* This document will no longer be updated and some of the information may not be current. The readers are encouraged to refer to the regulatory guidance by US FDA & the WHO PQ group in the meantime as well the publicly available clinical trial protocols of various developers. Further documents with specific focus on vaccine efficacy are being developed to address the emerging information and will be released shortly.

This Summary Document discusses the endpoint of clinically symptomatic COVID-19 in the context of trials assessing vaccine efficacy (VE). During the COVID-19 pandemic, clinical development of COVID-19 vaccines should focus on demonstrating VE against clinically symptomatic COVID-19 in the quickest possible way. Historically, vaccines for respiratory and other mucosal viruses have greater efficacy against severe disease than against mild disease, and greater efficacy against symptomatic disease than against asymptomatic infection.

The endpoints of clinically symptomatic COVID-19 have been aligned with the WHO COVID-19 severity grading. COVID-19 with signs and symptoms of pneumonia, defined in Box 1, should be considered for the primary efficacy assessment depending on the background incidence rate. In WHO’s severity grading, COVID-19 pneumonia is defined as fever or signs and symptoms of lower respiratory tract disease, corresponding with moderate, severe, or critical disease. The prevention of moderate to severe disease provides individual benefit and is likely to significantly reduce healthcare utilization. All clinically symptomatic COVID-19, irrespective of severity grade, may be considered for secondary or primary VE assessment, depending on the incidence rate of SARS-CoV-2 infection. Efficacy against severe disease should be considered as a secondary endpoint. The NEWS-2 severity score should be considered to define severe disease. SARS-CoV-2 infection capturing both symptomatic and asymptomatic disease merits consideration as an additional endpoint.

COVID-19 vaccines, like influenza vaccines may reduce the risk of disease and severity of symptoms following infection. If this is the case, the endpoint of clinically symptomatic COVID-19 of any severity grade, risks the inclusion in efficacy analysis of cases of vaccine-induced attenuated COVID-19 defined as mild, residual COVID-19 upon infection in a vaccinated person. This lowers the VE estimate and reduce its precision. The use of the COVID-19 with signs or symptoms of pneumonia as the primary efficacy endpoint may result in earlier demonstration of VE by limiting the number of vaccine-induced attenuated COVID-19 included in the primary efficacy analysis despite there being fewer overall cases.

All programs assessing VE in preventing COVID-19 clinical disease should consider implementing a committee for clinical endpoint adjudication, and to assess the severity of COVID-19 in a standardized manner. All COVID-19 vaccine interventional trials, starting with early-stage clinical development trials should prospectively collect data on incident COVID-19 cases. Standardized consistent endpoint definitions for clinical disease may facilitate pooled analysis of early and advanced stage trials.

All developers should consider the collection of detailed data on clinical signs and symptoms of COVID-19 cases ascertained during a clinical trial. This will allow possible iterations of clinical efficacy case definitions to be assessed for their performance characteristics and suitability for clinical efficacy endpoint trials. Of note, any such assessment should consider the sensitivity and specificity of the diagnostic assay used.