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In the global fight against AIDS, groundbreaking advancements in vaccine development shine like beacons in the night. Scientists are focusing on the cutting-edge approach of germline-targeting, aiming to activate specific B cells. The goal is to gradually produce broadly neutralizing antibodies (bnAbs) that target the less mutable regions of HIV.

Extensive research has confirmed the feasibility of this initial activation step. Now, in two new studies, researchers from the Ragon Institute have developed a comprehensive platform for HIV vaccine research. This platform not only enables preclinical validation of the next step in booster immunogens but also provides new insights into the underlying biology of the antibody response.

The relevant findings are published in the journals Science and Science Immunology, under the titles "mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies" and "mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models."

Meanwhile, scientists from the Scripps Research Institute have published two additional studies in the journals Science and Science Translational Medicine. These studies are titled "Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates" and "Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice." These four papers represent the culmination of years of close collaboration between these two research institutions and mark a significant step forward in the development of an HIV vaccine.

Dr. Facundo D. Batista, Deputy Director and Chief Scientific Officer at the Ragon Institute, explained, "Humanized mouse models are crucial for our HIV research projects. The human B cell receptors identified as potential bnAb precursors allow us to observe their response as part of a complete mammalian immune system to immunogens. By using a CRISPR-based approach, we have developed mouse strains to study several known conserved sites on the HIV envelope, and our collaborators at the Scripps Research Institute have developed immunogens targeting these sites."

Dr. Zhenfei Xie and Dr. Xuesong Wang, both primary authors of the study, completed their foundational research in Batista's lab at the Ragon Institute, focusing on various conserved sites on the HIV Env and different aspects of the basic biology of immunization. Both scientists concluded that the mRNA-LNP systems used in Pfizer and Moderna's COVID-19 vaccines are highly effective for HIV booster immunogens.

Dr. Xie emphasized that the consistency between the results from Professor William Schief's immunogen design team at the Scripps Research Institute and those from Batista’s lab in immunobiology is a critical factor. “bnAb against HIV-1 is an uncommon outcome in the prolonged course of HIV infection. Jon Steichen examined the co-evolutionary trajectory of bnAb and HIV to understand their structural interactions. We then brought everything back into in vivo models to observe more complex phenomena like antibody competition. This collaboration is essential for demonstrating that enhancing specificity at these types of sites is crucial.”

Credit: Science(2024),doi:10.1126/science.adk0582

This preclinical platform addresses more fundamental biological questions. B cell lineages that could produce bnAb are typically rare in humans. One approach the Scripps team uses to overcome this challenge is designing immunogens that can engage various B cell lineages with this potential. However, whether these B cells will compete and limit the effectiveness of immunogens remains uncertain.

Dr. Wang developed a model containing multiple bnAb precursor candidates with CD4 binding sites. She stated, “The prime-boost mRNA-LNP vaccine developed by Christ Cottrell not only induces multi-lineage precursor B cell responses but also initiates bnAb-like affinity maturation. The same mouse can mature multiple precursor B cells simultaneously.”

The current challenge is integrating their respective research efforts. Dr. Batista noted, “We are at a stage where there are increasing numbers of immunogens targeting different Env sites. Ultimately, we aim to combine these projects to determine the best methods for eliciting responses to multiple sites, thereby significantly reducing the virus's ability to escape. We are already conducting research in this area.”

References

[1] Zhenfei Xie et al. mRNA-LNP HIV-1 trimer boosters elicit precursors to broad neutralizing antibodies. Science, 2024, doi:10.1126/science.adk0582.

[2] Xuesong Wang et al. mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models. Science Immunology, 2024, doi:10.1126/sciimmunol.adn0622.

[3] Jon M. Steichen et al. Vaccine priming of rare HIV broadly neutralizing antibody precursors in nonhuman primates. Science Immunology, 2024, doi:10.1126/science.adj8321.

[4] Christopher A. Cottrell et al. Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice. Science Translational Medicine, 2024, doi:10.1126/scitranslmed.adn0223.