Overview:

This document summarizes key aspects related to the assessment of vaccine efficacy in four US based and one UK based, published COVID-19 (C-19) Phase 3 efficacy trial protocols. They cover efficacy objectives, C-19 case definitions, efficacy endpoints, censoring of early C-19 cases, null hypothesis, statistical methods, number of C-19 cases required for the primary efficacy endpoint analysis, and assumed C-19 background attack rates justifying the estimated sample size.

One C-19 case definition is included in Novavax’ UK protocol, two are included in the US-based Moderna, Janssen, and BioNTech/Pfizer protocols, while the AstraZeneca/Oxford’s US protocol also includes a third case definition. Each protocol has a unique protocol-specific C-19 case definition; this constitutes the primary efficacy endpoint (i.e. C-19 irrespective of disease severity) in four of the protocols (Moderna, BioNTech/Pfizer, AstraZeneca/Oxford, Novavax), but is a secondary in the Janssen protocol; Janssen’s primary endpoint is moderate to severe/critical C-19 only. All four US-based protocols include the US-FDA harmonized case definition as secondary endpoint, which mirrors the CDC case definition and may be updated as new information is made available. They also include a secondary endpoint evaluating efficacy based on censoring of cases occurring prior to 14 days after the second dose to align endpoints across COVID-19 vaccine studies and allow for cross trial comparisons.

AstraZeneca/Oxford’s US protocol includes a third case definition (i.e. secondary efficacy endpoint) based on the University of Oxford-defined symptom criteria that mirrors the current UK Public Health England case definition. None of the protocols define moderate or severe C-19 according to the WHO definition. All the protocols define severe C-19 according to the US-FDA recommended definition.

Two of the protocols include a Burden of Disease (BoD) endpoint. BoD is included as an exploratory efficacy endpoint in the Moderna protocol where scores of 0, 1, 2, and 3 represent asymptomatic SARS-CoV-2, symptomatic C-19 without hospitalization, hospitalization, and death, respectively. The Janssen protocol includes BoD as a secondary efficacy endpoint where 0, 1, and 2 represent asymptomatic SARS-CoV-2, mild and moderate C-19, and severe C-19 respectively, similar to the BOD endpoint discussed in the Mehrothra publication1. A separate Summary Document on BoD² has been published by CEPI.

There is a lack of guidelines and global consensus on which symptoms should trigger C-19 diagnostic work up. This is reflected in the trial protocols as significantly different triggering symptoms are included and are generally reflective of the protocol-defined case definitions.