Invasive infections (such as meningitis) and middle ear infections due to Haemophilus influenzas or Streptococcus pneumoniae (pneumococci) are a threat to infant health, and pneumococci are a hazard in the elderly. Relatively few capsular types account for the majority of such infections, which are preventable by antibody (Ab) to the respective capsular polysaccharides (CP). In infancy the challenge is the slow maturation of Ab responses to pure CP vaccines. Responsiveness can be accelerated by coupling CP antigens to a protein carrier (""""""""conjugate vaccines""""""""). Several biologics firms have devised candidate vaccines for H. influenzas type b (Hib, but the structural basis for immunogenicity (and failures thereof) is unclear. Our goal has been the definition of structural and other variables that determine immunogenicity of conjugate vaccines in the very young infant. Much progress has been made with the Hib CP although some variables remain to be clarified. The licensed multivalent pneumococcal CP vaccine appears ineffective for the institutionalized elderly and those with underlying disease. Part of the problem may be a decline in Ab responsiveness to particular CP serotypes. Specific goals in the continuation of this project are: 1) To further define structural factors governing immunogenicity of Hib oligosaccharides coupled to the protein CRM-197, 2) To analyze the role of T lymphocyte epitopes of the CRM-197 component upon its carrier activity, by testing the reactivity with a panel of CRM-197-reactive murine T cell clones and monoclonal Abs; 3) To pursue structure- immunogenicity relationships of conjugates of pneumococcal serotypes 6,14,18,19, and 23, which cause the bulk of infant disease and which, as CP, are poorly immunogenic in infancy, 4) To examine the immunogenicity of pneumococcal conjugates in elderly humans, especially serotypes (e.g., types 3 and 6) prevalent in old age and which, as cp, are poorly immunogenic. If the conjugates are immunogenic, we would examine whether (as in infants) """"""""priming"""""""" with the conjugate increases the capacity for a response to the CP alone. If so, an oligovalent conjugate of problematic serotypes might prime the elderly for a broadly consistent response to the extant 23-valent CP vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017938-13
Application #
2060594
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1981-03-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1995-06-30
Support Year
13
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Loeb, M R (1995) Ferrochelatase activity and protoporphyrin IX utilization in Haemophilus influenzae. J Bacteriol 177:3613-5
Anderson, P; Porcelli, S; Pichichero, M E (1992) Effect of phosphate ester residues on the immunogenicity of CRM197-coupled Haemophilus influenzae type b capsular saccharides in 2-month-old infants. J Infect Dis 165 Suppl 1:S160-1
Anderson, P W; Pichichero, M E; Stein, E C et al. (1989) Effect of oligosaccharide chain length, exposed terminal group, and hapten loading on the antibody response of human adults and infants to vaccines consisting of Haemophilus influenzae type b capsular antigen unterminally coupled to the diphtheria protein J Immunol 142:2464-8
Anderson, P; Betts, R (1989) Human adult immunogenicity of protein-coupled pneumococcal capsular antigens of serotypes prevalent in otitis media. Pediatr Infect Dis J 8:S50-3
Insel, R A; Anderson, P W (1988) IgG subclass distribution of antibody induced by immunization with the isolated and protein-conjugated polysaccharide of H. influenzae b and G2m(n) distribution of serum IgG2 in man. Monogr Allergy 23:128-37
Anderson, P; Pichichero, M; Edwards, K et al. (1987) Priming and induction of Haemophilus influenzae type b capsular antibodies in early infancy by Dpo20, an oligosaccharide-protein conjugate vaccine. J Pediatr 111:644-50
Insel, R A; Anderson, P W (1986) Oligosaccharide-protein conjugate vaccines induce and prime for oligoclonal IgG antibody responses to the Haemophilus influenzae b capsular polysaccharide in human infants. J Exp Med 163:262-9
Insel, R A; Anderson, P W (1986) Response to oligosaccharide-protein conjugate vaccine against Hemophilus influenzae b in two patients with IgG2 deficiency unresponsive to capsular polysaccharide vaccine. N Engl J Med 315:499-503
Anderson, P W; Pichichero, M E; Insel, R A et al. (1986) Vaccines consisting of periodate-cleaved oligosaccharides from the capsule of Haemophilus influenzae type b coupled to a protein carrier: structural and temporal requirements for priming in the human infant. J Immunol 137:1181-6
Anderson, P W; Pichichero, M E; Connor, E M (1985) Enhanced nasopharyngeal colonization of rats by piliated Haemophilus influenzae type b. Infect Immun 48:565-8

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