Joining forces to fight TB and HIV
Two biotechnology companies, Pharmexa-Epimmune and Bavarian Nordic, recently initiated a Phase I AIDS vaccine trial with funding from the US National Institutes of Health (NIH). This trial started at the end of April and is being conducted by the HIV Vaccine Trials Network (HVTN) at sites in three US cities-Nashville, Rochester, and San Francisco.
Investigators plan to enroll 108 volunteers to evaluate the safety and immunogenicity of two vaccine candidates administered consecutively in a prime-boost combination. The first candidate, EP1233, is a DNA vaccine candidate developed at Pharmexa-Epimmune with funding from the US National Institutes of Allergy and Infectious Diseases (NIAID). The second candidate was developed at Bavarian Nordic and uses a modified vaccinia Ankara viral vector to deliver HIV proteins matching those in the DNA candidate.
At the end of April the South African government released a new national AIDS plan, outlining the country's strategy to combat the epidemic. At the end of 2006, there were 5.5 million South Africans living with HIV/AIDS, according to estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS), and the number of HIV-infected individuals continues to rise. In response to these grim statistics, the 160-page plan includes a proposal for halving the number of new HIV infections by 2011 through improved prevention programs. It also proposes improving the diagnosis of HIV/AIDS, providing life-saving antiretroviral treatment to 80% of the estimated one million South Africans that are in need, and reducing the rate of mother-to-child transmission of HIV to below 5% over the next five years—all at an estimated cost of US$6 billion.
The "HIV and AIDS and STI Strategic Plan for South Africa, 2007-2011" was prepared following extensive consultation with government officials, UNAIDS, research institutions operating in the country, and several civil society representatives. The release of this comprehensive plan was lauded by many organizations, including the Treatment Action Campaign and the AIDS Law Project, which have been critical of the government's sluggish response to the AIDS epidemic, and was also endorsed by the recently restructured South African National AIDS Council.
The 10th annual World AIDS Vaccine Day was commemorated on May 18, with many organizations conducting AIDS vaccine education campaigns or events to stimulate awareness and support for the development of a preventive AIDS vaccine. The commemoration of World AIDS Vaccine Day originated in 1997 when then US President Bill Clinton delivered a speech at Morgan State University calling on the world's researchers to develop an AIDS vaccine within the next decade.
Although this goal was not met there has been substantial progress in the field. In the past decade the funding for AIDS vaccine research and development has quadrupled and scientists have made significant advancements in the understanding of HIV and its interaction with the immune system (see March 2007 Primer on Understanding Why an Effective AIDS Vaccine is Feasible). Researchers have also advanced promising AIDS vaccine candidates into preliminary efficacy trials, and there are now more than 30 ongoing preventive AIDS vaccine Phase I and II clinical trials.
In an editorial in the San Francisco Chronicle, Peggy Johnston, director of the Vaccine Research Program at NIAID, and Tony Fauci, director of NIAID, said, "We now know more about HIV, the virus that causes AIDS, and have more promising vaccines in development than at any other time in the history of the HIV/AIDS pandemic." Still there are many remaining scientific obstacles that must be overcome before Clinton's challenge will be realized (see April 2007Primer on Understanding the Challenges of AIDS Vaccine Development).
The urgent need for a vaccine that could help reverse the relentless spread of the AIDS pandemic remains unchanged since Clinton's speech. Currently 40 million people are living with HIV/AIDS around the world and each day an additional 12,000 new HIV infections occur. A preventive AIDS vaccine, even one that is partially-effective (seePrimer, this issue), would help to dramatically lower the number of new infections.
All articles written by Kristen Jill Kresge
What is a partially effective vaccine and how can it limit the spread of HIV?
The ultimate goal of AIDS vaccine research is to develop a vaccine that will completely protect an individual from HIV infection and the subsequent development of AIDS. Typically, vaccines that protect against other viruses work by inducing strong virus-specific antibody responses that control the virus and prevent development of disease (see February 2007 Primer on Understanding Neutralizing Antibodies). However the majority of AIDS vaccine candidates that are currently undergoing testing in clinical trials do not induce broadly neutralizing antibodies against HIV (see February 2007 Primer on Understanding Neutralizing Antibodies). Instead these candidates all primarily induce cellular-mediated immune responses, including CD8+ T cells or cytotoxic T-lymphocytes, which do not attack the virus directly but rather target and kill HIV-infected cells. Without stimulating a robust antibody response, many researchers think it is likely that these candidates will not offer complete protection against HIV infection.
