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Prior meningococcal A/C polysaccharide vaccine does not reduce immune responses to conjugate vaccine in young adults.

The immune responses induced in young adults by a meningococcal A/C polysaccharide-diphtheria toxoid conjugate vaccine (Mcj) and a meningococcal A/C plain polysaccharide vaccine (Mps) were evaluated in unvaccinated subjects and those who had received either vaccine previously. 195 subjects aged 17-30 years received either Mps or Mcj. After 12 months, they were randomised again to receive a second dose of either vaccine. Serogroup specific serum bactericidal assay (SBA) titers and IgG antibody responses were assayed before and 4-8 weeks after primary and booster immunisation. Both vaccines were immunogenic in previously unvaccinated subjects. Administration of a dose of Mps after previous Mps or Mcj induced lower bactericidal titers to group C Neisseria meningitidis than those seen after a single dose of Mps. Bactericidal antibody responses to Mcj were not reduced in subjects who had previously received Mps.

Adolescent↗

Effect of infant immunisation with meningococcus serogroup C-CRM(197) conjugate vaccine on diphtheria immunity and reactogenicity in pre-school aged children.

The majority of Men C conjugate vaccines given in the UK use CRM(197), a mutant diphtheria toxoid, as their protein carrier. We studied the effects of prior immunisation with Men C-CRM(197) conjugate vaccine on immunity to diphtheria in 193 children before and after a booster dose of Men C at 4 years. Baseline diphtheria antibodies were higher in children given four previous doses of Men C (P<0.0001) and tended to be higher following boosting in those who had received three or four doses. This enhanced immunity was not associated with increased reactogenicity.

Child, Preschool↗

Phase I study of detoxified Escherichia coli J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) complex vaccine in human subjects.

We previously observed that a detoxified Escherichia coli O111, Rc chemotype J5 lipopolysaccharide (J5dLPS)/group B meningococcal outer membrane protein (OMP) vaccine protected animals from experimental lethal sepsis when immune antibodies were given passively as treatment at the onset of fever or when vaccine was given actively as prophylaxis. To test the safety and immunogenicity of this vaccine, we administered doses of 5, 10 and 25 microg (based on dLPS) of vaccine at days 0, 28 and 56 to 24 human subjects (8 per group). Temperatures of 100.3, 99.5 and 99.4 degrees F occurred in three subjects. At 24h, pain at the injection site was moderate in 38%, mild in 44% and not present in 18%, while at 48 h, it was 1, 25 and 73%, respectively. No alterations in baseline renal, hepatic or hematologic functions occurred. There were two to three times mean-fold increases in anti-J5dLPS IgG (range: 1.9-5.1) and IgM (range: 1.2-9.2) levels in subjects receiving the 10 and 25 microg doses. At 12-month follow-up, three of the original responders had continued elevation of antibody levels. A 25 microg booster dose of vaccine did not increase antibody levels among those responders and did not elicit antibodies among three subjects with no previous antibody response. The plasma from the six volunteers inhibited LPS-induced cytokine generation in human whole blood ex vivo. We conclude that this J5dLPS/OMP vaccine was safe and well-tolerated with transient, local pain at the injection site. Vaccine formulations with different adjuvants are currently under investigation.

Adolescent↗

[Physiopathology and curative treatment of meningococcal diseases: current aspects].

Early administration of antibiotics as soon as the diagnosis of meningococcemia has been evoked is a significant therapeutic advance. However, the poor outcome of these diseases whose mortality remains high despite the current techniques of reanimation shows that improving the vaccination against meningococci is still of actuality. Diagnosing rapidly severe meningococcal disease is also a means for acting against the pathological activation of the inflammatory and coagulation pathways. Significant advances have been made in understanding the physiopathology of the meningococcal purpura fulminans especially about the deleterious role of the deficiency of the protein C and the antithrombin III. It is too soon to advance that the prognosis of these diseases has been improved by these new therapeutic approaches but the results of preliminary clinical studies are encouraging. However, informing parents about the first skin abnormalities seen in infants with purpura fulminans is essential in attempt to improve the efficiency of these new therapeutic strategies.

