Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

October 1998 Table of Contents

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Vaccine News from the 12th World AIDS Conference

Bruce Mirken

[Editor's note: Vaccines are preparations that stimulate an immune response. Usually they are made up of infectious organisms, pieces of organisms, or genetically engineered substitutes.

• Preventive (or prophylactic) vaccines are used to prevent infection by an organism. This is usually done by "priming" the immune system in advance to respond to an infectious organism that may be encountered later; this article deals with preventive vaccines.
  
  
• Post-exposure vaccines are given to people who have already been exposed to an infectious organism, in the hopes of preventing the organism from taking hold in the body; the rabies vaccine is an example of a post-exposure vaccine.
  
  
• Therapeutic (or treatment) vaccines are used to slow or reverse disease progression in a person who already has a disease. These vaccines attempt to strengthen the immune response so that the body can more effectively fight the existing disease; Remune is an example of a therapeutic vaccine.]

HIV vaccine researchers and advocates left the 12th World AIDS Conference in Geneva feeling cautiously optimistic, perhaps a shade more optimistic than they have been in recent years. Although the news from vaccine studies was mixed, there was a growing sense that, at long last, research aimed at creating a preventive HIV vaccine is finally beginning to get the attention it deserves.

Several circumstances helped to create the renewed focus on vaccines, starting with the grimly mounting numbers of the international AIDS epidemic: 30.6 million people living with HIV or AIDS at the end of 1997, according to the United Nations, with 2.3 million deaths last year and 16,000 new infections per day. With most of those people living in nations lacking the medical infrastructure needed to make widespread use of highly active antiretroviral therapy (HAART) -- even if they could somehow afford the expensive regimens -- the urgent necessity of a vaccine has become more apparent.

Secondly, the International AIDS Vaccine Initiative (IAVI) -- a nonprofit founded in 1996 with seed money from the Rockefeller Foundation that hopes to spur vaccine development -- used the conference to issue a detailed Scientific Blueprint for AIDS Vaccine Development sketching out the obstacles and outlining strategies for overcoming them. IAVI also announced that it had received a $1.5 million donation from Microsoft billionaire Bill Gates.

Shortly before the conference, VaxGen announced that it was beginning the first large-scale efficacy trial of its HIV vaccine, known as AIDSVax, a product based on the HIV envelope protein gp120. The VaxGen study is the first efficacy trial of an HIV vaccine ever undertaken.

The problem with gp120 vaccines is that while they produce a strong antibody response, they do not effectively stimulate the cellular component of the immune system. As Emilio Emini of Merck Research Laboratories noted, most vaccine researchers believe that "the anti-HIV-1 humoral antibody is not likely to be very effective" in generating real-world protection against the virus. Still, even skeptics seemed to feel that the start of the trial marked an important milestone -- partly because it represented something of a psychological breakthrough, and partly because it may produce data that is useful in further vaccine development.

But so far, IAVI scientific affairs vice president Margaret Johnston argued, practical work on HIV vaccines has not reflected the urgency the epidemic requires. "There are many designs that are languishing in the laboratory, that aren't moving forward into human trials, because of the lack of sufficient support," she said. Johnston characterized the current pipeline of candidate vaccines as "very poor." [Editor's note: Johnson is now Assistant Director for HIV/AIDS Vaccines at the National Institute of Allergy and Infectious Diseases]

The LAV Controversy

HIV vaccine research has concentrated most heavily on approaches using recombinant technology, including the genetically engineered gp120 vaccines, so-called "naked DNA," and vaccines involving HIV genes inserted into various harmless virus vectors such as canarypox (see DNA and Other Technologies for HIV Vaccines, BETA, April 1998). But in the last year, there has been discussion and considerable controversy about whether more effort should go into traditional types of vaccines, such as live attenuated virus (LAV). LAV is a weakened strain of the virus administered in the hope that it will generate protective immune responses without causing harm. The International Association of Physicians in AIDS Care (IAPAC) has strongly argued for accelerated testing of this approach.

So far the only work on live attenuated HIV vaccines has been done in animals. Scientists are understandably nervous about putting any form of HIV into humans until they have a clear understanding of just how weakened it must be to be truly harmless, and they have hoped to achieve a proof-of-principle by giving an attenuated form of simian immunodeficiency virus (SIV) to monkeys. Unfortunately, the news on this front has been discouraging.

That news and what it might mean for human LAV studies was debated in a pair of contrasting presentations in Geneva by Charles Farthing, MD, of IAPAC and Ruth Ruprecht of the Dana-Farber Cancer Institute. Farthing called LAV "the approach that we feel has the most likely chance of success of any of the candidate vaccines," and noted that IAPAC has had a very positive response to its call for volunteers for a LAV trial.

