The field of vaccine development is getting a boost from new research that has identified a promising vaccine delivery approach, which in animal studies produced long-term immune protection after just one immunization. University of Pittsburgh researchers, who report their findings in the journal Immunity, say the method has particular relevance for efforts aimed at preventing or controlling infectious diseases, such as HIV or influenza, or stopping the growth of cancer. In one set of studies using this delivery approach, a single immunization halted the progression of melanoma and significantly extended survival in a mouse model.
The approach makes use of an inactivated retrovirus, in this case, a modified lentiviral vector more commonly known for its ability to carry functional genes in certain types of gene therapy. Viral vectors in general have been of practical interest to vaccine researchers for their potential to deliver antigens from disease-causing microbes, or even cancer, in order to efficiently build immune defenses against such intruders. To date, the lentivirus has been overlooked in vaccine research. But, according to Pitt investigators, it has distinct advantages that make it a more promising approach for vaccine development than other viral vector or DNA-based vaccine approaches previously studied.
According to results of their studies, a single injection of the lentivector containing either a hepatitis B virus antigen, a melanoma tumor antigen, or a commonly studied model antigen induced a more potent and notably, long-lasting immune response compared to other immunization approaches. A population of specialized immune cells that reside within the top layers of the skin is due much of the credit, say the authors.
"Skin dendritic cells have long been considered the immune system's first line of defense," explains Louis D. Falo, Jr., M.D., Ph.D., professor and chairman of the department of dermatology, University of Pittsburgh School of Medicine, and the study's senior author. "But recent studies that looked at different viral vectors, including the most commonly studied vaccinia vector, have challenged this notion, suggesting that skin dendritic cells are not as important as the classical paradigm maintained. We find that with the lentivirus, it's precisely these skin dendritic cells that are responsible for the vector's more potent immune induction and sustained protection."
Because they exist on the surface of the skin, these cells are the first to recognize the presence of a foreign body, or antigen. Although no longer an active virus, the lentivector is cause enough for alarm, so the dendritic cells capture their prey and then journey to the lymph nodes with their captured invaders -- the vector, and the antigens in the vector as stowaway passengers. In the lymph nodes, the dendritic cells present their bounty to the waiting T cells and program them to attack the foreign invader, subsequently generating the appropriate immune response.
As the other studies have found, and the Pitt team confirms, skin-derived dendritic cells play a lesser role when other vectors are used, merely serving as the transport system to the lymph nodes, where another population of dendritic cells takes over and presents the antigen to the T cells.
Importantly, the investigators found that despite being a foreign intruder itself, the lentivirus seemed to escape the notice of the immune system, even when introduced a second time, suggesting that it could be used repeatedly in the same patients.
"You might say the other viral vectors are a one-shot deal because the immune system recognizes the virus and responds against it the second time around," suggests Dr. Falo. "With lentivirus, it seems feasible to use the immunization approach multiple times in the same patient, such as for annual flu vaccination, or in preventing multiple different infections or cancers in the same patient or in the general population."
Taken together, the investigators say their findings have implications for the development of vaccines that involve cell-mediated immunity, including viral and bacterial infections, and cancer. In the next three-to-five years, they expect to initiate a clinical trial of the approach, most likely for patients with melanoma.
In addition to Dr. Falo, other authors of the study are Yukai He, M.D., Ph.D., of the departments of dermatology and immunology, and Jiying Zhang, Ph.D., and Cara Donahue, of the department of dermatology.
The research was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institute of Allergy and Infectious Diseases and the National Cancer Institute, all of the National Institutes of Health.
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