Sa1869 Retinoic Acid Elicits a Coordinated Expression of Gut Homing Markers on T Lymphocytes With Oral Typhoid, but Not Viral, Vaccines in Zambian Men

Background Oral vaccines have been associated with diminished immunogenicity and efficacy in developing country populations.Rotavirus vaccine protection is much lower in Africa and Asia than in developed countries.There is an urgent need to identify ways to improve the immune responses of these oral vaccines.It has emerged over the past decade that retinoic acids can up-regulate expression of a4b7 and CCR9 gut homing molecules on lymphocytes and this can redirect the lymphocytes and vaccine responses towards the gut.We set out to establish whether giving oral vaccination alongside all-trans retinoic acid (ATRA) can improve the immune response to the vaccine by enhancing expression of gut homing molecules and immunoglobulin A (IgA).Methods and Results To evaluate effects of ATRA on gut homing lymphocytes and gut IgA responses to oral vaccines, adult male volunteers (n=94) were randomised to receive one of four oral vaccines: Vivotif, Dukoral, Rotarix, and Polio given with or without 10mg ATRA an hour before vaccination and then administered daily for 8 days.We measured IgA directed against lipopolysaccharide (LPS) preparations of the vaccines in serum and whole gut lavage fluid (wglf) one day prior to vaccination and on day 14.We also measured gut homing receptor phenotype on circulating CD4 + T cells.Vaccine-specific IgA in wglf was significantly increased (P=0.01)against LPS and so was a4b7 (P=0.003) and CCR9 (P=0.002)expression in the group that received Vivotif and ATRA.The increase in a4b7 and CCR9 was in an entirely coordinated ( r=0.83, P<0.0001) fashion and strongly (r= 0.82; P=0.02) associated with an increase in intestinal IgA.We also found that these individuals had low baseline concentrations of serum retinol (P=0.03).Conclusions ATRA induced a4b7 and CCR9 expression in a coordinated expression shift on CD4 + T cells only when given together with an oral typhoid vaccine.The coordinated phenotypic changes were strongly correlated with enhanced intestinal IgA expression.These findings suggest that ATRA could potentially be a useful oral adjuvant, but only for specific oral vaccines.