Vaccines present our immune systems with hallmark fragments of the targeted disease (a target antigen, such as Covid’s signature spike protein), spurring our B cells to crank out antibodies, which are designed to latch onto that antigen snugly, like jigsaw pieces. Should a virus drift by, these antibodies can lock on, tagging the invader for destruction by other immune cells.
But HIV barrels through this defense, owing to its staggeringly diverse array of variants. “Covid is nothing compared to it,” said Moderna’s Sunny Himansu. “The diversity of HIV in a single person can be comparable to the diversity of influenza in the whole world.”
Traditional vaccines train B cells to print out antibodies to neutralize a particular antigen. When it comes to defending against HIV, however, this strain-specific immune response won’t cut it. “You’re getting infected by a cocktail,” Himansu said. “You always carry multiple strains of HIV — not just a single variant.
“All it takes is a single variant to infect you, integrate its genome into you, and you’re positive,” he continued. “With HIV, neutralizing 99 percent of the variants isn’t good enough. It’s either ‘sterilizing immunity’ — 100-percent coverage — or nothing at all.”
But a specialized class of blood proteins known as “broadly neutralizing antibodies” (bnAbs) has shown promise in checking HIV’s diversity. These bnAbs, equipped with “very long arms,” said Himansu, can target an Achilles heel buried in the virus’s outer envelope: the CD4 binding site. Bind that common site, flag a breadth of variants for destruction, and we could block infection.
The challenge is how to make these bnAbs. Only a rare type of B cell can secrete them, so the first step is “priming” the production of this B cell, making the scarce variety more common. A vaccine, loaded up with a special antigen, can kickstart this priming process.
HIV researchers are aiming to further train these B cells to pump out a more diverse array of bnAbs to target a wider variety of HIV variants, inching us closer to total coverage. To nail this down, IAVI and Moderna are designing a second regimen of vaccines that will deliver a different antigen designed to shepherd B cells into diversifying their repertoire. The last round of vaccines involves fine-tuning the immune response to recognize a native, unaltered form of HIV.
So far, a 2021 clinical trial has nailed down that first priming step. The vaccine delivered an antigen that activated those sought-after B cells in 97 percent of participants. In a new clinical trial, IAVI is teaming with Moderna, hoping to leverage its mRNA technology, which has logistical advantages over a protein-based vaccine.
“With mRNA,” said Himansu, “instead of being made in a factory, this antigen can be made inside a human. So, you’re using a single facility to make any product that can be a vaccine.”