Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study [corrected].

BACKGROUND: A serogroup A meningococcal polysaccharide-tetanus toxoid conjugate vaccine (PsA-TT, MenAfriVac) was licensed in India in 2009, and pre-qualified by WHO in 2010, on the basis of its safety and immunogenicity. This vaccine is now being deployed across the African meningitis belt. We studied the effect of PsA-TT on meningococcal meningitis and carriage in Chad during a serogroup A meningococcal meningitis epidemic. METHODS: We obtained data for the incidence of meningitis before and after vaccination from national records between January, 2009, and June, 2012. In 2012, surveillance was enhanced in regions where vaccination with PsA-TT had been undertaken in 2011, and in one district where a reactive vaccination campaign in response to an outbreak of meningitis was undertaken. Meningococcal carriage was studied in an age-stratified sample of residents aged 1-29 years of a rural area roughly 13-15 and 2-4 months before and 4-6 months after vaccination. Meningococci obtained from cerebrospinal fluid or oropharyngeal swabs were characterised by conventional microbiological and molecular methods. FINDINGS: Roughly 1·8 million individuals aged 1-29 years received one dose of PsA-TT during a vaccination campaign in three regions of Chad in and around the capital N'Djamena during 10 days in December, 2011. The incidence of meningitis during the 2012 meningitis season in these three regions was 2·48 per 100,000 (57 cases in the 2·3 million population), whereas in regions without mass vaccination, incidence was 43·8 per 100,000 (3809 cases per 8·7 million population), a 94% difference in crude incidence (p<0·0001), and an incidence rate ratio of 0·096 (95% CI 0·046-0·198). Despite enhanced surveillance, no case of serogroup A meningococcal meningitis was reported in the three vaccinated regions. 32 serogroup A carriers were identified in 4278 age-stratified individuals (0·75%) living in a rural area near the capital 2-4 months before vaccination, whereas only one serogroup A meningococcus was isolated in 5001 people living in the same community 4-6 months after vaccination (adjusted odds ratio 0·019, 95% CI 0·002-0·138; p<0·0001). INTERPRETATION: PSA-TT was highly effective at prevention of serogroup A invasive meningococcal disease and carriage in Chad. How long this protection will persist needs to be established. FUNDING: The Bill & Melinda Gates Foundation, the Wellcome Trust, and Médecins Sans Frontères.

Chemoprophylaxis and vaccination in preventing subsequent cases of meningococcal disease in household contacts of a case of meningococcal disease: a systematic review.

Household contacts of an index case of invasive meningococcal disease (IMD) are at increased risk of acquiring disease. In revising WHO guidance on IMD in sub-Saharan Africa, a systematic review was undertaken to assess the effect of chemoprophylaxis and of vaccination in preventing subsequent cases of IMD in household contacts following an index case. A literature search for systematic reviews identified a single suitable review on chemoprophylaxis in 2004 (three studies meta-analysed). A search for primary research papers published since 2004 on chemoprophylaxis and without a date limit on vaccination was therefore undertaken. There were 2381 studies identified of which two additional studies met the inclusion criteria. The summary risk ratio for chemoprophylaxis vs. no chemoprophylaxis (four studies) in the 30-day period after a case was 0·16 [95% confidence interval (CI) 0·04-0·64, P = 0·008]; the number needed to treat to prevent one subsequent case was 200 (95% CI 111-1000). A single quasi-randomized trial assessed the role of vaccination. The risk ratio for vaccination vs. no vaccination at 30 days was 0·11 (95% CI 0·01-2·07, P = 0·14). The results support the use of chemoprophylaxis to prevent subsequent cases of IMD in household contacts of a case. Conclusions about the use of vaccination could not be drawn.

Timeliness of epidemiological outbreak investigations in peer-reviewed European publications, January 2003 to August 2013.

Timely outbreak investigations are central in containing communicable disease outbreaks; despite this, no guidance currently exists on expectations of timeliness for investigations. A literature review was conducted to assess the length of epidemiological outbreak investigations in Europe in peer-reviewed publications. We determined time intervals between outbreak declaration to hypothesis generation, and hypothesis generation to availability of results from an analytical study. Outbreaks were classified into two groups: those with a public health impact across regions within a country and requiring national coordination (level 3) and those with a severe or catastrophic impact requiring direction at national level (levels 4 and 5). Investigations in Europe published between 2003 and 2013 were reviewed. We identified 86 papers for review: 63 level 3 and 23 level 4 and 5 investigations. Time intervals were ascertained from 55 papers. The median period for completion of an analytical study was 15 days (range: 4-32) for levels 4 and 5 and 31 days (range: 9-213) for level 3 investigations. Key factors influencing the speed of completing analytical studies were outbreak level, severity of infection and study design. Our findings suggest that guidance for completing analytical studies could usefully be provided, with different time intervals according to outbreak severity.

