More Than A Cure
The Search for an HIV Vaccine
Just before World AIDS Day 1999, the United Nations released a report predicting that there will be some 5.6 million new HIV infections this year and that a sadly astounding 2.6 million will die as a result of HIV infection.
I am tempted to write that it goes without saying that we must continue to search for a cure for AIDS, but it never hurts to say it again. Still, we must do more than find a cure for those already infected. To stop this disease, we must prevent infection in the first place.
Although some countries have had notable success with behavioral prevention programs, most nations -- including the United States -- continue to show those efforts lagging. While a commitment to those efforts must also continue, any public health expert you talk to will tell you that the most effective way to halt a disease is with a vaccine.
Vaccine development programs exist in both the public and private sectors. But how familiar are you with these programs? Perhaps you know that President Clinton has given HIV vaccine development visibility in the last few years with his calls for a usable vaccine by 2007. Or perhaps you remember the controversial call from the International Association of Physicians in AIDS Care, IAPAC, a while back for testing of a live-attenuated vaccine in humans. Most people know little more than this.
In fact, the government, through programs sponsored by the National Institutes of Health, has been testing HIV vaccines in humans since 1988. Regrettably, until recently and despite initial testing of products in over 3,000 volunteers, none of these products was deemed successful enough to move into large-scale testing.
Bypassing the government, the private corporation VaxGen last year began large-scale testing of a candidate vaccine in over 5000 volunteers in the United States and Thailand. After the trial began, the U.S. government joined in with support for ancillary studies with this trial. While most of those in the field don't expect that this vaccine will be successful enough for release to the public, the trial should produce important and useful data.
Haven't heard of these? The problem is more than one of poor public relations. Some people believe that, because of HIV's notorious reputation for biological trickery, we may never develop a vaccine. Many others believe we can find the answers, but that tremendous challenges remain in the effort to develop a successful HIV vaccine. If we are truly to stop this disease, rather than just helping those already infected to survive, we must have a vaccine.
Why Not a Vaccine?
The United States is known for its problem solving character. This is not always a compliment. We have a deserved reputation for solving problems once they develop, but we have a short attention span when it comes to the often far more sensible option of preventing the problem in the first place. Our healthcare system, with its expensive cures and drugs for treatment but scant attention to prevention, is a perfect model.
Of course, we acknowledge prevention in most of our AIDS programs. Even here, though, in a way, there is a preference for treatment over prevention. We emphasize strategies that focus on treating perceived problems that lead to the disease, such as unsafe sex or IV drug abuse. Left in the dust, particularly when it comes to public perception, are strategies that may be as or more effective, such as needle exchange programs and vaccines, which focus on only one problem, prevention.
Why a Vaccine?
With treatment drugs unlikely to become affordable outside of the United States or Western Europe in the foreseeable future, a vaccine remains the only truly viable way of halting the worldwide AIDS pandemic. While no vaccine works 100 percent of the time, most of those with which we are familiar are over ninety percent effective. An initial licensed vaccine for HIV may be considerably less effective than that. Combined with other prevention strategies, however, even that less-than-optimal vaccine could begin to reverse the upward spiral of HIV infection. Such a vaccine would provide a benchmark from which to continue work toward a more effective vaccine, eventually leading to the development of a vaccine that can control HIV and ultimately eliminate it altogether.
Developing an HIV Vaccine
The largest player on the HIV vaccine field is the United States government. Industry involvement has been fitful. European governments by and large have not made significant investments in research for a vaccine, although this may be changing. A few developing countries, such as Thailand, South Africa, Uganda, and India, have vaccine programs. Private not-for-profits are also beginning to play a role.
The government program for clinical trials is centered in the newly formed HIV Vaccine Trials Network, or HVTN, composed of efforts formerly housed in the late AIDS Vaccine Evaluation Group (AVEG) and portions of the HIV Network for Prevention Trials (HIVNet). Significant work is also done at the new Vaccine Research Center, a building for which is still under construction on the NIH campus in suburban Washington D.C., and a smaller but focused program exists at the Walter Reed Army Institute of Research. The Centers for Disease Control also does some work on HIV vaccines, but is not yet a truly significant player.
