CHAVI: The Sequel

A $31 million award from NIAID will start two new centers

The US National Institute for AIDS and Infectious Diseases (NIAID) has awarded an initial US$31 million to Duke University and The Scripps Research Institute (TSRI) to head up the Centers for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). The centers are designed to build on the work of CHAVI, a virtual center created in 2005 to address some of the basic scientific problems impeding HIV vaccine design. CHAVI is now in the last months of its funding cycle. 

CHAVI-ID, which NIAID officials describe as a completely new initiative, will receive up to $186 million over six years, according to NIAID. A major focus of the centers will be a slew of broadly neutralizing antibodies (bNAbs) that have been uncovered in recent years. 

Many researchers believe that a close analysis of the binding mechanisms of these antibodies could reveal information crucial to designing vaccines that can prevent infection by a broad spectrum of HIV variants. The agency’s director, Anthony Fauci, noted in his announcement of the award that CHAVI-ID’s studies will provide “a rational foundation” for the design of such vaccines.
James Bradac, chief of the preclinical research and development branch of the vaccine and prevention research program at NIAID’s Division of AIDS (DAIDS), said the award doesn’t specify that the new centers must produce products for clinical testing by the end of the grant cycle. “But,” he said, “we are hoping there will be immunogens designed and manufactured and in clinical trials during the course of these awards.” 

The Duke center will largely focus on projects essential to the design of immunogens that might induce broadly neutralizing antibodies (bNAbs), including the structural analysis of the native Envelope trimer that all neutralizing anti-HIV antibodies target. The center will be testing multiple Env proteins for their ability to induce bNAbs. Researchers will also explore the pathways by which bNAbs mature, and try to create vaccine candidates and regimens that accelerate that process. 

Additionally, the center will explore strategies to induce CD8+ cytotoxic T cells—which kill HIV-infected cells—using mosaic vaccine antigens. As implied by the name, these computationally designed vaccine antigens are constructed by stitching together peptide sequences from variants of the same gene. When linked together, they should, in theory, induce CD8+ T-cell responses that provide coverage against a wide range of circulating HIV variants . 

“The field has come very far since 2005,” said Barton Haynes, who led the first iteration of CHAVI and will be the principal investigator of the CHAVI-ID center at Duke. “The new grants can be much more focused than in 2005. The field in 2005 did not have a good idea of the nature of the roadblocks” to the design of broadly effective AIDS vaccines. But now, he said, “the field has new bNAbs and good clues regarding the roles of host factors that limit the induction of bNAbs.” 

The other CHAVI-ID center will be led by principal investigator Dennis Burton, professor of immunology and microbial science and director of IAVI’s Neutralizing Antibody Center at TSRI, who said the grant will enable TSRI and its collaborators to “greatly expand the scope of some of the work we are already doing, as well as allowing us to start new studies.” 

Much of the focus of the Scripps center will be on furthering B-cell and antibody research to guide the development of immunogens that can elicit protective antibodies in animal models. But the money will also be devoted to a new avenue of research for TSRI—studies of CD4+ T cells, including follicular helper T cells, which drive the maturation and selection of B cells and so help to generate increasingly potent neutralizing antibodies (see A Slew of Science in Seattle, IAVI Report, Mar.-Apr. 2012). 

bNAbs are known to go through an extensive process of such maturation. Burton said the CHAVI-ID grant will allow them to bring in some new investigators who specialize in this area of research. “Hopefully, it will allow us to optimize immunization strategies,” he said. 

Duke will receive an initial $19.9 million and TSRI will receive an initial $11.1 million in fiscal year 2012. While the funds represent a significant investment by NIAID in AIDS vaccine research, the six year, $186 million CHAVI-ID award is somewhat less than the $300 million seven-year award that was appropriated to create CHAVI, which is winding down this year. Haynes acknowledged that the lower level of funding for CHAVI-ID has, inevitably, led to “fewer projects and fewer laboratories involved.”