Dual-specificity phosphatases 2: surprising positive effect at the molecular level and a potential biomarker of diseases.

Dual-specificity phosphatases (DUSPs) is an emerging subclass of the protein tyrosine phosphatase gene superfamily, a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. Recently, a series of investigations of DUSPs defined their essential roles in cell proliferation, cancer and the immune response. This review will focus on DUSP2, its involvement in different diseases and its potential as a therapeutic target.

Investigation of a large community-based outbreak of hepatitis B infection in the United Kingdom.

We describe the largest outbreak of hepatitis B virus infection reported to date in the UK. Between July 2001 and December 2005, 237 cases were identified in Avon, South West England. The likely route of transmission was injecting drug use in 44% (104/237) and heterosexual intercourse in 30% (71/237) of cases. A case-control study in injectors showed that injecting crack cocaine [adjusted odds ratio (aOR) 23·8, 95% confidence interval (CI) 3·04-186, P<0·001] and sharing injecting paraphernalia in the year before diagnosis (aOR 16·67, 95% CI 1·78-100, P=0·010) were strongly associated with acute hepatitis B. In non-IDUs number of sexual partners and lack of consistent condom use were high compared to a national sample. We describe the control measures implemented in response to the outbreak. This outbreak has highlighted the problems associated with the low uptake from the national hepatitis B vaccination policy which targets high-risk groups, the difficulties of identifying those at risk of acquiring hepatitis B infection through heterosexual sex, and injecting crack cocaine as a risk factor for hepatitis B.

What is the evidence for giving chemoprophylaxis to children or students attending the same preschool, school or college as a case of meningococcal disease?

We performed a systematic literature review to assess the effectiveness of chemoprophylaxis for contacts of sporadic cases of invasive meningococcal disease (IMD) in educational settings. No studies directly compared IMD risk in contacts with/without chemoprophylaxis. However, compared to the background incidence, an elevated IMD risk was identified in settings without a general recommendation for chemoprophylaxis in pre-schools [pooled risk difference (RD) 58·2/105, 95% confidence interval (CI) 27·3-89·0] and primary schools (pooled RD 4·9/105, 95% CI 2·9-6·9) in the ~30 days after contact with a sporadic IMD case, but not in other educational settings. Thus, limited but consistent evidence suggests the risk of IMD in pre-school contacts of sporadic IMD cases is significantly increased above the background risk, but lower than in household contacts (pooled RD for household contacts with no chemoprophylaxis vs. background incidence: 480·1/105, 95% CI 321·5-639·9). We recommend chemoprophylaxis for pre-school contacts depending on an assessment of duration and closeness of contact.

Serum transfer of collagen-induced arthritis in mice.

Immunization of DBA/1 mice with native chick type II collagen resulted in development of polyarthritis 4-5 wk later. Sera of these mice contained high levels of anticollagen antibodies, and immunoglobulin concentrates of their sera transferred arthritis to unimmunized recipients. Histopathologically, this passively transferred arthritis resembled the early disease of immunized donors. Immunofluorescence studies demonstrated the deposition of IgG and C3 on the articular surface but not in synovial tissue of arthritic joints. Transferred, isotopically labeled anticollagen antibodies rapidly localized to the limbs and to other cartilage-containing tissues. When transfer concentrate was administered to arthritis-resistant strains, they also developed arthritis. Indeed, immunoglobulin concentrates from rats with collagen-induced arthritis transferred arthritis to naive mice. The amount of concentrate required for transfer to B10.D2 resistant mice was reduced by immunizing them with collagen 4 wk before transfer. Although susceptibility to arthritis from immunization is H-2 linked, these studies clearly demonstrate that passive transfer of arthritis depends upon injection of specific antibody and not on other host factors.

Identification of an immunosuppressive epitope of type II collagen that confers protection against collagen-induced arthritis.

