Contribution of nonneutralizing vaccine-elicited antibody activities to improved protective efficacy in rhesus macaques immunized with Tat/Env compared with multigenic vaccines.

Previously, chronic-phase protection against SHIV(89.6P) challenge was significantly greater in macaques primed with replicating adenovirus type 5 host range mutant (Ad5hr) recombinants encoding HIVtat and env and boosted with Tat and Env protein compared with macaques primed with multigenic adenovirus recombinants (HIVtat, HIVenv, SIVgag, SIVnef) and boosted with Tat, Env, and Nef proteins. The greater protection was correlated with Tat- and Env-binding Abs. Because the macaques lacked SHIV(89.6P)-neutralizing activity prechallenge, we investigated whether Ab-dependent cellular cytotoxicity (ADCC) and Ab-dependent cell-mediated viral inhibition (ADCVI) might exert a protective effect. We clearly show that Tat can serve as an ADCC target, although the Tat-specific activity elicited did not correlate with better protection. However, Env-specific ADCC activity was consistently higher in the Tat/Env group, with sustained cell killing postchallenge exhibited at higher levels (p < 0.00001) for a longer duration (p = 0.0002) compared with the multigenic group. ADCVI was similarly higher in the Tat/Env group and significantly correlated with reduced acute-phase viremia at wk 2 and 4 postchallenge (p = 0.046 and 0.011, respectively). Viral-specific IgG and IgA Abs in mucosal secretions were elicited but did not influence the outcome of the i.v. SHIV(89.6P) challenge. The higher ADCC and ADCVI activities seen in the Tat/Env group provide a plausible mechanism responsible for the greater chronic-phase protection. Because Tat is known to enhance cell-mediated immunity to coadministered Ags, further studies should explore its impact on Ab induction so that it may be optimally incorporated into HIV vaccine regimens.

Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques.

Cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but the role of nonneutralizing antibodies is not defined. Previously, we reported that sequential oral/oral or intranasal/oral (I/O) priming with replication-competent adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibited equivalent, significant reductions of chronic viremia after rectal SIV(mac251) challenge. However, I/O priming gave significantly better control of acute viremia. Here, systemic and mucosal humoral immunity were investigated for potential correlates with the acute challenge outcome. Strong serum binding but nonneutralizing antibody responses against SIV(mac251) were induced in both groups. Antibody responses appeared earlier and overall were higher in the I/O group. Reduced acute viremia was significantly correlated with higher serum binding titer, stronger antibody-dependent cellular cytotoxicity activity, and peak prechallenge and 2-week-postchallenge antibody-dependent cell-mediated viral inhibition (ADCVI). The I/O group consistently displayed greater anti-envelope immunoglobulin A (IgA) antibody responses in bronchoalveolar lavage and a stronger rectal anti-envelope IgA anamnestic response 2 weeks postchallenge. Pre- and postchallenge rectal secretions inhibited SIV transcytosis across epithelial cells. The inhibition was significantly higher in the I/O group, although a significant correlation with reduced acute viremia was not reached. Overall, the replicating Ad5hr-SIV priming/envelope boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities. The pattern of elevated immune responses in the I/O group is consistent with its better control of acute viremia mediated, at least in part, by ADCVI activity and transcytosis inhibition.

Comparative evaluation of oral and intranasal priming with replication-competent adenovirus 5 host range mutant (Ad5hr)-simian immunodeficiency virus (SIV) recombinant vaccines on immunogenicity and protective efficacy against SIV(mac251).

Oral, replication-competent Ad-HIV vaccines are advancing to human trials. Previous evaluation of protective efficacy in non-human primates has primarily followed upper respiratory tract administrations. Here we compared sequential oral (O/O) versus intranasal/oral (I/O) priming of rhesus macaques with Ad5 host range mutant-SIV recombinants expressing SIV env/rev, gag, and nef genes followed by boosting with SIV gp120 protein. Cellular immune responses in PBMC were stronger and more frequent after I/O administration. Both groups developed mucosal immunity, including memory cells in bronchial alveolar lavage, and gut-homing receptors on PBMC. Following intrarectal SIV(mac251) challenge, both groups exhibited equivalent, significant protection and robust post-challenge cellular immunity. Our results illustrate the promise of oral replication-competent Ad-recombinant vaccines. Pre-challenge PBMC ELISPOT and proliferative responses did not predict protection in the O/O group, highlighting the need for simple, non-invasive methods to reliably assess mucosal immunity.