For decades, vaccinologists have been striving for the ultimate treatment for HIV and AIDS—a vaccine capable of neutralizing the virus and helping the 38 million people still living with the virus. Unfortunately, such a vaccine has proven elusive, mostly due to the nature of HIV itself. In short, to develop an effective vaccine against HIV, vaccinologists would have to create a single compound of broadly neutralizing antibodies (bnAbs) that can neutralize not just one, but several strains of HIV.
However, recently, researchers associated with Duke University have identified a new strategy to utilize a vaccine to stimulate a highly specific portion of the body’s immune response against HIV. The vaccine would promote bodily production of the desired bnAbs and assist their development into antibodies that can fight HIV. While still in the preclinical stages, this methodology holds great promise for the eventual development of an HIV vaccine.
Currently, vaccines exist that can stimulate a human bnAb response. However, these bnAbs are not affinity-matured or potent enough to combat the effects of HIV. For the most part, this is due to many amino acid substitutions acquired as the bnAbs mutate and mature. In the human body, the enzyme responsible for bnAb mutation does not target the nucleotide sequences responsible for the growth and mutation necessary to neutralize a wide range of HIV strains.
Researchers encountered similar limitations in animal models, leading to vaccine research that targeted bnAb precursors in the hopes of initiating the mutations necessary for broad-spectrum HIV neutralization. In this study, researchers hoped that they could use immunogens that bind with bnAb B cell precursors—especially those that have already acquired some of the necessary mutations—to begin a B cell lineage of the cells most likely to mutate. Then, further research could select for the key mutations necessary for HIV neutralization.
Researchers designed HIV envelope immunogens specifically to bind to precursor bnAb B cells that had already acquired the mutations that would make them more likely to become bnAbs that could neutralize multiple HIV strains. They then vaccinated mice and macaques with the immunogens to see whether the ideal bnAb mutations would occur. In both mice and macaques, the technique of biolayer interferometry indicated that these immunogens bound more strongly to optimally mutated precursors than other bnAb precursors.
In mice, researchers were able to isolate a monoclonal antibody stimulated by the vaccine, bearing the desired mutations and capable of neutralizing multiple HIV strains. After studying the antibody, researchers determined the exact mutations, antibody makeup, and the roles of each—including the role these desired mutations played in recognizing the envelope of multiple HIV strains. Thus, the antibody response inspired in both mice and macaques closely resembled the ideal response necessary to neutralize multiple HIV strains.
To develop a vaccine capable of halting the progress of HIV, researchers must continue to target precursor and early stages of bnAb B cells. If successful, we may find that human bnAb precursors can effectively mutate and mature into antibodies that can target the full array of HIV strains. As time goes on, researchers could use the technique to influence other B cell lineages that will target other pathogens, thereby inviting in a new era in vaccines and disease-fighting technology.