Controversial HIV vaccine enters phase III trials amid skepticism

Scientists criticize vaccine’s lack of live virus

Clinics across the country have begun enrolling volunteers in the first phase III trial of an HIV vaccine, in spite of disagreement over the vaccine’s potential.

The promise of a vaccine has been a hope for nearly two decades, but some leading scientists are skeptical, citing the vaccine’s lack of live virus as an insurmountable obstacle to its effectiveness. Many believe HIV pathogenesis must be better understood before an efficacious vaccine can be developed. A few have voiced their willingness, at great personal risk, to take an experimental live-attenuated HIV vaccine in order to advance the search for an effective vaccine.

More than 34 different HIV candidate vaccines have been tested in phase I, and three have made it to phase II.1 Another 74 possible vaccines are reportedly in basic research or animal testing.

How important is AIDSVAX, the vaccine currently in phase III trials? Can we realistically expect it to be the long-awaited HIV vaccine?

"It’s a very important first step," says William Heyward, MD, MPH, of the National Center for HIV, STD, and TB Prevention at the Centers for Disease Control and Prevention in Atlanta. "There’s much about HIV that we will probably never know simply through laboratory research. By moving forward with these trials, we can learn enough to improve this vaccine, enough to advance to the next step."

Like any vaccine, AIDSVAX is designed to train the human body’s immune system to protect itself against infection by creating antibodies. Significantly, the vaccine uses a genetically engineered protein (gp120) as the surface "envelope" of the vaccine virus. An injection of this recombinant protein stimulates production of the antibodies that would attack any invading HIV in the future, thus preventing the virus from binding to and infecting healthy T-cells, explains Donald Francis, PhD, president of VaxGen, the California-based company that created the vaccine. "It’s a classic approach to vaccinology, building around the virus’ external coating," says Francis.

Because AIDSVAX does not contain live virus, it is considered a safe "subunit vaccine" that cannot cause HIV-1 infection. However, because most successful vaccines have contained live virus, many scientists say the AIDSVAX approach will not work.

Heyward says a current live-attenuated virus vaccine candidate is too dangerous to be administered to humans. "It’s a live, healthy virus that is simply not safe at this point," he says. "Analyzing the data and the various vaccine candidates, the gp120 concept makes sense. Most people feel that there should be an adequate immune response to the virus’ envelope. Some people think that a broader immune response, either to different virus strains or to the core of the virus, is necessary. That may well be the case. I think it’s reasonable to start with a gp120 trial to see if it’s protective or partially protective, and go from there."

Also defending the company’s approach is VaxGen’s chief scientist Phillip W. Berman, PhD. "The data indicate that the virus has a two-target strategy, confirming the importance of gp120 in inducing a protective immune response," he says. "Our vaccine was specifically designed to address both these targets. Antibodies induced by our vaccines neutralize both T-cell and macro phage tropic viruses."

Developed over the past decade, the first generation of AIDSVAX was found to induce an immune response in humans. However, the immune response did not cover all strains of HIV circulating in the population. The current second-generation vaccine contains additional gp120 protein and now has a much broader representation of circulating HIV strains.

The vaccine’s antigens come from the surface of two viruses circulating in North America, Western Europe, and worldwide: HIV-1MN, a T-cell tropic virus, and HIV-GNE8, a macrophage tropic virus.

The North American trial, which began in June, will enroll volunteers who are at risk through sexual transmission — primarily gay males and women with HIV-positive partners. The trial will be conducted in nearly 40 clinics and will enroll 5,000 volunteers.

Over the course of 30 months, volunteers will be given seven injections, as well as counseling on methods to prevent HIV infection. (An unexpected result from earlier trials: Risky behavior actually decreases during participation in vaccine trials because of the counseling provided.)

A separate trial enrolling 2,500 volunteers began in Thailand this fall. The AIDSVAX vaccine formulated for that trial works against the HIV strain typical in Thailand, Japan, Korea, Taiwan, and Indonesia.

Peggy Johnston, PhD, who has worked for many years with the International AIDS Vaccine Initiative, defends the United States and Thailand trials. "If I were looking at the U.S. only, I would say maybe we should wait until something more potent comes along," says Johnston, who has since joined the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD, the NIH agency that is also researching the vaccine. "But I look at it from a world perspective, and the urgency worldwide is just too great. This is an emergency situation. We don’t need to know for sure what the degree of efficacy is."

