Science Spotlight

Building protection at HIV infection site

Antibody response rate in the mucosal compartment.
Figure modified from the paper.

Globally, 16 million women are infected with HIV, constituting the 50% of people living with HIV. Furthermore, the majority of infections in young people affects adolescent and young adult women, and occurs through heterosexual contact. Therefore, an imperative task for an efficacious HIV vaccine is to generate immune responses at the mucosal sites.

Although intramuscular injection has been proven to be efficacious in eliciting a systemic antibody response, it might not represent the most efficient way to induce mucosal antibody and T-cell responses. Other routes of administration, such as intravaginal or intranasal delivery could represent a valid alternative to induce an immune response in the female reproductive tract. Moreover, testing immune responses at the mucosal sites is required to understand whether a vaccine formulation and a delivery route can induce a protective immune response at the site of infection.

A clinical phase I trial took into account these aspects, and tested safety and immunogenicity of three HIVgp140 immunizations delivered by three different routes: intramuscular (IM), intranasal (IN) and intravaginal (IVAG). Moreover, immunogenicity was measured in serum as well as in cervicovaginal secretions. The results were published in PLoS One last month.  The study was run at two centers in the United Kingdom, and the Vaccine and Infectious Disease Division at Fred Hutch was involved as a main collaborator, as explained by the HIV vaccine trial network (HVTN) investigator Dr. Stephen De Rosa:  "We were involved in this study because the T cell ICS assays were conducted through the Gates' Foundation CAVD and we are part of the cellular testing core.  So we provided the T cell data."  Then Dr. De Rosa continues: "Although this was a small study in terms of number of participants, it is of interest because different modes of mucosal vaccination were tested, intra-nasal and intra-vaginal, and were compared with intra-muscular.  Each had a different adjuvant."

The trial evaluated the induction of IgG, as well as CD4+ and CD8+ T cell responses elicited by the administration of the trimeric form of Env gp140 from the clade C virus, which is predominant in sub-Saharan Africa, where the majority of heterosexual transmission of HIV occurs. The protein was administered either via intramuscular (IM) injections, in doses of 20 (IM20) or 100 ug (IM100), adjuvanted with glucopyranosyl lipid, intranasally (IN), adjuvanted with chitosan, or intravaginally (IVAG) as a gel formulation. The vaccination schedule consisted of three administrations of the protein 4 weeks apart; the IM100 and IN arms received two further IM100 boosts. For the IVAG arm, one IM prime was followed by two IVAG boosts.

The three formulations proved to be safe, with only mild to moderate adverse events reported and no differences between groups. As for immunogenicity, the best route to induce systemic as well as mucosal antibodies was the IM method. In fact, after the first three administrations, IgG antibodies were detected in serum and vaginal secretion in both IM groups, but not in the IN or IVAG groups. Interestingly though, after further IM boosting, serum IgG were detected in subjects who previously received IN administration. Moreover, IN immunization was shown to induce the stronger CD4+ T cell responses. Looking at the results, Dr. De Rosa commented: "The IVAG results were disappointing since it induced little immune response.  The IN results were interesting since that route induced the highest CD4 T cell response, and although it did not induce a detectable antibody response, it was able to prime the subsequent antibody response to a single IM boost.  Although there remain some questions about whether alternative adjuvants would have provided different results, the IM results for this vaccine candidate are encouraging and IN immunization could be an alternative to consider, at least as a prime."  

The study was supported by the Bill and Melinda Gates Foundation, the Wellcome trust and the Collaboration for AIDS Vaccine Discovery (CAVD).

Cosgrove CA,Lacey CJ,Cope AV,Bartolf A,Morris G,Yan C,Baden S,Cole T,Carter D,Brodnicki E,Shen X,Joseph S,DeRosa SC,Peng L,Yu X,Ferrari G,Seaman M,Montefiori DC,Frahm N,Tomaras GD,Stohr W,McCormack S,Shattock RJ. 2016. Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study. PLoS One, 11(5), e0152038.