Effective vaccine remains illusive as pursuit continues

30th June, 1998

The first clinical trial to test the efficacy of an HIV vaccine in HIV-negative but high-risk individuals in the US and Thailand began this past Tuesday. It’s apparent that another HIV vaccine could move to clinical efficacy trials in two years.

These large-scale, phase III studies seem to indicate that scientists and pharmaceutical companies are moving in the right direction. In the United States, staff at the National Institutes of Health have added HIV vaccine development to their list of priorities. The Joint United Nations Programme on HIV/AIDS (UNAIDS) is helping governments and scientists create the infrastructure for vaccine research, concentrating in the last few years on three countries--Brazil, Thailand, and Uganda. The International AIDS Vaccine Initiative (IAVI), an independent, global not-for-profit organisation, is working with several donors to create international teams of researchers, pharmaceutical manufacturers, and epidemiologists who will place HIV vaccine development on a fast track. Many community groups that have been instrumental in pushing for the development of drug treatments for HIV infection are now turning their attention to vaccines.

Some in the AIDS community feel, however, that much more could be done to promote vaccine development. Approximately SF300 million are spent every year worldwide for HIV vaccine research and development. To put that figure in perspective, José Esparza, Vaccine Development Adviser for UNAIDS, points out that one developing country –Brazil -- will invest SF900 million on drugs for treating AIDS this year. According to Seth Berkley, president of IAVI, at the peak of development of new drugs to treat individuals infected with HIV, pharmaceutical companies spent nearly SF3 billion a year.

The push for HIV vaccines should be growing, supporters say, because vaccines are probably the only way the HIV epidemic can be contained in developing countries [see adjacent article].

Nevertheless, many investigators feel there’s no reason to expect an effective HIV vaccine any time soon. "There have been some small advances, but we are at the same place now that we were three years ago," says Ronald Desrosiers, of the New England Regional Primary Research Center and Harvard Medical School in Boston.

According to Desrosiers, progress toward an HIV vaccine is sluggish mainly because of the virus’ ability to continue replicating even if assaulted by a battery of drugs. "When individuals are infected with HIV, they have strong antibody and cell-mediated immune responses, but the virus hardly blinks. Once HIV gets its foot in the door, it’s tough to stop. That is different from the vast majority of viruses for which there are successful vaccines," Desrosiers says.

Another problem is the multiplicity of strains of HIV. "In the case of the polio vaccine, there were only three strain types. In the case of HIV, we don’t know how many different strain types we need to include in a vaccine to provide broad-based coverage," Desrosiers emphasises.

The vaccine that is being tested in the United States has been designed by the company VaxGen to protect individuals from strains of HIV that occur in North and South America, Western Europe, and Australia. A similar vaccine is being developed by VaxGen to target strains of HIV prevalent in Thailand, Korea, Japan, Taiwan, and Indonesia. But no vaccine is being developed against the HIV strain that infects 48% of people worldwide, says Esparza.

The VaxGen vaccines have been genetically engineered to induce antibodies against gp 120, a glycoprotein that is found on the protein envelope that coats HIV. After 14 years of research the first generation of these gp 120 vaccines has been tested in more than 1,200 human volunteers. Both this first generation and the present form of the vaccine produced no significant side effects and stimulated antibody production in 99.5% of humans. However, generating antibodies against HIV may not be enough to ensure protection from infection; cell-mediated immunity may be essential.

Although no one can predict for certain how effectively gp 120 vaccines will protect healthy individuals from contracting HIV, few scientists have high hopes. "No scientist that I know in the vaccine field has any expectation at all that the vaccine is going to be effective, and I can list ten or 15 names at the drop of a hat," Desrosiers says.

But even if clinical testing proves the vaccines are effective in only a small number of individuals, the efficacy trials will be worth the effort, Esparza counters. "If the vaccine is 30% or 40% effective, with this information we may be able to identify what immunological parameters correlate with protection."

The next type of vaccine to progress to clinical efficacy trials most likely will be a live vector vaccine that places portions of HIV in a harmless virus, such as canarypox. However, Berkley cautions, "It will be at least 2000 before the canarypox virus vaccine moves forward, and there is some question whether or not it will progress to trials even then."

Next in line are naked or purified DNA vaccines, which transport pieces of HIV DNA to harmless bacterial DNA. The DNA vaccines are attractive because they can be adapted to different HIV strains, explains Esparza. But there is no specific timetable for taking DNA vaccines from phase I safety trials to clinical efficacy testing, Berkley asserts.

