The quest for an effective HIV vaccine presents new possibilities, challenges

By, Kathy Stover, EurekAlert, May 16, 2007

A vaccine that prevents HIV infection remains an important goal in the fight against AIDS, but the current top HIV vaccine candidates may not work in this way, say scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Rather, the first successful preventive HIV vaccines, if administered prior to HIV infection, may reduce HIV levels in the body, thereby delaying the progression to AIDS and the need to start antiretroviral drugs. These vaccines may also reduce the chance that a person infected with HIV would pass the virus on to other people, according to NIAID Director Anthony S. Fauci, M.D., and Margaret I. Johnston, Ph.D., director of NIAID’s Vaccine Research Program in the Division of AIDS.

In a review article in the May 17 issue of the New England Journal of Medicine, Drs. Johnston and Fauci examine the daunting challenges posed by HIV, the evolution of HIV vaccine research, the role T cells may play in HIV vaccine effectiveness, and how the first successful HIV vaccine may fit into a comprehensive HIV/AIDS prevention effort.

Vaccines typically work by mimicking the effects of natural exposure to a specific microbe. Because of initial exposure, the immune system develops the ability to recognize the specific microbe and can protect the human body against it if it reappears. HIV, however, has thwarted scientists’ efforts thus far to develop a classic preventive vaccine for the virus because of its ability to integrate into target cells and evade clearance by the immune system. The interaction between HIV and the immune system is complex, and how different HIV-specific immune responses help to control infection is only partially understood.

"The development of an HIV vaccine is a complex research challenge because the virus is unusually well-equipped to elude immune defenses," says Dr. Fauci. "Much progress has been made; however, we must continue research efforts to improve our understanding of HIV and how it evades the immune system, to design new vaccine candidates and to assess the most promising ones in clinical trials."

Dr. Johnston adds, "An important research challenge is to determine if these so-called T-cell vaccines that primarily induce a cellular immune response can have a beneficial effect by reducing viral levels and preserving critical cells needed to control infection. There will be a tremendous public health challenge as well, in an HIV vaccine that does not completely prevent the virus from establishing itself in the body."

Once HIV enters the body, it infects crucial CD4+ T cells, replicates, spreads throughout the body and establishes HIV reservoirs in lymphatic tissues. Within weeks of exposure, virus levels peak and then decline to levels that may remain low for months or years. It is believed that CD8+ T cells--so-called killer T-cells--are responsible for this reduction in HIV levels; however, their ability to continue to suppress the virus declines over time as the virus mutates and the immune system is progressively destroyed.

The infection of CD4+ T cells occurs very early in HIV disease, and virus persists indefinitely. Other viruses also replicate robustly but, unlike HIV, most do not establish a permanent reservoir of infected cells in the body. The window of opportunity to prevent long-term HIV infection may close permanently once a pool of latently infected cells is in place, Drs. Johnston and Fauci note. Neutralizing antibodies, which can attach to and eliminate free virus, only appear after HIV levels have declined substantially. Further, the effectiveness of these antibodies is stymied because of the rapid genetic changes that occur in HIV’s outer envelope protein, which allow the virus to escape detection.

While early efforts to develop an HIV vaccine focused on the viral envelope, an improved understanding of how HIV causes disease has brought increased attention to the role that T cells could play in an HIV vaccine by spurring cellular immunity. Numerous animal and human studies have confirmed how important cellular immunity is in the early and later stages of HIV infection, even though the virus is never completely eliminated. Vaccines that induce strong cellular immune responses may have some benefits, say the authors. In non-human primate models of HIV infection, T-cell vaccines have reportedly decreased the total amount of virus produced during early infection, caused a reduction in virus levels following the acute stage of infection, or produced some combination of these effects. In many of these animals, disease progression was also delayed.

Based on the scientific evidence, several questions remain, say Drs. Johnston and Fauci: Can a vaccine that does not prevent HIV infection but reduces virus levels and preserves a segment of uninfected CD4+ T cells from destruction benefit the immunized individual" Might people immunized with T-cell vaccines before HIV exposure remain disease-free for a prolonged period once they are infected"

Additionally, T-cell vaccines may reduce secondary HIV transmission if they can help the immune system keep viral replication at a very low level for a long time. Studies have suggested that people with high levels of virus--namely those in the early and late stages of infection--are most likely to infect their sexual partners. A preventive vaccine given before exposure to HIV might stifle the initial burst of virus, better control virus levels and potentially reduce that person’s ability to infect other people, Drs. Johnston and Fauci assert.

Vaccines of this type present several complications, however. T-cell-mediated control of HIV infection may not stave off disease forever. Additional human studies would be needed to determine if the vaccine also reduces the spread of HIV. Finally, an HIV vaccine that delays but does not completely prevent disease could not stand alone as a preventive measure; the public health community would need to include it as part of a broader HIV prevention program, so that recipients would minimize, or ideally, not engage in high-risk behaviors, according to the authors.

