Vaccination against meningococcal disease.
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Bacterial Vaccines↗
Biomedical subjects
J M Griffiss
Publications and source records attributed to J M Griffiss.
Immunological relationship between the capsular polysaccharides of Neisseria meningitidis serogroups Z and 29E.
The immunological relationship between serogroups 29E and Z of Neisseria meningitidis was investigated using bacterial agglutination, precipitin-in-gel, primary antigen binding and immune lysis assays. The two capsular polysaccharides were both cross immunogenic and cross reactive. Demonstration of the relationship using group Z antisera depended on which assay was used. It was most readily apparent in assays of immune lysis, less apparent when precipitins were sought in gel and inapparent when bacterial agglutination, the standard assay for determining serogroup, was employed. The cross reacting epitope was expressed 10-fold more within the group 29E polysaccharide than within the group Z polysaccharide. These findings imply that inclusion of either polysaccharide in a polyvalent meningococcal vaccine may obviate the need to include the other polysaccharide.
Agglutination Tests↗
Safety and immunogenicity of a group 29E meningococcal capsular polysaccharide vaccine in adults.
A serogroup 29E Neisseria meningitidis capsular polysaccharide vaccine at a dose of 50 micrograms was injected subcutaneously into 10 adult human volunteers. One vaccinate experienced a mild systemic reaction; one complained of moderate to severe local pain and tenderness. The vaccine induced significant homologous binding and bactericidal antibody by 2 weeks and significant binding antibody against the heterologous serogroup Z capsular polysaccharide by 4 weeks. Although binding antibody rose during the first 4 weeks and then declined slowly over the subsequent 4 months, bactericidal antibody response declined substantially by 4 and 8 weeks for both polysaccharides. The increase in group 29E bactericidal activity was no longer significant at 4 and 8 weeks; loss of bactericidal activity against group Z was significant by 8 weeks. Bactericidal activity again rose between 8 and 26 weeks, becoming significantly increased over prevaccination levels for group 29E and increased, though not significantly (P = 0.085), over prevaccination levels for group Z. As a result of the failure of induced antibody to increase bactericidal activity, only 40% of vaccinates achieved a greater than 2 log2 increase in lytic activity against group 29E, and none achieved this large an increase in lytic activity against group Z.
Adolescent↗
Influence of age on serogroup distribution of endemic meningococcal disease.
The age distribution of 126 infants and children with disseminated meningococcal disease hospitalized consecutively in Houston between January 1977 and June 1979, and between January 1981 and June 1981 was analyzed and compared with that in the United States as a whole and to that during outbreaks of group B disease in North America and epidemics of group C disease in South America. Eighty-one (64.3%) isolates from Houston cases were serogroup B and 37 (29.4%) were serogroup C Neisseria meningitidis. Children with serogroup C disease were significantly older than those with group B disease (P = .017). Of the children with serogroup B infections, 33% were less than 12 months of age and 8.6% were less than 3 months of age. Of those with serogroup C disease, only 2.7% were less than 3 months of age and the majority (73%) were more than 2 years of age. These age distributions are similar to those reported for the entire United States during endemic periods. In contrast, focal outbreaks of group B meningococcal infection occurred in populations that were significantly older (0.02 greater than P less than .05). Similarly, epidemic disease in South America due to serogroup C strains also occurred in older children when compared with the occurrence of endemic group C disease in the United States (P = .02).
Adolescent↗
IgA blocks IgM and IgG-initiated immune lysis by separate molecular mechanisms.
Circulating IgA which does not bind the first component of complement (C) and does not activate the classical C pathway, blocks the initiation of C-mediated immune effector mechanisms. In at least two clinical situations, epidemic meningococcal disease and severe hepatic dysfunction, IgA blockade of one such mechanism, immune lysis, results in susceptibility to hematogenous bacterial dissemination. The presence of strain-specific IgM, but not IgG, in the sera of susceptibles at the time of dissemination suggested that IgA blockade of IgM-initiated lysis involves a separate mechanism more sensitive to quantitative changes than that involved in IgA blockade of IgG-initiated lysis. We report here that whereas IgA blockade of IgG-initiated immune lysis is a competitive function of the ratio of IgA to IgG, the blocking of IgM-initiated lysis is a noncompetitive function of the ratio of IgA to target cells, independent of the concentration of IgM. In the presence of sufficient IgA to saturate binding sites, IgM is an impotent bystander unable to compete for sites or initiate lysis. Therefore, C-mediated effector mechanisms are more sensitive to quantitative changes in circulating IgA and target cells (binding sites) in the absence of IgG than in its presence. Neither mechanism appears related to binding kinetics.
Animals↗
A bactericidal microassay for testing serum sensitivity of Neisseria gonorrhoeae.
