Efficacy of RG1-VLP Vaccination against Infections with Genital and Cutaneous Human Papillomaviruses

Abstract

Licensed human papillomavirus (HPV) vaccines, based on virus-like particles (VLPs) self-assembled from major capsid protein L1, afford type-restricted protection against HPV types 16/18/6/11 (or 16/18 for the bivalent vaccine), which cause 70% of cervical cancers (CxCas) and 90% of genital warts. However, they do not protect against less prevalent high-risk (HR) types causing 30% of CxCa, or cutaneous HPV. In contrast, vaccination with the minor capsid protein L2 induces low-level immunity to type-common epitopes. Chimeric RG1-VLP presenting HPV16 L2 amino acids 17–36 (RG1 epitope) within the DE-surface loop of HPV16 L1 induced cross-neutralizing antisera. We hypothesized that RG1-VLP vaccination protects against a large spectrum of mucosal and cutaneous HPV infections in vivo. Immunization with RG1-VLP adjuvanted with human-applicable alum-MPL (aluminum hydroxide plus 3-O-desacyl-4′-monophosphoryl lipid A) induced robust L2 antibodies (ELISA titers 2,500–12,500), which (cross-)neutralized mucosal HR HPV16/18/45/37/33/52/58/35/39/51/59/68/73/26/69/34/70, low-risk HPV6/11/32/40, and cutaneous HPV2/27/3/76 (titers 25–1,000) using native virion- or pseudovirion (PsV)-based assays, and a vigorous cytotoxic T lymphocyte response by enzyme-linked immunospot. In vivo, mice were efficiently protected against experimental vaginal challenge with mucosal HR PsV types HPV16/18/45/31/33/52/58/35/39/51/59/68/56/73/26/53/66/34 and low-risk HPV6/43/44. Enduring protection was demonstrated 1 year after vaccination. RG1-VLP is a promising next-generation vaccine with broad efficacy against all relevant mucosal and also cutaneous HPV types.

Broad Cross-Protection Is Induced in Preclinical Models by a Human Papillomavirus Vaccine Composed of L1/L2 Chimeric Virus-Like Particles

“…An alternative strategy to broaden the protection of HPV vaccines that is also being considered is to use conserved epitopes from the L2 minor capsid protein incorporated into HPV L1 VLPs (22)(23)(24)(25)(26)(27)(28)(29). This strategy is supported by evidence that vaccines based on L2 peptides can confer broad protection in mouse or rabbit HPV challenge models and elicit neutralizing antibodies against a wide range of HPVs (27,(29)(30)(31)(32)(33).…”

“…Both experiments used PsVs representing HPV-11, -16, -35, or -58. The four viruses were chosen based on a range of anticipated outcomes (PsV-16, for harboring homology with HPV-16 L1, PsV-11 for harboring homology with L2 DE (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) , PsV-58 for harboring homology with L2 CT(56 -75) , and PsV-35 for harboring partial [90%] homology with either of the two L2 peptides). The first experiment also used PsVs representing HPV-45 and -59 [two viruses which have relatively low, i.e., Յ75%, similarity with the L2 peptide].…”

“…One L2 epitope (consisting of amino acid residues 17 to 36; L2 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ), recognized as a linear neutralizing epitope (RG1 epitope) (30)(31)(32), has been incorporated into the capsid surface DE loop of HPV-16 L1 or HPV-18 L1 to create chimeric L1/L2 VLP vaccines (24,25,27). Both L1/L2 vaccines (based on either HPV-16 or HPV-18 L1) provided protection in a mouse challenge model against a broad range of high-risk HPVs (25,27) and generated L2-specific neutralizing antibodies together with L1-specific neutralizing antibodies (24,25,27). However, the insertion of epitopes into the DE loop can also disrupt the epitope recognized by the V5 and J4 monoclonal neutralizing antibodies, thus disrupting epitopes important for HPV-16/18 neutralization (22).…”

“…The antigens were constructed by inserting the well-conserved L2 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] and L2 56 -75 neutralizing epitopes within the DE loop and/or C-terminal arm of HPV-16 or HPV-18 L1 proteins. The immunogenicity and/or efficacy of the different formulations was compared using mouse and rabbit models.…”

HPV vaccination for prevention of skin cancer

“…Vaccination with an HPV16-derived L2 peptide can generate antibodies which cross-neutralize in vitro the non-cognate cutaneous types HPV 2, HPV 3, HPV 5, HPV 8, HPV 23, HPV 27, HPV 38, HPV 57 and HPV 76. 52,58,59 Cross-neutralization could also be achieved in vivo by cutaneous challenge with pseudovirions, highlighting the potential of the L2-derived vaccines to confer protection to a broad range of cutaneous HPVs. However, the effectivity of such vaccines in preventing skin tumors has not been assessed so far, and fundamental questions remain to be addressed to confirm the prophylactic potential of these vaccines.…”