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New References (5th Edition)
The following pages add short comments to the papers published since the previous edition (June-October). The comments are from https://covidreference.com/daily-science.
If you have not read this article, read it next weekend: Krause P, Fleming TR, Longini I, Henao-Restrepo AM, Peto R; World Health Organization Solidarity Vaccines Trial Expert Group. COVID-19 vaccine trials should seek worthwhile efficacy. Lancet. 2020 Aug 27:S0140-6736(20)31821-3. PubMed: https://pubmed.gov/32861315. Full-text: https://doi.org/10.1016/S0140-6736(20)31821-3. 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.
SARS-CoV-2 Vaccine Candidates
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
Phase 3 vaccine candidates
ChAdOx1 (AstraZeneca)
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. 2020 Aug 15;396(10249):467-478. PubMed: https://pubmed.gov/32702298. Full-text: https://doi.org/10.1016/S0140-6736(20)31604-4
Andrew Pollard and colleagues report their Phase I/II 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.
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
ChAdOx1 vaccine (see also the July 20 Top 10) induced a balanced Th1/Th2 humoral and cellular immune response in rhesus macaques. 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.
BNT162b1 (Pfizer / BioNTech)
Mulligan MJ, Lyke KE, Kitchin N, et al. Phase 1/2 study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020 Aug 12. PubMed: https://pubmed.gov/32785213. 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 in 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.
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 III 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.
Sahin U, Muik A, Derhovanessian E, et al. Concurrent human antibody and TH1 type T-cell responses elicited by a COVID-19 RNA vaccine. medRxiv 2020, posted 20 July. Full-text: https://doi.org/10.1101/2020.07.17.20140533
The authors present antibody and T cell responses after BNT162b1 vaccination from a non-randomized open-label Phase I/II trial in healthy adults. BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those in a COVID-19 convalescent human serum panel. Most participants had Th1 skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon (IFN)γ was produced by a high fraction of RBD-specific CD8+ and CD4+ T cells.
Nat Biomed Eng (Editors). Fast-and-fit vaccines. Nat Biomed Eng 2020, published 10 August 2020. Full-text: https://doi.org/10.1038/s41551-020-00605-9
Two mRNA vaccine formulations against COVID-19, one developed by a collaboration between Pfizer and BioNTech, and the other by Moderna and the National Institute of Allergy and Infectious Diseases (NIAID) in the US (Nat Biomed Eng 2020), have the potential to be truly transformative; however, they have never been tested in large-scale human trials.
RNA-1273 (Moderna)
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 2020b, 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 Graham, Robert 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.
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.
CoronaVac© (Sinovac)
Gao Q, Bao L, Mao H, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020 Jul 3;369(6499):77-81. PubMed: https://pubmed.gov/32376603. Full-text: https://doi.org/10.1126/science.abc1932
The authors developed a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2–specific neutralizing antibodies in mice, rats, and non-human primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains.
CTII-nCoV (CanSino)
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. 2020 Aug 15;396(10249):479-488. PubMed: https://pubmed.gov/32702299. Full-text: https://doi.org/10.1016/S0140-6736(20)31605-6
Wei Chen and colleagues report results from a randomized Phase II 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 IIb trial, an additional dose might therefore be needed to induce a better immune response in an older population. Adverse events such as fever, fatigue, headache, or local site pain were comparable to the ChAdOx1 study above.
Sputnik V (Gamaleya)
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].
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?
Sinopharm Wuhan
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
NVX-CoV2373 (Novavax)
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 Sep 2. PubMed: https://pubmed.gov/32877576. 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 II has started.
Ad26.COV2.S (Janssen)
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.
The Future of SARS-CoV-2 vaccines
Questions
Bar-Zeev N, Moss WJ. Encouraging results from phase 1/2 COVID-19 vaccine trials. Lancet. 2020 Aug 15;396(10249):448-449. PubMed: https://pubmed.gov/32702300. Full-text: https://doi.org/10.1016/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 III 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?
Vaccine Approval
FDA 20200630. FDA News Release. Coronavirus (COVID-19) Update: FDA Takes Action to Help Facilitate Timely Development of Safe, Effective COVID-19 Vaccines. Published 30 June 2020. Full-text: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-action-help-facilitate-timely-development-safe-effective-covid
This press release announces guidance with recommendations for companies and researchers developing COVID-19 vaccines for the purpose of licensure. The guidance describes the agency’s current recommendations regarding the data needed to facilitate the manufacturing, clinical development, and approval of a COVID-19 vaccine. It also that the FDA would expect that a COVID-19 vaccine would prevent disease or decrease its severity in at least 50% of people who are vaccinated.
