Despite antiretroviral medications the rate of pediatric HIV-1 infections through breast-milk transmission has been staggering in developing countries. prime/systemic MVA-SIV boost vaccine for efficacy against multiple oral SIVmac251 challenges starting two weeks after the booster vaccination. The vaccine did not prevent SIV infection. However in vaccinated infants the level of SIV-specific plasma IgA (but not IgG) at the time of challenge was inversely correlated with peak viremia. In addition the levels of SIV-specific IgA in saliva and plasma were inversely correlated with viral load Puerarin (Kakonein) at euthanasia. Animals with tonsils that contained higher frequencies of SIV-specific TNF-α- or IFN-γ-producing CD8+ T cells and central memory T cells at euthanasia also had lower viremia. Interestingly a marked depletion of CD25+ FoxP3+ CD4+ T cells was observed in the tonsils as well as PPP2R1B Puerarin (Kakonein) the intestine of these animals implying that T regulatory Puerarin (Kakonein) cells may be a major target of SIV infection in infant macaques. Overall the data suggest that in infant macaques orally infected with SIV the co-induction of local antiviral cytotoxic T cells and T regulatory cells that promote the development of IgA responses may result in better control of viral replication. Thus future vaccination efforts should be directed towards induction of IgA and mucosal T cell responses to prevent or reduce virus replication in infants. Introduction Antiretroviral therapy (ART) provided to the HIV-1-infected mother and/or her newborn child can dramatically reduce the risk of HIV vertical transmission [1-3]. A large clinical trial in Malawi recently demonstrated that vertical transmission of HIV could be further reduced if the period of ART to the newborn was extended for several weeks [4 5 However in many resource-poor countries access to ART is still limited. Thus pediatric HIV infections continue to occur at a staggering rate. Considering that there is no HIV vaccine available for preventing HIV transmission in adults and that the majority of newly infected people are women of child-bearing age the development Puerarin (Kakonein) of a pediatric HIV vaccine should be pursued in parallel with improved antiretroviral intervention strategies and adult HIV vaccine development [6-10]. A large proportion of pediatric HIV infections are due to breast milk transmission. In infant rhesus macaques the tonsil and intestinal tissues represent the primary sites of viral replication after oral SIV infection [11]. Therefore we reasoned that a vaccine intended to prevent oral HIV infection of infants should induce immune responses at these sites. A pediatric HIV vaccine should also be administered as early after birth as possible with accelerated boosting intervals to protect the newborn against the frequent and continuous exposure to HIV in breast milk. We previously showed that systemic administration of poxvirus-based SIV Puerarin (Kakonein) vaccine candidates to newborn macaques provided partial protection against oral SIV challenge and prolonged the survival of infants that became infected [12]. Recently we demonstrated that an Puerarin (Kakonein) oral prime with replication-attenuated Vesicular Stomatitis Virus vector containing multiple SIV genes (VSV-SIV) followed by a systemic boost with Modified Vaccinia Ankara virus containing SIV genes (MVA-SIV) induced SIV-specific T and B cell responses in blood and tissues of infant macaques [13]. Although SIV-specific T cell responses were relatively low they were detectable in multiple lymphoid and mucosal tissues. Systemic antibody responses to SIV were consistently induced in all vaccinated animals by 4 weeks. Therefore in the current study we used a new cohort of infant macaques to test whether the neonatal VSV-SIV/MVA-SIV vaccine regimen was effective for preventing oral SIV infection. While vaccine-induced immune responses did not prevent infection and viral dissemination the vaccinated animals with SIV-specific IgA at the time of oral challenge and with mucosal and systemic SIV-specific antibody and T cell responses after challenge had lower levels of virus replication than animals in which T and B cell responses were low and detected in fewer tissues. Materials and Methods Animals Newborn rhesus macaques (Macacca mulatta) born to animals from the HIV-2 SIV type D retrovirus and simian T-cell.