February 28, 2014

Momentum Seen in AIDS Vaccine Research and Development

Data Unveiled at Leading Scientific Conference Shows Promising Advances on Several Fronts

The annual AIDS Vaccine 2009 conference, held in Paris from October 19-22, brought together more than 1,000 scientists from across the world engaged in an exciting new phase of AIDS vaccine research and development.  “There are many reasons for hope,” Michel Sidibé, executive director of the Joint United Nations Programme on HIV/AIDS, told participants at the opening session of the conference. “Your program is full of exhilarating sessions reporting developments which will animate the AIDS vaccine field. It is clear that your perseverance is paying off. One cannot predict the duration of your journey to licensable HIV vaccines, but one does begin to feel that the wind is in your sails.”

Much of the excitement at the Paris conference focused on the results of the efficacy  trial in Thailand that demonstrated, for the first time, a benefit in humans from an AIDS vaccine candidate, in this case a combination of two experimental AIDS vaccines. The trial sponsors announced in September that the combination candidate reduced the risk of HIV infection by 31.2%, according to an analysis of the results that included everyone who participated in the trial except for seven volunteers who were, it turned out, HIV infected before they received any injections. This result was statistically significant but, due to the relatively small numbers of HIV infections in the trial, the estimate of 31.2% had large confidence intervals. 

At the conference, Dr. Supachai Rerks-Ngarm and Colonel Nelson Michael presented two additional analyses. Using all trial participants, including the seven who were HIV infected at the beginning of the trial, the candidate’s efficacy was calculated at 26.4%. This analysis did not reach statistical significance. Using only trial participants who both received all six injections at times prescribed in the trial protocol and did not become infected until after the six month vaccination period, the vaccine combination was calculated to reduce the risk of HIV infection by 26.2%. This analysis also was not statistically significant due to the smaller number of persons in the analysis.

“All three analyses are qualitatively similar,” said infectious disease epidemiologist Seth Berkley, CEO of the International AIDS Vaccine Initiative (IAVI), which was not involved in the study. “With all the data in front of us, we can see there is a signal there, although it is modest.”

“It’s a consistent story,” said Lawrence Corey, head of the combined programs in infectious diseases at the Fred Hutchinson Cancer Research Center and the Virology Division of the University of Washington’s Department of Laboratory Medicine.  “There seems to be some effect.”

AIDS vaccine researchers now face the challenge of determining how the candidate tested in the Thai trial worked—that is, specifically what immune responses it provoked. This information could help researchers design novel candidates and improve upon and prioritize among candidates that have emerged in the decade since the candidates in the Thai trial were developed. “This study becomes a landmark. You can put it on a map and begin to figure out where you go from here,” said Colonel Jerome Kim, deputy director of science at the U.S. Military HIV Research Program. The trial was a collaborative effort of, among others, the U.S. military, the U.S. National Institutes of Health and the Thai Ministry of Health.

Among the other scientific advances reported at the Paris conference were the following: 

1. Researchers at and affiliated with IAVI have discovered two new antibodies capable of neutralizing a broad range of HIV types, and it is anticipated that more such antibodies will be found in the coming year. The Vaccine Research Center of the U.S. National Institutes of Health reported discovering another such antibody.  These findings open new opportunities for designing vaccines that can elicit such antibodies and ultimately block HIV infection.

Promising data was reported on the effort to improve cell-mediated immune responses against HIV. Robust T-cell responses were obtained with new combinations of AIDS vaccine candidates, novel viral vectors and newly crafted HIV inserts (so-called mosaic antigens—combinations of different pieces of HIV genetic sequences). Vectors are viruses other than HIV that are modified to shuttle inserts—man-made copies of some of HIV’s genes—into the body. An IAVI-funded study by Louis Picker, director of the pathobiology and immunology division of the Oregon National Primate Research Center, achieved an unprecedented control of infection by SIV (the simian cousin of HIV). An experimental vaccine based on a novel replicating viral vector kept SIV viral loads in more than 50% of the non-human primates in the experiment at undetectable levels. It was the first time such a result was observed with a viral vector-based vaccine model. The further testing of this and other promising novel AIDS vaccine approaches is ongoing. The most promising are expected to enter clinical trials in the coming few years.

2. Valuable new information was also obtained from clinical research.  AIDS vaccine research continues to be informed by additional data being generated from two large-scale clinical trials, for which vaccinations were halted two years ago for lack of efficacy.  The trials, termed STEP and Phambili, tested an AIDS vaccine candidate constructed using a modified version of a virus called Adenovirus Type 5 (Ad-5) as a vector. When the results showed a trend—more HIV infections in participants who received the vaccine candidate than the placebo—it appeared that male vaccinees who were at greatest risk of HIV infection were those who had pre-existing immunity to Ad-5 and were not circumcised.  A two-year follow-up revealed new HIV infections in both the STEP and Phambili cohorts, with the data pointing toward lack of circumcision as the primary reason for increased numbers of infections in the vaccinees.  

3. New data was presented that shed additional light on the characteristics of the particular variant of HIV that is transmitted from one person to another. Individuals who are infected with HIV are infected with millions of different HIV variants. However, there is a bottleneck effect when it comes to virus transmission, with only a single “founder” virus taking hold in the majority of heterosexually transmitted cases, according to a study of couples in which one HIV-infected partner infected his or her uninfected partner.  In a related development, the spread of SIV during the first few days of infection was elegantly demonstrated in a non-human primate study presented in Paris, providing scientists more information regarding what happens in the earliest phases of infection before the virus replicates and diversifies within the body.  This information re-affirmed the need for a vaccine to both prevent HIV infection and to generate immune responses that rapidly clear the virus, before it establishes persistent infection.

This important progress in AIDS vaccine R&D comes at a time of pressure on funding for this type of research, fueled in part by the economic downturn. In 2008, for the first time in ten years, the investment in AIDS vaccine R&D globally fell by some 10% to US $868 million.  “It’s a little frightening to think that we may not be able to take full advantage of the scientific momentum created by these advances because we’re unable to fund the work,” said Berkley.

Sidibé called on “all those who support” AIDS vaccine R&D, “public and private donors, investors, the academy, the broader scientific community, government officials and regulators, communities, the international community of which UNAIDS is a part,” to now redouble their “backing, commitment and investment” so that researchers could accelerate their efforts “and close the gap between the promise of an AIDS vaccine and the reality.”

The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996 and operational in 25 countries, IAVI and its network of collaborators research and develop vaccine candidates.  IAVI was founded with the generous support of the Alfred P. Sloan Foundation, The Rockefeller Foundation, The Starr Foundation, and Until There’s A Cure Foundation.  Other major supporters include the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, The John D. Evans Foundation, The New York Community Trust, the James B. Pendleton Charitable Trust; the Governments of Canada, Denmark, India, Ireland, The Netherlands, Norway, Spain, Sweden, the United Kingdom, and the United States, the Basque Autonomous Government, the European Union as well as The City of New York, Economic Development Corporation; multilateral organizations such as The World Bank; corporate donors including BD (Becton, Dickinson & Co.), Bristol-Myers Squibb, Continental Airlines, Google Inc., Henry Schein, Inc., Pfizer Inc, and Thermo Fisher Scientific Inc.; leading AIDS charities such as Broadway Cares/Equity Fights AIDS; other private donors such as The Haas Trusts; and many generous individuals from around the world.  For more information, see www.iavi.org.