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

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.

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

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.

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.

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.