The use of serology in trials of antiviral drugs or physical prophylaxis (masks or condoms) varies by the pathogen under study. For trials to prevent infection with human immunodeficiency virus, in which seroconversion (evidence of a new antibody response to infection) is the gold standard for evidence of new infection, serological measurements at baseline and during and after the trial are routine9. On the other hand, trials of prophylactic drugs or physical prophylaxis are often performed for infections, such as infection with the malaria pathogen Plasmodium falciparum10 or with influenza virus11, respectively, for which immunity is partial and short-lived and is therefore hard to measure at baseline and perhaps difficult to interpret. For this reason, baseline testing has been variable. Nonetheless, in trials of antiviral drugs for prophylaxis of influenza, serology has sometimes been used to assess the proportion of infections that are symptomatic8.

For vaccines with very high efficacy, the bias in efficacy estimates due to unobserved infections is small, so it may not affect estimates much7. That is why vaccine trials rarely (never, to our knowledge) attempt to correct efficacy estimates for undetected or subclinical infections through the use of post-trial serology. They also, to our knowledge, rarely use serostatus at the time of enrollment to stratify analyses, despite recommendations for such analyses in clinical trial guidelines12. For COVID-19, there is little basis on which to predict vaccine efficacy, as no vaccine against coronavirus has been tested for efficacy.

Vaccines are also typically tested for efficacy either in populations with low baseline immunity (e.g., vaccines against measles, for infants) and/or for diseases for which natural immunity is partial and/or short-lived, so it would be difficult to measure (e.g., pneumococcal vaccines)13. Nonetheless, simulations have shown that such trials can be complicated by the interplay between naturally induced immunity and vaccine-induced immunity14. For the Dengvaxia vaccine against dengue fever, researchers gathered but did not immediately analyze serological samples from trial participants. After publication of the original trial results, a secondary analysis of the data showed that the vaccine was most beneficial for people with a prior seropositivity to infection with dengue virus, but that if a person received Dengvaxia while seronegative to infection with dengue virus, the vaccine could prime an ‘enhancement’ of infection that made the symptoms more severe15. This critical aspect of vaccine safety and efficacy could not have been fully understood if serum samples had not been available.

Serological measurement of infection at the end of a vaccine trial is especially important for infections for which asymptomatic infections are very important. This includes infections such as infection with SARS-CoV-2, in which asymptomatic transmission contributes to spread, or infections such as infection with Zika virus, in which asymptomatic infection can produce sequelae with potentially severe consequences, such as congenital Zika syndrome. Serological measurement also matters when failing to do so biases efficacy measurement downward. In sum, serology at the start and end of trials should be more common than it is.