Setbacks
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!)
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.
Human Challenge Studies
Callaway E. Dozens to be deliberately infected with coronavirus in UK ‘human challenge’ trials. Nature 2020, published 20 October. Full-text: https://www.nature.com/articles/d41586-020-02821-4
Proponents of the trials say they can be run safely and help to identify effective vaccines, but others have questioned their value.
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.
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.”
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.
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.
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.
Preview
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.
Vaccine distribution
Kupferschmidt K. ‘Vaccine nationalism’ threatens global plan to distribute COVID-19 shots fairly. Science 2020, 28 July. Full-text: https://www.sciencemag.org/news/2020/07/vaccine-nationalism-threatens-global-plan-distribute-covid-19-shots-fairly
‘We will not sell it at cost.” (We will sell it for profit.) That was the statement, a few days ago, of a company that is receiving almost 1,000,000,000 dollars from US tax payers for developing a COVID-19 vaccine. Fortunately, other companies, too, are producing vaccines and good old WHO and other international organizations have set up a system to accelerate and equitably distribute vaccines, the COVID-19 Vaccines Global Access (COVAX) Facility. Kai Kupferschmidt summarizes the current state-of-affairs.
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 doses 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 doses of vaccines. One billion are for 92 low- and middle-income countries and economies (LMICS), which make up half the world’s population.
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).
Impact of vaccines on the pandemic
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.
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.
Immunization Fundamentals
Passive immunization against SARS-CoV-2
Convalescent plasma
Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939. PubMed: https://pubmed.gov/33093056. Full-text: https://doi.org/10.1136/bmj.m3939
Convalescent plasma (CP; giving neutralizing antibodies of people who made it through SARS-CoV-2 infection) has been one of the biggest hopes. This open label randomized controlled trial (RCT; the largest to date with results) investigated the effectiveness of CP in adults with moderate COVID-19 in 39 public and private hospitals across India. In total, 235 patients were assigned to two doses of 200 mL CP and 229 to standard of care only (control arm). Progression to severe disease or all-cause mortality at 28 days after enrolment occurred in 44 (19%) participants receiving CP and in 41 (18%) in the control arm. Moreover, CP treatment did not show anti-inflammatory properties and there was no difference between patients with or without neutralizing antibodies at baseline (who had produced their own antibodies or not). The main limitation: the authors did not measure the antibody titers in CP before transfusion because validated, reliable commercial tests were not available when the trial started. Let’s hope that low antibody titers were the reason for the lack of efficacy.
Pathak EB. Convalescent plasma is ineffective for covid-19. BMJ. 2020 Oct 22;371:m4072. PubMed: https://pubmed.gov/33093025. Full-text: https://doi.org/10.1136/bmj.m4072
A strong statement, after all (and some thoughts on how to deal with the bad results of the PLACID trial).
Monoclonal antibodies
Cohen J. Designer antibodies could battle COVID-19 before vaccines arrive. Science 2020, published 4 August. Full-text: https://www.sciencemag.org/news/2020/08/designer-antibodies-could-battle-covid-19-vaccines-arrive
Science writer Jon Cohen describes how the competition is heating up to produce targeted monoclonal antibodies which could both prevent and treat COVID-19. Read about treatment and prevention trials, antibody cocktails and the role monoclonal antibodies might play even after the general availability of effective vaccines. Read also about the final problem of monoclonal antibodies: their cost, especially for the higher doses needed for treatment. Don’t expect monoclonals to be affordable globally. Rather, they might split the world into the haves and have-nots, like many previous drugs. Another reason why accessible vaccines are so important!
Ledford H. Antibody therapies could be a bridge to a coronavirus vaccine — but will the world benefit? Nature 2020, published 11 August. Full-text: https://www.nature.com/articles/d41586-020-02360-y
Are monoclonal antibodies a bridging solution before the general availability of a vaccine? Heidi Lenford reminds us that monoclonals are complex and expensive to produce, leaving people from poor countries locked out.
Ledford H. The race to make COVID antibody therapies cheaper and more potent. Nature 2020, published 23 October. Full-text: https://www.nature.com/articles/d41586-020-02965-3
Injections of antibodies might prevent mild COVID-19 from becoming severe, but the treatments are expensive and difficult to make.