A reproducible gonococcal serum bactericidal microassay is described which has easily determined endpoints and lends itself to large scale tests. The microassay may be used to assess sensitivity to normal human serum among strains of gonococci, and to define the antigens conferring this sensitivity. It may be readily adapted to test for bactericidal activity in hyperimmune antisera and to evaluate antigens which inhibit serum bactericidal activity.
Antigens, Bacterial↗
Serum IgA: modulation of complement activation and induction of susceptibility to bacterial dissemination.
Data are presented that support the conclusion that serum IgA functions as a regulatory Ig that modulates activation of complement by bacteria entering the circulation in showers of low inoculum from mucosal sites of colonization, and that preserves the antigenic mass by shunting such low inocula into macrophages and away from polymorphonuclear leukocytes, thus permitting immunologic processing. This regulation is an integral part of the physiologic immune response to environmental antigens and occurs during the peripheralization of the IgA response following stimulation of Peyer's patches and their analog in the lung. Down-regulation of complement mediated immune effector mechanisms by circulating IgA is balanced delicately. Pathologic states that increase the level of circulating IgA or decrease the phagocytic capacity of the monocyte/macrophage compartment may result in an oligospecific increase in susceptibility to bacterial dissemination. Fortuitous, co-temporal colonization of both gut and distal mucosal lymphoid tissue may result in augmentation of the serum IgA response to levels which induce monospecific susceptibility. This latter mechanism appears to account for the epidemic acquisition of susceptibility to disseminated meningococcal disease. A model of the relation of serum IgA to other components of mucosal immunity is presented.
Blood Bactericidal Activity↗
Immunological basis of serum resistance of Neisseria gonorrhoeae.
The immunological basis for resistance of certain strains of Neisseria gonorrhoeae to the bactericidal action of normal human serum was studied by investigating the potential role of factors which are known to interfere with each of the sequential steps that result in immune lysis of Gram-negative bacteria. Strains of N. gonorrhoeae were characterized as serum-sensitive (sers) or serum-resistant (serr) on the basis of their sensitivity to lysis by the sera of six normal individuals. Neither intrinsic resistance to the lytic action of activated human complement nor inaccessibility of the cell membrane to C5b accounted for serr. Outer membrane lipopolysaccharide (LPS) was the target antigen for lytic antibody in normal human sera. The gross chemical composition and molecular size of the LPS of the strains were heterogeneous and no consistent patterns of differences between those extracted from serr and from sers strains were found. Neither IgA nor IgG 'blocking' antibody in normal human serum was responsible for serr. We conclude that serr results from the absence from the LPS of the strains of antigenic loci for the lytic antibody in most normal human sera, or, expressed as a function of the host, the absence from the sera of most normal humans of lytic antibody directed against LPS antigenic loci for immune lysis.
Antibodies, Bacterial↗
Epidemiological value of lipopolysaccharide and heat-modifiable outer-membrane protein serotyping of group-A strains of Neisseria meningitidis.
The lipopolysaccharide (LPS) and heat-modifiable outer-membrane protein (P') serotypes of 39 coded strains of group-A Neisseria meningitidis isolated from patients during seven geographically and temporally separate outbreaks of infection were determined blindly. LPS serotype discriminated between strains from different outbreaks and between strains of differing sulphadiazine sensitivity within a single outbreak. Thirty-seven strains were of three separate serotypes and no strain was of multiple serotypes. In contrast, P' serotypes did not discriminate between strains. Multiple serotypes for single strains and among strains from a single outbreak were the rule. LPS serotyping appears to be a useful epidemiological tool for distinguishing group-A strains of N. meningitidis.
Bacterial Outer Membrane Proteins↗
Human immune response to various doses of group Y and W135 meningococcal polysaccharide vaccines.
A divalent vaccine containing equal weights of Neisseria meningitidis group Y and group W135 capsular polysaccharides was inoculated subcutaneously into groups of 32 military recruit volunteers at doses of 10, 25, 50, and 100 micrograms in 10-microliter/microgram volumes. At 4 weeks, the two higher doses induced significantly greater binding antibody responses than did the two lower doses. Differences in response were not found between the two higher doses or between the two lower doses. An additional 32 volunteers received a dose of 25 micrograms in a 20-microliter/microgram volume. Binding antibody response to this vaccine did not differ from the response to doses of 10 and 25 microgram in 10-microliter/microgram volumes. In contrast, bactericidal antibody responses did not differ among doses. Bactericidal antibody was induced in 100% of individuals with low (greater than 4 log2) preexisting serum bactericidal activity, regardless of dose. Bactericidal antibody nonresponse was restricted to individuals with high preexisting serum bactericidal titers. The discrepant dose response between binding and bactericidal antibody resulted from the induction of nonlytic antibody by the higher doses. We conclude that there are no advantages to doses in excess of 5 micrograms of these two chemically similar polysaccharides for the target population of young adult military recruits.
