It was 10 years ago that the Kenya AIDS Vaccine Initiative (KAVI) became involved in the search for an AIDS vaccine. But the seeds of this organization, which is headquartered at the University of Nairobi and was created by local researchers with funding from IAVI and the Medical Research Council’s Human Immunology Unit at Oxford University, were planted much earlier. In the early 1980s, a number of Kenyan scientists—in partnership with researchers from the University of Manitoba—started to notice that a small percentage of commercial sex workers remained HIV uninfected over time despite repeat exposure to HIV (see VAX September 2008 Spotlight article, Individual armor against HIV).

Three leading Kenyan scientists involved in this research helped establish KAVI in 1999—Professor Omu Anzala, KAVI’s Program Director; Professor Walter Jaoko, Deputy Program Director of KAVI; and the late Professor Job Bwayo, a co-founder of KAVI, who was tragically killed in 2007. “Until KAVI, vaccine research had never really been carried out in this country,” says Anzala. “KAVI really raised a lot of community awareness to make people understand that vaccines just don’t fall from heaven.”

When KAVI was first established, some people were skeptical that an institution of this kind in Kenya would be able to meet the “level and standards” needed to conduct clinical trials, according to Anzala. But he says KAVI has not only met those standards, but raised the bar, both scientifically and ethically.

KAVI has been a productive partner in vaccine research and development, conducting four Phase I trials and a Phase IIa trial of a clade A HIV-DNA/modified vaccinia Ankara prime-boost candidate at Kenyatta National Hospital (KNH) in Nairobi. KAVI is also participating in an IAVI-sponsored project known as Protocol G, which seeks to find broadly neutralizing antibodies—Y-shaped molecules that can latch onto and neutralize HIV—from HIV-infected individuals.

To mark its 10-year anniversary, KAVI is hosting a scientific forum, “Emerging Vaccines: A Public Health Priority” on March 26. The forum will highlight efforts to develop vaccines against HIV/AIDS, tuberculosis, malaria, and human papilloma virus. Key guests include IAVI President Seth Berkley; Andrew McMichael, director of Oxford’s Weatherall Institute of Molecular Medicine; and Adrian Hill, an investigator at Oxford’s Jenner Institute. KAVI will also recognize the work of its community stakeholders on World AIDS Vaccine Day, which is observed annually on May 18.

While a primary goal is testing AIDS vaccine candidates, Anzala says KAVI also has the capacity to test preventive vaccines for malaria and tuberculosis, and he hopes KAVI can broaden its scope to include more basic research. Anzala says talks are underway to establish a mentorship program for young investigators to come work at KAVI. “The virus is here, the patients are here,” says Anzala. “We must be able to also begin to engage in basic research.” —By Regina McEnery

What strategies are being explored to design better inserts for inclusion in AIDS vaccine candidates?

Many vaccines contain an intentionally weakened or attenuated form of the pathogen the vaccine is designed to protect against. The vaccine against influenza (flu) is one example. It contains a live influenza virus but the vaccine is not able to cause any harm because researchers purposely disable parts of the virus. Even though it doesn’t make people sick, the attenuated flu virus does trigger the immune system to make immune responses against it. Some of these immune responses are stored away in the body as memory cells. If the immune system detects that same flu virus in the future, these memory cells “remember” the virus and can act quickly to destroy it before an infection is established and illness occurs.

Some vaccines use an inactivated or killed version of the pathogen they are designed to protect against to train the immune system. The vaccine against hepatitis A virus, for example, contains a whole, but killed virus. Unfortunately, the nature of HIV—including its ability to rapidly change or mutate—makes using a live-attenuated or killed version of HIV in a vaccine both impractical and potentially dangerous. Researchers are concerned that a live-attenuated version of HIV could conceivably mutate and regain its ability to cause disease. Using a killed version of HIV in a vaccine candidate is also impractical because it is difficult to prove that the virus is completely inactivated. This has led scientists to look for better and safer strategies for developing an AIDS vaccine.

One method under investigation is using only fragments of HIV’s genetic material rather than the whole virus to try to trigger cellular (T-cell) and antibody (B-cell) responses against HIV (see VAX July 2008 Special Issue, Understanding the Immune System and AIDS Vaccine Strategies). By using only a small part of the virus’s genetic material, scientists can be sure that the vaccine candidate cannot cause HIV infection. The fragments of HIV that are included in vaccine candidates are referred to as antigens. These antigens can be delivered into the body many different ways, including via a viral vector—a virus other than HIV that is intentionally attenuated so it can’t cause disease (see VAX September 2004 Primer on Understanding Viral Vectors). The aim is to get the immune system to recognize the HIV antigen—just as it does other foreign substances—and generate an immune response against it. Antigens that can induce immune responses are referred to as immunogens.

One of the biggest questions is which HIV antigens will induce potent immune responses, including long-lived T and B memory cells that will be critical for vaccine-induced protection against HIV in the future. Scientists are employing a number of different strategies to try to design such immunogens.

Clues from HIV-infected individuals

One strategy involves analyzing long-term nonprogressors (LTNPs)—HIV-infected individuals who can control the virus without the aid of antiretroviral therapy. Researchers have found that cellular immune responses are usually involved in control of HIV in these individuals. These cellular immune responses target specific regions of HIV known as epitopes. By studying which HIV epitopes the T cells of LTNPs are directed against, researchers hope to be able to identify the HIV fragments that might make the best antigens for inclusion in a vaccine candidate that would induce primarily T-cell responses.

