Lessons from a large-scale COVID-19 vaccine trial

Abstract

Global vaccination coverage remains indispensable in combatting the ongoing SARS-CoV-2 pandemic. Safety, efficacy, and durability of immune protection are the key parameters of randomized controlled trials (RCTs) and are essential for vaccine approvals, global distribution, and comprehensive population-vaccination programs. Immune protection from either vaccination or natural infection decreases over time, further challenged by rapid viral evolution. In this issue of the JCI, Sobieszczyk and colleagues report an update on the safety, efficacy, and durability of immune protection of AZD12222 in a large-scale, multinational, Phase III RCT. They report that protection lasted through 6 months, with immunity waning after 180 days. The study also highlights challenges facing vaccine trials, including the need for early unblinding for vulnerable participants, which may affect outcome measurements. Another challenge is to ensure fair representation of marginalized and minority ethnic groups in vaccine safety and efficacy studies worldwide.

Figure 1. Lessons and questions from a large-scale COVID-19 vaccine trial.

(A) Immune imprinting and durability of protection. The immunogenic components in SARS-CoV-2 vaccines are derived from early (2019 to 2020) WT or Wuhan-like (Wu-like) viral isolates. Vaccine-stimulated immunity results in antibodies that neutralize infection by homologous or closely related viral strains (solid lines), but does not confer long-lasting protection. Immune imprinting from either vaccination or infection with early SARS-CoV-2 strains means that subsequent infections with newer SARS-CoV-2 variants stimulate existing memory cells specific for previously encountered SARS-CoV-2 variants, rather than recruiting additional immune cells better suited to the new variants. Therefore, the antibodies produced may not efficiently neutralize subsequent variants (dashed lines). Over time, protection and cross-protection are further diminished due to declining antibody levels. The Omicron variant and emerging lineages bear numerous immune escape mutations and are poorly neutralized by antisera specific for older SARS-CoV-2 strains. The durability and breadth of immune protection may be enhanced with booster dose vaccination and updated vaccines. (B) Trade-offs of placebo controls. Placebo control blinding and unblinding are a trade-off between the accuracy of RCTs’ primary and secondary outcome measures and ethical/social justice concerns.