Adult↗
Safety and immunogenicity of group Y and group W135 meningococcal capsular polysaccharide vaccines in adults.
Serogroup Y and W135 Neisseria meningitidis capsular polysaccharide vaccines were tested as monovalent and divalent preparations in groups of 10 adult human volunteers at a dose of 50 (monovalent) or 100 micrograms (divalent) injected subcutaneously. Reactogenicity was low for the group Y vaccine and the group Y-W135 combined vaccine; 3 of 10 volunteers developed systemic reactions after group W135 vaccination. All three vaccines induced significant homologous and heterologous binding and bactericidal antibody. Except for group W135 bactericidal antibody, homologous responses exceeded heterologous responses, and divalent and monovalent vaccines induced equivalent homologous responses. Homologous bactericidal antibody responses were maintained for 4 weeks in 85% of group W135 vaccinates and in 100% of group Y vaccinates. Bactericidal antibody was induced in 11 of 11 group Y and 12 of 15 group W135 volunteers without preexisting respective bactericidal activities, regardless of which vaccine they received. For all three vaccines, antibody levels declined only slightly over 6 months. Prevaccination antibody levels positively affected postvaccination binding antibody levels, but not bactericidal levels.
Antibodies, Bacterial↗
Immunological cross-reaction between a naturally occurring galactan, agarose, and an LPS locus for immune lysis of Neisseria meningitidis by human sera.
An immunological cross-reaction between agarose, a naturally occurring galactan, and an antigenic determinant which is a locus for human bactericidal antibody within the LPS of group Y strains of N. meningitidis was investigated. Bactericidal antibody in the convalescent serum of a child from whom a group Y, type IX strain was isolated could be absorbed by highly purified agarose in bead form (Sepharose), but not by a dextran gel (Sephadex). It was inhibited by agarose as a linear polymer and by the strain's LPS, but not by a heterologous LPS from a group B, type II strain of N. meningitidis, nor by the homologous capsular polysaccharide. Both LPS contained galactose; neither was anti-complementary. Agarose antiserum, raised in a rabbit, was bactericidal for the group Y strain, but not for the group B strain. Bactericidal activity in the agarose antiserum could be inhibited by agarose. Immunization with agarose induced haemagglutinating antibody against the group Y strain's LPS which could be absorbed by the group Y, but not the group B strain, and could be reduced by absorption with Sepharose. Absorption with Sepharose also removed the lytic activity against group Y strains of serotypes II and IV from a normal human serum without group Y capsular polysaccharide antibody. We conclude that the cross-reaction resides in the fine structure of the galactose constituent of the group Y strains' LPS.
Bacteriolysis↗
IgA-dependent, monocyte-mediated, antibacterial activity.
IgA purified from the sera of patients convalescing from disseminated group C meningococcal disease induced human monocyte-mediated anti-meningococcal activity in vitro in the absence of complement. Both IgA- and IgG-dependent activity were directed against the group C meningococcal polysaccharide (Csss) capsule. The amount of IgA that was effective bound less than 1 ng of Csss. Antibacterial activity was dependent upon the length and the temperature of the test incubation and on the concentration of monocytes. The implications of this mechanism for local cell-mediated antibacterial immunity are discussed.
Antibody-Dependent Cell Cytotoxicity↗
Elaboration of both the group W135 and group Y capsular polysccharides by a single strain of Neisseria meningitidis.
A single strain (8021) of Neisseria meningitidis, isolated from a child with disseminated meningococcal disease, was found to elaborate two serogroup-specific capsular polysaccharides-Y and W135. The original isolate as well as the progeny of ten single colony sub-isolates each agglutinated with both group Y and group W135 serogrouping antisera. The capsular polysccharide of strain 8021 contained the chemical constituents of both the W135 and Y capsular polysaccharides in a ratio of about 2.5:1. The patient responded immunologically to both capsular polysaccharides with haemagglutinating antibodies. Analysis by double diffusion in agar revealed that the capsular polysaccharide of strain 8021 contained individual molecules of group W135 and group Y capsular polysaccharides as well as a mosaic molecule containing both antigenic determinants.
Antigens, Bacterial↗
Antibody-dependent mononuclear cell-mediated antimeningococcal activity. Comparison of the effects of convalescent and postimmunization immunoglobulins G, M, and A.
