Profiles of Human Serum Antibody Responses Elicited by Three Leading HIV Vaccines Focusing on the Induction of Env-Specific Antibodies

Abstract

In the current report, we compared the specificities of antibody responses in sera from volunteers enrolled in three US NIH-supported HIV vaccine trials using different immunization regimens. HIV-1 Env-specific binding antibody, neutralizing antibody, antibody-dependent cell-mediated cytotoxicity (ADCC), and profiles of antibody specificity were analyzed for human immune sera collected from vaccinees enrolled in the NIH HIV Vaccine Trial Network (HVTN) Study #041 (recombinant protein alone), HVTN Study #203 (poxviral vector prime-protein boost), and the DP6-001 study (DNA prime-protein boost). Vaccinees from HVTN Study #041 had the highest neutralizing antibody activities against the sensitive virus along with the highest binding antibody responses, particularly those directed toward the V3 loop. DP6-001 sera showed a higher frequency of positive neutralizing antibody activities against more resistant viral isolate with a significantly higher CD4 binding site (CD4bs) antibody response compared to both HVTN studies #041 and #203. No differences were found in CD4-induced (CD4i) antibody responses, ADCC activity, or complement activation by Env-specific antibody among these sera. Given recent renewed interest in realizing the importance of antibody responses for next generation HIV vaccine development, different antibody profiles shown in the current report, based on the analysis of a wide range of antibody parameters, provide critical biomarker information for the selection of HIV vaccines for more advanced human studies and, in particular, those that can elicit antibodies targeting conformational-sensitive and functionally conserved epitopes.

Robust Neutralizing Antibodies Elicited by HIV-1 JRFL Envelope Glycoprotein Trimers in Nonhuman Primates

“…The tier 2 neutralizing capacity of the elicited sera did not appear to be dependent upon priming with cell surface-cleaved JRFL Env, as priming with soluble trimer DNA also generated such activity. Consistent with these data, previous studies have demonstrated improved neutralization following HIV-1 Env DNA prime-protein boost regimens compared to inoculation of Env gp120 protein alone (51)(52)(53)(54)(55). In the more sensitive A3R5 assay, we observed high to modest tier 2 neutralization of all clade B and clade C isolates tested in the serum of most trimer-inoculated animals.…”

“…These other DNA delivery means prime B cell responses that can be boosted by subsequent protein inoculation, but with lower titers than detected here. That two proteins in adjuvant elicited similar binding titers to a single boost of protein primed by DNA suggested that a DNA prime was essentially equal to a protein prime at the quantitative level of binding antibodies, as has been observed in several other studies using a similar DNA prime-protein boost format (51)(52)(53)(54)(55).…”

Mucosal Immunization of Lactating Female Rhesus Monkeys with a Transmitted/Founder HIV-1 Envelope Induces Strong Env-Specific IgA Antibody Responses in Breast Milk

“…Inducing broadly neutralizing antibodies by vaccination has proven to be difficult. Most vaccines tested to date, including the moderately protective RV144 vaccine regimen, elicited tier 1 but not tier 2 neutralizing responses (38,47,48). As passive immunization studies have shown that neutralizing antibodies are able to protect from SHIV infection (50,51), inducing this immune response is an important goal for an HIV vaccine.…”

“…boost regimens. Although most HIV Env vaccines tested to date have been able to induce strong systemic binding antibody responses, only tier 1 and occasionally tier 2 neutralization responses have been elicited through vaccination (38,47,48). Thus, inducing potent, broadly neutralizing antibody responses remains an important goal for future HIV vaccine candidates.…”

Sequential Immunization with a Subtype B HIV-1 Envelope Quasispecies Partially Mimics the In Vivo Development of Neutralizing Antibodies

“…This strategy did not result in the induction of broad heterologous NAbs, but this may have been due to the vaccine delivery system used and/or to the fact that sequences were derived from an SHIV-infected macaque after less than 2 years of infection. Naked DNA plasmids have long been considered a weak delivery system to induce protective immune responses (30,31), but recent studies showed that DNA prime-protein boost approaches can induce neutralizing antibodies in rabbits and in humans (52,53). Additional experiments are in progress using env variants cloned from the plasma of HIV-infected human subjects who developed more potent NAbs than did macaque A141 to determine the broader utility of this approach, as well as to further explore the use of key individual variants that arise during infection as immunogens.…”