The future of meningococcal vaccines.
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Protection from routine vaccination at the age of 14 months with meningococcal serogroup C conjugate vaccine in the Netherlands.
Routine vaccination with a single dose of conjugated meningococcal C vaccine at 14 months and a catch-up campaign have reduced the incidence of meningococcal C disease in the Netherlands. In contrast to countries where routine vaccination is given in infancy, vaccine failures were not reported. This suggests that one dose of conjugated vaccine in the second year of life might offer longer lasting protection against meningococcal C disease than 3 doses in infancy.
Adult↗
Immune memory in children previously vaccinated with an experimental quadrivalent meningococcal polysaccharide diphtheria toxoid conjugate vaccine.
BACKGROUND: In a previous study, a meningococcal diphtheria toxoid conjugate vaccine (MCV-4) triggered robust bactericidal antibody responses against serogroups A, C, Y, and W-135 in 2- to 10-year-old children. A subset of participants, 2 to 3 years of age at the initial vaccination, was evaluated for persistence of antibody, immune memory, and antibody avidity. METHODS: Participants were healthy children vaccinated 23 to 36 months earlier with MCV-4 (primed) or newly recruited meningococcal vaccine-naive 4-year-olds. Participants in both groups were alternately allocated to provide sera 8 or 28 days after administration of one tenth of the recommended dose of a meningococcal polysaccharide vaccine (PSV-4). Immune responses were assessed in sera obtained at baseline and either 8 or 28 days after reduced-dose PSV-4 administration. Safety was monitored. RESULTS: Before PSV-4 challenge, serum bactericidal antibody geometric mean titers (SBA GMTs) were higher for all 4 serogroups in the MCV-4-primed group than in the vaccine-naive group. SBA GMTs, geometric mean concentrations of immunoglobulin G (IgG) and geometric mean avidity indices for all 4 serogroups were significantly higher among MCV-4-primed versus vaccine-naive participants in the cohorts evaluated at 8 or 28 days after PSV-4 challenge. Adverse events were generally mild, self-limited, and comparable in all groups of children. CONCLUSIONS: Persistence of bactericidal antibody was seen for 23 to 36 months after a primary dose of MCV-4 in young children. Booster responses and avidity maturation were evident after a challenge with reduced-dose polysaccharide vaccine.
Antibodies, Bacterial↗
Recent trends in meningococcal epidemiology and current vaccine recommendations.
PURPOSE OF REVIEW: In 2005, a new meningococcal vaccine, tetravalent meningococcal conjugate vaccine (MCV4) was approved for use. This review discusses the population for whom it is recommended and the logic underlying these recommendations. RECENT FINDINGS: The older meningococcal vaccine, composed of capsular polysaccharide, had limited use in civilian populations. The Centers for Disease Control and the American Academy of Pediatrics now recommend the routine vaccination of adolescents with MCV4. This recommendation is largely based on newer epidemiologic data showing a considerable risk of meningococcal disease in late adolescence, most of which is preventable with vaccine. CONCLUSION: The new MCV4 vaccine should be used in primary-care practices for the immunization of all adolescents and high-risk children and adults. In the future, further studies are likely to show it to be safe and effective for younger children too.
Adolescent↗
Immunization with recombinant class 1 outer-membrane protein from Neisseria meningitidis: influence of liposomes and adjuvants on antibody avidity, recognition of native protein and the induction of a bactericidal immune response against meningococci.
The porA gene from Neisseria meningitidis was cloned into the pRSETA vector and recombinant class 1 outer-membrane protein expressed at high levels in Escherichia coli. The protein was readily purified by affinity chromatography on a Ni2+ matrix and used for immunization of mice with conventional AI(OH)3 adjuvant, with experimental adjuvants which have the potential for human use, and with liposomes. The resulting sera were analysed for the magnitude, subclass distribution and antigenic specificity of the immune response. In addition, surface plasmon resonance (SPR) was used to quantify antibody avidity by analysis of the kinetics of binding to native class 1 protein. Immunization with conventional and experimental adjuvants induced antibodies of low avidity that did not recognize native class 1 protein. In contrast, immunization with recombinant protein in liposomes induced antibodies of high avidity which recognized native class 1 protein, as measured by their ability to label meningococcal cells in immunofluorescence assays and to inhibit the binding of a protective mAb. These properties were associated with the presence in sera of high levels of antibodies with the ability to induce complement-mediated killing of meningococci. These data show that liposomes containing recombinant class 1 protein represent a potential basis of future vaccines, of defined composition, designed for the prevention of group B meningococcal infections.
