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Fall 2010, Issue 12

Creating Better Vaccines

John SchreiberJohn R. Schreiber, MD, MPH&TM, joined Floating Hospital for Children at Tufts Medical Center in 2007. He is chairman and pediatrician-in-chief, as well as chief administrative officer, for Floating Hospital. He is also the David and Leona Karp Professor of Pediatrics at Tufts University School of Medicine. Schreiber studies host response to encapsulated bacterial pathogens and to conjugate vaccines in order to create better vaccines that will prevent devastating diseases in children. He received his MPH&TM from Tulane University School of Public Health and Tropical Medicine in New Orleans, Louisiana, and his MD from Tulane University School of Medicine. His internship and residency were in pediatrics at Children's Hospital in Boston, Massachusetts, and his fellowships were in infectious disease at Children's Hospital (Boston) and Harvard Medical School. Before coming to Tufts, Schreiber was chairman of the Department of Pediatrics and pediatrician-in-chief at the University of Minnesota Children’s Hospital.

“I am a pediatrician, and my focus has always been on preventable diseases in children,” says Schreiber. “I got interested in encapsulated bacteria years ago because they were the major causes of meningitis and sepsis in children. They’re covered by polysaccharide capsules that have the unique quality of evading the immune system of children under the age of two.” Unable to defend themselves against these encapsulated bacteria, infants can develop serious and even deadly infections. Vaccines that worked for older children and for adults did not work for infants. The discovery that crosslinking the capsular polysaccharide to a carrier protein could elicit an immune response in children under the age of two allowed the development of vaccines against encapsulated bacteria for this age group. However, these vaccines (known as conjugate vaccines) are expensive and require four doses for infants to build up effective immunity, limiting their usefulness in developing countries. “We’re interested in developing a conjugate vaccine that would prevent disease in children after one dose,” says Schreiber. “If you could figure out how the vaccine worked at a more molecular level, you could then figure out how you would design a second generation vaccine that would be better.”

Schreiber and his research associate Zengzu Lai are currently investigating how antigen processing cells, the first cells that see the vaccine after injection, process and present vaccine protein fragments to T cells to obtain T cell help. (An antigen is a foreign substance that stimulates the production of antibodies, and T cells are involved in the production of antibodies.) Assistance from T cells is critical for the enhanced effect of conjugate vaccines in small infants. Schreiber and Lai work with a conjugate vaccine that is given to millions of infants worldwide to prevent Streptococcus pneumoniae infections. The vaccine is a combination of seven serotypes (strains) of S. pneumoniae. “Thanks to a collaboration with Wyeth who manufactures the vaccine, we have all seven of the components separated, and we have all the components both conjugated and unconjugated, so we’re able to look at a lovely model system,” says Schreiber.

Although the carrier protein is the expected major immunity-producing component of the conjugate vaccine, Schreiber and Lai suggested, and have found evidence of, the importance of the polysaccharide component. Working in their mouse model, they found that both polysaccharide and protein components end up on the surface of the antigen-presenting cells, and that the polysaccharide appears to increase the efficiency of antigen processing. “So we’re rolling ahead and investigating that,” says Schreiber, “and we believe that may have implications to immunogenicity and how effective the vaccine could be. We’re picking out the one [polysaccharide] that’s best and trying to figure out what’s unique about the structure of the polysaccharide that’s driving the APC [antigen-presenting cells] to have very efficient processing of the carrier protein.”

Schreiber and Lai are beginning collaborative research with the genetics group of Alexander Poltorak (Sackler School), working with a mouse strain that has more wild-type genes than traditional laboratory mice. Hypothesizing that the more wild-derived mouse is a better model for human immunology, the group will look at how this mouse responds to various components of encapsulated bacteria and vaccines, comparing its response to that of mice from traditional laboratory strains that they've used in previous research. They will also identify genes involved in the immune response, especially those involved in the response to the polysaccharide components of vaccines. To advance this work further, Schreiber would like to collaborate with someone with expertise in polysaccharide/carbohydrate biochemistry. He invites anyone interested in collaborative research to contact him either by phone or email (see below).

For more information, please contact Dr. Schreiber at jschreiber@tuftsmedicalcenter.org or (617) 636-8031.

 

 

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