lancet Infect Dis 2021, published 1 January. Full-text: https://doi.org/10.1016/S1473-3099(20)30949-X
If everything goes according to plan, November 2020 will be remembered as the beginning of the end of the COVID-19 pandemic. Countries will have to ensure that they have the infrastructure for mass immunization campaigns. Those without experience in distributing influenza vaccines must learn how to establish platforms for adult vaccination. Vaccine hesitancy will have to be overcome.
Lucia VC, Kelekar A, Afonso NM. COVID-19 vaccine hesitancy among medical students, Journal of Public Health. J Pub Health 2020, published 26 December. Full-text: https://doi.org/10.1093/pubmed/fdaa230
Medical students are among the group of frontline healthcare providers likely to be exposed to COVID-19 patients. It is important to achieve high COVID-19 vaccination coverage rates in this group as soon as a vaccine is available. In this survey completed by 168 of 494 medical students (response rate = 34%), the vast majority had positive attitudes regarding immunizations in general and the importance of vaccines for themselves and patients. 53% indicated they would participate in a COVID-19 vaccine trial; only 23% were unwilling to take a COVID-19 vaccine immediately upon FDA approval.
Pollard AJ, Bijker EM. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol (2020). Full-text: https://doi.org/10.1038/s41577-020-00479-7
2021 may be the perfect time for immunologists to be involved in designing the next generation of powerful immunogens. In this review, Andrew Pollard and Else Bijker provide an overview of vaccines, immunization and related issues.
Oliver S, Gargano J, 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. ePub: 20 December 2020. DOI: http://dx.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.
Ball P. The lightning-fast quest for COVID vaccines — and what it means for other diseases. Nature 2020, published 18 December. Full-text: https://www.nature.com/articles/d41586-020-03626-1
The speedy approach used to tackle SARS-CoV-2 could change the future of vaccine science. “It shows how fast vaccine development can proceed when there is a true global emergency and sufficient resources,” says Dan Barouch, director of the Center for Virology and Vaccine Research at Harvard Medical School in Boston, Massachusetts.
Rubin EJ, Baden LR, Barocas JA, Morrissey S. Covid-19 Vaccine Fundamentals. Audio interview (19:46). N Engl J Med 2020; 383: e146. Access: https://doi.org/10.1056/NEJMe2035370
The editors discuss the five types of COVID-19 vaccine under study, as well as trial results of the therapeutic agent baricitinib.
Dai L, Gao GF. Viral targets for vaccines against COVID-19. Nat Rev Immunol 18 December 2020. Full-text: https://doi.org/10.1038/s41577-020-00480-0
Which viral elements are used in COVID-19 vaccine candidates, why might they act as good targets for the immune system and what are the implications for protective immunity? This review addresses these questions.
Ewer KJ, Barrett JR, Belij-Rammerstorfer S. et al. T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial. Nat Med December 18, 2020. Full-text: https://doi.org/10.1038/s41591-020-01194-5
A detailed description of the immune response after administration of one dose of ChAdOx1 nCoV-19 in 88 adults (ages 18-55 years). The authors define, in detail, the isotypes, subclasses and antibody avidity induced after vaccination. They also performed multiplex cytokine profiling and intracellular cytokine staining analysis, demonstrating that ChAdOx1 nCoV-19 vaccination induces a predominantly Th1-type response (that appears to be good).
Editorial. COVID-19 vaccines: the pandemic will not end overnight. The Lancet Microbe December 18, 2020. Full-text: https://doi.org/10.1016/S2666-5247(20)30226-3
See title. Even a global mass immunization program will not immediately end the COVID-19 pandemic. Although control over the infection’s most harmful effects is expected and limiting its spread can be hoped for, it will likely be a few years before the virus can be brought under control worldwide.
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
Moderna’s messenger RNA vaccine (mRNA-1273) seems to work in older people. In this 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.
Rid A, Lipsitch M, Miller FG, et al. The Ethics of Continuing Placebo in SARS-CoV-2 Vaccine Trials. JAMA December 14, 2020. Published online December 14, 2020. Full-text: https://doi.org/10.1001/jama.2020.25053
Participants who received placebo in the vaccine trials have made an essential contribution to testing vaccine safety and efficacy. This important viewpoint argues that given limited vaccine supply for at least several months, only the participants receiving placebo who would be eligible for vaccination outside the trial should be offered access to the vaccines at this point. What did the informed consent say? Did it contemplate a EUA or other vaccines getting to market before their specific trial finishes?
Wang W, Wu Q, Yang J, et al. Global, regional, and national estimates of target population sizes for covid-19 vaccination: descriptive study. BMJ 15 December 2020; 371. Full-text: https://doi.org/10.1136/bmj.m4704
For the record: The adult population willing to be vaccinated is estimated at 3.7 billion (95% confidence interval 3.2 to 4.1 billion).
Bubar KM, Reinhold K, Kissler SM, et al. Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. medRxiv 2020, posted 7 December. Full-text: https://doi.org/10.1101/2020.09.08.20190629
Over the coming months, the supply of SARS-CoV-2 vaccine will be limited. Who should receive the first available vaccine doses? It depends. If your priority is preventing as many transmissions as possible, give the vaccine to adults aged 20-49. If you want to minimize mortality and years of life lost, vaccine the 60+ years old.
Oliver S, Gargano J, 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. ePub: 13 December 2020. Full-text: http://dx.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.
Noval Rivas M, Ebinger JE, Wu M, et al. BCG vaccination history associates with decreased SARS-CoV-2 seroprevalence across a diverse cohort of healthcare workers. J Clin Invest. 2020 Nov 19:145157. PubMed: https://pubmed.gov/33211672. Full-text: https://doi.org/10.1172/JCI145157
A history of BCG vaccination was associated with decreased seroprevalence of anti-SARS-CoV-2 IgG and reduced reported COVID-19-related clinical symptoms in a cohort of healthcare workers in Los Angeles. Of the 6201 HCWs, 29,6% reported a history of BCG vaccination whereas 68,9% did not receive BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as incidence of self-reported clinical symptoms associated with COVID-19 were significantly decreased among HCWs with a history of BCG vaccination compared to those without BCG vaccination.
See also the comment by Netea MG, van der Meer JW, van Crevel R. BCG vaccination in healthcare providers and the protection against COVID-19. J Clin Invest. 2020 Dec 11:145545. PubMed: https://pubmed.gov/33306484. Full-text: https://doi.org/10.1172/JCI145545
Rubin EJ, Longo DL. SARS-CoV-2 Vaccination — An Ounce (Actually, Much Less) of Prevention (Editorial). N Engl J Med 2020, published 10 December. Full-text: https://doi.org/10.1056/NEJMe2034717
Before December 2020, no existing vaccines had been shown to be effective against infection with any beta-coronavirus; strategies to increase the speed of vaccine development had never been tested; and no vaccines based on mRNA technologies had yet been approved. Now, with the paper by Polack et al. that we presented yesterday, all this has been done and the NEJM editors qualify it as a triumph that holds the promise of saving uncounted lives. Rightly, they continue questioning: “Will unexpected safety issues arise when the number grows to millions and possibly billions of people? Will side effects emerge with longer follow-up? Implementing a vaccine that requires two doses is challenging. What happens to the inevitable large number of recipients who miss their second dose? How long will the vaccine remain effective? Does the vaccine prevent asymptomatic disease and limit transmission? And what about the groups of people who were not represented in this trial, such as children, pregnant women, and immunocompromised patients of various sorts?” The story will continue…
Singh JA, Upshur EG. The granting of emergency use designation to COVID-19 candidate vaccines: implications for COVID-19 vaccine trials. Lancet Infect Dis 2020, published 8 December. Full-text: https://doi.org/10.1016/S1473-3099(20)30923-3
In the next weeks, SARS-CoV-2 candidate vaccines will be granted emergency use authorizations after only months of clinical experience. The authors caution that emergency use designations could inadvertently threaten ongoing vaccine research that is yet to define immunological correlates of protection against COVID-19, which could vary according to the vaccine platform, individual characteristics, age groups, and population subset.
Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020, published 10 December. Full-text: https://doi.org/10.1056/NEJMoa2034577
Safety and efficacy findings from the 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.
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; 383:2320-2332. 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.
Voysey M, Clemens SA, 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 December 08, 2020. 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.
Knoll MD, Wonodi C. Oxford–AstraZeneca COVID-19 vaccine efficacy. Lancet December 08, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)32623-4
In their comment on the ChAdOx1 paper, Maria Deloria Knoll and Chizoba Wonodi are enthusiastic: “Despite the outstanding questions and challenges in delivering these vaccines, it is hard not to be excited about these findings”. They believe that “perhaps by this time next year, we can celebrate the global control of SARS-CoV-2, in person”. We‘ll see.
On December 10, Pfizer and its partner, the German company BioNTech, will be publicly reviewed by the FDA. Find here two documents (53 and 92 pages, respectively) which go into the details of the Phase III trial on 44.000 volunteers recruited in the United States, Brazil and Argentina. Among the first 170 infected persons, 162 had received the placebo and 8 the vaccine – an effectiveness of 95%. The documents disclose more details about protection after the first vaccine dose as well as the protection of elderly people, obese people and those suffering from co-morbidities. There seem to have been no significant differences between the vaccinees and the placebo group in the few serious complications recorded. However, moderate side effects were recorded after the second injection: headache, fatigue, muscle pain and chills affected up to 50% of the vaccinees, particularly those under 55 years old.
Ledford H, Cyranoski D, Van Noorden R. The UK has approved a COVID vaccine — here’s what scientists now want to know. Nature 2020, published 3 December. Full-text: https://www.nature.com/articles/d41586-020-03441-8
The Pfizer–BioNTech vaccine has passed safety and efficacy tests — but scientists still have many questions about how this and other vaccines will perform as they’re rolled out to millions of people.
Danaiya Usher A. South Africa and India push for COVID-19 patents ban. Lancet 2020, published 5 December. Full-text: https://doi.org/10.1016/S0140-6736(20)32581-2
South Africa and India want the World Trade Organization to temporarily suspend intellectual property rights so that COVID-19 vaccines and other new technologies are accessible for poor countries. Right on.
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.
Dooling K, McClung N, Chamberland M, et al. The Advisory Committee on Immunization Practices’ Interim Recommendation for Allocating Initial Supplies of COVID-19 Vaccine — United States, 2020. MMWR Morb Mortal Wkly Rep. ePub: 3 December 2020. Full-text: http://dx.doi.org/10.15585/mmwr.mm6949e1
Over the coming weeks and months, demand for vaccines will exceed supply. In the initial phase of the COVID-19 vaccination program, both health care personnel and residents of long-term care facilities should be offered priority vaccination.
WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation. Placebo-Controlled Trials of Covid-19 Vaccines — Why We Still Need Them. N Engl J Med 2020, published 2 December. Full-text: https://doi.org/10.1056/NEJMp2033538
In this Perspective, the participants in a World Health Organization ad hoc consultation on the next steps for COVID-19 vaccine evaluation recommend on how to proceed clinically as the first commercial vaccines increasingly become available. Yes, continue with placebo-controlled trials (the bedrock of modern clinical decision-making) because we still need more data on longer-term safety and duration of protection; on whether waning of vaccine-induced protection may lead to vaccine-enhanced disease if a vaccinee becomes infected after exposure to SARS-CoV-2; on information on protection against clinically severe forms of COVID-19; and knowledge of any associations between the degree of protection and the recipient’s age or co-existing conditions. No, refrain from observational studies which are subject to substantial biases and are much less amenable to unambiguous interpretation.
Branswell H. The Covid-19 vaccines are a marvel of science. Here’s how we can make the best use of them. STAT 2020, published 2 December. Full-text: https://www.statnews.com/2020/12/02/how-society-can-make-the-most-of-covid-19-vaccines/
Will 95% efficacy vaccines show the way to a straight road back to Normalville? Or will the route back be a meandering country lane with detours and potholes? Pothole 1: Vaccine skepticism. Pothole 2: Pregnant women. Pothole 3: Children. Pothole 4: How to continue important Phase III randomized trials while vaccines are already on the market? Pothole 5: Understanding SARS-CoV-2 transmission by vaccinated individuals. Have enough time before starting this long-read article.
Behr MA, Divangahi M, Schurr E. Lessons from BCG for SARS-CoV-2 vaccine candidates. J Infect Dis 2020, published 30 November. Full-text: https://doi.org/10.1093/infdis/jiaa637
A note of caution: according to Marcel Behr and colleagues from Montréal, developers of SARS-CoV-2 vaccines should consider some of the lessons from a ‘new’ vaccine introduced in 1921, where BCG introduced to great fanfare had no measurable effect on the global epidemic, despite evidence of protection at the individual level.
Sanchez-Felipe L, Vercruysse T, Sharma S et al. A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate. Nature December 1, 2020. Full-text: https://doi.org/10.1038/s41586-020-3035-9
Yellow Fever 17D (YF17D) is a small RNA live-attenuated virus with limited vector capacity. The YF17D vaccine is known to rapidly induce broad multi-functional innate, humoral and cell-mediated immune responses that may result in life-long protection following a single vaccine dose in nearly all vaccinees. These favorable characteristics translate also to vectored vaccines based on the YF17D backbone. Consequently, YF17D is used as vector in two licensed human vaccines, generated by swapping genes encoding the YF17D surface antigens for those of Japanese encephalitis or dengue viruses. Here, the authors describe the discovery of a live virus-vectored SARS-CoV-2 vaccine candidate using the YF17D vaccine as vector to express a non-cleavable prefusion form of the SARS-CoV-2 Spike antigen. Safety, immunogenicity and efficacy after a single dose are shown in several animal models such as hamsters, mice and macaques.
MacPherson A, Hutchinson N, Schneider O, et al. Probability of Success and Timelines for the Development of Vaccines for Emerging and Reemerged Viral Infectious Diseases. Ann Int Med 24 November 2020. Full-text: https://doi.org/10.7326/M20-5350
If a SARS-CoV-2 vaccine is licensed within 18 months of the start of the pandemic, it will mark an unprecedented achievement for non-influenza viral vaccine development. The authors took a look at other vaccines for emerging and re-emerged viral infectious diseases at ClinicalTrials.gov: in total, 606 clinical trials that formed part of 220 distinct development trajectories were identified. The probability of vaccines progressing from Phase II to licensure within 10 years was 10,0%, with most approvals representing H1N1 or H5N1 vaccines. The average timeline from Phase II to approval was 4,4 years. The probabilities of advancing from Phase I to II, Phase II to III, and Phase III to licensure within the total available follow-up time were 38,2%, 38,3%, and 61,1%, respectively.
