Below are two articles published Friday about the Merck vaccine tests and other HIV vaccine developments.

Glimmerings of Hope From the Bottom of the Well

Jon Cohen, Science Mag--July 30,1999

The number of AIDSvaccines entering clinical trials is at an all-time low, but researchers are planning to begin testing new approaches soon

Five years ago the AIDS vaccine field went into a tailspin when the two leading vaccines failed critical laboratory tests, and it still has not recovered. The number of new vaccines entering early testing in the U.S. trials network set up by the National Institutes of Health (NIH) has reached an all-time low; three trials were begun last year and none has been launched so far this year, compared with an average of six a year from 1990 through 1997. And earlier this month, researchers gave a decidedly mixed reception to results from preliminary trials of a combination vaccine--a strategy deemed more promising than the one that derailed 5 years ago. But some researchers now see glimmerings of hope.

Science has learned that Merck & Co., a pharmaceutical powerhouse that dropped out of the HIV vaccine field in the early 1990s, is aggressively reentering the arena with plans to launch tests of two different vaccines before the end of the year. And researchers are experimenting with new combination vaccines that they hope to move into early clinical trials next year. AIDS vaccine researchers are especially encouraged by the rebirth of Merck's program. "The more [players] we can get in with good ideas, the more the whole field benefits," says Donald Burke, who heads AIDS vaccine clinical trials at Johns Hopkins University. "The momentum right now is less than optimal."

The momentum virtually halted in June 1994, when NIH declined to fund large-scale efficacy trials of vaccines made by Chiron and Genentech. Both vaccines were based on genetically engineered versions of HIV's surface protein, gp120. The hope was that these viral proteins would raise antibodies that would attach to the virus in the bloodstream, before it infected cells, but NIH got cold feet when test tube experiments showed that the antibodies these vaccines produced could only stop laboratory-grown strains of HIV--not ones freshly isolated from patients (Science, 24 June 1994, p. 1839). (Genentech's vaccine now is in efficacy trials, funded privately by a new offshoot, VaxGen.)

When it pulled back from supporting the gp120 vaccines, NIH had high hopes that another approach would soon be ready for efficacy trials. As Jack Killen, a top AIDS official at NIH, predicted at the time, "the very realistic likelihood is within 2 to 3 years we would be ready to go with a different concept."
Manufacturer Vaccine Location
VaxGen gp120 U.S., Canada,
Chiron gp120 Thailand
Pasteur MŽrieux
Connaught gp160 U.S.
Pasteur MŽrieux
Connaught canarypox with
various HIV genes U.S., France,
Pasteur MŽrieux
+ Chiron canarypox with
various HIV genes
gp120 U.S.
Pasteur MŽrieux
Connaught lipopeptide France
Pasteur MŽrieux
+ VaxGen canarypox with
various HIV genes
gp120 U.S.
Wyeth-Lederle DNA vaccine with
various HIV genes U.S.
Pasteur MŽrieux
+ Wyeth-Lederle canarypox with
various HIV genes
DNA vaccine U.S.
Therion vaccinia with
HIV envelope gene U.S.
St. Jude Children's
Research Hospital 23 HIV envelope
proteins in 23
vaccinia vectors Memphis,
Univ. of Maryland
+ VaxGen salmonella
with gp120
gp120 U.S.
Cel-Sci p17 Europe

The "different concept" Killen and others had in mind was a combination of a gp120 vaccine and a vaccine manufactured by Pasteur MŽrieux Connaught that consists of various HIV genes spliced into a live, but harmless, canarypox virus "vector." The logic behind this so-called "prime-boost" approach is that the two vaccines activate different arms of the immune system, which theoretically should work in concert to thwart HIV. The gp120 vaccine triggers antibodies, while the canarypox vaccine stimulates cell-mediated immunity, which occurs when the immune system dispatches cytotoxic T lymphocytes (CTLs) and other forces to rid the body of cells that the virus has infected.Two weeks ago, researchers at a conference on sexually transmitted diseases in Denver, Colorado, revealed results from the largest test yet done of a prime-boost vaccine. The study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), began in May 1997 and involved 435 people, more than 80% of whom had a high risk of HIV infection because of drug use or sexual behavior. Although the study was not designed to determine whether the vaccines worked--it aimed to assess safety and the various immune responses triggered by the approach--researchers can glean hints of the vaccine's chances of success from the results.