Adjuvants, Immunologic↗
Antibodies to meningococcal class 1 outer-membrane protein and its variable regions in patients with systemic meningococcal disease.
Antibodies to the meningococcal serosubtype-specific P1.7,16 protein and its variable regions (VR) were analysed in 28 convalescent sera drawn 8-36 months after systemic meningococcal disease by immunoblotting and enzyme immunoassay (EIA) methods. EIA antigens were the meningococcal P1.7,16 protein, produced in Bacillus subtilis, and peptides covering its VR1 (P1.7 region) and VR2 (P1.16 region) inserted into a bacterial penicillinase protein. In the immunoblotting method, three meningococcal reference strains were used; they expressed either the P1.7,16 protein, or only its VR1 or VR2 epitopes in their class 1 proteins. Both methods showed a strong IgG response in four sera to P1.7,16 and VR2, but not to VR1; 18 sera had no or weak anti-class 1 protein activity. The six remaining sera were positive only on blots. The VR2-specific sera had 30-fold higher bactericidal activity than those with negligible P1.7,16 responses. Previous vaccination of the patients with a B:15:P1.7,16 meningococcal vaccine was associated with a strong anti-P1.7,16 and anti-VR2 booster response that declined with time. The subtype-specific antibody activity in some sera indicated colonisation after disease by meningococci with class 1 proteins different from the strain that had caused disease.
Amino Acid Sequence↗
Impact of meningococcal vaccination with combined serogroups A and C polysaccharide vaccine on carriage of Neisseria meningitidis C.
Two studies of meningococcal carriage state were carried out in Galicia (Spain) before and after a mass vaccination campaign between December 1996 and January 1997 against Neisseria meningitidis serogroup C with meningococcal serogroups A and C polysaccharide vaccine. The studies covered two areas with different incidence rates of meningococcal disease in 1996 (high and low incidence). Carriage rates of serogroup C showed a decrease in both areas, 47 and 65 % respectively, before and after the vaccination. Results showed a decrease in carrier state in the age groups 10-14- and 15-19-year-olds, but not in the 5-9-year-olds. These results demonstrate the effect of immunization on the reduction of the carriage state.
Adolescent↗
Meningococcal serogroup C-specific IgG antibody responses and serum bactericidal titres in children following vaccination with a meningococcal A/C polysaccharide vaccine.
In the UK, a co-ordinated series of phase II studies is being undertaken with meningococcal serogroup C conjugate (MCC) vaccines. The use of meningococcal A/C polysaccharide (MACP) vaccines in control arms in young children has been avoided because of the well recognised short comings of these vaccines. Following a cluster of serogroup C disease centred on a day nursery, intervention by MACP vaccination was performed as an outbreak control measure. Using this cohort, serogroup C-specific IgG ELISA and serum bactericidal assays (SBA) were performed using both de-O-acetylated (Oac(-)) and acetylated (Oac(+)) serogroup C antigen, the measurement of primarily high avidity antibody and using baby rabbit or human complement in the SBA. The effect of subject age (either less than or greater than 2 years of age) was assessed for the different assays and significant differences (P<0.05) were found using both antigen sources in the high avidity ELISA and in the rabbit complement SBA but not in the standard ELISA. When assessing results from different studies it is important that methodologies utilised allow such comparisons since the choice of reagents can have a profound influence. The importance of standardised assays is paramount at a time where immunogenicity trials are replacing efficacy trials for the introduction of MCC vaccines.
Animals↗
Neisseria meningitidis serogroup B: laboratory correlates of protection.
Meningococcal disease in the Western countries is frequently caused by Neisseria meningitidis serogroup B. Major efforts have been made to develop a safe and efficacious vaccine against this serogroup which is suitable for use in infants and young children. To assess the quality of the immune response after vaccination with candidate vaccines, laboratory correlates of protection are needed. For serogroups A and C, serum bactericidal activity (SBA) is a well established predictor for protection, but for serogroup B other mechanisms besides SBA may also be involved in conferring protection from disease. Several laboratory methods for identification and evaluation of the immunogenicity of possible vaccine antigens are described in this review.
