Abstract
Mucosal immunity is central to sexual transmission and overall pathogenesis of HIV-1 infection, but the ability of vaccines to induce immune responses in mucosal tissue compartments is poorly defined. Because macaque vaccine studies suggest that inguinal (versus limb) vaccination may better target sexually-exposed mucosa, we performed a randomized, double-blinded, placebo-controlled Phase I trial in HIV-1-uninfected volunteers, using the recombinant Canarypox (CP) vaccine vCP205 delivered by different routes. 12 persons received vaccine and 6 received placebo, divided evenly between deltoid-intramuscular (deltoid-IM) or inguinal-subcutaneous (inguinal-SC) injection routes. The most significant safety events were injection site reactions (Grade 3) in one inguinal vaccinee. CP-specific antibodies were detected in the blood of all 12 vaccinees by Day 24, while HIV-1-specific antibodies were observed in the blood and gut mucosa of 1/9 and 4/9 evaluated vaccinees respectively, with gut antibodies appearing earlier in inguinal vaccinees (24–180 versus 180–365 days). HIV-1-specific CD8+ T lymphocytes (CTLs) were observed in 7/12 vaccinees, and blood and gut targeting were distinct. Within blood, both deltoid and inguinal responders had detectable CTL responses by 17–24 days; inguinal responders had early responses (within 10 days) while deltoid responders had later responses (24–180 days) in gut mucosa. Our results demonstrate relative safety of inguinal vaccination and qualitative or quantitative compartmentalization of immune responses between blood and gut mucosa, and highlight the importance of not only evaluating early blood responses to HIV-1 vaccines but also mucosal responses over time.Trial RegistrationClinicalTrials.gov NCT00076817
Highlights
As of 2010, 34 million people were living with HIV-1 infection and 2.7 million new infections occurred that year alone (UNAIDS World AIDS Day report 2011)
Three of the inguinal vaccinees (Subjects G, Q, and M) had a predominance of responses in the gut only, and the fourth (Subject F) had responses in the blood only; none had concordant CD8+ T lymphocytes (CTLs) responses in both compartments. Note that because these are measurements with peptide pools, concordance of CTL responses against peptide pools may overestimate concordance of recognized epitopes. These results suggest that deltoid vaccination preferentially induces CTL responses in blood with some concordance in gut mucosa, while inguinal vaccination tends to induce more responses only in the gut mucosal compartment at the time points evaluated
No large scale clinical HIV-1 vaccine trial has evaluated immunity in this compartment, and only one vaccine has demonstrated any hint of clinical efficacy
Summary
As of 2010, 34 million people were living with HIV-1 infection and 2.7 million new infections occurred that year alone (UNAIDS World AIDS Day report 2011). The development of a safe and effective vaccine against HIV-1 remains a critical goal to stem the pandemic. Of over 30 vaccine candidates tested in human trials, only one has shown a hint of efficacy [1] in preventing HIV-1 acquisition, and none have had any effect on immune control after infection [2]. The vast majority of HIV-1 transmissions occur through sexual contact and exposure of mucosal surfaces. Mucosal tissues of the genital and intestinal tracts are pro-inflammatory environments rich in activated CD4+ T-cells, which are the preferred targets for HIV-1 infection. It is clear that the mucosa is a key site for eliciting protective immunity by novel vaccine strategies against HIV-1
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