Heterologous Envelope Immunogens Contribute to AIDS Vaccine Protection in Rhesus Monkeys

Abstract

Because a strategy to elicit broadly neutralizing anti-human immunodeficiency virus type 1 (HIV-1) antibodies has not yet been found, the role of an Env immunogen in HIV-1 vaccine candidates remains undefined. We sought to determine whether an HIV-1 Env immunogen genetically disparate from the Env of the challenge virus can contribute to protective immunity. We vaccinated Indian-origin rhesus monkeys with Gag-Pol-Nef immunogens, alone or in combination with Env immunogens that were either matched or mismatched with the challenge virus. These animals were then challenged with a pathogenic simian-human immunodeficiency virus. The vaccine regimen included a plasmid DNA prime and replication-defective adenoviral vector boost. Vaccine regimens that included the matched or mismatched Env immunogens conferred better protection against CD4؉ T-lymphocyte loss than that seen with comparable regimens that did not include Env immunogens. This increment in protective immunity was associated with anamnestic Env-specific cellular immunity that developed in the early days following viral challenge. These data suggest that T-lymphocyte immunity to Env can broaden the protective cellular immune response to HIV despite significant sequence diversity of the strains of the Env immunogens and can contribute to immune protection in this AIDS vaccine model.

Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens

“…7). Such findings are reminiscent of previous vaccine studies in nonhuman primates, which showed that efficacy was improved by the inclusion of envelope antigens, but in a manner that did not correlate with neutralizing antibody titers (4,5). Nevertheless, we do not dismiss the possibility that higher titers of conventional neutralizing activity at the time of challenge might enhance protection in this model.…”

“…This view stems from demonstrations that the passive transfer of broadly cross-reactive, neutralizing antienvelope antibodies affords sterilizing protection in nonhuman primate models for HIV infection (1)(2)(3). Moreover, certain vaccine strategies are more effective in suppressing infection in nonhuman primate models when viral envelope is included in the vaccine (4,5). Recent evidence indicates that anti-envelope antibody-dependent cellular cytotoxicity activity correlates with protection against HIV challenge (6).…”

DNA Vaccines: Progress and Challenges

“…DNA primes with viral vector boosts also may enhance protective responses to HIV env, although in most such studies the anti-env responses induced by this approach did not include neutralizing Abs (66). Studies of CTL precursor frequencies and circulating tetramer-positive and IFN-␥-producing CD8 ϩ CTL in response to DNA vaccines also showed that, although DNA alone could generate a primed CD8 ϩ T cell population, viral vectors were more effective at inducing expanded populations of circulating effector CTL.…”

Immune-response profiles induced by human immunodeficiency virus type 1 vaccine DNA, protein or mixed-modality immunization: increased protection from pathogenic simian–human immunodeficiency virus viraemia with protein/DNA combination

“…DNA vaccines were shown to induce both humoral and cellular immune responses in rodents, but in non-human primates and in humans, only low-level immunogenicity has been reported (Estcourt et al, 2004;Robinson, 1999). Efforts have been directed at improving these responses by boosting with viral vectors (Amara et al, 2002;Brave et al, 2007;Casimiro et al, 2005;Doria-Rose et al, 2003;Hel et al, 2006;Koopman et al, 2004;Letvin et al, 2004). DNA vaccines are generally effective at stimulating CD8 responses, whilst subunit vaccines are more effective at eliciting antibody responses (Barouch et al, 2000;Earl et al, 2001Earl et al, , 2002Patterson et al, 2004;Robinson, 1999).…”