HELP, I NEED A VACCINE! (OR H.I.V. FOR SHORT)

By | December 12, 2005 | archive, textbook

Andrina Simengwa, like any ordinary 23-year old basketball fan, loves to watch Vince Carter soar into the air, rotate 360º, and thunderously dunk a basketball into the hoop. Andrina, however, is in fact an extraordinary individual who leads an anything but ordinary life. She resides in the town of Lilongwe in the sub-Saharan African nation of Malawi, and is presently employed by the United Nations Global Fund to Fight AIDS, Tuberculosis and Malaria (herein referred to simply as the Global Fund). As an advocate with the Global Fund, she recently spent a few months in Canada promoting youth awareness about the human immunodeficiency virus (HIV), the virus responsible for the worldwide pandemic known as Aquired Immunodeficiency Syndrome (AIDS). During her stay in Canada, I had the chance to spend some time with Andrina and learn a little more about what it is like to live in Africa and be HIV-positive.

Before I met Andrina, I had this mental picture of an HIV-positive African woman who was physically weak and emotionally devastated by the terminal illness with which she was afflicted. The more I interacted with Andrina, however, the more I realized that my stereotypical image was not an accurate representation of reality. Andrina embodies courage, hope and resilience; not once did I see fear in her youthful eyes. She is generally healthy and enjoys every day to the fullest. As an employee of the Global Fund, she is paid just enough money in order to take care of her son, mother, and orphaned nephews, as well as to purchase the antiretroviral (ARV) drugs she must take every day for the rest of her life, like all other HIV-positive patients. In short, she is a real-life heroine who is battling one of the deadliest killers currently confronting humankind.

Now that Andrina has returned to Malawi, I realize what an eye-opening and humbling experience it was to interact with her. I am also surprised that, among all the conversations that we had, we never once talked about the one item that could dramatically improve her life, the lives of the 40 million other HIV-positive people in the world, as well as all the estimated 14,000 people who will continue to contract the virus every single day after this article has been written. Stephen Lewis, the United Nations (UN) Special Envoy for HIV/AIDS in Africa, has also proclaimed that the world needs this one item “…more urgently than it needs any single medical discovery.” (1) If you haven’t guessed it already, I am referring to an AIDS vaccine. In fact, the phrase used by Mr. Lewis was made at the opening of the 2005 AIDS Vaccine International conference this past September.

As a scientist, particularly one with an interest in biological and health research, my first reaction to Mr. Lewis’ statement was basically: “Aren’t you preaching to the converted?” The more I think about Mr. Lewis’ statement, however, the more I wonder whether research scientists feel the same urgency for an AIDS vaccine as Mr. Lewis so emphatically conveys every time he stands in front of a lectern. (And, I note, he does this on a remarkably frequent basis.) Now, it may seem a trifle senseless to compare whether Stephen Lewis feels more intensity and passion on the subject of HIV/AIDS than research scientists in the field, but the point that I am trying to make is that, if the enormity of the problem is understood, it is time for scientists to become better advocates for the urgency of their research. If HIV/AIDS researchers took a quick glance at their counterparts in cancer research, they would quickly realize that they must do a better job to educate the public about the importance of their research, to recruit bright, young minds to join them in their research, and to lobby their governments for support both with respect to the finances and infrastructure needed to find a vaccine. I am by no means suggesting that HIV/AIDS research is more important than cancer research. Indeed, with current predictions that one in four Canadians will be diagnosed with cancer at some point in their lifetime, cancer research is vital for maintaining the health of our society. I am merely stating that, if we don’t react quickly enough, we will soon find that more than one in four sub-Saharan Africans already lives with HIV/AIDS. To emphasize this point, even after taking into account my risk of contracting cancer, my estimated life expectancy is 79 years, while Andrina’s life expectancy is a mere 38 years; less than one half of my projected lifespan! (2)

Admittedly, the hunt for an AIDS vaccine is not an easy one. I think it is important, however, that scientists become more vocal, both amongst themselves and with the general public, about the prospects and challenges of developing such a vaccine. Such a discussion is vital in deciding the most effective course of action. For instance, if an AIDS vaccine is on the horizon, nations should be urgently preparing the necessary infrastructure to perform large-scale vaccination programs. If, on the other hand, an AIDS vaccine is still a distant reality, other strategies for reducing HIV transmission (e.g. microbicides, prophylactic protection, and HIV/AIDS awareness programs) need to be implemented rapidly, particularly by the many African nations who are already in the process of losing entire generations of people to the disease.

