Meningococcal vaccines in China

ABSTRACT

Meningococcal meningitis caused by Neisseria meningitidis is a reportable infectious disease in China, due to the high incidence of meningitis in the era before the availability of vaccines. The disease incidence was markedly reduced after meningococcal vaccination was introduced in the 1980s. Currently, there are polysaccharide, conjugate, and combined vaccine formulations against meningococcal meningitis in the Chinese market, almost all of which are produced by domestic manufacturers. It is necessary to further enhance national meningococcal surveillance to improve the level of prevention and control of meningococcus. However, the immune efficacy and persistence of immunity of vaccines should be monitored. More importantly, additional investments should be made to develop serogroup B meningococcal vaccines.

KEYWORDS:

• Neisseria meningitidis
• invasive meningococcal disease
• polysaccharides vaccines
• conjugate vaccines
• quality control
• China

1. Introduction

Neisseria meningitidis is a leading cause of invasive meningococcal disease (MD).¹ According to the different structures of its extracellular polysaccharide capsule, 12 distinct capsular groups of meningococcus have been classified; MD is mainly caused by 6 meningococcal capsular groups: A, B, C, W, Y, and X.² MD is characterized by a broad clinical spectrum that can involve meningitis, meningococcemia, or both, as well as other clinical presentations, with a 6–10% case-fatality rate.³ Furthermore, permanent sequelae associated with MD, such as brain damage and amputations of limbs or digits, can occur.³ To date, the only recognized reservoirs of N. meningitidis are humans. It is reported that asymptomatic nasopharyngeal carriage is frequent and involves ~10% of the general population.⁴ Transmission of the bacterium from an infected individual to another person occurs via direct contact with droplet respiratory secretions. An estimated 1.2 million cases of MD are reported each year worldwide, including 135,000 deaths, and most cases occur in developing and underdeveloped countries. The incidence of MD is highest for children <1 year, but in epidemic outbreaks, older children and adolescents can have high incidence of this disease.^5,6

In China, meningococcal meningitis is a reportable infectious disease due to the high incidence of MD before the introduction of meningococcal vaccination.^7–9 In this review, we briefly describe the epidemiological characteristics of MD and summarize the development of various meningococcal vaccines in China. Quality control assessments of meningococcal vaccines currently used in the country are also reviewed.

2. Meningococcal meningitis in China

In the era when vaccines were unavailable, five pandemics of MD were recorded in China, and nationwide pandemics appeared every 8–10 years, each of which lasted approximately 3–4 years.^8,9 The highest incidence of MD occurred in the spring of 1967. More than 3.04 million cases were reported, with greater than 160,000 deaths and a 5.5% fatality rate. The next largest pandemic happened in 1977, and had a morbidity of 59.7 cases per 100,000 and a 4.0% fatality rate. Meningococcal polysaccharide vaccines (MenPV) have been used since the 1980s; the incidence of the disease has been sharply reduced and continues to be reduced.^7,8,10 According to the data from the Chinese infectious disease reporting system, the incidence of MD is less than 1 per 100,000 since the 1990s and only 104 and 111 MD cases were reported in 2018 and 2019, respectively (Figure 1). The incidence is higher in children <5 years, and the younger the child, the higher the incidence.¹¹ Previous studies have investigated N. meningitidis carriage rates among the healthy population from different provinces in China, and recent meta-analysis estimates that the overall N. meningitidis carriage rate was 2.7% (95% CI 2.0–3.5%) in 2005–2015.¹²

Figure 1. Reported meningococcal meningitis and death cases in China, 2002–2019

Red columns and the blue line represent the annual reported and death cases, respectively.

