Understanding Partially Effective AIDS Vaccines

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.

Delaying therapy

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.

Determining efficacy

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.

Reducing infectiousness

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.