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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Biomarkers of Vaccine Safety and Effectiveness for Encapsulated Bacterial Pathogens

Principal Investigator: Margaret C. Bash, MD, MPH
Office / Division / Lab: OVRR / DBPAP / LBP


General Overview

Certain types of bacteria are surrounded by a capsule made of polysaccharides--a type of carbohydrate. The capsule protects the bacteria and helps them to cause infections. Vaccines against such bacteria are made by removing and purifying the polysaccharide. When injected into individuals, the vaccine stimulates the immune system to make antibodies against these bacteria. Since the polysaccharides differ from one type of bacteria to another, the vaccines also differ in composition. For some vaccines, the polysaccharide is conjugated (attached) to a special protein that increases the ability of the vaccine to stimulate the immune system.

Polysaccharide vaccines used to prevent diseases caused by the bacteria Streptococcus pneumoniae (e.g., pneumonia, otis media [ear infection]) Haemophilus influenzae (e.g., pneumonia, meningitis), and Neisseria meningitidis (e.g., meningitis) have been very successful.

However, the ability to evaluate the safety and effectiveness of these vaccines poses ongoing challenges. This is especially true in the case of N. meningitidis, which causes meningitis (inflammation of the delicate covering of the brain and spinal cord) and sepsis (widespread infection in the body that can lead to organ failure, shock, and death). The infection can leave survivors with hearing loss, and other serious conditions. The makeup of the capsule of N. meningitidis can vary, and these variations require that vaccines also be modified.

Currently, meningococcal vaccines are licensed for individuals who are at least two years old. In order to expand the use of these vaccines to prevent meningococcal disease, researchers must determine if they work effectively in infants. In addition, more vaccines are needed to protect against a group of these bacteria called B N. meningitidis, for which none yet exist.

Our laboratory studies ways to determine the effectiveness of new N meningitidis vaccines, specifically, new vaccines for use in infants and for protecting individuals against the B N. meningititis group of bacteria. Since it is not possible to compare new vaccines to licensed vaccines in infants, we are trying to develop laboratory assays that enable us to evaluate the ability of vaccines to stimulate the immune system.

We are also studying the various B N. meningititis bacteria, whose capsules do not readily trigger immune responses, even when conjugated to a protein. Therefore, they are not included in the licensed vaccines made to protect against several forms of N. meningititis. Our laboratory is trying to determine if certain proteins on the surface of the bacteria might be useful in making a vaccine against these bacteria. A major obstacle to this approach is that there are many different proteins on these bacteria and each of these proteins may have many different variations that might differ between different strains. We are now studying ways to choose particular proteins and assess their ability to work as vaccines that protect against a wide variety of different strains.


Scientific Overview

The primary goals of this research program are to 1) investigate through genetic, protein structure-function, and immunogenicity studies the natural history of outer-membrane protein (OMP) diversification as it relates to vaccine development, and evaluation of vaccine safety and efficacy; and 2) improve the characterization and standardization of assays used to assess meningococcal vaccine efficacy.

Our laboratory will study the antigenic diversity of pathogenic Neisseria using genetic sequence analysis and molecular epidemiology, and by protein structure and function studies aimed at evaluating the effects of antigenic changes on strain fitness, pathogenesis, and protein immunogenicity and antigenicity.

Using a geographically and temporally representative sample of over 300 group B meningococcal isolates from Brazil, we are examining the DNA sequence diversity of six genes encoding relevant outer membrane proteins. The strains are also characterized by multi-locus sequence type (MLST) and clonal complex (CC) using an established method based on seven housekeeping genes. Diversity within groups of closely related strains and between different clonal complexes can be compared using population genetic and evolutionary analyses. We will identify and analyze specific regions of sequence diversity for novel genome derived antigens, as well as the predominant well-characterized outer membrane proteins.

While immunologic pressure can serve to increase the diversity of Neisseria's outer membrane proteins, there is also evidence that the diversity is limited even at the specific regions known to be variable. We hypothesize that sequence variation of the surface-exposed antigenic regions has structural and functional consequences that affect strain fitness or pathogenicity. We will conduct detailed structure-function studies of the major outer membrane protein PorB to evaluate the influence of single loop changes on strain fitness, antigen epitopes, and immunogenicity. This will be accomplished by constructing a panel of isogenic strains with hybrid porB genes expressing PorB with specific individual loop changes. We will use this panel of strains to evaluate changes to monoclonal antibody binding, functional antibody activity, and specificity of immune responses to these hybrid PorB proteins.