Farthing cited the well-publicized Australian case involving eight transfusion recipients who received HIV-infected blood from the same man, whose virus turned out to be missing the nef gene. Although some of the individuals eventually died from apparently non-AIDS-related causes, Farthing noted, "none have developed illness or significant immune suppression that can be attributed to HIV alone," in follow-up periods ranging up to 17 years after infection. This experience, he argued, "clearly shows that these people have been infected with a significantly attenuated strain of HIV... Even if these patients go on to develop immunosuppression in the future, they clearly show that a nef-deleted strain of HIV is attenuated and relatively safe."

Farthing argued that more effort should go into LAV research. Lack of funding, he said, "is proving a problem in developing deleted HIV strains into purified vaccine preparations. Resource allocation seems to be all the wrong way around."

Farthing largely dismissed the monkey data that Ruprecht was about to present, much of which involved newborn monkeys. "I question the relevance of this data, especially the neonatal monkey data," Farthing argued. "We never inject neonatal humans with live attenuated vaccines... The adult monkey data is more concerning, but again may not be relevant. SIV is not HIV and monkeys are not humans." Farthing concluded that the safety concerns about human LAV trials "are being way overplayed."

Ruprecht, who has worked extensively with attenuated, nef-deleted SIV strains in monkeys, took precisely the opposite view, presenting what she termed "sobering data." The bulk of Ruprecht's experiments have involved an attenuated SIV strain called SIV delta3, with the nef gene and several other genes deleted. In early experiments, she noted, a vaccine using this strain was "about 50% effective in protecting adult animals against challenge with wild-type virus."

Ruprecht pointed out that, although giving LAV vaccines to human newborns is not standard practice, Albert Sabin, MD, did successfully give live attenuated polio vaccine to human infants in 1963. But when given to four newborn monkeys, she said, "the live attenuated SIV delta3 was 100% pathogenic"; all four developed AIDS and three have died.

Ruprecht described in detail what happened when blood from one of these unfortunate newborns was given to another baby monkey and its mother. At first both animals seemed to do well, their immune systems successfully suppressing the SIV delta3. But since then, signs of active infection and immune dysfunction have emerged in both animals. "This is occurring after innoculation with a biologically low dose of virus and in the presence of low levels of RNA copies in the plasma," Ruprecht noted. "These two animals tell us that this indeed is happening. The [attenuated] virus can become persistently present in the blood and lead to immune dysfunction."

Overall, Ruprecht continued, of nine infant monkeys given the attenuated SIV, six have developed AIDS and five have died. Adult monkeys have done better, but four of 15 have become "persistently viremic [with] persistently inverted CD4/CD8 ratios. One has succumbed to AIDS." She cited four other researchers who had produced similar results.

The gene deletions tried so far, Ruprecht argued, weaken the virus' ability to replicate, but have not rendered it non-pathogenic. This replication impairment can be compensated for by host factors including "age, immune status, or co-infection."

Ruprecht argued that the most crucial reason for caution is that "unlike all the other live attenuated viruses we have heard about, the live attenuated lentiviruses [retroviruses such as HIV and SIV] persist. The other viruses are inoculated into the vaccine recipient, they replicate, they induce immunity, and then the host gets rid of them -- they're all gone...It is different in this case." The persistent presence of a virus that depends on error-prone reverse transcriptase to replicate means that the possibility that the weakened virus might eventually mutate into a more virulent form cannot be ruled out.

So, Ruprecht asked, "is the concept of a live attenuated virus [HIV vaccine] dead?" Not completely, she answered, because it should theoretically be possible "to find the molecular determinants of pathogenicity." If those elements, whatever they are, can be identified and deleted, it might be possible to create "a truly avirulent virus." But she left no doubt that she does not think such a virus is anywhere in sight at present.

At a separate session, Mark Lewis presented further unhappy news from tests of live attenuated SIV. A U.S./Canadian team gave two different versions of attenuated SIV, both with the nef gene deleted, to 20 monkeys each. In half of the monkeys given one of the vaccines and in two of 20 given the second, the weakened virus still led to uncontrolled infection. Though the vaccines effectively protected the monkeys against challenge with intact versions of the same strain of SIV, they did not always protect against other variants. Worse, the monkeys who developed uncontrolled infection with the attenuated virus "were more susceptible to the challenge virus and disease progression" than controls.

Other Vaccine Research

Several researchers presented small, early studies of candidate vaccines, some in humans and some in animals, which added interesting pieces to the puzzle. A live attenuated SIV study in monkeys presented by Rigmor Thorstensson of the Swedish Institute for Infectious Disease Control added further evidence that the beta chemokines RANTES and MIP-1-alpha play a role in protective immunity. Those monkeys that were fully or partly protected against challenge with pathogenic SIV had higher levels of the two chemokines than those who became infected but, strikingly, they had higher chemokine levels than the other monkeys prior to vaccination. It remains unclear whether chemokine activity can be harnessed to bolster vaccine-induced protection.