Although at work since 1988, recruiting some 3,000 volunteers for over thirty trials, the NIH program has in some ways been a frustrated effort. Despite the number of trials, testing has fallen largely into only two basic concepts. These trials have focused almost exclusively on a small set of subunit concepts and a live-vector concept using canary pox, or some combination of the two. There has been some testing of a DNA vaccine and of a salmonella vector vaccine, as well as new adjuvants, substances that are given with a vaccine that help boost its effectiveness.
The subunit trials have looked at various glycoprotein (gp) constructs, focusing mostly on use of gp120. Glycoproteins are sugar proteins that occur in parts of the virus. Most of these studies have been Phase I studies focusing primarily on safety questions. A few have reached Phase II studies, which further measure safety and from which initial ideas of immunogenicity may emerge. One product almost reached Phase III testing, which is needed to provide statistically valid results of effectiveness, but in a still sometimes controversial decision, the National Institutes of Allergies and Infectious Diseases (NIAID), in which the Division of AIDS is housed at the NIH, decided not to proceed. NIAID believed that the product lacked sufficient evidence of success to justify expending the resources for such a large-scale trial involving thousands of volunteers.
There is no question that researchers started with research approaches they believed would pose the least safety questions. This is understandable, given the politics of AIDS and fears about the causes and spread of AIDS among the populations that would eventually receive a vaccine in Phase III trials. Some of those people believe, at worst, that the same government sponsoring the vaccine trials created and spread the original disease or, at best, did little to stop the disease because that government despised them. Caution might well be in order for a government program testing vaccines to be injected into the bodies of skeptical people.
Vaccines based on gp120 create only humoral, or antibody, immune responses. Totally aside from the question of how strong those responses are on their own, researchers have come to believe that a cellular immune response is also needed. Their answer for the time being is a live-vector vaccine using canary pox. As its name implies, this is a disease of birds and is harmless in humans. Portions of HIV have been genetically engineered into the canary pox. This product is intended to develop a cellular immune response.
Several programs focused on preclinical research (research prior to testing in humans) have also been established by the NIH. As one might imagine, these are a jumbled alphabet soup of programs that even relatively experienced vaccine advocates like myself have trouble figuring out. The hope is that the newly formed Vaccine Research Center will bring a better sense of coordination to this work.
Whatever one thinks of the work of bureaucracies, the NIH program is increasingly well-funded, with an annual budget now at almost $200 million (of $1.8 billion total on AIDS). And, despite what sometimes seems to be constant reorganization, the situation seems to be settling down.
The Private Sector
Industry is another matter. Spending has been spotty at best, and some of the world's largest pharmaceutical companies have only minimal HIV vaccine programs, or none at all. Involved in some significant ways are Chiron, Glaxo-Wellcome, Merck, Pasteur Merieux Connaught, and Wyeth Lederle. Despite the huge resources available to these large companies, according to 8 Years and Counting... What Will Speed Development of an AIDS Vaccine? a 1999 report from the not-for-profit AIDS Vaccine Advocacy Coalition, it is unlikely that any one of these companies spends more than $40 million annually on HIV vaccine development.
Smaller biotechnology companies are involved in vaccine research in significant ways. Companies include AlphaVax, Cel-Sci, Immune Response Corporation, Therion, and VaxGen. VaxGen is notable in that it decided to embark, with no government sponsorship, on the first Phase III trial of a candidate HIV vaccine. The trial involves 5,000 volunteers in the United States and Thailand and is testing a multi-clade (clades are subtypes of HIV) gp120 product. As mentioned earlier, the government has begun working with VaxGen on related studies involving the trial.
VaxGen is also notable for its commitment to a product which, at best, will induce only antibody responses, while most other research programs have moved their focus toward cellular responses as measured by cytotoxic lymphocyte (CTL) responses.
Of companies working on cellular-oriented products, Pasteur Merieux Connaught (PMC) perhaps has received the most attention because it provides the canary pox vector products used in NIH clinical trials. Initially, vCP205 was its product of choice, used in a "prime/boost" strategy (an initial prime vaccination followed with one or more booster shots) in combination with a gp120 product, the aim being to stimulate both arms of the immune system. Results from a Phase II trial conducted by AVEG were released in mid-1999. Depending on whom one listens to, the results were either disappointing or somewhat hopeful. No one claims a home run.
