Abstract
As demonstrated by the recent COVID pandemic, vaccines can reduce the burden arising from infectious agents. Adenoviruses (Ads) with deletion of the early region 1B55K (ΔE1B Ad) are currently being explored for use in vaccine delivery. ΔE1B Ads are different from Ads with deletions in early region 1 and early region 3 (ΔE1/E3) used in most Ad vaccine vectors in that they contain the Ad early region 1A (E1A), and therefore the ability to replicate. Common to almost all Ads that are being explored for clinical use is the Ad early region 4 (E4). Among the E4 genes is open reading frame 1 (E4orf1), which mediates signals through the PI3-kinase/Akt pathway that is known to modulate immune responses. This suggests that E4orf1 might also modulate immune responses, although it has remained unexplored in ΔE1B Ad. Here, we show that cells infected with an E1B55K and E4orf1-deleted (ΔE41) Ad exhibited reduced levels of phosphorylated Akt (Ser473 and Thr308)) and expressed different intrinsic innate immune cytokines from those induced in cells infected with an E4orf1-containing, ΔE1B parental Ad that exhibited elevated levels of phosphorylated Akt. Rhesus macaques immunized with a ΔE41 Ad that expressed rhFLSC (HIV-1BaL gp120 linked to rhesus CD4 D1 and D2), exhibited higher levels of rhFLSC-specific interferon γ-producing memory T-cells, higher titers of rhFLSC-specific IgG1 binding antibody in serum, and antibodies able to mediate antibody-dependent cellular cytotoxicity (ADCC) with greater killing capacity than the ΔE1B Ad. Therefore, E4orf1, perhaps by acting through the PI3-kinase/Akt pathway, limits intrinsic innate and system-wide adaptive immune responses that are important for improved ΔE1B Ad-based vaccines.
Highlights
IntroductionOf the COVID-19 vaccines available worldwide, 6 of 8 are based on adenovirus (Ad) vectors [1] deleted in early region 1 and early region 3 (∆E1/E3 Ad)
It is widely accepted that vaccine-mediated protection should elicit polyfunctional immune responses, including Fc-mediated antibody-dependent cellular cytotoxicity (ADCC)
We showed in mice and rhesus macaques that ∆E41−4 Ad induces higher HIVHIV-specific binding antibody and cytokine-producing memory T-cells compared to ΔE3 specific binding antibody that andeither cytokine-producing memory to ∆E3 Ad [12]
Summary
Of the COVID-19 vaccines available worldwide, 6 of 8 are based on adenovirus (Ad) vectors [1] deleted in early region 1 and early region 3 (∆E1/E3 Ad). In one study a phenotypic wild type ∆E3 Ad HIV vaccine vector was shown to induce a higher frequency of HIV-specific interferon gamma-secreting and proliferating T-cells, higher anti-HIV binding and neutralizing antibody titers, and better induction of ADCC than the ∆E1/E3 Ad [4]. E1B55K acts to lessen the effects of E1A by suppressing the expression of immune response genes [6] and by countering the effect of the virus-induced interferon responses [7]. Besides E1B55K, products of the Ad early region
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