Age effects on humoral and cellular adaptive immune responses to SARS-CoV-2 infection and vaccination

Abstract

SARS-CoV-2 emerged to cause the COVID-19 pandemic with devastating impacts, resulting in over 750 million cases and 6.9 million deaths by August 2023. As a novel virus, there was no population immunity, leading to mass infection ranging in severity. Vaccines aiming to protect against infection, transmission, severity, and mortality were rapidly developed, with inactivated CoronaVac and mRNA BNT162b2 available in Hong Kong, followed by booster doses used to protect against antigenically distinct Omicron subvariants. Neutralising antibodies emerged as a major focus of the adaptive immune response to infection and vaccination. However, non-neutralising and cellular responses likely play an important role, especially where neutralising responses do not fully explain the differences in outcomes between children and adults or in vaccine efficacy of different technologies.

This thesis used cohort studies of mildly infected individuals, vaccine cohort studies and clinical trials of CoronaVac and BNT162b2 vaccines, across both children and adults to understand the non-neutralising humoral and cellular adaptive responses by different first exposures. Overall we found that Fc Receptor (FcR)-binding antibodies, indicative of antibody dependent cytotoxicity and phagocytosis functions, as well as CD4+ and CD8+ T cellular responses are induced by infection and vaccination in different age groups and vaccine technologies, and that age and antigen content impacts primary immune response and shapes future response.

Children were found to have intrinsic immune differences to adults. Specifically, high baseline broadly reactive IgM, early elevated Tfh and decreased monocytes compared to adults resulted in lower levels of specific IgG, CD4+ and CD8+ T cell responses upon infection. However, IgG avidity and FcR-binding were higher in children than adults suggesting robust generation of class-switched, affinity matured antibodies. Adaptive response to first SARS-CoV-2 exposure in adults may be shaped by lifelong prior infection by common cold coronaviruses (CCCoV), resulting in higher magnitudes of SARS-CoV-2 antibody and cellular responses. CCCoV IgG may interfere with complete SARS-CoV-2 affinity maturation thus generating lower avidity and functional responses compared to children.

Vaccination with different technologies expectedly generated different primary immune responses. BNT162b2-generated S-antibody quantity and quality was significantly higher than CoronaVac in both adults and children, with significantly higher antibody responses amongst the latter group. CoronaVac generated Nucleocapsid antibodies and greater CD4+ and CD8+ T cells against combined structural proteins than BNT162b2, acting as additional immune mechanisms that may contribute to protection from severe disease. Homologous (with the same vaccine) and heterologous (with different vaccines) boosters showed distinct patterns whereby BNT162b2 boosters generated significantly higher Spike antibody quantity, quality, and Omicron cross-reactivity, regardless of initial priming. CoronaVac priming influenced the ability to generate non-Spike antibodies and T cells upon booster vaccination, with only homologous CoronaVac recipients generating additional N antibodies with FcR binding.

Overall, evaluation of antibodies and T cells with diverse functions and targets revealed distinct patterns dependent on age and vaccine technology. This may have implications on protection against severe disease in children and CoronaVac recipients where neutralising antibodies are lacking, and may shape future responses through priming of different antigens.