Elsevier

Vaccine

Volume 36, Issue 15, 5 April 2018, Pages 1983-1989
Vaccine

Prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B strains, China

https://doi.org/10.1016/j.vaccine.2018.02.112Get rights and content

Abstract

Objective

To systematically investigate the prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B (NmB) in China.

Methods

A total of 485 NmB strains isolated in 29 provinces of China between 1968 and 2016 were selected from the culture collection of the national reference laboratory according to the isolation year, location, and source. Multi-locus sequence typing (MLST) and porA gene sequencing were performed on all 485 study strains; PCR was used to detect the fHbp, nadA, and nhba gene of 432 strains; positive amplification products from the fHbp and nadA genes from all strains, as well as those of the nhba gene from 172 representative strains, were sequenced.

Results

MLST results showed that the predominant (putative) clonal complexes (CCs) of NmB isolates have changed over time in China. While strains that could not be assigned to existing (p)CCs were the biggest proportion, CC4821 was the most prevalent lineage (36.0%) since 2005. PCR and sequence analysis revealed that the 4CMenB and rLP2086 vaccine candidates were highly diverse. Respectively, 152 PorA genotypes and 83 VR2 sequences were identified with significant diversity within a single CC; the complete nadA gene was found in ten of 432 study strains; fHbp was present in most strains (422/432) with variant 2 predominating (82.9%) in both patient- and carrier- derived isolates; almost all strains harbored the nhba gene while sequences were diverse.

Conclusions

With regards to clonal lineages and vaccine candidate proteins, NmB isolates from China were generally diverse. Further studies should be performed to evaluate the cross-protection of present vaccines against Chinese NmB strains.

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)

  • P.C. Richmond et al.

    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

    (2012)
  • L.K. McNeil et al.

    Detection of LP2086 on the cell surface of Neisseria meningitidis and its accessibility in the presence of serogroup B capsular polysaccharide

    Vaccine

    (2009)
  • J. Holst et al.

    Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease

    Vaccine

    (2003)
  • R.Z. Jafri et al.

    Global epidemiology of invasive meningococcal disease

    Popul Health Metr

    (2013)
  • N. Crum-Cianflone et al.

    Meningococcal vaccinations

    Infect Dis Ther

    (2016)
  • S. Ghanem et al.

    Quadrivalent meningococcal serogroups A, C, W, and Y tetanus toxoid conjugate vaccine (MenACWY-TT): a review

    Expert Opin Biol Ther

    (2013)
  • D.M. Granoff

    Review of meningococcal group B vaccines

    Clin Infect Dis

    (2010)
  • J. Lucidarme et al.

    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

    (2010)
  • D. Toneatto et al.

    Emerging experience with meningococcal serogroup B protein vaccines

    Expert Rev Vaccines

    (2017)
  • D. Serruto et al.

    Neisseria meningitidis GNA2132, a heparin-binding protein that induces protective immunity in humans

    Proc Natl Acad Sci USA

    (2010)
  • V. Masignani et al.

    Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870

    J Exp Med

    (2003)
  • M. Comanducci et al.

    NadA, a novel vaccine candidate of Neisseria meningitidis

    J Exp Med

    (2002)
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