Immune responses against major outer membrane antigens of Neisseria meningitidis in vaccinees and controls who contracted meningococcal disease during the Norwegian serogroup B protection trial

Abstract

Sera from vaccinees and controls who contracted serogroup B meningococcal disease during the blinded and open parts of a two-dose protection trial in Norway were compared for antigen-specific and bactericidal antibodies against vaccine strain 44/76 (B:15:P1.7,16). From 16 of 20 (80%) vaccinees and 26 of 35 (74%) controls, one or more serum samples (n = 104) were collected during the acute phase (1 to 4 days), early convalescent phase (5 to 79 days), and late convalescent phase (8 to 31 months) after onset of disease. Binding of immunoglobulin G (IgG) to the major outer membrane antigens (80- and 70-kDa proteins, class 1, 3, and 5 proteins, and lipopolysaccharide [LPS]) on immunoblots was measured by digital image analysis. Specific IgG levels in vaccinees increased from acute to early convalescent phases, followed by a decline, while controls showed a small increase over time. Vaccinees had significantly higher levels than controls against class 1 and 3 porins and LPS in acute sera, against all antigens during early convalescence, and against class 1 and 3 porins in the later sera. Vaccinees who were infected with strains expressing subtype P1.7,16 proteins demonstrated a level of IgG binding to protein P1.7,16 with early-convalescent-phase sera that was fourfold higher than that of those infected with other strains. Bactericidal titers in serum against the vaccine strain were 192-fold higher for vaccinees than those for controls during early convalescence, but similarly low levels were found during late convalescence. A vaccine-induced anamnestic response of specific and functional antibody activities was thus shown, but the decrease in protection over time after vaccination indicated that two vaccine doses did not induce sufficient levels of long-term protective antibodies.

FIG. 1

Binding of IgG to OMV vaccine protein P1.7,16 at different times after onset of disease in vaccine failures infected with serogroup B meningococci of different subtypes. Sera were collected during acute phase (1 to 4 days), early convalescent phase (5 to 79 days), and late convalescent phase (8 to 31 months) after onset of disease from vaccinees infected with strains expressing either P1.7, P1.16, or variant epitopes thereof (P1.7/16) or with strains expressing other or unknown subtypes (P1.n/x). IgG binding was measured by digital scanning of immunoblots; bars represent median scan values in arbitrary units. Only early-convalescent-phase sera showed significant differences in antibody binding (P = 0.003). conv., convalescent.

FIG. 2

Binding of IgG to L3 and L8 bands of LPS in the OMV vaccine at different times after onset of disease in vaccine failures (vacc) and controls (cont). For serum samples and IgG measurements, see the legend to Fig. 1. Acute- and early-convalescent-phase sera from vaccinees had significantly higher L8 antibody levels than controls (P < 0.002), whereas only early-convalescent-phase sera showed significant differences for the L3 band (P = 0.02). conv., convalescent.

FIG. 3

BTs against vaccine strain 44/76-SL of paired sera collected after onset of disease. Individuals designated K-80 and X-100 were vaccine failures, and K-168, K-177, K-188, and X-78 were controls who suffered from group B meningococcal disease during the protection trial.