The primary goal of vaccination is to induce antigen-specific or cross-protective immune responses against a target pathogen. However, several vaccines, particularly live-attenuated vaccines such as Bacillus Calmette-Guerin (BCG), have beneficial off-target effects. With widespread administrations of COVID-19 vaccines, potential off-target immunological effects have important implications for global health. In this sub-study of participants enrolled in an international randomised controlled trial (BRACE trial, NCT04327206)1, we sought to determine if the adenovirus vector ChAdOx1-S (Oxford-Astra Zeneca) vaccine and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccine have off-target effects on immune responses to unrelated (heterologous) pathogens.
Blood samples were collected from 264 healthcare workers before and 28 days after vaccination with ChAdOx1-S or BNT162b2 vaccine. SARS-CoV-2-specific antibodies were measured by ELISA2,3 and whole blood cytokine responses following in vitro stimulation with specific (irradiated SARS-CoV-2)4 or heterologous stimuli (e.g. heat-killed (HK) pathogens or TLR agonists) were measured by multiplex bead array.
ChAdOx1-S vaccination was associated with increased cytokine responses to HK C. albicans and HK S. aureus and decreased cytokine responses to HK E. coli and BCG. Cytokines with altered responses included those involved in T cell responses, lymphocyte homeostasis, pro-inflammatory responses, growth factors and chemokines. BNT162b2 vaccination was associated decreased cytokine responses to HK E. coli and had variable effects on cytokine responses to BCG and R848. Despite decreased responses to BCG and HK E. coli following both vaccines, clusters of cytokines positively correlated with the strongly increased SARS-CoV-2-specific cytokine responses. Direct comparison of the two vaccines also revealed differences in specific and off-target effects of ChAdOx1-S and BNT162b2, manifest as differential cytokine responses, particularly to BCG, HK E. coli, and R848 stimulation.
Overall, ChAdOx1-S and BNT162b2 vaccines alter in vitro cytokine responses to unrelated pathogens, indicative of off-target immunological effects. In contrast to the generalized boosting of immune responses to unrelated pathogens proposed for BCG vaccination, off-target effects of ChAdOx1-S and BNT162b2 vaccination are pathogen-dependent and are likely mediated by different mechanisms. These findings have implications for vaccine selection and future vaccine development strategies.