Scripps CHAVD

Overall, we consider that the most likely final format for a successful bnAb-based HIV vaccine is one that induces bnAbs to at least 2 sites by sequential administration of 3-4 immunogens per specificity. Ideally, the immunogens for different specificities would be combined in a single product (e.g., one protein), or if this is not possible, then co-administered.

We are currently researching multiple bnAb sites rather than a single site for two major reasons. First, comprehensive neutralization coverage is more likely to be achieved by vaccine targeting of more than one site, so the chances of vaccine failure are reduced. Second, the basis for these vaccine regimens is worked out in animal models before going into the clinic. Given the uncertainties involved in translation into humans, we consider it wise not to restrict study to a single site. We therefore propose to focus on the induction of bnAbs to several sites, with the ultimate goal of combining the corresponding immunogens to achieve the requisite breadth and potency.

• For the VRC01-class of Env CD4bs-targeting bnAbs, we developed eOD-GT8, a “germline-targeting” (GT) immunogen, assembled as a particle incorporating 60 copies. A sequence of sequential immunogens that begins with eOD-GT8 will be advanced into clinical trials as our top vaccine candidate to elicit bnAbs against this target.

• The V3-glycan site is the most commonly recognized bnAb site in HIV+ individuals and an important vaccine target. Our initiating immunogen to stimulate bnAb responses against this region is now under GMP manufacture and will be evaluated in a Phase I trial through the HVTN in the near future.

• For the induction of V2-apex bnAbs, we’re following two strategies: 1) Germline Targeting to select for a given specificity to boost/shepherd the immune response along a chosen pathway and 2) Immunofocusing to direct initial Ab responses to the trimer apex, followed by boosting to focus on the apex bnAb epitope region. Phase 1 clinical trials of immunogens under both approaches are high priorities for the Scripps CHAVD.

• Two other targets are being explored for vaccine development: 1) MPER targeting which uses a promising Germline Targeting strategy, and 2) Fusion Peptide targeting, which adopts an immunofocusing sequential vaccine regimen worked out in animal studies. Further preclinical development studies are needed to determine if either targeted immunization strategy should advance to evaluation in humans.

The overall administrative and scientific management of the Consortium is centralized at The Scripps Research Institute, the Sponsoring Institution. The Management and Operations Unit is adaptable and flexible as priorities, programs, collaborations, and responsiveness to the various subaward institutions within the Consortium evolve.

By leveraging product development experts and leaders at the International AIDS Vaccine Initiative, as well as partnering with an established network of Contract Manufacturing and Contract Research organizations, this unit provides end-to-end services for vaccine development and advancing vaccines from bench to clinic. Its expertise is established through collaboration with funders focused on translating vaccine candidates to Phase I/II clinical trials.

By working closely with the HIV Vaccine Trials Network and its Laboratory Center, this Unit implements studies and assesses the outcome of vaccine concepts by using state-of-the-art technologies tailored specifically for immunogens of interest. Determining the comparability of various preclinical models for predicting human responses to vaccination saves time and leads to more focused evaluations of promising concepts in the laboratory before moving to human clinical trials.

Immunogen design is reliant on the availability of bnAbs to identify epitope targets on HIV Env, and to identify suitable antibody precursors to prime, expand and boost by immunization. Novel bnAbs may identify new targets for immunogen design and improve the quality of current designs. Identifying diverse viral Env sequences is essential for assessing the neutralization breadth and potency of antibodies and for determining whether serum responses from immunization experiments are on target.

To expedite vaccine design, antibody responses elicited by candidate immunogens need to be rapidly and reliably measured for both sequence and function. High-throughput assay platforms can provide such sequence and functional read-outs with increased efficiency and decreased cost. This information helps to identify promising immunogens for advancement to manufacturing and to clinical trials, and is of enormous benefit for the HIV vaccine field.

Structure-based vaccine design focuses on the Env protein as the main target for neutralizing antibody responses. At the forefront of Env-antibody structure determination is the use of X-ray crystallography and cryoEM which have proven invaluable for structure-based vaccine design. Structures of Env trimers, germline targeting and epitope-focused immunogens with vaccine-elicited antibodies are also critical for immunogen evaluation and provide key molecular insights for design improvements.

The surface of the HIV Env trimer is covered with sugar molecules called N-linked glycans. They are the shield that protects the protein epitopes below from the immune system. Because vaccine immunogens designed to mimic the Env on the virus might substantially differ in glycan structure or the location from the authentic Env pattern, analysis of glycosylation patterns is needed to inform vaccine design.

Designing proteins with specific characteristics is the core of rational vaccine development. It led to discovering germline-targeting immunogen design, epitope scaffold development, stabilization of native-like Env trimers and development of self-assembling nanoparticles for multimerization of Env variants. This unit accelerates protein design, increases accuracy and throughput and extends capabilities by using methods tailored to the sequential HIV vaccine strategy advanced by Scripps CHAVD.

To produce bnAbs after vaccination, B cells must recognize HIV epitopes and undergo affinity maturation to further increase the efficiency of the antibodies they produce. Technologies to probe the human immune system were developed to directly screen human naive B cell populations for several ongoing vaccine candidates. This experimental approach is now used as a pre-Phase I ex vivo human evaluation test to probe the naive B cell repertoire for precursors of interest for human vaccine design.

A major roadblock for vaccine development and pre-clinical testing has been overcome by the generation of knock-in mouse models that express human antibody genes or their precursors. Such models are proving to be invaluable when it comes to evaluating germline targeting, boosting and polishing immunogens and validating vaccine regimens. They serve as a useful platform to evaluate novel immunogens alone or in a combination that supports a germline targeting, shepherding and polishing approach.

Non-human primates, including rhesus macaques, are the only animals that are susceptible to AIDS-like viruses without a prior extensive genetic or experimental manipulations. These animals serve science as a valuable resource for conducting evaluations of immunogenicity and protection studies in vaccinated rhesus macaques. They have proven to be a fundamental component of the vaccine development pipeline.

T cells play an essential role in helping B cells, and that CD4+ T cell “help” may influence antibody responses among participants receiving the same candidate vaccine or contribute to different responses to the same vaccine immunogen formulated with a variety of adjuvants. Novel technologies are used to define antigen-activated CD4+ T cell function and phenotype in a holistic approach, and to identify unique immune correlates of vaccine-induced CD4+ T cell help and resulting B cell responses.

Induction of a durable protective antibody response by an HIV vaccine requires a right set of carefully designed immunogens and immunization strategies that promote each step of the humoral immune response. Key factors in this process are potent adjuvants and vaccine kinetics – timing and duration of responses that the vaccine immunogen and adjuvant stimulate in the regional lymph nodes. These aspects can be optimized with novel adjuvants and delivery approaches.

Effective RNA-based vaccine platforms have the potential to significantly reduce the time and cost associated with the production of recombinant protein immunogens for clinical testing of vaccine candidates. The lead candidate platform under development is comprised of self-replicating alphavirus RNA formulated as a nanoparticle in synthetic lipids. It could be used for delivery of native trimer immunogens in multiple forms and become a cell-free universal manufacturing path for any immunogen.

New technologies for measuring immunologic, virologic and genomic data during vaccine trials have significantly increased the depth by which vaccine-induced immune responses can be measured, and that led to more comprehensive assessments of vaccine immunogenicity and immune correlates. As such, this Unit’s objective is to stay at the forefront of these advancements when it comes to study design, data management and computational analysis in vaccine research programs.