Hansen J, Baum A, Pascal KE, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science. 2020 Aug 21;369(6506):1010-1014. PubMed: https://pubmed.gov/32540901. Full-text: https://doi.org/10.1126/science.abd0827
Researchers from Regeneron generated a large panel of antibodies against the spike protein from humanized mice and from three recovered patients. From this panel, approximately 40 antibodies with distinct sequences and potent neutralization activities were chosen for additional characterization, including antibody pairs that do not compete for binding to the receptor binding domain (RBD). REGN10987 and REGN10933 represent such a pair of antibodies: REGN10933 binds at the top of the RBD, extensively overlapping the binding site for ACE2. The epitope for REGN10987 is located on the side of the RBD, away from the REGN10933 epitope, and has little to no overlap with the ACE2 binding site.
Baum A, Fulton BO, Wloga E, et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science. 2020 Aug 21;369(6506):1014-1018. PubMed: https://pubmed.gov/32540904. Full-text: https://doi.org/10.1126/science.abd0831
Proof of principle in a cell model, using vesicular stomatitis virus pseudoparticles expressing the SARS-CoV-2 spike protein. Simultaneous treatment with REGN10933 and REGN10987 precluded the appearance of escape mutants. Thus, this cocktail did not rapidly select for mutants, presumably because escape would require the unlikely occurrence of simultaneous viral mutation at two distinct genetic sites, so as to ablate binding and neutralization by both antibodies in the cocktail.
Baum A, Ajithdoss D, Copin R, et al. REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters. Science 2020b, published 9 October. Full-txt: https://doi.org/10.1126/science.abe2402
The authors evaluate REGN-COV2, a cocktail of two neutralizing antibodies (REGN10987+REGN10933) targeting non-overlapping epitopes on the SARS-CoV-2 spike protein, in rhesus macaques and golden hamsters. REGN-COV-2 can reduce virus load and decrease virus-induced pathological sequalae in rhesus macaques. In hamsters, the cocktail limited weight loss and evidence of pneumonia in the lungs. It is too early to predict the clinical usefulness of this cocktail in COVID-19 patients. It is currently being tested in clinical trials.
Hunting for antibodies to combat COVID‑19. Biopharma dealmakers 2020, published 1 September. Full-text: https://www.nature.com/articles/d43747-020-01115-y
The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities. Is there room for monoclonals for prevention or treatment of severe COVID-19 before the general availability of vaccines and efficient antiviral drugs? Find out how the ‘COVID-19 antibodysphere’ (Amgen, AstraZeneca, Vir, Regeneron, Lilly, Adagio) is building partnerships.
Active immunization against SARS-CoV-2
SARS-CoV-2 vaccine platforms
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
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 in the world.
Questions for the Future
Longevity of the immunological memory against SARS-CoV-2
Wajnberg A, Amanat F, Firpo A, et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science 2020, published 28 October. Full-text: https://doi.org/10.1126/science.abd7728
Assessing the antibody response to SARS-CoV-2 infection in mild and asymptomatic cases is of high importance since they constitute the majority of infections. Now, Ania Wajnberg, Florian Krammer, Carlos Cordon-Cardo and colleagues show that the vast majority of infected individuals with mild-to-moderate COVID-19 experience had robust IgG antibody responses against the viral spike protein. The authors from Icahn School of Medicine at Mount Sinai, New York, analyzed a dataset of 30,082 individuals. Titers were relatively stable for at least a period approximating 5 months. Anti-spike binding titers correlated with neutralization of authentic SARS-CoV-2. The data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses.
Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med 2020, published 1 September. Full-text: https://doi.org/10.1056/NEJMoa2026116
How long will people be protected from reinfection by SARS-CoV-2? Generally, many months, as may be expected from a coronavirus infection. In this study by Kari Stefansson, Daniel Gudbjartsson and colleagues, over 90% of 1215 qPCR-positive persons tested positive with two pan-Ig SARS-CoV-2 antibody assays and remained seropositive 120 days after diagnosis, with no decrease of antibody levels. Another piece of good news: the infection fatality risk in Iceland was 0.3%. Less good news: only 0.9% of Icelanders were infected with SARS-CoV-2 indicating that the Icelandic population is vulnerable to a second wave of infection.
