A Change of Tune

Following the first trial showing efficacy and continuing progress in other areas of research, a new chord of optimism was struck at AIDS Vaccine 2010

By Kristen Jill Kresge and Regina McEnery

Although the prime-boost vaccine regimen tested in the controversial RV144 trial in Thailand provided only modest efficacy (31.2%) in preventing HIV infection, it was enough to make Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (NIH), a convert.

“It is feasible to block acquisition of HIV infection. We know from the Thai trial that it can be done. Before, I was not so sure it was feasible,” Fauci said at AIDS Vaccine 2010, held in Atlanta, Georgia, from Sep. 28 to Oct. 1. “The proof of concept here is huge. Our task now is to use the science to get us closer to a much more effective vaccine,” he said. “I don’t think there’s any question we’re going to get there.”

During his signature overview talk at the annual conference, Fauci highlighted recent progress in the isolation of HIV-specific broadly neutralizing antibodies—proteins that bind to viruses and prevent them from infecting human cells—and the novel approaches researchers are now employing to try to visualize which parts of the virus’ surface these proteins target. He also discussed plans to build on the results of RV144 and strategies for designing clinical trials.

Alan Bernstein, executive director of the Global HIV Vaccine Enterprise, which co-hosted AIDS Vaccine 2010 with Emory University’s Center for AIDS Research, echoed Fauci’s upbeat mood. “I believe we are seeing a real reason for optimism,” said Bernstein.

RV144: The search continues

Without a doubt, the results of the RV144 trial helped galvanize AIDS vaccine research (see VAX October 2009Spotlight article, Vaccine Research Gains Momentum). Now, researchers are mining the samples from the trial in the search for possible immune correlates of protection—the specific immune responses that were present in vaccinated individuals who did not become HIV infected—that could enable researchers to try to build upon what Nelson Michael, director of the US Military HIV Research Program (MHRP), called the “early but nondurable efficacy” of the prime-boost vaccine regimen tested in the RV144 trial. One year into the three-and-a-half-year trial the efficacy was as high as 60%.

Michael reported that MHRP and the 35 investigators at 20 different institutions who are collaborating on the analysis of RV144 samples are still evaluating a broad range of laboratory tests that may be used, come January 2011, to compare the immune responses of different subsets of RV144 volunteers. Even though these studies aren’t yet underway, researchers at MHRP have already made some intriguing observations. In an exploratory analysis of 60 vaccinated volunteers from RV144 who remained HIV uninfected, researchers observed that these individuals had a high frequency of T-cell responses to two distinct areas on the surface of HIV that were not seen in 68 volunteers who became HIV infected during the trial, and which are very rarely seen in HIV-infected Thais (only one individual from a natural history study of HIV infection was found to have a T-cell response to the same region of HIV). Michael said researchers may be “on the pathway” to determining why the vaccine provided modest efficacy in preventing HIV infection, but he cautioned that the finding was far from conclusive.

In addition to studying the RV144 samples, researchers are also planning several follow-up studies to help elucidate the correlates of protection. There are also plans for two additional efficacy studies with either the same or similar candidates to those tested in RV144, which will start in 2013 or 2014.

The first efficacy trial is a Phase IIb trial in Thailand that Michael called a “top priority” because it has the potential to lead to licensure of the vaccine candidate in this region. This trial, which will be funded by the US Army, the Thai government, the NIH, and Sanofi Pasteur, will test the RV144 prime-boost regimen with an additional booster shot six months after the fourth vaccination (12 months after the first vaccination). This trial will enroll men who have sex with men (MSM) at high risk of HIV infection, a much different population than the low- to moderate-risk heterosexual men and women in RV144.

Another Phase IIb efficacy trial, which would also start in 2014, is being planned in southern Africa. This trial will involve high-risk heterosexual volunteers and is being funded by the Bill & Melinda Gates Foundation, the NIH, the HVTN, Sanofi Pasteur, and Novartis RSA, among others, according to Michael. He said the objective of this trial is to see if the efficacy seen in RV144 can be extended to other geographic regions where there is greater diversity of viral strains.

