Vaccine 23 (2005) 977–983
Naturally-acquired immunity to Neisseria meningitidis group A Jacob Amira , Lesile Louieb , Dan M. Granoffb,∗ a b
Schneider Children’s Medical Center of Israel, Petach Tikva, Israel Children’s Hospital Oakland Research Institute, Oakland, CA, USA
Received 2 June 2004; received in revised form 23 July 2004; accepted 27 July 2004 Available online 16 September 2004
Abstract Group A meningococcal disease is epidemic in Sudan, less common in Uganda, a country bordering the “meningitis belt,” and rare in North America. The basis of naturally-acquired group A immunity is unknown but in North America protection has been attributed to a high prevalence of serum anticapsular antibodies elicited by cross-reacting bacteria. We measured group A anticapsular antibody concentrations and bactericidal titers in sera from 236 adults (47 from the Sudan obtained at the height of a group A epidemic, 57 from Uganda, and 132 from North America). Anticapsular antibody concentrations were higher in Sudanese sera than in North American or Ugandan sera (geometric mean of 31.5 versus 5.4 and 5.3 g/ml, respectively, P < 0.0001). Bactericidal titers of ≥1:4 (presumed to be a protective titer when measured with human complement) were detected in 66% of Sudanese sera as compared with 27 and 23%, respectively, of North American and Ugandan sera (P < 0.0001). Bactericidal activity was inhibited by group A polysaccharide in 58% of the Sudanese bactericidal sera as compared to 17 and 6% of North America and Ugandan bactericidal sera (P < 0.0005). Approximately 50% of non-bactericidal Sudanese sera had high IgA anticapsular antibody concentrations, which were rare in bactericidal Sudanese sera. Thus, serum anticapsular antibodies and bactericidal activity are prevalent in Sudanese exposed to a group A epidemic. Cross-reacting group A anticapsular antibodies are prevalent in North American and Ugandan sera, but bactericidal activity is infrequent and when present is largely directed at non-capsular antigens. © 2004 Elsevier Ltd. All rights reserved. Keywords: Meningococcal vaccine; Bactericidal activity; IgA anticapsular antibody; Sub-Saharan Africa
1. Introduction Since the second world war, epidemic meningococcal disease caused by group A organisms has been largely confined to developing countries, especially in sub-Saharan Africa, the so-called “meningitis belt” where large epidemics occur every 5–10 years [1,2]. Between epidemics, the annual rate of endemic meningococcal disease in sub-Sahara is also much higher than in industrialized countries (approximately 10–40/100,000 population [1,3], as compared to rates of 1–3/100,000 in Europe and North America) [2,4]. With the notable exception of a recent epidemic in Burk∗ Corresponding author. Present address: 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. Tel.: +1 510 450 7640; fax: +1 510 450 7915. E-mail address:
[email protected] (D.M. Granoff).
0264-410X/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2004.07.042
ina Faso caused by a capsular group W-135 strain [5], most epidemic meningococcal disease in sub-Saharan Africa is caused by group A strains [1], which rarely cause colonization [6,7] or disease in industrialized countries [2,4]. Why group A strains are endemic and cause cyclic epidemics in sub-Saharan Africa but have virtually disappeared in the United States and Europe, is unknown. The group A polysaccharide capsule (PS) is a homopolymer of (1 → 6)-2-acetamido-2-deoxy-a-D-mannopyranosyl phosphate (mannosaminephosphate). Robbins and colleagues in the 1970s first pointed out that serum group A anticapsular antibodies were prevalent in the U.S. despite absence of the pathogen from nasopharyngeal specimens and blood or cerebrospinal fluid. They postulated that crossreacting antigens were responsible for eliciting group A anticapsular antibodies, and they identified certain strains of Escherichia coli and Bacillus pumilus in normal flora that
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expressed polysaccharides that cross-reacted with group A polysaccharide [8–10]. However, little information is available on the role of serum cross-reactive group A anticapsular antibodies in eliciting complement-mediated bactericidal activity, a major protective mechanism of naturally-acquired immunity against meningococci [11]. We recently reported the results of a meningococcal polysaccharide vaccine immunogenicity study conducted in Khartoum, Sudan during the 1999 group A epidemic [12]. Serum samples obtained from un-immunized children and adults at the peak of the epidemic showed high concentrations of group A anticapsular antibody and bactericidal activity, which likely reflected recent widespread exposure to the epidemic strain. In the present study, we compared the antigenic binding characteristics and complement-mediated bactericidal activity of naturally-acquired group A antibodies in sera from a new group of adults living in the Sudan who had been exposed to the group A epidemic, and sera from adults in North America who were unlikely to have been exposed to group A meningococci. As a third contrast group, we performed similar studies on sera from healthy adults living in Uganda, a country located south of Sudan, and outside of the traditional African “meningitis belt” [13,14], where group A meningococcal disease is less common [1].
