Prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B strains, China
Introduction
As a leading cause of invasive bacterial infections, Neisseria meningitidis causes significant morbidity and mortality globally [1]. Based on the structure of the capsule polysaccharide, N. meningitidis have been classified into 12 serogroups, among which serogroup A, B, C, Y, W, and X are primarily responsible for most invasive cases [1], [2]. The serogroups exhibit dynamic epidemiological characteristics according to time and geography [2]. On the basis of systematic surveillance, different countries have developed and applied appropriate vaccines specifically against the prevalent serogroups [3]. Many of the vaccines target the capsular polysaccharide and so function at the serogroup level, they are broadly effective against the corresponding serogroups [4]. Vaccines for Neisseria meningitidis serogroup B (NmB) are atypically directed at outer membrane proteins because the capsular polysaccharide of NmB is poorly immunogenic and therefore not recommended as a suitable vaccine component [5]. Unlike capsular polysaccharide, which has a limited number of types, outer membrane proteins can be highly diverse between different clonal complexes (CCs) and even have diversity within a single CC [6]. Moreover, serogroup B has been demonstrated to have higher genetic diversity than other serogroups [7]. Therefore, the development of a universally effective vaccine against all serogroup B strains circulating in different geography regions is extremely challenging.
At present, two NmB vaccines (4CMenB and rLP2086) have been licensed. The 4CMenB vaccine mainly includes the outer membrane vesicle (OMV, P1.7-2,4), Factor H binding protein (FHbp, variant 1.1), Neisserial Heparin Binding Antigen (NHBA, peptide 2), and Neisseria adhesion A (NadA, variant 3.1) [8]; rLP2086 contains two variants of FHbp (variant 1.55 and 3.45). Each vaccine includes a limited number of proteins and variants of the protein. Consequently, they cannot be universally effective against diverse NmB strains across different regions. Therefore, while these different vaccines provide multiple options, they are not ready to be used for a country before an appropriate baseline evaluation is performed. Given the significant antigenicity of the vaccines targeting corresponding protein types as described previously [9], [10], [11], [12], the effectiveness mainly depends on cross-reactivity of vaccine antigens among NmB population, their expression level and levels of human serum bactericidal antibody elicited by the vaccine.
Before the 1980s, several countries in Europe and South America experienced a high disease burden due to NmB [13]. Comparatively, more invasive cases were associated with non-serogroup B strains in other countries [13], [14], [15]. However, due to unknown factors, serogroup B infections have increased in many regions over the last 30 years [16], [17], [18], [19]. According to data from national surveillance, China reflects this change in epidemiology. In general, serogroups A, C, and W appeared sequentially and constitute the most prevalent serogroups at present [20], [21]. Serogroup B has tended to be associated with sporadic cases, and has not caused significant public health concern until its proportion recently increased both as an invasive organism and as a carriage strain [data from population-based meningococcal disease surveillance system in China, not published]. Moreover, previous studies have revealed that ST-4821 complex (CC4821) has become one of the predominant clonal lineages and possessed both serogroup C and B strains [7], [22]. Considering the hypervirulence of CC4821 serogroup C [20], the spread of CC4821 NmB is a cause for concern.
To clarify the applicability of present vaccines targeting NmB in China and consider novel vaccine formulas, we performed extensive analysis on genetic diversity of vaccine proteins in this study, while also performing molecular typing of NmB strains.
Section snippets
Selection of NmB strains and DNA preparation
There is a population-based meningococcal disease surveillance system throughout China. Suspected N. meningitidis strains are collected from invasive cases by local Center for Disease Control and Prevention (CDC). For outbreak investigation, carrier strains were also collected from close contacts. In surveillance sites, healthy carriage of N. meningitidis is surveyed periodically and carrier strains are isolated. All the strains are sent to our laboratory for identification and other testing.