Animals↗
Immunologic memory response induced by a meningococcal serogroup C conjugate vaccine using the P64k recombinant protein as carrier.
In this study, we used an adoptive lymphocyte transfer experiment to evaluate the ability of the P64k recombinant protein to recruit T-helper activity and induce immunologic memory response to the polysaccharide moiety in a meningococcal serogroup C conjugate vaccine. Adoptive transfer of splenocytes from mice immunized with the glycoconjugate conferred antipolysaccharide immunologic memory to naive recipient mice. The observed anamnestic immune response was characterized by more rapid kinetics, isotype switching from IgM to IgG and higher antipolysaccharide antibody titers compared with those reached in groups transferred with splenocytes from plain polysaccharide or phosphate-immunized mice. The memory response generated was also long lasting. Sera from mice transferred with cells from conjugate-immunized mice were the only protective in the infant rat passive protection assay, and also showed higher bactericidal titers. We demonstrated that priming the mice immune system with the glycoconjugate using the P64k protein as carrier induced a memory response to the polysaccharide, promoting a switch of the T-cell-independent response to a T-cell dependent one.
Adoptive Transfer↗
Safety and preliminary immunogenicity of MenC/P64k, a meningococcal serogroup C conjugate vaccine with a new recombinant carrier.
This study reports the preliminary assessment of the safety and immunogenicity of the first serogroup C conjugate vaccine candidate that includes meningococcal P64k recombinant protein as the carrier (MenC/P64k). Twenty volunteers were recruited for a double-blind, randomized, controlled phase I clinical trial, receiving a single dose of MenC/P64k (study group) and a single dose of the commercial polysaccharide vaccine AC (control group). Only mild reactions were observed. No statistical differences were detected between the antipolysaccharide C IgG responses of both groups as well as between bactericidal serum titre (P > 0.05). The MenC/P64k vaccine was found to have a good safety profile, to be well tolerated and immunogenic.
Adult↗
Vaccination against meningococcal disease in Europe: review and recommendations for the use of conjugate vaccines.
At the end of 2005, six European countries had implemented public immunization campaigns with serogroup C conjugate vaccines, and all had experienced substantial declines in the incidence of serogroup C disease. A quadrivalent ACWY meningococcal vaccine is in use in the USA, but serogroup A is extremely rare in Europe and serogroups Y and W135 are infrequent causes of disease. This paper outlines recommendations on the use of conjugate vaccines in Europe based on the experience with meningococcal C conjugate (MCC) vaccines so far.
Europe↗
An indirect haemagglutination test for demonstration of gonococcal antibodies using gonococcal pili as antigen. I. Methodology and preliminary results.
An indirect haemagglutination (IHA) test for detection of gonococcal antibodies in human sera was established using purified pili as antigen. The majority of sera (44/51), positive in the gonococcal complement fixation test, were also positive in the IHA test with titres within the range 320-10,000. The results obtained for the following three groups of sera indicate a comparatively high speicificity of the IHA test; 1) 52 sera from children below 12 years of age were all negative, 2) 98% (184/188) of sera from blood donors were negative, 3) only sera from three adults out of 21 patients with meningococcal infections gave a positive reaction.
Adult↗
Precipitating antibodies against Neisseria meningitidis in normal sera and their possible origin.
Crossed immunoelectrophoresis was used to study precipitating antibodies against Neisseria meningitidis in sera from 214 normal persons and in human gammaglobulin. A polyspecific meningococcal antigen preparation and a corresponding rabbit antiserum constituted the reference system. All the sera contained one to five precipitins against N. meningitidis which could be identified and quantified by means of the reference system. The precipitin score, which expresses the number and titre of precipitins in each serum, increased with age. More than 25 precipitins were found in the gammaglobulin preparation, including antibodies against the groupspecific polysaccharides A, B and C. Absorption of three of the five normally occurring precipitins (nos. 4, 19, 22) with antigens from various bacteria showed that precipitins nos. 4 and 19 could be completely absorbed by antigens from other Neisseria species, but not by antigens from other genera. This indicates that these two precipitins may have been induced by non-pathogenic Neisseria species or by meningococci. The finding of protective antibodies in gammaglobulin might indicate the possibility of its use in prophylaxis or therapy meningococcal infections.
