The overall goal of this project is to develop a safe and effective multivalent M protein-base d vaccine to prevent acute rheumatic fever (ARF). Rheumatic fever is triggered by group A streptococcal infections of the throat. Although the incidence of ARF has declined markedly in the U.S. and other developed countries over the past 50 years, the disease remains rampant in developing countries of the world. Rheumatic heart disease (RHD) is the leading cause of heart disease in children throughout the world. An estimated 12 million people suffer from chronic RHD and 400,000 die from the disease each year. Thus, the development of an effective vaccine designed to prevent the streptococcal infections that cause ARF and RHD could significantly improve the health of millions of children around the world.
The aims of this proposal are: 1) To determine the distribution of group A streptococcal serotypes causing acute pharyngitis in countries where ARF is common, 2) to determine the optimal formulation and route of delivery of multivalent group A streptococcal vaccines using an established mouse model, 3) to identify T cell epitopes within multivalent vaccines in order to enhance the overall protective antibody responses to the multivalent vaccines, 4) to translate these findings into the design, construction, GMP production, and formulation of a multivalent vaccine to prevent rheumatic fever, and 5) to perform a phase I clinical trial to assess the safety and immunogenicity of the vaccine in adult volunteers. Prospective studies will be conducted in Mall, West Africa and Leon, Nicaragua to identify the prevalent rheumatogenic serotypes. This information will be combined with available data on the emm-type distribution of clinical isolates from around the world. Laboratory studies in animals will establish the optimal formulation and route of delivery for the vaccine. The final vaccine will be produced and manufactured to GMP standards by ID Biomedical Corporation. The proposed phase I clinical trial will be performed at the University of Maryland and will establish the safety and immunogenicity of the vaccine in human adult volunteers. Successful completion of these studies will bring us one step closer to determining whether acute rheumatic fever is a vaccine preventable disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI060592-03
Application #
7113104
Study Section
Special Emphasis Panel (ZAI1-MH-M (M3))
Program Officer
Rubin, Fran A
Project Start
2004-09-01
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$509,707
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
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Niedermeyer, Shannon E; Penfound, Thomas A; Hohn, Claudia et al. (2014) Group A streptococcus expresses a trio of surface proteins containing protective epitopes. Clin Vaccine Immunol 21:1421-5
Dale, James B; Penfound, Thomas A; Tamboura, Boubou et al. (2013) Potential coverage of a multivalent M protein-based group A streptococcal vaccine. Vaccine 31:1576-81
Dale, James B; Penfound, Thomas A; Chiang, Edna Y et al. (2011) New 30-valent M protein-based vaccine evokes cross-opsonic antibodies against non-vaccine serotypes of group A streptococci. Vaccine 29:8175-8
Paar, John A; Berrios, Nubia M; Rose, John D et al. (2010) Prevalence of rheumatic heart disease in children and young adults in Nicaragua. Am J Cardiol 105:1809-14
Penfound, Thomas A; Chiang, Edna Y; Ahmed, Elwaleed A et al. (2010) Protective efficacy of group A streptococcal vaccines containing type-specific and conserved M protein epitopes. Vaccine 28:5017-22
Penfound, Thomas A; Ofek, Itzhak; Courtney, Harry S et al. (2010) The NH(2)-terminal region of Streptococcus pyogenes M5 protein confers protection against degradation by proteases and enhances mucosal colonization of mice. J Infect Dis 201:1580-8
Bronze, Michael S; Dale, James B (2010) Progress in the development of effective vaccines to prevent selected gram-positive bacterial infections. Am J Med Sci 340:218-25
Ahmed, E A; Penfound, T A; Brewer, S C et al. (2010) Streptococcal protective antigens (Spa): a new family of type-specific proteins of group A streptococci. Eur J Clin Microbiol Infect Dis 29:51-7

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