More than 90% of those who received a "prime" shot of canarypox and a "boost" of gp120 developed antibodies that, in a test tube, could stop a laboratory-grown strain of HIV, and some 30% produced CTLs against the virus. These results meet milestones that NIAID has said must be achieved before launching an efficacy trial (Science, 1 March 1996, p. 1227). "This trial is a necessary step toward initiating an efficacy trial," says Peggy Johnston, head of NIAID's AIDS vaccine effort. "But," she adds, "several questions remain."

One question is whether newer canarypox vaccines made by Pasteur MŽrieux stimulate higher levels of CTLs. A comparative trial of these vectors should be completed this summer. Johnston says another small-scale trial of this concept is also needed to determine the best timing of the booster shot and whether a different gp120 vaccine might work better. So even if these tests pan out, an efficacy trial is at least 1 year away.

Some AIDS vaccine researchers, however, have serious reservations about the results so far. Oxford University's Andrew McMichael, a CTL expert, is underwhelmed by the fact that killer cells were elicited in only one-third of the vaccinees. "Two-thirds of the people [may have had] no CTL response, and, if CTLs are important, they wouldn't be protected," he says. Similarly, HIV antibody specialist John Moore of the Aaron Diamond AIDS Research Center in New York City has strong doubts about the value of the antibody response, which still only blocks laboratory-grown HIV. "It's a completely meaningless antibody response," says Moore. "It just gives them a security blanket. They might as well not use [the gp120 boost] at all."

McMichael, with support from the privately funded International AIDS Vaccine Initiative (IAVI), plans next spring to start trials of a different prime-boost approach that he hopes will produce much higher levels of CTLs. He believes that priming with the poxvirus presents the immune system with too many proteins from poxvirus as well as HIV, so he intends to use a prime vaccine that contains HIV genes stitched into a stretch of DNA called a plasmid. He theorizes that this so-called DNA vaccine, which can infect cells and produce viral proteins, will focus the immune system's attention; he then hopes to boost these primed CTL responses with a modified vaccinia virus that holds HIV genes.

Although Merck is sketchy about its vaccine plans, it, too, is focusing on triggering strong CTL responses. Emilio Emini, a virologist who heads the company's vaccine program, says that, like McMichael, the company is working on a DNA vaccine. It also is developing a live, but defective, viral vector that Emini declines to discuss publicly. "One of the reasons we've kept a low profile is we don't want to raise expectations," he says. "The likelihood for failure is pretty high." Then again, he says, Merck is putting a lot of resources into the project. "It's a big program for us."

Wayne Koff, who formerly headed the AIDS vaccine program at NIAID and now is scientific director at IAVI, hopes Merck is more committed to its vaccine program than in the past. More support from the pharmaceutical industry is sorely needed, says Koff, who notes that NIH has fewer trials under way now than he has seen in 10 years. "Right now we're at a nadir. But it's clear there will be a lot more vaccines in trials in a few years."

Merck Is Scheduled to TestAIDS Vaccines on Humans

MICHAEL WALDHOLZ, Wall St Jnl, July 30

As the AIDS pandemic spreads largely unabated outside the U.S., public-health officials have been waiting hopefully for a breakthrough in the development of a vaccine.

Now Merck & Co., after numerous years of effort and failed attempts, appears to have made one.

Merck scientists are laying plans to begin the first human tests of two promising experimental vaccines developed as part of an intense top-secret research effort. Merck's top vaccine-research executive, in a telephone interview this week, confirmed the vaccines' existence and the company's plans to begin administering them in a small number of healthy, uninfected volunteers by year's end.

The official, Emilio Emini, said he didn't want to raise undue expectations. He said the human tests will be undertaken simply to help Merck scientists determine if the vaccines can produce in people the kind of immune-system reaction generated in animal studies. Those studies themselves are so preliminary that the company hasn't completed their analysis, or presented their results to the AIDS-vaccine research community, Dr. Emini noted.

Still, researchers familiar with the project say that if Merck's vaccines produce a powerful immune reaction, the company is capable of swiftly embarking upon larger trials. Merck, based in Whitehouse Station, N.J., is one of the world's premier commercial vaccine makers.

