DNA-MVA Vaccine Protection after X4 SHIV Challenge in Macaques Correlates with Day-of-Challenge Antiviral CD4⁺Cell-Mediated Immunity Levels and Postchallenge Preservation of CD4⁺T Cell Memory

Abstract

The ability of vaccines to induce immunity both in mucosal and systemic compartments may be required for prevention of HIV infection and AIDS. We compared DNA-MVA vaccination regimens adjuvanted by IL-12 DNA, administered intramuscularly and nasally or only nasally. Most of the vaccinated Rhesus macaques developed mucosal and systemic humoral and cell-mediated SHIVspecific immune responses. Stimulation of mucosal anti-Env IgA responses was limited. After rectal challenge with SHIV 89.6P, all vaccinated and naive animals became infected. However, most of the vaccinated animals showed significant control of viremia and protection from CD4 + T cell loss and AIDS progression compared to the control animals. The levels of CD4 + and CD8 + T cell virusspecific responses measured on the day of challenge correlated with the level of viremia control observed later during the chronic infection. Postchallenge viremia levels inversely correlated with the preservation of SHIV-specific CD4 + /IL-2 + and CD8 + /TNF-α + T cells but not with CD4 + /IFN-γ + T cells measured over time after challenge. We also found that during the early chronic infection SHIV vaccination permitted a more significant preservation of both naive and memory CD4 + T cells compared to controls. In addition, we observed a more significant and prolonged preservation of memory CD4 + T cells after SHIV vaccination and challenge than that observed after SIV vaccination and challenge. As the antiviral immunity stimulated by vaccination is present in the memory CD4 +

Immunogenicity of a Vaccine Regimen Composed of Simian Immunodeficiency Virus DNA, rMVA, and Viral Particles Administered to Female Rhesus Macaques via Four Different Mucosal Routes

“…Secretions were eluted from the sponges by centrifugation as described previously (44). Antiviral and total IgA and IgG in secretions and IgG in serum were measured in an ELISA as described previously (19,21). Briefly, for the SIV ELISAs, microtiter plates were coated overnight with 100 ng/well SIV recombinant gp140mac239 (rgp140mac239) (Immune Technology, New York, NY) or 100 l per well of 1/400 SIVmac251 viral lysate (Advanced Biotechnologies Inc., Columbia, MD) that lacked detectable envelope protein at this dilution.…”

“…However, protection from progression to AIDS was achieved (19,20). The same vaccine administered intranasally was more efficient in eliciting cellular and humoral virus-specific responses at mucosal sites than the same regimen administered systemically (i.m.)…”

Long-Term Control of Simian Immunodeficiency Virusmac251 Viremia to Undetectable Levels in Half of Infected Female Rhesus Macaques Nasally Vaccinated with Simian Immunodeficiency Virus DNA/Recombinant Modified Vaccinia Virus Ankara

“…Antiviral and total IgA in rectal and vaginal secretions and IgG in serum were measured by ELISA, as described (4,7). Briefly, for the ELISAs, microtiter plates were coated overnight with 100 ng/well SIV mac251 rgp130 (ImmunoDiagnostics, Woburn, MA) or 100 ml/ well of 1/400 SIV viral lysate (Advanced Biotechnologies, Columbia, MD) that lacks detectable envelope protein at this dilution.…”

“…555029; BD Biosciences) and 1 mg/ ml anti-CD49d and anti-CD28. The PBMCs and MNCs were stained and evaluated for expression of cytokines according to previously described procedures and reagents (4). Two additional Abs, AT-1 (CD38) and Act-1 (a4b7) (41), were also used in this study.…”

“…In this study, two vaccine regimens administered via the nasal route were evaluated in female rhesus macaques, one being a vaccine previously tested in male rhesus macaques (3,4,7) and the other including as adjuvants TNF-a, IL-12, and GM-CSF DNAs. The goals were 1) to evaluate which of the two nasal SIV DNA/ recombinant modified vaccinia virus Ankara (rMVA) prime/boost regimens provided the broadest, qualitatively more diverse immune responses, as well as the level of protection from SIV infection and progression to AIDS; and 2) to investigate immunological correlates of protection.…”