HIV infection is spreading faster in Botswana than in any other country in the world. In Francistown, in the east, where a decade ago HIV was rare, nearly half of the pregnant women are already infected.

"That explosion happened in five years," says Sheila Tlou, senior lecturer at the University of Botswana. "Our rates shot up from nothing to more than 30 percent in some populations."

When Tlou left her home country in 1988 to pursue a doctorate in public health at the University of Illinois, only a handful of AIDS cases had been reported in Botswana. The earlier cases, which had occurred among immigrants and men who had studied abroad, did not cause widespread concern about the nation’s public health.

When Tlou returned three years later, better informed about the insidious nature of the HIV epidemic, she looked around and saw "a disaster waiting to happen." That prediction has proved sadly accurate: public health officials now estimate that over 10 percent of the country’s population is infected. "If an effective vaccine had been available five years ago, it would have made quite a difference," Tlou says.

Worlds Apart
Unfortunately, Botswana’s recent story is far from unique. The epidemic is tearing through the developing world like a tornado, causing devastation far more severe than that experienced by more affluent countries. Each day, an estimated 16,000 men, women, and children in developing countries become infected with HIV. In contrast, in the industrialized world, new infections spread at the rate of 500 per day. This disparity between rich and poor nations has increased dramatically over the course of the epidemic. In 1980, roughly twice as many adults were infected in sub-Saharan Africa as in North America; today, 14 times as many are infected. Altogether, the UNAIDS estimates that over 90 percent of the world’s more than 30 million HIV-infected people live in developing countries.

As HIV infection rampages through Africa, the Caribbean, Latin America, and Southeast Asia, prevention programs have proved to be speed bumps - not roadblocks - in its path. Worldwide, about $1.5 billion has been spent each year on everything from one-on-one counseling to comic books, radio spots, and massive condom rallies. About 86 percent of prevention funds come from taxpayers in the United States and other industrialized nations, according to Daniel Tarantola, director of the International AIDS Program, François-Xavier Bagnoud Center for Health and Human Rights at the Harvard School of Public Health. UNAIDS calculates that if affluent countries dug deeper and spent 10 to 15 times more on global prevention programs, the number of new infections could be reduced by as much as half. Although that would be progress, it’s clear that social and behavioral interventions alone cannot win the battle against AIDS. What is needed to turn the tide is a safe, effective, and affordable preventive HIV vaccine.

A vaccine would complement ongoing prevention efforts. "Studies of programs that aim to slow transmission by treating sexually transmitted diseases and teaching safer sex practices show that, over 10 years, transmission rates fall by about 30 percent," Tarantola said. "If we could achieve that decrease with one vaccine, then that would be quite effective." In economic terms, a preventive vaccine could save developing nations billions of dollars in future treatment costs, enabling them to invest more heavily in education, public works, and other essentials.

A Humanitarian Urgency
If a vaccine does not become available soon, women and children in poor countries will be hit even harder by HIV. For 15 years, the United Nations’ Expanded Programme of Immunization (EPI) has helped developing nations protect infants and children against polio, diphtheria, tetanus, pertussis, tuberculosis, and measles, giving parents renewed hope that their children will survive to adulthood. But the hopes of many are being dashed by the rise of HIV among young mothers, who become infected through sex with their partners and unwittingly pass the virus to their babies. If the epidemic continues on its current path, notably in Africa and Asia, infant mortality rates will increase by 10 to 15 percent, and the achievements of EPI and other childhood health programs will be lost.

Down the road, the tragic, premature deaths of so many children and young adults will slash overall life expectancy in high-incidence countries. If there were no such thing as HIV, the average Thai infant born in 2010 could anticipate celebrating his or her 75th birthday. Factor AIDS into the equation, and the child’s life expectancy plunges to 45 years.

An Economic Necessity
In addition to its humanitarian urgency, the development of an HIV vaccine is a matter of economic necessity. AIDS typically strikes people between the ages of 20 to 40, whose level of sexual activity makes them vulnerable and whose productivity makes them essential to a healthy economy. The loss of one working adult, in a country where children account for a large proportion of the population, can impoverish an entire family. And a nation that loses too many young adults will no longer have the skilled workers it needs to elevate its economic status.

This scenario could unfold in Botswana, for example, which only climbed out of the lowest income category after diamonds were discovered there. Newfound wealth has enabled the government to aggressively promote literacy and training for skilled workers. But many of the nearly 200,000 people infected with HIV in Botswana are believed to be professionals or skilled workers, and when they develop full-blown AIDS, Tlou predicts, "there will be great hardships ahead."

In African nations where HIV got an early foothold, the high cost of treatment is already wiping out family savings and driving up government health care spending. Indirect costs are even more enormous, as the premature loss of hard-to-replace workers causes a decline in traditional economic indicators. The World Bank predicts, for example, that by the year 2010, AIDS will shrink Tanzania’s economy by 15 to 25 percent.

