Development of an mRNA-based vaccine to prevent HSV-2 disease

다국어 초록 (Multilingual Abstract)

Despite the high infection and genital ulcer disease (GUD) prevalence, as well as lifelong recurrences, HSV-2 continues to be an unmet medical need owing to the absence of commercialized prophylactic and therapeutic vaccines. The failure of the large-scale Phase 3 clinical trial for the HSV-2 prophylactic vaccine suggested that insufficient T cell responses and HSV-2 neutralization evasion were the causes, which remain major challenges in vaccine design. This study aimed to develop an mRNA-based quadrivalent prophylactic vaccine encoding HSV-2 glycoproteins B (gB2), C (gC2), D (gD2), and E (gE2) to elicit effective neutralization and enhance immune responses. mRNA-based platforms offer immunological advantages by augmenting the diversity and activity of CD4+ and CD8+ T cells through efficient antigen presentation. The immunogenicity and protective efficacy of the vaccine were evaluated in a murine intravaginal challenge model. Strong neutralizing antibody responses were induced in mice immunized with the quadrivalent mRNA vaccine and were sustained for at least 16 weeks. The vaccine generated T cell responses against all four target glycoproteins, and these responses, including both CD4+ and CD8+ T cells, remained significant after 16 weeks. When challenged 16 weeks after vaccination, the mice were completely protected from genital disease, and vaginal viral replication was significantly suppressed to undetectable levels. Additionally, HSV-2 DNA levels in the dorsal root ganglia were markedly lower than those in the mock control group, indicating that the establishment of latent infection was inhibited. The immunogenicity and efficacy of the multivalent mRNA vaccine were further compared according to formulation strategy. The co-formulated lipid nanoparticle formulation had a monodisperse size distribution suitable for mRNA vaccine delivery and comparable encapsulation efficiency to that of the admixed lipid nanoparticle formulations. Both admixed and co-formulations exhibited comparable humoral immunogenicity and protective efficacy, suggesting potential flexibility in the manufacturing process, which was further supported by the co-formulation-induced T-cell immune responses to each of the four antigens. Overall, the quadrivalent mRNA vaccine effectively induced both humoral and cellular immune responses and provided robust protection against HSV-2 infection and genital herpes, demonstrating its potential as an HSV-2 vaccine candidate.

목차 (Table of Contents)

• I. Overall Abstract １
• II. Overall Introduction ３
• 1. Classification of HSV ３
• 2. HSV Genome and Gene Products ６
• 2.1 UL Region ８
• 2.2 US Region １４
• 2.3 Repeat Regions.１６
• 3. Transmission and Prevalence of HSV １９
• 4. Clinical Trials of HSV-2 Vaccine２１
• 5. Immunological Mechanism of mRNA Vaccine ２７
• 5.1 Adjuvanticity of mRNA-LNP ２７
• 5.2 Antigen Presentation Pathways of mRNA Vaccine ３０
• 5.3 Adaptive Immune Responses and Memory Formation ３７
• III. Design and Immunogenicity of a Quadrivalent mRNA Vaccine
• Targeting HSV-2 with Comparative Evaluation of Co-formulated and
• Admixed Formulations ４３
• 1. Abstract４４
• 2. Introduction ４６
• 3. Materials and Methods ４９
• 4. Results６０
• 5. Discussion９２
• IV. References １００