We have previously reported that collagen-induced arthritis can be suppressed by intravenous injection of native type II (CII) but not type I collagen. We have now identified denatured fragments of CII capable of suppressing collagen-induced arthritis and inducing tolerance. Purified CII was cleaved with cyanogen bromide (CB), and the major resulting peptides were isolated. Female DBA/1 mice were administered OVA, native CII, or one of the CB peptides, intravenously, before immunization with native CII, 6 wk after immunization, mice tolerized with CII and CB11 had a markedly lower incidence of arthritis compared with controls. There was a correlation between the overall antibody response and the incidence of arthritis. In addition, animals tolerized with either CII or CB11 had a decreased antibody response not only to CII, but also to each of the other CB peptides tested. To identify the epitope involved in suppression of arthritis, five synthetic peptides, 21-26 amino acids in length, corresponding to selected regions of CB11, were generated. Each of the peptides was injected intravenously into mice before immunization. Only one of these, CB11 122-147, was capable of suppressing arthritis. In addition, mice given the synthetic peptide CB11 122-147 neonatally were suppressed for arthritis and antibody responsiveness when immunized with CII at 8 wk of age. Thus, we have identified CB11 122-147 as an epitope of CII important in induction of tolerance and suppression of disease. Further experiments narrowing down the pivotal amino acids for the immunogenicity of this epitope and the role this epitope plays in induction and regulation of disease will enhance our understanding of how the immune response to collagen affects autoimmune arthritis.

Possible role of V beta T cell receptor genes in susceptibility to collagen-induced arthritis in mice.

Arthritis was induced by immunization of type II collagen in adjuvant in mice from H-2q-bearing crosses between SWR (H-2q/q) and B10 (H-2b/b mice), two strains known to be resistant to collagen-induced arthritis (CIA). The resistance of B10 is known to be due to its MHC haplotype, but it was postulated that the resistance of SWR mice which expresses the susceptible MHC haplotype could be due to the deletion of close to 50% of the V beta genes of the T cell receptor (TCR) in them. 17% of the F1 hybrids, 33% of the SWR backcrosses, 68% of the B10 backcrosses, and 52% of the F2 hybrids developed arthritis on follow-up to 5 mo after primary immunization with collagen. There was no significant difference in anti-type II collagen antibody titers between the arthritic and nonarthritic mice in each of these crosses. The segregation of the TCR genes with arthritis was determined in the F2 population by typing with F23.1 mAb that reacts with T cells using V beta 8 subfamily genes in their TCRs. SWR mice are F23.1- as V beta 8 genes are deleted in them. All six of arthritic mice homozygous for H-2q, and thus with an H-2 haplotype similar to SWR mice, expressed the F23.1 marker. These studies indicate that for complete susceptibility to collagen-induced arthritis, not only is a susceptible MHC haplotype (H-2q) important, but possibly also the presence of a subset of T cells using certain specific V beta genes in their TCRs. Other background genes may, however, modulate the severity of arthritis.

Type II collagen-induced arthritis in rats. Passive transfer with serum and evidence that IgG anticollagen antibodies can cause arthritis.

We have found that serum from rats with type II collagen-induced arthritis, when fractionated with 50% ammonium sulfate and concentrated, would transfer arthritis to nonimmunized recipients. The arthritis in recipients developed within 18-72 h and displayed all of the major histopathologic characteristics of the early lesion in immunized animals but was transient and less severe. Although consideration was given to the possibility that a circulating immune complex was involved, no evidence of such a complex was detected. Further fractionation of the serum yielded an IgG anticollagen antibody that was fully active in transferring disease. The antibody's reaction was inhibited by the native bovine type II collagen used for immunization of donors and the antibody strongly cross-reacted with homologous type II collage but not with denatured collagen. These studies demonstrate that arthritis in rats can be induced with anti-type II collagen antibodies and suggest that an autoimmune process is involved. Because antibodies to collagen have also been detected in human rheumatic diseases, further investigation of the characteristics of collagen antibodies capable of inducing arthritis seems warranted.

Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates.

A model of arthritis was established by the injection of type II collagen into mice. Only mice bearing the H-2q haplotype were susceptible to the disease. Susceptibility was further mapped by the use of recombinant strains on the Iq locus. Type II collagen arthritis was observed in the (resistant X susceptible) F1 cross. Mice strains were designated high, intermediate, or low responders with respect to the anti-type II antibody levels measured by radioimmunoassay. Arthritis-susceptible strains were all classified as high antibody responders. The clinical and histological appearance of type II collagen arthritis in the mouse indicates that it may be a good animal model for the investigation of various immunogenetic traits in rheumatoid arthritis.

Auricular chondritis in rats. An experimental model of relapsing polychondritis induced with type II collagen.