In mainland China, routine epidemiological surveillance, including acute MD case reports, outbreak surveys, and collections of cerebrospinal fluid and blood of suspected cases, have been conducted, and the National Centers for Disease Control and Prevention and its provincial branches are legally required to formally report MD cases to the Ministry of Health monthly. However, considering MD is clinically diagnosed by physicians, and not all hospitals diagnose MD using the current laboratory methods, this suggests a significant underestimation of burden of N. meningitidis infection in China.¹⁰

N. meningitidis serogroup A is the most common serogroup involved in MD pandemics; the earliest serogroup A strain was isolated in the 1950s in China. Several historic large outbreaks were caused by serogroup A before the 1980s.¹³ Serogroup distribution of 922 N. meningitidis strains isolated from 22 provinces in China from 1956–2002 included 638 serogroup A (69.2%), 254 serogroup B (27.6%), 9 serogroup C (1.0%), and another group of 21 strains (2.3%),¹⁴ suggesting serogroup C seldom caused MD before 2000 in China. However, serogroup C ST4821 has emerged and caused a large MD outbreak in Anhui province, China during 2003–2004.¹⁵ The new strain appears to be more invasive, causing serious complications and a higher case-fatality rate than serogroup A. It is interesting that the ST4821 lineage became the predominant clone and rapidly spread nationwide, causing several local outbreaks.¹⁶ Zhou et al reported that 47.1% serogroup C (n = 164), 35.3% serogroup A (n = 123), and 12.9% serogroup B (n = 45) strains were found in 348 laboratory-confirmed patients with MD from 2005–2012, and almost all serogroup C (92.4%, 123/131) and 34.5% (10/29) of serogroup B strains belonged to the ST4821 clonal complex.¹⁷ Genomic analysis has demonstrated that the serogroup C ST4821 clonal complex is likely the origin of serogroup B ST4821.¹⁸ The emergence and circulation of serogroup B ST4821 may increase the incidence of MD, which causes epidemics and outbreaks in China.^18,19 Recently, phylogenetic analysis has suggested that successive recombination events within genes encoding surface antigens and acquisition of quinolone resistance mutations may have contributed to the emergence of the ST4821 clone in China.²⁰ Furthermore, a few cases of serogroup W ST4821 MD were reported in southeast China in 2013,²¹ although all 14 serogroup W strains isolated from 2005–2012 were ST11 complex.¹⁷ Other serogroup N. meningitidis strains, including serogroup Y and X have occasionally been reported in China.^17,22

3. Meningococcal vaccines in the Chinese market

Licensed vaccines against MD have been available for more than 50 years. It has been demonstrated that vaccination of at-risk populations is the most viable strategy to control MD.²³ In China, the history of meningococcal vaccine-related studies can be traced back to 1939, but failed to be used. In 1963, an inactivated whole cell vaccine was developed, but this type of vaccine was not widely used due to adverse reactions.

There are polysaccharide, conjugate, and combined vaccine formulations available in the Chinese market. Almost all meningococcal vaccines are produced by domestic manufacturers. One imported bivalent (A and C) MenPV, has been licensed since the 2000s, but no products were sent to the National Institutes for Food and Drug Control (NIFDC) for lot release after 2013. Untill now, no meningococcal protein-polysaccharide conjugate vaccines (MenCV) from other countries have been licensed in China. This may be due to the fact that there are various domestic meningococcal vaccines available in the Chinese market. Currently, the routine vaccination schedule for MenPV in China includes a total of four doses, two of which include doses of serogroup A univalent MenPV for children ages 6–18 months and another two doses of serogroups A and C bivalent MenPV (one dose for children at 3 years and one dose for children at 6 years).²⁴ Vaccination via conjugate and combined vaccines for children are paid by the parent. It has been shown that the reported routine vaccination coverage of meningococcal vaccines was more than 99% in China (not including Hong Kong, Macao, and Taiwan) in 2015.²⁵

Many studies have demonstrated that serum bactericidal antibody (SBA) activity is highly correlated with immunity to meningococcal disease.^26–29 To date, it is generally accepted that SBA is the best surrogate of protection for all serogroups. An SBA titer of either ≥ 4 or ≥ 8 using human or rabbit complement, respectively, or a ≥ 4-fold rise in SBA pre- to post-vaccination are considered as the cutoff value for protection after vaccination with meningococcal polysaccharide or conjugate vaccines.²⁴ Therefore, the immunogenicity of meningococcal polysaccharide or conjugate vaccines is commonly evaluated using seroconversion to SBA-positivity.^30–32

