Prime–boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: Efficacy against repeated mucosal R5 clade C SHIV challenges

Abstract

We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus >90%; these RM also had strong SIV Gag-specific proliferation of CD8+ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4+ T cells; the latter have been implicated as preferential virus targets in-vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection.

Novel Biopanning Strategy To Identify Epitopes Associated with Vaccine Protection

“…In the present study, we examined Ab responses in vaccinated RMs described elsewhere (15)(16)(17)(18)(19). After completion of all immunizations (multimeric HIV-1 clade C [HIV-C] gp160, HIV-1 clade B Tat, or SIV Gag-Pol particles) and virus challenges (SHIV-1157ipEL-p) (20), SHIV-1157ip, or SHIV-1157ipd3N4 (21), respectively, we observed different levels of protection among the vaccinees (Table 1).…”

“…We studied Indian-origin RMs (Macaca mulatta) that had been enrolled in three different vaccine/challenge studies described elsewhere (15)(16)(17). They were housed at the Yerkes Regional Primate Research Center (Atlanta, GA), and all procedures were approved by the Animal Care and Use Committees of Emory University and the Dana-Farber Cancer Institute (DFCI).…”

“…Table 1 examined in this study and lists the immunogens and challenge viruses used. The levels of protection are given according to the original publications (15)(16)(17), with minor changes for vaccinees RGe-11 and RFo-11 and control animal RAk-11 (15) since only immune responses during the low-dose challenge phase were analyzed in the present study. For all vaccinees, plasma samples collected at two different time points were evaluated for Ab responses: week 0, after the completion of all immunizations but before the first virus challenge, and week 7, after multiple live-virus exposures.…”

Efficiency of Neutralizing Antibodies Targeting the CD4-Binding Site: Influence of Conformational Masking by the V2 Loop in R5-Tropic Clade C Simian-Human Immunodeficiency Virus

“…Two R5-tropic clade C SHIVs (SHIV-Cs) that carry env related to a pediatric HIV clade C (HIV-C) isolate, HIV1157i, have been developed by our laboratory and used in challenge studies (9,10,23). SHIV-1157ipEL-p carries the recently transmitted env and has a tier 1 neutralization profile (20).…”

Importância da resposta aos epítopos subdominantes, da proliferação e da recirculação de linfócitos T CD8+ durante a vacinação experimental contra a infecção pelo Trypanosoma cruzi.

“…These new strategies include (i) prime with plasmid DNA in the presence of cytokine genes such as IL-12 or GM-CSF (Lai et al, 2011;Winstone et al, 2011), (ii) genes encoding multimeric proteins (Lakhashe et al, 2011), (iii) boost of adenovirus-immunized animals with an optimized plasmid DNA (Hutnick et al, 2012), (iv) prime with rhesus cytomegalovirus (Hansen et al, 2011), and (v) prime with a different heterologous strain of adenovirus (Barouch et al, 2012). …”