Anti-Bacterial Agents↗

Rupert Waterhouse and Carl Friderichsen: adrenal apoplexy.

The Waterhouse-Friderichsen (WFS) syndrome, also known as purpura fulminans, is described as acute hemorrhagic necrosis of the adrenal glands and is most often caused by meningococcal infection. This clinical entity is more frequently seen in the pediatric than the adult population and is associated with a high morbidity and mortality. The initial presenting complaints for patients with the WFS usually include a diversity of nonspecific, vague symptoms such as cough, dizziness, headache, sore throat, chills, rigors, weakness, malaise, restlessness, apprehension, myalgias, arthralgias, and fever. These symptoms are usually abrupt in their onset. Petechiae are present in approximately 50-60% of patients. The clinical diagnosis of WFS may be relatively straightforward or extremely challenging. Patients who appear in the initial and nontoxic-appearing stage without any skin lesions may be difficult to distinguish from a benign viral illness. When a patient presents with fever and petechiae, WFS must be considered, even when the patient has a non-toxic appearance. Due to the rapid progression and often devastating consequences, therapy should be instituted as soon as the diagnosis is suspected.

Denmark↗

Vaccinating first-year college students living in dormitories for Meningococcal disease: an economic analysis.

BACKGROUND: Surveillance of meningococcal disease among U.S. college students found an elevated rate of this disease among first-year students living in dormitories. OBJECTIVE: This study examines the economics of routinely vaccinating a cohort of 591,587 incoming first-year students who will live in dormitories for > or =1 years. METHODS: A cost-benefit model (societal perspective) was constructed to measure the net present value (NPV) of various vaccination scenarios, as well as the cost/case and cost/death averted. Input values included hospitalization costs from $10,924 to $24,030 per hospitalization; immunization costs (vaccine plus administration costs) from $54 to $88 per vaccine; 30 nonfatal, vaccine-preventable cases over a 4-year period (includes 3 with sequelae); 3 premature deaths; value of human life from $1.2 million to $4.8 million; and long-run sequelae costs from $1298 to $14,600. Sensitivity analyses were also conducted on vaccine efficacy (80% to 90%); discount rate (0% to 5%); and coverage (60% to 100%). RESULTS: The costs of vaccination outweighed the benefits gained with NPVs ranging from -$11 million to -$49 million. The net cost per case averted ranged from $0.6 million to $1.9 million. The net cost per death averted ranged from $7 million to $20 million. The break-even costs of vaccination (when NPV=$0) at 60% coverage ranged from $23 (90% vaccine efficacy) to $5 (80% efficacy). CONCLUSIONS: The model showed that the vaccination program is not cost-saving. Key variables influencing the results were the low number of vaccine-preventable cases and the high cost of vaccination. However, from the perspective of students and parents, the cost of vaccination might be worth the real or perceived benefit of reducing the risk to an individual student of developing meningococcal disease.

Adolescent↗

Meningococcal vaccines.

Global control and prevention of meningococcal disease depends on the further development of vaccines that overcome the limitations of the current polysaccharide vaccines. Protein-polysaccharide conjugate vaccines likely will address the marginal protective antibody responses and short duration of immunity in young children derived from the A, C, Y, and W-135 capsular polysaccharides, but they will be expensive to produce and purchase, and may not offer a practical solution to the countries with greatest need. In addition, OMP vaccines have been tested extensively in humans and hold some promise in the development of a serogroup B vaccine, but are limited by the antigenic variability of these subcapsular antigens and the resulting strain-specific protection. Elimination of meningococcal disease likely will require a novel approach to vaccine development, ideally incorporating a safe and effective antigen or antigens common to all meningoccocal serogroups. As a solely human pathogen, however, N. meningitidis has developed many tools with which to evade the human immune system, and likely will pose a formidable challenge for years to come.

Adolescent↗

Meningococcal disease and travel.

