Immunization with live, replication-competent Ad-HIV or Ad-SIV envelope recombinant vaccines primes strong antibody responses that develop following administration of booster immunizations with envelope protein. These antibodies display a variety of functional activities. The most desirable for an HIV/AIDS vaccine is neutralizing activity that is able to prevent infection following exposure to the virus. We have elicited such antibodies in the rhesus macaque model that conferred apparent sterilizing immunity following challenge with an HIV/SIV chimeric SHIV virus. Our vaccine regimen also elicits antibodies with other functional activities mediated by Fc-receptor bearing cells such as NK cells. HIV/SIV infection is initially manifested as small foci of infected cells. Within 2 to 6 days, virus spreads from these cell foci to draining lymph nodes, subsequently leading to systemic infection. These additional functional activities can help control of the initial viral burden by limiting the spread of virus from these foci of infection. Such activities include antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cell-mediated viral inhibition (ADCVI). Our recent studies demonstrate that these non-neutralizing antibody activities are correlated with lower viral burdens. Since HIV is transmitted mainly at rectal/genital mucosal sites, a key goal of HIV vaccine development is to elicit mucosal immunity. The Ad-recombinant prime/protein boost strategy induces antibodies in mucosal secretions which can inhibit transcytosis of SIV across an epithelial cell barrier, suggesting another mechanism which may contribute to protection. We have shown that vaccine-elicited viral-specific mucosal IgA antibodies are correlated with delayed infection following challenge with infectious SIV. The goal of vaccination is to develop immune memory. We have developed methodology to investigate memory B cells, which secrete antibodies. The ability of vaccines to elicit long lasting memory B cells is a critical property if immunization is to provide long-lasting, and potentially life-long protection. We have comprehensively investigated the dynamics of memory B cells in blood and tissues of SIV-infected rhesus macaques during treatment and therapeutic immunization. The knowledge gained will facilitate our further design and evaluation of vaccine strategies. We have shown that the quality of the antibody response and the level of anamnestic response following viral exposure are key features that impact a protective outcome. Overall, our recent studies continue to demonstrate that our vaccine strategy induces long-lasting, high-titered antibodies with a spectrum of activities both in serum and mucosal secretions, which together contribute to strong protection against viral challenge in non-human primate models. These findings have advanced the approach toward phase I clinical trials of the HIV/AIDS vaccine.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Thomas, Michael A; Demberg, Thorsten; Vargas-Inchaustegui, Diego A et al. (2014) Rhesus macaque rectal and duodenal tissues exhibit B-cell sub-populations distinct from peripheral blood that continuously secrete antigen-specific IgA in short-term explant cultures. Vaccine 32:872-80
Vargas-Inchaustegui, Diego A; Tuero, Iskra; Mohanram, Venkatramanan et al. (2014) Humoral immunity induced by mucosal and/or systemic SIV-specific vaccine platforms suggests novel combinatorial approaches for enhancing responses. Clin Immunol 153:308-22
Sholukh, Anton M; Byrareddy, Siddappa N; Shanmuganathan, Vivekanandan et al. (2014) Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: outcome depends on IgG dose. Retrovirology 11:8
Mohanram, Venkatramanan; Demberg, Thorsten; Tuero, Iskra et al. (2014) Improved flow-based method for HIV/SIV envelope-specific memory B-cell evaluation in rhesus macaques. J Immunol Methods 412:78-84
Tuero, Iskra; Robert-Guroff, Marjorie (2014) Challenges in mucosal HIV vaccine development: lessons from non-human primate models. Viruses 6:3129-58
Vaccari, Monica; Halwani, Rabih; Patterson, L Jean et al. (2013) Antibodies to gp120 and PD-1 expression on virus-specific CD8+ T cells in protection from simian AIDS. J Virol 87:3526-37
Hidajat, Rachmat; Xiao, Peng; Zhou, Qifeng et al. (2009) Correlation of vaccine-elicited systemic and mucosal nonneutralizing antibody activities with reduced acute viremia following intrarectal simian immunodeficiency virus SIVmac251 challenge of rhesus macaques. J Virol 83:791-801
Demberg, Thorsten; Robert-Guroff, Marjorie (2009) Mucosal immunity and protection against HIV/SIV infection: strategies and challenges for vaccine design. Int Rev Immunol 28:20-48
Demberg, Thorsten; Boyer, Jean D; Malkevich, Nina et al. (2008) Sequential priming with simian immunodeficiency virus (SIV) DNA vaccines, with or without encoded cytokines, and a replicating adenovirus-SIV recombinant followed by protein boosting does not control a pathogenic SIVmac251 mucosal challenge. J Virol 82:10911-21
Patterson, L Jean; Beal, Jennifer; Demberg, Thorsten et al. (2008) Replicating adenovirus HIV/SIV recombinant priming alone or in combination with a gp140 protein boost results in significant control of viremia following a SHIV89.6P challenge in Mamu-A*01 negative rhesus macaques. Virology 374:322-37

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