As a first step in a discussion about the prospects of an AIDS vaccine, I would like to review some of the scientific challenges that lay ahead. Before I begin, however, I would like to add a disclaimer: I have no formal training or education in immunology, infectious diseases, or even medicine. Clearly, I am in no position to write an in-depth scientific review of the research conducted in the area of HIV/AIDS. However, in the spirit of a public discussion, I have made a concerted attempt to learn about the present state of AIDS vaccine research, and am now making a concerted attempt to convey what I have learned. For more in-depth, technical reviews on the field, I refer the interested reader to the following excellent articles. (3-5)

A Basic Primer on HIV and Vaccines

Vaccines have been proven to be an effective strategy for improving public health, as exemplified by the total eradication of smallpox due to global vaccination programs, as well as the containment of hepatitis B and polio transmission that has been enabled by their respective vaccines. Although none of these vaccines confers 100% immunity to the vaccinated individuals, they effectively reduce the chances of transmission and infection to low levels such that, at the population level, the number of infections rapidly declines. In order to understand some of the challenges that lie ahead in the development of an AIDS vaccine research, it is important to have a cursory knowledge of the human immunodeficiency virus (HIV) as well as the nature of vaccines.

Firstly, HIV is a classified as a retrovirus, meaning that the genome of HIV is composed of ribonucleic acid (RNA), instead of deoxyribonucleic acid (DNA) as in the case of the human genome. Chemically, RNA and DNA differ simply by one oxygen atom; however, this difference plays an important role in molecular biology. In particular, RNA is the intermediate molecule that all living cells create in order to convert their DNA-encoded genetic information (pejoratively called the “genetic blueprint”) into functional protein units. In addition to containing an RNA genome, retroviruses like HIV contain an enzyme called reverse transcriptase. Transcription is the process whereby cells use DNA template molecules to create RNA; thus, reverse transcriptase enables the inverse operation in which the viral RNA is converted into DNA. The important note to make here is that when HIV infects human cells, reverse transcription of its RNA genome allows the virus to produce DNA which can, in turn, integrate into the human host-cell genome. Once this genetic alteration of host cells has occurred, an HIV-positive patient has been left with a viral trace that is not eliminated merely by removing all of the circulating viruses present in the infected body.

Vaccines can be broadly classified under one of two categories: preventative vaccines and therapeutic vaccines. In common parlance, the term vaccine is usually associated with a preventative vaccine, which prevents vaccinated individuals from being infected by the targeted pathogenic (“disease-causing”) bacteria or virus. In contrast, a therapeutic vaccine does not prevent individuals from being infected by the pathogen; instead, it prevents or delays disease progression in infected individuals. The general strategy of both preventative and therapeutic vaccines is to expose individuals to innocuous mimics of relevant pathogens (e.g. attenuated viruses that have been genetically engineered such that they are unable to infect human cells). These vaccinations, in turn, stimulate some form of response from the immune system of vaccinated individuals. For example, a common immune response to a viral vaccine is the production of antibodies that specifically bind to the pathogenic virus, thus disabling its ability to infect and replicate inside the host organism. The immune system of vaccinated individuals has been shown to retain “memory” of the initial pathogen mimic, which subsequently allows it to mount a more powerful attack if and when it is actually exposed to the pathogen in the future. Frequently, vaccinations must be repeated throughout one’s lifespan in order to restore the memory of the immune system for the pathogen.

Toward an AIDS Vaccine

With this basic knowledge of HIV and vaccines, we can now begin to understand some of the challenges that face developers of an AIDS vaccine. These challenges can be classified into two major categories:

1) The human immune system appears to have no natural clearing mechanism for HIV. In the case of polio and smallpox infections, the immune system is able to produce specific antibodies that bind to the pathogen and prevent its ability to infect and replicate inside the host. Subsequently, vaccines that amplify this immune response have been effective in the complete and near eradication of smallpox and polio, respectively. Unlike the polio and smallpox viruses, however, HIV appears to have evolved the ability to resist antibody killing. This resistance to antibody killing is best exemplified by the recent failure of VaxGen’s AIDSVAX, the only vaccine candidate that has been tested in Phase III clinical trials to date, which proved ineffective at producing antibodies to the HIV gp120 protein to confer resistance to vaccinated individuals. (4) The inability of antibody-killing methods to neutralize HIV means that the virus is able to infect host cells and rapidly integrate into the host-cell genome (see Basic Primer on HIV above). This situation is particularly problematic for researchers seeking to develop an AIDS vaccine, who are forced to seek “correlates of immunity” different from typical neutralizing antibodies; that is, they are forced to develop vaccine candidates without the ability to amplify an immune response known to attack both HIV and HIV-infected cells. Thus far, vaccine candidates tested in laboratory animals have not conclusively identified any such correlates of immunity for HIV. As a result, the generally accepted strategy of current AIDS vaccine researchers is the development of vaccine candidates that promote the activity of cytotoxic T cells in the immune system that are characterized by a protein surface marker called CD8. CD8 T cells are known to control HIV infection by preventing viral entry into host cells, suppressing viral replication inside host cells, as well as by killing infected cells. (6) Importantly, the latter ability of CD8 T cells to kill HIV-infected cells provides a general strategy to rid an infected individual entirely of any remaining trace of the pathogenic virus.

