Abstract
BackgroundCurrent data suggest that an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine should elicit both adaptive humoral and cell mediated immune responses. Such a vaccine will also need to protect against infection from a range of heterologous viral variants. Here we have developed a simian-human immunodeficiency virus (SHIV) based model in cynomolgus macaques to investigate the breadth of protection conferred by HIV-1W61D recombinant gp120 vaccination against SHIVsbg and SHIVSF33 challenge, and to identify correlates of protection.ResultsHigh titres of anti-envelope antibodies were detected in all vaccinees. The antibodies reacted with both the homologous HIV-1W61D and heterologous HIV-1IIIB envelope rgp120 which has an identical sequence to the SHIVsbg challenge virus. Significant titres of virus neutralising antibodies were detected against SHIVW61D expressing an envelope homologous with the vaccine, but only limited cross neutralisation against SHIVsbg, SHIV-4 and SHIVSF33 was observed. Protection against SHIVsbg infection was observed in vaccinated animals but none was observed against SHIVSF33 challenge. Transfer of immune sera from vaccinated macaques to naive recipients did not confer protection against SHIVsbg challenge. In a follow-up study, T cell proliferative responses detected after immunisation with the same vaccine against a single peptide present in the second conserved region 2 of HIV-1 W61D and HIV-1 IIIB gp120, but not SF33 gp120.ConclusionsFollowing extended vaccination with a HIV-1 rgp120 vaccine, protection was observed against heterologous virus challenge with SHIVsbg, but not SHIVSF33. Protection did not correlate with serological responses generated by vaccination, but might be associated with T cell proliferative responses against an epitope in the second constant region of HIV-1 gp120. Broader protection may be obtained with recombinant HIV-1 envelope based vaccines formulated with adjuvants that generate proliferative T cell responses in addition to broadly neutralising antibodies.
Highlights
Current data suggest that an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine should elicit both adaptive humoral and cell mediated immune responses
Recombinant HIV-1 envelope based AIDS vaccines have progressed to phase 3 trials [4,5,6] but they failed to demonstrate any evidence that the vaccine formulations tested (bivalent gp120 envelope antigen adjuvanted with Alum (AIDSVAXW B/E) were able to prevent acquisition of infection
It is essential that we identify adaptive immune responses elicited by vaccination that have the potential to increase the breadth of protection with HIV-1 envelope based vaccines
Summary
Current data suggest that an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine should elicit both adaptive humoral and cell mediated immune responses. Such a vaccine will need to protect against infection from a range of heterologous viral variants. We have developed a simian-human immunodeficiency virus (SHIV) based model in cynomolgus macaques to investigate the breadth of protection conferred by HIV-1W61D recombinant gp120 vaccination against SHIVsbg and SHIVSF33 challenge, and to identify correlates of protection. The experimental infection of macaques with defined SIV/HIV-1 (SHIV) chimeric viruses provides a model to establish the breadth of protection of candidate vaccines and characterise the key vaccine responses that correlate with the protection observed in a highly controlled manner which cannot be done readily in clinical trials [8]. Recent studies have questioned the role of neutralising antibodies alone, since vaccine protection was observed against neutralising antibody resistant virus challenge [19] and with persistence of T cell responses [20]
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