The phenomenon of HLA antigen modification in meningococcal infection

212 patients with the generalized forms of meningococcal infection have been examined. The intensity and quality of lymphocytotoxic reaction in the acute phase and the convalescence period of the disease have been analyzed and the blank calculation has been made at different clinical forms of meningococcal infection. The formation of modified tissue antigens at the acute stage of the disease in the presence of intoxication is shown and the probable role of the intensity of bacteremia in this formation is discussed.     

Characteristics of the meningococcal carrier state in organized collectives and its role in the development of generalized forms of meningococcal infection

Complex (epidemiological and bacteriological) investigations of the level and structure of meningococcal carriership among the members of organized collective bodies differing in the epidemiological situation with respect to meningococcal infection have been carried out. The absence of differences between the total level of meningococcal carriership and the morbidity rate with respect to the generalized forms of meningococcal infection has been shown. The presence of cases of meningococcal meningitis in the groups under study has been found to depend on the intensity of the circulation of certain meningococcal serogroups. The possibility of the ecological reservation of the causative agents of meningococcal infection as polyagglutinable forms has been suggested.     

Characterization of the foci of meningococcal infection in closed groups of males

A total of 257 foci of meningococcal infection in groups of servicemen were selectively examined in 1982-2002. From these groups 353 patients with generalized forms of the disease underwent hospitalization. Most of the foci had a single infection, the proportion of foci with 10-40 patients was 82.6%. The meningococcal infection rate among humans in the foci was 25-37%, group A meningococci playing the leading role. In the structure of meningococcal infection generalized forms of infection constituted 16%, localized forms constituted 25% and inapparent forms (carriers)--59%. The formation of the morbidity structure was influenced by the type of the focus (with a single or multiple infection) and the character of morbidity for many years (during epidemic or at the period between epidemics). No absolute dependence of the level of meningococcal carrier state in the groups of servicemen on the appearance of the generalized forms of meningococcal infection was noted. Thus, both during epidemic and at the period between epidemics the population of meningococci, heterogeneous in its serological structure and differing in its clinical and epidemiological importance, constantly circulated with the leading role played by group A meningococci.     

Relationship of eicosanoids to cellular and humoral immunity factors in meningococcal infection

The dynamics of the content of thromboxane B2, 6-keto-prostaglandin F1 alpha, T- and B-lymphocytes and titers of antibodies to group polysaccharides of meningococci, groups A, B and C, have been studied in 44 patients with generalized forms of meningococcal infection. As shown in this study, in patients with the clinical course of moderate severity a decrease in the number of T-lymphocytes in the first days of infection correlates with a decrease in the concentration of thromboxane B2. In some cases the concentration of thromboxane B2 and 6-keto-prostaglandin F1 alpha has been found to correlate with the titers of antibodies to group polysaccharide of group A meningococci. The severe course of meningococcal infection is characterized by the absence of correlation between eicosanoids and the immunity factors under study.     

Immunological factors in the evolution of the epidemic process in meningococcal infection

The results obtained in 1987 in the study of the immunostructure of the population of Yaroslavl with respect to meningococcal polysaccharides, groups, A, B, C, and lipopolysaccharide are presented in comparison with earlier results obtained in 1976. The regulating role of the immunological factor in the evolution of the epidemic process of meningococcal infection has been confirmed. The level of antibodies to meningococcal polysaccharides, groups A and B, has been found to reflect the intensity of the circulation of the infective agent among the population. The comparison of the results of investigations carried out in 1976 and 1987 has revealed the essential role of the lipopolysaccharide antigen in the formation of the postinfection immunity of the population to meningococcal infection, irrespective of the group of the infective agent.     

