The cAMP pathway and not Interferons regulate the IgG response to ALVAC.
Studies focused on prime-boost vaccines believed to be crucial in creating both humoral and cellular immunity. Prime-boost vaccines consist of prime vaccine (canary pox recombinant vaccine) to activate cytotoxic lymphocytes (CTL), followed by rgp120 vaccine to boost humoral immunity. VPC 1521: The prime vaccine used was VPC 1521, cultivated from canary pox virus, which included a particular gene isolated from Thailand. B/E gp120: The boost vaccine was developed from viruses extracted from patients and laboratory- cultured sub-types E and B.
RV144 remains the only HIV-1 vaccine trial to demonstrate efficacy against HIV-1 acquisition. The analysis of immune correlates of risk showed that antibodies directed against the V1V2 region of gp120: showed 31% protection of exposed vaccinees at 3.5 years. RV144 and recent nonhuman primate challenge studies suggest that Env is essential, and perhaps sufficient, to induce protective antibody responses against mucosal HIV-1 acquisition. There was little understanding of the mechanisms that led to protection. RV144 generated weak neutralizing Ab and CD8 responses whiles Anti-HIV-1 V1V2 envelope loop antibodies (IgG3) may contribute to protection against HIV-1 infection (ADCC). High levels of Env-specific IgA antibodies (V3) may mitigate the effects of protective antibodies (inhibits ADCC).
Study 36 (Sekaly/Haynes) is a Macaque study of ALVAC mirroring the prime boost regimen of the RV-144 trial. We are asking the following questions. What is the effect/role of the ALVAC-AEgp120 insert in the ALVAC prime on antibody induction to A244 gp120 /MN gp120? What features are induced early at boost (w14) that is persistent at durability (wk53).
We have determined that Poxvirus (ALVAC) activation of cGAS/cGAMP results in chemokine production, leukocyte migration, immune activation and vaccine immunogenicity. At the site of immunization in Macrophace/DCs, Poxvirus (ALVAC) activation of cGAS/cGAMP results in chemokine production, leukocyte migration, immune activation and vaccine immunogenicity, whiles Extravasating leukocytes migrate to the site of immunization.
To date we see that ALVAC- AEgp120 insert trigger the cGAS and cGAMP pathways in DCs; Both innate and adaptive immune subsets contribute to the IgG and IgA Ab responses; Distinct pathways demarcate those that correlate with IgA and IgG responses. Interferons and Interferon regulated genes are triggered by the vectors but do not correlate with IgG or IgA Ab Titters; cAMP pathway is correlated at all time points with the IgG and not the IgA response. The TGF-beta pathway is correlated to the IgA Ab response.
We are currently Validating in vivo correlates using cellular and molecular protocols to identify cGAMP/p-TBK1 activation in vaccine samples, Impact of pox vector on STING activation, and Activation of P2Y receptors by cGAMP.