Leading AIDS vaccine researchers gather to discuss priorities in AIDS vaccine funding
Just a few days after many of the leading researchers in the AIDS vaccine field gathered for the HIV Vaccine Summit (see Spotlight, this issue), they reconvened in vastly different environs for the annual joint Keystone Symposia on HIV Vaccines and HIV Pathogenesis. This year’s meeting took place from March 26 to April 1 in Banff, Canada, and like the field itself, was more focused on fundamental immunology and discovery research.
Many speakers remarked in some way on the results of the STEP trial and its repercussions. Larry Corey of the University of Washington said during his opening keynote presentation that the STEP trial has “recalibrated” the HIV vaccine field, but he dismissed the notion that nothing positive has come out of it and made it clear that in his estimation, the results from the STEP trial do not mark the end for vaccine candidates that stimulate T-cell responses and not neutralizing antibodies (see Primer, this issue). “The ability to make such vaccines may be more approachable than getting effective neutralizing antibody vaccines,” Corey said.
Researchers presented some updated data from the ongoing analyses of the trial. Susan Buchbinder of the San Francisco Department of Public Health, and a principle investigator on the STEP trial, said there was a two- to three-and-a-half-fold increase in risk of HIV infection in the vaccine group as the level of antibodies against adenovirus serotype-5 (Ad5), which was the modified cold virus used as the vaccine vector, increased. Corey and Buchbinder addressed possible explanations for this observation. The majority of volunteers in the trial were men who have sex with men and so one possible mechanism is that more Ad5-specific CD4+ T cells were present in the rectal mucosal tissues, creating more targets for HIV, according to Corey. He also said an indirect biological mechanism could be at play and that perhaps the vaccine candidate interfered with the body’s innate or natural immune responses against HIV. Buchbinder said analyses of other potential confounding factors—including sexual networks, clusters of infections, and changes in sexual behavior—which may also help explain this observation are still ongoing (see VAXFebruary 2008 Primer on Understanding Biostatistics and the STEP Trial).
Efforts to more fully understand mucosal immunology (see VAX January 2008 Primer on Understanding HIV Transmission), the types of T-cell responses a vaccine should induce (see Primer, this issue), and the mysteries of individuals who are HIV infected but are able to control the virus (long-term nonprogressors), all figured prominently at this meeting and remain clear priorities for the field. “There isn’t one way forward or one simple way forward,” said Alan Bernstein, executive director of the Global HIV Vaccine Enterprise. “If anyone says there is they’ve got a crystal ball that I don’t have.” —By Kristen Jill Kresge
Dan Barouch and colleagues at the Beth Israel Deaconess Medical Center in Boston began enrolling volunteers in April for a Phase I clinical trial to evaluate the safety of an adenovirus serotype-26 (Ad26) vector-based vaccine candidate compared to an inactive placebo. The trial is being conducted at the Brigham and Women’s Hospital, also in Boston, and will involve 48 volunteers randomly assigned to receive either two or three doses of the vaccine candidate. The Ad26 vector is used to carry an HIV fragment in the hope that it will trigger immune responses against HIV. The vaccine candidate itself can not cause HIV infection.
There are several serotypes of adenovirus, which is one cause of the common cold, and AIDS vaccine candidates based on adenovirus serotype-5 (Ad5) have already been tested in clinical trials. Merck’s vaccine candidate, which was tested in the Phase IIb test-of-concept trial known as STEP, used an Ad5 vector, but this is the first time an Ad26-based vaccine candidate is being analyzed in human volunteers. Ad26 was chosen because fewer people are naturally exposed to this serotype of adenovirus and therefore levels of pre-existing immunity to Ad26 are much lower throughout the world. Pre-existing antibody immunity to the vaccine vector could potentially limit an individual’s immune responses against HIV.
In preclinical studies in nonhuman primates, Barouch and colleagues also found that the Ad26 vaccine candidate was more effective than an Ad5 candidate at protecting against infection with the monkey equivalent of HIV, known as simian immunodeficiency virus (SIV). This Ad26 vector “outperforms Ad5 vectors in rhesus macaques,” said Barouch. The vaccine candidate is manufactured by the Dutch biotechnology company, Crucell. —By Kristen Jill Kresge
What is known about cellular immune responses against HIV?