Outbred Wistar rats immunized with native type II collagen developed ear lesions resembling those of human relapsing chondritis. As in human disease, these lesions were characterized by intense chondritis, positive immunofluorescence reactions to IgG and C3, and circulating IgG reactive with native type II collagen. Furthermore, electron-dense deposits were seen near the surface of chondrocytes and corresponded with deposits of IgG and C3. These observations suggest a causal relation between humoral immunity to type II collagen and auricular chondritis in the rat and support the hypothesis than human relapsing polychondritis is an autoimmune disease mediated by immunity to type II collagen.

Induction of arthritis in monkeys by immunization with type II collagen.

Immunization of two cynomolugus and three rhesus monkeys with purified type II collagen resulted in the development of polyarthritis. Arthritis first became clinically apparent 7 wk after primary immunization and persisted for 16 mo. Radiologic examination of the limbs demonstrated soft tissue swelling with severe joint destruction including loss of cartilage and bone. Involved joints eventually became ankylosed with permanent loss of some motion. All of the monkeys developed a response to the immunizing collagen as determined by ELISA of serum for antibodies. Arthritis was associated with weight loss and constitutional symptoms, including lethargy and refusal to eat. One monkey became so debilitated that it was necessary to euthanize it. Histologic examination of the joints showed synovial hypertrophy with pannus formation. A control monkey immunized with type I collagen suffered no apparent ill effects.

Collagen-induced arthritis in mice. Localization of an arthritogenic determinant to a fragment of the type II collagen molecule.

Purified chick type II collagen was cleaved with cyanogen bromide (CB), and the resulting peptides isolated and renatured. Sera from arthritic DBA/1 mice, immunized with chick type II collagen, were tested for reactivity with each peptide. The sera preferentially recognized peptides 11, 10, and 8, in that order. Some reactivity was also detected to peptides 9, 7, and 12. Because arthritis depends upon binding of antibody to autologous type II collagen in the joint, sera were also tested for reactivity with mouse type II collagen. There was a strong positive correlation between reactivity with peptide 11 and reactivity with mouse collagen, but no correlation was found with any of the other peptides. Peptides 11, 10, and 8 were also used for immunization. Antibodies were detected in response to each of these peptides, but arthritis developed only in mice immunized with peptide 11. We conclude that a major immunogenic and arthritogenic epitope on type II collagen resides in the region of the molecule represented by CB peptide 11.

An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen.

Rheumatoid arthritis (RA) is an autoimmune disease that is strongly associated with the expression of several HLA-DR haplotypes, including DR1 (DRB1*0101). Although the antigen that initiates RA remains elusive, it has been shown that many patients have autoimmunity directed to type II collagen (CII). To test the hypothesis that HLA-DR1 is capable of mediating an immune response to CII, we have generated transgenic mice expressing chimeric (human/mouse) HLA-DR1. When the DR1 transgenic mice were immunized with human CII (hCII), they developed a severe autoimmune arthritis, evidenced by severe swelling and erythema of the limbs and marked inflammation and erosion of articular joints. The development of the autoimmune arthritis was accompanied by strong DR1-restricted T and B cell responses to hCII. The T cell response was focused on a dominant determinant contained within CII(259-273) from which an eight amino acid core was defined. The B cell response was characterized by high titers of antibody specific for hCII, and a high degree of cross-reactivity with murine type II collagen. These data demonstrate that HLA-DR1 is capable of presenting peptides derived from hCII, and suggest that this DR1 transgenic model will be useful in the development of DR1-specific therapies for RA.

Type II collagen autoimmunity in otosclerosis and Meniere's Disease.

Antibodies to collagen types I, II, and IV were measured in patients with otosclerosis and patients with Meniere's disease. Levels of antibodies to type II collagen were significantly higher in these patients than in control subjects, while no differences were found among levels of antibodies to collagen type I or type IV. These observations suggest a possible role for type II collagen autoimmunity in the etiology of otosclerosis and Meniere's disease.

A gene expression map for Caenorhabditis elegans.

We have assembled data from Caenorhabditis elegans DNA microarray experiments involving many growth conditions, developmental stages, and varieties of mutants. Co-regulated genes were grouped together and visualized in a three-dimensional expression map that displays correlations of gene expression profiles as distances in two dimensions and gene density in the third dimension. The gene expression map can be used as a gene discovery tool to identify genes that are co-regulated with known sets of genes (such as heat shock, growth control genes, germ line genes, and so forth) or to uncover previously unknown genetic functions (such as genomic instability in males and sperm caused by specific transposons).

