March 28, 2013

A team of researchers at The Scripps Research Institute (TSRI) and IAVI report in the current issue of Science a novel strategy to aid the design of vaccines that can elicit broadly neutralizing antibodies against HIV. Their approach, which applies pioneering computational and genetic engineering techniques to create an HIV immunogen—the active ingredient of a vaccine—could have significant implications for the design of preventive vaccines against a wide variety of other pathogens as well.

The current research derives from a recent surge in the structural and biological analysis of broadly neutralizing antibodies (bNAbs) isolated from people infected with HIV from around the world. Researchers suspect that if such antibodies could be elicited by vaccination, they might stop HIV in the earliest stages of infection. The immunogen devised by the TSRI-IAVI team is designed to elicit antibodies similar to a bNAb known as VRC01, which was isolated by the Vaccine Research Center (VRC) of the US National Institute of Allergy and Infectious Diseases. It has been shown in laboratory studies to neutralize more than 90% of the globally circulating variants of HIV.

The immune system produces many antibodies in response to HIV. But most of them do not stop infection because the molecular structures they target on the outer envelope protein of HIV keep changing as the virus mutates. bNAbs, however, target rare molecular features of the envelope that are relatively resistant to such change. Recent research has revealed that these bNAbs tend to be produced by B cells derived from unique subsets of precursors, or germline cells, which undergo a lengthy process of maturation. The trouble is that the germline cells typically stimulated by vaccines often fail to recognize and become activated by immunogens that bind bNAbs. The current research is aimed at designing immunogens that can stimulate a relevant subset of germline B cells and begin to guide them down the path of maturation that leads to the production of certain types of bNAbs.

To accomplish this feat, the TSRI and IAVI researchers whittled down the HIV envelope protein to the simplest, stable structure recognized by VRC01. They then applied sophisticated computational and genetic engineering techniques to further manipulate and refine that molecule and create an immunogen named eOD-GT6. This immunogen is recognized not only by VRC01 and other antibodies like it, but also by germline B cells that mature into the kinds of cells that produce those antibodies. Finally, the researchers created a ball-like structure bearing 60 eOD-GT6 immunogens and showed that this virus-like particle potently activated germline B cells of interest.

The generation of the eOD-GT6 immunogen is a significant step forward in efforts to design vaccines that can elicit bNAbs against HIV—a cherished goal of the AIDS vaccine field. The researchers’ next step will be to assess their new immunogen in animal models and, if results are encouraging, prepare it for evaluation in clinical trials. They will also apply similar strategies to devise immunogens to accelerate the process of antibody maturation that culminates in broadly neutralizing antibodies against HIV. 
For more details about the study, read the news release prepared by TSRI.

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