Schief: Experimental Medicine FIH of mRNA-HIV Immunogens
The primary outcome of this investment is to determine the safety and immunogenicity of mRNA delivered eOD-GT8 60mer and core-60mer as per the IAVI G002 Phase I clinical trial. The trial will test the concept that sequential vaccination by a germline-targeting prime followed by directional boost immunogens can induce specific classes of B cell responses and guide their early maturation toward bnAb development, and that these results can be achieved using a rapid and economical mRNA vaccine platform. The trial will test eOD-GT8 60mer priming by mRNA as well as mRNA-delivered core-60mer as a first directional boost after eOD-GT8 60mer priming. At the conclusion of this investment, it will be determined whether (i) Moderna mRNA-delivered eOD-GT8 60mer is safe and effective for priming VRC01-class responses in humans, and (ii) Moderna mRNA-delivered core-60mer is safe and effective for maturing eOD-GT8-primed VRC01-class responses in humans.
The long-term goal of this work is to develop a vaccine that induces bnAbs that can potently neutralize the vast majority of circulating HIV isolates. Data from the G001 clinical trial demonstrate that the germline-targeting immunogen eOD-GT8 60mer delivered as a protein with AS01B adjuvant is safe and highly effective for priming VRC01-class responses in humans (97% positivity). To build on this result, and to develop a complete sequential vaccination regimen that induces bnAbs, will require iterative human clinical testing. To carry out such iterative studies as rapidly and economically as possible, an alternative to GMP protein manufacturing is needed. The Moderna mRNA technology offers substantial improvements in speed and cost for the production of GMP clinical material, combined with strong immunogenicity, as demonstrated by their COVID-19 vaccine.
IAVI G002 will be an open-label, randomized trial comprising 4 groups and 56 volunteers. IAVI is the trial sponsor, and collaborating institutions include Fred Hutchinson Cancer Research Center, George Washington University, Scripps Research, and Moderna, Inc.
1) Assess immunogenicity and reactogenicity of Moderna mRNA-delivered self-assembling nanoparticle vaccines; compare to immunogenicity/reactogenicity data from G001.
2) Assess positivity of VRC01-class priming and heterologous boosting, with either one or two priming shots; determine if the true response rate is likely to be >50% (at the 95% confidence level)
3) Assess the degree of VRC01-class maturation induced by the priming and boosting steps, via sequence analyses and SPR analyses of vaccine-induced VRC01-class antibodies.
4) Make an overall determination as to which if any of the vaccine regimens tested represents a promising starting point for a longer sequential vaccination regimen to induce VRC01-class bnAbs in humans, taking into account safety and VRC01-class positivity and maturation.
5) Identify/confirm candidates for the next boosting step.