Effectiveness of Meningococcal C Conjugate Vaccine in Salvador,Brazil: A Case-Control Study

Background

During a citywide epidemic of serogroup C meningococcal disease in Salvador in 2010, Brazil, the state government initiated mass vaccination targeting two age groups with high attack rates: individuals aged <5 years and 10–24 years. More than 600,000 doses of meningococcal serogroup C conjugate vaccines were administered. We performed a case-control study to evaluate vaccine uptake, document vaccine effectiveness and identify reasons for non-vaccination.

Methods and Findings

Population-based surveillance identified patients with laboratory-confirmed invasive meningococcal C (MenC) disease during 2010. Information on MenC vaccination was obtained from case patients and age-matched individuals from the same neighborhoods. MenC vaccine effectiveness was estimated based on the exact odds ratios obtained by conditional logistic regression analysis. Of 51 laboratory-confirmed cases of serogroup C meningococcal disease among patients <5 and 10–24 years of age 50 were included in the study and matched with 240 controls. Overall case-fatality was 25%. MenC vaccine coverage among controls increased from 7.1% to 70.2% after initiation of the vaccination campaign. None of the 50 case patients but 70 (29.2%) of the 240 control individuals, including 59 (70.2%) of 84 matched with cases from the period after MenC vaccination, had received at least one MenC vaccine dose. Overall effectiveness of MenC was 98% with a lower 95% exact confidence limit of 89%.

Conclusions

MenC vaccines administered during the meningococcal epidemic were highly effective, suggesting that rapid vaccine uptake through campaigns contributed to control of meningococcal disease.     

Primary antibody-forming cells and secondary B cells are generated from separate precursor cell subpopulations

Two precursor cell subpopulations have been isolated from the spleen cells of nonimmune mice. The major B cell subpopulation binds high levels of the J11D monoclonal antibody and, upon T cell-dependent antigenic stimulation, gives rise to primary antibody-forming cell clones but not secondary B cells. A minority of the 10%-14% of Ia+ precursors that bind low levels of J11D (J11Dlo) also generate antibody-forming cell clones after primary stimulation. However, over 70% of J11Dlo precursors yield no primary antibody-forming cell clones but instead give rise to secondarily responsive B cells. The existence of a distinct precursor cell subpopulation that is responsible for the generation of B cell memory is further evidenced by the distribution of variable region clonotypes among J11Dlo primary precursors, which resembles the clonotype patterns of secondary B cells, and by the accumulation of somatic mutations in their clonal progeny.     

Functional characterization of the N-terminal domain of subunit H (Vma13p) of the yeast vacuolar ATPase

The yeast Saccharomyces cerevisiae vacuolar H(+)-ATPase (V-ATPase) is a multisubunit complex responsible for acidifying intracellular organelles and is highly regulated. One of the regulatory subunits, subunit H, is encoded by the VMA13 gene in yeast and is composed of two domains, the N-terminal domain (amino acids (aa) 1-352) and the C-terminal domain (aa 353-478). The N-terminal domain is required for the activation of the complex, whereas the C-terminal domain is required for coupling ATP hydrolysis to proton translocation (Liu, M., Tarsio, M., Charsky, C. M., and Kane, P. M. (2005) J. Biol. Chem. 280, 36978-36985). Experiments with epitope-tagged copies of Vma13p revealed that there is only one copy of Vma13p/subunit H per V-ATPase complex. Analysis of the N-terminal domain shows that the first 179 amino acids are not required for the activation and full function of the V-ATPase complex and that the minimal region of Vma13p/subunit H capable of activating the V-ATPase is aa 180-353 of the N-terminal domain. Subunit H is expressed as two splice variants in mammals, and deletion of 18 amino acids in yeast Vma13p corresponding to the mammalian subunit H beta isoform results in reduced V-ATPase activity and significantly lower coupling of ATPase hydrolysis to proton translocation. Intriguingly, the yeast Vma13p mimicking the mammalian subunit H beta isoform is functionally equivalent to Vma13p lacking the entire C-terminal domain. These results suggest that the mammalian V-ATPase complexes with subunit H splice variant SFD-alpha or SFD-beta are likely to have different activities and may perform distinct cellular functions.     