Chasing a Dream Vaccine?
Scientists have no trouble making wish lists about a product that could stop - or at least slow - the spread of HIV. It should be as safe as possible and should protect people against the HIV subtypes they are most likely to encounter. "An ideal vaccine for the developing world should be cheap, be given orally, and not require refrigeration," adds Edmund Tramont, a long-time vaccine researcher and director of the Medical Biotechnology Center at the University of Maryland. Another asset would be to include a marker that enables health care workers to distinguish between people who test positive for HIV due to vaccination and those who are already infected. A key consideration in vaccine design, according to Harvard AIDS Institute Chairman Max Essex, is that there are really two AIDS epidemics, each with its own viral subtypes and routes of transmission. In the West, most people who have been infected through anal intercourse or the exchange of blood have one subtype. In developing nations, where the virus is typically spread through vaginal intercourse, as many as five subtypes may be circulating at once. Although a single vaccine may someday protect against all HIV subtypes, such a development is not imminent.

The only way to ensure that an experimental vaccine prevents infection - or overt disease - is to immunize large numbers of people in carefully designed clinical trials. Scientists lay the groundwork for such studies by determining which subtype is present, how it is being transmitted, what proportion of the population is already infected, and what risk factors make people vulnerable. With this information, they can tell whether vaccinated people are more likely to resist a life-threatening infection than those who weren’t immunized. Because researchers will not deliberately expose participants to HIV, they must wait to see what unfolds in the natural course of events - who becomes infected and who does not. As a result, clinical trials take several years. Experimental AIDS vaccines have been tested in the developing world since 1986, when the first small trial was undertaken in Zaire. In 1989, a World Health Organization consensus conference spelled out ethical guidelines and scientific criteria for experiments involving people in developing nations.

With these humanitarian safeguards in place, countries in Asia, Latin America, and Africa joined an international vaccine readiness program that recruits volunteers and gathers baseline information. Today, more than 5,000 well-characterized volunteers are standing by. These include Brazilian men who have sex with men, injection drug users in Bangkok, and military recruits and postpartum women in Uganda. A number of small Phase I studies - in which the primary goal is to determine the safety of a vaccine - have been conducted in these cohorts. A new round of trials, which will test an immunization strategy that uses two types of vaccines, may begin in the coming year.

Developing an AIDS Vaccine
Conducting safe, well-designed vaccine trials in humans is a critical step in vaccine development. Yet HIV vaccine development efforts were dealt a sharp blow in June 1994 when the National Institutes of Health halted plans to conduct field trials of the first generation of bioengineered AIDS vaccines. Opponents feared there was not enough evidence of efficacy to warrant large-scale field trials, but other research scientists argued that vaccinology is by nature a trial-and-error science in which progress sometimes requires the courage to conduct human trials to test theory and to revise vaccine designs accordingly. "Although some experimental vaccines provide clues for efficacy, such as preventing related infection in an animal model, most do not," says Richard Marlink, executive director of the Harvard AIDS Institute. "The only animal able to test whether a human vaccine is going to work is the human animal.

 "Had the trials been approved in 1994," Marlink says, "they could have been completed in three years, costing some $20 million annually. And, had the vaccines worked in people, the entire expense of the trials would have been recouped by the first 500 AIDS cases prevented.

"One day, when we have an AIDS vaccine, even if it’s not yet the most ideal one," Marlink adds, "we’ll look back and make the sad calculation as to how many lives we could have saved had we gone ahead with earlier large-scale human vaccine trials."

For a safe, effective AIDS vaccine to become a reality, HIV researchers are urging substantive changes in how federal research efforts proceed. To get the program back on track, some scientists recommend that applied research activity be carried out by a single-purpose organization, whose leadership works closely with the White House and industry to pursue all potential vaccine strategies. In the face of a public health emergency, say researchers, a different kind of organization that can run an expedited vaccine program is warranted. Trials also must be conducted internationally to ensure that successful vaccines protect against all subtypes of HIV.

"We should learn from proven track records in delivering successful products," Essex says. "The March of Dimes gave us both polio vaccines, and our military’s applied research system developed dozens of vaccines, sometimes in record time to meet war needs." A revitalized program, Essex adds, is our only hope for realizing a safe, effective vaccine for worldwide use.

The Price of a Vaccine
Many experts predict that a preventive HIV vaccine will be available within a decade. As with most advances, financial considerations will dictate whether it reaches the people who need it most. The higher the cost of the vaccine, the less widely used it will be. At a Harvard AIDS Institute symposium, a team of international experts agreed that from a financial perspective, an ideal vaccine would require no more than three doses and cost $1 a dose, a useful one could cost $10 for each of three doses, and a poor vaccine would require three doses costing $30 each.

Although prevention may sound expensive, it pales in comparison to the price of AIDS treatment. Even in countries where only minimal care is available, the cost of treating one case is higher than the per capita gross national product. Industrialized countries subsidize these costs as well. One of the basic tenets of public health is that prevention is more cost-effective than treatment. A safe, effective HIV vaccine, used in tandem with other risk reduction programs, might someday relieve the public health crisis in Botswana and around the world.