The characteristics of the serological diagnosis of meningococcal infection in children in the 1st years of life

The results of clinico-immunological examination of 181 children, aged 1 month to 6 years, with generalized forms of meningococcal infection are presented. In children under observation antimeningococcal antibodies to group-specific meningococci of the main groups A, B and C were determined over the course of the disease by passive hemagglutination (PHA) test and enzyme immunoassay (EIA). The level and frequency of seroconversion were found to depend on the patient's age and the severity of the clinical course of meningococcal infection. Antibody level was found to increase simultaneously with respect to several meningococcal polysaccharides: A, B in 18.5% and A, B, C in 3.3% of cases. In the clinical interpretation of data obtained in the PHA test and EIA not only the patient's age, the form and duration of meningococcal infection, but also serotherapy should be taken into consideration, as the latter may distort the serological results.     

Antibodies to meningococcal antibodies in the sera of patients and donors

The comparative study of sera taken from healthy persons (pooled sera of 100 donors, 6 individual serum specimens) and sera taken from patients with meningococcal meningitis (pooled sera of 10 patients with meningococcal infection, group A, and 6 individual serum specimens from patients with meningococcal infection, groups A, B, C) was carried out by the method of immunoblotting. All proteins from healthy donors were found to contain antibodies to meningococcal iron-regulated protein (IRP) of 85 kD, designated as TbpB. In 30% of donor sera the presence of antibodies to meningococcal IRP of 34 kD (FbpA) was registered. Moreover, donor sera were found to contain antibodies to meningococcal IRP of 45 kD. The sera taken from convalescents were found to have the increased content of antibodies to IRP of 70 and 85 kD and somewhat lesser content of antibodies to proteins of 98, 44 and 34 kD. As regards other (non iron-regulated) proteins, in the process of convalescence the most intensive antibody production was observed with respect to minor protein with a molecular weight of 50 kD, as well as proteins of class 5, characterized by molecular weights of 30 kD and less.     

A field trial with the liquid multicomponent meningococcal vaccine ABC

The morbidity rates of generalized forms of meningococcal infection in persons immunized with different doses of liquid meningococcal vaccine ABC were compared. The vaccine was introduced subcutaneously by means of a jet injector. Altogether 3,920 males aged 18 years and older were immunized. 1,966 vaccinees received this vaccine in a dose of 200 micrograms and 1,954 vaccinees, in a dose of 400 micrograms. Meningococcal multicomponent vaccine ABC used in these doses showed moderate reactogenicity and did not prevent the development of generalized forms of meningococcal infection.     

Evaluation of the role of specific antimeningococcal antibodies in the spread of meningococcal carrier states in collectives]

The results of serological, bacteriological and epidemiological studies carried out in populations with different epidemic pattern of meningococcal infection are presented. A-group specific antibody was found to have the leading role in the intensity of the spread of meningococcal infection in the populations. The presence of antibody to this antigen in 16.7% of serum samples inhibited dissemination of meningococci in the populations. Simultaneously with an increase in the herd immunity level to 34.8% the attenuation of the active meningococcal dissemination cycle was observed. Meningococci isolated in the populations with different epidemic patterns of meningococcal infection were shown to have different ecological properties.     

Structure and immunochemistry of meningococcal lipopolysaccharides

The structures of the largest dephosphorylated oligosaccharides (OS) obtained by mild acid hydrolyses of the L2, L3 and L5 serotype lipopolysaccharides (LPS) of Neisseria meningitidis have been elucidated. The OS have extensive regions of structural similarity of which some are responsible for cross-reactivity among the meningococcal LPS. However, the fact that the LPS are predominantly serotype-specific antigens implies that the terminal lacto-N-neotetraose unit, common to all the above OS, is not immunodominant, and that the major LPS serotype specificity originates in the inner core region of the OS.This is N.R.C.C. No. 26392.     

