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By Madeline McCurry-Schmidt

The human body holds an arsenal of antibodies—powerful molecules produced by the immune system to recognize and neutralize viruses and other threats.

Traditional vaccine strategies have failed against HIV, in part because the virus mutates rapidly, changing its structure to evade recognition by the immune system.

However, researchers have discovered antibodies that can neutralize diverse HIV variants by targeting relatively constant surface patches on the virus. These antibodies, called broadly neutralizing antibodies (bnAbs), develop in only a minority of HIV-infected individuals over a period of years—yet they have inspired vaccine-design efforts to elicit similar responses to protect against HIV infection.

Now two new studies, which included leaders at The Scripps Research Institute (TSRI) and the International AIDS Vaccine Initiative (IAVI), show that vaccines can teach the immune system to produce HIV bnAbs by using a series of "priming" and “boosting” shots to gradually educate the system.

“This seems like an ever-more-promising approach to making a vaccine,” said TSRI Professor William Schief, who also serves as Director of Vaccine Design for IAVI’s Neutralizing Antibody Consortium and Center (NAC) at TSRI.

The studies, published September 8, 2016, in the journals Immunity and Cell, were co-led by Schief and Michel Nussenzweig of the Howard Hughes Medical Institute and The Rockefeller University.

Gradually Meeting the Enemy

To develop this new vaccine strategy, the researchers devised vaccines based on a key part of HIV’s outer shell—the “trimer” protein that mediates infection of human cells and is targeted by bnAbs to block the infection process. Previous studies had shown that the trimer is defended by a constantly shifting layer of sugar molecules, called “glycans,” which keep most antibodies from recognizing and binding to it. Many bnAbs have learned how to bypass this defense and bind at least in part to glycans on the trimer, but scientists did not know how to design vaccines to induce this kind of response.

In the Immunity study, spearheaded by TSRI Research Associate Jon Steichen and Staff Scientist Daniel Kulp of IAVI and TSRI, the researchers engineered molecules, called immunogens, to prompt the development of a class of bnAbs to “grab” the glycans and the underlying protein surface.

In a major breakthrough in immunogen design, the researchers developed new methods and employed them to engineer stabilized HIV trimers to serve as "priming" and "boosting" immunogens and gradually instruct the immune system how to produce bnAbs.

The researchers tested the priming immunogen in a mouse model and found that it could indeed activate cells containing precursors to HIV-neutralizing antibodies.

In the same paper, the researchers also proposed designs for a “cocktail” of immunogens that mimic some of the variations in HIV. The idea is that a cocktail could be given as the final shot in a series of boosters—a final set of instructions to teach the immune system to produce antibodies that can act against diverse HIV variants.

Steichen and colleagues also proposed a total of seven candidate sequential vaccination strategies to induce bnAbs.

Putting the Strategy to the Test

In the Cell study, with Steichen and Amelia Escolano of The Rockefeller University as first authors, the researchers put the idea of sequential vaccination to the test in mouse models that had immune cells with potential to develop into those that produce bnAbs. Using the immunogens developed in the Immunity paper, the authors tested the priming shot followed by a series of boosters and, finally, a cocktail. Although the booster proteins were designed to be given in certain sequences, the authors did not know which if any of the proposed sequences would work.

To experimentally select a boosting scheme, the researchers screened mouse antibodies after each immunization against the remaining booster candidates. This process resulted in testing one of the seven candidate vaccination strategies proposed in the Immunity paper and led to the elicitation of bnAbs that work against a range of HIV strains in laboratory tests.

The results of the Cell study provide proof of principle that sequential vaccination with designer proteins can teach the immune system to produce bnAbs.

The researchers said the next steps are to refine the immunogens and develop strategies to optimize the chances of success in human clinical studies.

These studies included important contributions from Dennis Burton, the James & Jessie Minor Chair of Immunology, Chair of the TSRI Department of Immunology and Microbial Science, and Scientific Director of the IAVI NAC at TSRI and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID); Ian Wilson, the Hansen Professor of Structural Biology and Chair of the Department of Integrative Structural and Computational Biology at TSRI; Andrew Ward, Associate Professor in the Department of Integrative Structural and Computational Biology at TSRI; and Darrell Irvine of the Massachusetts Institute of Technology (MIT), the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard, and the Howard Hughes Medical Institute.

The Immunity study, “HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies,” included additional authors from the NIH’s CHAVI-ID at TSRI; the Ragon Institute of MGH, MIT and Harvard University; and MIT. This study was supported by the IAVI NAC; Collaboration for AIDS Vaccine Discovery (CAVD) funding for the IAVI NAC, the Ragon Institute and the NIH National Institute of Allergy and Infectious Diseases (CHAVI-ID 1UM1AI100663, P01 AI110657 and R01 AI084817).

The Cell study, “Sequential Immunization Elicits Broadly Neutralizing and-HIV-1 Antibodies in Ig Knock-in Mice,” included additional authors from the Ragon Institute of MGH, MIT and Harvard University. The study was supported by CAVD (grants OPP1033115 and OPP1124068); CHAVI-ID (grant 1UM1 AI100663); the National Institute of Allergy and Infectious Diseases (grants AI100148 and AI109632) (M.C.N.); the IAVI NAC Center; CAVD funding for the IAVI NAC Center; the Ragon Institute; The Robertson Foundation; The Rockefeller University; the Clarin COFUND-Marie Curie program (PCTI-FICYT); the Swedish Research Council; and an Medical Scientist Training Program grant (T32GM07739) to the Weill Cornell/ Rockefeller/ Sloan-Kettering Tri-Institutional MD-PhD Program.

See also additional Science and Cell studies on HIV/AIDS vaccine work led by TSRI scientists and published on September 8.

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A structural analysis shows how scientists might stabilize a key part of HIV’s outer shell—its “trimer”—to elicit antibodies in a future vaccine.