++ Vaccines ++

3 December

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.


2 Dezember

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.


1 Dezember

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.


30 November

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.


29 November

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.


28 November

Editors. The COVID vaccine challenges that lie ahead. Nature. 2020 Nov;587(7835):522. PubMed: https://pubmed.gov/33235368. Full-text: https://doi.org/10.1038/d41586-020-03334-w

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.


27 November

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.


25 November

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.


24 November

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.


23 November

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.


22 November

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.


20 November

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.


19 November

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…


18 November

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.


17 November

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.


16 November

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.


12 November

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.


11 November

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.


10 November

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.


1 November

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.


31 October

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.


29 October

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).


Lipsitch M, Dean NE. Understanding COVID-19 vaccine efficacy. Science. 2020 Oct 21:eabe5938. PubMed: https://pubmed.gov/33087460. Full-text: https://doi.org/10.1126/science.abe5938

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.


28 October

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.


27 October

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

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


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.


24 October

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.


23 October

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.


21 October

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.


17 October

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.


15 October

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.


13 October

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.


8 October

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.


29 September

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.


28 September

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.


26 September

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.”


25 September

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?


10 September

Abbasi J. COVID-19 and mRNA Vaccines-First Large Test for a New Approach. JAMA. 2020 Sep 3. PubMed: https://pubmed.gov/32880613. Full-text: https://doi.org/10.1001/jama.2020.16866

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.


9 September

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!)


8 September

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.


6 September

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.


5 September

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.


3 September

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.


2 September

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.


27 August

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?


25 August

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.


23 August

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.


20 August

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.


15 August

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


12 August

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.


11 August

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

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

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


6 August

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


2 August

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.


30 July

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.


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

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


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.


29 July

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.


28 July

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.


27 July

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.


20 July

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?


16 July

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.


2 July

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.


1 July

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.


20 June

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.


24 May

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.


22 April

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.


11 April

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

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


31 March

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.


April 2020