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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011058-06
Application #
8763327
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$2,279,616
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Musich, Thomas; Robert-Guroff, Marjorie (2016) New developments in an old strategy: heterologous vector primes and envelope protein boosts in HIV vaccine design. Expert Rev Vaccines 15:1015-27
Robert-Guroff, Marjorie (2016) The Yin and Yang of ADCC-Mediating Antibodies. EBioMedicine 3:10-1
Shytaj, Iart Luca; Nickel, Gabrielle; Arts, Eric et al. (2015) Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection. J Virol 89:7521-35
Musich, Thomas; Demberg, Thorsten; Morgan, Ian L et al. (2015) Purification and functional characterization of mucosal IgA from vaccinated and SIV-infected rhesus macaques. Clin Immunol 158:127-39
Vargas-Inchaustegui, Diego A; Xiao, Peng; Demberg, Thorsten et al. (2015) Therapeutic envelope vaccination in combination with antiretroviral therapy temporarily rescues SIV-specific CD4⁺ T-cell-dependent natural killer cell effector responses in chronically infected rhesus macaques. Immunology 145:288-99
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
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
Lakhashe, Samir K; Byrareddy, Siddappa N; Zhou, Mingkui et al. (2014) Multimodality vaccination against clade C SHIV: partial protection against mucosal challenges with a heterologous tier 2 virus. Vaccine 32:6527-36
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

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