Background:..A central problem for HIV vaccines is the elicitation of antibodies capable of neutralizing primary isolates. Here we compare an SHIV-89.6 vaccine delivered in the presence or absence of GM-CSF with a nonpathogenic SHIV-89.6 infection for the ability to elicit cross-reactive neutralizing antibodies for primary isolates of HIV-1.

Methods:  Rhesus macaques were immunized with 0.25 mg of a SHIV-89.6 DNA with or without 0.25 mg of GM-CSF DNA at 0 and 8 weeks and boosted with a SHIV-89.6 MVA at 24 weeks. At 53 weeks the vaccinated animals were challenged with SHIV-89.6P, a neutralization escape mutant of SHIV-89.6. A third group was infected with SHIV-89.6. Neutralizing activity (50% neutralization in a Luc reporter assay) and the avidity of the polyclonal anti-Env sera (determined using NaSCN treatments of solid-phase ELISA) were followed over time.

Results:  The SHIV-89.6 immunizations were found to prime better cross-reactive neutralizing antibodies than the SHIV-89.6 infection. This neutralizing activity required time and was first detected at 6 months after the boost. The neutralizing activity underwent a strong anamnestic expansion post the SHIV-89.6P challenge, at which time neutralization titers for a panel of primary isolates ranged from 20 to more than 500. The GM-CSF-adjuvanted vaccine group had the broadest neutralizing activity and neutralized SHIV-89.6, HIV-1 isolates BX-08, JR-FL, 692, 6101, 515, and SHIV-89.6P. The nonadjuvanted vaccine group neutralized the same viruses but had less consistent activity for 6101 and SHIV-89.6P and no activity for 515. In contrast, the SHIV-89.6-infected group neutralized only SHIV-89.6 and BX-08, with inconsistent activity for JR-FL. Neutralizing activity was associated with the avidity maturation of the anti-Env-binding antigen. This avidity was low post the MVA boost, requiring only 0.65 M NaSCN for 50% displacement from 89.6 gp140. However, the avidity increased over the next 6 months to 2.1 M NaSCN for 50% displacement. The avidity of the anti-Env-antigen response also increased with time in the SHIV-89.6 infected macaques, but failed to reach the levels observed in the vaccinated macaques.

Conclusions:  DNA/MVA SHIV-89.6 vaccines can support the avidity maturation of the anti-Env-antigen response and prime antigen capable of neutralizing primary isolates. This potential is further enhanced by GM-CSF DNA.

Keywords: vaccine; neutralizing Ab; GM-CSF