3.1 Polysaccharide vaccines

Since the 1960s, serogroup A MenPV have been successfully developed.²⁷ Randomized, controlled trials have been conducted in many countries and regions,^28,33,34 demonstrating the safety and effectiveness of serogroup A MenPVs in children and young adults. To date, they are available in bivalent (A and C), trivalent (A, C, and W135), and quadrivalent (A, C, W135, and Y) polysaccharide vaccines licensed by different countries.²³

In China, MenPV-related studies were conducted in the 1970s and a MenPV was successfully developed in 1980.³⁵ Different from the serogroup A MenPVs of other countries,²³ a single-dose serogroup A MenPV containing 30 μg of polysaccharides is used in China.⁷ It is reported that more than 10 million subjects were immunized with serogroup A MenPV from 1977–1980, and the efficacy of the vaccine was 86.5–92.3%. Between 3.8–12.8%, and 0.8–1.3% of 3,874 subjects developed local reactions at 6 and 24 h after vaccination, respectively.⁷ Many studies have demonstrated that extensive use of serogroup A MenPV to immunize children greatly contributed to reduce the burden of MD in China.³⁶ To date, serogroup A MenPVs are still included in the national vaccination program. In 2019, more than 20 million human doses of serogroup A MenPVs were released by the NIFDC onto the market (Figure 2).

Figure 2. Number of lot release of different types of meningococcal vaccines in China, 2010–2019

Hib-MenAC represents a combination vaccine based on Haemophilus influenza type b (Hib) and meningococcal A and C polysaccharide conjugated with tetanus toxoid; MenPV and MenCV represent meningococcal polysaccharide vaccines and protein-polysaccharide conjugate vaccines, respectively.

Due to the national rapid spread of N. meningitidis serogroup C, a national vaccination program using a serogroup A and C bivalent MenPV was initiated to replace the serogroup A polysaccharide-based vaccines in 2005.¹⁰ The immunogenicity and clinical efficacy of serogroup A and C MenPVs are well established in China.^37,38 In the past five years, more than 20 million human doses of bivalent (A and C) MenPV were released onto the Chinese market each year (Figure 2). Furthermore, trivalent or pentavalent MenPVs, which should protect against more serogroups, have also been shown to be as well-tolerated and immunogenic in other countries.^39,40 A phase III clinical trial has also been performed to evaluate the efficacy and safety of quadrivalent (A, C, W135, and Y) vaccines produced by Chinese manufacturers in children aged ≥ 2 years and in adults in China.³² Adverse reactions to quadrivalent (A, C, W135, and Y) MenPVs were mild and no significant difference was found when compared to bivalent (A and C) MenPVs. Consistent with other studies, more than 90% of subjects showed a ≥ 4-fold increase of SBAs against the four serogroups after vaccination with a single dose of test vaccine, confirming the efficacy of quadrivalent vaccines.³² Since 2006, serogroup A, C, W135, and Y MenPVs have been licensed for use in China and the vaccination cost is paid by the individual. Six local manufacturers produce the quadrivalent (A, C, W135, and Y) vaccine and approximately 3.3 million human doses of quadrivalent vaccines were released in 2019 (Figure 2).

