ATLANTA -- AIDS researchers at Yerkes Regional Primate Research Center have created a DNA vaccine that protects monkeys against a formidable challenge HIV virus. Achieving protection with this vaccine, made with harmless components from a SHIV -- a blend of parts from HIV and SIV (simian or monkey immunodeficiency virus) -- marks a significant and promising step toward the development of an effective AIDS vaccine. The study results are reported in the May issue of Nature Medicine by Dr. Harriet Robinson, Chief of Microbiology and Immunology at Yerkes Primate Center.
In a three-year study, Dr. Robinson compared combinations of three different vaccine approaches and two different delivery methods for administering them. The most effective vaccination involved two steps: first "priming" the immune system with a DNA vaccine, which consisted of genes taken from a SHIV. The genes express specific SHIV proteins that help the body produce an initial immune response. This was followed 46 and 66 weeks later with "booster" immunizations with the same SHIV DNA inserted into a pox virus. The pox virus deftly invades the host's cells, expressing very high levels of the useful SHIV proteins. However, once in the cells, the virus itself does not replicate. Thus it poses no risk of unwanted dissemination in the vaccinated individual.
Dr. Robinson also tested two different ways of introducing the DNA vaccine. Innoculation through the skin (intradermal) proved more effective in containing viral challenges than did administration with a "gene gun," which bombards cells with DNA-coated gold beads.
Dr. Robinson's vaccine was successful in containing the virus over a 62-week period, during which a series of three SHIV challenge infections were administered. The containment was remarkably effective, preventing detectable levels of virus in blood at all times post-challenge -- in contrast to unvaccinated animals, which had viral loads of up to one billion.
"This holds promise for the development of a vaccine capable of seriously reducing viral replication and thus stemming the transmission of AIDS," says Dr. Robinson.
Challenges For Finding An AIDS Vaccine
Most scientists believe an AIDS vaccine will be completely effective only if it involves both components of the immune response: humoral and cellular immunity. Humoral immunity refers to the process in which B lymphocytes (a type of white cell in the immune system's army) secrete antibodies that recognize and fight off viruses and other invading microbes. This occurs while the intruders are still in the blood and lymph systems, before they can invade individual cells in the body. The second line of defense is cellular immunity, where T lymphocytes recognize when host cells have become infected and destroy them. T cells do not secrete antibodies; they must come near or actually make contact with the infected cell to destroy it.
Development of an AIDS vaccine has proven particularly challenging because the HIV virus is able to elude the antibody response, as well as destroy the helper T cells that are central to raising a cellular immune response. In addition, HIV is capable of establishing a latent reservoir of viral DNA which the immune system fails to recognize, thus re-emerging later to cause disease even if the initial infection has been contained.
The Making Of A Vaccine
Among the AIDS vaccines that have previously been tested in macaque models, only live attenuated viruses, with their potential risks for actually causing disease, were able to protect the animals against highly pathogenic challenges. Three safer approaches for vaccination have held promise, but only against less virulent strains of HIV. They are safer because they use only non-pathogenic pieces of the virus instead of the entire virus to stimulate an immune response. For this reason they are called "subunit" vaccines.
Dr. Robinson decided to test different combinations of three subunit approaches. "It was important to test whether vaccines that were providing some success when used individually could have synergy and elicit a stronger response when used together," she said.
The subunit methods include: 1) DNA vaccines - segments of DNA that code for and express the proteins from a microbe, thus allowing a vaccinated person to generate his own immunizing proteins; 2) recombinant viral vector vaccines - segments of DNA which will express the desired proteins are inserted into a pox virus. The pox virus itself is quite powerful and can elicit a strong immune response, adding to the power of the response generated by the inserted DNA. 3) purified protein vaccines - proteins for the viral envelope are produced in culture, outside the body, and are then injected.
In testing combinations of these three subunit approaches, Dr. Robinson's results show that the animals able to combat SHIV challenge infections were the ones who received intradermal DNA vaccine "primes" plus recombinant pox virus "booster" shots (methods 1 and 2). The containment of the virus was apparently cell-mediated, as neutralizing antibodies were undetectable. Future studies for Dr. Robinson's group include expanded testing in preclinical models of the protective qualities of her two-step protocol and extending trials into phase I studies in humans.
The study was funded by the National Institute for Allergy and Infectious Diseases. Collaborators include scientists from Duke University Medical Center, New England Regional Primate Center, AIDS Research Center of Harvard Medical School, Centers for Disease Control, NCI-Frederick Cancer Research Center, M.D. Anderson Cancer Center, University of Massachusetts Medical Center, Washington Regional Primate Research Center, Therion Biologics Corp., GTC-Mason Laboratories.
Yerkes Primate Research Center is the oldest scientific institution dedicated to primate research. Its programs cover a wide range of biomedical and behavioral sciences.
Journal
Nature Medicine