Currently, several vaccines that induce primarily T-cell responses are in or will soon enter expanded human clinical trials to determine if they impact HIV infection. Researchers also continue to give high priority to creating an HIV vaccine that induces broadly neutralizing antibodies, which might prevent the establishment of HIV infection. Although rare, such antibodies do exist, giving hope to scientists that a vaccine to induce such antibodies can be designed.

Drs. Johnston and Fauci conclude that a vaccine that prevents HIV infection by clearing the virus before cells become latently infected remains the goal. In addition, they believe that even a vaccine that does not prevent infection could prove beneficial if it prolongs the disease-free period and possibly even reduces virus transmission. If such a vaccine is shown to be successful and is eventually licensed, it would need to be delivered as part of a comprehensive, multifaceted HIV prevention program.

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NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)--The Nation's Medical Research Agency--includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

Reference: MI Johnston and AS Fauci. An HIV vaccine--evolving concepts. The New England Journal of Medicine DOI: 10.1056/NEJMra066267 (2007).

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.


Source: http://www.eurekalert.org/pub_releases/2007-05/nioa-tqf051007.php

Analysis: Advances in HIV, TB vaccines

By, Adrianne Appel, United Press International, May 9, 2007

Scientists are zeroing in on discovering vaccines to control malaria, tuberculosis and HIV in poorer nations, say health experts involved in the effort.
The diseases kill more than 6 million people each year and impact hundreds of millions of lives, many of them children in Latin America, Africa, Asia and Eastern Europe, Tadataka Yamada, president of the Bill and Melinda Gates Foundation, told United Press International.

"Knowing the impact of the death of one child on one family, it is too much," Yamada said at the BIO International Convention held this week in Boston.

Within a couple of years, vaccines against malaria and TB will be brought to the developing world for final-stage testing, while advanced trials of a few HIV vaccines are already under way in Africa and China, experts said.

The vaccines are specific for the strains of HIV found locally in those regions, said Seth Berkley, president and founder of the International AIDS Vaccine Initiative.

"We are most proud of our clinical trials in Zambia, Rwanda and India. We are seeing extraordinary enrollment rates," Berkley said.

The treatments are likely to be only moderately effective, he said. But given the large number of people with HIV and the devastation of the disease, even a small reduction in its incidence is worth going forward, he added.

In the meantime, scientists will keep searching for a more potent vaccine. In the laboratory, they have their sights on a form of a simian immunodeficiency virus, which attacks monkeys, that is altered to be harmless.

"We know it works better than anything else so far. We should have focused on it long ago," Berkley said.

Non-profit foundations, rather than the private sector, are largely leading and funding the vaccine effort against malaria, HIV and TB, said Christian Loucq, interim director of the Malaria Vaccine Initiative.

Big drug companies see the small profits to be made on vaccines in developing nations and thus have not taken the initiative to develop them, Loucq said.

"It's viewed as a problem of no market," Loucq said. Malaria is especially challenging in attracting private companies, he noted.

"It's a slightly bigger problem to raise interest in malaria because it doesn't affect the developed world; it's mainly (a disease of) poor people."

However, the non-profit groups are moving to fill the gap, having raised and spent hundreds of millions of dollars so far.

The Malaria Vaccine Initiative has raised about $275 million from the Gates Foundation, the Rockefeller Foundation and USAID. The initiative gives the funds to drug companies such as GlaxoSmithKline to develop the vaccines.

Within a year the initiative is preparing to bring a malaria-prevention vaccine to 16,000 children in Africa, Loucq said. It is one of 10 possible anti-malaria vaccines in various stages of development.

Malaria, a blood parasite transmitted by mosquitoes, infects 300 million to 500 million people each year and causes the death of 1 million, mostly children.

The group's goal is to have a vaccine by 2015 that prevents malaria in 50 percent of people for at least one year, he said.

On the TB front, the group hopes to have that disease under "global control" within 15 to 20 years, said Jerald Sadoff, president and chief executive officer of Aeras Global TB Vaccine Foundation.

To that end, the foundation will bring a tuberculosis vaccine for final testing to South Africa and the south of India by 2008, Sadoff said.

TB is an airborne bacterial disease that infects 8 million people a year and kills 2 million, many who also have HIV, he said.

Sadoff noted that some TB strains have become resistant to treatment, including the deadly XDR strain. It was found in South Africa last year, when 51 of 52 people infected with it died within 20 days, he said.


Source: http://www.upi.com/Health_Business/Analysis/2007/05/09/analysis_advances_in_hiv_tb_vaccines/