Date of Award

2-4-2026

Thesis Type

PhD

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Divisions

Institute for Advanced Studies

Institution

Universiti Malaya

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has led to a complex immunological landscape shaped by combinations of SARS-CoV-2 infection and vaccination. Immune imprinting, wherein initial antigenic exposure may limit response breadth, poses a significant barrier to achieving durable and broad immune protection. This study aimed to evaluate humoral and cellular immune responses elicited by different SARS-CoV-2 vaccination strategies. The study hypothesized that an individual’s prior SARS-CoV-2 exposure history differentially influences the magnitude, durability, and functional profile of their immune response. A 12-month longitudinal sampling was conducted involving 267 participants, categorized into five groups based on their sequence of vaccination and COVID-19 exposure. Serum IgM, IgA, IgG, and neutralizing antibodies (NAb) were quantified by ELISA. At month-12, a cross-sectional analysis was performed on peripheral blood mononuclear cells (PBMCs) from a randomized subset (n=45). B cell immunophenotyping was conducted via flow cytometry, functional memory B and T cell responses were assessed by ELISpot, and cytokine, chemokine, and growth factor profiles were characterized using a Bio-Plex multiplex immunoassay. Longitudinal analysis revealed that antibody durability was differentially differed by exposure history. Hybrid immunity (5-COVID+ve/E/VAC(any)) provided the most sustained IgG and NAb levels, maintaining >98% inhibition and correlating with the lowest re-infection incidence (p< 0.001). Breakthrough infections after vaccination (3-VAC(BNT)/COVID+ve/E and 4-VAC(non-BNT)/COVID+ve/E) mounted a robust anamnestic response, sustaining at least 99% NAb levels. At Day-14 post-infection, breakthrough infections in BNT162b2-vaccinated individuals (3-VAC(BNT)/COVID+ve/E) showed 52% higher IgG levels than those who had received other vaccine types (4-VAC(non-BNT)/COVID+ve/E). Recipients of only primary BNT162b2 series (1-E/VAC(BNT)/COVID-ve and 2-E/VAC(BNT)/COVID+ve) exhibited significant antibody waning by Day-90, though levels were restored by booster vaccination or breakthrough infection. A strong positive correlation was identified between IgG and NAb titers (Spearman rs=0.71, p< 0.001), supporting IgG's primary role in neutralization. Cellular analysis at month-12 observed distinct immune memory patterns in different vaccine platforms. A homologous BNT162b2 regimen elicited a significantly higher percentage of Spike++ memory B cells (0.48%) vs. homologous ChAdOx1 (0.22%, p< 0.01) and CoronaVac (0.27%, p< 0.01). A heterologous CoronaVac/BNT162b2 regimen generated the most functional RBDspecific IgG-producing B cell response (260 SFU/10⁶ cells vs. 42 in unvaccinated controls, p< 0.05) and the highest median IFN-γ-producing T cell responses against S1 and SNMO peptide pools, though not statistically significant across all groups. Homologous CoronaVac showed the broadest significant upregulation of cytokines, chemokines, and growth factors upon stimulation (including IL-6, IL-12(p70), TNF-α, IL-10; p< 0.05). A positive correlation between IL-6 fold-change and class-switched (Spearman rs=0.32) and memory B cell (Spearman rs=0.49) frequency suggested a role in promoting B cell differentiation. These findings suggest that SARS-CoV-2 exposure history differentially influences immune responses. Specifically, hybrid immunity was associated with more durable antibody, while heterologous CoronaVac/BNT162b2 vaccination showed higher functional B cell memory and broad immune activation, thereby providing a mechanistic basis for population immune heterogeneity and supports the development of exposure-tailored vaccination strategies to overcome immune imprinting and enhance long-term protection.

Initial

khm

Additional Information

Thesis (PhD) – Institute for Advanced Studies, Universiti Malaya, 2026.

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