See also the editorial by Galit Alter and Robert Seder: Alter G, Seder R: The Power of Antibody-Based Surveillance. N Engl J Med 2020, published 1 September. Full-text: https://doi.org/10.1056/NEJMe2028079. In particular, they stress the utility of antibody assays as highly cost-effective alternatives to PCR testing for population-level surveillance, which is critical to the safe reopening of cities and schools.
Ibarrondo FJ, Fulcher JA, Goodman-Meza D, et al. Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19. N Engl J Med. 2020 Sep 10;383(11):1085-1087. PubMed: https://pubmed.gov/32706954. Full-text: https://doi.org/10.1056/NEJMc2025179
Comments:
Bölke E, Matuschek C, Fischer JC. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl J Med. 2020 Oct 22;383(17):1694-1695. PubMed: https://pubmed.gov/32966710. Full-text: https://doi.org/10.1056/NEJMc2027051
Terpos E, Mentis A, Dimopoulos MA. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl J Med. 2020 Oct 22;383(17):1695. PubMed: https://pubmed.gov/32966711. Full-text: https://doi.org/10.1056/NEJMc2027051
Kutsuna S, Asai Y, Matsunaga A. Loss of Anti-SARS-CoV-2 Antibodies in Mild Covid-19. N Engl J Med. 2020 Oct 22;383(17):1695-1696. PubMed: https://pubmed.gov/32966712. Full-text: https://doi.org/10.1056/NEJMc2027051
The controversy about anti-SARS-CoV-2 antibody decay continues. Some groups found a marked decline while others obtained conflicting results that suggest stability over time.
Seow J, Graham C, Merrick B, et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat Microbiol (2020). Full-text: https://doi.org/10.1038/s41564-020-00813-8
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. But how long will antibody responses be maintained, and will they provide protection from reinfection? To answer these questions, Katie Doores, Jeffrey Seow and colleagues collected sequential serum samples up to 94 d post onset of symptoms from 65 individuals with SARS-CoV-2 infection. They show that the kinetics of the neutralizing antibody response to SARS-CoV-2 is typical of an acute viral infection where a peak response is detected 3–4 weeks post-infection, which then wanes. Their results suggest that for individuals who develop a low neutralizing antibody response (ID50 100–300), titers can return to baseline over a relatively short period, whereas those who develop a robust neutralizing antibody response maintain titers > 1,000 despite the initial decline. Should we already reconsider widespread serological testing and antibody protection against reinfection with SARS-CoV-2? The authors conclude that vaccine boosters might be required to provide long-lasting protection.
Pre-existing immune responses against SARS-CoV-2
Posten D, Weisblum Y, Wise H, et al. Absence of SARS-CoV-2 neutralizing activity in pre-pandemic sera from individuals with recent seasonal coronavirus infection. medRxiv 2020, published 11 October. Full-text: https://doi.org/10.1101/2020.10.08.20209650
Bad news from Rockefeller University. Paul Bieniasz, Daniel Poston and colleagues measured neutralizing activity against SARS-CoV-2 in pre-pandemic sera from patients with prior PCR-confirmed seasonal coronavirus infection. While neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable. The authors conclude that while it is possible that there are rare instances of individuals possessing antibodies from prior seasonal HCoV infection may be able to also target SARS-CoV-2 S, their data would argue against a broad role for pre-existing protective humoral immunity against SARS-CoV-2. These findings have not yet been peer reviewed.
Outlook
Vaccine Skepticism
Burki T. The online anti-vaccine movement in the age of COVID-19. Lancet Digit Health. 2020 Oct;2(10):e504-e505. PubMed: https://pubmed.gov/32984795. Full-text: https://doi.org/10.1016/S2589-7500(20)30227-2
About 31 million people follow anti-vaccine groups on Facebook, with 17 million people subscribing to similar accounts on YouTube. Within a decade, the anti-vaccination movement could overwhelm pro-vaccination voices online. If that came to pass, the consequences would stretch far beyond COVID-19. This article discusses some strategies.
Speed
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?
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.
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
The authors provide a paradigm for rapid vaccine development: a generalizable vaccine solution for Betacoronavirus and a commercial mRNA vaccine delivery platform; a vaccine development programme initiated on the basis of pathogen sequences alone; a proof of concept for the prototype-pathogen approach to pandemic preparedness and response that is predicated on identifying generalizable solutions for medical countermeasures within virus families or genera. The authors anticipate a huge potential for future vaccine research: “There are 24 other virus families that are known to infect humans, and sustained investigation of those potential threats will improve our readiness for future pandemics.”
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.
Comprenhensive vaccine testing
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 III 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.