PMC has been fiddling with its canary pox, and testing is under way on two slightly different constructions, vCP1433 and vCP1452. The hope is to move to Phase II-B or test-of-concept trial (the size of which falls somewhere between Phase II and Phase III numbers, in this case about 1,000 in the U.S. and several other countries), using one of these products, probably in 2001.
Other programs are also looking at new constructs and are working with the NIH program or independently to develop ideas that include DNA vaccines and vectors such as Venezuelan equine encephalomyelitis (VEE) and modified vaccinia ankara (MVA).
In the private not-for-profit sector, the International AIDS Vaccine Initiative (IAVI) has been the most active, working a variety of issues around international development, including access and funding of new concepts. The American Foundation for AIDS Research (AmFAR) has begun to fund vaccine research, in addition to its longtime spending for treatment research. The AIDS Vaccine Advocacy Coalition (AVAC) has emerged as a national network of advocates, focusing on illuminating and eliminating the obstacles to development of a vaccine.
Is It Happening?
AVAC has been producing annual reports on progress toward an AIDS vaccine, pivoting on President Clinton's 1997 call for a vaccine in ten years. It's 1999 report, 8 Years and Counting..., says that the road is indeed still full of obstacles.
The report is organized into three areas: government, industry, and community work. As the U.S. government has by far the largest development program, it comes in for the longest portion of the report. AVAC says the NIH program is beset by a kind of leadership paralysis, with no one really taking a clear leadership role in vaccine research. Programs are scattered across institutional boundaries, and there is no unifying vision of how to proceed. Lacking an invigorating vision, the government program has been characterized by constant reorganizing of one kind or another.
Nonetheless, the report is not totally pessimistic. Citing several key personnel appointments in the vaccine program, the coordination the new Vaccine Research Center should bring, and a studied hope that the new HVTN will settle down the clinical side, the report calls for everyone to get to work and "move faster."
The AVAC report is perhaps most discouraging in its outline of industry activity. The report observes a risk-aversive climate characterized by "place holding" funding to maintain intellectual property and patent rights, rather than a vigorous investment. AVAC believes that industry must be involved in any successful effort for an AIDS vaccine, but that its interest is at best tentative.
8 Years and Counting... is more neutral in its section on community work needed, reserving criticism but pointing to the need for direct funding of research, advocacy for research needs and priorities, mobilization of public will, and support for ethical and scientific trial designs. Citing past examples of community work, such as the massive public mobilization for a polio vaccine, the report calls for much greater involvement. Cited in particular for work they are doing are IAVI, the Elizabeth Glaser Pediatric AIDS Foundation, and AmFAR, along with a small set of foundations.
The report also takes to task what it calls the "big six" AIDS organizations in the U.S. for a failure to integrate vaccine work into their programs. They are AIDS Action Boston, AIDS Project Los Angeles, Gay Men's Health Crisis (New York), Northwest AIDS Foundation (Seattle), San Francisco AIDS Foundation, and Whitman-Walker Clinic (Washington D.C.). Of these, only Gay Men's Health Crisis and AIDS Project Los Angeles have ever even had staff dedicated to research advocacy.
Some of these problems may be circular. If the government and industry programs are characterized by tentativeness, it is perhaps because of the huge scientific questions that remain about an HIV vaccine. If there were findings pointing in some clear direction, activity would likely flourish. But, if research is tentative, how are those questions to be answered? The bottom line, of course, is that the research must happen, and the community's most important role is to pressure those who should be doing it.
There are also basic philosophical questions percolating through the effort. A major one is about how best to move forward on research. Some argue, citing historical example, that we must simply do the research. Some questions, important ones, will never be answered, they argue, until large-scale human trials are undertaken. We may need several large-scale trials and must move to prepare the public and HIV-affected communities for this. Many scientific advances have been made by this empirical method (discovery based primarily upon actual experimentation and experience), and sometimes it is simply what is required. If we wait for the "right product" to do large trials, proponents of this approach say, we'll never get that right product.
Others argue equally strongly that the science must be hypothesis driven. Their position is that we must frame questions based on existing knowledge and answer them systematically, moving forward in a coherent and strategic way. Otherwise our research is just so much looking for a needle in a haystack, with probably not much better chances for success. The resources are too few, they say, and the task too large to approach the scientific questions in what they believe to be the more haphazard empirical approach.
Nowhere is this tension more visible than in the question of whether to move forward to a Phase III trial, involving thousands, maybe tens of thousands, of volunteers and the expenditure of tremendous fiscal and personnel resources.