2) Mutations of the human immunodeficiency virus have also been particularly problematic for AIDS vaccine developers. The reverse transcription process of the HIV RNA genome into DNA (see Basic Primer on HIV above) is known to be an error-prone process; as a result, there are various strains (clades) of HIV that are characterized by different genetic sequences. Since the immune system creates antibodies and T cells that target pathogens very specifically based on their genetic sequence, the tendency for HIV to create errors during reverse transcription provides the virus with an evolutionary mechanism to evade the host immune system. To further complicate the issue, humans are thought to be susceptible to multiple infections with different strains of HIV (“superinfection”), and these different viral strains may subsequently recombine to form completely new strains of HIV. The sequence variability of different strains of HIV directly implies that an AIDS vaccine would have to protect against many different viral strains in order to effectively protect humans from contracting the disease.

Reasons for Hope

Despite the seemingly enormous scientific obstacles that must be overcome, recent advancements and discoveries in AIDS vaccine research provide hope that ultimate success is, in fact, achievable. A new generation of DNA vaccines, which inject HIV-specific DNA sequences followed by immune-reactive, antibody-inducing agents, has demonstrated some success in promoting a cytotoxic T cell response toward HIV-infected cells (6). These vaccines are presently undergoing clinical trials. Individuals who are highly exposed, yet remain uninfected by HIV, such as some commercial sex workers in Africa, may also help uncover correlates for HIV immunity (7). Similarly, researchers are also working to identify a protective immune response exhibited by primates toward simian immunodeficiency virus (SIV), a virus closely related to HIV (4).

Clearly, the need to fund AIDS vaccine research has never been greater. Studies performed by the International AIDS Vaccine Initiative (IAVI) estimate that, once developed, hundreds of millions of courses of vaccination will be required throughout the world (8). Significant increases in funding will be needed in order to achieve such production levels, particularly since vaccine research is already hundreds of millions of dollars short of the estimated $1.2 billion needed annually (1). Until an AIDS Vaccine is found, the international community will need to increase access of antiretroviral (ARV) drugs to the tens of millions of individuals who, unlike Andrina, are not able to afford these much-needed drugs. In fact, the Global Fund, which provides Andrina with the money needed to buy her ARVs, is also under-funded by $300 million for 2006-7 (9). Importantly, it must be remembered that even when all HIV-infected patients finally have access to ARVs, the fight is not over. ARVs are not a cure for AIDS. An AIDS vaccine is the only answer.

In the end, this gargantuan achievement will not be possible without effective advocacy about the urgency and necessity of AIDS vaccine researchers both by politicians and by scientists. As James Orbinski, former President for the Nobel Peace Prize-winning Médecins sans Frontières (Doctors Without Borders), so aptly stated, “You can change the world with your voice”. (10) On that note, it’s time to bring on the noise!

References

1. Lewis, Stephen. Opening Ceremony, 2005 AIDS Vaccine International Conference. September 6, 2005.
[http://www.stephenlewisfoundation.org/news/2005-06-09-aids_vaccine_conference.html]

2. Malawi: Facts at a Glance. Canadian International Development Agency. July 26, 2005.
[http://www.acdi-cida.gc.ca/CIDAWEB/webcountry.nsf/VLUDocEn/Malawi-Factsataglance]

3. Klausner, R.D., et al. The need for a global HIV vaccine enterprise. (2003) Science, 300: 2036-9.

4. Desrosiers, R.C. Prospects for an AIDS Vaccine. (2004) Nature Medicine, 10: 221-3.

5. Lythgo, P.A. Molecular Virology of HIV-1 and Current Antiviral Strategies. (2004) Bioteach, 2: 81-7.
[http://www.bioteach.ubc.ca/Journal/V02I01/HIV.pdf]

6. Amara, R.R., Robinson, H.L. A new generation of HIV vaccines. (2002) Trends in Molecular Medicine, 8:489-95.

7. Levy, JA. What can be achieved with an HIV Vaccine? (2001) Lancet, 357: 223–24.

8. Demand for a Preventive HIV Vaccine. (April 2005). International AIDS Vaccine Initiative.
[http://www.iavi.org/viewfile.cfm?fid=10825]

9. Funding Gap. (2005) The Global Fund to fight AIDS, Tuberculosis and Malaria.
[http://www.theglobalfund.org/en/funds_raised/funding_gap/]

10. Orbinski, J. Engineers Without Borders National Conference 2003. January 2003.
[http://conference2003.ewb.ca/audio/orbinski.mp3]

(artwork by Arthur Kwan)

About anupamsinghal

Anupam Singhal is a graduate student at the University of British Columbia who lives, eats, and breathes science. Sometimes he dreams that someone will prove that science is a pointless endeavour, giving Anupam a lot more free time.