The Bay Area Reporter - April 15, 1996
William Snow, ACT UP/Golden Gate Writers' Pool

Many scientists believe it will be possible to develop a vaccine to protect against HIV infection or disease. But they don't begin to agree what such a vaccine would look like or how it would work. The most reasonable approaches, similar to vaccines for other viral diseases, are in different stages of development and testing, but the only real test to see if a vaccine works will be a carefully designed field efficacy trial for each plausible approach, without knowing the answer in advance. Here's why.

Unlike treatments for sick people, vaccines are only put to the test when vaccinated individuals are later exposed to HIV. The early, Phase 1 and Phase 2 tests of candidate vaccines look for safety and the nature of the immune response that the vaccine elicits. But we don't know yet what immune response it would take to protect someone, so these immune responses can't really be used to predict the outcome of an efficacy trial.

Even if some participants in a Phase 1 or Phase 2 trial get infected (which happened with gp120), this only means that the vaccine is not 100% effective, and no vaccine is. In order to determine efficacy at all you must have a large trial with an equally large placebo group for comparison. You absolutely have to put vaccines of unknown efficacy into otherwise healthy people, some of whom must become exposed and infected during the trial. This immediately raises several important problems.

Who is at risk?

You need to be able to find out who is at risk and what their level of risk is in order to enroll those people in the trial, and to determine how big the trial must be, and how long. This is because you need a certain number of infections in the placebo group for comparison to the vaccine group.

The higher the risk, the fewer participants you need and the sooner you'll have an answer. The highest documented seroconversion rates are currently certain populations in Asia and Africa. So plans are underway to do some vaccine trials in Thailand, Uganda, and other countries. There are two potential drawbacks to this approach. First, several of the candidate vaccines are only available for the strain of HIV in the Americas and Europe. Second, the countries' willingness to participate is often colored by the seriousness of their epidemic and the lack of other ways to treat it. Great care must be taken not to use these countries strictly as testing sites (guinea pigs) for Western medicine. In addition ,there are logistical complications in places where medical technology is less readily available: refrigeration, lab facilities for analysis, ability to get participants to return many times over a long period of vaccinations and follow up.

Consequently, it is generally thought that these same vaccines also need to be tested here, for scientific, ethical, and marketing reasons. In the U.S., which has the highest AIDS rates in the developed world, the most easily identifiable vulnerable populations are gay men, injection drug users, and women who have been to STD clinics. Vaccine preparedness studies are occurring at eight sites around the country with these populations, where it is believed the rate of new infections is around 2% per year even with regular testing and counseling. These preparedness studies are looking at actual infection rates, behavior change, willingness to participate in efficacy trials, and other prevention interventions such as microbicides or behavior change programs.

Will their risk change?

Researchers are ethically obligated to make every reasonable effort to reduce this rate of infection, in spite of needing infections to prove if a vaccine works. This potential conflict is well recognized, and researchers are aware of their obligations to do risk reduction counseling with trial participants. There are also discussions of what level of behavioral training should be required. If participants in a vaccine trial change their rate of exposure, less because they are getting counseling and regular testing, or more because they think they are protected, you may not be able to evaluate the vaccine accurately.

How can you tell who was exposed?

You can't. So you need enough participants to guarantee an overall average exposure rate.

How can you determine the level of protection?

With a randomized, blinded clinical trial. One of the great discoveries of modern science is the power of randomized clinical trials. This marriage of medicine and statistics is the only known way to compensate for bias and chance to determine the efficacy of a treatment or vaccine. The basic idea is seductively simple. Give the treatment to some people and withhold it from an equal number. See how many get better (or get infected). If there is a statistically significant difference you can be mathematically certain that the treatment or vaccine is better than no treatment, or a comparative one. This is particularly true for vaccines where you really have no idea who has been exposed and who may otherwise have become infected. If you get enough people to participate and put them totally randomly into the different parts, or arms of the trial, statisticians can tell you how large the trial must be, how long it must last, and with what degree of certainty you can answer your research question, based on the expected number of infections.

For example, with a 2% annual infection rate, with one year to enroll and vaccinate participants, follow up for 2.5 years to count infections, and 5% loss from follow up, you would need roughly 3000 participants in each arm (vaccine and placebo) of a trial. This size and length of trial would allow you to determine if the vaccine is 40% or more effective with very good predictive ability. The cost of such a trial, in addition to the time until an answer (3.5 years), and commitment of the thousands of at risk volunteers, would be as much as $25 or $30 million. So you can see why companies or the government might be hesitant to jump into such a trial unless there is hope that the trial would help move the vaccine effort forward, even if the vaccine is found to be less effective than desired.

Intermediate-sized trials

An alternative approach to make this decision easier to swallow is to run an intermediate or 'proof of concept' trial with half as many participants (about 1500 per arm). This would only generate one fourth as much data with considerably less certainty, but it would allow for a faster trial (2 years vs. 3.5), less cost and risk, and would give the ability to tell if the tested vaccine was poor and not worth pursuing (less than 30% effective), very good (greater than 60% effective), or somewhere in the middle. This might mean that another full efficacy trial would have to follow to get a more exact indication of efficacy, but it would answer some very important questions. General thinking now is that this is the size of trial that would occur first with current products in development. It has definite advantages and drawbacks but is seen as more politically and logistically feasible.

It is very important to understand that a successful trial is one that asks important research questions and answers those question definitively, not necessarily one that leads to a licensable vaccine. One great hope is that initial efficacy trials will help answer important secondary questions that will help develop better vaccine candidates, and make later trials easier to decide upon and design.

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