2. Methods 2.1. Serum samples We investigated convenience samples of stored sera that had been collected from 236 adults, ages 18–52 years, who were participants in previous studies conducted in the Sudan, Uganda or North America [12,15,16]. Selection of the sera was based on having sufficient volumes available for the different serologic studies described below. The 47 sera from the Sudan were obtained immediately before vaccination from subjects living in Khartoum who were participants in a meningococcal vaccine immunogenicity study [12], and who had no previous history of meningococcal immunization. These subjects had been excluded from our previous immunogenicity analysis because of failure to return for follow-up after the immunization. The 57 samples from Uganda came from healthy control adults living in Kampala who were enrolled in an unpublished study of genetic factors affecting progression of tuberculosis in HIV-infected persons. These controls had no evidence of active tuberculosis and had negative serologic studies for HIV infection. The only identifiers available were subject number, age and sex. Although information on meningococcal vaccination of these subjects was not available, it is unlikely that they would have been given meningococcal polysaccharide vaccine since this vaccine is used infrequently in Kampala. The 132 sera from North America were obtained before immunization from 27 subjects enrolled in a meningococcal polysaccharide vaccine trial in
eastern Ontario, Canada [15], and 105 subjects enrolled in meningococcal vaccine trials conducted at Children’s Hospital & Research Center at Oakland, California. None of these individuals had a previous history of meningococcal immunization. The 132 North American samples included 26 sera that had been assayed for group A antibodies as part of the previous report [12]. Use of each of the stored serum collections for investigation of meningococcal immunity was approved by the Institutional Review Board (IRB) of Children’s Hospital and Research Center at Oakland. 2.2. Serology The serum concentrations of total group A anticapsular antibody (IgM, IgG and IgA) were measured by a radioantigen binding assay (RABA), preformed as previously described [17]. The concentrations of IgG and IgA anticapsular antibody to group A polysaccharide were measured by ELISA using group A polysaccharide derivatized with adipic dihydrazide as the target antigen, prepared as previously described [17]. Antibody concentrations were assigned to the test sera using a standard curve generated from assaying serial dilutions of the CDC1992 reference serum (IgG group A antibody concentration of 91.8 g/ml, and IgA concentration of 20.6 g/ml) [18]. Complement-mediated bactericidal titers were measured against group A strain Z1092 [19] (strain provided by Dr. Mark Actman, Berlin, and also referred in some publications as “129E”). All test sera were heated at 56 ◦ C for 30 min to inactivate internal complement. The assay used washed, logphase broth-grown bacteria. The source of complement was serum from a healthy adult. This serum had no detectable intrinsic bactericidal activity when tested at final serum concentrations of 20 or 40% (two-fold higher than that used to test bactericidal activity in the test sera), and supported killing of human immune serum that had been heat-inactivated to remove endogenous complement activity. In all other respects, the assay was performed as previously described [20].