Building a mosaic antigen

Researchers are also attempting to design HIV antigens that could address the overwhelming diversity of HIV. Because HIV mutates so rapidly, there is tremendous variation among the different viruses circulating in a population, and even in a single individual. Scientists at the Los Alamos National Laboratory in the US oversee a massive database that catalogues the genetic characteristics or sequences of many of the currently circulating versions of HIV. From this database, they can identify the regions of HIV that are consistent or conserved across many different viruses. Researchers can then combine these conserved regions into a single antigen, which is referred to as a mosaic. Vaccine candidates with mosaic HIV antigens have so far only been tested in animal studies.

Antigens to induce antibodies

Another strategy is also being used to design HIV antigens that can induce neutralizing antibodies against the virus (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Antibodies that can effectively neutralize many different forms of HIV are referred to as broadly neutralizing antibodies. Only a handful of broadly neutralizing antibodies have been identified to date.

Researchers are now using X-rays to carefully study precisely at which location on HIV some of these broadly neutralizing antibodies bind. A fragment of HIV from this binding site could be used as an antigen, which, if included in a vaccine candidate, would hopefully induce this broadly neutralizing antibody.

Not knowing which HIV antigens will induce the necessary immune responses is a major barrier to the development of an effective AIDS vaccine. While researchers are actively investigating ways to design better antigens to put into a vaccine candidate, they are also exploring different viral vectors and other techniques to deliver HIV immunogens into the body.

What strategies are being explored to design better inserts for inclusion in AIDS vaccine candidates?

Many vaccines contain an intentionally weakened or attenuated form of the pathogen the vaccine is designed to protect against. The vaccine against influenza (flu) is one example. It contains a live influenza virus but the vaccine is not able to cause any harm because researchers purposely disable parts of the virus. Even though it doesn’t make people sick, the attenuated flu virus does trigger the immune system to make immune responses against it. Some of these immune responses are stored away in the body as memory cells. If the immune system detects that same flu virus in the future, these memory cells “remember” the virus and can act quickly to destroy it before an infection is established and illness occurs.

Some vaccines use an inactivated or killed version of the pathogen they are designed to protect against to train the immune system. The vaccine against hepatitis A virus, for example, contains a whole, but killed virus. Unfortunately, the nature of HIV—including its ability to rapidly change or mutate—makes using a live-attenuated or killed version of HIV in a vaccine both impractical and potentially dangerous. Researchers are concerned that a live-attenuated version of HIV could conceivably mutate and regain its ability to cause disease. Using a killed version of HIV in a vaccine candidate is also impractical because it is difficult to prove that the virus is completely inactivated. This has led scientists to look for better and safer strategies for developing an AIDS vaccine.

One method under investigation is using only fragments of HIV’s genetic material rather than the whole virus to try to trigger cellular (T-cell) and antibody (B-cell) responses against HIV (see VAX July 2008 Special Issue, Understanding the Immune System and AIDS Vaccine Strategies). By using only a small part of the virus’s genetic material, scientists can be sure that the vaccine candidate cannot cause HIV infection. The fragments of HIV that are included in vaccine candidates are referred to as antigens. These antigens can be delivered into the body many different ways, including via a viral vector—a virus other than HIV that is intentionally attenuated so it can’t cause disease (see VAX September 2004 Primer on Understanding Viral Vectors). The aim is to get the immune system to recognize the HIV antigen—just as it does other foreign substances—and generate an immune response against it. Antigens that can induce immune responses are referred to as immunogens.

One of the biggest questions is which HIV antigens will induce potent immune responses, including long-lived T and B memory cells that will be critical for vaccine-induced protection against HIV in the future. Scientists are employing a number of different strategies to try to design such immunogens.

Clues from HIV-infected individuals

One strategy involves analyzing long-term nonprogressors (LTNPs)—HIV-infected individuals who can control the virus without the aid of antiretroviral therapy. Researchers have found that cellular immune responses are usually involved in control of HIV in these individuals. These cellular immune responses target specific regions of HIV known as epitopes. By studying which HIV epitopes the T cells of LTNPs are directed against, researchers hope to be able to identify the HIV fragments that might make the best antigens for inclusion in a vaccine candidate that would induce primarily T-cell responses.

Building a mosaic antigen

Researchers are also attempting to design HIV antigens that could address the overwhelming diversity of HIV. Because HIV mutates so rapidly, there is tremendous variation among the different viruses circulating in a population, and even in a single individual. Scientists at the Los Alamos National Laboratory in the US oversee a massive database that catalogues the genetic characteristics or sequences of many of the currently circulating versions of HIV. From this database, they can identify the regions of HIV that are consistent or conserved across many different viruses. Researchers can then combine these conserved regions into a single antigen, which is referred to as a mosaic. Vaccine candidates with mosaic HIV antigens have so far only been tested in animal studies.

Antigens to induce antibodies

Another strategy is also being used to design HIV antigens that can induce neutralizing antibodies against the virus (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Antibodies that can effectively neutralize many different forms of HIV are referred to as broadly neutralizing antibodies. Only a handful of broadly neutralizing antibodies have been identified to date.

Researchers are now using X-rays to carefully study precisely at which location on HIV some of these broadly neutralizing antibodies bind. A fragment of HIV from this binding site could be used as an antigen, which, if included in a vaccine candidate, would hopefully induce this broadly neutralizing antibody.

Not knowing which HIV antigens will induce the necessary immune responses is a major barrier to the development of an effective AIDS vaccine. While researchers are actively investigating ways to design better antigens to put into a vaccine candidate, they are also exploring different viral vectors and other techniques to deliver HIV immunogens into the body.