A Novel Chimpanzee Adenovirus Vector with Low Human Seroprevalence: Improved Systems for Vector Derivation and Comparative Immunogenicity

Matthew D J Dicks,Sarah C Gilbert,Alexandra J Spencer,Nick J Edwards,Kalifa Bojang,Göran Wadell,Matthew G Cottingham,Adrian V S Hill,Eric J Kremer

doi:10.1371/journal.pone.0040385

Abstract

Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1∶200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.

Highlights

Recombinant adenoviruses were originally developed for gene therapy [1], but the strong and sustained transgene-specific immune responses elicited by these delivery agents, together with their broad tissue tropism, has prompted their use as vaccine vectors [2]
human adenoviruses (HAdV)-4 is the sole representative of Human adenovirus E derived from humans, many of the chimpanzee adenoviruses group phylogenetically within species E, including vaccine vector candidates ChAd63, AdC68 (SAdV-25), AdC7 (SAdV-24) and AdC6 (SAdV-23) [5,18,28,29]
In order to assess cross-neutralization of Y25 by another chimpanzee adenovirus belonging to Human adenovirus E, we used serum from a recent Phase I clinical trial in which volunteers vaccinated with a recombinant ChAd63 malaria vaccine developed extremely high neutralization titers against ChAd63 (.1:1,000) [10]

Summary

Introduction

Recombinant adenoviruses were originally developed for gene therapy [1], but the strong and sustained transgene-specific immune responses elicited by these delivery agents, together with their broad tissue tropism, has prompted their use as vaccine vectors [2]. Deletion of a single transcriptional unit, E1, renders the virus replication incompetent, reducing the potential for side effects in clinical applications. The first generation of vaccine vectors based on human adenovirus type 5 (HAdV-5), the most widely studied adenoviral serotype, showed poor efficacy in HIV-1 clinical trials despite encouraging pre-clinical data [3,4]. Neutralising antibodies have the potential to reduce the potency of viral vector vaccines by inhibiting vector mediated delivery of the encoded transgene. Pre-existing anti vector immunity has since been addressed through the development of new vectors based on serotypes to which the human population is less exposed, including those of chimpanzee origin [5,6,7]. Chimpanzee adenoviral vectors have been shown to be highly immunogenic in animal models [8,9] and recently in clinical malaria vaccine trials [10,11]

Methods

Results

Conclusion