Safety and immunogenicity of Shigella sonnei and Shigella flexneri 2a O-specific polysaccharide conjugates in children.
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O-specific polysaccharide conjugates of shigellae were safe and immunogenic in young adults, and a Shigella sonnei conjugate conferred protection [1-3]. Shigellosis is primarily a disease of children; therefore, the safety and immunogenicity of S. sonnei and Shigella flexneri 2a conjugates were studied in 4- to 7-year-old children. Local and systemic reactions were minimal. The first injection of both conjugates elicited significant rises in geometric mean levels of serum IgG only to the homologous lipopolysaccharide (LPS) (S. sonnei, 0.32-8.25 ELISA units [EU]; S. flexneri 2a, 1.15-20.5 EU; P<.0001). Revaccination at 6 weeks induced a booster response to S. flexneri 2a LPS (20.5-30.5 EU, P=.003). Six months later, the geometric mean levels of IgG anti-LPS for both groups were higher than the prevaccination levels (P<.0001). Similar, but lesser, rises were observed for IgM and IgA anti-LPS. The investigational Shigella conjugates were safe and immunogenic in children and merit evaluation of their efficacy. (+info)
Meningococcal serogroup C conjugate vaccine is immunogenic in infancy and primes for memory.
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The safety, immunogenicity, and immunologic priming of 2 dosages (2 microgram or 10 microgram) of a meningococcal C oligosaccharide-CRM197 conjugate vaccine was evaluated in 114 infants vaccinated at ages 2, 3, and 4 months. Antibody persistence and response to boosting with 10 microgram of meningococcal C polysaccharide were assessed. The meningococcal conjugate vaccine produced fewer local reactions than concurrent routine immunizations. Total serogroup C-specific immunoglobulin geometric mean concentration (GMC) increased from 0.3 microgram/mL before vaccination to 13.1 microgram/mL at age 5 months. Serum bactericidal antibody (SBA) geometric mean titers (GMTs) rose from <1:4 to 1:1057 at 5 months and fell by 14 months to 1:19. Following boosting, anti-C-specific immunoglobulin GMC rose to 15.9 microgram/mL and SBA GMT to 1:495. Antibody responses in the 10-microgram dose cohort were significantly higher at 5 months (P<.01) than in the 2-microgram dose cohort but were lower after polysaccharide boosting (P=.02). This meningococcal conjugate vaccine was well tolerated and immunogenic and induced immunologic memory in infants. (+info)
Development of lyme arthritis in mice deficient in inducible nitric oxide synthase.
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Nitric oxide (NO) is a powerful antimicrobial agent and an important regulatory molecule of the innate immune response. To determine if NO has a role in experimental Lyme disease, arthritis-resistant DBA/2J and arthritis-susceptible C3H/HeJ mice were bred to be genetically deficient for inducible NO synthase (iNOS). Following footpad injection of Borrelia burgdorferi, arthritis was similar between iNOS-deficient and control animals regardless of their genetic background. Histologic examination and arthritis severity scores of ankles revealed no differences in arthritis development between iNOS-deficient and control animals. Despite being deficient in a key antimicrobial agent, iNOS-deficient mice had tissue levels of B. burgdorferi similar to those in control mice. Thus, NO does not have a critical role in susceptibility to Lyme arthritis through tissue damage via an overexuberant inflammatory response, nor is it required in resistance through the clearance of spirochetes from tissues. (+info)
Cross-reactivity between six Enterobacteriaceae complete lipopolysaccharide core chemotypes.
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To gain insight into the value of lipopolysaccharide (LPS) core determinants for cross-protective immunisation the serological relationships between six complete (LPS) core types from Enterobacteriaceae were investigated. Hyperimmune sera were raised in mice by repeated immunisation with heat-killed strains of Salmonella choleraesuis (Ra core type) or Escherichia coli (core types R1, R2, R3, R4 and K12) and characterised for reactivity with complete and incomplete core chemotypes by ELISA and immunoblotting. Three sera (anti-Ra, anti-R2 and anti-R3) reacted strongly with 3-5 different complete core types whereas the other three (anti-R1, anti-R4 and anti-K12) reacted strongly only with their homologous core types in these assays. Two approaches were used to examine further the structural bases for cross-reactivity between these cores. By the first approach the anti-complete-core sera were tested for cross-reactivity with truncated forms of the Salmonella species core (incomplete cores) derived from core-defective mutants. By the second approach, antisera raised against some core-defective mutants were tested for cross-reactivity with complete cores. The results of these investigations revealed that several pair-wise combinations of core types can be used as immunogens to elicit immune responses that recognise all six core types and that the major determinants which mediate cross-reactivity between complete cores are localised in the outer core region. (+info)
An essential role for DNA adenine methylation in bacterial virulence.
