Perfect vaccine for HIV not likely, researcher warns
Advances in science have helped effort
(Editor’s note: This special issue of AIDS Alert contains exclusive coverage of the XIII International AIDS Conference, held July 9-13 in Durban, South Africa. More than 15,000 physicians, scientists, clinicians, and other health care providers from around the world attended the biennial conference that is intended to provide a forum for education and sharing knowledge regarding the AIDS crisis.)
Unlike traditional vaccines that prevent infection, in the case of HIV, a vaccine that would prevent AIDS or even delay the progression of the disease would be a tremendous achievement, said Margaret Liu, MD, vice president for Vaccines Research and Gene Therapy at Chiron Corp. in Emeryville, CA.
Liu said the clinical goal for an HIV vaccine differs from other vaccine projects because of the urgent need to make an impact on the global pandemic, but she 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 during her address at the XIII International AIDS Conference, held in Durban, South Africa.
The search for a suitable HIV vaccine faces enormous challenges. "At the start of this epidemic, no one even knew enough about the virus or 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, Liu said.
"Although we don’t fully understand correlates of immunity or how and where to gener-ate immune responses, we have gained many insights from animal studies and human populations. These inform and guide our vaccine development efforts," she said. "Secondly, while we have accumulated a great deal more knowledge, for example, regarding the genotype of different strains, we still have much to learn."
Liu cautioned that researchers should not be dogmatic and always should 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."
Progress looks promising for vaccines
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. Likewise, their immune responses provide clues as to what a vaccine should elicit," she said.
Great progress also has been made illuminating the structure of HIV and in understanding what processes and structures need to be interfered with in order to prevent infection or its spread, Liu said. "And of course, 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."
A range of vaccine candidates are in the early stages of development. Some of those are live virus vaccines, viral vectors, and gene-based vaccines such as plasmid DNA vaccines. Still others being evaluated are vaccines combining more than one type of entity (the mixed-modality vaccines) and protein-based vaccines using other forms of envelope or other viral proteins, along with more advanced candidates such as the recombinant envelope glycoproteins, which are currently in phase III efficacy trials.
Renewed efforts to induce cellular responses
Turning to the issue of the progress made by studying humans who had generated effective human responses against HIV, Liu said that those individuals had provided evidence of "natural immunity" that could have considerable efficacy and appeared to have been generated by exposure to and/or infection by either HIV-1 or HIV-2.
Recently, there have been increased efforts in vaccine research to induce cellular responses instead of or in addition to antibody response, Liu said. Those approaches were based on the rationale that because T lymphocytes recognize pieces of the virus displayed on the surface of infected cells, the T-cell responses could be directed against conserved regions of the virus. In addition, cellular responses appeared to play a role in controlling HIV.
One way to make a vaccine that has broad efficacy against different strains of the virus might be to take advantage of the conservation of certain proteins or regions of proteins among different strains, she noted, even if the protein is on the viral surface where it might be susceptible to antibody targeting.
Scientists have a better understanding
The ability of cytolytic T lymphocytes (CTL) to kill HIV-infected cells is not the only mechanism for cellular immunity. "The multiple mechanisms of cellular immunity provide another reason for efforts to induce cellular responses," Liu said. "In addition to killing virus-infected cells, CTL releases molecules that may play a crucial role for a preventive or therapeutic AIDS vaccine. And, of course, cellular responses include helper as well as cytolytic T-cells."
Important advances have been made in understanding the virus, she said. "Our global battle against HIV is nothing less than a war, and just as in war, where it is important to understand the enemy in order to outsmart it, we must understand HIV, what its structure is like, and how it infects and causes diseases in order to be able to defeat it."
A lot has been learned about HIV and how it causes disease, said Liu, but researchers need insights into how to induce antibodies that will broadly neutralize viruses both within a clade and between clades. They should not assume that making a vaccine from one clade would be the solution for all the strains within that clade.
Likewise, researchers should not assume that novel immunogens made starting from one clade would not induce antibodies, which can neutralize virus from another clade. Those decisions must be based on scientific data, said Liu, and not on assumptions.
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