National vaccine effort seen as insufficient
World can’t afford to wait for new candidates
Three years ago, after the National Institute of Allergy and Infectious Diseases put the brakes on a large human efficacy trial of an HIV vaccine known as GP-160, AIDS vaccine development came to a standstill. Even with President Clinton’s May 18th announcement of a national HIV vaccine effort, virologists say his goal of having a vaccine ready to test in 10 years may not be possible.
Now, a group of AIDS physicians are betting that an existing vaccine deemed unsafe for human testing is the best shot for effective immunization against the virus. They are betting with their lives and if they are right, a vaccine could be available in five years or less.
"For the first 10 years of the epidemic, I never thought a vaccine was possible," said Charles Farthing, MD, medical director of the AIDS Healthcare Foundation in Los Angeles and head of the International Association for Physicians in AIDS Care’s (IAPAC) live attenuated HIV vaccine initiative subcommittee. "If the disease itself never stimulated the immune system sufficiently to eradicate the infection and establish immunity from repeated infection, then how could we expect a vaccine, invariably a weaker stimulus than the disease itself, to work?"
Today, Farthing believes differently. Research on a live-attenuated HIV vaccine tested in monkeys has bolstered a growing conviction among AIDS researchers that a live virus has the best chance of providing protection against HIV, just as it has for polio, yellow fever, mumps, and rubella. Among the various vaccine approaches, it is also the most unsafe. And therein lies the rub.
Last month, when Farthing and other IAPAC members announced that they would volunteer for a Phase I safety trial of the vaccine candidate, their initiative was seen as courageous but not based on good science. NIAID Director Anthony Fauci, MD, who nixed the GP-160 vaccine trial, has argued that the safety risks are too high to test the vaccine. Nobel laureate David Baltimore, MD, who heads the president’s AIDS Vaccine Research Committee, has said a live-attenuated vaccine has the best chance of protecting against HIV but also has voiced concern over its safety. And at a recent symposium in Singapore, Baltimore warned that a vaccine could be more than a decade away and, even then, it would most likely be one that would protect against the HIV symptoms rather than preventing infection.
Vaccine efficacy questioned
Work by Boston researchers has shown that monkeys injected with a strain of SIV in which the nef gene was deleted offered protection against SIV. However, further studies of the vaccine Farthing would use, known as HIV-1 Delta 4, which has four deleted genes, call to question its efficacy. Most recently, a study by the Dana-Farber Cancer Institute found that neonate monkeys injected with the weakened live vaccine fell ill.
Those results have not stopped the IAPAC initiative from going forward.
"Why should we test it?" he recently asked. "Because it already exists. It just needs to be evaluated for efficacy and safety. No other vaccine candidate exists which can be shown to protect against widely varying HIV strains in an animal model, and it may be decades before an alternative to a live virus vaccine can be found."
IAPAC’s initiative has not only spurred the debate but has set in motion an effort to have HIV-1 Delta 4 approved for a Phase I trial. IAPAC announced at the conference that the vaccine’s manufacturer, Therion Biologics Corp. in Cambridge, MA, would complete its manufacturing plans by the end of the year and would initiate discussions with the FDA for a safety trial. The earliest the trial could start would be 2000 seven years ahead of Clinton’s goal. Farthing also reported that the White House’s Office of National AIDS Policy would support the trial if it received FDA approval. The safety trial would begin with five volunteers who would be monitored for CD4 counts, viral load, and immune response. If the vaccine appeared to be safe, it would be expanded, possibly launched in developing countries or inner U.S. cities where infection rates are high, or offered to sex partners of HIV-positive people.
No different from other vaccine trials
Despite safety concerns, IAPAC argues that similar risks were faced in the testing of many of the most successful vaccines and that risk is implicit in vaccine trials.
"For half of the successful vaccines in humans we had no clear understanding whether they would work," Richard Marlink, MD, executive director of the Harvard AIDS Institute, said at the IAPAC conference, adding that for some vaccines, such as for meningococcus, animal studies predicted failure.
Aside from safety, the degree of efficacy needed for a vaccine must consider the risk of infection for populations that would be taking it. The Salk polio vaccine, for example, had only a 72% rate of protection. And while a more safe and effective polio vaccine was eventually developed, the Salk vaccine saved thousands of lives. The lesson, Marlink noted, is that the promise of a better vaccine tomorrow should not exclude a potentially life-saving one now.
In an article published in the Journal of the International Association of Physicians in AIDS Care, Marlink estimated that had the GP-160 trial been approved for a Phase III trial and it was found effective, the $20 million annual cost to complete the study would have been recouped in the first 500 cases of AIDS prevented.1
With the cost of combination therapy out of reach for most countries and no vaccine candidates close to human testing, Marlink has proposed launching a national vaccine campaign modeled on previous successful public health initiatives and provided with funding far beyond the $117 million earmarked for HIV vaccine research next year. The Salk polio vaccine effort had the March of Dimes. The Apollo space program had NASA. Without a well-funded, dynamic vaccine effort, HIV-1 Delta 4 faces too many hurdles to overcome. The mandate from this campaign should be goal-oriented, fast-track, and independent of the National Institutes of Health, Marlink said.
Additionally, a recent vaccine symposium sponsored by the Harvard AIDS Institute issued a call for action for vaccine solutions in developing countries. It includes:
• expanded human testing of vaccines. The group consensus was that choosing the best vaccine candidates requires testing in humans, specifically multiple, nonredundant Phase II trials.
• increased international vaccine trials. Trials should be designed for vaccines relevant to developing countries, because different countries may require different types of HIV vaccines. Risk/benefit concerns should be consistent with the concerns of the population tested.
• increased market incentives for industries to develop a vaccines and depoliticization of vaccine efforts.
Rationale for HIV-1 Delta 4 trial
In recent years scientists have discovered a total of 10 people who have been infected with a strain of HIV that, like HIV-1 Delta 4, has no nef gene. All 10 were infected more than 10 years ago and the three who have died have succumbed to causes not related to their HIV infection. None of the patients have experienced falling CD4 counts. Four of the seven remaining patients have no detectable viral load and the other three have only low levels of viremia.
These findings provide the greatest rationale for testing the vaccine, Farthing noted. Justification also rests on evidence from humans infected with HIV-2, a weaker virus than HIV-1. Studies have shown that people infected with HIV-2 and then exposed to HIV-1 have a 70% reduction in risk of becoming infected with HIV-1, Marlink noted. "It tells us that immunity to infection in humans is possible," he added.
Farthing also dismisses other safety concerns, such as the possibility that the vaccine could mutate back to a more virulent form. Such mutation has not been seen in monkeys, he said, adding that the nef gene deletion in the 10 patients had shown no sign of reverting to a whole nef gene.
Although there are concerns that a person given a life-attenuated virus could transmit the virus to a sexual partner, Farthing noted that it is unlikely because the study patients had low viremia. And what about long-term toxicity? Virologists can never be certain a vaccine is safe until inoculated patients are followed throughout their life span. As subjects age and their immune systems weaken, a virus could possibly threaten their health. Farthing noted, however, that two of the three patients who died lived into their 80s.
"The virus could cause immunosuppression after 20 to 30 years," he said, "but can we wait that long?"
Reference
1. Marlink R. Achieving an HIV vaccine: The need for an accelerated national campaign. J IAPAC 1997; 3:35-37.
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