3. Results 3.1. Geographic differences in serum bactericidal activity Fig. 1, Panel A, shows the respective reverse cumulative distributions of the bactericidal titers of the serum samples from adults in the Sudan, North America and Uganda. Titers ≥1:4, which predict protection against group C meningococcal disease [11], were found in 66% of the Sudanese, as compared with 27 and 23%, respectively, of the adults from North America and Uganda (P < 0.0001). The respective reciprocal geometric mean titers were 15.7, 3.2 and 3.1 (P < 0.0001).
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equal to four-fold decrease in titer, or a change from a titer of 1:4 to 2 g/ml were prevalent in all three populations (100% of Sudanese, 91% of Ugandan and 84% of North American sera), concentrations >10 g/ml were more common in the Sudanese sera (89% as compared with 28 and 25% of those from North America and Uganda adults, respectively (P < 0.0001) (Panel B). Seventy-two percents of the Sudanese had IgG antibody concentrations >10 g/ml as compared with 14 and 5% of the other two groups (P < 0.0001) (Panel C). 3.4. Inhibition of group A anticapsular antibody binding by soluble group A polysaccharide We selected a subset of all sera with >7 g/ml of total anticapsular antibody (22 sera from the Sudan, 17 from Uganda and 21 from North America), which were diluted to an antibody concentration of 0.4 g/ml and assayed for binding to radio-labeled antigen in the presence of different concentrations of unlabeled group A polysaccharide (range: 0.01–0.3 g/ml). For each serum, the antigen concentration required for inhibition of 50% antibody binding was determined graphically. The respective means ± S.E. of the antigen concentrations required for 50% inhibition of binding of the Sudanese and Ugandan sera were not significantly
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Table 1 Inhibition of serum bactericidal activity by soluble group A polysaccharide Samples
Sudan North America Uganda
Number of sera testeda
31 36 13
Number of sera inhibited (%) at antigen concentration (g/ml) 10*
1*
0.1**
18 (58.1) 6 (16.6.) 1 (7.7)
18 (58.1) 6 (16.6) 1 (7.7)
8 (25.8) 3 (8.3) 0 (0.0)
Sera with bactericidal titers ≥1:4. Inhibition was defined by a decrease in titer to 15 g/ml. Data are shown for eight sera with bactericidal titers 1:8. The horizontal lines designate the respective geometric mean concentrations (see also Table 2).
antibody concentrations to meningococcal A polysaccharide in the Sudanese sera with total anticapsular antibody concentrations >15 g/ml. The results are stratified by sera with bactericidal titers 1:8. The serum IgA anticapsular antibody concentrations of the individual Sudanese subjects with bactericidal titers 1:8 are shown in Fig. 2. The IgG anticapsular antibody concentrations of the Sudanese sera with bactericidal titers 1:8 (geometric means of 12.8 g/ml and 29.8 g/ml, respectively, P = 0.01). However, the reverse was true for the IgA anticapsular antibody concentrations, which were higher in the Sudanese sera with bactericidal titers 1:8, P < 0.0001). There was no significant
Table 2 Anticapsular antibody concentrations of Sudanese sera in relation to bactericidal activitya
Number of sera tested Total anticapsular antibody (geometric mean, g/ml by RABA) IgG anticapsular antibody (geometric mean, g/ml by ELISA) IgA anticapsular antibody (geometric mean, g/ml by ELISA) Group A polysaccharide concentration for 50% inhibition of anticapsular antibody binding by RABA (mean, g/ml) a ∗ ∗∗ ∗∗∗
Selected sera with >15 g/ml of anticapsular antibody as measured by RABA. P < 0.0001. P = 0.06. P < 0.01.
Bactericidal titer, 1:8
8 30** 12.8*** 11.2* 0.037
18 52** 29.8** 0.7* 0.048
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difference in the group A polysaccharide antigen concentrations required for inhibition of anticapsular antibody binding in the two groups (means of 0.037 and 0.048 g/ml, respectively, P ≥ 0.4). This result suggests that the average avidity of the anticapsular antibodies in the bactericidal and nonbactericidal sera was similar.