In 1994, the NIH said no to a Phase III trial of a gp120 vaccine. The effort was spearheaded by Don Francis, best known to many as the hero of And The Band Played On... by Randy Shilts. Francis believes we must move forward with large-scale trials. He helped organize a new company, VaxGen, and tinkered with his product to improve it. He then moved forward with a Phase III trial with no government assistance whatsoever. Volunteers began enrolling in 1998 in the U.S. and in 1999 in Thailand. The study lasts for three years (that is, each volunteer participates and is studied for three years).
In contrast, the NIH has moved much more cautiously. After its negative decision in 1994, it turned its attention to a combination approach characterized by the gp120/canary pox construct. It has tested these products in a number of permutations, along with possible adjuvants. It plans to choose a final construct this year and move to its intermediate Phase II-B trial in 2001. Note that even this isn't a true Phase III trial. It will yield results in 2004 at the earliest, and only then will the HVTN know whether it wants to move forward to a full-scale Phase III trial.
Regardless of how the science moves, interwoven in all of this are difficult ethical questions about the research itself and what sort of product eventually to release.
Most prominent in the ethical arena is the "guinea pig" phenomenon. AIDS in the U.S. disproportionately affects disenfranchised and marginalized groups; worldwide, it most affects poorer, less developed nations. In the U.S., these populations have an unhappy history with scientific research. The infamous Tuskeegee experiments still loom large in the African-American community. In both the African-American and gay communities, suspicion can be rampant. Some still believe HIV is not the cause of AIDS. Others believe that HIV may be the cause of AIDS, but that it was a genetically engineered disease released upon stigmatized people. Some believe it may have been released accidentally, but others believe it was deliberate.
Internationally, a similar antipathy to the U.S. government plays an equally important role. Scientists say they must test a vaccine in the populations that will eventually use it, but those populations fear that this is an excuse to test a product on the powerless internationally because the U.S. public would not accept the risks involved. This feeling has been exacerbated by controversies over testing of AIDS treatments and is tied up with problems in access to treatment. Some argue that provision of a high standard of care in trials is an unethical incentive to participate, because it provides care that would otherwise be entirely out of reach. Others say that if such treatments are available, it is criminal to deny them to those taking the risk of trial participation.
Another looming question is at what level of effectiveness a vaccine should be released for public use. The answers are easy if a vaccine fails miserably or is extremely effective. The answers aren't so easy if the vaccine is, say, fifty percent effective.
First is the question of what "fifty percent effective" means. Are half the people well-protected from infection while the other half have no protection at all? Or do most recipients have a moderate immunization, meaning they are more resistant, but not completely immune to infection. The answer for our first "successful" vaccines may well be "all of the above."
I have heard arguments, backed up by charts and presentations, that a fifty percent effective vaccine should be licensed for public use. While less than perfect, the argument goes, such a vaccine will work well enough to begin to knock the wind out of the pandemic. Enough people will have enough immunity that they will resist becoming infected, will therefore not infect the next person, and on down the line, stemming the rise in new infections.
With 5.6 million new infections in a year, I confess to finding merit in this argument. But what if the vaccine is only forty percent effective? thirty percent effective? Where is the line? And how do we create an effective behavioral prevention program, which must necessarily accompany such a vaccine? How do you explain such ambiguities to someone who doesn't even understand the germ theory of disease?
The questions are daunting indeed. One way in which the NIH has responded has been to mandate the formation of local site and national Community Advisory Boards (CABs, sometimes also called Community Constituency Groups) for all HIV research. CABs are supposed to be composed of members of the communities affected by the research, and they should have support for learning the science and reimbursement of expenses incurred.
Ideally, CAB members should be involved in all aspects of developing research, usually signing confidentiality documents so that they may have access to everything, without fear of compromising proprietary knowledge. CABs can be particularly important, if they are used advantageously, in such thorny issues as trial design and protection of participant rights.
But NIH CABs, unfortunately, are notoriously uneven in their effectiveness. The work is difficult. These are laypeople, after all, trying to understand extremely complicated, cutting-edge science. Some researchers have been quite supportive and confer with their CABs with enthusiasm, while others clearly don't see the point.
