STD Quarterly-Don't look for the perfect HIV vaccine
The clinical goal of an HIV vaccine differs from other such projects because of the urgent need to make an impact on the global pandemic. Unlike traditional vaccines that prevent infection, an approach that would prevent AIDS or even delay the progression of the disease would be a tremendous achievement in the case of HIV, said Margaret Liu, MD, vice president for vaccines research and gene therapy at Chiron Corp., an Emeryville, CA-based biotechnology company.
Liu, who addressed attendants at the 13th International AIDS Conference in Durban, South Africa, cautioned scientists against setting their sights on the "perfect" vaccine. "For a pathogen such as HIV that is capable of entering the genome of cells, the challenge to make a vaccine that would prevent any infection at all is indeed great and may be too big a first step," she said.
At the start of the epidemic, no one even knew enough about the virus or its immunology to know what questions to ask, Liu said. Advances in the fields of virology, immunology, and cell biology during the past two decades have added impetus and knowledge to the vaccine effort, she said. "Although we don't fully understand correlates of immunity or how and where to generate immune responses, we have gained many insights from animal studies and human populations," she explained. "These inform and guide our vaccine development efforts."
While scientists have accumulated more knowledge in such areas as the genotype of different strains, there is still much to learn, Liu observed. Because of that, she cautioned that researchers should not be dogmatic and should always be guided by the proof provided by scientific data.
"We must be careful to not make any assumptions, for example, about which strains to use for vaccines that would hinder the development of an effective candidate," she noted.
Advances made so far are encouraging, Liu said. They include the elucidation of immune responses in highly exposed uninfected individuals, such as commercial sex workers, and in patients whose disease did not progress as rapidly as expected, the so-called "long-term nonprogressors."
"These individuals provide evidence for the power of the immune response to contain and restrain the viral infection," Liu observed. "Likewise, their immune responses provide clues as to what a vaccine should elicit."
Progress also has been made in illuminating the structure of HIV, as well as in understanding what processes and structures need to be altered to prevent infection or its spread, Liu said. "Given the types of immune responses that are thought necessary for an HIV vaccine, the novel and dramatic advances in vaccine technologies promise to provide the means for making an HIV vaccine."
Candidates in the wings
Several vaccine candidates are in the early stages of development, reported Liu. These include live virus vaccines, viral vectors, and gene-based vaccines such as plasmid DNA vaccines. Others in evaluation are vaccines combining more than one type of entity (known as "mixed-modality" vaccines), protein-based vaccines utilizing other forms of envelope or other viral proteins, and recombinant envelope glycoproteins, now in phase III efficacy trials.
There have been increased efforts in vaccine research to induce cellular responses instead of or in addition to antibody response, Liu said. Because T lymphocytes appear to recognize pieces of the virus displayed on the surface of infected cells, the T-cell responses can be directed against conserved regions of the virus, she explained.
As one way to make a vaccine with broad efficacy against different strains of the virus, Liu said, scientists might be able to take advantage of the conservation of certain proteins or regions of proteins between different strains, even if the protein is on the viral surface.
The ability of cytolytic T lymphocytes (CTL) to kill HIV-infected cells is not the only mechanism for cellular immunity, she observed. "The multiple mechanisms of cellular immunity provide another reason for efforts to induce cellular responses. In addition to killing virus-infected cells, CTLs release molecules that may play a crucial role for a preventive or therapeutic AIDS vaccine."
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