The vaccines for SARS-CoV-2/COVID-19 weren’t rushed

The timeline of approval for some vaccines in routine use. Plotkin SA, Orenstein W, Offit DPA, Edwards KM. 2017. Plotkin’s Vaccines. 7th ed. Elsevier Table 4.3
  1. Phase 0, Pre-Clinical (and Exploratory) Work: Studying the pathogen in vitro and in animal models, identifying viable leads for antigens, considering choice of adjuvant, considering the type of vaccine that would be appropriate. Testing the vaccine in a relevant animal model. This typically involves challenging the animal model with a dose of the pathogen (typically something much higher than what would be encountered in nature) to evaluate efficacy. There is nothing going to humans at this point. It is also at the preclinical stage that toxicity and safety testing is done. There are two phases for this: pre-trial requirements and in-trial studies. Pre-trial studies examine the safety, immunogenicity, reactivity, and toxicity. Once clinical trials begin, population-specific studies can be conducted including fertility and embryofetal development.
  2. Phase I Clinical Trials: The manufacturer files an investigational new drug application (IND) with the regulatory body at this point (in the US, the FDA). These are the first time the vaccine gets put into humans. These studies typically have on the order of 10–100 healthy volunteers who are given the vaccine candidate. The phase exists mainly to figure out the pharmacokinetics and pharmacodynamics of the pharmaceutical. Doses get calibrated to balance the adverse effect profile with the therapeutic (or prophylactic) benefit, typically by progressive escalation to the limit of tolerability in the form of SAD (single ascending dose, where subjects receive one dose of a drug) and MAD trials (multiple ascending dose, where subjects receive multiple doses of the drug), usually with about 10 subjects per group. For a vaccine, samples may be taken from patients to evaluate immunogenicity. Placebos may or may not be used, but as efficacy is not being measured, tend to be less important. The point of this phase is to function as a preliminary safety evaluation. The principal question being answered is essentially “Is this vaccine acutely toxic to the vaccinee?” and we really hope the answer is “No.” This is also where considerations start emerging for a dosing schedule.
  3. Phase II Clinical Trials: Similar to Phase 1 trials, the primary goal here is to evaluate safety and immunogenicity again in a larger group, usually a few hundred people. They have largely the same goals as far as figuring out how to dose the vaccine and the schedule for it. If this seems somewhat redundant with phase I, that’s because it is (more on this shortly).
  4. Phase III Clinical Trials: After confirming that your vaccine is safe and stimulates an immune response, it’s time to see if it actually works. You recruit thousands of people (usually at least 30,000, but the trials for the polio vaccine had 2 million people before it was approved) and randomize them to receive placebo or vaccine. The placebo depends on the type of vaccine. For example, today we give MMR-II, which is a second-generation MMR vaccine. MMR-II was compared with the first generation vaccine as placebo. This is because of a fundamental principle in ethics: you cannot withhold the standard of care. If already an effective therapy (or prophylaxis) exists, you cannot give someone placebo. The safety profile of the first-generation vaccine is at that point well understood because it has made it through clinical licensure and has been subject to post-marketing surveillance. I only expound upon this point because some people have an obsession with vaccines being compared to “true placebo.” Additionally, an important aspect of this stage is blinding. Subjects in the trial might modify their behavior if they know they are in the vaccine group (for instance, being less careful about risky behaviors), which they might infer from their reactions (e.g. if they get a fever), so it’s very valuable to have a control that has a similar side effect profile so you can get accurate information on efficacy. If you want further information, here’s a great read on that. Even though the fundamental goal of Phase III is an efficacy evaluation, safety is still being considered at every step. Participants in the trial are expected to report their experiences back to the manufacturer and that goes to a data safety monitoring board (DSMB), an independent organization responsible for evaluating the data in the trial to judge safety and efficacy. If the vaccine manages to pass this stage (which happens ONLY if it meets its primary endpoint), the manufacturer can petition for licensure.
  5. Petitioning for licensure via BLA (Biologics License Application): At this point the manufacturer compiles all the data and sends it to the regulatory body (in the case of the US, the FDA) who evaluates it. If approved, the vaccine can be added to the national vaccination program. After FDA approval, in the US it is also considered by the Advisory Committee on Immunization Practices (ACIP), an independent body of 15 experts, and
  • Even though vaccinology is transitioning into a more rigorous science where scientists work to understand the interactions of the pathogen with its host in detail, this is still very hard to do. Sometimes the incorrect antigens are targeted. Sometimes the incorrect correlate of protection is selected for. I discuss
  • What works in a laboratory animal doesn’t always work the same way, or at all, in a human. Immune systems in particular (as compared to other body systems) are highly variable across species.
  • Sometimes when all the components of a vaccine are combined, unexpected things happen (but that’s why we put them through clinical trials as an entire vaccine rather than test every single component). This tends to be most relevant, however, for combination vaccines e.g. MMR, MMRV, DTaP, DTaP-IPV-Hib-Hep B.

