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38 An Effective AIDS Vaccine Based on Live-Attenuated Vesicular Stomatitis Virus Recombinants
N. Rose1, P. Marx2,3, A. Luckay3, D. Nixon4, W. Moretto4, S. Donahoe4, D. Montefiori5, A. Roberts1, and J. Rose*1
1Yale Univ. Sch. of Med., New Haven, CT, USA; 2Aaron Diamond AIDS Res. Ctr., New York, NY, USA; 3Tulane Reg. Primate Ctr., Covington, LA, USA; 4Gladstone Inst., San Francisco, CA, USA; and 5Duke Univ. Med. Ctr., Durham, NC, USA
Background: We have developed a new AIDS vaccine approach based on live-attenuated vesicular stomatitis virus (VSV) vectors expressing env and gag genes.
Methods: Rhesus macaques (n = 7) were vaccinated and boosted with live-attenuated VSV vectors expressing the HIV-1 (89.6) env and SIV (mac239) gag genes. Vaccinations were given by a combination of oral and intramuscular, or intranasal and intramuscular routes. Two boosts were given with the same VSV vectors expressing the HIV and SIV proteins except that for each boost the VSV G protein was replaced with a G protein of another VSV serotype. These vectors avoid neutralization by antibody to VSV generated in the previous immunization and are highly effective at boosting immune responses.
Results: No detectable pathogenesis was associated with vaccination. Cellular immune responses were detected to Env and Gag using ELISPOT and cytokine flow cytometry assays. ELISA antibody titers to the HIV 89.6 envelope were boosted to levels comparable to those seen in long-term SHIV-infected monkeys. Neutralizing antibodies directed to the HIV Env protein and the VSV G proteins were detected also. At 2, 3, or 6 months after the final boost, the vaccinees were challenged I.V. with highly pathogenic SHIV89.6P, which contains the SIV(mac239) gag gene, and an HIV env gene diverged from the 89.6 env gene present in the vaccine vectors. CD4+ lymphocyte counts fell to near zero in control animals (n = 8) within 4 weeks after challenge, but 2 showed some recovery of CD4+ cells. Seven of 8 control animals developed AIDS within 171 days after challenge, and 6 of these had high viral loads (>105/ml). In all vaccinees, CD4 counts dropped initially but then rebounded. There were rapid CTL, total antibody, and neutralizing antibody recall responses in the vaccinees. Viral loads in the vaccinees were detectable initially, but were then controlled to low or undetectable levels. All 7 vaccinees have remained healthy since the challenge. Additional experiments indicate that VSV vector delivery solely by an intranasal route is highly effective in macaques.
Conclusions: VSV vectors provide significant protection against AIDS mortality (p = 0.001; Fisher’s exact test) in the macaque model. Attenuated VSV vectors expressing HIV proteins are promising candidates for HIV vaccine trials in humans because they can be propagated to very high titers and delivered without the need for injection.
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