The advent of COVID-19 vaccines will play a major role in helping to end the pandemic that has killed millions worldwide. Vaccine candidates have demonstrated robust humoral responses and have protected against infection. However, efficacy trials were focused on individuals with no prior exposure to SARS-CoV-2, and, as a result, little is known about immune responses induced by these mRNA vaccines in individuals who recovered from COVID-19. Here, we evaluated immune responses in 32 subjects who received two-dose BNT162b2 mRNA vaccination. In individuals naive to SARS-CoV-2, we observed robust increases in humoral and antigen-specific antibody-secreting cell (ASC) responses following each dose of vaccine, whereas individuals with prior exposure to SARS-CoV-2 demonstrated strong humoral and antigen-specific ASC responses responses to the first dose but muted responses to the second dose of the vaccine for the time points studied. These data highlight an important gap in our knowledge and may have major implications for how these vaccines should be used to prevent COVID-19.

The use of coronavirus disease 2019 (COVID-19) vaccines will play the major role in helping to end the pandemic that has killed millions worldwide. COVID-19 vaccines have resulted in robust humoral responses and protective efficacy in human trials, but efficacy trials excluded individuals with a prior diagnosis of COVID-19. As a result, little is known about how immune responses induced by mRNA vaccines differ in individuals who recovered from COVID-19. Here, we evaluated longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who had experienced COVID-19, compared to 21 adults who did not have prior COVID-19. Consistent with prior studies of mRNA vaccines, we observed robust cytotoxic CD8 + T cell responses in both cohorts after the second dose. Furthermore, SARS-CoV-2–naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses after each dose of vaccine, whereas SARS-CoV-2–experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but these responses were not further enhanced after the second dose of the vaccine at the time points studied. Together, these data highlight the relevance of immunological history for understanding vaccine immune responses and may have implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including for the deployment of booster shots.

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