4. Discussion In the 1940s, Group A meningococcal strains caused large epidemics in the United States with annual incidence rates as high as 300 per 100,000 [2]. These epidemics subsided after World War II, and during the last two decades nearly all disease in the U.S. has been caused by group B, C, Y or W-135 strains, with annual rates ranging from 0.5 to 1.5 per 100,000 [2,23]. The lack of group A disease in the U.S. is notable since there would appear to be ample opportunities for group A strains to enter the country from persons traveling from sub-Saharan Africa where group A disease is hyperendemic and is associated with periodic massive epidemics. The reasons for persistence of group A disease in sub-Saharan Africa and its disappearance from the U.S. and other industrialized countries are poorly understood. Naturally-acquired group A anticapsular antibodies can be elicited by nasopharyngeal colonization by N. meningitidis group A organisms, which likely accounted for the high prevalence and high concentrations of anticapsular antibody in the Sudanese sera collected during the height of the 1999 group A epidemic (Fig. 1, Panel B). The prevalence of serum anticapsular antibody also was high in the Ugandan and North American sera although the concentrations of anticapsular antibody in these sera were much lower than in the Sudanese sera (Fig. 1, Panel B). The antigenic source stimulating serum anticapsular antibodies in persons living in North America sera is likely colonization by microorganisms other than group A N. meningitidis that express group A cross-reacting polysaccharides [8,10], since group A colonization and disease are rare in North America. The antigenic stimulus of the group A anticapsular antibodies in the Uganda sera is unknown but could have been exposure to cross-reacting bacteria and/or group A meningococci since group A strains cause disease in Uganda, although epidemics are rare. The results of inhibition studies of anticapsular antibody binding in the RABA indicated that the avidity of the anticapsular antibody in the Uganda sera was closer to that of the antibodies in the Sudanese sera than the antibodies in the North American sera. Only a quarter of the North American or Uganda sera had bactericidal titers of 1:4 or greater (presumed to be a protective titer when measured with human complement [11]), and absorption studies indicated that most of the serum bactericidal antibodies in these sera were directed at non-capsular antigens (Table 1). In contrast, the bactericidal antibodies in the majority of the Sudanese sera appeared to be directed at the group A polysaccharide.
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Ample evidence indicates that vaccine-induced group A serum anticapsular antibodies confer protection against meningococcal disease by eliciting complement-mediated bactericidal activity and, possibly, by opsonization (reviewed in [24]). However, little is known about the role of naturallyacquired group A cross-reacting anticapsular antibodies in protection. Several lines of evidence suggest that crossreacting serum group A anticapsular antibodies may be less functionally active than serum antibodies elicited by meningococcal group A polysaccharide. First, the naturallyacquired cross-reactive group A anticapsular antibodies in the North American sera appeared to have lower avidity than that of the anticapsular antibodies in the Ugandan or Sudan sera, as suggested by the requirement for 1.8- to 2.5-fold higher concentrations of group A polysaccharide to inhibit group A antibody binding in the North American sera. In previous studies, lower avidity anticapsular antibodies were less effective in eliciting complement-mediated bacteriolysis and/or opsonization of a variety encapsulated bacterial pathogens, including Haemophilus influenzae type b [25], Streptococcus pneumonia [26] and N. meningitidis group C [16,17,27]. The lower avidity anticapsular antibodies also were less effective in conferring passive protection in animal models of bacteremia caused by these pathogens [16,17,26–28]. Secondly, experimental polysaccharide–protein conjugate vaccines prepared from cross-reacting group A polysaccharides failed to elicit serum bactericidal antibodies in mice, whereas similar conjugate vaccines prepared from the native group A polysaccharide elicited high serum bactericidal titers [29]. The results of the present study indicate that group A cross-reacting anticapsular antibodies have only a minor role in eliciting serum