Meningococcal disease continues to be a worldwide problem. This review examines the impact meningococcal disease has on international travel and vice versa the impact international travel has on the intercontinental spread of meningococci. The risk of meningococcal disease to the endemic population differs from that of travellers. The best documented risk of meningococcal disease among travellers has been in Hajj pilgrims for Mecca and Madina in Saudi Arabia. In response to the recent Hajj associated outbreak of W135 meningococcal disease, quadrivalent meningococcal vaccine (against serogroups A/C/Y/W135) became a visa requirement. In view of increasing worldwide reports of Y and W135 meningococcal disease, there should be a switch in recommendation from the bivalent (against A& C) to the quadrivalent vaccine for all travellers.

Disease Outbreaks↗

W135 meningococcal carriage in association with the Hajj pilgrimage 2001: the Singapore experience.

An international outbreak among pilgrims returning from the Hajj (pilgrimage to Mecca) and their close contacts was caused by W135 Neisseria meningitidis. In Singapore, this strain is a new emerging problem, clearly associated with this outbreak. We investigated the extent of transmission of N. meningitidis in Hajj pilgrims and their contacts, in order to provide evidence for developing a rational public health policy. We found a high acquisition rate of W135 N. meningitidis in Singaporean pilgrims during the Hajj with substantial transmission to their household contacts. These findings would support a policy of eradication of pharyngeal carriage in returning pilgrims to prevent introduction and dissemination of meningococci.

Carrier State↗

Meningococcal carriage among local inhabitants during the pilgrimage 2000-2001.

The first international outbreak of Neisseria meningitidis serogroup W135 occurred in 2000, in direct association with the annual Hajj in Saudi Arabia. In anticipation of the following Hajj, we conducted a survey of oropharyngeal carriage rates of N. meningitidis both pre- and post-pilgrimage in the King Khalid National Guard Hospital (KKNGH) employees preparing to attend the Hajj. These KKNGH employees were native to the Mecca-Jeddah area. Pre-Hajj throat cultures were obtained 1 week prior to Hajj, and post-Hajj cultures within 10 days after completing the Hajj pilgrimage. A total of 327 throat culture samples were collected from 218 persons. Overall meningococcal carriage rate was found to be 4.7%. Serogroup W135 accounted for 40% of all recovered pre-Hajj strains of N. meningitidis. Only one post-Hajj sample was positive for N. meningitidis W135. This high rate of colonization with N. meningitidis serogroup W135 indicates this strain predominates amongst the population indigenous to the Mecca-Jeddah area. This 'nidus' of N. meningitidis W135 is a potential reservoir for future outbreaks. More worrying, there is real risk of future W135 endemicity in this vulnerable local population. These preliminary findings warrant larger surveillance studies examining both transmission and carrier rate acquisition of N. meningitidis in the Mecca-Jeddah area. These vital data are needed to curb further epidemic outbreaks during future Hajj pilgrimages.

Adolescent↗

Effect of conjugation methodology on the immunogenicity and protective efficacy of meningococcal group C polysaccharide-P64k protein conjugates.

Neisseria meningitidis serogroup C polysaccharide (CCPS) was conjugated to the carrier protein P64k using two different conjugation procedures, condensation mediated by carbodiimide with adipic acid dihydrazide as spacer and the reductive amination method. BALB/c mice were immunized with the resultant polysaccharide-protein conjugates and the immune response was evaluated. All conjugates assayed generated at least 10-fold higher antibody titers than the free polysaccharide. The reductive amination method rendered the best conjugate (CCPS-P64kR) that was able to elicit antibody titers statistically higher than the titer elicited by the plain CCPS (P<0.001). The sera of the group immunized with CCPS-P64kR showed a three-fold higher bactericidal response than the sera of the group immunized with the plain CCPS and they were able to protect against challenge with meningococci in the infant rat protection model. In addition, three different conjugates were obtained from polysaccharides with molecular relative sizes of 2000-4000 Da, 4000-10,000 Da or 10,000-50,000 Da, but no differences were detected in the immune response obtained against the three conjugates. Our experiments demonstrate that it is possible to generate a protective, T-cell-dependent response against CCPS using the P64k protein as carrier.

Adipates↗

Endemic meningococcal disease in Cerdanyola, Spain, 1987--93: molecular epidemiology of the isolates of Neisseria meningitidis.

