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Merck Makes Surprise Announcement of Human Vaccine Trial, Currently Underway

“Still Could Fail”

While a handful of companies are testing or have tested potential HIV vaccines in human volunteers, none of these trials have generated nearly as much excitement as the latest announcement from officials at Merck. After shifting its vaccine screening program into overdrive some four years ago, Merck may now have something to show for its efforts. TAG’s Mark Harrington was one of a very limited number of activists invited to the company’s closed-door presentation late last month. While there remain many unanswered questions, in an era where news of potential therapeutic break-throughs is harder and harder to come by, we thought it prudent and perhaps even inspiring to briefly summarize the few hard facts currently at hand.

Late last month Merck announced that it has begun human trials of a new experimental HIV vaccine that has generated quite a bit of excitement within the scientific community. The trial, which began just a few weeks ago, is first being conducted to assess safety in healthy, uninfected adult volunteers.

While full details of the vaccine and the research protocol are being withheld until their presentation at the April Keystone meeting in Colorado, the company held a special meeting with a handful of community AIDS activists at its Whitehouse Station, NJ headquarters several weeks ago. It has also presented its preliminary data to the AIDS Vaccine Advisory Committee of the National Institutes of Health.

According to what little information is available about the vaccine, it has apparently been shown to be capable of preventing laboratory monkeys exposed to a virulent strain of HIV from getting sick. Most of the unvaccinated control monkeys, by contrast, died or developed AIDS.

The vaccine does not, however, prevent infection with HIV. In this experiment the monkeys became infected with HIV but somehow were able to keep the virus in check. While the monkeys, to date, reportedly show no signs of disease, it must be noted that the follow-up observation period in this preclinical study is still rather short. At this time, no one can say just how long the apparent protection provided by the vaccine will last. It is not at all unlikely that the monkeys will eventually get sick and die — even after an initial disease-free period.

But even if the vaccine ends up merely postponing the onset of disease, it could still represent a major advance in the control of the AIDS epidemic. If, for example, the use of the vaccine results in lower blood levels of HIV, this may translate into a greatly reduced likelihood of transmitting the virus. And if it can keep HIV-infected individuals alive longer without the need for complicated oral antiretroviral regimens, the vaccine might offer both a new hope for impoverished regions of the world (considering, of course, that it is made available through some sort of subsidized distribution program) as well as lend a new lease on life for persons currently enslaven to — or failing because of — the intricate requirements of current anti-HIV therapies.

Traditionally, vaccines have worked by stimulating the immune system to produce antibodies to the virus in question. But with HIV infection, vaccines designed to stimulate the production of anti-HIV antibodies have met with mixed success or outright failure (e.g., the AIDSVAX product of the VaxGen Corp., currently in Phase III studies in Thailand, Tanzania and the U.S.).

The Merck vaccine is said to be designed to stimulate the cellular arm of the immune response rather than the one mediated by antibody responses. Most viral infections, perhaps with the notable exceptions of hepatitis B and rabies, are brought under control by the cellular arm of the immune system with or without the assistance of an antibody response. By revving up the activity of the body’s killer T-cells, the boosted cellular immune response is then capable of attacking the virus by destroying the cells it has already infected. Merck had earlier attempted a similar approach through the use of so-called “naked DNA.” Naked DNA involves the injection of bits of the HIV genes directly into an individual. Unfortunately, the killer T-cell responses generated by this approach were not quite up to the job.

By fine-tuning this earlier approach, Merck appears to have come up with a much more immunogenic product this time. The key, it appears, turns out to be the addition of an adenovirus “vector” to the mix. A common component to many gene therapy and vaccine research programs, the adenovirus is a virus capable of causing the common cold. Careful tinkering with the adenovirus, however, renders it incapable of causing illness but, apparently, a very useful component to an effective vaccine. Other possible viral vectors under investigation by various vaccine manufacturers include canarypox, vaccinia, salmonella, Venezuelan equine encephalitis virus (VEE), modified vaccinia virus Ankara (MVA), bacillus Calmette-Geurin (BCG), herpesvirus vector, and yellow fever virus.

The use of this adenovirus greatly facilitates the delivery of the naked DNA genes directly into the targeted immune cells. The approach that Merck found the most effective was the familiar “prime-boost” succession of immunizations. The immune system is first “primed” with an injection of just the naked DNA vaccine. Once this has been done, the “booster” injection of the adenovirus-engineered product is administered. As a result, the levels of killer T-cells capable of attacking HIV are greatly increased.

Despite all the excitement surrounding the announcement, Merck is not the first company to pursue this “partial protection” vaccine strategy. Scientists at Harvard University have also reported similar success with such an approach — although they are using a different vaccine construct (see the January 2001 TAGline). Similarly, collaborative research teams at Emory University/NIAID and Yale University/Aaron Diamond Research Center have also presented similar results with their approaches.

But the Merck product is the first of these to actually enter human clinical trials. The Yale/Aaron Diamond vaccine, however, may also soon enter human trials.

Part of the excitement over the Merck announcement stems from the company’s long history of vaccine research and development. Merck is one of the world’s largest and most experienced vaccine manufacturers (along with SmithKline and Pasteur Merieux).

Even as Merck plays down expectations for its newest vaccine strategy, it is not ruling out the possibility that the vaccine might still prove to be protective in humans. Part of this speculation derives from the fact that the challenge dose in the laboratory animals was much greater and much more virulent than what a human to human inoculum would typically entail. But at the current time, this possibility is purely speculative.

In fact, Merck appears to be quite concerned that even the snippets of information that have been allowed to leak out up to this point may result in undue expectations and inevitable disappointment. Even if the vaccine were to prove successful, Merck officials caution, it would still not be available for years. And it is still very possible that the vaccine could simply fail.

One additional possible benefit to this partial protection approach — whether with the Merck candidate or the Harvard, Emory, or Yale construct — is the additional application to individuals already infected with HIV. Simply put, if any of these vaccines do eventually prove capable of augmenting the body’s natural immune defense against the virus, they might be reasonably expected to be useful as treatment.

And Merck seems amenable to just such a two-pronged development strategy. The company has said that it is quite willing to test whether the vaccine might be useful for the treatment of people already infected with HIV. In fact, a recent company announcement reported that Merck will test the vaccine on HIV-positive people within the next three months. For now all we can do is watch and wait, fingers crossed.

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