3.2 Protein-polysaccharide conjugate vaccines

It is reported that MenPVs are T cell-independent antigens which induce humoral responses but not T-cell responses or immunological memory, which means that immune protection will be relatively short-lived.⁴¹ To address the limitations posed by MenPVs, meningococcal capsular polysaccharides were chemically conjugated to protein carriers, such as tetanus toxoid (TT), diphtheria toxoid, and a nontoxic mutant of diphtheria toxin, the Corynebacterium diphtheriae cross-reactive material 197 (CRM-197), which was shown to stimulate a T-cell response, since the 1990s.^23,30,31 Many studies have demonstrated that meningococcal conjugate vaccines are safe and immunogenic, and result in immunologic memory when administered as vaccines to infants.^{29–31,42,43} Licensed MenCV are currently monovalent (A or C), bivalent (A and C) or quadrivalent (A, C, W135, and Y) worldwide.²³

To offer better protection against MD, conjugated formulations were also developed during the last decades in China. Different from other countries, only bivalent (A and C) MenCV are currently licensed.⁴⁴ The conjugate vaccines contain 10 μg each of the individual polysaccharides conjugated to the TT carrier (except for a MenB outer membrane protein used as the carrier), and do not contain preservatives or adjuvants. The vaccine has been demonstrated to be safe and immunogenic in subjects aged 6–23 months, 2–15 years, and 16–30 years after 1–3 doses, inducing higher SBA titers against serogroup A and C, and no severe systemic adverse reaction has been observed.⁴⁵ No significant difference for local reaction rates were found when compared to the previously licensed monovalent A or bivalent A and C MenPVs. A post-marketing study on the safety of bivalent A and C MenCV has shown that the overall incidence rate of systemic and local adverse effects is 1.6% (565/34 411; 95% CI: 1.5%–1.8%) and 1.6% (554/34 411; 95% CI: 1.5%–1.7%), respectively.⁴⁶ Similar results have also been found in other safety studies of serogroup A and C MenCV from Chinese manufacturers.⁴⁷ A lower rate of adverse reactions to the examined vaccine in comparison to a previous post-marketing examination of a MenCV in another country may be associated with differences in national definitions of adverse reactions that resulted in the underestimation of certain mild adverse reactions.⁴⁷ Consistent with the results from other countries, immune memory after immunization of different ages of infants and children persisted to at least 3 years of age following 2–3 doses of serogroup A and C MenCV,⁴⁸ further indicating long-term protection induced by conjugate vaccines in children. Bivalent A and C MenCV made by three local manufacturers are available on the Chinese market; approximately 7.9 million human doses of conjugate vaccines were released in 2019 (Figure 2).

Furthermore, quadrivalent A, C, W, and Y MenCV providing broader protection have been developed by Chinese local manufacturers. According to the data shown, phase II and III clinical trials of quadrivalent A, C, W, and Y MenCV from two local manufacturers have recently been finished (http://www.chinadrugtrials.org.cn).

3.3 Combination vaccines

It is generally accepted that the development of combined vaccines would be advantageous to increase the coverage of a vaccine. Considering both N. meningitidis A and C capsular groups, together with Haemophilus influenza type b (Hib), are responsible for most of the cases of MD in China, a combination vaccine based on Hib and meningococcal A and C polysaccharide conjugated with TT (Hib-MenAC) has been developed. Clinical trials demonstrated that the seroconversion rate after administration with Hib-MenAC was 99.0%, 96.1%, and 97.7% for rSBA-MenA, rSBA-MenC, and anti-polyribosyl-ribitol phosphate antibodies, respectively, in the 3–5-month-old group, 95.3%, 97.1%, and 96.9% in 6–23-month-old group, and 96.0%, 94.6%, and 94.6% in the 5-year-old group, respectively.^49,50 Most adverse reactions were mild or moderate; no serious adverse event were judged to be related to the vaccination, suggesting the vaccine is well-tolerated.⁵¹

In 2014, a Hib-MenAC was approved in China, which contains 10 μg each of the individual polysaccharides conjugated to the TT carrier absorbed with the adjuvant Al(OH)₃. To obtain sustained protection, a primary series of three doses for the 2–5-month age group or two doses for the 6–11-month age group with a 1-month interval, or one dose administered at 12–71 months of age is recommended by the manufacturer.⁴⁴