Antibodies, Bacterial↗
Granulocyte functions and Neisseria meningitidis: influence of properdin-deficient serum.
Granulocyte-mediated reactions such as opsonization, chemotaxis, and release of granulocyte myeloperoxidase and lactoferrin were studied in properdin-deficient and normal human serum incubated with serogroup A and W-135 meningococci. There were no differences between the sera when serogroup A meningococci were studied. Opsonic and chemotactic activity were impaired against serogroup W-135 meningococci in properdin-deficient serum. Restitution with properdin restored both activities. We found similar release of myeloperoxidase and lactoferrin from granulocytes challenged with serogroup A or W-135 meningococci in either sera. These findings are in accordance with the clinical observations of meningococcal infections caused by serogroup W-135 in properdin-deficient patients as well as the absence of infections caused by serogroup A meningococci.
Chemotaxis, Leukocyte↗
Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England.
Meningococcal C conjugate (MCC) vaccines were licensed on the basis of serological correlates of protection without efficacy data. The original correlate of protection was established by using a serum bactericidal antibody assay (SBA) with human complement (hSBA), with titers > or =4 predicting protection. However, the antibody data supporting licensure were largely generated by SBA with rabbit complement (rSBA), which gives higher titers than hSBA. While rSBA titers > or =128 reliably predict protection, as measured by hSBA, sera with rSBA titers in the range of 8 to 64 may not have hSBA titers > or =4. For rSBA titers in this equivocal range, a fourfold rise pre- to postvaccination with the MCC vaccine and/or a characteristic booster response to a polysaccharide challenge was proposed as a correlate of protection. To validate this proposed rSBA correlate, age-specific efficacy estimates for MCC vaccines obtained from postlicensure surveillance in England were compared with the efficacy predicted by the percentage of individuals in these age groups with rSBA titers above different cutoffs at 4 weeks and at 7 to 9 months after vaccination with the MCC vaccine. The average time since vaccination in the cohorts in whom efficacy was measured ranged from 8 to 10 months. The rSBA cutoff of > or =128 was shown to significantly underestimate efficacy, with rSBA cutoffs of > or =4 or > or =8 at 4 weeks postvaccination with the MCC vaccine being the most consistent with observed efficacy. When the levels obtained 7 to 9 months postvaccination with the MCC vaccine were used, all rSBA cutoffs significantly underestimated efficacy, suggesting that continuing protection is less dependent on the SBA level at the time of exposure but is more reliant on immunologic memory.
Child↗
Assignment of Neisseria meningitidis serogroups A, C, W135, and Y anticapsular total immunoglobulin G (IgG), IgG1, and IgG2 concentrations to reference sera.
Meningococcal serogroup-specific immunoglobulin G (IgG), IgG1, and IgG2 concentrations were assigned to three reference sera, CDC 1992, 89-SF, and 96/562, for meningococcal serogroups A, C, Y, and W135 via the method of cross standardization. The sum of the serogroup-specific IgG1 and IgG2 concentrations determined for the four meningococcal serogroups showed good agreement with the serogroup-specific IgG either determined here or as previously represented. Following the assignment of meningococcal serogroup-specific IgG1 and IgG2 concentration to these reference sera, a meningococcal serogroup-specific IgG1 and IgG2 enzyme-linked immunosorbent assay protocol was developed. The serogroup A and C specific subclass distribution of a panel of adult sera collected following vaccination with any combination of meningococcal serogroup C conjugate, bivalent, or tetravalent polysaccharide vaccines was determined. For the determination of serogroup W135 and Y specific subclass distribution, an adolescent panel 28 days following a single dose of either tetravalent polysaccharide or conjugate vaccine was used. The sum of the serogroup-specific IgG1 and IgG2 showed strong correlation with the serogroup-specific total IgG determined. The assignment here of IgG1 and IgG2 subclasses to these reference sera will allow more detailed evaluation of meningococcal conjugate and polysaccharide vaccines.
Adolescent↗