Issue 13: The Pace of COVID-19 Vaccine Development

Jul 08, 2020

By John P. Moore, PhD.

Professor of Microbiology and Immunology Weill Cornell Medicine New York


COVID-19 vaccine development must proceed at a pace that allows full safety and efficacy evaluations of each candidate.

Festina lente can be translated as “make haste slowly”. It seems an appropriate phrase when considering the uncertainties about the outcome of the US government’s Warp Speed COVID-19 vaccine program. 

Every vaccine supporter wishes to see this program end successfully as soon as possible. We all recognize that an effective vaccine is the best solution to the COVID-19 pandemic. But safety and efficacy are two indissoluble properties of a vaccine(s) for use by billions of people globally. Multiple editorials, perspectives, and reviews have discussed safety issues that could arise with COVID-19 vaccines, and have urged that the Warp Speed program proceeds at a pace that allows full safety evaluations of every candidate that moves into large scale human trials. Here, I reiterate some of these concerns.

The first Warp Speed candidates to enter human trials involve vaccine designs that could be rapidly produced in very large amounts (millions to billions of doses). Typically, existing constructs were repurposed to now use SARS-CoV-2 gene sequences. These first-generation vaccines include ones based on mRNA and non-replicating adenovirus vectors. DNA vaccines are also being developed, as they too can be designed and produced rapidly. The SARS-CoV-2 immunogen expressed by these vaccines is the spike protein (S-protein), the sole viral target for neutralizing antibodies (NAbs). Although some designs will induce cellular immunity at varying efficiencies, the emphasis has been on triggering NAb responses. The goal is to induce a NAb titer after one, or perhaps two, vaccine doses that can either protect against infection (sterilizing immunity), or reduce the severity of disease in any recipient who still becomes infected. 

One or more of these initial vaccines may succeed. SARS-CoV-2 has a well-recognized site of vulnerability on its S-protein, the receptor-binding domain (RBD). Antibodies to this site prevent the virus from attaching to its cell surface receptor (ACE2) and thereby neutralize its infectivity. The RBD, given either as a stand-alone protein or as part of the S-protein, is quite immunogenic, eliciting high NAb titers in animals after one or two immunizations carried out over a one- to three-week period. These are encouraging findings. 

For efficacy, the key question is whether the first-generation vaccines will elicit a NAb titer high enough to protect a substantial fraction of human recipients. The protective titer is presently unknown, cannot be inferred from COVID-19 patients, and can only be roughly estimated from animal challenge experiments. Vaccine potency, in general, is highly variable, with NAb titers spanning a range of well over 100-fold in human (and animal) cohorts. A vaccine is only useful if the protective threshold is exceeded in a substantial fraction of recipients. 

The longevity of vaccine-induced immunity is another important consideration; antibody responses to coronaviruses generally decay significantly over 6-12 months, and a rapid titer decline is now being seen in convalescent COVID-19 patients. Perhaps vaccines will trigger longer-lasting, protective immune memory responses, but this remains to be determined.

Extrapolation from other viruses and inspection of animal immunization data does, however, suggest that adenovirus, mRNA, and DNA vaccines are relatively poor at inducing NAbs compared to other vaccine designs, such as adjuvanted killed viruses or recombinant S-proteins or RBD-proteins. It is, therefore, possible that first-generation Warp Speed vaccines may not induce protective NAb titers. If so, the focus will shift to more immunogenic recombinant protein vaccines that take much longer to produce in bulk (there are no announced killed virus vaccine projects in the US, although China is investing heavily in this traditional technology).

Speed Cannot Trump Safety and Efficacy

There are, however, potentially worse consequences than just losing valuable time. While most vaccines are safe, some are not. It is unlikely that first-generation COVID-19 vaccines will cause problems in uninfected individuals. But we do not know what will happen when vaccinated people become infected. Animal studies on vaccines for SARS-CoV-1 (the original SARS), MERS-CoV, and other coronaviruses are replete with examples of exacerbated disease, including lung pathologies, post-infection. The mechanisms of these responses are not always well understood, but usually involve an intersection between the infecting virus and vaccine-induced antibodies that have poor or no neutralizing activity. 

Small-scale animal studies (notably in monkeys) have generally shown that the first-generation COVID-19 vaccines do not induce sterilizing immunity, but rather reduce the severity of the (already mild) disease without obvious indications of adverse events post-infection. While these observations are encouraging, they are not sufficient to preclude the possibility of problems in humans, particularly older people who are most in need of protection. 

There is an irrational antagonism towards vaccines nowadays, particularly in the US. If a COVID-19 vaccine(s) turned out to be unsafe, the inevitable publicity could seriously harm vaccine uptake in general, with catastrophic effects on the future health of our children. 

recent New York Times opinion piece argued strongly that the safety and efficacy of all COVID-19 vaccines must be proved before they are authorized for large-scale use. It urged the US Food and Drug Administration (FDA) to reject any political pressure for Emergency Use Approval, based solely on immunogenicity data, in the run-up to November’s election. In this context, statements the FDA Director made to Congress last week (6/30/20) were reassuring, as they were consistent with the above positions (although perhaps not absolutely definitive). 

Most scientists who advise the federal government are highly capable and respected. The vaccine advocacy community can support them by educating the public, directly and via the media, why the need for speed cannot trump the requirements for a vaccine to be both effective AND safe.


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