Of Mice and Men and Streptococci
Abstract & Commentary
By Joseph F. John, Jr., MD, FACP, FIDSA, FSHEA, Associate Chief of Staff for Education, Medical Subspecialty Services, Ralph H. Johnson Veterans Administration Medical Center, Professor of Medicine, Medical University of South Carolina, Charleston, SC, is Co-Editor for Infectious Disease Alert.
Dr. John does research for Merck, is a consultant for Cubist, Roche, and bioMerieux, and is on the speaker’s bureau for Pharmacia, GSK, Merck, Bayer, and Wyeth.
Synopsis: Group A Streptococcal Carbohydrate is both immunogenic and protective against GAS infections.
Source: Sabharwal H, et al. Group A Streptococcus (GAS) Carbohydrate As An Immunogen for Protection Against GAS Infection. J Infect Dis. 2006;193:129-135.
Microbiologists have been trying for years to make an effective vaccine against infections caused by the Group A Streptococcus (GAS). The best hope has been a vaccine that targets the outer carbohydrate (CHO) coat, since antibodies to these antigens increase with age and there is less GAS disease as humans age.
Workers at Rockefeller University in New York have been hot on the path of a CHO-based vaccine. They previously showed that linking CHO to tetanus toxoid produces an improved response over CHO alone. Infectious disease providers are familiar with the relative success of CHO-based pneumococcal vaccine, so tweaking the CHO of GAS seems a reasonable approach to preventing infection with this streptococcus. Sabharwal and colleagues asked 3 new questions: 1) Are antibodies to the new CHO preparation protective in a mouse model?; 2) Is oral colonization affected by parenteral vaccine in mice?; and 3) Is oral GAS correlated with serum antibodies against CHO?
It is of interest that one of the study strains is a descendent of original isolate—now called D58X—now known to be an M protein-negative mutant.
The production of the CHO is the meat of this work. Then comes its binding to tetanus toxoid (TT). The final conjugate actually contains about 3 polysaccharide chains/mole of tetanus toxoid.
In this study, immunization was through the intranasal route as a QOD administration of 27 ug/20uL. The nasal vaccine was mixed with cholera toxin. The mice were allowed to recover for 3 weeks. Challenge with GAS was through the intraperitoneal, as well as the oral route. There was also a passive immunization arm using antibody raised against the CHO-TT in complete Freund’s adjuvant, as well as an active immunization arm, in this case using the CHO-TT with 2 doses given 3 weeks apart.
There was a human part of the study: 306 Mexican children were tested for their anti-CHO antibody and to determine if they were GAS carriers.
Finally there was a substudy done to determine if the anti-CHO reacted with a variety of human tissue. Those tissues were harvested within 12 hours of death.
The results were very encouraging. The passive immunization study showed good protection from intraperitoneal challenge with GAS. In active immunization studies, mice survived at a rate approaching 80%, much better than the controls 80% of which died. The intranasal studies (even though older mice are not well colonized with GAS) showed reduction of colonization rates in young mice.
In the human studies, high titres of anti-GAS-CHO correlated well with colonization of GAS. Anti-GAS-CHO titres correlated with lower rates of GAS-positive cultures in throats of Mexican children.
In the cross reaction studies, the anti-CHO did not cross react with human tissue including brain, heart, and kidney.
Mice are not men, and Sabharwal et al tried to include aspects of human colonization by showing that anti-CHO antibody could protect from invasive disease in mice, as well as reduce the colonization in throats of Mexican children.
The bottom line is that we are ready for human studies, and these human studies can be based on the good immunogenicity of the GAS-CHO-TT, as well as the lack of cross reaction in autopsy tissue from human heart, kidney, and brain. Will this be the vaccine we have waited a century to be developed? It is hard to say, since invasive GAS disease is sporadic and will be hard to study in a human cohort and throat colonization and, thus, subsequent GAS pharyngitis may move in waves through populations.
A vaccine study with GAS-CHO-TT may have to rest its laurels, if any, on reducing throat colonization with the hope that invasive disease will be lower in the vaccine group. Issues remain as to what is a good target population, can the study be done in the United States, and what are the long term sequelae of such a vaccine when antibodies have cross reacting potential even though preliminary studies suggest that anti-GAS-CHO may not be highly tropic for human tissues prepared soon after autopsy.
This will be an interesting story to follow. A story that reminds us that we continue in the debt of Rebecca Lancefield whose early work presented us with our early streptococcal ABC’s.