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Researchers at the University of North Carolina and the Fred Hutchinson Cancer Research Center in Washington have developed a way to evaluate vaccines' long-term efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19). The team conducted a series of simulation studies mimicking the trial of the Pfizer/BioNTech vaccine BNT162b2 to investigate the duration of protection under various blinded and unblinded crossover designs. Dan-Yu Lin and colleagues recommend the "rolling crossover" design, where participants that were previously placebo recipients are vaccinated in a timely manner. Under this design, the team's approach can be used to determine when a booster vaccination would be required. This information is also useful for modeling the impact of COVID-19 vaccines at the population level. The approach only requires minimal assumptions and can be applied to both blinded and unblinded crossover designs, irrespective of the length of further follow-up. A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.
Interim trial results only provide data on short-term efficacy
The large-scale administration of vaccines that provide long-term protection against SARS-CoV-2 infection would help bring the COVID-19 pandemic to a halt. Interim results from a number of phase 3 clinical trials have demonstrated vaccine efficacy that far exceeds the thresholds required by the World Health Organization and US Food and Drug Administration. Given that vaccine efficacy can wane over time as immune memory declines and viral antigens change, it is crucial to establish how long protection lasts and when booster doses may be required, says the team.
How might long-term vaccine efficacy be estimated?
Once a vaccine receives Emergency Use Authorization (EUA), placebo-controlled data is still collected in ongoing trials for as long as possible, but at some point, all placebo recipients should be offered the vaccine. Under one approach called "rolling crossover," placebo participants are vaccinated at around the same time that general population members of the same priority tier are vaccinated. The researchers have now shown how to estimate long-term vaccine efficacy in trials that apply this staggered vaccination under both blinded and unblinded crossover strategies. The method fully adjusts for staggered enrollment, change of background incidence over time, and the prioritization of higher-risk individuals during the crossover process.
How effective is the approach?
The approach provides an unbiased estimation for the entire curve of placebo-controlled vaccine efficacy as a function of time passed since vaccination, up to the point where most placebo recipients have been vaccinated. In a series of simulation studies of the BNT162b2 vaccine trial, the researchers considered 40,000 participants who had been randomly assigned to vaccine or placebo over the course of 4 months. Following approval of the vaccine during the 5th month based on interim results, participants underwent staggered vaccination over the following 5 months. The outcome of interest was time to development of symptomatic COVID-19. The estimated curve of time-varying vaccine efficacy could be used to determine when a booster vaccination would be required to ensure sustained protection. This information is also important for mathematical modeling of the impact COVID-19 vaccines have at the population level.....
Cites research available in medRxiv (Jan.21, 2021):