The human immune system uses both innate and adaptive immune responses to combat pathogens such as viruses and bacteria (see VAX March 2004 Primer on Understanding the Immune System, Part II). Innate immune responses are always on standby and can act quickly, usually within hours, to either snuff out or help limit an initial infection. If more help is needed, adaptive immune responses—which include both antibodies and cellular immune responses—kick in. These take longer to activate because they are designed to target a specific pathogen. The immune system generates HIV-specific antibodies and cellular immune responses against the virus, both of which are critical in either preventing or controlling the infection, and are therefore of great interest to AIDS vaccine researchers.
Antibody responses are Y-shaped molecules that primarily latch on to viruses and prevent them from infecting cells (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Once cells are already infected, cellular immune responses come into play. These responses involve a subset of immune cells known as CD4+ T helper cells that orchestrate the activities of activated CD8+ T cells, known as cytotoxic T lymphocytes (CTLs), which can kill cells already infected by the virus.
The role of cellular immune responses in HIV infection is complicated because the very cells that play a role in limiting infection are under attack—the virus preferentially targets and infects CD4+ T cells, severely hampering the immune system’s ability to fight back. However, both CD4+ and CD8+ T cells still play a critical role in the control of HIV infection and are also likely to be important to the development of an AIDS vaccine. Researchers are now studying the ideal types of antibodies and cellular immune responses that a vaccine should induce to best prevent or control HIV infection.
Inducing T-cell responses
Developing AIDS vaccine candidates that are capable of inducing neutralizing antibody responses against HIV is challenging and so far the strategies tested have been unsuccessful. However, several AIDS vaccine candidates have been identified that can induce cellular immune responses, both CD4+ and CD8+ T cells, against HIV. Many of these have been evaluated in clinical trials, including Merck’s MRKAd5 vaccine candidate that was recently tested in the STEP trial (see VAX September 2007 Special Report).
Typically, researchers measure the size of the cellular immune responses that are induced by different candidates, as well as the ability of these cells to secrete cytokines, which are proteins produced by immune cells in response to viruses or bacteria (see VAX August 2007 Primer on Understanding Immunogenicity). Merck’s MRKAd5 candidate induced T cells secreting a cytokine known as interferon-γ (IFN-γ) in more individuals than any candidate tested in Phase I clinical trials, prior to it being advanced to a Phase IIb test-of-concept trial. In Phase I trials, 80% of MRKAd5 recipients, who did not have high levels of pre-existing immunity to the cold virus used as a vector, developed T cells that secreted IFN-γ.
The majority of vaccine recipients in the STEP trial also developed both CD4+ and CD8+ T-cell responses against HIV after receiving MRKAd5. But these immune responses were not sufficient to protect against infection. Researchers have not observed any correlation so far between the size of HIV-specific immune responses in vaccine recipients and whether or not they subsequently became infected with HIV through risk behaviors, such as unprotected sex with an HIV-infected partner or injection-drug use.
Researchers have also found that the quantity of T-cell responses does not seem to correlate with control of the virus in some HIV-infected individuals, known as elite controllers, either. Elite controllers are a group of long-term nonprogressors who are HIV infected yet have very low levels of virus (viral loads) and do not progress to AIDS, even without the aid of antiretroviral therapy (see VAX September 2006 Primer on Understanding Long-term Nonprogressors). The magnitude of HIV-specific cellular immune responses are actually lower in elite controllers than those seen in individuals with typical viral loads who have normal disease progression.
Quantity vs. quality
Together these findings indicate that the size of the T-cell response may not be the key factor in either preventing or controlling HIV infection. Instead, the capability of the T cells to perform a particular function may be more important. Some immunologists suggest that it is not the size of the initial T-cell response to vaccination that matters, but the ability of these T cells to multiply later on, when the individual encounters the pathogen they were vaccinated against, that is most critical.
Other researchers are studying the direct ability of the T cells induced by an AIDS vaccine candidate to kill virus-infected cells. Researchers can extract T cells from volunteers in an AIDS vaccine clinical trial through blood samples and test them in a laboratory against HIV to see if they are actually capable of killing virus-infected cells. This method is now being used by some researchers to prioritize vaccine candidates in Phase I clinical trials.
Another approach is to study different viral and bacterial vectors that may be used for AIDS vaccine candidates to see if they induce different types of T-cell responses. Researchers have conducted preclinical experiments in mice to compare the T cells induced by different viral vectors. The results indicate that the choice of vector does affect the type of T cells that are induced upon vaccination.
Researchers are also currently studying the characteristics of effective T-cell responses in other viral infections, in which cellular immune responses are at least partly responsible for protection, to determine what types of T cells an AIDS vaccine candidate should ideally induce. More research on T-cell responses to HIV, as well as other pathogens, will shed light on these questions and help researchers design more effective AIDS vaccine candidates.