Vaccine Vectors Derived from a Large Collection of Simian Adenoviruses Induce Potent Cellular Immunity Across Multiple Species

Abstract

Replication defective Adenovirus vectors based on the human serotype 5 (Ad5) have been shown to induce protective immune responses against diverse pathogens and cancer in animal models and to elicit robust and sustained cellular immunity in humans. However, most humans have anti-Ad5 neutralising antibodies that can impair the immunological potency of such vaccines. Here we show that most other human Adenoviruses from rare serotypes are far less potent as vaccine vectors than Ad5 in mice and non-human primates, casting doubt on their potential efficacy in humans. To identify novel vaccine carriers suitable for vaccine delivery in humans we isolated and sequenced over a thousand Adenovirus strains from chimpanzees (ChAd). Replication-defective vectors were generated from different ChAd serotypes and were screened for neutralization by human sera and for ability to grow in human cell lines already approved for clinical studies. Most importantly, we devised a screening strategy to rank the ChAd vectors by immunological potency in mice which predicts their immunogenicity in non-human primates and humans. The vectors studied varied by up to a thousand-fold in potency for CD8 T cell induction in mice. Two of the Europe PMC Funders Group

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

“…rAd serotype 5 (rAd5) is the most potent vector in preclinical and clinical studies but has high seroprevalence in human populations due to natural infection (8,9), which may limit optimal CD8 immunity. This led to the development of alternative rAds based on serotypes with low seroprevalence (2,3,7), but these vary substantially in their potency and protective capacity (7)(8)(9)(10). Of note, a chimpanzee-derived rAd, chAd3, has recently entered accelerated phase I clinical trials for Ebola virus infection, after inducing a high level of protection in a preclinical nonhuman primate model (11).…”

“…While there were clear differences in transcript level across rAds, expression of transcript may not reflect protein expression. Additionally, different adenovirus serotypes can use different receptors to enter target cells (2,3,7,23), which could alter the distribution of Ag across DC subsets and affect CD8 T cell immunity. To assess this directly, mice were vaccinated with rAd5, rAd35, chAd3, and chAd63 encoding EGFP.…”

Transient IL-10 receptor blockade can enhance CD8+T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen

“…Serum IL-10 concentration was measured in BABL/c mice 24 hours after intradermal immunization with 5 x 10 9 viral particles of ChAdV9.ME.TRAP, a vector that belongs to the same serogroup as ChAdV63. 6 IL-10 was quantified using a BD Cytometric Bead Array Mouse Inflammation Kit (BD Biosciences) according to the manufacturer's instructions.…”

“…3 The field has now turned to rare human adenoviruses (HAdVs 26 and 35) and simian adenovirus ChAdV63 for which seroprevalence in humans is low. 5 However, such vectors may be less potent than HAdV5, 6 though capable of eliciting strong immune responses when included in heterologous primeboost regimens. 5 A potential approach to increasing the immunogenicity of adenovirus vectors is to modulate inhibitory signals, such as interleukin-10 (IL-10), that are induced alongside pro-inflammatory cytokines and chemokines as a compensatory anti-inflammatory response.…”

Vaccine Targeting of Subdominant CD8+ T Cell Epitopes Increases the Breadth of the T Cell Response upon Viral Challenge, but May Impair Immediate Virus Control

“…Previous studies have documented that targeting the most immunogenic epitopes may induce high numbers of Ag-specific CD8 + T cells, but it may also focus the immune response on the selected epitope/Ag, and thus a potential drawback of this approach could be a narrow CD8 + T cell repertoire (24). Adenoviral vectors have been extensively studied as potential vaccine candidates for a number of diseases in which the induction of a robust and long-lasting CD8 + T cell response is considered pivotal (25)(26)(27)(28). We have previously shown that linkage of the vaccine Ag to the MHC class II invariant chain (Ii) can broaden and enhance the Ag-specific CD8 + T response, resulting in improved antiviral protection (29,30).…”