Wadman M. Public needs to prep for vaccine side effects. Science 27 November 2020: Vol. 370, Issue 6520, pp. 1022. Full-text: https://doi.org/10.1126/science.370.6520.1022
Expect a rough night after vaccination: A subset of people may face intense, if transient, side effects, called reactogenicity. In this interesting article, Meredith Wadman argues that transparency is key. Rather than minimizing the chance of fever, vaccine administrators could alert people that they may experience a fever that can feel severe but is temporary.
Large clinical trials of four vaccine candidates are showing remarkable promise, with three exceeding 90% efficacy — all unexpectedly high. None reported worrying safety signals and one has shown promise in older adults who are particularly vulnerable to SARS-CoV-2 but sometimes respond less well to vaccines. But, there remains a lot of work to do for researchers and clinicians.
Cohen J. After dosing mix-up, latest COVID-19 vaccine success comes with big question mark. Science 2020, published 25 November. Full-text: https://www.sciencemag.org/news/2020/11/after-dosing-mix-latest-covid-19-vaccine-success-comes-big-question-mark
Callaway E. Why Oxford’s positive COVID vaccine results are puzzling scientists. Nature 2020, published 23 November. Full-text: https://www.nature.com/articles/d41586-020-03326-w
Preliminary data from the AstraZeneca vaccine are puzzling. Two full doses given a month apart would be 62% effective, but a half dose followed by a full dose would be 90% effective. Now researchers are trying desperately to instill meaning into these results. Let Jon Cohen and Ewen Callaway explain, sort of.
Editors. Nanomedicine and the COVID-19 vaccines. Nat. Nanotechnol 2020, published 27 November. Full-text: https://doi.org/10.1038/s41565-020-00820-0
If approved, BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna/NIH), credited in press releases with sky-rocketing efficacy, would be the first messenger RNA (mRNA)-based vaccines to be used in large populations. mRNA vaccines use nanotechnology platforms to deliver the genetic sequence of specific viral proteins to the host cells. Find more about the founding principles of nanomedicine in this short editorial.
Wang J. New strategy for COVID-19 vaccination: targeting the receptor-binding domain of the SARS-CoV-2 spike protein. Cell Mol Immunol 2020, published 26 November. Full-text: https://doi.org/10.1038/s41423-020-00584-6
Junzhi Wang comments on a study by Yang J, Wang W, Chen Z et al. [A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 2020, published 29 July. Full-text: https://doi.org/10.1038/s41586-020-2599-8] we presented on 30 July. The authors show that a recombinant spike receptor-binding domain (RBD) protein of SARS-CoV-2 prepared from insect cells could induce a potent functional antibody response in mice, rabbits and non-human primates as early as 7 or 14 days after a single dose injection. Even one dose of the vaccine generated viral neutralizing activity. The vaccine protected non-human primates from live SARS-CoV-2 challenge 28 days after the first vaccination.
Ma X, Zou F, Yu F, et al. Nanoparticle Vaccines Based on the Receptor Binding Domain (RBD) and Heptad Repeat (HR) of SARS-CoV-2 Elicit Robust Protective Immune Responses. Immunity November 25, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.11.015
A promising new vaccination approach: Xiancai Ma and colleagues from Guangdong, China developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for longer than three months.
Sun W, Leist SR, McCroskery S, et al. Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate. EBioMedicine November 21, 2020. Full-text: https://doi.org/10.1016/j.ebiom.2020.103132
The Newcastle disease virus vector vaccine has some advantages similar to those of other viral vector vaccines. The NDV vector can be amplified in embryonated chicken eggs, which allows for high yields and low costs perdose. Also, the NDV vector is not a human pathogen, therefore the delivery of the foreign antigen would not be compromised by any pre-existing immunity in humans. Weina Sun and colleagues describe NDV vector vaccines expressing the spike protein of SARS-CoV-2 in its wild type format or a membrane-anchored format lacking the polybasic cleavage site. The NDV vector vaccines elicited high levels of antibodies that are neutralizing when the vaccine is given intramuscularly in mice. Importantly, these COVID-19 vaccine candidates protect mice from a mouse-adapted SARS-CoV-2 challenge with no detectable viral titer and viral antigen in the lungs. The results suggested that the NDV vector expressing either the wild type S or membrane-anchored S without the polybasic cleavage site could be used as live vector vaccine against SARS-CoV-2.
McClung N, Chamberland M, Kinlaw K, et al. The Advisory Committee on Immunization Practices’ Ethical Principles for Allocating Initial Supplies of COVID-19 Vaccine — United States, 2020. MMWR Morb Mortal Wkly Rep. ePub: 23 November 2020. Full-text: http://dx.doi.org/10.15585/mmwr.mm6947e3
Four ethical principles will assist the Advisory Committee on Immunization Practices (ACIP) in formulating recommendations for the initial allocation of COVID-19 vaccine: 1) maximizing benefits and minimizing harms; 2) promoting justice; 3) mitigating health inequities; and 4) promoting transparency. Read how application of ethical principles to four candidate groups for initial COVID-19 vaccine allocation is planned in the US.
Lederer K, Castaño D, Atria DG, et al. SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation. Cell November 21, 2020. Full-text: https://doi.org/10.1016/j.immuni.2020.11.009
A systematic comparison between two vaccine platforms, nucleoside modified mRNA lipid nanoparticle and recombinant protein formulated with the MF59-like adjuvant AddaVax (rRBD-AddaVax), evaluating quantitatively and qualitatively the germinal center (GC) responses to SARS-CoV-2 upon immunization. The authors found that SARS-CoV-2 mRNA vaccines had a superior capacity, in comparison to rRBD-AddaVax, to elicit potent SARS-CoV-2 specific GC B cell responses after the administration of a single vaccine dose. Importantly, they demonstrated that GC B cells and Tfh cells strongly correlated with the production of nAbs.
Lewis JR. What Is Driving the Decline in People’s Willingness to Take the COVID-19 Vaccine in the United States? JAMA Health Forum. 2020; 1(11):e201393. Full-text: https://doi.org/10.1001/jamahealthforum.2020.1393
People in the US are ready to move on from the COVID-19 pandemic, but when it comes to a vaccine, many have a wait-and-see attitude. Jarrett Ramos Lewis addresses the reasons. As we move toward having an approved COVID-19 vaccine, it is important to understand that for many, it will take time to feel comfortable and confident in getting the vaccine. While the politicization of the vaccine is to blame for some of that delay, the increased reluctance of people to get a COVID-19 vaccine runs much deeper than politics.
Editorial. COVID-19 vaccines: no time for complacency. Lancet 2020, published 21 November. Full-text: https://doi.org/10.1016/S0140-6736(20)32472-7
“‘Yes. Yes. Yes.’ That was the response of John Bell, Regius Professor of Medicine at the University of Oxford, when asked whether we could be confident that life will be returning to normal by spring.” Of course, we will not return to normal life within 6 months. Let’s lean back and be satisfied that in less than a year, we have characterized a novel illness, sequenced a new viral genome, developed diagnostics, produced treatment protocols, and established the efficacy of drugs and vaccines in randomized controlled trials. There is no hurry. If we can achieve some kind of pre-COVID-19 ‘normalcy’ by 2022, it would be a feat remembered by generations.
