Adenovirus based HPV L2 vaccine induces broad cross-reactive humoral immune responses

Abstract

Oncogenic high-risk human papillomavirus (HPV) infections cause a substantial number of genital and non-genital cancers worldwide. Approximately 70% of all cervical cancers are caused by the high-risk HPV16 and 18 types. The remaining 30% can be attributed to twelve other high-risk HPV-types. Highly efficacious 2-valent, 4-valent and 9-valent L1 protein based prophylactic HPV vaccines are available however with limited cross-protection. To further increase the coverage, development of a multivalent cross-protective HPV vaccine is currently focused on the conserved N-terminus of HPV's L2 protein. We have developed a vaccine candidate based on the rare human adenovirus type 35 (HAdV35) vector that displays a concatemer of L2 protein epitopes from four different HPV-types via protein IX (pIX). A mix of two heterologous HAdV35 pIX-L2 display vectors present highly conserved linear epitopes of nine HPV-types. Each HAdV35 pIX-L2 display vector exhibits a good manufacturability profile. HAdV35 pIX-L2 display vaccine vectors were immunogenic and induced neutralizing antibodies against HPV-types included in the vaccine and cross-neutralizing antibodies against distant a HPV-type not included in the vaccine in mice. The HAdV35 pIX-L2 display vectors offer an opportunity for a multivalent HAdV-based prophylactic HPV vaccine.

Longevity of adenovirus vector immunity in mice and its implications for vaccine efficacy

“…AdV is a common human pathogen, and there are more than 60 different types of HAdVs that are known to infect humans, so that the majority of individuals are infected with one or more AdV types early in their lives leading to a high occurrence of pre-existing AdV vector immunity [17, 18, 34]. Therefore, several less prevalent HAdV types, as well as nonhuman AdVs including ChAdV, BAdV, and others, have developed as gene delivery systems to circumvent pre-existing vector immunity [5, 35–39].…”

Production and characterization of virus-like particles of grapevine fanleaf virus presenting L2 epitope of human papillomavirus minor capsid protein

“…High-risk genotypes of human papillomavirus (HPV) are responsible for cancers in females and males. Around 70 % of the cervical cancers are due to HPV16 and 18 genotypes [37]. The current vaccines are based on the major capsid protein (L1) giving rise to a HPV type-restricted protection.…”

Progress in Adenoviral Capsid-Display Vaccines

“…The potential of alternative AdV types for the generation of pIX-display vectors was confirmed by HAdV35 [ 77 , 78 ] and HAdV48 vectors [ 75 ], which induced potent antigen-specific immune responses in mice. HAdV35 displaying a ~15 kDa malaria CS antigen and encoding a CS transgene in E1 elicited higher immune responses than the transgene-only vector or CS protein alone.…”

“…This effect could not be achieved by mixing the CS protein with the vector, suggesting that the antigen needs to be displayed on the outer capsid surface for induction of enhanced antigen-specific humoral responses [ 77 ]. HAdV35 vectors displaying HPV protein L2 epitope-repeats via pIX (e.g., HPV type 6, 31, 33, 16 (93 aa)) elicited L2-specific immune responses against the HVP types included and not included in the vaccine, demonstrating the potential of using pIX to display multiple linear epitopes in a repetitive confirmation from a single AdV vector to generate a multivalent AdV display vaccine [ 78 ]. In some instances, alternative AdV vectors were shown be more potent at inducing antigen-specific immune responses.…”