A Broadly Protective HIV Vaccine Shows Promising Results in Monkeys

Despite decades of research, scientists have not been able to develop a vaccine against human immunodeficiency virus (HIV). The primary challenges that researchers face are that HIV has many diverse strains and rapidly mutates. This has driven researchers to favor vaccine strategies that focus on activating B cells that produce broadly neutralizing antibodies (bnAbs) which recognize specific regions of a viral protein that is consistent across strains.¹

However, these bnAbs exist in the B cell repertoire in low numbers. Since B cells often undergo rounds of division during which they mutate the genes for their B cell receptor and, by extension, antibodies, developing a vaccination scheme that will direct precursor B cells toward the desired bnAb is complicated.

In a new study, a team of researchers used an optimized version of a HIV envelope protein antigen to successfully induce bnAb-precursor B cells in rhesus macaques. These precursor B cells bound the vaccine antigen as well as versions that more closely resembled the natural HIV protein. ² These findings, published in Science Immunology today, provide support that similar vaccination strategies could produce bnAbs in humans.

First, the researchers generated different mutated versions of a specific region of HIV envelope protein. Then, using mammalian cell display, the researchers screened the mutant that effectively bound their target bnAb precursor B cells. Once they identified their candidate, they developed this as a protein-based vaccine with a lipid-based adjuvant and as an mRNA-based vaccine encased in a lipid nanoparticle.

When the researchers provided two doses of the respective vaccines to rhesus macaques eight weeks apart, they saw that both vaccine types induced robust production of bnAb precursor B cells, including memory B cells in the blood.

To determine whether B cells activated by the optimized antigen recognized the structure, the researchers used antigens that resembled what this protein region looks like in natural viruses. They saw that, after two doses of either vaccine type, the animals produced B cells that could recognize these protein regions.

Finally, cryoelectron microscopy revealed that the features of the bnAb B cell binding to its target antigen in rhesus macaques resembled the structural complexes observed in humans in other studies. Given the similarities between rhesus macaque and human B cell repertoires and the above structural activity, these findings offer a promising approach to developing an effective HIV vaccine.