In
STs and lineages of NmB isolates
A total of 270 STs were identified from the 485 NmB isolates. One hundred and seven STs (representing 211 strains) were assigned to ten CCs: CC4821, CC41/44, CC11, CC32, CC5, CC269, CC162, CC364, CC8, and CC92. The other STs (representing 274 strains) could not be assigned to currently defined CCs and were thus termed UA (unassigned) in this study. UA accounted for the largest proportion of strains isolated in both periods: between 1968 and 2000 and between 2005 and 2016. From the minimum
Discussion
In addition to previous studies [29], [30], [31], this study revealed more about the extreme complexity of the NmB population. Except the existing CCs, several new clonal lineages (pCCs) were identified and a large number of strains remained clonally unassigned (singleton). According to previous studies [7], [32], [33], other serogroups prevalent in China, specifically serogroups A, C, and W, had significantly lower diversity. The complexity of the NmB population represents an important
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81602903), the State Key Laboratory for Infectious Disease Prevention and Control (2015SKLID502), and the Medical Scientific Research Foundation of Hubei Province, China (No. JX6B23).
References (45)
- et al.
Global epidemiology of meningococcal disease
Vaccine
(2009) - et al.
Clonal characteristics of invasive Neisseria meningitidis following initiation of an A + C vaccination program in China, 2005–2012
J Infect
(2015) - et al.
Prevalence of meningococcal meningitis in China from 2005 to 2010
Vaccine
(2015) - et al.
Meningococcal disease in Europe: epidemiology, mortality, and prevention with conjugate vaccines. Report of a European advisory board meeting Vienna, Austria, 6–8 October, 2000
Vaccine
(2001) - et al.
The changing and dynamic epidemiology of meningococcal disease
Vaccine
(2012) - et al.
Identification of a new Neisseria meningitidis serogroup C clone from Anhui province, China
Lancet
(2006) - et al.
Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease
Vaccine
(2009) - et al.
Genetic characteristics of serogroup A meningococci circulating in China, 1956–2005
Clin Microbiol Infect
(2008) - et al.
Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein based vaccine to prevent serogroup B meningococcal disease
Vaccine
(2010) - et al.
A phase 2 open-label safety and immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy adults
Vaccine
(2013)
A bivalent Neisseria meningitidis recombinant lipidated factor H binding protein vaccine in young adults: results of a randomised, controlled, dose-escalation phase 1 trial
Vaccine
Detection of LP2086 on the cell surface of Neisseria meningitidis and its accessibility in the presence of serogroup B capsular polysaccharide
Vaccine
Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease
Vaccine
Global epidemiology of invasive meningococcal disease
Popul Health Metr
Meningococcal vaccinations
Infect Dis Ther
Quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT): a review
Expert Opin Biol Ther
Review of meningococcal group B vaccines
Clin Infect Dis
Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine
Clin Vaccine Immunol
Emerging experience with meningococcal serogroup B protein vaccines
Expert Rev Vaccines
Neisseria meningitidis GNA2132, a heparin-binding protein that induces protective immunity in humans
Proc Natl Acad Sci USA
Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870
J Exp Med
NadA, a novel vaccine candidate of Neisseria meningitidis
J Exp Med
Cited by (5)
Comparison of the Pathogenicity of Neisseria meningitidis Isolates of Hyperinvasive Sequence Type 7 Belonging to Serogroups A, B, C, and X
2020, Biomedical and Environmental SciencesComparative genomic analyses of Chinese serogroup W ST-11 complex Neisseria meningitidis isolates
2020, Journal of InfectionCitation Excerpt :The fact that the isolates from the other countries largely preceded the estimated emergence of W:cc11 in China suggests that the corresponding variation would have been imported into China rather than exported. Historically, only certain lineages, such as serogroup A ST-3, ST-5, and ST-7 complexes, and serogroup C/B ST-4821 complex, have expanded in China.30–33 Other lineages which are frequent outside of China, such as serogroup C cc11, were occasionally isolated and have not increased in prevalence.32,34
Screening of protective antigen of factor H binding protein of different variants of serogroup B Neisseria meningitidis in China
2021, Chinese Journal of BiologicalsEpidemiological and Etiologic Characteristics of Meningococcal meningitis in Xinjiang Uygur Autonomous Region,1960-2019
2021, Chinese Journal of EndemiologyInvestigation on carrying status of Neisseria meningitidis in healthy population in Baoshan City
2021, Chinese Journal of Biologicals