Nature and specificity of the immune response to collagen in type II collagen-induced arthritis in mice.

To determine the role of collagen-immunity in the development of collagen-induced arthritis, DBA/1 mice were immunized with type II collagen and observed for the development of polyarthritis. 96% of the mice immunized with native type II collagen developed inflammatory arthritis between 4 and 5 wk after primary immunization. Immunization with denatured type II collagen in exactly the same manner was not effective in inducing arthritis. Cell-mediated immunity in arthritic mice was assessed by measuring [3H]thymidine incorporation by mononuclear cells cultured in the presence of collagen. The maximal proliferative response to collagen occurred at 2 wk after immunization. Equally good incorporation of label occurred when cells were cultured with native or denatured type II collagen or type I collagen. The cellular response of nonarthritic mice immunized with denatured collagen was indistinguishable from that seen in arthritic mice. Humoral immunity was assessed by an ELISA assay for antibodies to collagen. The immunoglobulin M (IgM) response peaked at 2 wk and the IgG response at 5 wk after immunization. Antisera from arthritic mice immunized with native type II collagen were relatively specific for conformational determinants on the native type II molecule although some reactivity with denatured collagen was noted. Antisera from nonarthritic mice immunized with denatured collagen primarily recognized covalent structural determinants. It was concluded that native type II collagen was essential for the induction of arthritis and that an antibody response specific for native type II collagen may be important for the development of arthritis.

HTLV-1 induced molecular mimicry in neurological disease.

As a model for molecular mimicry, we study patients infected with human T-lymphotropic virus type 1 (HTLV-1) who develop a neurological disease called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease with important biological similarities to multiple sclerosis (MS) (Khan et al. 2001; Levin et al. 1998, 2002a; Levin and Jacobson 1997). The study of HAM/TSP, a disease associated with a known environmental agent (HTLV-1), allows for the direct comparison of the infecting agent with host antigens. Neurological disease in HAM/TSP patients is associated with immune responses to HTLV-1-tax (a regulatory and immunodominant protein) and human histocompatibility leukocyte antigen (HLA) DRB1*0101 (Bangham 2000; Jacobson et al. 1990; Jeffery et al. 1999; Lal 1996). Recently, we showed that HAM/TSP patients make antibodies to heterogeneous nuclear ribonuclear protein A1 (hnRNP A1), a neuron-specific autoantigen (Levin et al. 2002a). Monoclonal antibodies to tax cross-reacted with hnRNP A1, indicating molecular mimicry between the two proteins. Infusion of cross-reactive antibodies with an ex vivo system completely inhibited neuronal firing indicative of their pathogenic nature (Kalume et al. 2004; Levin et al. 2002a). These data demonstrate a clear link between chronic viral infection and autoimmune disease of the central nervous system (CNS) in humans and, we believe, in turn will give insight into the pathogenesis of MS.

Quality of in-hospital care for adults with acute bacterial meningitis: a national retrospective survey.

BACKGROUND: Most adults with bacterial meningitis and meningococcal septicaemia present to junior doctors who have limited experience of these conditions. In contrast to paediatric practice, data from industrialized countries with regard to current hospital management practice are lacking. AIM: To examine whether current practice meets recommended standards in hospital management of community-acquired bacterial meningitis and meningococcal septicaemia among adults. DESIGN: National audit of medical records. METHODS: We conducted a survey of all patients with acute bacterial meningitis and meningococcal septicaemia admitted to 18 randomly selected acute hospitals in England and Wales between 1 January 2000 and 31 December 2001. All stages of care, including pre-hospital management, initial hospital assessment, record keeping, and ongoing hospital and public health management, were assessed. RESULTS: We identified 212 cases of bacterial meningitis and meningococcal septicaemia; 190 cases remained in the final analysis. Clinical record keeping did not meet acceptable standards in 33% of cases. Parenteral antibiotics were given within 1 h of hospital arrival in 56% of cases, increasing to 79% among those with an initial differential diagnosis that included bacterial meningitis or meningococcal septicaemia. A full severity of illness assessment was made in 27%. The quality of clinical practice varied widely between hospitals. This was most pronounced in the timeliness of consultant review (p < 0.0005). DISCUSSION: The quality of adult clinical practice for bacterial meningitis and meningococcal septicaemia needs improvement. This study provides a tool for developing targeted interventions to improve quality of care and outcome among adults with life-threatening infections, both in the UK and in other countries.