Live-Attenuated HSV-1 VC2 Vectoring Capsid-Displayed HPV-16 E7m Elicits Th1-Polarized CD8+ T Cell Responses and Protection Against Cervical Cancer Challenge
Year: 2026
Type: preprint
Abstract: Cervical cancer is a major cause of mortality worldwide and has been attributed to long-lasting (persistent) infections with the human papillomavirus (HPV). Although more than 50 types of HPVs are known the infect the genital tract, fewer than a dozen of them are regularly linked to cervical cancers leading to these types being designated as “high risk” HPVs. Worldwide, over 90% of cervical cancers arise from persistent high-risk human papillomavirus (HPV) infection and the infectious nature of the virus procures the need for preventative vaccines against cervical cancer. To address this, we have developed a live-attenuated herpes simplex virus type 1 (HSV-1) VC2-vectored vaccine expressing a catalytically inactive mutant of HPV-16 E7 (E7m) fused to the viral capsid protein VP26. Incorporation of E7m into the VC2 backbone resulted in stable incorporation of VP26-E7m fusion protein in cell free viral particles and detectable intracellular expression within infected cells. The recombinant virus (E7m VC-2) maintained growth kinetics comparable to parental VC2 in vitro, though plaque size was modestly reduced, suggesting a minimal fitness cost associated with transgene insertion. To evaluate prophylactic efficacy, mice received a one-dose vaccine schedule of E7m VC-2 prior to challenge with syngeneic HPV-16 E6/E7-expressing tumor cells. In mice that did develop tumors, growth kinetics were attenuated relative to unvaccinated animals. Importantly, neither E7m VC-2 nor adjuvanted E7m protein alone achieved statistically significant protection versus untreated controls. Immunohistochemical analysis of tumor tissue revealed markedly increased CD8+ T cell infiltration in E7m VC-2 vaccinated mice, demonstrating that vaccination promotes a cytotoxic immune microenvironment capable of restricting tumor progression. Three-dose vaccination of mice with E7m VC-2 induced a robust Th1-polarized immune response characterized by strong interferon-gamma (IFN-γ) secretion in response to HPV16 E7 expressing syngeneic cell lines, consistent with the induction of cell-mediated antitumor immunity and superior to responses elicited by adjuvanted E7m protein alone. With an extended three-dose vaccination schedule E7m VC-2 conferred significantly greater protection against tumor establishment relative to untreated controls (80% vs. 20% tumor-free). Collectively, these findings establish proof-of-concept for the HSV-1 VC2 platform as an effective vector for HPV-targeted cancer immunotherapy, delivering statistically significant prophylactic protection alongside potent induction of tumor-reactive CD8+ T cells. Future studies will incorporate both E6 and E7 antigens to broaden antigenic coverage, evaluate therapeutic efficacy in established tumor models, and optimize dosing regimens with the long-term goal of advancing this Louisiana-developed platform toward IND-enabling studies and clinical translation.
Source: Preprints.org
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7202285753
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