The scientific debate

While AIDSVAX is a "classic" vaccine, Francis says even he has questions. "Have we selected the right strains, or have we made the gp120 so homogeneous that it doesn’t reflect the imperfections of natural viral infections? Those are real questions that cannot be answered until you do a trial."

The virus’ genetic variability is just one discussion point among vaccine developers searching for a broadly effective or "global" HIV vaccine. There is little agreement, and in fact heated debate, on many other issues. The immune "correlates of protection" are at the heart of the debate.2

What should be the immunologic characteristics of a vaccine? Should the response it induces be humoral, cell-mediated, or mucosal — or all of these responses? What is the significance of animal protection experiments? Should the vaccine produce "sterilizing" immunity to prevent infection, or is this goal unattainable? Would a vaccine that controls viral replication be more realistic? How much more basic research is still needed?

"Theorists" and "empiricists" in the scientific community are at odds on how to proceed. Theorists argue that much more basic research is needed to address the questions fully before proceeding with development of a vaccine. Empiricists, usually clinicians and public health officials, are more pragmatic. Some of the current vaccine candidates that have been shown to be safe and immunogenic in humans and protective in animal challenge experiments should be tested in large-scale efficacy trials, they say.

"We do not know that neutralizing antibodies injected in the chimpanzee will actually correlate with protection in humans," Francis acknowledges. "In reality, vaccine trials often serve to uncover the correlates of protection. You can’t get any answers until you do a study. Usually, you will get something from these studies, a piece of information. Even if your vaccine isn’t 100% efficacious, you will learn the correlate of protection or at least get some insight into what the next step should be."

Francis, who was a protégé of Jonas Salk (developer of the first polio vaccine) and a clinical scientist in the development of the hepatitis B vaccine, is prepared for the long haul. "You take the best basic science and the best empirical approach, and see how it works," he says. "Ultimately, we have vaccines that are very, very effective. Some have been home runs the first time around; some have required half a dozen efficacy studies. That’s what the naysayers miss. They haven’t been through this process before."

Johnston of NIAID agrees that the current trial is one of "many, many steps" toward finding a vaccine. "If the trial yields information about correlates of protection, about whether neutralization correlates with ability to provide protection, then it is useful regardless of the vaccine’s degree of efficacy," she says.

Considering all the perceived obstacles and imponderables of HIV vaccine development, what can we realistically expect for the future?

Historically, many important vaccines have been developed over several decades. For more than 20 years, researchers have sought a vaccine for malaria. "Many times we’ve been very optimistic about a malaria vaccine, yet it’s never come to pass," says Heyward. Others, like the rotavirus and hepatitis B vaccines, have been developed relatively quickly, before scientists clearly understood the type of immunity needed to prevent disease.

HIV doesn’t play by the rules

"Uncertainties should not discourage or obstruct HIV vaccine development," says Heyward. Multi ple trials and case-control studies may indeed be necessary to identify the correlates of protection and the factors that affect vaccine efficacy — HIV genetic variation, the route of transmission, possible effects of population genetics, nutritional factors, and the presence of co-existing diseases.

HIV doesn’t play by the rules, Heyward adds. "Smallpox did, so we were able to eliminate it. It has a short incubation period, it doesn’t mutate, and it causes a very recognizable disease that isn’t confused with any other." Because HIV is sexually transmitted and there are no good animal models for it, research efforts are further complicated.

The efficacy of the AIDSVAX vaccine will be determined over the next three years through the United States and Thailand phase III trials. Heyward remains "guardedly optimistic" about the trials’ outcomes. "Vaccine development is generally characterized by incremental, methodical advances before a highly effective vaccine is available. It is likely that we are still in the very early days of creating an HIV vaccine."

(Editor’s note: In next month’s AIDS Alert, we look at other vaccine candidates. Would a live-attenuated HIV vaccine create a public health nightmare?)

References

1. Heyward W, MacQueen K, Goldenthal K. HIV vaccine development and evaluation: realistic expectations. AIDS Res Hum Retroviruses 1998; 14:S1-S6.

2. Heyward W, MacQueen K, Jaffe H. Obstacles and progress toward development of a preventive HIV vaccine. Journal of the International Association of Physicians in AIDS Care 1997; 8:28-34.