Standardizing Clinical Endpoints for COVID-19 Vaccine Efficacy Trials

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To facilitate harmonized evaluation and comparison of the efficacy of COVID-19 vaccines, study authors proposed a general set of clinical endpoints, along with considerations to guide the selection of primary endpoints.

To facilitate a harmonized evaluation and comparison of vaccine trials, a general set of clinical endpoints for coronavirus disease 2019 (COVID-19) vaccine trials was proposed in the Annals of Internal Medicine.

Study authors proposed and defined 6 clinical endpoints for severe acute respiratory disease coronavirus 2 (SARS-CoV-2) to be used in COVID-19 vaccine trials:

  • SARS-CoV-2 infection: the first of either positive RNA polymerase chain reaction result or SARS-CoV-2 seroconversion
  • COVID-19 (symptomatic infection): cases meeting a protocol-specified list of symptoms with virologic confirmation of infection
  • Asymptomatic infection: SARS-CoV-2 seroconversion without prior diagnosis of the COVID-19 endpoint
  • Severe COVID-19: the COVID-19 endpoint with at least 1 protocol-specified severe disease event
  • Non-severe COVID-19: the COVID-19 endpoint with 0 protocol-specified severe disease events
  • Burden of disease (BOD): a composite endpoint score of 0 for no COVID-19, 1 for non-severe COVID-19, and 2 for severe COVID-19

According to the authors, while prevention of severe COVID-19 is an important and expected benefit of a vaccine, the broader encompassing endpoint of symptomatic COVID-19 disease is needed because severe cases are a relatively small proportion of cases overall and vary widely based on other factors. The statistical power to show adequate efficacy against severe cases may be lower than what is needed in non-severe cases.

The addition, the BOD endpoint can provide more information than the COVID-19 endpoint, as it defines severe disease as being worse than non-severe cases. A BOD endpoint also provides more statistical power in situations were a vaccine offers greater protection against severe disease. An asymptomatic endpoint was included because a vaccine decreasing the incidence of symptomatic infections may be accompanied by a shift toward asymptomatic infections, the authors noted.

Follow-up of at least a year after randomization was recommended by the authors for several reasons: allow greater sensitivity for the detection of vaccine effects on smaller proportions of severe cases, provide information on the duration of protection, and assist with planning immunization campaigns for vaccines that are safe and show efficacy against 1 or more clinical endpoints. This follow-up time will be needed to determine the potential for disease enhancement and assess for waning efficacy.

The authors stress the importance of adopting a standard set of clinical endpoints for evaluation efficacy across all trials as several candidates are entering phase 3 testing simultaneously. This will enable uniform, comprehensive assessments of benefits and risk, and support pooling of data for further analysis. Three of the endpoints proposed: COVID-19, severe COVID-19, and BOD can be based on sets of prescribed symptoms whose definitions could vary between trials.

“It is important to define a common COVID-19 endpoint that can be used consistently across trials, both for interpretation of results and for facilitation of meta-analyses of trials,” the authors concluded.


Mehrotra DV, Janes HE, Fleming TR, et al. Clinical endpoints for evaluating efficacy in COVID-19 vaccine trials. Ann Intern Med. Published online October 22, 2020. doi:10.7326/M20-6169.