| Group A rotavirus (RV) is the most important cause of viral gastroenteritis in young children and animals worldwide and the need for effective vaccines against RV is urgent. The main goals of this thesis were: (1) to study the efficacy, immunogenicity and correlates of protective immunity after oral vaccination with virus-like particles (VLP) with or without attenuated human rotavirus (AttHRV) in a prime/boost strategy; (2) and (3) to understand the impact of high and low titer circulating MatAb to RV on protective immunity and B cell responses induced by RV vaccines (replicating vs. non-replicating); and (4) to examine the transfer of cytokines from mothers to neonates and the implications of such transfer for immunomodulation of neonatal immunity.; We evaluated antibody responses and protection induced by a replicating vaccine consisting of an oral dose of AttHRV for priming and two intranasal doses of a 2/6VLP(100 or 250ug)/ISCOM vaccine for boosting (AttHRV/VLP) or an intranasal VLP/ISCOM prime/boost vaccine (VLP/ISCOM3x) in gnotobiotic (Gn) pigs and compared them with the 3 doses AttHRV (AttHRV3x) oral vaccine. The AttHRV-VLP250mug/ISCOM and AttHRV3x groups had significantly higher serum IgA and IgG and intestinal IgA antibody titers to HRV pre-challenge than the 3-doseVLP100mug/ISCOM group (VLP/ISCOM3x) and controls (diluent/ISCOMmatrix).; We next investigated effects of high titer MatAb on protection and immune responses induced by the above AttHRV/VLP and VLP/ISCOM3x vaccines. Passive circulating MatAb (hyperimmune sow serum) injected into Gn pigs contributed to partial protection against virulent HRV challenge; however, MatAb interference led to no or low intestinal IgM, IgA and IgG antibody titers and significantly reduced intestinal IgA and IgG antibody secreting cell (ASC) and memory B cell responses in the AttHRV/VLP pigs pre- and post-challenge.; We then investigated the effect of low titer circulating MatAb (LoMatAb) on protection and immune responses induced by these two vaccine regimens. Protection rates in the AttHRV/VLP groups with and without LoMatAb were similar against viral shedding and diarrhea when challenged with virulent HRV. The LoMatAb had both enhancing and suppressive effects on B cell responses, depending on antibody isotype, tissue and vaccine.; We investigated IL-6 and TNF-alpha (pro-inflammatory), IFN-gamma and IL-12, (Th1), IL-10 and IL-4 (Th2) and TGF-beta1 (Th3) cytokine concentrations in sow serum and colostrum/milk and in serum and intestinal contents of their suckling piglets at 0--13 post-partum days (PPD) or post-weaning. All cytokines except for TNF-alpha were detected in sow colostrum/milk. No IL-6, TNF-alpha, IFN-gamma, IL-4 and IL-10 were detected in piglet sera at PPD0 documenting absence of transplacental transfer, whereas IL-12 and TGF-beta1, present at birth, may be constitutively produced or maternally-derived. (Abstract shortened by UMI.)... |
