Multimodality vaccination against clade C SHIV: Partial protection against mucosal challenges with a heterologous tier 2 virus

Abstract

We sought to test whether vaccine-induced immune responses could protect rhesus macaques (RMs) against upfront heterologous challenges with an R5 simian-human immunodeficiency virus, SHIV-2873Nip. This SHIV strain exhibits many properties of transmitted HIV-1, such as tier 2 phenotype (relatively difficult to neutralize), exclusive CCR5 tropism, and gradual disease progression in infected RMs. Since no human AIDS vaccine recipient is likely to encounter an HIV-1 strain that exactly matches the immunogens, we immunized the RMs with recombinant Env proteins heterologous to the challenge virus. For induction of immune responses against Gag, Tat, and Nef, we explored a strategy of immunization with overlapping synthetic peptides (OSP). The immune responses against Gag and Tat were finally boosted with recombinant proteins. The vaccinees and a group of ten control animals were given five low-dose intrarectal (i.r.) challenges with SHIV-2873Nip. All controls and seven out of eight vaccinees became systemically infected; there was no significant difference in viremia levels of vaccinees vs. controls. Prevention of viremia was observed in one vaccinee which showed strong boosting of virus-specific cellular immunity during virus exposures. The protected animal showed no challenge virus-specific neutralizing antibodies in the TZM-bl or A3R5 cell-based assays and had low-level ADCC activity after the virus exposures. Microarray data strongly supported a role for cellular immunity in the protected animal. Our study represents a case of protection against heterologous tier 2 SHIV-C by vaccine-induced, virus-specific cellular immune responses.

Oral clade C SHIV challenge models to study pediatric HIV-1 infection by breastmilk transmission

“…In contrast, SHIV-1157ipd3N4-exposed animals with high peak viremia (>10 6 copies/ ml) in the acute phase, seroconverted rapidly. This result is remarkably similar to the outcome of the clade C SHIV-2873Nip intrarectal challenge in adult macaques (55). The former study established that viremia below 10 4 copies of viral RNA/ml was insufficient to result in seroconversion.…”

“…The former study established that viremia below 10 4 copies of viral RNA/ml was insufficient to result in seroconversion. Therefore, to achieve “persistent systemic infection” (PSI) in the acute phase, viral challenges should be continued until the threshold of 10 4 copies of viral RNA/ml is reached, because a certain duration and magnitude of viremia is necessary for sufficient antigen stimulation to trigger a humoral response (55). The dose of 20-40 TCID 50 /ml of SHIV-1157ipd3N4 applied in the current study was likely a contributing factor to the transient viremia observed in two of the infant macaques.…”

Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial

“…The results showed that SHIV infected CD4 cells were no longer detectable in the peripheral blood 2 months after SHIV challenge in all macaques vaccinated with Tat Oyi and one of these animals retro seroconverted [ 18 ]. The efficacy of Tat Oyi was recently confirmed in another heterologous SHIV challenge [ 19 ]. It was also possible to identify a highly conserved surface on Tat variants and Tat Oyi has specific mutations that transform this highly conserved surface in a 3D épitope [ 20 ].…”

Vaccination against Clostridium difficile by Use of an Attenuated Salmonella enterica Serovar Typhimurium Vector (YS1646) Protects Mice from Lethal Challenge

“…Although they are logistically more complicated and considered inelegant by some, heterologous prime-boost and multimodality vaccination strategies are gaining traction for a wide range of infections and other complex conditions, such as cancers (34–36). Of particular interest to the current proposal, such combined-modality approaches have shown promise in eliciting effective immune responses against mucosal pathogens, such as human immunodeficiency virus/simian-human immunodeficiency and influenza virus (35, 36).…”