Other trials

Along with the post-RV144 studies moving through the pipeline, several other clinical trials are expected to start within the next few years, many of them to test viral vector-based vaccine candidates. These candidates use viruses to deliver fragments of HIV’s genetic material into the body, with the aim of inducing the immune system to respond to HIV. Some of the viral vector-based candidates in development employ strains of a common cold virus known as adenovirus (Ad). The current crop of Ad vectors now advancing in clinical trials include an Ad35 candidate developed by IAVI and an Ad26 candidate developed by Dan Barouch, an associate professor of medicine at the Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School. These vectors are now being evaluated alone and in combination in a Phase I trial (see Global News). There are also plans to test the Ad26 candidate in combination with another viral vector-based candidate that uses modified vaccinia Ankara (MVA), a weakened vaccinia virus, in a Phase I trial to start next year.

Researchers are also working to optimize what goes inside viral vectors—the HIV fragments known as antigens. One approach being explored is to computationally design antigens to deal with the overwhelming genetic diversity of HIV (see VAX March 2009 Primer on Understanding How Inserts for Vaccine Candidates are Designed). These antigens, called mosaics, have only been tested in animal models so far, but there are now plans for three clinical trials evaluating mosaic antigens in Phase I clinical trials in the next couple of years.

Antibody frenzy continues

Another area of recent progress in the HIV vaccine field is the discovery of several antibodies that can neutralize a remarkably high percentage of virus strains in laboratory tests (see VAX March 2010 Primer on Understanding Advances in the Search for Antibodies Against HIV). These broadly neutralizing antibodies (bNAbs) continued to create a buzz in Atlanta, where researchers reported on several new antibodies that were isolated from HIV-infected individuals and also on the incremental progress in understanding how these antibodies form and how they might be induced through vaccination.

Researchers from NIAID’s Vaccine Research Center (VRC) reported on the isolation of two bNAbs that were identified from IAVI’s cohort of chronically HIV-infected individuals. IAVI’s Neutralizing Antibody Center at The Scripps Research Institute (TSRI) in California reported the isolation of 13 new monoclonal antibodies from four so-called elite neutralizers—individuals whose blood can neutralize a large number of HIV isolates—also from IAVI’s cohort. Three of the antibodies identified by the NAC team target an area on the exterior of the virus that is not the target of the other bNAbs described so far. Additionally, researchers from the consortium known as the Center for HIV/AIDS Vaccine Immunology (CHAVI) reported on five other neutralizing antibodies isolated from their cohorts of both acutely and chronically HIV-infected individuals.

As researchers home in on the structures of the new crop of antibodies, they are developing a clearer picture of some of their unique attributes, including the degree to which some of them evolve and mature to become more potent neutralizers of HIV. Researchers in Atlanta described how they are using high-level genetic sequencing techniques to track the evolution of these antibodies in HIV-infected individuals, which may help researchers design more effective antibody-based AIDS vaccines.

More attention has also been directed toward understanding another type of antibody function; instead of neutralizing the virus by binding directly to it, the antibody binds to cells already infected with HIV, thus facilitating the killing of these cells by other immune cells (see VAX January 2010 Primer on Understanding Antibody Functions: Beyond Neutralization). There are now several studies underway to try to understand this antibody mechanism better. Researchers in Atlanta presented both animal and clinical data suggesting that being able to trigger this kind of non-neutralizing antibody function could potentially improve vaccine efficacy.

There was also progress reported on new approaches to design vaccine antigens that could coax the immune system to produce such bNAbs. One method for designing these antigens involves stitching the precise part of HIV to which the bNAb binds into a computationally designed protein structure. This method, referred to as scaffolding, has shown promise in a recent animal study and was touted at the meeting by several researchers as a promising avenue of work.