We have compared the abilities of immunoglobulin (Ig)G, IgM, and IgA to induce either mononuclear cell-mediated (complement-independent) or complement-mediated (cell-free) antibacterial activity against group C meningococci. In each of these assays, immunoglobulins purified from the sera of individuals immunized with meningococcal group C polysaccharide were compared with those purified from sera of patients convalescing from disseminated meningococcal disease. Our data support three conclusions. First, although nonbactericidal in cooperation with complement, IgA can induce cell-mediated antibacterial activity as well as IgG. Second, the amount of IgG required to induce cell-mediated antibacterial activity is similar to the amount required for complement-mediated killing. Third, although the amount of either postimmunization or convalescent IgM required to induce complement-mediated killing is 16- to 20-fold less than the amount of respective IgG required, IgM is inferior to IgG in its ability to induce cell-mediated antibacterial activity because in the cell-mediated system (a) postimmunization IgM is ineffective; (b) the amount of convalescent IgM required for minimal activity is eightfold more than the amount of convalescent IgG required; and (c) the maximal antibacterial index induced by convalescent IgM is 50% less than that which can be induced by IgG. These data suggest that IgG and IgA may play a greater role than IgM in mononuclear cell-mediated antibacterial host immune defense.
Antibodies, Bacterial↗
Heterogenity of serotypes of Neisseria meningitidis that cause endemic disease.
Three collections of strains of Neisseria meningitidis that caused meningococcal disease during nonepidemic periods were serotyped to determine whether serotypes that cause endemic disease are more heterogeneous than those responsible for epidemic disease. Thirty-four strains isolated from pediatric patients in Houston, Texas, from February 1977 to March 1978 were of three separate serogroups and 11 serotypes; 27 contemporary (1977-1978) strains from predominantly military populations, obtained nationwide, were of six serogroups and six serotypes, while 11 strains isolated at military posts in the southwest United States from 1970 through 1976 were of four serogroups and five serotypes. Between 9% and 20% of the strains were nontypable, while type II strains which were responsible for the epidemics in the Northern and Western Hemispheres earlier in the 1970's, accounted for only 20%-44% of the strains. In contast to epidemics, which appear to be caused by a single serotype, endemic meningococcal disease appears to be caused by a broad, heterogeneous distribution of serotypes. Thus, development of a serotype-specific vaccine may have limited application to the prevention of endemic meningococcal disease.
Adult↗
Complex of meningococcal group B polysaccharide and type 2 outer membrane protein immunogenic in man.
A noncovalent complex of meningococcal group B polysaccharide and type 2 outer membrane protein has been characterized and its potential as a vaccine against group B meningococcal disease investigated. The polysaccharide component was found to have a partition coefficient, K(d), of 0.34 on Sepharose CL-4B in the presence of sodium deoxycholate. The protein consisted of four to five major proteins including the principal outer membrane protein. Hydrophobic binding between the protein and polysaccharide was demonstrated by gel filtration and isopycnic CsCl density gradient centrifugation and found to involve all of the proteins. After demonstrating safety and immunogenicity in animals, two lots of vaccine were tested in a total of eight volunteers. Two 120-mug doses were given subcutaneously at 0 and 5 wk. Mild local reactions occurred in all eight volunteers, but no systemic reactions were observed. 2 wk after the first dose, six of the volunteers had increased levels of bactericidal antibodies against both the group B polysaccharide and the outer membrane proteins. Antibody rises to the group B polysaccharide (mean 6-fold) were confirmed by passive hemagglutination assays and rises to the proteins (mean 10-fold) by a solid phase radioimmunoassay. The second dose resulted in little or no increase in antibody titers. Antibody titers declined over a period of 14 wk but mostly remained above preimmunization levels. Bactericidal antibodies with specificity for the group B polysaccharide were mostly of the immunoglobulin (Ig)M class, and were directed against a determinant associated only with high molecular weight polysaccharides. We conclude that both the group B polysaccharide and the outer membrane protein are immunogenic in man when presented as a complex and that the complex warrants further testing and development as a vaccine against group B meningococcal disease.
Adult↗
Disease due to serogroup W135 Neisseria meningitidis.
Five cases of disseminated meningococcal disease due to serogroup W135 Neisseria meningitidis are presented. The cases ranged in age from 16 months to 23 years, and spanned a clinical spectrum from mild meningitis without rash or evidence of meningococcal septicemia to severe meningoencephalitis with fulminant meningococcemia, disseminated intravascular coagulation, and death. These cases demonstrate that serogroup W135 N meningitidis is fully pathogenic for man and capable of producing the full spectrum of disseminated meningococcal disease associated with other serogroups. Since this serogroup has recently emerged as a significant cause of disease in Europe, attention should be focused on the correct serogroup designation of strains of N meningitidis isolated from clinical material and reported as "nongroupable" by clinical laboratories, so that additional clinical and epidemiologic information may be obtained.
Adolescent↗