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.
See also the comment by Andrew MK, McElhaney JE. Age and frailty in COVID-19 vaccine development. Lancet 2020, published 18 November. Full-text: https://doi.org/10.1016/S0140-6736(20)32481-8
Knipe DM, Levy O, Fitzgerald KA, Mühberger E. Ensuring vaccine safety. Science 2020, published 17 November. Full-text: https://doi.org/10.1126/science.abf0357
Vaccines are among the most successful medical and public health measures ever implemented and prevent ~6 million deaths globally per year. Efficient SARS-CoV-2 vaccines might prevent a similar number of deaths over the coming years. However, caution the authors, the urgent need for COVID-19 vaccines must be balanced with the imperative of ensuring safety and public confidence in vaccines by following the established clinical safety testing protocols throughout vaccine development, including both pre- and post-deployment.
Wadman M. Fever, aches from Pfizer, Moderna jabs aren’t dangerous but may be intense for some. Science 2020, published 18 November. Full-text: https://www.sciencemag.org/news/2020/11/fever-aches-pfizer-moderna-jabs-aren-t-dangerous-may-be-intense-some
Both the BioNTech/Pfizer and the Moderna/NIH mRNA vaccine reached 95% efficacy in clinical trials of tens of thousands of people. The trials revealed no serious safety concerns. We will learn to accept fever and aches as signs that the vaccine works. Even bone and muscle aches and an almost unbearable 38.9°C fever that lasts 12 hours…
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.
Bar-Zeev N, Kochhar S. Expecting the unexpected with COVID-19 vaccines. Lancet November 17, 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30870-7
According to this detailed comment, like all Phase II trials, the results must be interpreted with caution until Phase III results are published. Neutralising titers were substantially lower than those seen in 117 convalescent patients who previously had COVID-19 tested in the same laboratory. A demonstration of longevity of response and of empiric protection from this vaccine candidate will be important.
Callaway E. COVID vaccine excitement builds as Moderna reports third positive result. Nature NEWS November 16, 2020. Full-text: https://doi.org/10.1038/d41586-020-03248-7
Moderna’s vaccine comprises RNA instructions for cells to produce a modified form of the coronavirus spike protein, the immune system’s key target against coronaviruses. Of note, the vaccine remains stable in conventional refrigerators for a month and ordinary freezers for six months. Ewen Callaway summarizes preliminary data showing that the immunization is 94% effective and seems to prevent severe infections.
Halstead SB, Katzelnick L. COVID-19 Vaccines: Should We Fear ADE? J Infect Dis. 2020 Nov 13;222(12):1946-1950. PubMed: https://pubmed.gov/32785649. Full-text: https://doi.org/10.1093/infdis/jiaa518
Scott B. Halstead and Leah Katzelnick say no. Antibody-dependent enhanced (ADE) breakthrough infections are unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological, or pathological attributes of ADE disease exemplified by dengue viruses (DENV). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages.
Strassle C, Jardas E, Ochoa J, et al. Covid-19 Vaccine Trials and Incarcerated People — The Ethics of Inclusion. N Engl J Med 2020; 383:1897-1899; published 12 November. Full-text: https://doi.org/10.1056/NEJMp2025955
The most severe COVID-19 outbreaks in the US are no longer occurring in nursing homes or meat packing plants, but in correctional facilities. Find an audio interview (19:26) with Holly Taylor on the ethical issues involved in conducting COVID-19 vaccine research in correctional facilities (19:26).
Teerawattananon Y, Dabak SV. COVID vaccination logistics: five steps to take now. Nature 2020, published 9 November. Full-text: https://www.nature.com/articles/d41586-020-03134-2
The authors point out that creating a safe and effective vaccine is just Act 1 of the 2021 Vaccine Play. Developing a comprehensive and strategic plan for vaccine roll-out is Act 2.
Walls AC, Fiala B, Schäfer A, et al. Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2. Cell. 2020 Oct 31:S0092-8674(20)31450-1. PubMed: https://pubmed.gov/33160446. Full-text: https://doi.org/10.1016/j.cell.2020.10.043
Are self-assembling protein nanoparticles that display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) and induce neutralizing antibody titers comparable to those produced by people after SARS-CoV-2 infection? That’s what Neil King and David Veesler and colleagues from University of Washington, Seattle, US, report. The authors anticipate that manufacture of the nanoparticle vaccines might be very scalable.
McPartlin SO, Morrison J, Rohrig A, Weijer C. Covid-19 vaccines: Should we allow human challenge studies to infect healthy volunteers with SARS-CoV-2? BMJ. 2020 Nov 9;371:m4258. PubMed: https://pubmed.gov/33168564. Full-text: https://doi.org/10.1136/bmj.m4258
The need for COVID-19 vaccines has prompted thousands of otherwise healthy people to volunteer to be infected with the virus to test candidate vaccines. Seán O’Neill McPartlin, Abie Rohrig, and Josh Morrison urge us to embrace the altruism of volunteers, but Charles Weijer argues that it would be dangerous and unjustified.
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.
Che Y, Liu X, Pu Y, et al. Randomized, double-blinded and placebo-controlled phase II trial of an inactivated SARS-CoV-2 vaccine in healthy adults. Clinical Infectious Diseases, 09 November 2020 ciaa1703. Full-text: https://doi.org/10.1093/cid/ciaa1703
In this randomized, double-blinded Phase II trial, 742 healthy adults received a medium (MD) or a high dose (HD) of an inactivated vaccine at an interval of either 14 days or 28 days. Neutralizing antibody (NAb) and anti-S and anti-N antibodies were detected at different times, and adverse reactions were monitored for 28 days after full immunization. The seroconversion rates of NAb in MD and HD groups were 89% and 96% at day 14 and 92% and 96% at day 28 after immunization. Of note, the vaccine was safe (still an issue with inactivated vaccines), and no severe adverse effects were reported.
Kahn JP, Henry LM, Mastroianni C, et al. Opinion: For now, it’s unethical to use human challenge studies for SARS-CoV-2 vaccine development. PNAS October 29, 2020. Full-text: https://doi.org/10.1073/pnas.2021189117
Important comment: see title. According to the authors, human challenge studies (HCS) to address SARS-CoV-2 face unacceptable ethics challenges, and, further, undertaking them would do a disservice to the public by undermining already strained confidence in the vaccine development process. Ultimately, the social value of these HCS (in terms of deaths averted) hinges on the premise that people at greatest risk of COVID-19-related mortality will receive a safe and efficacious vaccine sooner than they would without HCS. Read why this will be probably not the case and why HCS would do more harm than good.
Kirby T. COVID-19 human challenge studies in the UK. Lancet October 30, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30518-X
Some thoughts about feasibility and ethics of human challenge trials that could potentially accelerate the development of vaccines. The first study phase, which could begin in January 2021, aims to discover the smallest amount of virus it takes to cause the infection in up to 90 healthy young people, aged between 18 and 30 years. The study will probably take place in the high-level isolation unit of the Royal Free Hospital, London, UK. Some commentators have questioned both the timing and the ethical dilemmas presented by the study.