Measurements of lipopolysaccharide (endotoxin) in meningococcal protein and polysaccharide preparations for vaccine usage

Lipopolysaccharide (LPS, i.e. endotoxin) present in meningococcal outer-membrane protein and polysaccharide preparations made for vaccine use was quantitated by a silver-stain method following SDS-PAGE. The reactivities of LPS in the preparations were also measured by rabbit pyrogenicity and Limulus amoebocyte lysate (LAL) assay. Although rabbit pyrogenicity and LAL assay are more sensitive than the silver stain method, the latter provided an actual amount of LPS present in the protein or in the polysaccharide. For a meningococcal protein preparation, rabbit pyrogenicity showed about one-tenth, and even less by LAL assay, of the actual amount of LPS. This is because protein-bound LPS in meningococcal protein preparations is about 10-fold less active in causing fever in rabbits, and 20- to 40-fold less active in the gelation of LAL than the same amount of a purified free LPS which is generally used as a reference in quantitating LPS in these two assays. As for the small amount of LPS present in a meningococcal polysaccharide preparation, similar LPS content was obtained when measured by the three methods suggesting that the LPS is not bound to the polysaccharide in contrast to that in the proteins mentioned above. The purified meningococcal LPS was pyrogenic in rabbits at 1 ng/kg.     

Characteristics of the mechanism of the development of the epidemic process in meningococcal infection in organized collectives

The specific features of the epidemiology of meningococcal infection in organized groups have been established after comprehensive (epidemiological, microbiological and immunological) studies, evaluated from the viewpoint of the law of the autoregulation of the epidemic process. The studies have revealed the phenomenon of the adaptive biological variability of meningococci with their prolonged reservation due to the transformation of typical bacterial forms of meningococci characterized by strict serogroup specificity and typical fermentative activity into serologically and biochemically undifferentiated forms, capable of prolonged persistence in human populations. The model demonstrating the development of the epidemic process in meningococcal infection in an organized group has been worked out.     

Spectrum of antibodies to iron-regulated proteins in the blood sera of patients with meningococcal infection

55 paired sera from 25 patients with meningococcal infection (meningitis, meningococcemia) were studied with the use of immunoblotting. In these sera antibodies to 15 iron-regulated proteins (IRP) were detected. In the process of the development of meningococcal infection an increase in the content of specific antibodies to IRP with molecular weights of 35 kDa (38%), 43 kDa (52%) and 47 kDa (38%) was found to occur. The induction of antibodies did not depend on the group of the infecting strain, as well as on the patient's age.     

Distribution of HLA antigens in patients with meningococcal infection at different times of year

The character of the distribution of the antigens of the HLA system at different seasons has been studied in 160 patients with generalized forms of meningococcal infection. The occurrence of HLA-Bw16 (the marker of the population gene of susceptibility to meningococcal infection) has proved to be inversely correlated with the seasonal morbidity level.     

Serum immunoglobulin levels in various forms of meningococcal infection and in meningococcus carriers

The levels of serum IgG, IgA and IgM were examined in 191 adults including 103 patients with various forms of meningococcal infection, 32 meningitis convalescents and 56 carriers, in order to elucidate the causes of different susceptibility to the meningococcal infection. The IgD level was determined in 54 meningitis patients as well as in convalescents and carriers. The amount of immunoglobulins was determined by radial immunodiffusion. The level of IgG at the beginning of the disease in patients with the generalized forms of meningococcal infection (meningitis, meningitis combined with meningococcaemia, meningococcaemia) was found to be considerably lower than in healthy subjects. The levels of all immunoglobulins, particularly of IgA and IgM, increased in the course of the disease. The levels of IgG, IgA and IgM in meningitis convalescents a year after recovery were found to be the same as in the controls. The levels of IgG, IgA and IgM in patients with meningococcal nasopharyngitis were significantly lower than in healthy subjects. The carriers showed a decreasd level of IgA and a considerably increased level of IgG while the levels of IgM and IgD did not differ from the control.     

Evaluation of the level of antibodies to purified meningococcal antigens

Group B meningococcal antigens, such as polysaccharide, lipopolysaccharide, protein preparation, as well as sonicates obtained from meningococcal cells, groups A, B and C, have been isolated. On the basis of these preparations the parameters of an enzyme immunoassay system for the detection of antibodies to individual meningococcal antigens have been established, and the specificity of the system and the possibility of using it for the evaluation of the level of antibodies to meningococci in human sera have been studied.     

