Exploring the Potential of Using Retinoic Acid as an Oral Adjuvant

Abstract

Background: Oral vaccines have been associated with diminished immunogenicity and efficacy in developing country populations. Rotavirus, cholera and oral polio vaccines have shown much lower protection in Africa and Asia than in developed countries. In view of this, there is an urgent need to identify ways to improve the immune responses of these oral vaccines in the settings where they are most needed. It has emerged over the past decade that retinoic acids can up-regulate expression of α4β7 and CCR9 gut homing molecules on lymphocytes and this can redirect the lymphocytes and vaccine responses towards the gut. Objective: 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: In order to evaluate the 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 ATRA 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. Results: Vaccine-specific IgA in WGLF was significantly increased (P=0.01) against LPS in the group that received Vivotif alongside ATRA. α4β7 (P=0.003) and ix CCR9 (P=0.002) expression was also increased in the same group and that this enhanced expression was in an entirely coordinated (ρ=0.83, P<0.0001) fashion in 57% of the participants. The change in α4β7 on CD4+ T cells was strongly (ρ= 0.82; P=0.02) associated with an increase in specific IgA response to Vivotif LPS in WGLF. We also found that these individuals had low baseline concentrations of serum retinol (median1.41μmol/L, IQR 1.06-2.48μmol/L; P=0.03). HIV had no effect on any response measured. Conclusions: ATRA induced α4β7 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 in a subset of individuals.