Evolution of long-term hybrid immunity in healthcare workers after different COVID-19 vaccination regimens: a longitudinal observational cohort study

Both infection and vaccination, alone or in combination, generate antibody and T cell responses against SARS-CoV-2. However, the maintenance of such responses - and hence protection from disease - requires careful characterisation. In a large prospective study of UK healthcare workers (Protective immunity from T cells in Healthcare workers (PITCH), within the larger SARS-CoV-2 immunity & reinfection evaluation (SIREN) study) we previously observed that prior infection impacted strongly on subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. Here, we report longer follow up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. We make three observations: Firstly, the dynamics of humoral and cellular responses differ; binding and neutralising antibodies declined whereas T and memory B cell responses were maintained after the second vaccine dose. Secondly, vaccine boosting restored IgG levels, broadened neutralising activity against variants of concern including omicron BA.1, BA.2 and BA.5, and boosted T cell responses above the 6 month level post dose 2. Thirdly, prior infection maintained its impact driving larger as well as broader T cell responses compared with never-infected people - a feature maintained until 6 months after the third dose. In conclusion, broadly cross-reactive T cell responses are well maintained over time - especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity) - and may contribute to continued protection against severe disease.