Shattock: Novel Antigens for Mucosal Protection

OVERVIEW

To overcome the roadblock to the induction of effective immunity against sexually transmitted infection, and HIV in particular, we are developing novel strategies for repeated and/or sustained vaccine delivery to induce vaginal immune responses. Mucosal immune responses are typically short-lived, may fail to induce durable memory, and direct application of soluble antigens in the absence of a mucosal adjuvant may induce systemic tolerance. This likely reflects a number of factors including: inefficient targeting of mucosal antigen presenting cells (APCs); rapid leakage from the administered sites; degradation of antigens by enzymes in mucosal secretions; and differences in immune responses over the menstrual cycle. Here we are developing immunogens and delivery mechanisms that target mucosal APC, with the intent of inducing prolonged humoral, T-helper and CTL effector and memory responses. A combination of modification of the HIV envelope protein and the design of delivery vehicles and devices are being evaluated in laboratory, animal studies and human Phase I clinical trials. These approaches are expected to induce potent, broadly-based and durable immune responses at the virus site of entry.

RESEARCH OBJECTIVES

The primary focus of this program is development a number of innovative strategies to target soluble trimeric gp140 (HIV-1 CN54 clade C gp140) to professional APC present in the mucosal environment.

PROGRESS

First generation strategies have been successfully assessed for safety and immunogenicity in macaque (Vaccine; 2011;29:1421-30) and human studies (PLoS One; 2011;6(9):e25165) of intravaginal administration of gp140 formulated in aqueous gels. Second generation approaches to intravaginal (IVAG) immunization using vaginal rings for controlled release of antigen have been evaluated in sheep, the model of choice for human-sized rings. When co-formulated with the TLR-7/8 adjuvant resiquimod, gp140 delivered from rings induced the strongest vaginal antibody responses measured to date. Additional ongoing macaque studies have indicated that mucosal immunization can be effectively boosted following IM immunization when formulated with aqueous GLA adjuvant (Infectious Disease Research Institute). To test this concept in humans the Shattock-led research team has started a four arm clinical trial in healthy women – ‘MUCOVAC2’ (trial design summarized the table below). The objective of the trial is to assess the safety and immunogenicity of three HIV CN54gp140 immunizations administered through the IM, IN and IVAG routes in a variety of combination regimens. Primary and secondary immunogenicity endpoints will include specific vaginal IgA and IgG, and serum IgG measured within our consortium. A wider range of ‘exploratory’ assays will be performed by this consortium and by the CAVD Central Service Facilities, including assessment of antibody function (neutralization, aggregation, ADCC, epitope specificity) and cellular responses (breadth, magnitude and poly-functionality of CD4/CD8 T cells)

This work is funded under the Grand Challenges in Global Health (GCGH) initiative, with the Wellcome Trust funding clinical trial activity and the Bill & Melinda Gates Foundation funding pre-clinical and laboratory activities.