Harnessing innate immunity to enhance the quality of adaptive vaccine responses

Vaccine designs are continuously improved to induce better protection, specifically in subjects with weakened immune responses such as older adults and immunocompromised individuals. Therefore, new adjuvant systems are being developed to induce a more potent and prolonged immune activation while innovative vaccine techniques are being explored. In 2020, mRNA vaccines against SARS-CoV- 2 marked a revolutionary moment, overcoming limited response rated with strong immune activation but with consequently stronger induction of local inflammation at the side of vaccination (reactogenicity). This cumulative thesis explored the correlation between vaccine-induced local inflammation and adaptive immune responses in different clinical scenarios, elucidating various aspects of innate immune activation by vaccines and their adjuvants. The first manuscript of the cumulative thesis investigates potential molecular mechanisms contributing to local reactogenicity in a mRNA COVID-19 vaccination cohort of healthy subjects, that could be harnessed to enhance adaptive vaccine responses. The study focused on local temperature reactions as an objective marker of post-vaccination immune activation, revealing a strong positive correlation with vaccine-induced uncoupling protein 2 (UCP2) and protein kinase R-like endoplasmic reticulum kinase (PERK) activation. The study suggests a temperature-dependent effect on mRNA vaccine antigen translation, with indications that the UCP2 effect may arise from trained immunity based on epigenetic analysis. The association between strong local temperature and high-quality adaptive immunity highlights a positive outcome of robust innate immune activation. The second manuscript explores a cohort of healthy subjects with inadvertent influenza vaccine injection into the shoulder joint or bursae causing shoulder injury related to vaccine administration (SIRVA). We illustrate how vaccine misapplication may trigger a prolonged local reaction, enhanced adaptive immunity against the vaccine, and potentially induce local autoimmunity. SIRVA cases experienced strong adaptive immune responses, likely attributed to prolonged antigen persistence and innate immune activation. However, evidence of auto-reactive T cells and antibodies in SIRVA cases, along with significant innate immune activation of osteoclasts by a vaccine adjuvant, underpins the potential harm of an overshooting innate immune activation resulting from vaccine misapplication. Finally, the third manuscript uses a clinical case of innate immune hyperactivation to demonstrate the differential effects of mRNA and vector vaccines on innate signaling pathways, aiming to extract general perspectives on vaccine reactogenicity. We investigated immune overactivation in a patient with a STAT3-mediated disease who experienced a severe immunological reaction to an first mRNA vaccine dose. In vitro analysis revealed an overactive response to the mRNA vaccine but not the adenoviral vector vaccine. Completing the immunization with a vector vaccine was well-tolerated and suggested that the appropriate level of immune activation may depend on the patient’s intrinsic factors.
Based on what we have learned from the work in this thesis, we describe possible applications for improving vaccine efficiency, including temperature modulation or adjuvant-induced trained immunity.