Development of a combination vaccine against N. Meningitidis and SARS-CoV-2 and analysis of MIS-C plasma and extracellular vesicles in relation to disease severity in pediatric patients

Abstract

Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD). Serogroup B remains the leading cause of IMD, representing 62% of documented serogroup cases overall, and is the most prevalent across all age groups under 65. In Türkiye, Serogroups B and W are responsible for most cases, accounting for over 75%. IMD has a case fatality rate of 10%, and 10% to 20% of survivors experience lifelong, disabling complications. Coronavirus disease 2019 (COVID-19), caused by the highly contagious SARS-CoV-2 virus, has had a devastating impact globally, leading to over 7 million deaths. It has become the most significant global health crisis since the influenza pandemic in 1918. Since the introduction of the first COVID-19 vaccine in the U.S., it is estimated that over 18 million hospitalizations and 3 million deaths have been prevented. Like flu vaccines, COVID-19 vaccines are expected to be introduced seasonally. In this thesis, we aim to develop a combination vaccine for populations where the prevalence of both COVID-19 and meningitis presents significant health risks. Our previous data indicated that our OMV-based bivalent vaccine, targeting B and W serogroups of Neisseria meningitidis, generates a broader humoral response and exhibits strong bactericidal activity. Similarly, our lab has developed a virus-like particle-based SARS-CoV-2 vaccine incorporating all four virus structural proteins, eliciting both humoral and cell-mediated immunity. Herein, we combined these two platforms and assessed their respective protective potencies in mice. Data revealed that combining the OMV and VLP vaccines with Alum adjuvant produced the most robust anti-meningococcal and anti-SARS-CoV-2 responses. The second part of the study focused on uncovering the immune parameters present in the plasma of MIS-C patients and investigating the role of extracellular vesicles in influencing disease severity. The data revealed that plasma from MIS-C patients contained significantly elevated levels of proinflammatory cytokines, including TNF-α, IFN-γ, IL-6, and IL-17. We also investigated the pathological role of extracellular vesicles (EVs) in MIS-C. Our findings showed that patient-derived EVs induced significantly higher levels of IRF9 in the THP1-dual reporter cell line. Contrary to our expectations, however, we did not observe EV-specific NF-κB induction in the THP1 cells.