Vaccine Briefs

AIDS Vaccine Blueprint Launched: A Challenge to the Field

The AIDS Vaccine Blueprint 2008, IAVI’s biennial report on the state of AIDS vaccine research and development and a roadmap for the field, was released at the XVII International AIDS Conference in Mexico City August 3-8. It issues several challenges to AIDS vaccine researchers, setting interim goals and key milestones by which the field can measure progress.

Among the key scientific challenges it highlights are determining the mechanisms responsible for control of HIV infection in elite controllers, individuals who naturally suppress HIV replication to undetectable levels without the help of antiretroviral therapy, and elucidating the mechanism by which live-attenuated simian immunodeficiency virus (SIV) protects nonhuman primates against viral challenge. The Blueprint also recommends shifting resources away from the development of the majority of AIDS vaccine candidates that are currently in the clinical pipeline, since they are unlikely to be effective.

The publication, which IAVI has been producing since 1998, strikes a different theme and tone than two years ago, when more than two dozen AIDS vaccine candidates were moving through the clinical pipeline, including Merck’s cellular immunity vaccine MRKAd5, which many researchers regarded as the most promising. This vaccine candidate was based on a genetically altered adenovirus serotype 5 (Ad5) vector that carried HIV gag, pol, andnef genes.

Merck stopped immunizations in the Phase IIb test-of-concept STEP trial last September after the vaccine candidate failed to prevent transmission of HIV or reduce the viral load in vaccine recipients that subsequently became HIV infected.

“Two years ago, we all thought we had a signal of hope from Merck,” said Seth Berkley, president and CEO of IAVI. “What has happened is we’ve learned a lot about the science.” Because most of the AIDS vaccine candidates in clinical development employ similar strategies to Merck’s, the IAVI Blueprint urges stakeholders to “review their portfolios and drop candidates considered to have a low probability of success.”

IAVI suggests that the resources being spent on the current pipeline of candidates should be reallocated to developing a more diverse clinical pipeline. “Science is not a straight line,” said Alan Bernstein, president of the Global HIV Vaccine Enterprise, commenting about the recent setbacks in the AIDS vaccine field. “Failure is part of the game. It’s clear after 25 years that we are on a long journey.” Bernstein added that any long journey requires a roadmap, and that the Blueprint fulfills that role.

To develop new and improved vaccine candidates, the Blueprint suggests greater focus be placed on research to identify the best HIV immunogens for inducing both cellular and antibody responses against the virus. “Until now, the field has focused more on how to deliver antigens and less on the antigens themselves,” the document’s authors write.

But the Blueprint also recommends the exploration of live replicating viral vector-based vaccine candidates. To determine which of these candidates to advance into clinical trials, IAVI suggests that they be evaluated in comparative studies in the nonhuman primate model and that a “useful initial yardstick” would be comparing them against the Ad5 vector used in Merck’s vaccine candidate.

Other recommendations set forth include enhancing discovery efforts to identify new broadly neutralizing antibodies and translating the information about the binding sites of these antibodies into the design of new HIV immunogens, conducting small efficacy trials on leading candidates to see if they achieve pre-determined criteria, establishing incentives to enhance innovation in AIDS vaccine discovery, and training the next generation of AIDS vaccine scientists.

Omu Anzala, an AIDS vaccine researcher at the University of Nairobi School of Medicine, said it would be a big mistake to abandon research efforts in developing countries. “We cannot afford not to be part of [vaccine discovery],” said Anzala.

Peter Piot, the executive director of the Joint United Nations Programme on HIV/AIDS (UNAIDS) said despite declines reported by his agency in the number of HIV infections in some of the hardest-hit countries, there are still 33 million people living with the virus and an estimated 7,500 new HIV infections reported every day. “We are making progress through antiretroviral therapy, but there is no doubt we need a vaccine,” said Piot. —Regina McEnery

Passage of PEPFAR

President Bush recently signed into law a revised version of the President’s Emergency Plan for AIDS Relief (PEPFAR) authorizing US$48 billion in funding over the next five years to expand existing HIV/AIDS prevention, treatment, and care efforts worldwide. The original five-year, $15 billion plan was due to expire in September. The revised version more than doubles the amount of funding for HIV/AIDS prevention, treatment, and care programs, and also authorizes $9 billion in funding for malaria and tuberculosis programs.

