Novel vaccine approach stimulates protective immunity against listeria

Could also protect against other intracellular bacterial pathogens

BOSTON–March 20, 2006–When bacterial pathogens attack the surface of a cell, vaccine-induced antibodies can mount a formidable defense and fend off the bad bugs. The trouble comes when antibodies cannot recognize the pathogen because the bacteria have infected the cell and are hidden, growing inside the cell's wall.

To mount a defense against these cloaked attackers, Darren Higgins, Associate Professor of Microbiology at Harvard Medical School, and H.G. Archie Bouwer, Immunology Research Scientist at the Earle A. Chiles Research Institute and Portland VA Medical Center, have developed a vaccine strategy for generating an attenuated strain of an intracellular bacterial pathogen. The study appears in the PNAS online early edition the week of March 20, 2006. The vaccine approach could also protect against other intracellular bacterial pathogens, such as tularemia.

The team has initially applied their strategy to Listeria monocytogenes, which affects the most vulnerable humans – the chronically ill, the elderly, pregnant women, and young children, who are susceptible to a serious infection caused by eating food contaminated with the bacteria. In the United States, an estimated 2,500 persons become seriously ill with the infection each year. Of these, 500 die.

After absorption by antigen presenting cells, the attenuated Listeria strain does not replicate, and is readily killed. Unlike other attenuated Listeria strains that do not replicate in host cells, vaccine studies in animals showed that the new strain provided protection from challenge with a virulent, disease-causing, Listeria strain.

"For the first time, an attenuated strain of Listeria that does not replicate in an animal and does not require any manipulation of the bacterium or host prior to immunization still provides protective immunity," Higgins said.

The team found the replication-deficient vaccine strain of Listeria was cleared rapidly in both normal and immunocompromised mice. At the same time, a required class of T-cells – coordinators of the immune system – was stimulated following immunization. As a result, animals immunized with the vaccine strain were resistant to 40 times the lethal dose of virulent Listeria.

"In theory, we could apply this vaccine strategy to other bacterial pathogens like Salmonella," said Higgins. "All we need is to use existing strains that do not replicate inside host cells."

The new Listeria vaccine was based on a 2002 study performed by the Higgins group in which they developed killed E. coli strains as vehicles for delivering antigens to professional antigen presenting cells in the body. In the prior study, Higgins showed that the E. coli-based vaccines protected mice from developing tumors when challenged with melanoma producing cells.

"We have now taken our E. coli-based cancer vaccine work and expanded it into infectious disease areas," Higgins said. "Our Listeria studies demonstrate the potential to generate vaccine strains of bacteria that are effective, yet safe for both healthy and immunocompromised individuals."

The Higgins and Bouwer team is continuing to improve and expand their approach to other intracellular bacteria.

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The study was supported by U.S. Public Health Service Grants from the National Institutes of Health.

For information on the 2002 study, please go to http://focus.hms.harvard.edu/2002/Oct25_2002/index.html

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Harvard Medical School has more than 7,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, the CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and VA Boston Healthcare System.


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