Investigating the candidacy of LPS-based glycoconjugates to prevent invasive meningococcal disease: immunology of glycoconjugates with high carbohydrate loading

We investigated the immune responses of rabbits that were immunised with lipopolysaccharide (LPS)-based glycoconjugates by measuring the reactivity of the derived sera to a panel of selected wild-type and mutant strains of Neisseria meningitidis. In all cases, high titers of antibodies capable of recognising LPS elaborating the identical structure as presented on the immunising glycoconjugate were obtained, and in most cases the derived sera also recognised heterologous strains including wild-type, but at lower titers. However, although serum bactericidal antibodies were consistently obtained against strains elaborating the same LPS structure as the immunising antigen, this functional response was not observed against wild-type strains. We identified several potentially competing neo-epitopes that had been introduced via our conjugation strategies, which might compete with the conserved inner core oligosaccharide target region, thus reducing the antibody titers to epitopes which could facilitate bactericidal killing. This study has therefore identified key factors that are crucial to control in order to increase the likelihood of obtaining bactericidal antibodies to wild-type meningococcal cells with LPS-derived glycoconjugates. Glycoconjugates utilised in this study, have been found to contain epitopes that do not contribute to the derivation of antibodies that may facilitate bactericidal killing of wild-type strains and must be avoided in future LPS-based glycoconjugate preparations.     

Epidemiological characteristics of meningococcal infection in a number of territories of the RSFSR (1969-1984)

In this work the dynamics and morbidity level in respect of meningococcal infection at 11 territories of the RSFSR at the period of 1969-1984 are analyzed. The study covered altogether 16 cities and 211 districts. The role of big cities as the sources of infection spreading into rural areas and further "fixation" of this infection mainly in regions with a population of 60,000 and more had been established. The data on meningococcal morbidity and carriership among different age groups are presented. The study has shown a pronounced increase in the incidence rate of meningococcal infection among children aged up to 2 years, as well as an increase in the proportion of these children among patients with meningococcal infection in recent years.     

Evaluation of the prophylactic effect of gamma globulin in meningococcal infection.

Results of two controlled epidemiological tests evaluating the prophylactic effect of gamma globulin of Monogolian and Soviet production against meningococcal infection are presented. Observations were carried out on children aged 3 months to 4 years, not attending children's establishments. The results of the observation revealed the following prophylactic effect of gamma globulin of Mongolian production in the first two months after administration: index of efficiency--5.0, coefficient of efficiency--80%, P greater than 0.01. The efficiency of the prophylactic effect of Soviet gamma globulin was limited to one month: the index of efficiency amounted to 5.3, the coefficient of efficiency to 82.2%, P greater than 0.01. The course of meningococcal infection in the children who had received gamma globulin was less severe than in the children of the control group. Lethal outcome was recorded only in the group of children who had not received gamma globulin. The duration of the prophylactic effect of gamma globulin was found to depend on the height of the titres of specific antibodies in the preparation. The preparations are recommended as prophylactic means for children aged from 3 months to 4 years in doses of 1.5 ml (one dose) in the foci of meningococcal infection.     

The epidemiological characteristics of meningococcal infection in the USSR

The epidemiological analysis of morbidity in meningococcal infection in the USSR in the period of 1969-1987 showed that the second rise of the morbidity level occurred in 1984 and was followed by its decrease in most of the regions of the USSR. This study also revealed that the characteristic feature of the second rise of morbidity in meningococcal infection was a considerable involvement of young children (aged up to 3 years), as well as the increased etiological role of group B meningococci in cases of meningococcal infection and the circulation of these microorganisms among the population. Besides, the preservation of the etiological importance of group A meningococci in many regions of the USSR, especially among adults, was noted. In this connection, the use of Soviet group A meningococcal polysaccharide vaccine on epidemiological indications was considered to be epidemiologically substantiated.