Improving the evidence base for COVID-19 vaccines

Abstract

The beginning of the COVID-19 pandemic marked an unprecedented time when safe and effective vaccines were developed, authorized, and approved for use within months of the initial identification of the novel coronavirus¹. These authorizations and approvals were based on large, placebo-controlled trials powered to characterize safety and efficacy against clinically significant infection — appropriate designs given the use of vaccine platforms, such as mRNA technology, and antigens, including the prefusion spike protein, that had not previously been studied at large scale in humans. These early studies were among the largest clinical trials in recent history, enrolling tens of thousands of participants and providing definitive evidence of the safety and efficacy of the SARS-CoV-2 vaccines.

Since then, the evolution of SARS-CoV-2 has prompted annual updates to COVID-19 vaccine composition to match the predominant circulating strain. Multiple national surveillance platforms provide data on the effectiveness of current vaccines to inform the need for updates⁵. As with other seasonal vaccines (for example, influenza), these updates are based on immunobridging studies that compare neutralizing antibody titers induced by vaccines with new variant inserts to those induced by approved vaccines⁶. Licensure by a regulatory body typically requires non-inferiority of the investigational vaccine versus the approved vaccine, meaning that the investigational vaccine is not clinically significantly worse than the approved vaccine (Fig. 1b). For seasonal vaccines, this is appropriate for several reasons. Annual vaccine updates require considerable lead time for production. For influenza, strain selection decisions are typically made 4–6 months in advance at a semiannual meeting convened by the World Health Organization, followed by a meeting of the US Food and Drug Administration’s Vaccine and Related Biologics Advisory Committee, which recommends strains to domestic vaccine manufacturers. To match the vaccine to circulating strains while also giving manufacturers sufficient time to produce the necessary doses for distribution, strain selection recommendations are made using immunobridging studies that show neutralization of new circulating variants. The timeline for COVID-19 vaccine updates might differ based on the evolution of the virus as well as use of mRNA technology, though it still requires lead time for production and distribution. Immunobridging is a well-established approach for seasonal vaccine strain selection and is standard practice in many countries.