Project 1:   “Development of a maternal vaccine to passively-immunize infants against clade C HIV-1 infection”
If an HIV-1-free generation is to be achieved, mother-to-child HIV-1 transmission (MTCT) of HIV-1 must be eradicated.  While antiretroviral prophylaxis strategies effectively prevent MTCT, they do not eliminate transmission in high-risk settings such as acute maternal infection, development of maternal drug-resistant variants, and lack of antiretroviral drug access or adherence.  An attractive solution is the development of immunologic interventions for MTCT, such as vaccines.  Project 1 will focus on developing a maternal vaccination strategy to passively immunize the infant via placental transfer of IgG and mucosal delivery of breast milk antibody.  Project 1 will compare the specificity and function of previously-identified breast milk-derived HIV-1 Env-specific IgG and IgA antibodies elicited by maternal MVA prime/Env T/F 1086.C boost immunization to define the potential benefits of breast milk antibody response induction and determine whether maternal placentally transferred or breast milk-derived vaccine-elicited antibodies confer protection against acute oral SHIV challenge in infants, simulating acute maternal infection during lactation.  This preclinical study of the immunogenicity and effectiveness of maternal HIV-1 Env immunization for reduction of infant virus acquisition will define the feasibility of maternal HIV-1 immunization for elimination of pediatric HIV-1 infections. 

Project 2:   “Development of a pediatric vaccine to protect infants against clade C HIV-1 infection”
Project 2’s goal in this effort is to develop a pediatric HIV-1 vaccine that induces HIV Env antibody responses that can protect against oral SHIV acquisition.  We will optimize a pediatric HIV-1 vaccine regimen by testing different prime/boost modalities and intervals, and systemic and mucosal routes of immunization.  We will also determine whether vaccine interference by maternal vaccine- or SHIV infection-induced antibodies alters pediatric vaccine responses and efficacy. Thus, if successful, our innovative combined maternal-infant HIV-1 vaccine strategy could provide protection throughout the breastfeeding period and end the global pediatric HIV-1 epidemic.

Immunogenicity and Vector Development Core—Core 1
Core 1 will support mother and infant immunogenicity studies in the Program’s two Projects and three Cores by providing vaccine immunogens (recombinant HIV-1 1086.C gp120 Envelope (Env)) and modified vaccinia Ankara (MVA) vectors expressing HIV-1 1086.C Env, SIV gag, and SIV pol (Aim 2). In addition, a major emphasis of Core 1 will be to conduct studies to optimize vaccine regimens that also improve safety for use in pregnant women and infants. Core 1 will optimize intranasal immunization with recombinant HIV-1 1086.C for induction of antibody responses in breast milk and in the infant GI tract without the use of added adjuvant. Taken together, successful completion of Core 1’s Aims will provide essential support for the MTCT HIVRAD Program by providing novel vaccine vectors and vaccine formulations that are safe and effective in mothers and infants that could help lead to prevention of MTCT of HIV-1.

B Cell Core—Core 2
The B Cell Core will quantify those responses that may correlate with infection risk to determine those responses critical for protection and to provide preliminary data for future human studies. We will quantify the functional activity, avidity, and recognized epitopes of antibodies elicited by maternal and infant vaccine regimens. In Aim 2, we will create a recombinant Env protein antigen-specific reagent to quantify the frequency and phenotype of vaccine-elicited Env-specific B cell responses in mothers and infants. The B Cell Core will provide critical data to the Program and significantly advance our understanding of B Cell responses required for protection against MTCT of HIV-1.

Non-Human Primate Core—Core 3
The Non-Human Primate (NHP) Core is an integral component of the overall HIVRAD program and provides direct support to the Projects by coordinating and implementing all the NHP experiments. The NHP Core will support Project 1, “Development of a maternal vaccine to passively-immunize infants against clade C HIV-1 infection” (P.I. Dr. S. Permar, Duke University) aimed at studying the impact of maternal immunization, and Project 2 “Development of a pediatric vaccine to protect infants against clade C HIV-1 infection” (Dr. K. Abel, Univ. of North Carolina, Chapel Hill), aimed at studying the effects of infant vaccination and the impact of combined maternal/infant immunization against oral SHIV transmission.  This work will be performed in settings that mimic both acute maternal infection and chronic, ARV-treated maternal infection. Together, the data obtained in the proposed NHP studies will provide understanding of the efficacy and protective mechanisms of combined maternal and infant immunization - information that is crucial to the design of effective maternal and infant HIV-1 vaccines and necessary to end the pediatric HIV-1 epidemic and achieve an HIV-1-free generation.