In a study presented by Stephen Kent of the McFarlane Burnet Center for Medical Research, a two-step vaccination using HIV DNA followed by a recombinant avipox virus encoded with HIV env and gag/pol genes successfully protected four monkeys against challenge with infectious virus, while four control animals became infected. The combination vaccine boosted cytotoxic T-lymphocyte (CTL) and helper T-cell responses by as much as 20-fold.

Human studies of DNA vaccines are still in early stages. An ongoing AIDS Vaccine Evaluation Group (AVEG) study of one such candidate vaccine, developed by Apollon Inc., has shown good safety results in 39 HIV negative volunteers. Immunogenicity data will be looked at after volunteers receive 6-month booster shots.

Canarypox vector vaccines are further along in human testing. Thomas Evans, MD, discussed a group of AVEG studies of canarypox vectors into which a variety of HIV genes had been inserted. In cells taken from human volunteers at various time points after immunization, researchers were able to demonstrate improved CTL responses that persisted two years after vaccination.

Vectors encoded with a larger number of HIV genes produced a broader CTL response. But across the various protocols, roughly 30% of vaccine recipients did not show any CTL response to vaccination. "We're not sure" why some did not respond, Evans noted. Whether these CTL responses will be sufficiently protective also remains to be determined.

Several other studies of candidate vaccines also showed some level of immunogenicity and apparent safety, but all were small, early-stage studies. As Michael Keefer put it while presenting the results of 2-stage approach involving a vaccinia virus vector boosted with recombinant gp120, "this is truly the first step of the puzzle."

The failure of the body's antibody response to effectively protect against HIV remains a subject of great interest -- and of potentially great import for VaxGen's efficacy trial. Paul W.H.I. Parren of the Scripps Research Institute discussed one possible explanation for this failure. In lab tests of antibodies from infected individuals, his team found that the antibodies bound most effectively to non-mature forms of HIV envelope, i.e., "viral debris," with only suboptimal binding to mature HIV envelope and poor neutralizing abilities.

While small trials can be used to show that a vaccine is safe and induces an immune response, much larger studies involving thousands of volunteers are required to demonstrate efficacy. For that reason, researchers have put considerable effort into examining the issues around recruitment, counseling, and retention of vaccine trial volunteers.

A study of women at high risk for HIV infection reported by Pamela Brown-Peterside of the New York Blood Center illustrated some of the difficulties involved. A group of 865 women at risk for HIV infection due to injection drug use or sexual contact was followed for two years, with periodic counseling, HIV antibody testing, risk assessment interviews, and distribution of vaccine trial information. Eighty-six percent of the women were unemployed, and many were dealing with issues such as inadequate housing, substance abuse, and domestic violence that could easily interfere with trial participation. Brown-Peterside and colleagues were able to retain 82% of the volunteers over the two years by utilizing a variety of strategies, including "reimbursement for participation, distributing free prevention supplies, assisting with transportation and childcare when possible, and engaging in intense outreach efforts to locate the hard to reach."

Researchers from the University of California at San Francisco found potential participants to be somewhat skeptical about vaccine trials. Detailed interviews with San Francisco gay men from a variety of ethnic/racial backgrounds, Philadelphia injection drug users, and African-Americans from Durham, NC, suggested that these people would approach possible participation methodically and seriously, gathering as much information as they could from sources outside the trial, including AIDS service organizations, personal physicians, health workers, and the gay press. Of one sample of gay men, researcher Robert Hays reported, "The men want mutually respectful dialogue with trial staff, including detailed presentations that give all sides of the story."

Describing one survey, Susan Kegeles went further, noting that "some even used very strong language like, 'Don't lie to us. Don't cover things up. Be honest and put things on the table.' " A matter of particular concern was guaranteed compensation and medical care should an experimental vaccine prove harmful, as well as ongoing support and assistance if positive HIV antibody tests generated by a vaccine create difficulties involving health insurance, employment, or foreign travel.

Can Progress be Accelerated?

Perhaps of greater interest than the specific vaccine study results presented in Geneva was the general sense of a growing commitment to expanded and accelerated HIV vaccine research. In a somewhat unusual move, the talk concluding one major session on human vaccine trials was not a presentation of study data, but rather a description by Steve Bende of the National Institute of Allergy and Infectious Diseases of a variety of new and expanded grant programs for vaccine research. Separate pools of money, he said, have been established for early testing of new concepts and to move promising ideas into human trials. Sounding almost like a salesman, Bende concluded, "If you have a concept and you want to get it into trials, we're here to help."

IAVI, meanwhile, is hoping to supplement ongoing government and private efforts, arguing in a statement that President Bill Clinton's stated goal of having an effective vaccine by the year 2007 "appears to have been largely ignored in the new grant programs announced by the U.S. National Institutes of Health and others." IAVI is putting together product development teams of scientists and industry people, each of which will focus on moving one specific vaccine approach through the development process as efficiently as possible. IAVI expects this effort to cost between $350 million and $500 million over and above present expenditures over the next nine years.

"The urgent need," Johnston said during the conference, "demands that all reasonable approaches be pursued."

Page last updated 6 October 1998

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