3.4 MenB vaccines

N. meningitidis serogroup B (MenB) is one of the world’s major epidemic serogroups.⁵² Although various meningococcal polysaccharide and conjugate vaccines with four (A, C, W, and Y) serogroups are currently available, it is a great challenge to develop a broadly protective polysaccharide-based MenB vaccine. This is because its chemical composition is identical to polysaccharides decorating the human fetal neural cell-adhesion, which is crucial for central and peripheral nervous systems. This similarity between host and organism cell surface molecules results in poor immunogenicity and the theoretical risk of developing autoantibodies.⁵³

Although outer membrane vesicles (OMV) purified from MenB have also been developed in several countries, OMV vaccines induce immunity mostly against the highly variable membrane protein, which have shown serosubtype-specific protection.⁵⁴ With the development of reverse vaccinology approaches, 4CMenB containing three main Neisseria protein antigens and OMV from the MenB outbreak strain have been successfully developed.^55,56 In September 2015, the UK was the first country to introduce the 4CMenB vaccine into their national immunization program. One year after the introduction of 4CMenB, the number of MenB cases in vaccine-eligible infants decreased 50% compared with the prevaccine period, indicating two-dose 4CMenB vaccination was highly effective in preventing Men B disease in infants.⁵⁷ To date, 4CMenB has been licensed in many countries.⁵⁶Furthermore, a second MenB vaccine, rLP2086, containing two fHbp variants, was licensed in the USA for active immunization in 10–25-year-olds in 2014 and in the EU for individuals aged ≥ 10 years in 2017.^58,59 To date, these two broadly protective MenB vaccines have not been licensed in China. Previous studies demonstrated that current circulating serogroup B N. meningitidis in China is dominated by the ST4821 clone group, which is different from the existing serogroup B protein vaccines in the world. The effectiveness and impact of these MenB vaccines in China is unknown. Several MenB-related studies have been reported, but all are in preclinical studies in China.

4. Quality control of meningococcal vaccines in China

4.1 Lot release system in China

Since vaccines are used in healthy populations, it is essential to ensure consistent quality in each vaccine lot released to the market. A system was piloted for five EPI vaccines on December 31, 2001, in China. Monovalent A and bivalent (A and C) MenPV were included in October 1, 2005. Accordingly, the Chinese government has required since January 1, 2006, that all marketed preventative vaccines be released, lot by lot, by the national regulatory authority,^8,60 following review and independent testing. The review evaluates whether critical raw materials and manufacturing processes are consistent with approved parameters, and whether the vaccine bulk and final product meet the current national pharmaceutical criteria.^8,61 Independent tests include tests of identity and sterility. In addition, the key test (such as a polysaccharide content test) for vaccine quality control is required to be conducted in 10–30% of vaccine products.

After reviewing the relevant protocols, the vaccine test data from the manufacturer’s and NIFDC are collected, and used to perform trend analysis. The polysaccharide contents of the products are the most important parameters in the quality control of meningococcal vaccines. It is suggested that through trend analysis any significant deviation or shift from the trends could be detected. Usually, the following parameters are used in the analysis: mean, standard deviation (SD), ± 2 SD, and ± 3 SD. Results outside the ranges of the ± 2 SD and ± 3 SD lines are taken as the warning and actions limits, respectively, and trigger actions by the regulator and manufacturer. The trend analysis has shown that almost all results of the content of four polysaccharides have been within the alert limit (mean ± 2 SD) for quadrivalent A, C, W, and Y MenPVs in 2012–2013, and no significant difference has been found in the four polysaccharide contents of 27 different lots by NIFDC compared to that of the manufacturer, suggesting that the quality of domestic MenPV products is stable.⁶²

4.2 Quality control tests for meningococcal vaccines

Vaccine bulk is the most important intermediate product in the vaccine production process, and the meningitis vaccine bulk is a uniform substance used for the final product. Both the bivalent and tetravalent polysaccharide meningitis vaccines are prepared from a monovalent serogroup bulk. The quality control of vaccine products should be based on the characteristics of vaccine strains, the composition of the culture medium, the metabolites in the cultivation process, the chemical agents used in the purification process, the protective agents for vaccines, and the raw and auxiliary materials used.

