Immunization with a consensus epitope from human papillomavirus L2 induces antibodies that are broadly neutralizing

Abstract

Vaccines targeting conserved epitopes in the HPV minor capsid protein, L2, can elicit antibodies that can protect against a broad spectrum of HPV types that are associated with cervical cancer and other HPV malignancies. Thus, L2 vaccines have been explored as alternatives to the current HPV vaccines, which are largely type-specific. In this study we assessed the immunogenicity of peptides spanning the N-terminal domain of L2 linked to the surface of a highly immunogenic bacteriophage virus-like particle (VLP) platform. Although all of the HPV16 L2 peptide-displaying VLPs elicited high-titer anti-peptide antibody responses, only a subset of the immunogens elicited antibody responses that were strongly protective from HPV16 pseudovirus (PsV) infection in a mouse genital challenge model. One of these peptides, mapping to HPV16 L2 amino acids 65–85, strongly neutralized HPV16 PsV but showed little ability to cross-neutralize other high-risk HPV types. In an attempt to broaden the protection generated through vaccination with this peptide, we immunized mice with VLPs displaying a peptide that represented a consensus sequence from high-risk and other HPV types. Vaccinated mice produced antibodies with broad, high-titer neutralizing activity against all of the HPV types that we tested. Therefore, immunization with virus-like particles displaying a consensus HPV sequence is an effective method to broaden neutralizing antibody responses against a type-specific epitope.

Robust In Vitro and In Vivo Neutralization against Multiple High-Risk HPV Types Induced by a Thermostable Thioredoxin-L2 Vaccine

“…Despite recent progress in the optimization of L2-based immunogens (11,13,30), the current benchmark of HPV protection is set by the licensed VLP vaccines. HPV16 neutralization endpoints measured with the HPV16-L1-VLPs we used as a surrogate L1-vaccine reference were nearly identical to those achieved with PfTrx-L2, both the monovalent and the mix formulation.…”

“…Taking into account the above scaffold improvement, the availability of different neutralization assays and the need for a L1-VLP comparison, we present here the results of a comprehensive immunization study evaluating the relative performance of monovalent P. furiosus thioredoxin-HPV16 L2 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) 3 (PfTrx-16L2), a mixture of thioredoxin-L2 antigens derived from HPV16, 31, 51 (PfTrx-L2 mix), and HPV16-L1-VLPs. The PfTrx-L2 antigens were administered at moderate doses and formulated in the human-compatible adjuvant aluminum hydroxide-monophosphoryl lipid A (MPLA).…”

Preclinical refinements of a broadly protective VLP-based HPV vaccine targeting the minor capsid protein, L2

“…As an alternative to vaccines based on L1 VLPs, we and others have focused on developing broadly protective cost-effective next-generation HPV vaccines targeting highly conserved epitopes in the HPV minor capsid protein, L2 [9, 16, 17, 25-29]. Our group has developed candidate next-generation HPV vaccines based on bacteriophage VLPs displaying conserved L2 epitopes from HPVs and has shown that these vaccines provide broad protection from infection by diverse HPV types [9, 15-18].…”

“…As an alternative to the current type-specific HPV vaccines, we have developed vaccines that target highly conserved, broadly neutralizing epitopes from the HPV minor capsid protein, L2 [9, 15-18]. Immunization with L2-displaying VLPs elicits high-titer and broadly neutralizing antibodies against HPV.…”

The True Story and Advantages of RNA Phage Capsids as Nanotools

“…First, the success of an experimental human papilloma virus (HPV) vaccine based on PP7 single-chain-dimer VLPs [191,205,206,207,208,209] developed in preclinical studies [210] must be mentioned. A similar HPV vaccine candidate was constructed on MS2 single-chain-dimer VLPs and tested in preclinical studies [210,211].…”