Abstract

Licensed human papillomavirus (HPV) vaccines contain virus-like particles (VLPs) self-assembled from L1 major-capsid proteins that are remarkably effective prophylactic immunogens. However, the induced type-restricted immune response limits coverage to the included vaccine types, and costly multiplex formulations, restrictive storage and distribution conditions drive the need for next generation HPV vaccines. Vaccine candidates based upon the minor structural protein L2 are particularly promising because conserved N-terminal epitopes induce broadly cross-type neutralizing and protective antibodies. Several strategies to increase the immunological potency of such epitopes are being investigated, including concatemeric multimers, fusion to toll-like receptors ligands or T cell epitopes, as well as immunodominant presentation by different nanoparticle or VLP structures. Several promising L2-based vaccine candidates have reached or will soon enter first-in-man clinical studies. RG1-VLP present the HPV16L2 amino-acid 17–36 conserved neutralization epitope “RG1” repetitively and closely spaced on an immunodominant surface loop of HPV16 L1-VLP and small animal immunizations provide cross-protection against challenge with all medically-significant high-risk and several low-risk HPV types. With a successful current good manufacturing practice (cGMP) campaign and this promising breadth of activity, even encompassing cross-neutralization of several cutaneous HPV types, RG1-VLP are ready for a first-in-human clinical study. This review aims to provide a general overview of these candidates with a special focus on the RG1-VLP vaccine and its road to the clinic.

Highlights

  • Mucosal human papillomavirus (HPV) can be further grouped into high-risk or low-risk types based upon their oncogenic potential, the former being the causative agent of a variety of anogenital cancers, predominantly cervical cancer (CxCa), and vaginal, vulva, penile, and anal cancers, and a subset of oro-pharyngeal cancers [10,11]

  • This review aims to provide a general overview of L2-based broad-spectrum vaccine candidates— RG1-virus-like particles (VLPs)—and their advancement in clinical studies

  • Results indicated that adjuvanting with bacterial enzymatic combinatorial chemistry (BECC)/Alhydrogel allowed for 75% reduction in antigen dose while still retaining equivalent magnitudes of responses to the full RG1-VLP dose with Alhydrogel

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Summary

Mucosal HPV

Mucosal HPV can be further grouped into high-risk (hr) or low-risk (lr) types based upon their oncogenic potential, the former being the causative agent of a variety of anogenital cancers, predominantly cervical cancer (CxCa), and vaginal-, vulva-, penile-, and anal cancers, and a subset of oro-pharyngeal cancers [10,11]. CxCa is the fourth most common cancer around the world, from which more than a quarter million of women die each year. Such a high number is attributed to CxCa cases in developing countries that cannot afford routine cytological cervical screening nor costly

Cutaneous HPV
Licensed HPV Vaccines
L2-Based Vaccine Candidates
Concatemeric Peptides
VLP-Based L2-Approaches
Bacterial Presentation of L2
L2 Fusion to Immunostimulatory Molecules
L2-Based Prophylactic and Therapeutic Vaccine Combinations
Pre-Clinical Data
Challenges of an L2-Based Vaccine Candidate
Findings
Conclusions
Full Text
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