In addition to the identification test, the quality control for MenPV bulks is mostly chemical testing, such as protein, nucleic acid content, O-acetyl content, phosphorus content (for serogroup A), sialic acid content (for serogroup C, Y, and W135), molecular size determination, an endotoxin/pyrogen test, and a sterility test (Table 1).⁶² It was also noted that several test items for the serogroup A polysaccharide bulk, such as the amount of protein content, and nucleic acid and molecular size determination was slightly different from the group A + C polysaccharide vaccine (Table 1). Different from the bulk, the quality control for the final products involved the test of the final product reconstituted with diluents, as well as the diluents themselves.

Table 1. Quality control tests for the bulk of different meningococcal vaccines used in China

	Release specifications
Test	Serogroup A MenPV	Serogroup A/C MenPV	Serogroup A\C/Y/W135 MenPV	Serogroup A/C MenCV*
Bulk
Identity test	Positive	Positive	Positive	Positive
Phosphorus content (mg/g)	Serogroup A ≥ 80	Serogroup A ≥ 80	Serogroup A ≥ 80	Serogroup A ≥ 80
Sialic acid content (mg/g)	N/A	Serogroup C ≥ 800	Serogroup C ≥ 800; Both serogroup Y and W135 ≥ 560	Serogroup C ≥ 800
O-acetyl content (mmol/g)	≥ 2	Serogroup A ≥ 2; Serogroup C ≥ 1.5	Serogroup A ≥ 2; Serogroup C ≥ 1.5; Both serogroup Y and W135 ≥ 0.3	Serogroup A ≥ 2; Serogroup C ≥ 1.5
Protein content (mg/g)	< 10	Both < 8	Both serogroup A and C < 8; Both serogroup Y and W135 < 10	Both < 8
Nucleic acid (mg/g)	< 10	Serogroup A < 8; Serogroup C < 9	Both serogroup A and C < 8; Both serogroup Y and W135 < 10	Both < 8
Molecular size (KD)	≤ 0.4	Both ≤ 0.4	All ≤ 0.4	All ≤ 0.4
Distribution of molecular size (Recovery rate of KD < 0.5)	> 76%	Serogroup A > 76%; Serogroup C > 80%	Both serogroup A > 76%; Serogroup C, Y and W135 > 80%	Serogroup A > 76%; Serogroup C > 80%
Polysaccharide derivatization rate	N/A	N/A	N/A	Should meet approval requirements
Sterility test	Sterile	Sterile	Sterile	Sterile
Endotoxin test (EU/µg)	≤ 25	Both ≤ 12	All ≤ 12.5	Both ≤ 25

All data are from The Chinese Pharmacopoeia (2020 version) 3rd Part. MenPV and MenCV represents meningococcal polysaccharide vaccines and protein-polysaccharide conjugate vaccines, respectively; *The content of bound polysaccharide, free polysaccharide, protein, polysaccharide/protein ratio, molecular size distribution, and sterility tests are further required for the quality control of conjugated bulks,

Different methods are used to determine the content of the vaccine main component polysaccharide. Monovalent A or bivalent A + C vaccines are often determined by chemical methods. The content of serogroup A polysaccharides can be determined by the phosphorus content; each gram of polysaccharide contains 75 mg of phosphorus. The group C polysaccharides can be determined by the content of sialic acid, and each gram of polysaccharide contains 750 mg N-acetylneuraminic acid (sialic acid).⁶² The polysaccharide content of serogroup A/C/Y/W135 MenPVs cannot be detected by chemical methods, and can only be detected by immunological methods, such as rocket electrophoresis assays. It is reported that a high-performance liquid chromatography with pulsed amperometric detector method has been used for serogroup quantitation of multivalent polysaccharide and polysaccharide-conjugate meningococcal vaccines.⁶³ Meanwhile, an immune rate turbidimetric method for determination of polysaccharide content in Hib-MenAC combined vaccines has been developed. The specific antibody against various polysaccharides shows a reaction only to the corresponding polysaccharide antigens, whereas no interference was observed between various polysaccharide antigens.⁶⁴