Industry has no mandate for CABs at all. To my knowledge, no pharmaceutical company has established a CAB for Phase I or II research. VaxGen established local CABs and a national CAB for its Phase III study, but it has been criticized for putting more talk than action into its real support for a CAB infrastructure.
What of sites in countries that have no traditions of citizen participation and questioning of authority, whether for cultural or political reasons? That's tough enough in the United States. I don't pretend to understand fully the difficulties in setting up CABs outside the US.
Raising the Bar
I've heard so many friends and associates talk of finding a cure for AIDS. That is not my goal. Yes, I want to find a cure, but I want to do more. We must expand our vision. Truly to conquer AIDS means not only curing those already infected but preventing the uninfected from ever getting AIDS. It means both. It means a vaccine.
How Vaccines Prevent Illness
To understand the context of HIV vaccine development and its challenges, it is first necessary to understand something of how any vaccine works.
What Is a Vaccine?When the body is exposed to a disease-causing organism, the organism causing infection produces antigens, or substances that cause the body's immune system to spring into action. There are two basic immune responses relevant to vaccines. A humoral response produces antibodies, which circulate in the blood to inhibit infection. A cellular response is when the body produces specialized cells which circulate and kill already infected cells. A third kind of immunity is mucosal, in which the body fights infection on the mucosal surfaces of the body to prevent infection. HIV infects the body through mucosal routes when it is sexually transmitted. When a body successfully fights off a disease, or doesn't become infected at all, it is because the body has responded in one of these ways.
A vaccine is simply a benign, or relatively benign, substance that, when put into the body, boosts or causes one or more of these immune responses to an infectious organism.
The first vaccine was developed in the 1700s in England by Edward Jenner. He noticed that milkmaids infected with cowpox rarely became infected with smallpox, one of the deadliest diseases ever known to humankind. Cowpox is related to smallpox, but is a considerably less harmful disease. In a landmark experiment, Jenner took some fluid from a lesion of a cowpox-infected milkmaid and administered it to a healthy boy who had never had either disease. Several weeks later he exposed the boy to fluid from a smallpox sore. The boy remained healthy. This experiment demonstrated the basic principle of vaccines: Introduce a relatively less (preferably not at all) harmful substance to prevent infection by a more harmful organism.
According to a 1998 NIH publication called Understanding Vaccines, at the time of publication 35 vaccines had been licensed for use in the United States. The result of these vaccines has been the worldwide elimination of smallpox, elimination of polio in the western hemisphere, and in the United States the disappearance of numerous childhood diseases as major mortality threats.
Testing for a candidate vaccine is focused on a variety of factors, among the most important:
Kinds of Vaccines
The classically successful vaccines have been what are known as live-attenuated vaccines. These contain weakened versions of the infectious organism itself, so that they have only a small ability to cause actual infection. The hope is that the body will react to this weakened version, eliminate the risk of actual disease, and retain a memory of how to fight the infection. The idea is that when the genuinely infectious organism appears, the body can then fight off the more virulent version. Smallpox, oral polio, measles, and mumps vaccines are versions of this type. With this type of vaccine, however, disease rather than its prevention can occasionally occur.
Historically, success in vaccines has often been a shot in the dark. When scientists understand why a vaccine works, they know the correlates of immunity, that is, which immune response creates or correlates with immune protection. Many vaccines have been found to work even though the correlates of immunity were not known. Nonetheless, it is better to know than not to know. Knowing makes it easier to improve effectiveness and apply the knowledge to work on other vaccines.
It is this combination of factors that led IAPAC members to volunteer themselves for the testing of a live-attenuated vaccine for HIV. Live-attenuated vaccines have been the classic vaccine strategy and generally confer the best immunity. But there is controversy: We don't know what the correlates of immunity for AIDS are, and, particularly given the propensity of HIV to mutate, a live-attenuated vaccine could end up causing the disease it is meant to prevent. Because of this, scientists have focused on other types of vaccine strategies.
Unlike live-attenuated vaccines, inactivated or whole killed vaccines use dead organisms which cannot cause infection. Unfortunately, these vaccines often don't confer long-term immunity and do require multiple doses or boosts. This presents delivery problems in areas with poor healthcare systems -- precisely those areas most in need of an HIV vaccine. The flu vaccine that is given annually is the best known of this type.
