Marjorie Robert-Guroff, Ph.D.
Building 41, Room D804
Bethesda, MD 20892-5065
Historically, live viral vaccines have been most effective, eliciting essentially life-long immunity. Based on this rationale, my lab is developing a human immunodeficiency virus (HIV) vaccine based on replication-competent adenovirus (Ad) vectors with a focus on Env-specific humoral immunity. We have employed a prime/boost strategy, immunizing first mucosally with Ad-recombinants, and then boosting intramuscularly with Env protein. We have conducted extensive studies using an Ad5 host range mutant vector able to replicate in rhesus macaques as a prototype vaccine. Based on these pre-clinical findings showing strong immunogenicity and potent protective efficacy, we have achieved a major goal of translating this approach to the clinic for evaluation in humans alongside non-replicating Ad-HIV vaccines and other approaches.
As the replicating Ad4-HIV platform has now reached clinical trials, we are focused on improving the vaccine regimen and elucidating immune correlates of protection and their mechanisms of action, taking advantage of the rhesus macaque model as an effective way to efficiently test new vaccine concepts and strategies. We have shown that anti-Env antibodies possess multiple activities and characteristics associated with protective efficacy. In addition to neutralization, these include non-neutralizing activities such as ADCC and ADCVI, antibody avidity and viral-specific B cell memory. We have also shown that vaccine-elicited anti-Env-specific antibodies in rectal secretions mediate transcytosis inhibition and are significantly correlated with delayed SIV acquisition following a challenge exposure.
While we believe all components of the immune system will be needed to develop an effective HIV vaccine, we are currently focused on improving mucosal immunity, as HIV is primarily transmitted across mucosal epithelium. Our recent study of the biodistribution of replicating Ad in the macaque showed that regardless of administration route, it is broadly distributed and elicits comparable levels of mucosal IgA in rectal, vaginal, and nasal secretions. The vector also targets professional antigen presenting cells, and persists for at least 25 weeks after administration in rectal macrophages. We have a major interest in B cell development and maturation, as we believe antibody responses are crucial for a protective HIV vaccine. In view of the broad array of antibody activities that can mediate protection, we are also investigating effector cells that mediate antibody activities. Finally, we are initiating studies of combined vaccine approaches, taking advantage of mucosal immunity elicited by the replicating Ad vector.
Vargas-Inchaustegui DA, Demers A, Shaw JM, Kang G, Ball D, Tuero I, Musich T, Mohanram V, Demberg T, Karpova TS, Li Q, Robert-Guroff M. Vaccine Induction of Lymph Node-Resident Simian Immunodeficiency Virus Env-Specific T Follicular Helper Cells in Rhesus Macaques. J Immunol. 2016;196(4):1700-10.
Mohanram V, Demberg T, Musich T, Tuero I, Vargas-Inchaustegui DA, Miller-Novak L, Venzon D, Robert-Guroff M. B Cell Responses Associated with Vaccine-Induced Delayed SIVmac251 Acquisition in Female Rhesus Macaques. J Immunol. 2016;197(6):2316-24.
Tuero I, Mohanram V, Musich T, Miller L, Vargas-Inchaustegui DA, Demberg T, Venzon D, Kalisz I, Kalyanaraman VS, Pal R, Ferrari MG, LaBranche C, Montefiori DC, Rao M, Vaccari M, Franchini G, Barnett SW, Robert-Guroff M. Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge. PLoS Pathog. 2015;11(8):e1005101.
Patterson LJ, Kuate S, Daltabuit-Test M, Li Q, Xiao P, McKinnon K, DiPasquale J, Cristillo A, Venzon D, Haase A, Robert-Guroff M. Replicating adenovirus-simian immunodeficiency virus (SIV) vectors efficiently prime SIV-specific systemic and mucosal immune responses by targeting myeloid dendritic cells and persisting in rectal macrophages, regardless of immunization route. Clin Vaccine Immunol. 2012;19(5):629-37.
Xiao P, Zhao J, Patterson LJ, Brocca-Cofano E, Venzon D, Kozlowski PA, Hidajat R, Demberg T, Robert-Guroff M. Multiple vaccine-elicited nonneutralizing antienvelope antibody activities contribute to protective efficacy by reducing both acute and chronic viremia following simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques. J Virol. 2010;84(14):7161-73.
Related Scientific Focus Areas
Microbiology and Infectious Diseases
This page was last updated on February 4th, 2019