Due to the different production processes, the quality control of the MenCV is not only involved with the polysaccharide bulk, but also the conjugated bulks. On the basis of the polysaccharide bulk, the detection of the polysaccharide derivatization rate has been added (Table 1). For the quality control of conjugated bulks, the content of bound polysaccharide, free polysaccharide, protein, polysaccharide/protein ratio, molecular size distribution, and sterility tests are required. In addition to the appearance and pH value, the identification tests, sterility inspection, the content of polysaccharide, free polysaccharide, free protein content, and pyrogen inspection are required for the final conjugated vaccine product. To further strength the quality control according to requirements in China and to evaluate the antibody response induced by MenCV, a potency assay based on immunogenicity in a mouse model is used. The anti-A and C polysaccharide IgG titers in the serum of immunized mice (two-dose regimen) are determined by ELISA; the seroconversion rates should be at least 80%.⁵⁰ Due to the addition of Al(OH)₃, the adjuvant content should also be tested in the Hib-MenAC.

5. Conclusion

This remarkable progress toward MD control is followed by new challenges. The rapidly changing epidemiology of N. meningitidis strains, the waning of vaccine-induced immune responses over time, the variable impact of vaccination in carriage and herd immunity, and the increased reactogenicity observed after coadministration of meningococcal and routine vaccination must be properly addressed to constantly maintain an acceptable level of protection. Continuous surveillance and coverage studies are hence required so that national vaccination programs can be promptly adapted and optimized.

To further improve the level of prevention and control of meningococcus, it is necessary to further enhance meningococcal surveillance in China. The current content of meningococcal surveillance includes cases, vaccination rates, antibiotic resistance, population antibody levels, and carrier infection rates in healthy populations. It is necessary to carry out surveillance of encephalitis/meningitis cases so that early detection, early diagnosis, and early treatment of all suspected cases are possible. According to spatiotemporal sequence analysis, actively detecting cases of meningococcal clusters is required to prevent meningococcal outbreaks or epidemics. According to the actual situation in various places, the serogroups, types and subtypes of meningococcal cases need to be actively monitored.⁴⁴

Additionally, the immune efficacy and persistence of the vaccine should be monitored. Meta–analysis has shown that the prevalence of N. meningitidis serogroup A and C antibodies is 70.9 and 23.6% in the healthy 0–4 year population, respectively.¹² The lower seroprevalence of serogroup C within the population may be associated with the more than 90% use of bivalent A and C MenPVs before 2015 in China. It is generally accepted that immunogenicity and persistence of conjugated vaccines are better than MenPVs, especially serogroup C, in children aged 0–2 years.⁶⁵ Based on epidemiology, vaccinology and health economics, replacing MenPVs with conjugated vaccines should be considered in the future in China. It is also noted that a difference exists in the immunization program recommended by the current bivalent A and C conjugate vaccines manufacturers, which has caused problems for vaccinating personnel. It is recommended that relevant departments strengthen joint research and unify the vaccination procedures recommended by vaccine instructions. Furthermore, to simplify the vaccination procedure, reduce injection times, reduce the risk of adverse reactions, and save cost, combination vaccines need to be investigated.⁶⁵

Although widespread vaccination with meningococcal vaccine has caused the incidence of meningoencephalitis nationwide to be lower than that of some developed countries, there has been an obvious upward trend in MenB cases in China. Various types of MenB vaccines have been used in other countries.^52,56,59 but they are unavailable in the Chinese market. Therefore, we should strengthen guidance and focus on supporting the development of MenB vaccines in China.

Acknowledgments

This work was supported by the National Key R&D Program of China (No. 2018YFC1603900) and Medical Microbiology Resources Sub-platform Operation and Service Funds, China (NIMR-2019).

Disclosure of potential conflicts of interest

The authors declare that they have no competing interests.

Additional information

Funding

This work was supported by the Key Technologies Research and Development Program [2018YFC160390].