Circumventing anti-vector immunity towards adenoviral vectored vaccines

ABSTRACT

Replication deficient (RD) adenoviruses (Ad) are the most widely administered viral vectors, with licensed SARS-CoV-2 vaccines using vectors derived from human Ad type 5 (Ad5) and 26 (Ad26), and chimpanzee Ad ''ChAdOx1''. Ad vectored vaccines generate robust cellular and humoral immunity, against both the transgene-encoded protein and the Ad vector itself. It's unclear how many times a single Ad vector can be readministered before this anti-vector immunity impairs generation of the desired transgene-specific adaptive responses. Antivector immunity also arises from naturally acquired Ad infections. In the absence of anti-Ad5 immunity, Ad5 is a goldstandard vector with robust vaccine immunogenicity, however widespread Ad5 seroprevalence hampers its use as a vector for the global population. We developed novel pseudotyped Ads as RD vectored vaccines encoding SARS-CoV-2 spike protein. These vectors exhibit fiber knob swaps from low seroprevalence Ads grafted onto an Ad5 backbone. We characterised innate immune responses following administration of these vectors in mice, and spikespecific adaptive responses three weeks later. Furthermore, we quantified the effects of anti-vector humoral immunity against these vectors in an in vitro transduction assay using human plasma. The pseudotyped vectors exhibit many desirable vaccine characteristics as the equivalent Ad5 vector, including CD4+ and CD8+ T cell responses against multiple spike epitopes. Importantly, fiber knob pseudotyping can substantially circumvent the direct, humoral, anti-vector immunity induced through Ad exposure in humans. These data indicate the fiber knob plays an important role in anti-vector immunity, and can be manipulated for evasion of such responses without hampering vaccine immunogenicity.