Subunit vaccines are composed of fragments of the disease-causing organism, again unable to cause infection. The hope is to find the right fragment that causes an effective immune response -- in other words, a correlate of immunity. These vaccines may be made by using pieces of the actual organism or by genetic engineering.A vector vaccine is made by inserting a genetically engineered synthetic gene of the infectious organism into another live but harmless organism. This strategy is the one most actively pursued in government programs at this time.
Some other types of vaccines are naked DNA, peptide, toxoid, and conjugate. These all involve different strategies for presenting different pieces of the target organism to the immune system in the hope that it will produce the proper immune response to prevent infection or illness.
Of course, the major challenge with HIV is that its primary attribute is its success at disabling immune response. Most researchers have come to believe that, in order to be successful against HIV, a vaccine must develop specialized antibody responses that prevent infection of cells and an effective cellular response that overcomes HIV's ability to disable cellular immunity. The focus has been on products that are injected into the body, but some research has looked at delivering a vaccine on mucosal surfaces to develop mucosal immune responses.
Whatever the approach, a vaccine is most needed in areas of the world that have little or no healthcare resources and facilities. The most successful HIV vaccine, therefore, must be inexpensive to produce and stable in transport and storage. Even a comparatively expensive vaccine will be far more useful than treatment drugs, which cost tens of thousands of dollars a year for indefinite periods of time.
How a Vaccine Is Tested
Any vaccine used in the United States must be licensed by the FDA. In order to become licensed, the vaccine candidate must first undergo rigorous testing for safety and efficacy. The basic research phases for licensing of vaccines are:
Pre-Clinical Testing: Studies done in the lab and on animals prior to any human testing.
Phase I Clinical Trial: Studies in very small numbers of people in low-risk populations to test the vaccine candidate's safety. In HIV vaccine research, Phase I trials have usually been done on less than a hundred people -- sometimes as few as fifteen or twenty.
Phase II Clinical Trial: Slightly larger studies in low-risk and, occasionally, high-risk populations, primarily to test safety further. Whether there is an immune response (immunogenicity) may also begin to emerge in this phase. Immune response, however, is not a guarantee of efficaciousness (protection from disease).
Phase II Clinical Trial: Large-scale trials of subjects numbering in the thousands in high-risk populations to see whether the vaccine actually protects against disease in statistically significant number.
If a vaccine is found highly protective in Phase III clinical trials, the next move would be licensure; if less protective, it might be to adjust the product or even move on to other concepts.
Glossaryadjuvant -- substance given with a vaccine to boost its effectiveness
antibody -- a substance that inhibits infection
antigen -- a substance produced by a disease-causing organism and that triggers immune response
cellular response -- an immune response that produces specialized cells that kill already infected cells
correlates of immunity -- which immune response corresponds to immune protection
glycoproteins -- sugar proteins that occur in parts of the virus
humoral response -- an immune response that produces antibodies
inactivated vaccine -- see "whole killed vaccine"
live-attenuated vaccine -- vaccine containing a weakened form of the infectious organism itself
mucosal immunity -- a type of immunity in which the body fights infection on the mucosal surfaces
subunit vaccine -- vaccine composed of fragments of the disease-causing organism
vector vaccine -- vaccine made by inserting a genetically engineered synthetic gene of the infectious organism into an another live but harmless organism
whole killed vaccine -- vaccine that contains a dead organism
Alphabet SoupAmFAR -- American Foundation for AIDS Research
AVAC -- AIDS Vaccine Advocacy Coalition
AVEG -- AIDS Vaccine Evaluation Group
HIVNet -- HIV Network for Prevention Trials
HVTN -- HIV Vaccine Trials Network
IAPAC -- International Association of Physicians in AIDS Care
IAVI -- International AIDS Vaccine Initiative
NIAID -- National Institutes of Allergies and Infectious Diseases
NIH -- National Institutes of Health
PMC -- Pasteur Merieux Connaught
AIDS Vaccine Advocacy Coalition, 1701 K Street NW, #600, Washington, D.C. 20009; (202 387-5510; www.avac.org.
Jim Thomas is Editor of the News-Telegraph, a newspaper for the gay and lesbian communities of St. Louis and Kansas City. He is chair of the National Community Advisory Board for the HIV Vaccine Trials Network and a board member of the AIDS Vaccine Advocacy Coalition. He lives in St. Louis.
This article was provided by Body Positive. It is a part of the publication Body Positive.