Schwartz JL. Evaluating and Deploying Covid-19 Vaccines — The Importance of Transparency, Scientific Integrity, and Public Trust. N Engl J Med 2020; 383:1703-1705. Full-text: https://doi.org/10.1056/NEJMp2026393
The situation in the US is dire, public confidence in vaccination is fragile. Jason Schwartz insists that COVID-19 vaccination programs will succeed only if there is widespread belief that available vaccines are safe and effective and that policies for prioritizing their distribution are equitable and evidence-based. He clearly sees that trust in science and expertise are threatened, as the pandemic has shown with catastrophic results. Listen also to the audio interview (12:02).
Marc Lipsitch and Natalie Dean publish the shortest abstract in months: “Vaccine efficacy in high-risk groups and reduced viral shedding are important for protection.” Explore strategic prioritization plans.
Hodgson SH, Mansatta K, Mallett G, Harris V, Emary KWR, Pollard AJ. What defines an efficacious COVID-19 vaccine? A review of the challenges assessing the clinical efficacy of vaccines against SARS-CoV-2. Lancet Infect Dis 2020, published 27 October. Full-text: https://doi.org/10.1016/S1473-3099(20)30773-8
A vaccine against SARS-CoV-2 might act against infection, disease, or transmission and a vaccine capable of reducing any of these elements could contribute to disease control. However, the most important efficacy endpoint, protection against severe disease and death, is difficult to assess in Phase III clinical trials. In this review, Susanne Hodgson and colleagues explore the challenges in assessing the efficacy of candidate SARS-CoV-2 vaccines, discuss the caveats needed to interpret reported efficacy endpoints, and provide insight into answering the seemingly simple question, “Does this COVID-19 vaccine work?” Remember: the fundamental understanding of the pathogen is still evolving.
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.
Hensel J, McAndrews KM, McGrail DJ, et al. Protection against SARS-CoV-2 by BCG vaccination is not supported by epidemiological analyses. Sci Rep 10, 18377 (2020). Full-text: https://doi.org/10.1038/s41598-020-75491-x
Preliminary epidemiological analyses suggested that BCG vaccination might be associated with reduced COVID-19 cases and mortality. Might the BCG vaccine provide protection against infection with SARS CoV-2? (Seventeen clinical trials are currently registered to investigate the potential benefits of BCG vaccinations on exposure to CoV-2.) Now, Raghu Kalluri, Janine Hensel and colleagues challenge this assumption. After correction for confounding variables, most notably testing rates, they found no association between BCG vaccination policy and COVD-19 spread rate or percent mortality.
Mehrotra DV, Janes HE, Fleming TR, et al. Clinical Endpoints for Evaluating Efficacy in COVID-19 Vaccine Trials. Ann Int Med October 21, 2020. Full-text: https://doi.org/10.7326/M20-6169
Guidance from the FDA recommends minimal Phase III success criteria for approval of a vaccine: an estimated reduction in the primary endpoint of at least 50% in the vaccine group versus the placebo group, with the 95% CI providing assurance of at least a 30% reduction. The FDA guidance also indicates that acceptable primary endpoints for approval could include SARS-CoV-2 infection, symptomatic infection, severe COVID-19, or some combination of these. Biostatistician Devan V. Mehrotra and colleagues emphasize the need to facilitate harmonized evaluation and comparison of the efficacy of these vaccines. They propose a standard set of clinical endpoints to support pooling data for analyses of immunologic surrogate endpoints.
Bell BP, Romero JR, Lee GM. Scientific and Ethical Principles Underlying Recommendations from the Advisory Committee on Immunization Practices for COVID-19 Vaccination Implementation. JAMA. 2020 Oct 22. PubMed: https://pubmed.gov/33090194. Full-text: https://doi.org/10.1001/jama.2020.20847
Discover how the US wants to distribute a vaccine. This viewpoint discusses possible prioritization scenarios. “Phase Ia” includes health care personnel who have the potential for direct or indirect exposure to patients or infectious materials. This group comprises an estimated 20 million (!) people. We will later come back to Phase Ib (and the rest) maybe in 2022.
Kreps S, Prasad S, Brownstein JS. Factors Associated With US Adults’ Likelihood of Accepting COVID-19 Vaccination. JAMA Netw Open. 2020;3(10):e2025594. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.25594
But who will accept such a vaccine (see previous paper). And when? Sarah Kreps and colleagues asked 1971 US adults, analyzing factors associated with willingness and individual preferences. Some interesting findings: The marginal mean willingness to receive a vaccine was lowest when the vaccine was recommended by President Trump. Willingness was slightly (but not significantly) higher with former Vice President Biden and significantly higher given a CDC or WHO endorsement. Respondents who indicated Democratic political partisanship were significantly more likely to report willingness than those who indicated Republican political partisanship. A vaccine originating in China was associated with a 10% lower willingness.
Bangaru S, Ozorowski G, Turner HL, et al. Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate. Science 2020, published 20 October. Full-text: https://doi.org/10.1126/science.abe1502
Andrew Ward, Sandhya Bangaru and colleagues describe the structure of a leading SARS-CoV-2 S vaccine candidate (NVAX-CoV2373, under development by Novavax Inc. and Novavax AB, Uppsala) based on a full-length S, residues 1-1273 which includes the transmembrane (TM) and the cytoplasmic tail (CT). The authors found that NVAX-CoV2372 is stable, homogeneous, and locked in the antigenically preferred pre-fusion conformation. After structural, biophysical, and antigenic characterization, the candidate vaccine will not face the true proof-of-principle: evaluation in humans.
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
Krause PR, Grubner MF. Emergency Use Authorization of Covid Vaccines — Safety and Efficacy Follow-up Considerations. N Engl J Med 2020, published 16 October. Full-text: https://doi.org/10.1056/NEJMp2031373
There should be no emergency use authorization (EUA) of any COVID-19 vaccine without a median follow-up duration of at least 2 months after completion of the full phase 3 vaccination regimen. Normally, the FDA requires at least 6 months of safety follow-up for serious and other medically attended adverse events in a sufficient number of vaccinees. Philip Krause and Marion Gruber warn that any curtailment of this minimum follow-up could destroy the scientific credibility for future vaccines in the United States. Also see FDA’s Vaccines and Related Biological Products Committee Open Hearing, 22 Oct 2020, https://www.youtube.com/watch?v=1XTiL9rUpkg&feature=youtu.be.
Kurup D, Wirblich C, Ramage H, et al. Rabies virus-based COVID-19 vaccine CORAVAX™ induces high levels of neutralizing antibodies against SARS-CoV-2. npj Vaccines 5, 98 (2020). Full-text: https://doi.org/10.1038/s41541-020-00248-6
The authors show the rapid development of a novel, efficient, and safe COVID-19 vaccine using a rabies virus-based vector. Both a live and an inactivated rabies virus containing the SARS-CoV-2 spike S1 protein induces potent virus-neutralizing antibodies at much higher levels than seen in the sera of convalescent patients.
Walsh EE, Frenck RW, Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med 2020, published 15 October. Full-text: https://www.nejm.org/doi/full/10.1056/NEJMoa2027906?query=featured_home
Safety and immunogenicity data from a phase 1 trial of RNA-based Pfizer/BioNTech vaccines. In both younger (18 to 55 years of age) and older adults (65 to 85 years of age), the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers, comparable or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. The data presented here by Judith Absalon, Edward Walsh and colleagues include those that guided the companies’ decision to advance BNT162b2 at the 30-μg dose level to the phase 2–3, international trial to evaluate its safety and efficacy in participants 18 to 85 years of age.
