The majority of the current crop of HIV vaccine candidates are designed to induce CD4 and CD8 T cell responses targeting the virus. So far, efforts to induce effective neutralizing antibodies against HIV have been stymied by the virus’s mutable, sugary envelope which has evolved to fend off antibody attacks. Because the induction of neutralizing antibodies is generally considered critical for successful vaccines, there is much uncertainty about the prospects for T cell-based HIV vaccine approaches.
Two new studies attempt to shed further light on this issue using the animal model of rhesus macaques challenged with HIV’s simian sibling, SIV. Encouragingly, the results suggest that T cell-based HIV vaccines might show a useful degree of efficacy.
The two studies use slightly differing approaches. The first, led by Norm Letvin’s research group at Harvard, is an analysis of macaques that received various vaccine regimens (an adenovirus vector or DNA followed by the adenovirus vector, encoding SIV Env, Gag/Pol, or Gag/Pol/Env) and were subsequently challenged intravenously with a high dose of the highly pathogenic SIVmac251. The authors report that vaccine-induced T cell responses were correlated with: prolonged survival after challenge, the preservation of an important subset of CD4 T cells dubbed “central memory” T cells and diminution of acute SIV viral load. Importantly, none of the macaques possessed the immune response gene Mamu A*01 which (like HLA B*57 in humans) which has been associated with prolonged survival in SIV-infected macaques even in the absence of vaccination.
The second study was led by David Watkins and explored the efficacy of a similar DNA+adenovirus vector vaccine strategy (encoding the Gag, Tat, Rev, and Nef proteins from SIV) against repeated low-dose mucosal (intrarectal) challenges with a highly pathogenic SIV known as SIVmac239. Vaccine recipients and unvaccinated control animals all became infected after ~5 low-dose challenges, but the vaccine recipients showed significantly reduced SIV viral loads during both the acute and chronic phase of infection. Memory CD4 T cells were also preserved in the vaccinees. The researchers note that these results were far better than those obtained in a prior study in which the vaccines had encoded only SIV gag, suggesting that the inclusion of additional genes broadens the virus-specific T cell response leading to enhanced control of SIV replication. One caveat is that, unlike the Letvin study, the macaques all possessed the Mamu A*01 gene and thus would be expected to fare somewhat better than animals lacking the gene. However, this applies equally to both the vaccine recipients and controls and macaques with another potentially salutary immune response gene (Mamu B*17) were not included in the study.
Vaccine regimens similar to those used in these animal studies are being evaluated in humans. Results from the ongoing Merck efficacy trial, which employs an adenovirus vector encoding HIV’s gag, pol and nef genes, are expected sometime next year. Another large efficacy trial of a DNA vaccine followed by an adenovirus vector encoding multiple HIV genes (including env, which the Merck vaccine omits) is due to start soon; this vaccine was developed by the Vaccine Research Center at the National Institutes of Health.
Science. 2006 Jun 9;312(5779):1530-3.
Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys.
Letvin NL, Mascola JR, Sun Y, Gorgone DA, Buzby AP, Xu L, Yang ZY, Chakrabarti B, Rao SS, Schmitz JE, Montefiori DC, Barker BR, Bookstein FL, Nabel GJ.
Vaccine-induced cellular immunity controls virus replication in simian immunodeficiency virus (SIV)-infected monkeys only transiently, leading to the question of whether such vaccines for AIDS will be effective. We immunized monkeys with plasmid DNA and replication-defective adenoviral vectors encoding SIV proteins and then challenged them with pathogenic SIV. Although these monkeys demonstrated a reduction in viremia restricted to the early phase of SIV infection, they showed a prolonged survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates of vaccine efficacy should guide the evaluation of AIDS vaccines in humans.
J Virol. 2006 Jun;80(12):5875-85.
Vaccine-induced cellular immune responses reduce plasma viral concentrations after repeated low-dose challenge with pathogenic simian immunodeficiency virus SIVmac239.
Wilson NA, Reed J, Napoe GS, Piaskowski S, Szymanski A, Furlott J, Gonzalez EJ, Yant LJ, Maness NJ, May GE, Soma T, Reynolds MR, Rakasz E, Rudersdorf R, McDermott AB, O'Connor DH, Friedrich TC, Allison DB, Patki A, Picker LJ, Burton DR, Lin J, Huang L, Patel D, Heindecker G, Fan J, Citron M, Horton M, Wang F, Liang X, Shiver JW, Casimiro DR, Watkins DI.
The goal of an AIDS vaccine regimen designed to induce cellular immune responses should be to reduce the viral set point and preserve memory CD4 lymphocytes. Here we investigated whether vaccine-induced cellular immunity in the absence of any Env-specific antibodies can control viral replication following multiple low-dose challenges with the highly pathogenic SIVmac239 isolate. Eight Mamu-A*01-positive Indian rhesus macaques were vaccinated with simian immunodeficiency virus (SIV) gag, tat, rev, and nef using a DNA prime-adenovirus boost strategy. Peak viremia (P = 0.007) and the chronic phase set point (P = 0.0192) were significantly decreased in the vaccinated cohort, out to 1 year postinfection. Loss of CD4(+) memory populations was also ameliorated in vaccinated animals. Interestingly, only one of the eight vaccinees developed Env-specific neutralizing antibodies after infection. The control observed was significantly improved over that observed in animals vaccinated with SIV gag only. Vaccine-induced cellular immune responses can, therefore, exert a measure of control over replication of the AIDS virus in the complete absence of neutralizing antibody and give us hope that a vaccine designed to induce cellular immune responses might control viral replication.