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Objective Few data are available on the association between SARS-CoV-2 and secondary bacterial infections. Such an association was described for flu and invasive meningococcal disease (IMD). We aimed exploring such a correlation between COVID-19 and IMD as well as the impact of the lockdown on IMD. Results We compared IMD cases received at the French National Reference Centre for meningococci and Haemophilus influenzae that are sent as part of the mandatory reporting of IMD. We compared these data during the period 01 January-15 May 2020 to those from the same period in 2018 and 2019. IMD cases that were associated with respiratory presentations significantly increased in 2020 compared to 2018 ( P  = 0.029) and 2019 ( P  = 0.002), involved elderly and were due to unusual isolates. However, IMD cases due to hyperinvasive isolates decreased during the lockdown. Enhancing IMD surveillance and anti-meningococcal vaccination in elderly should be addressed.

Background Invasive meningococcal disease (IMD) cases declined upon the implementation of non-pharmaceutical interventions (NPI) (social distancing and mask wearing) to control the COVID-19 pandemic but rebounded in 2022 in numbers with genotypical changes of the strains. We explored here associated modifications in the clinical presentations of IMD. Methods We conducted a retrospective descriptive study using the Database of the French National Reference Centre for meningococci and Haemophilus influnezae for IMD cases between 2015 and 2022. We scored serogroups, sex, age groups, clinical presentations and clonal complexes of the corresponding patients and isolates. Findings Non-meningeal forms of IMD increased significantly upon easing of NPI, such as bacteremic meningococcal pneumonia and bacteremic abdominal forms. They represented 6% and 8% of all IMD forms and were significantly linked to serogroups Y and W respectively, to older adults for bacteremic pneumonia and to young adults for bacteremic abdominal presentations. These forms were significantly associated with more early mortality and clonal complexes 23, 11 and 9316. Interpretation The increase in atypical IMD forms may lead to higher burden of IMD due to delayed diagnosis and management. Updating prevention may be needed through by adapting the current vaccination strategies to epidemiological changes.

BackgroundSince the appearance of COVID-19 in January 2020, invasive bacterial infections have decreased significantly worldwide. However, alterations in age and sex distributions, clinical forms, phenotypes, and genotypes of isolates have not been analyzed. Our goal is to present and discuss these data considering the current COVID-19 pandemic situation. Methods: The data of the national reference center for meningococci and Haemophilus influenzae in France were mined to examine the above aspects of invasive bacterial infection before (2018–2019) and after (2020–2021) the COVID-19 pandemic. Detailed epidemiological, clinical, and microbiological data were collected, and whole genome sequencing was carried out on meningococcal isolates (n = 1466). Results: In addition to the overall decline in the number of cases, various changes in age, sex, and phenotypes of isolates were also noted. As for N. meningitidis, more cases were observed in adults, as well as more invasive pneumopathies. Furthermore, fewer hyperinvasive meningococcal genotypes have circulated since COVID-19 emerged. The situation has been different for H. influenzae, as the number of invasive cases among adults decreased due to a reduction in non-typeable isolates. In contrast, cases due to serotypeable isolates, particularly serotypes a and b, increased in children <5 years-old. Conclusions: It is possible that measures implemented to stop COVID-19 may have reduced the circulation of N. meningitidis and H. influenzae isolates, but to a variable extent. This may be due to differences in circulation between these two species according to age groups. Vaccination schedules against these two species may have also influenced the evolution of these invasive bacterial infections since the emergence of the COVID-19 pandemic.

Background Neisseria meningitidis is a human pathogen, carried asymptomatically in the nasopharynx, that can also cause invasive meningococcal disease. Understanding the carriage/invasiveness balance is crucial, and bacterial genetic factors may impact this balance. A previous genome-wide association study reported that the gene porB class 3 was significantly associated with carriage isolates. This study aimed to examine the impact of porB variants on virulence in carriage and invasive meningococcal isolates. Results For this, 24 isolates were used (13 invasive and 11 carriage) belonging to different genogroups (B, C, W, Y, and cnl) and selected based on the presence of the genetic variant porB class 2 or class 3. Transgenic BALB/c mice expressing human transferrin were infected intraperitoneally with these isolates. After 3 and 24 h of infection, clinical scores (fur quality, strength, and temperature) and bacterial load in blood were used to evaluate bacterial virulence. The concentrations of inflammatory cytokines were determined from blood. PorB - mutants were created from a carriage and an invasive isolate, and were tested in transgenic mice. The invasive isolates provoked significantly more severe infections compared to the carriage isolates, and the carriage isolates of porB class 3 were significantly less virulent than the invasive isolates of porB class 2 or 3. The invasive PorB - isolate caused milder infections than the parental isolate. Conclusions This study confirms the ability of invasive isolates of N. meningitidis to cause more severe infections than carriage isolates in transgenic mice. The porB expressed in invasive isolates seems to contribute to their higher virulence compared to carriage isolates, although this effect may depend on the genomic context. Notably, differences in virulence were mainly observed among serogroup C and W isolates.

Abstract The rebound of invasive meningococcal disease cases in France since the fall of 2022 was accompanied by an increase in adult epiglottitis. These cases were provoked mainly by isolates of serogroup W belonging to the clonal complex 11 of Neisseria meningitidis. Awareness and surveillance should be reinforced.