Dong Y, Dai T, Wei Y, et al. A systematic review of SARS-CoV-2 vaccine candidates. Sig Transduct Target Ther 5, 237 (2020). Full-text: https://doi.org/10.1038/s41392-020-00352-y
The 11-page review for your next weekend. The authors provide an overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials, and highlight certain potential safety issues that require consideration when developing vaccines. Learn more about antigen design, important and unimportant epitopes, structure design, suitable delivery system and adjuvants.
McAuley AJ, Kuiper MJ, Durr PA, et al. Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein. npj Vaccines 5, 96 (2020). https://doi.org/10.1038/s41541-020-00246-8
The D614G mutation of the SARS-CoV-2 spike protein has been speculated to adversely affect the efficacy of vaccines. In this article, S. Vasan, Alexander McAuley and colleagues claim that there is no experimental evidence to support this speculation. They performed virus neutralization assays using sera from ferrets that received two doses of the INO-4800 COVID-19 vaccine, and Australian virus isolates (VIC01, SA01 and VIC31) which either possess or lack this mutation.
Helfland BK, Webb M, Gartaganis SL, et al. The Exclusion of Older Persons From Vaccine and Treatment Trials for Coronavirus Disease 2019—Missing the Target. JAMA Intern Med, September 28, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.5084
Those most in need are excluded: in this important review, Benjamin Helfland and colleagues analyzed clinical COVID-19 trials for age exclusions. In 232 Phase 3 clinical trials, 38 included age cut-offs and 77 had exclusions preferentially affecting older adults. Of 18 vaccine trials, 11 included age cut-offs, and the remaining 7 had broad non-specified exclusions. These findings indicate that older adults are likely to be excluded from more than 50% of COVID-19 clinical trials and 100% of vaccine trials. Why? Such exclusion will limit the ability to evaluate the efficacy, dosage, and adverse effects of the intended treatments.
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.
Cookson C. UK to test vaccines on volunteers deliberately infected with Covid-19. Financial Times 2020, published 23 September. Full-text: https://www.ft.com/content/b782f666-6847-4487-986c-56d3f5e46c0b
In the world’s first COVID-19 ‘human challenge trials’ healthy volunteers will be deliberately infected with SARS-CoV-2 to assess the effectiveness of experimental vaccines. See also the CR Top 10, June 4: Jamrozik E, Selgelid MJ. COVID-19 human challenge studies: ethical issues. Lancet Infect Dis. 2020 May 29:S1473-3099(20)30438-2. PubMed: https://pubmed.gov/32479747. Full-text: https://doi.org/10.1016/S1473-3099(20)30438-2
Human challenge studies could accelerate vaccine development, helping to test multiple candidate vaccines. This personal view on ethical issues explains why this will be difficult. The authors argue that human challenge studies can “reasonably be considered ethically acceptable insofar as such studies are accepted internationally and by the communities in which they are done, can realistically be expected to accelerate or improve vaccine development, have considerable potential to directly benefit participants, are designed to limit and minimise risks to participants, and are done with strict infection control measures to limit and reduce third-party risks.”
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).
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?
mRNA vaccines like BNT162b2 from BioNTech and Pfizer and mRNA-1273 by Moderna have ‘the potential to be truly transformative’ (Drew Weissman) but have never been tested in large-scale human trials. Now both vaccines have entered Phase 3 trials, which together will enroll an estimated 60,000 volunteers. Follow Jennifer Abbasi on a tour of ‘proof in the pudding’ and mRNA vaccines beyond COVID-19.
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.
Shah S, Patel J, Alchaki AR. Development of Transverse Myelitis after Vaccination. A CDC/FDA Vaccine Adverse Event Reporting System (VAERS) Study, 1985–2017. Neurology April 10, 2018; 90. Abstract: https://n.neurology.org/content/90/15_Supplement/P5.099
In the meantime, you may read this review of 119 cases of transverse myelitis (TM) occurring after vaccination, reported during a period of over 30 years to the FDA. Although the reporting rate of post-vaccination TM was in the range expected in the general population, the unbalanced distribution of these cases in the first 6 weeks after vaccination suggested that the association between vaccination and some cases may not be coincidental. (For antivaxxers: this is rare!)
Jeyanathan M, Afkhami S, Smaill F, et al. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol 2020, published 4 September. Full-text: https://doi.org/10.1038/s41577-020-00434-6
In this review, Zhou Xing, Mangalakumari Jeyanathan and colleagues describe the immunological principles of SARS-CoV-2 vaccine development and analyze the current vaccine candidates, their strengths and potential shortfalls. They also make inferences about their chances of success. A hazardous undertaking.
Tostanoski LH, Wegmann F, Martinot AJ, et al. Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters. Nat Med. 2020 Sep 3. PubMed: https://pubmed.gov/32884153. Full-text: https://doi.org/10.1038/s41591-020-1070-6
It’s not only protection from infection but also from severe disease. In hamsters, a single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against weight loss, pneumonia and mortality.
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, published 4 September. Full-text: https://doi.org/10.1016/S0140-6736(20)31866-3
It was high time to see some data on an “approved” vaccine. See also the comment by Naor Bar-Zeev and Tom Inglesby [Bar-Zeev N, Inglesby T. COVID-19 vaccines: early success and remaining challenges. Lancet 2020, published 4 September. Full-text: https://doi.org/10.1016/S0140-6736(20)31867-5].
Fisher KA, Bloomstone SJ, Walter J, et al. Attitudes Toward a Potential SARS-CoV-2 Vaccine: A Survey of U.S. Adults. Ann Intern Med 2020, published 4 September. Full-text: https://doi.org/10.7326/M20-3569
In a few months, when we have a vaccine, will people get vaccinated? In a study of 991 participants, Kimberly Fisher and colleagues found that 57.6% of (n = 571) intended to be vaccinated, 31.6% (n = 313) were not sure, and 10.8% (n = 107) did not intend to be vaccinated. Factors independently associated with vaccine hesitancy (a response of “no” or “not sure”) included younger age, Black race, lower educational attainment, and not having received the influenza vaccine in the prior year. The authors conclude that targeted and multipronged efforts will be needed to increase acceptance of a COVID-19 vaccine.
Keech C, Albert G, Cho I, et al. Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. NEJM September 2, 2020, Full-text: https://doi.org/10.1056/NEJMoa2026920
NVX-CoV2373 is a recombinant SARS-CoV-2 nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. In 83 participants younger than 60 years of age, two injections of NVX-CoV2373 delivered in the deltoid muscle on day 0 and 21 appeared to be safe. Immune responses exceeded levels in COVID-19 convalescent serum, showing high neutralizing antibody responses and T cells with a predominant Th1 phenotype. Phase 2 has started.
Giamarellos-Bourboulis EJ, Tsilika M, Moorlag S. ACTIVATE: randomized clinical trial of BCG vaccination against infection in the elderly. Cell 2020, published 31 August. Full-text: https://doi.org/10.1016/j.cell.2020.08.051
In this double-blind, randomized trial, 198 elderly patients received BCG or placebo vaccine at hospital discharge and were followed for 12 months. At interim analysis (78 patients allocated to placebo vaccination and 72 patients allocated to BCG vaccination), Evangelos Giamarellos-Bourboulis et al. found that BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% after placebo vaccination and 25.0% after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin. Any effect on SARS-CoV-2 infection? The number of individuals participating in the trial was too low to allow for any conclusions. Larger trials will provide the answer.
