In-depth characterisation of the immune response upon COVID-19 vaccination in cancer patients

COVID-19 vaccination in cancer patients is complicated by underlying disease and treatment related immunosuppression, which is associated with attenuated vaccine responses and increased risk of severe COVID-19 after SARS-CoV-2 infection. In addition, due to their immunosuppressed status, cancer patients were excluded from pivotal COVID-19 vaccine trials, leaving critical knowledge gaps regarding vaccine safety, immunogenicity, and long-term outcomes in this vulnerable population. This thesis investigates how COVID-19 vaccination shapes humoral and cellular immunity in cancer patients. Across three prospective Belgian studies (B-VOICE, Tri-VOICE, REAL-V) including 760 cancer patients on active anti-neoplastic treatment, mRNA vaccines elicited higher IgG and IgA antibody responses than adenoviral vector vaccines, with responses that were particularly impaired in patients receiving chemotherapy or B-cell depleting therapy. However, administration of an mRNA booster dose after initial dual-dose vaccination with a viral vector vaccine restored IgG antibody levels to those seen with schedules including three mRNA vaccination doses and elicited enhanced T-cell responses. An IgG antibody-based correlate of protection of 20.42 BAU/mL was identified for the pre Omicron period, but this association disappeared once Omicron variants predominated, underscoring the limitations of antibody centric metrics and the growing relevance of cellular immunity. Functional T-cell analysis and T-cell receptor sequencing showed that COVID-19 vaccination induces polyfunctional SARS-CoV-2-specific T-cells and durable CD4 clonal memory, while natural infection predominantly expanded CD8 clonotypes, indicating complementary vaccine versus infection induced cellular immunity. Overall, this work supports personalised vaccination strategies that prioritise mRNA vaccines, systematic booster administration, and combined monitoring of humoral and cellular immunity, while emphasising the long-term supportive needs of cancer patients in the evolving COVID-19 landscape.