Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

Abstract

Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. IMPORTANCEAlthough there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. R ecombinant adenoviruses (Ads) are currently being explored as candidate vaccine vectors for multiple pathogens (1-6), as a result of their safety profile, manufacturability, and ability to induce broad and strong immune responses (7-16). Multiple human and chimpanzee adenovirus vectors have been developed to date (8,9,(11)(12)(13). The majority of these adenovirus vectors are from species B, C, D, and E. Adenovirus vectors from avian, bovine, and other species have also been constructed, but their different genomic structures may necessitate the development of a novel manufacturing platform for clinical development (17, 18). Old World monkey adenoviruses have been hypothesized to be distinct from both human and chimpanzee adenoviruses and may offer unique advantages, such as the ability to more efficiently bypass preexisting immunity to human adenoviruses (12,(19)(20)(21)(22)(23)(24), while maintaining the genomic structure and growth properties of human adenoviruses.We isolated simian adenoviruses from fecal samples from rhesus monkeys (Macaca mulatta) that were positive for adenoviruses by metagenomics sequencing (25). We performed whole-genome sequencing of these novel adenoviruses and determined their phylogeny in comparison with that of other human and simian adenoviruses. The basic genetic structure of these novel rhesus monkey adenoviruses proved similar to that of human adenoviruses (7,16,26). We vectorized three rhesus monkey adenoviruses and then assessed humans in sub-Saharan Africa for seroprevalence of these adenoviruses and ...

Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys

“…5). Rhesus adenovirus vectors have the potential advantage of minimal baseline vector-specific neutralizing antibodies in human populations (16). …”

“…To evaluate the immunogenicity and protective efficacy of gene-based and vector-based ZIKV vaccines, we immunized 12 rhesus monkeys with a plasmid DNA vaccine (15) or a rhesus adenovirus serotype 52 (RhAd52) vector-based vaccine (16) (Fig. S1).…”

New developments in an old strategy: heterologous vector primes and envelope protein boosts in HIV vaccine design

“…However, such T-cell-based heterologous vaccine regimens failed to protect rhesus macaques from a repeated low-dose SIV challenge [62]. Simian Ads (sAd11 and sAd16) have also been used as vectors, and recently three novel Ads were isolated from rhesus monkeys and vectorized [63]. Like chimpanzee Ads, simian Ads have low seroprevalence in humans [64].…”

Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination

“…Of the candidate Zika vaccines described to date, only a rhesus adenovirus platform (RhAd52) has been shown to confer protection after a single immunization in NHPs; however, the efficacy of the RhAd52 vector in humans is currently undefined. Additionally, pre-existing immunity to adenovirus serotypes can limit the efficacy of such vectors 13,14 , and low neutralizing titers to rhesus adenoviruses, including RhAd52, have been detected in humans 15 .…”