The reauthorization aims to prevent 12 million new HIV infections and provide antiretrovirals (ARVs) to at least three million HIV-infected people in need over the next five years. It also allows for spending on support services for 12 million people affected by HIV/AIDS, including five million orphans and vulnerable children, and for training 140,000 new healthcare workers.

The US Senate passed the legislation last month after lengthy discussions concerning appropriate funding levels for prevention, treatment, and care efforts. The new plan does not require that one-third of total funding be spent on abstinence programs, a controversial stipulation in the original legislation, and instead calls for the Global AIDS Coordinator to provide “balanced funding” for prevention programs. However, another controversial component remains in the new legislation—all recipients of PEPFAR funding must sign a pledge demonstrating their opposition to prostitution.

The reauthorization took an important step in the process of overturning a two-decade restriction that banned visitors or immigrants living with HIV/AIDS from entering the US by removing from the bill a provision of the Immigration and Nationality Act. This restriction was partly why the US has not hosted one of the large biannual International AIDS Conferences since 1990, when it was held in San Francisco. The US Department of Health and Human Services now must remove HIV from the list of “communicable diseases of public health significance” for the ban to be completely lifted.

A section of the new PEPFAR bill also contains provisions related specifically to facilitating the development of vaccines, including those against HIV/AIDS, tuberculosis, and malaria. The reauthorization allows the US to negotiate with organizations—including the World Bank and the GAVI Alliance—to pursue the use of advanced market commitments, a novel market incentive that is meant to stimulate vaccine research and development efforts for diseases that primarily affect developing country populations.

The PEPFAR legislation also requires the US President to report to Congress within one year on a strategy for accelerating the development of vaccines for HIV/AIDS, malaria, and tuberculosis, as well as other infectious diseases. This strategy would include details on creation of economic incentives for research, development, and manufacture of these vaccines, as well as the efforts taken by the US to support clinical trials of vaccines in developing countries and to prepare these countries for the introduction of new vaccines.

During the deliberation process, many individuals and organizations involved in HIV/AIDS prevention, treatment, and care praised President Bush and Congress for initially authorizing PEPFAR, as well as for the plan’s accomplishments to date. The original bill in 2003 was the largest single funding commitment by any government to combat a single disease. Over the past five years, PEPFAR has supported the provision of life-saving antiretroviral treatment for approximately 1.7 million HIV-infected people. —Jonathan Grund, contributing writer

Treating People to Prevent the Spread of HIV

Researchers from the British Columbia Centre for Excellence in HIV/AIDS presented a study at the XVII International AIDS Conference, held in Mexico City from August 3-8, that used mathematical modeling to determine that expanding access to life-saving highly-active antiretroviral therapy (HAART) could potentially reduce the number of new HIV infections by up to 60% over the next 25 years (J. Infect. Dis. 198, 550, 2008).

Researchers involved with the study say they included three major high-risk populations for HIV infection in the model—men who have sex with men (MSM), injection-drug users (IDUs), and MSM who were also IDUs. They also varied the model to account for different adherence rates and guidelines for initiating therapy, and still their mathematical model consistently predicted that providing ARVs to at least 75% of individuals worldwide who are clinically eligible for treatment would result in a substantial decrease in the number of new HIV infections. “Basically the more people you treat and the faster you engage people in treatment, the greater the impact you will have on the epidemic,” said Julio Montaner, president-elect of the International AIDS Society.

HIV-infected individuals on HAART who adhere to treatment often decrease their plasma HIV RNA levels to below the levels of detection by currently available assays. Initiation of HAART has also been associated with marked reductions in HIV RNA levels in genital secretions in men and women, suggesting they will be less likely to transmit HIV to others (AIDS 14, 415, 2000). More recently, HAART has been shown to be associated with a decrease in HIV transmission between serodiscordant heterosexual couples, despite repeat exposure (J. Acquir. Immune Defic. Syndro. 29, 275, 2002; J. Acquir. Immune Defic. Syndro. 40, 96, 2005).

Montaner and his colleagues on this study advocated strongly at the Mexico City conference for a major expansion of access to ARVs in developing countries as a way of reducing the number of new HIV infections. —Regina McEnery