Effects of MHC and gender on lupus-like autoimmunity in Nba2 congenic mice

The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC- and non-MHC-encoded genes. Studies in this model have indicated that the H2d/z MHC type, compared with H2d/d or H2z/z, is critical for disease development. C57BL/6 (B6) mice (H2b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2b/z F1 offspring that develop severe lupus nephritis. Despite the importance of H2z in past studies, we found no enhancement of autoantibody production or nephritis in H2b/z vs H2b/b B6.Nba2 mice, and inheritance of H2z/z markedly suppressed autoantibody production. (B6.Nba2 x NZW)F1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.     

Alleles and haplotypes of tumor necrosis factor (TNF) alpha and beta genes in three ethnic populations of Sulawesi Indonesia

Polymorphic variation in two cytokine genes, tumor necrosis factor (TNF) -alpha and -beta, was examined in three ethnic groups, the Bugis, the Makassans, and the Torajans, who inhabit Sulawesi, a large island in the Indonesian archipelago, and formerly a Dutch colony. TNF-alpha and -beta are key molecules in immune responses to infection, and both have been implicated in the pathogenesis and clinical manifestations of parasitic diseases. Several polymorphic variants with the potential to affect cytokine levels in autoimmune diseases and parasitic and bacterial infection have been reported. Two loci in the promoter region of TNF-alpha and two sites in the first intron of TNF-beta were scored in a maximum of 150 Bugis, 168 Makassans, and 58 Torajans. Genotypes at the two TNF-alpha loci are not in Hardy-Weinberg equilibrium because of a deficit of heterozygotes (p < 0.05). However, genotypes at the TNF-beta loci exhibit Hardy-Weinberg equilibrium. A comparison of allelic and genotypic frequencies at all TNF loci across the ethnic groups reveals that the differences are significant for TNFalpha(308) (p < 0.01) and for TNFbeta(NcoI) (p < 0.05). Overall, the distribution of the alleles differs from that seen in the few Asian populations for which data are available (p < 0.05). Construction of 4-locus haplotypes showed that, in addition to the five previously reported, four novel haplotypes were present in Sulawesi. These novel haplotypes were in low frequency, and two were seen only in Bugis (haplotypes F and J) and one (haplotype K) only in Makassans. The other, haplotype D, was present in Makassans and Torajans. Preliminary sampling of other ethnic groups suggests that three of these haplotypes (D, F, and J) may be restricted to Asian or Asian-derived populations. The frequency of the common TNF haplotypes differed between Dutch and Sulawesi populations, and these data also indicated that haplotype E, which has a relatively high frequency in the Dutch (25%), may be a useful marker of Dutch/European admixture in Indonesian populations, in which it is either rare (1%) or absent. The results suggest that unique allelic combinations with potential to influence cytokine secretion are present in Sulawesi, possibly as a consequence of parasite-driven selection, and argue for more extensive investigation of haplotype distribution in parasite-endemic areas.     

Mice lacking Dad1, the defender against apoptotic death-1, express abnormal N-linked glycoproteins and undergo increased embryonic apoptosis

Dad1 has been shown to play a role in preventing apoptotic cell death and in regulating levels of N-linked glycosylation in Saccharomyces cerevisiae and the BHK hamster cell line. To address the in vivo role of Dad1 in these processes during multicellular development, we have analyzed mice carrying a null allele for Dad1. Embryos homozygous for this mutation express abnormal N-glycosylated proteins and are developmentally delayed by embryonic day 7.5. Such mutants exhibit aberrant morphology, impaired mesodermal development, and increased levels of apoptosis in specific tissues. These defects culminate in homozygous embryos failing to turn the posterior axis and subsequent lethality by embryonic day 10.5. Thus, Dad1 is required for proper processing of N-linked glycoproteins and for certain cell survival in the mouse.