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

The short version: Even though the vaccines for SARS-CoV-2/COVID-19 were made at an unbelievably fast rate, we have no basis to believe that there were corners cut from the perspective of the science or the efficacy. The cutting of the time in research and development is the result of two things: the existence of an extensive body of research that indicated which strategies for a vaccine and targets were viable and inviable (as well as considerations for which kinds of vaccines could be made rapidly, given the pandemic), financial limitations that are normally present for pharmaceutical research were not applicable, there was an enormous pool of willing subjects for the vaccines, and there was extensive streamlining of the regulatory process on the part of the FDA. If these vaccine candidates make it through EUA and then licensure, we should have every reason to believe that these are safe and effective vaccines and should not be worried about getting them.

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 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.
  2. 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).
  3. 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.
  4. 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
  • 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

I would like to credit and extend my sincerest gratitude to my dear friend, Andrea Bailey PhD, Senior Regulatory Affairs Specialist, for her thorough vetting of the content of this blog post for accuracy, and insightful suggestions for how to improve it. It would not have been possible without her.

References

  1. Bailey, Andrea, Written Correspondence, 11/27/20
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  19. Wind-Mozley, Magdalen Rose, Written Correspondence, 11/27/20

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)