We will also develop and evaluate improved methods to assess the efficacy of meningococcal vaccines. The source of complement used in bactericidal assays, typically rabbit complement or human complement, can affect the assay results and the reproducibility and standardization of the assay. We have developed screening criteria for human complement for use in bactericidal assays and shown that by using pooled complement, human bactericidal assays are reproducible. Through a Cooperative Research and Development Agreement with the Meningitis Vaccine Project, we will evaluate the human complement bactericidal activity (hSBA) of sera from clinical vaccine trials. We will compare the results with other serologic assays, including rabbit SBA, anti-polysaccharide IgG antibody and opsonophagocytosis activity.


Publications

J Infect Dis 2012 Jun;205(12):1821-9
Impact of fluoroquinolone resistance mutations on gonococcal fitness and in vivo selection for compensatory mutations.
Kunz AN, Begum AA, Wu H, D'Ambrozio JA, Robinson JM, Shafer WM, Bash MC, Jerse AE

PLoS One 2012;7(3):e33016
Molecular epidemiology of Neisseria meningitidis serogroup B in Brazil.
de Filippis I, de Lemos AP, Hostetler JB, Wollenberg K, Sacchi CT, Harrison LH, Bash MC, Prevots DR

FEMS Immunol Med Microbiol 2011 Oct;63(1):16-24
Capsular serotype of Staphylococcus aureus in the era of community acquired MRSA.
Sutter DE, Summers AM, Keys CE, Taylor KL, Frasch CE, Braun LE, Fattom AI, Bash MC

Vaccine 2010 Jun 23;28(29):4539-47
Utilization of serologic assays to support efficacy of vaccines in nonclinical and clinical trials: meeting at the crossroads.
Madore DV, Meade BD, Rubin F, Deal C, Lynn F, Meeting Contributors

Clin Vaccine Immunol 2009 Jul;16(7):969-77
Investigation of different group A immunoassays following either one dose of meningococcal group A conjugate vaccine or A/C polysaccharide vaccine in adults.
Findlow H, Plikaytis BD, Aase A, Bash M, Chadha H, Elie C, Laher G, Martinez J, Herstad T, Newton E, Viviani S, Papaspyridis C, Kulkarni P, Wilding M, Preziosi MP, Marchetti E, Hassan-King M, La Force FM, Carlone G, Borrow R

Infect Immun 2008 Aug;76(8):3700-9
Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain P1a porin sequences confer a selective advantage for urogenital tract infection.
Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM, Jerse AE

BMC Evol Biol 2007 Jun 1;7:84
Distinguishing importation from diversification of quinolone-resistant Neisseria gonorrhoeae by molecular evolutionary analysis.
Pérez-Losada M, Crandall KA, Bash MC, Dan M, Zenilman J, Viscidi RP

J Clin Lab Anal 2007;21(4):237-43
Evaluation of PorB variable region typing of Neisseria gonorrhoeae using PCR-ELISA in samples collected from men who have sex with men.
Ling AE, Bash MC, Lynn F, Lister NA, Zhu P, Garland SM, Fairley CK, Tabrizi SN

Curr Infect Dis Rep 2006 Mar;8(2):132-8
Extragenital Manifestations of Neisseria gonorrhoeae.
Spencer SE, Bash MC

Emerg Infect Dis 2005 Aug;11(8):1326-7
Neisseria meningitidis endotoxin and capsule transmission by transplantation.
Roubinian N, Kirkpatrick BD, Lynn F, Zenilman J, Bash M

J Clin Microbiol 2005 Apr;43(4):1522-30
por Variable-Region Typing by DNA Probe Hybridization Is Broadly Applicable to Epidemiologic Studies of Neisseria gonorrhoeae.
Bash MC, Zhu P, Gulati S, McKnew D, Rice PA, Lynn F

J Clin Microbiol 2005 Jan;43(1):368-75
Genetic Typing of the Porin Protein of Neisseria gonorrhoeae from Clinical Noncultured Samples for Strain Characterization and Identification of Mixed Gonococcal Infections.
Lynn F, Hobbs MM, Zenilman JM, Behets FM, Van Damme K, Rasamindrakotroka A, Bash MC

J Infect Dis 2004 Jun 1;189(11):2085-93.
Quinolone Resistance-Determining Region Mutations and por Type of Neisseria gonorrhoeae Isolates: Resistance Surveillance and Typing by Molecular Methodologies.
Giles JA, Falconio J, Yuenger JD, Zenilman JM, Dan M, Bash MC

Curr Infect Dis Rep 2004 Apr;6(2):129-134
Gonorrhea Update.
Bash MC

     
 

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