bactericidal activity, the traditional hallmark of protective meningococcal immunity. However, it is possible that the low avidity cross-reacting group A anticapsular antibodies that lack bactericidal activity can elicit opsonization and, thereby, confer protection against disease. Thus, our data do not rule out a contribution of cross-reactive group anticapsular antibodies in conferring immunity against meningococcal disease in North America. Group A epidemics in sub-Saharan Africa begin during the dry season and resolve rapidly at the onset of the rainy season [1], which underscore the importance of climatic factors on susceptibility of the population to meningococcal disease [30]. The presence of certain microorganisms in the normal flora may inhibit acquisition of group A strains [31], while colonization by group A N. meningitidis or cross-reacting bacteria can stimulate protective IgM or IgG antibodies, or elicit serum IgA anticapsular antibodies that do not activate complement and, therefore, have a minimal role, if any, in eliminating bloodstream infection. Serum IgA anticapsular antibodies also have been reported to inhibit complementmediated immune lysis of meningococci by IgG or IgM anticapsular antibodies, which could increase susceptibility to group A disease [21,22,32]. Therefore, a combination of both immune and environmental factors may render some
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populations resistant and others susceptible to epidemics of group A disease. The main factors that contribute to group A epidemics in sub-Sahara include an increased risk of exposure to virulent strains, a susceptible population of young children who have not yet acquired natural immunity, and a small portion of adults (35%) who lack serum bactericidal activity according to our data (Fig. 1, Panel B). Environmental factors include crowding, exposure to smoke from indoor cooking with charcoal stoves and, most importantly, dust storms that blow from the Sahara during the dry season [1]. The Uganda population also are exposed to group A organisms but large epidemics are infrequent despite a low sero-prevalence of group A bactericidal activity, which was similar to that in the North American sera (Fig. 1, Panel A), and poor socio-economic conditions in Uganda that are not dissimilar to those in Sudan. The principal difference between Uganda and the Sudan may be climatic conditions that distinguish countries in sub-Sahara from those located further south in Africa. Given the low sero-prevalence of group A serum bactericidal activity in North America, we assume that small group A epidemics can occur if the population is exposed to a virulent group A meningococcal strain, as happened in Finland in the 1970s [33] and Russia in the 1990s [34]. The main question, therefore, is why do group A meningococcal strains readily circulate in sub-Saharan African and, to a lesser extent in neighboring countries such as the Uganda, but not in North America where N. meningitidis group B or Y strains colonize 5–10% of healthy individuals [7,35]. The North America population lack the very poor socio-economic conditions and climatic conditions of sub-Sahara. Understanding the possible role of low avidity cross-reacting anticapsular antibodies that lack bactericidal activity in protection against disease, and how host and environmental factors contribute to the dynamics of spread of group A meningococci in different populations, will be critical for implementing successful vaccination strategies for prevention of group A epidemics in sub-Sahara [36–42].
Acknowledgements This work was supported, in part, by grants RO1 AI046464 and AI058122 from the National Institutes of Allergy and Infectious Disease, NIH. Sera from the adults in Oakland were obtained in the Pediatric Clinical Research Center of Children’s Hospital & Research Center at Oakland, which was supported by Grant M01-RR01271 from National Center for Research Resources, NIH. We are grateful to Drs. Noni MacDonald and James King, Children’s Hospital of Eastern Ontario, Ottawa, Canada for providing the samples from Canada; and Drs. Roy D. Mugerwa and Alphonse Okwera, Makerere University, Kampala and Kevin Newell, Kampala, for collecting the serum samples from subjects in Uganda. Betty Flores obtained the serum samples from the subjects from Oakland California. Dr. F. Marc LaForce, Meningitis
Vaccine Project, Ferney-Voltaire, France, provided helpful comments on the manuscript.
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