490    

Background:  The ability of vaccines to induce mucosal immunity may be required for prevention of HIV infection and AIDS.

Methods:  We have compared vaccination regimens in which multiple antigens were given via the nasal route or were administered intramuscularly (Gag) and nasally (Env), or both (Gag). Fifteen male rhesus macaques, divided into 3 groups, received DNA vaccinations on weeks 1, 9, and 25. A SHIV plasmid producing noninfectious viral particles and an IL-12 plasmid were administered nasally (groups 1 and 3). Group 2 received SHIV Gag and IL-12 plasmids intramuscularly (IM), and HIV 89.6P Env and IL-12 received the plasmids nasally. On week 33, group 1 was boosted nasally with recombinant modified vaccinia virus Ankara (rMVA) expressing SIV Gag-Pol and HIV 89.6P Env. Group 2 was boosted with IM SIV Gag-Pol  rMVA and with intranasal HIV 89.6P Env rMVA. Group 3 received IM boosts with SIV Gag-Pol rMVA and intransally with HIV gp 41 protein in adjuvant.

Results:  Humoral responses were evaluated by measuring SHIV-specific IgG and neutralizing antibodies in plasma, and SHIV-specific IgA in rectal secretions. Cellular responses were monitored by evaluating blood-derived virus-specific interferon-g secreting cells; Il-2 and IFN-g expressing CD4+ cells; TNF-g expressing CD8+ T cells; and blood- and rectally derived p11C tetramer+ T cells. Many of the vaccinated animals developed both mucosal and systemic humoral and cell-mediated SHIV-specific immune responses, although they were not homogenous among animals in the different groups. Stimulation of mucosal anti-gp120 and gp41 IgA that could play a role in preventing infection at the time of exposure needs to be significantly improved. After rectal challenge of vaccinated and naïve animals with SHIV 89.6P, all macaques became infected. However most of the vaccinated animals, including all group 2 animals, controlled viremia and were protected from CD4+ T cell loss.

Conclusions:  The data indicate that the intramuscular vaccination with SHIV Gag antigen may provide a better control of peak viremia than its nasal administration but that there is no significant difference in long-term protection from CD4 loss in the groups. In addition, we observed that the control of viremia paralleled the presence of SHIV-specific CD4+/IL-2 secreting cells, which are thought to be important for virus containment. Priming of these cells occurred during vaccination but we cannot establish whether their persistence after infection is the cause or the consequence of the viremia control.

Keywords: vaccine; mucosal immunization; disease progression