Acknowledgements

References

  1. Bailey, Andrea, Written Correspondence, 11/27/20
  2. Center for Biologics Evaluation, Research. 2019. Vaccines and Related Biological Products Advisory Committee. Fda.gov. https://www.fda.gov/advisory-committees/blood-vaccines-and-other-biologics/vaccines-and-related-biological-products-advisory-committee.
  3. Center for Biologics Evaluation, Research. 2020. Vaccine Development — 101. Fda.gov. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101.
  4. Cohen J. 2020. The $1 billion bet: Pharma giant and U.S. government team up in all-out coronavirus vaccine push. Science. doi:10.1126/science.abc0056. https://www.sciencemag.org/news/2020/03/1-billion-bet-pharma-giant-and-us-government-team-all-out-coronavirus-vaccine-push.
  5. Development and Licensure of Vaccines to Prevent COVID-19 Guidance for Industry. Fda.gov. https://www.fda.gov/media/139638/download.
  6. Ellis R. PPI advisory group. Nihr.ac.uk. 2020 Nov 12. https://oxfordbrc.nihr.ac.uk/ppi/ppi-advisory-group/
  7. Fact sheet: Data safety monitoring boards. 2014 Feb 13. Avac.org. https://www.avac.org/data-safety-monitoring-boards.
  8. Griffin R, Armstrong D. 2020 Nov 9. Pfizer vaccine’s funding came from Berlin, not Washington. Bloomberg News. https://www.bloomberg.com.
  9. Hagai, T., Chen, X., Miragaia, R.J. et al. Gene expression variability across cells and species shapes innate immunity. Nature 563, 197–202 (2018). https://doi.org/10.1038/s41586-018-0657-2
  10. Jiang S, He Y, Liu S. 2005. SARS Vaccine Development. Emerg Infect Dis. 11(7):1016.
  11. O’Callaghan KP, Blatz AM, Offit PA. 2020. Developing a SARS-CoV-2 vaccine at warp speed. JAMA. 324(5):437–438.
  12. Pallesen J, Wang N, Corbett KS, Wrapp D, Kirchdoerfer RN, Turner HL, Cottrell CA, Becker MM, Wang L, Shi W, et al. 2017. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A. 114(35):E7348–E7357.
  13. Plotkin SA, Orenstein W, Offit DPA, Edwards KM. 2017. Plotkin’s Vaccines. 7th ed. Elsevier.
  14. Principles and considerations for adding a vaccine to a national immunization programme. Who.int. https://apps.who.int/iris/bitstream/handle/10665/111548/9789241506892_eng.pdf;jsessionid=E3B4D2C2110AA558F00D517543C10358?sequence=1.
  15. Sanofi and GSK initiate Phase 1/2 clinical trial of COVID-19 adjuvanted recombinant protein-based vaccine candidate. Sanofi.com. https://www.sanofi.com/en/media-room/press-releases/2020/2020-09-03-07-00-00.
  16. Singh K, Mehta S. 2016. The clinical development process for a novel preventive vaccine: An overview. J Postgrad Med. 62(1):4–11.
  17. Topol EJ. 2020 Oct 27. For COVID-19 vaccines, ACIP will be a critical gatekeeper. Medscape.com. https://www.medscape.com/viewarticle/938494.
  18. Vaccine Platforms: State of the Field and Looming Challenges. Centerforhealthsecurity.org. https://www.centerforhealthsecurity.org/our-work/pubs_archive/pubs-pdfs/2019/190423-OPP-platform-report.pdf.
  19. Wind-Mozley, Magdalen Rose, Written Correspondence, 11/27/20

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I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)

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Edward Nirenberg

Edward Nirenberg

I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)

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