Clinical Endpoints for Evaluating Efficacy in COVID-19 Vaccine Trials

Abstract

Several vaccine candidates to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) have entered or will soon enter large-scale, phase 3, placebo-controlled randomized clinical trials. To facilitate harmonized evaluation and comparison of the efficacy of these vaccines, a general set of clinical endpoints is proposed, along with considerations to guide the selection of the primary endpoints on the basis of clinical and statistical reasoning. The plausibility that vaccine protection against symptomatic COVID-19 could be accompanied by a shift toward more SARS-CoV-2 infections that are asymptomatic is highlighted, as well as the potential implications of such a shift.

Figure 1.. Clinical endpoint relationships, definitions, and example sampling scheme for diagnosed COVID-19 cases.

BOD = burden of disease; COVID-19 = coronavirus disease 2019; NAAT = nucleic acid amplification test; PCR = polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Top. Structural relationships among study endpoints in a COVID-19 vaccine efficacy trial. Middle. Study endpoint definitions. Bottom. Example schedule of disease severity monitoring and virologic sampling for COVID-19 cases, with data or sample collection beginning at COVID-19 diagnosis and extending past COVID-19 diagnosis, in a setting where frequent follow-up of confirmed cases can be assured. Participants diagnosed with virologically confirmed, symptomatic SARS-CoV-2 infection (COVID-19) enter a postdiagnosis sampling schedule to monitor viral load and COVID-19–related symptoms (types, severity levels, and durations). This follow-up continues through resolution of all symptoms, enabling distinction of the nonsevere and severe COVID-19 endpoints. * Seroconversion is assessed via a validated assay that distinguishes natural vs. vaccine-induced SARS-CoV-2 antibodies. † Alternatively, the asymptomatic infection endpoint can also include an RNA PCR positive test result obtained through testing regardless of symptoms (e.g., as a requirement for travel, return to school or work, or elective medical procedures) and follow-up to confirm that the participant remains asymptomatic. ‡ Timed to be as close to day 28 after symptom onset as possible.

Figure 2.. Hypothetical example of results of a COVID-19 vaccine efficacy trial with 2:1 (vaccine–placebo ratio) randomization, with the analysis done for 147 total COVID-19 cases.

BOD = burden of disease; COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. Top. Number of uninfected and infected participants in each group, along with breakdown by endpoint for infected trial participants. Bottom. Vaccine efficacy point estimates and 95% CIs against 6 clinical endpoints. The black, dashed vertical line in the forest plot marks the lower 95% confidence bound of 30% given in guidance from the U.S. Food and Drug Administration.