Replicating Ad-SIV recombinant vaccines elicit mucosal humoral immunity in rhesus macaques at both rectal and vaginal sites with potential protective efficacy

Abstract

Abstract Humoral immunity, especially at mucosal sites, is important for preventing HIV acquisition. Replicating adenovirus (Ad)-SIV priming/gp120 boosting regimens have elicited mucosal immunity and protection against intrarectal SIV challenge in Rhesus macaques. Here we investigated mucosal responses in female macaques primed intranasally/orally, then intratracheally with Ad5hr-SIV(Env/gag/nef), boosted twice intramuscularly with SIV gp120, and challenged vaginally with repeated low-dose SIVmac251. Vaginal washes and rectal swabs and biopsies were obtained 3-weeks post-immunizations. gp120-specific antibodies were assayed by ELISA and memory B-cells by flow cytometry. Gp120-specific rectal memory B-cells increased post-Ad priming but waned post-boosting, whereas rectal and vaginal antibodies increased post-boosting. Compared to pre levels, rectal gp120-specific IgA (p = 0.011) and IgG (p< 0.0001) were elevated post-2nd boost; vaginal IgA/IgG antibodies differed post-1st boost (both p<0.0001) and IgG levels > IgA post-2nd boost (p=0.001). Rectal memory B cells post- 1st and 2nd Ads positively correlated with gp120-specific rectal IgA (p = 0.015, p = 0.0013, respectively) post-1st Ad, indicating vaccine targeting to mucosal effector sites. Significantly delayed SIV acquisition was not seen, but vaginal IgG post-1st Ad correlated with number of challenges (p=0.029). Vaccinated animals had lower acute viremia than controls (p = 0.054), consistent with higher vaginal gp120-specific IgG 2 weeks post-infection (p < 0.0001). Our data show that upper respiratory tract immunization with replicating Ad vectors elicits strong mucosal immunity with potential protective efficacy against rectal/genital transmission.