OBJECTIVE: To establish the relationships between 30 Neisseria meningitidis strains isolated in Cerdanyola (Spain) from 30 out of 36 sporadic cases of meningococcal disease (MD) during 1987--93 and their spread in this population by multilocus enzyme electrophoresis (MEE) and by pulsed-field gel electrophoresis (PFGE), and to evaluate the usefulness of PFGE versus serologic typing methods and MEE as an alternative epidemiologic marker to study meningococcal infection. METHODS: Serotyping, electrophoretic mobility of seven isoenzymes determined by MEE and chromosomal DNA macrorestriction with NheI resolved by PFGE were analyzed. RESULTS: Of these 30 strains, 25 were serogroup B and the remaining five were serogroup C, with the 4:P1.15 and the 2b:NT as the most common antigenic phenotypes, respectively. There were 13 electrophoretic types (ETs) by MEE, with 14 isolates showing an identical ET, 8. Sixteen pulse types (PTs) were generated by PFGE. The 14 ET 8 isolates were clustered into six PTs, A1, A2, A4, A5, A6 and A8. However, by combining both methods, 19 genetically distinct groups were obtained. Eleven of these groups (20 serogroup B strains) and two of these (four serogroup C strains) were genetically related. CONCLUSIONS: We conclude that, according to the clonal population structure, these 30 N. meningitidis strains are heterogeneous although a great number are related. Moreover, PFGE is a useful method to establish clonal structure in N. meningitidis strains under endemic conditions. Finer discrimination of these strains was achieved by combining both MEE and PFGE methods.

Journal Article↗

Vaccination campaign against meningococcal disease in army recruits in Italy.

A high attack rate (17.3/100,000) of meningococcal disease in army recruits in Italy, with 95% of the cases due to serogroup C, constituted the motivating factors to make bivalent serogroup A + C meningococcal vaccination compulsory by law for army recruits starting January 1987. Because the vaccine was given only to the new recruits entering the army, full coverage was not achieved until January 1988. Nearly 900,000 subjects (300,000 yearly) were vaccinated between January 1987 and December 1989. There were no reports of any untoward reactions to the vaccine. Of the 300,000 recruits in service each year, 52, 21, 15, 5 and 4 cases of the disease occurred in 1985, 1986, 1987, 1988 and 1989, respectively (P less than 0.001). Of the 24 cases occurring since the start of the vaccination, only two (due to serogroup C) were attributable to vaccine failure. The remaining cases were in unvaccinated recruits (15 cases) or were due to serogroups other than A or C (7 cases). The cumulative incidence of meningococcal serogroup C in the 600,000 vaccinated recruits during the period 1988-89 was 0.2/100,000 (1 case amongst 600,000 recruits), while the corresponding figure in the 600,000 unvaccinated recruits during the period 1985-6 was 11.3/100,000 (68 cases amongst 600,000 recruits) (P less than 0.001). The protective efficacy of the vaccine in 1987 was 91.2% (12 cases of meningococcal serogroup A and C disease from an average of 150,000 unvaccinated recruits observed for 1 year, and 1 case from the corresponding average of 150,000 vaccinated ones). In 1988 and in 1989 this figure could not be calculated because all recruits were vaccinated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Investigating the aetiology of and evaluating the impact of the Men C vaccination programme on probable meningococcal disease in England and Wales.

The aims were to (1) investigate the aetiology of probable meningococcal disease, where a clinical diagnosis is made in the absence of laboratory data, and (2) evaluate the impact of the Men C vaccination programme in England and Wales. Multiple linear regression analyses were carried out using data reported to Enhanced Surveillance of Meningococcal Disease (ESMD) and laboratory reports of isolates of organisms causing symptoms that mimic meningococcal disease. Confirmed meningococcal disease appeared to be a significant predictor of probable disease. Thus, an additional reduction in meningococcal disease attributable to the serogroup C vaccination campaign was evident in probable disease over and above that observed in confirmed cases alone. Enteroviruses were a significant contributor to cases of probable meningitis and influenza appeared to be a significant contributor to probable cases of septicaemia. This analysis confirms the success seen following the Men C vaccination campaign and gives an indication of the aetiologies of other causes of probable meningitis and septicaemia reported to ESMD.

Adolescent↗