AVRS meeting focuses on immunogen design

As a rule, scientific subcommittee meetings aren’t the sort of things people—even certifiable geeks—flock to unless they’re looking for a quick snooze on a workday afternoon. The US National Institutes of Health’s (NIH) AIDS Vaccine Research Subcommittee (AVRS) meeting, however, appears to be an exception. 

A surprisingly large audience gathered on the NIH campus in Bethesda, Maryland on Feb. 6 to hear more about the plans of two newly-minted HIV vaccine research consortia, each indistinguishably named Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID).

The two CHAVI-IDs, respectively led by Dennis Burton at The Scripps Research Institute (TSRI) and Bart Haynes at Duke University, were tapped last year by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) to focus exclusively on the design of vaccines to induce broadly neutralizing antibodies (bNAbs) against HIV. 

If the name CHAVI-ID sounds vaguely familiar, this is because the current consortia are the progeny of the previous CHAVI, whose seven-year, $300 million contract ended last year (see July 20, 2012 IAVI Reportblog, CHAVI ID: The Sequel.
 
Shortly before that happened, a study it supported described in PLoS Pathogens how CHAVI researchers used single genome sequencing to identify HIV Envelope genes of founder viruses—the one or two viruses that initially infect a person—in three HIV-infected individuals. They then employed an array of high-tech tools to assess neutralizing antibody responses at various stages of the Envelope protein’s subsequent evolution. They concluded that, in rare instances, some individuals might be able to mount neutralizing antibody responses of reasonable potency very soon after the body launches its initial antibody assault on the virus—just a couple of weeks after infection. 

The CHAVI-ID center led by Duke, which solely and proudly headed up CHAVI  père is building on that study in the hope of finding clues to the swift elicitation of bNAb responses through vaccination. To that end it will, most immediately, pin much of its attention on tracking and analyzing the co-evolution of HIV variants and bNAbs isolated from a cohort of individuals infected with different subtypes of HIV-1. 

At the AVRS meeting, Haynes provided some detail about the lineage of a bNAb dubbed CH103 that was isolated from a Malawian infected with a single clade C virus roughly 31 months after infection. The work  traced the potential pathways this particular nAb took on its journey to becoming a bNAb. (Haynes diplomatically noted at the start of his talk that this was very much a team effort.) 

Haynes said the first autologous antibody responses—those aimed at the earliest transmitted/founder virus—were picked up at week 14 post-infection. But by week 20 the group began to see heterologous neutralizing activity in their antibody samples. Within several months, that antibody response had become sufficiently heterologous to neutralize Tier-2 laboratory strains of clade A and B HIV, which are more representative of the HIV that circulates in nature.
 
The researchers also looked at how the virus in the Malawian evolved to evade that response. Bette Korber, a laboratory fellow in Theoretical Biology and Biophysics at the Los Alamos National Laboratory, said the earliest and strongest evidence of selective immune pressure was at week 14, when the virus developed escape mutations to evade CD8+ T cells, which kill HIV-infected cells. 

But they also found mutations in one of the loops on HIV’s Envelope protein that is targeted by many antibodies, including the broadly neutralizing CH103. Still, while there was early evidence of neutralizing activity in this individual, CH103 did not appear to have great breadth. It neutralized only about 50% of a panel of over 100 pseudoviruses, considerably less than is achieved by many other bNAbs, including VRC01, which neutralizes 90 % of viral isolates. 

“The CHAVI 103 antibody doesn’t have the perfect angle of attack,” Haynes explained, describing how it approaches the virus’ surface. “The result is there is quite a gap in strains covered compared to VRC01, which does have a good angle of attack.” 

While it is still unclear why the CH103 developmental timeline was so compressed in this individual, Haynes said one can begin to “devise an immunization strategy” based on data from these studies. While much of the work by both CHAVI-IDs is focused on antibodies, the seven teams of the Duke-led effort are also exploring ways of inducing effective CD8+ cytotoxic T cell responses using either conserved or mosaic antigens (see Jan. 2013 Primer on Understanding How Researchers are Tackling HIV’s Genetic Variability.) 

The first mosaic vaccine trial is expected to begin this summer, said Korber, who helped design the mosaic immunogens for that trial.
 
The CHAVI-ID center led by TSRI, which includes eight other collaborators, is just getting its engines going. But its leader, Burton, also directs the IAVI-led Neutralizing Antibody Consortium, which is just as engaged in devising immunogens to elicit bNAbs. 

Burton too described how they have used deep sequencing technology to trace the evolution of another bNAb called PGT126, which is much more potent than CH103 and was isolated in an individual from IAVI’s Protocol G.  Burton too noted that many of the intermediate antibodies isolated in their studies neutralized viruses, though not as broadly as the fully-mature PGT126. Burton said the work showed clearly that as the antibody evolved—through a process known as somatic hypermutation—it began neutralizing a broader spectrum of HIV variants.
 
“What you are also noticing, even for those viruses that were well-neutralized by the precursor antibody, is that the neutralizing titer of the mature antibody is even better,” he said. “This kind of pattern is seen again and again, suggesting that the antibody is being honed in [such] a way that it homes in on a highly conserved region or a “sweet spot.” 

Bill Schief, an IAVI researcher and associate professor of immunology at TSRI who is funded by the Scripps arm of CHAVI-ID, gave an update on computational methods to reconstruct the epitopes bound by bNAbs. Some of this was previously presented at the AIDS Vaccine Conference in Boston (see Shaping the Battlefield,IAVI Report, Sep.-Oct. 2012). 

There were also presentations by Bruce Walker, director of The Ragon Institute in Boston, on harnessing CD4+ T cell responses for long-term protective immunity against HIV, and by Michel Nussenzweig, a professor and senior physician at The Rockefeller University on humanized mouse models (see Will Humanized Mice Move Us Closer To An AIDS Vaccine, IAVI Report, Nov.-Dec. 2012).
 
Needless to say, not a snore was heard at this semiannual subcommittee meeting. And from the looks of things, the next AVRS meeting, scheduled for September, is shaping up to be just about as bracing.