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?
Price WN 2nd, Rai AK, Minssen T. Knowledge transfer for large-scale vaccine manufacturing. Science. 2020 Aug 21;369(6506):912-914. PubMed: https://pubmed.gov/32792464. Full-text: https://doi.org/10.1126/science.abc9588
Identifying an effective SARS-CoV-2 vaccine and prove its safety in huge clinical trials is only the first step. The next step is not less challenging: manufacturing vaccines at enormous scale. In this Policy Forum, law school scholars Nicholson Price, Arti Rai and Timo Minssen explain that fast manufacturing will require not only physical capacity but also access to knowledge not contained in patents or in other public disclosures. Follow the authors on a path through the jungle of licenses, know-how transfer, hostage taking and manufacturing secrecy, and discover why large biopharmaceutical firms are now willing to share information that they might previously have viewed as providing competitive advantage.
Callaway E. The unequal scramble for coronavirus vaccines — by the numbers. Nature 2020, published 24 August. Full-text: https://www.nature.com/articles/d41586-020-02450-x
Will SARS-CoV-2 vaccines be only for the rich? Ellen Callaway shows how wealthy countries have struck deals to buy more than two billion doses of coronavirus vaccine. Find out that the UK is the world’s highest per-capita buyer, with 340 million purchased: around 5 doses for each citizen. And read more about COVAX, spearheaded by GAVI, a Geneva-based funder of vaccines for low-income countries, along with CEPI and the World Health Organization. It aims to secure 2 billion vaccine doses. One billion are for 92 low- and middle-income countries and economies (LMICS), which encompass half the world’s population.
Feng L, Wang Q, Shan C, et al. An adenovirus-vectored COVID-19 vaccine confers protection from SARS-COV-2 challenge in rhesus macaques. Nat Commun 11, 4207 (2020). Full-text: https://doi.org/10.1038/s41467-020-18077-5
Ling Chen, Liqiang Feng and colleagues report the generation of a replication-incompetent recombinant serotype 5 adenovirus, Ad5-S-nb2, which elicited systemic S-specific antibody and cell-mediated immune (CMI) responses in mice and rhesus macaques both after intramuscular injection and intranasal inoculation. At 30 days after a single vaccination with Ad5-S-nb2, macaques were protected against SARS-CoV-2 challenge.
Hassan AP, Kafai NM, Dmitriev IP. A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2. Cell August 19, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.08.026
In their animal experiments on mice expressing the ACE receptor, Ahmed Hassan and colleagues from St. Louis, US show the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized Spike protein. Of note, intramuscular dosing induced robust systemic humoral and cell-mediated immune responses but did not confer sterilizing immunity. In contrast, a single intranasal dose induced high levels of neutralizing antibodies, promoted systemic and mucosal IgA and T cell responses, and virtually completely prevented SARS-CoV-2 infection in both the upper and lower respiratory tracts.
Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA. 2020 Aug 13:e2015543. PubMed: https://pubmed.gov/32789505. Full-text: https://doi.org/10.1001/jama.2020.15543
An Pan, Xiaoming Yang and colleagues provide the first interim safety, tolerability, and immune response results for a β-propiolactone–inactivated whole-virus vaccine adjuvanted in 0.5 mg of aluminum hydroxide. The incidence rate of adverse reactions in the current study (15.0% among all participants) was not significantly different between the vaccine groups and the active control (alum) groups; it was also lower compared with results of other SARS-CoV-2 candidate vaccines. The neutralizing antibody response suggested that the inactivated vaccine may effectively induce antibody production, but the optimal interval between injections and times of booster injections of the inactivated vaccine remains unclear. In the discussion, find more about ADE and VAERD. See also the comment by Mark Mulligan: An Inactivated Virus Candidate Vaccine to Prevent COVID-19. JAMA. 2020 Aug 13. PubMed: https://pubmed.gov/32789500. Full-text: https://doi.org/10.1001/jama.2020.15539
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.
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:
- Antigen selection and engineering
- Pre-clinical challenge studies in non-human primate models
- Immune correlates of protection
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 (see Corbett et al., Top 10 July 29). Read also the last paragraph of this week’s paper where Corbett et al. describe a new paradigm for rapid vaccine development.
See also a Nat Biomed Eng editorial: Fast-and-fit vaccines. Published 10 August 2020. Full-text: https://doi.org/10.1038/s41551-020-00605-9
Gu H, Chen Q, Yang G, et al. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science 2020 Jul 30:eabc4730. PubMed: https://pubmed.gov/32732280. Full-text: https://doi.org/10.1126/science.abc4730
First, adapt a clinical isolate of SARS-CoV-2 by serial passaging in the respiratory tract of aged BALB/c mice. When the mouse-adapted strain shows increased infectivity in mouse lung after 6 passages, leading to interstitial pneumonia and inflammatory responses following intranasal inoculation, sequence the virus genome and look for adaptive mutations which might be associated with the increased virulence. That’s what Yusen Zhou, Cheng-Feng Qin, Shihui Sun, Shibo Jiang and colleagues did. They found an N501Y mutation located at the receptor binding domain (RBD) of the spike protein. They also showed the protective efficacy of a recombinant RBD vaccine candidate. They conclude that this MASCp6 could be of value in evaluating vaccines and antivirals against SARS-CoV-2.
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 (see the July 20 Top 10) 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.
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.
Yang J, Wang W, Chen Z et al. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 2020, published 29 July. Full-text: https://doi.org/10.1038/s41586-020-2599-8
The authors show that a recombinant vaccine comprising residues 319-545 of the Spike protein receptor-binding domain (S-RBD) can induce a potent functional antibody response in mice, rabbits and non-human primates as early as 7 or 14 days after a single dose injection. Antibodies shared common binding epitopes from infected patients, neutralizing activity was strong, and a simple adjuvant like Alum could further enhance the immune response. Even one dose of the vaccine generated viral neutralizing activity. The vaccine protected non-human primates from live SARS-CoV-2 challenge 28 days after the first vaccination.
Rubin EJ, Baden LR, Morrissey S. New SARS-CoV-2 Vaccine Results. N Engl J Med 2020; 383:e57. Access: https://www.nejm.org/doi/full/10.1056/NEJMe2026514
Audio interview (19:56) with Peter Piot who talks about his own experience with COVID-19, as well as recent developments in SARS-CoV-2 vaccines.
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.
Liu G, Carter B, Bricken T, Jain S, Viard M, Carrington M, Gifford DK. Computationally Optimized SARS-CoV-2 MHC Class I and II Vaccine Formulations Predicted to Target Human Haplotype Distributions. Cell Systems 2020, published 27 July. Full-text: https://www.cell.com/cell-systems/fulltext/S2405-4712(20)30238-6
Do you want to optimize peptide vaccine formulations for SARS-CoV-2? David K. Gifford and colleagues from MIT now give you a combinatorial machine learning method. They also encourage the early publication of vaccine designs to enable collaboration and rapid progress toward safe and effective vaccines for COVID-19. Consequently, they provide an open-source implementation of their design methods (OptiVax), vaccine evaluation tool (EvalVax), as well as the data used in their design efforts: https://github.com/gifford-lab/optivax.
