A novel mutation in the C3 gene and recurrent invasive pneumococcal infection: a clue for vaccine development.

Background: We identified a 4 year-old boy born to a consanguineous marriage with C3 deficiency after three episodes of invasive pneumococcal disease. The efficacy of anti-pneumococcal vaccination in C3 deficient patients is not clear.

Objectives: Our objective was to identify the genetic defect resulting in his C3 deficiency and measure his ability to mount an adaptive immune response.

Methods: Fibroblast cell lines were generated from the patient and parents. DNA was isolated and the C3 gene sequenced. Quantitation of C3 expression was performed by immunoprecipitation of (35)S-methionine labeled protein. Isotype specific anti-pneumococcal antibodies present in the patients sera was quantitated after administration of Prevnar-7 and Pneumovax vaccines.

Results: Pneumococcal types 14, 10B and 29 were identified from the blood on three separate occasions over a period of 20 months. C3 levels in the blood was <10, 71, and 66 for the patient, mother and father, respectively (90-180mg/dl, normal). Sequencing revealed a homozygous deletion of one nucleotide located in exon 31 (delA in position 3997 of cDNA) which resulted in a transcriptional stop signal thirteen codons later. The parents were heterozygous for the mutation. No detectable C3 was noted by immunoprecipitation. The patient mounted adequate antibody responses to the protein-conjugated Prevnar and tetanus vaccines but not to the polysaccharide antigen based Pneumovax vaccine. Major immunoglobulin class levels were normal.

Conclusion: C3 deficiency results in the selective impairment to mount a response against polysaccharide-based antigens. Protein-conjugated vaccines are likely to be efficacious in immunizing against encapsulated organisms in these patients.