Other forms of HIV vaccine are still further away from actual testing in humans, including the ones that are considered to be the most promising and the most controversial--live attenuated vaccines. Vaccines that inject live but weakened forms of primate HIV have been most effective in protecting monkeys and chimpanzees from subsequent infection. They are created by deleting one or more of the virus’ nine genes from its genome. "Most scientists in the field agree that live attenuated HIV vaccines have far outperformed other vaccine approaches in terms of efficacy in animals," Desrosiers says.

According to Ruth Ruprecht, these vaccines are dangerous due to their residual potential for causing AIDS. It was thought that live attenuated vaccines would cause a short-term viral surge but then provide long-term protection against subsequent challenge with HIV. In experiments on both adults and newborn monkeys, however, Ruprecht, an associate professor at Harvard Medical School, has found that a live attenuated vaccine made from the primate version of HIV -- simian immune deficiency virus (SIV) -- causes AIDS in animals. Of the eight newborn monkeys who received the SIV vaccine, five are dead of AIDS, one has full-blown AIDS, and two have signs of early HIV disease. "We see the same spectrum of disease that we see with the wild type virus," she summarises.

In order to assure that live attenuated vaccines could be made safe enough for use in humans, Desrosiers has been trying to define a wide range of attenuation. "We’ve shown we can achieve virtually any level of attenuation simply by varying the number and the location of deletion mutations in SIV," he explains. He’s also discovered, however, that the more attenuated the vaccine becomes, the less effective it is. "For the development of a live attenuated vaccine to be practical, one has to strike an appropriate balance." He concludes that "the prospects for a [live attenuated] vaccine that works are pretty bleak."

However, most researchers would agree the jury is still out on which vaccine avenue to pursue and for how long. It’s clear that prevention efforts on all fronts must continue until we have one or more definitive prevention measures accessible to all people at risk for HIV.

Vaccines needed in resource-poor countries

30th June, 1998

Despite 17 years of experience with drug therapies and preventive measures, the rate of new HIV infections continues unabated in the South. These resource poor countries simply do not have the economic power, and often the political leadership, to stanch the HIV epidemic. "Poor countries do not have sufficient financial and human resources to implement effective prevention measures. Nor do they have the resources to treat people who become infected," explains José Esparza, Vaccine Development Adviser for the Joint United Nations Programme on HIV/AIDS (UNAIDS).

But while scientists one day may know enough about HIV to create an effective vaccine, current knowledge is inadequate. And the pace of vaccine development will remain slow until pharmaceutical companies see a financial advantage and governments feel pressure from activists, Esparza acknowledges.

The effect of the HIV epidemic in the developing world is well known: 90% of all new HIV infections occur in poor countries. Also obvious is the fact that nations in the South cannot afford to pay SF30,000 a year per person for the drugs that treat the infection, not to mention the costs of monitoring therapy.

An HIV vaccine would be a potent tool in the developing world not only because of its low cost but also because of its logistic simplicity. "Even if HIV therapeutic drugs were free, getting somebody a supply of 40 drugs a day and keeping that supply available is a mind-boggling problem in a village setting. A vaccine involves only one or two injections, and you don’t have to monitor people afterward," asserts Seth Berkley, president of the International AIDS Vaccine Initiative (IAVI) in the US.

It has been difficult to entice pharmaceutical companies to invest the time and money in vaccine development, however. According to Berkley, SmithKline Beecham, the biggest vaccine manufacturer in the world, does not have an HIV vaccine program. Until recently, Merck & Co. had only one part-time staff person working on vaccine strategies.

IAVI has been trying to create such a market. "Seth Berkley and IAVI have been using loans from the World Bank and other international agencies to create incentives for the pharmaceutical industry to get involved in HIV vaccines," Esparza continues. Typically, vaccines are created in the United States or Europe and targeted to strains of disease that are prevalent in the developed world. Eventually, the vaccines trickle down to developing countries. "I would much rather see developing countries make their own vaccines. That gives them intellectual property rights," Berkley says.

Critical to mobilising policy-makers in these countries will be the work of community groups. "The AIDS Vaccine Advocacy Coalition in the United States is the only recognised non-governmental organisation that is pushing for the development of HIV vaccine. Community involvement has to increase if we want decision-makers to push ahead," Esparza adds.

Developing a vaccine for HIV "may be a solvable problem or it may not," Berkley sums up, "but we ought to give it our best shot."

these stories can also be found in The Bridge, the onsite print newspaper          

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