Development and Standardization of Serological Criteria for Evaluation of New Vaccines

Principal Investigator: Milan Blake, PhD
Office / Division / Lab: OVRR / DBPAP / LBP

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Overview

Public Health Issue: Pneumococcal disease continues to be a major cause of morbidity and mortality among both the elderly and the very young. Global estimates suggest that approximately ten million childhood deaths per year result from pneumonia and that about 40% of childhood deaths can be attributed to pneumococcal disease. The existing seven-valent pneumococcal conjugate vaccine was licensed following protective efficacy trials in California and subsequently efficacy trials have been completed with nine-valent vaccines in South Africa and Europe. It is accepted that efficacy trials will be impractical for the licensure of further serotypes and higher valency formulations, as well as expanded indications for use in the elderly population. Instead, licensure will depend on the evidence of a functional immune response to vaccination. There is a substantial and compelling body of evidence that the rapid clearance of pneumococci from the blood is due to opsonophagocytosis mediated by type-specific antibody and complement. Thus, the ability of a pneumococcal disease or vaccination to elicit opsonophagocytic antibodies is widely accepted as evidence of a protective immune response. The further development of pneumococcal conjugate vaccines by both developed and developing country manufacturers alike requires a robust, standardized opsonophagocytic antibody (OPA) assay.

Regulatory Contribution: The aim of this proposal is intended to fulfill OVRR FY08 priorities III and IV, more specifically, to facilitate the development of an effective, efficacious pneumococcal conjugate vaccine for the elderly. To facilitate this development, it has been recognized by all the pneumococcal experts and regulatory bodies that a standardized opsonophagocytic assay (OPA) needs to be developed and agreed upon for use as a serological surrogate of protection in the elderly population. Although a standardized ELISA assay has been used to monitor and evaluate pneumococcal conjugate vaccine in the pediatric population, using the 89SF sera as the reference standard, ELISA resultsdo not correlate well with efficacy in the elderly population. All current data suggest that the OPA is a better predictor of efficacy in this population. There is currently no OPA standard serum based on the killing OPA assay with assigned titers that have been agreed to by key laboratories.

Research Approach: In 2006, a protocol for immunizing human volunteers with the licensed pneumococcal 23 valent polysaccharide vaccine (PNEUMOVAX® 23 (Merck) with subsequent collection of sera from these volunteers was written and subsequently approved. In collaboration with and matching funds from DMID, NIAID, the University of Iowa School of Medicine was selected to execute the protocol under the guidance of Dr. Jack Stapleton. Samples from each of the volunteers were shipped to our laboratory for evaluation of the immune response elicited by the vaccination. We evaluate antibody levels to the six most decisive pneumococcal serotypes. In addition 100 samples were tested in the Pneumococcal Reference Laboratory for OPA titers. A select set of sera will be set aside to form a panel to further standardize pneumococcal assays. It is anticipated that out of the 240 volunteers, the serum from approximately 220 will be available for further processing. A contractor has been identified who will aseptically pool all of the selected sera, filter sterilize the pool, and fill into 6 ml aliquots. Samples from this filling will be tested and used to bridge back to the 89SF reference sera.

Mission Relevance & Outcomes: The aim of this proposal is intended to fulfill OVRR FY08 priorities III and IV, more specifically, to facilitate the development of an effective, efficacious pneumococcal conjugate vaccine for the elderly.

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Publications

Cell Microbiol 2007 May;9(5):1297-310
Neisseria meningitidis type C capsular polysaccharide inhibits lipooligosaccharide-induced cell activation by binding to CD14.
Kocabas C, Katsenelson N, Kanswal S, Kennedy MN, Cui X, Blake MS, Segal DM, Akkoyunlu M

Vaccine 2006 Jun 12;24(24):5093-107
Neisseria meningitidis group B correlates of protection and assay standardization--international meeting report Emory University, Atlanta, Georgia, United States, 16-17 March 2005.
Borrow R, Carlone GM, Rosenstein N, Blake M, Feavers I,Martin D, Zollinger W, Robbins J, Aaberge I, Granoff DM,Miller E, Plikaytis B, van Alphen L, Poolman J, Rappuoli R,Danzig L, Hackell J, Danve B, Caulfield M, Lambert S, Stephens D

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

J Infect Dis 2006 Jan 1;193(1):129-35
Group A streptococcus (GAS) carbohydrate as an immunogen for protection against GAS infection.
Sabharwal H, Michon F, Nelson D, Dong W, Fuchs K, Manjarrez RC, Sarkar A, Uitz C, Viteri-Jackson A, Suarez RS, Blake M, Zabriskie JB

Infect Immun 2005 Oct;73(10):6383-9
Doubly branched hexasaccharide epitope on the cell wall polysaccharide of group a streptococci recognized by human and rabbit antisera.
Michon F, Moore SL, Kim J, Blake MS, Auzanneau FI, Johnston BD, Johnson MA, Pinto BM

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