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. See also the ChAdOx1 Phase 1/2 randomized trial of a chimpanzee adenovirus-vector vaccine (nCoV-19) published a week ago: https://covidreference.com/top-10-july-20.
Martin C, Lowery D. mRNA vaccines: intellectual property landscape. Nat Rev Drug Discov 2020, 27 July. Full-text: https://www.nature.com/articles/d41573-020-00119-8
Cecilia Martin and Drew Lowery generate an intellectual property landscape surrounding mRNA vaccine development. Overall filing activity aims at protecting methods to improve mRNA delivery efficiency as well as pharmacological modifications to reduce mRNA instability and innate immunogenicity. Moderna, CureVac, BioNTech and GSK own nearly half of the mRNA vaccine patent applications.
Zhang NN, Li XF, Deng YQ. A thermostable mRNA vaccine against COVID-19. Cell 2020, ublished: July 23. Abstract: https://www.cell.com/cell/fulltext/S0092-8674(20)30932-6. Full-text: https://doi.org/10.1016/j.cell.2020.07.024
The authors describe the development of an LNP-encapsulated mRNA vaccine (termed “ARCoV”) which targets the RBD of SARS-CoV-2. The vaccine induces neutralizing antibodies and T cell immunity in mice and non-human primates. Two doses of ARCoV immunization in mice conferred complete protection against the challenge of a SARS-CoV-2 mouse adapted strain. Phase 1.
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.
Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet, 20 July 2020. Full-text: https://www.thelancet.com/lancet/article/s0140-6736(20)31605-6
Wei Chen and colleagues report results from a randomized Phase 2 trial of an Ad5-vector COVID-19 vaccine from a single center in Wuhan. More than 90% of participants had T cell responses, seroconversion of binding antibody occurred in more than 96%, and neutralizing antibodies were seen in about 85%. The authors found that compared with the younger population, older people had a significantly lower immune response, but higher tolerability, to the Ad5-vector COVID-19 vaccine. In a Phase 2b trial, an additional dose might therefore be needed to induce a better immune response in the older population. Adverse events such as fever, fatigue, headache, or local site pain were comparable to the ChAdOx1 study above.
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?
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.
Arnold C. How computational immunology changed the face of COVID-19 vaccine development. Nat Med. 2020 Jul 15. PubMed: https://pubmed.gov/32669667. Full-text: https://doi.org/10.1038/d41591-020-00027-9
After more than two decades of work, computational immunology now enables the development of a candidate vaccine in just a few hours. However, no in silico analysis, no matter how high-quality the input and how exacting the computational algorithms, will ever be a substitute for experimental data.
Mathew D, Giles JR, Baxter AE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 2020 Jul 15. PubMed: https://pubmed.gov/32669297. Full-text: https://doi.org/10.1126/science.abc8511
Patients differ: Analysing 125 COVID-19 patients, the authors identified three “immunotypes” associated with poorer clinical trajectories versus improving health. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching > 30% of circulating B cells. However, another subgroup had lymphocyte activation comparable to uninfected subjects. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. This study provides a compendium of immune response data and also an integrated framework as a “map” for connecting immune features to disease. By localizing patients on an immune topology map built on this dataset, we can begin to infer which types of therapeutic interventions may be most useful in specific patients.
Le Bert N, Tan AT, Kunasegaran K, et al. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature. 2020 Jul 15. PubMed: https://pubmed.gov/32668444. Full-text: https://doi.org/10.1038/s41586-020-2550-z
Is there a natural immunity? In this study, T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 were analyzed in 36 COVID-19 convalescents. In all of them, CD4 and CD8 T cells recognizing multiple regions of the NP protein were found. Surprisingly, the authors also frequently detected SARS-CoV-2 specific T cells in 37 individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients. These T cells exhibited a different pattern of immunodominance, frequently targeting the ORF-1-coded proteins NSP7 and 13 as well as the NP structural protein. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to “common cold” human coronaviruses but conserved amongst animal betacoronaviruses. Thus, infection with betacoronaviruses induces multispecific and long-lasting T cell immunity to the structural protein NP.
Deming ME, Michael NL, Robb M, et al. Accelerating Development of SARS-CoV-2 Vaccines — The Role for Controlled Human Infection Models. NEJM July 1, 2020. Full-text: https://doi.org/10.1056/NEJMp2020076. Full-text: https://www.nejm.org/doi/full/10.1056/NEJMp2020076
The authors review practical considerations relevant to the development of a SARS-CoV-2 controlled human infection models (CHIMs) and the prerequisites for using such a model. Large, randomized, controlled trials of SARS-CoV-2 vaccines are still the most efficient, generalizable, and scientifically robust path to establishing vaccine efficacy. However, SARS-CoV-2 CHIM development might be able to accelerate the development of later rounds of vaccine candidates.
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.
Fuller DH, Berglund P. Amplifying RNA Vaccine Development. NEJM, June 18, 2020. N Engl J Med 2020; 382:2469-2471. Full-text: https://doi.org/10.1056/NEJMcibr2009737
Recent interest in messenger RNA (mRNA) vaccines has been fueled by methods that increase mRNA stability and protein production and improve delivery. The mRNA vaccines do not need to enter the nucleus to express the antigen. Avoidance of the risk of integration into the host genome is thus considered a comparative advantage. The authors describe new techniques in this field. The most promising seems to be a strategy that is based on two RNA vectors — one retaining the replicase-encoding gene and the other encoding the antigen.
Huo J, Zhao Y, Ren J, et al. Neutralisation of SARS-CoV-2 by destruction of the prefusion Spike. Cell Host Microbe June 19, 2020. Full-text: https://doi.org/10.1016/j.chom.2020.06.010
The monoclonal antibody CR3022 tightly binds the receptor binding domain (RBD) and neutralizes SARS-CoV-2. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. The mechanism of neutralisation is new and was not seen before for coronaviruses, suggesting that the CR3022 epitope should be a major target for therapeutic antibodies.
Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020 Jun 13;395(10240):1845-1854. PubMed: https://pubmed.gov/32450106. Full-text: https://doi.org/10.1016/S0140-6736(20)31208-3 l (Important)
Open-label Phase I trial of an Ad5 vectored COVID-19 vaccine, using the full-length spike glycoprotein. A total of 108 healthy adults aged between 18 and 60 years from Wuhan, China, were given three different doses. ELISA antibodies and neutralising antibodies increased significantly and peaked 28 days post-vaccination. Specific T cell response peaked at day 14 post-vaccination. Follow-up is still short and the authors are going to follow up the vaccine recipients for at least 6 months, so more data will be obtained. Of note, adverse events were relatively frequent, encompassing pain at injection sites (54%), fever (46%), fatigue (44%) and headache (39%). Phase II studies are underway.
Callaway E. Hundreds of people volunteer to be infected with coronavirus. Nature 22 April 2020. Full-text: https://www.nature.com/articles/d41586-020-01179-x
What about a ‘human challenge’ vaccine study? Such a trial would be much faster: a much smaller group of young, healthy volunteers would receive a candidate vaccine and then be intentionally infected with the virus, to judge the efficacy of the immunization. No trial is yet planned, but the debate is on. The approach is also gaining some political support.
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!
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.