This Summary Document discusses the endpoint of SARS-CoV-2 infection 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 have greater efficacy against symptomatic disease
than against asymptomatic infection.
COVID-19 with signs and symptoms of pneumonia, should be considered for the primary efficacy
assessment depending on the background incidence rate. This corresponds with moderate, severe, or
critical disease in WHO’s COVID-19 severity grading. 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. SARS-CoV-2 infection, capturing both symptomatic disease and asymptomatic infection, merits
consideration as an additional endpoint. The endpoint of SARS-CoV-2 infection can be assessed by
demonstration of virus using RT-PCR or by seroconversion.
Systematic assessment of infection by RT-PCR requires prospective sampling at regular intervals
irrespective of symptoms. This will result in a very large numbers of samples. Even with a RT-PCR
specificity of 99.9% in a trial setting, false positive tests will result in hundreds of ‘cases’, outnumbering
actual incident SARS-CoV-2 infections and posing a significant challenge. False positive test results are
evenly spread between treatment arms, which biases the VE towards the null hypothesis, resulting in a
lower VE estimate or failure to demonstrate VE against infection.
Alternatively, infection can be measured by seroconversion using an antibody assay that distinguishes
between anti-SARS-CoV-2 antibodies induced by vaccine and natural infection. The sensitivity and
usefulness of such assays to substantiate asymptomatic infection remains to be determined.
It is unclear whether COVID-19 vaccines will be able to entirely prevent infection. Early animal challenge
data suggest they may not induce sterilizing immunity and prevent infection in the upper respiratory
tract despite protecting against SARS-CoV-2 pneumonia. Where sterilizing immunity cannot be elicited,
vaccines might still be able to reduce viral load and shorten the duration of viral shedding, thereby
preventing or ameliorating subsequent disease.
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