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Salmonella typhimurium lacking DNA adenine methylase (Dam) were fully proficient in colonization of mucosal sites but showed severe defects in colonization of deeper tissue sites. These Dam- mutants were totally avirulent and were effective as live vaccines against murine typhoid fever. Dam regulated the expression of at least 20 genes known to be induced during infection; a subset of these genes are among those activated by the PhoP global virulence regulator. PhoP, in turn, affected Dam methylation at specific genomic sites, as evidenced by alterations in DNA methylation patterns. Dam inhibitors are likely to have broad antimicrobial action, and Dam- derivatives of these pathogens may serve as live attenuated vaccines. (+info)
Access of antibody or trypsin to an integral outer membrane protein (P66) of Borrelia burgdorferi is hindered by Osp lipoproteins.
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The outer membrane of Borrelia burgdorferi, the Lyme disease agent, contains lipoproteins anchored by their lipid moieties and integral proteins with membrane-spanning regions. We used the techniques of in situ proteolysis, immunofluorescence, in vitro growth inhibition, and cross-linking with formaldehyde to characterize topological relationships between P66, an integral membrane protein, and selected Osp lipoproteins of B. burgdorferi. Protease treatment of intact spirochetes cleaved P66 and Osp proteins but not the periplasmic flagellin or the BmpA protein of the cytoplasmic membrane. P66 of cells lacking OspA, OspB, and OspC was more susceptible to trypsin cleavage than was P66 of cells with these Osp proteins. A monoclonal antibody against the surface loop of P66 bound, agglutinated, and inhibited the growth of viable spirochetes lacking OspA, OspB, OspC, and OspD but not of the cells that expressed OspA, OspC, and/or OspD. When cells were fixed, the antibody bound to cells that express OspD and OspC but still not to cells with OspA. The close association of OspA and P66 was confirmed by the crosslinking of the two proteins by formaldehyde. These results show that Osp proteins, particularly OspA, limit the access of antibody or trypsin to the surface loop region of P66. The proximity and possible contact between P66 and OspA (or other Osp proteins) may hinder the effectiveness of antibodies to what otherwise would be an appropriate vaccine target. (+info)
Look, Ma! No pneumococcus!
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Pneumococcal diseases, caused by the bacterium Streptococcus pneumoniae, include pneumonia and otitis media, which accounts for some 12 million doctor visits per year in the United States alone. Each year around the world, pneumococcus causes 1.2 million deaths due to pneumonia, 39% of which are in children under the age of five. In a three-year Phase III clinical trial involving 38,000 children, in which half of the infants received a new pneumococcal vaccine and half received a placebo vaccine, the new vaccine demonstrated an efficacy rate of 100% against bacterial meningitis and bacteremia, the two most deadly pneumococcal afflictions. (+info)
The cost effectiveness of vaccinating against Lyme disease.
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To determine the cost effectiveness of vaccinating against Lyme disease, we used a decision tree to examine the impact on society of six key components. The main measure of outcome was the cost per case averted. Assuming a 0.80 probability of diagnosing and treating early Lyme disease, a 0.005 probability of contracting Lyme disease, and a vaccination cost of $50 per year, the mean cost of vaccination per case averted was $4,466. When we increased the probability of contracting Lyme disease to 0.03 and the cost of vaccination to $100 per year, the mean net savings per case averted was $3,377. Since few communities have average annual incidences of Lyme disease >0. 005, economic benefits will be greatest when vaccination is used on the basis of individual risk, specifically, in persons whose probability of contracting Lyme disease is >0.01. (+info)