"The studies are designed to help us quickly see if we are on the right track," said Dr. Emini, director of Merck's infectious-disease research operations. He added: "We are at the point in our research where we need to know if they will trigger the response in people we've seen in animals. And the only way to learn that is by giving them to people." Still, Merck is uncertain if the immune response it has generated in animals is of the type that will protect people against infection.

'Naked DNA'

Several other companies are testing prototype vaccines in large and small trials in the U.S. and abroad. But one of the Merck vaccines will be among the first of a class of so-called "naked DNA" vaccines for HIV to go into humans. These are vaccines composed of a gene or genes extracted from the virus. No naked DNA vaccines yet exist, and Merck and others have to date been unsuccessful in testing such agents against the flu and other microbes.

Merck declined to provide much detail about the AIDS vaccines. Rumors of the company's testing plans have surfaced in the last week or so, and limited information about them has been shared with some research groups and research physicians who will help conduct the small trials. Information from scientists familiar with the company's program suggests that Merck's efforts incorporate the latest technology and knowledge emerging in recent months about what's needed to produce a protective response in people.

"What's exciting and important is that Merck believes it's far enough along to test something," says Margaret Johnston, assistant director for AIDS-vaccine research at the federal government's National Institute of Allergies and Infectious Diseases . "It's good to see Merck involved, and testing an approach that is right now thought to be on the cutting edge."

Specifically, Merck wants to see if its DNA vaccine can stimulate the immune system to release white blood cells often referred to as killer or cytotoxic T-cells. Recent studies by several other research groups show that people exposed to HIV, the virus that causes AIDS, who produce large amounts of killer T-cells and other so-called helper T-cells are able to keep the disease in check. Additional recent studies in monkeys show that triggering such T-cells can also keep the virus at bay for limited periods.

Dr. Emini says animal studies Merck is conducting show that the company has been able to make a DNA vaccine that can prompt a killer and helper T-cell response. The company's trials are designed to see if the same biological response occurs in humans, a test that could be accomplished within a few months.

The human trial will be watched closely by AIDS-vaccine researchers because it will provide a critical test of whether DNA vaccines are useful. Most other experimental vaccines have produced antibodies against HIV that, while able to neutralize the virus outside of infected cells, don't appear to be powerful enough to overcome infection. Scientists are hopeful about the DNA approach because such vaccines also stimulate a cascade of T-cells that are able to target and destroy virus particles that enter the cells during a viral infection.

The trick in making a DNA vaccine, however, is identifying which genes from HIV to put into the vaccine. While Merck declined to disclose the gene or genes it is using, Dr. Emini confirmed that the company is using genetic material from the virus that it has altered in an effort to elicit a desired response.

'Humanize' the Genes

Information about Merck's efforts will appear in the soon-to-be-published August newsletter of the International AIDS VaccineInitiative, a private New York organization that promotes vaccinedevelopment. David Gold, who monitors AIDS-vaccine research for the organization, will report that Merck has been able to "humanize" the genes, making the DNA produce a more powerful immune response than has been produced in any previous efforts by Merck or others.

Mr. Gold will also report that at a recent meeting of vaccineresearchers, Merck said that in monkey studies, the altered DNA induced a stronger and longer T-cell response than other test vaccines. Dr. Emini confirmed Mr. Gold's account.

Recent research, however, suggests that a DNA vaccine alone likely won't be powerful enough to fully protect against infection. As a result, Merck confirms that it also will test a vaccine in which bits of the virus are inserted into a defused animal or human virus. The company declined to identify the composition of its virus-based vaccine. "The current sense is that a vaccine against AIDS will require a combination of a DNA vaccine to prime the immune system followed by a booster of a vaccine involving another virus," says Dr. Johnston of the government's NIAID.

Indeed, several weeks ago Pasteur Merieux Connaught, the vaccine-making unit of the French drug company Rhone-Poulenc SA, reported results of a phase-two test of vaccine in which parts of the AIDS virus are inserted into a weakened virus that causes canarypox, a bird virus. Michel Klein, who directs Pasteur Merieux's HIV-vaccine effort, says the company's test vaccine produced some T-cell response, and it expects to test the vaccine further. The company also is developing a DNA vaccine, Dr. Klein says.