A Trimeric, V2-Deleted HIV-1 Envelope Glycoprotein Vaccine Elicits Potent Neutralizing Antibodies but Limited Breadth of Neutralization in Human Volunteers

A successful preventative human immunodeficiency virus (HIV) vaccine will likely need to generate a combination of broad cellular immunity and broadly cross-neutralizing antibody responses. Twenty-five years of research and development of HIV vaccines have not yet succeeded in the generation of a candidate vaccine that achieves this goal. Two phase 3 trials of recombinant subunit gp120 envelope protein vaccines demonstrated that the limited humoral responses generated by this approach had no protective efficacy [1, 2]. The Merck-HIV Vaccine Trials Network (HVTN) phase 2b trial of the MRK Ad5 HIV-1 gag/pol/nef vaccine, commonly known as the STEP trial, demonstrated that this prototypical cytotoxic T-lymphocyte (CTL)–based vaccine did not protect volunteers from infection and failed to reduce the viral load setpoint [3]. Recently, a phase 3 trial of a recombinant canarypox prime followed by a gp120 boost provided the first evidence that some protective efficacy can be achieved by a preventive HIV vaccine. Results from the RV144 trial revealed that, in the modified intent-to-treat analysis, the vaccine efficacy rate was 31.2%, while showing no effect on subsequent viremia or T cell count in individuals who became infected [4]. Further understanding of the mechanism underlying the modest and transient protection seen in this trial is warranted. The DNA and protein vaccines used in the present trial represented an attempt to elicit both cellular and humoral responses against HIV and, in particular, to generate neutralizing antibodies that would neutralize not just highly neutralization-sensitive (tier 1) viruses, but also heterologous isolates that exhibit a more typical neutralization phenotype (tier 2) of primary isolates [34]. The envelope immunogen was a recombinant, purified gp140 protein that was trimeric and derived from the SF162 primary isolate of HIV [5]. To enhance exposure of the coreceptor binding site, a deletion was introduced in the V2 loop. This deletion enhanced binding of CD4-induced antibodies 17b and 48d, indicating that the coreceptor binding site was indeed more accessible [5]. Gag and Env DNA priming was performed in a formulation with polylactide coglycolide (PLG) microparticles and followed by trimeric Env protein boosting. This approach appeared promising in small animals and generated an enhanced breadth of neutralization in nonhuman primates [5, 6]. Here, we report results from the first human trial of this vaccination approach. CD4+ T cell responses against Env were generated, whereas CD8+ CTL responses were not successfully elicited by this approach. Remarkably high titers of neutralizing antibodies were generated against the homologous SF162 virus. Nevertheless, the approach failed to elicit antibodies capable of neutralizing heterologous, tier 2 clade B viruses.