Polyfunctional antibody responses to COVID-19 vaccination of immunologically vulnerable populations
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2025
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Melbourne Authors
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Microbiology & Immunology
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PhD thesis
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Open Access
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© 2025 Ruth Amy Purcell
Abstract
Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were developed with remarkable speed and are estimated to have reduced coronavirus disease 2019 (COVID-19)-related mortality by 40-60%. However, vaccine efficacy is impaired in high-risk groups such as immunocompromised patients with comorbidities. Even among healthy adult vaccinees without clinically defined comorbidities, vaccine immunogenicity is highly variable and the mechanisms underlying heterogenous vaccine responses remain poorly described. Consequently, to facilitate design of improved vaccines that elicit optimised responses in high-risk individuals, an understanding of how comorbidities and other host factors modulate vaccine immunogenicity is required. In this thesis, the impacts of host immunogenetic variation and solid tumour malignancy (STM) upon COVID-19 vaccine-induced antibody responses were explored.
In Chapter 2 and Chapter 3, the influence of immunoglobulin G (IgG) single nucleotide polymorphisms (SNPs) upon functional antibody responses to COVID-19 vaccination was explored. Prior studies of other infectious diseases have suggested that certain IgG haplotypes are associated with increased pathogen-specific antibody responses or protection against disease. The influence of these haplotypes upon COVID-19 vaccine-induced functional antibodies was unknown. We identified that following primary COVID-19 vaccination, IgG responses against antigenically conserved SARS-CoV-2 epitopes within the spike 2 (S2) domain were elevated in G1m1,17 homozygous vaccinees as compared to G1m-1,3 homozygous vaccinees. Consequently, G1m1,17 homozygous vaccinees displayed increased capacity for SARS-CoV-2 spike trimer-specific engagement of Fc gamma receptors—activation of which may induce protective Fc effector functions. In contrast, no differences in antibody responses against the relatively more antigenically novel SARS-CoV-2 receptor binding domain (RBD) were observed between G1m1,17 homozygous and G1m-1,3 homozygous vaccinees. Importantly, we validated the antibody detectors used in this study for equivalent capacity to bind the different IgG variants of interest, given the potential for IgG SNPs to alter binding by different IgG detectors, as detailed in Chapter 2.
In Chapter 4, we explored the influence of STM-associated inflammation upon polyfunctional antibody responses to COVID-19 vaccination. We demonstrated that elevated inflammatory biomarkers such interleukin (IL)-6, IL-18, agalactosylated IgG, and IgD-CD27-CD21-CD11c- double negative 3 memory B cells were negatively associated with SARS-CoV-2 RBD-specific neutralising antibody responses. In contrast, we demonstrated that Fc effector functions targeting antigenically conserved epitopes such as the SARS-CoV-2 S2 were comparable in STM patients and age-matched healthy controls, despite STM-associated inflammatory dysregulation. Critically, these comparable Fc functions in STM and control vaccinees were preserved across SARS-CoV-2 variants of concern. These data demonstrate the resilience of Fc functional antibodies following COVID-19 vaccination of STM patients and suggest that extra-neutralising functional responses may provide some protection against disease, including against viral variants, in vaccinees who fail to develop robust neutralising responses.
Overall, our studies highlight how both immunogenetics and chronic inflammatory comorbidities may alter functional antibody responses to COVID-19 vaccination. Furthermore, in the context of both immunogenetic variation and STM-associated inflammatory dysregulation, we demonstrate distinct regulation of IgG responses against antigenically conserved SARS-CoV-2 epitopes, such as the S2 domain, versus antigenically novel epitopes, such as the RBD. These data offer insights into a subset of mechanisms underlying heterogenous COVID-19 vaccine immunogenicity and suggest potential avenues for design of rational vaccination strategies that may promote enhanced protection of high-risk individuals and diverse populations.
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Antibody, Humoral Immunity, Vaccine, SARS-CoV-2, COVID-19, Variant of Concern, Fc effector function, IgG subclass, IgG Fc glycosylation, High-risk population, Comorbidities, Solid tumour malignancy, Inflammation, Immunogenetics, IgG allotype, FcγR polymorphism