The more realistic goal currently is the development of a vaccine candidate that can induce strong cellular immune responses capable of lowering the levels of virus circulating in the body (known as the viral load) in individuals who do become infected despite vaccination, enabling them to control their HIV infection for prolonged periods of time. This non-classical approach is often referred to as the development of a partially-effective or partially-protective vaccine.
In the past the idea of a partially-effective vaccine has had different meanings—referring to a vaccine that only protects some people who receive it, or a vaccine that only protects against disease some of the time. But in the AIDS vaccine field nowadays a partially-effective vaccine means one that doesn't protect against HIV infection or entirely against the development of disease, but can delay the progression to AIDS in individuals who receive the vaccine and later become HIV infected anyway.
A first-generation vaccine that accomplishes this goal could have many significant benefits. First it could delay the time until a person must begin antiretroviral (ARV) treatment. It could also help prevent vaccinated individuals who do become HIV infected from transmitting the virus to others. This would be a significant achievement and could shrink the global epidemic by helping to roll back the approximately 12,000 new HIV infections that still occur worldwide every day.
The health of the immune system is characterized by the total number of CD4+ T cells measured in a sample of blood. These immune cells are responsible for orchestrating the body's defenses against invading pathogens and if too many are lost an individual is susceptible to many serious and potentially fatal infections. Normally an individual will have between 600-1200 CD4+ T cells in a milliliter of blood. An HIV-infected individual is diagnosed with AIDS when this number falls below 200. On average it takes up to a decade after a person is initially infected with HIV for the virus to deplete the immune system to the point that the onset of AIDS occurs and ARV therapy becomes necessary.
If a partially-effective vaccine is able to suppress the virus during the early stages of HIV infection, it may help preserve some of these critical CD4+ T cells that are the primary target of HIV. Results from some studies indicate that giving ARVs to an individual very early in the course of their HIV infection correlates with better control of the virus over the long term because it helps spare the immune system from some of the damage inflicted early on by the virus. A similar outcome is predicted with a partially-effective vaccine that could defend the massive number of immune cells in the mucosal tissues that are destroyed by HIV during the initial stages of infection (see VAX April 2006 Primer onUnderstanding the Early Stages of HIV Infection).
Such a vaccine could help bolster the immune system and allow an individual to control HIV for much longer than a decade, postponing the need for ARVs. Although these drugs are incredibly effective at controlling HIV infection and allow HIV-infected individuals to live longer and healthier lives, they can also cause many unpleasant side-effects and are expensive. Delaying ARV therapy could therefore dramatically improve the quality of life of HIV-infected individuals.
It is impossible to follow individuals for more than a decade during clinical trials to see if a vaccine candidate is effective at delaying, or even preventing, the onset of AIDS. So instead researchers rely on indicators that occur much earlier in infection to predict a person's disease outcome. One of these indicators is called viral set-point and it refers to the point during the first weeks of infection when the body's HIV-specific immune responses kick in and, as a result, the HIV viral load drops dramatically. After this drop, the viral load stabilizes at a level called the set-point. Generally, the lower the viral set-point, the longer a person can control HIV. A partially-effective vaccine could help lower the viral set-point even further than in natural infection, extending the time until AIDS develops.
There is good evidence suggesting that the likelihood of HIV transmission, both sexually and from mother-to-child, is directly correlated with the viral load of the infected person—the higher a person's viral load, the more likely they are to pass on the virus to others. Therefore a partially-effective vaccine that blunts HIV viral load could reduce the possibility that an individual could infect others.
Although a preventive AIDS vaccine that is able to protect against infection with HIV is the only way to end the AIDS pandemic, developing a first generation, partially-effective AIDS vaccine would be a very important step in rolling back the ever-expanding pandemic.