Background: Haemophilus influenzae (Hi), a Gram-negative bacterium, is divided into two broad categories: encapsulated and non-capsulated isolates, also called non-typeable Hi isolates (NTHi). NTHi has become prevalent since the introduction of the vaccine against Hi of serotype b. Hi can cause local infections on respiratory mucosal surfaces and urogenital infections, which can lead to septic abortion in pregnant women. It can also cause invasive infections such as meningitis and septicemia. Moreover, NTHi isolates are becoming increasingly resistant to antibiotics. Vaccines targeting NTHi are not yet available. As these NTHi isolates are not encapsulated, vaccines should target proteins at the bacterial surface. However, vaccine development is hindered by the high variability of these proteins. We aimed to identify conserved outer membrane proteins (OMPs) for vaccines against NTHi. Methods: We analyzed core-genome multilocus sequence typing (cgMLST) of 1144 genomes of Hi collected between 2017 and 2022 and, of these, identified 514 conserved genes that encoded OMPs. We focused on two specific OMPs: Haem1295, encoding the protein P5 (P5), and Haem1040, encoding the protein 26 (P26). P5 is known to bind human complement regulatory protein factor H (FH), while both P5 and P26 are involved in enhancing immune responses. The genes encoding these proteins were cloned, overexpressed, purified, and tested in both active and passive protection models using systemic infection in mice. Results: P5 and P26 were found to be immunogenic during human infections. Vaccination with these proteins conferred protection against both homologous and heterologous NTHi isolates in mice, suggesting broad cross-protection. Conclusions: P5 and P26 are promising vaccine candidates showing cross-protection against NTHi and offering the additional benefit of targeting bacterial virulence factors, enhancing vaccine efficacy against NTHi isolates.

Meningococci spread via respiratory droplets, whereas the closely related gonococci are transmitted sexually. Several outbreaks of invasive meningococcal disease have been reported in Europe and the United States among men who have sex with men (MSM). We recently identified an outbreak of serogroup C meningococcal disease among MSM in Germany and France. In this study, genomic and proteomic techniques were used to analyze the outbreak isolates. In addition, genetically identical urethritis isolates were recovered from France and Germany and included in the analysis. Genome sequencing revealed that the isolates from the outbreak among MSM and from urethritis cases belonged to a clade within clonal complex 11. Proteome analysis showed they expressed nitrite reductase, enabling anaerobic growth as previously described for gonococci. Invasive isolates from MSM, but not urethritis isolates, further expressed functional human factor H binding protein associated with enhanced survival in a newly developed transgenic mouse model expressing human factor H, a complement regulatory protein. In conclusion, our data suggest that urethritis and outbreak isolates followed a joint adaptation route including adaption to the urogenital tract.

Background Haemophilus influenzae serotype b (Hib) conjugate vaccine was introduced in France in 1992 as a 3 + 1 scheme at 2, 3, and 4 months (primary vaccination) with a booster at the age of 16–18 months. The vaccination was simplified in 2013 to a 2 + 1 scheme at 2 and 4 months (primary immunization) and a booster at the age of 11 months. The coverage was 95.4% in France at 24 months in 2017. During the period 2017–2019 the number of Hib invasive infections increased with several cases of vaccine failure. Methods The numbers and proportions of Hib invasive isolates during the period 2017–2019 were compared and vaccine failure cases were explored. A seroprevalence study was performed by measuring anti-polyribosyl-ribitol phosphate (PRP) IgG concentrations by ELISA among children < 5 years of age at the time of sampling covering the periods of the 3 + 1 or 2 + 1 schemes of Hib vaccination. A collection of residual 232 sera was tested (group 3 + 1 n  = 130) and (group 2 + 1, n  = 102) was used. Results Anti-PRP IgG concentrations were significantly higher in toddlers of 2 years (median 2.9 μg/ml) in the 3 + 1 group while these concentrations showed a median of 0.58 μg/ml among children in 2 + 1 group. The proportion of children of 2 years of age who achieved 1 μg/ml threshold (56%) was higher in the 3 + 1 group than that observed in the 2 + 1 group (25%). All the detected cases of vaccine failure received the 2 + 1 scheme and anti-PRP IgG levels were less than 1 μg/ml at the admission. However, these levels increased significantly 1 month after the admission suggesting a secondary immune response to the Hib infection. Conclusions The simplification of the vaccination to a 2 + 1 scheme seems to reduce the level of anti PRP IgG. Hib antibodies wane rapidly after the 11 months booster and may not be enough to ensure long term protection. Surveillance of cases and monitoring of titres need to be continued to inform future vaccination policy.

Background/Objectives: In France, non-pharmaceutical interventions (NPIs) implemented to control COVID-19 led to a significant decline in invasive meningococcal disease (IMD) cases. However, a rebound in cases, particularly for serogroups W and Y, was observed after the gradual lifting of NPIs, raising questions about an “immunity gap” due to reduced circulation of the bacteria. During the study period, vaccination against MenC was mandatory from 2018, and vaccination against MenB has been recommended since 2022. Methods: We conducted a retrospective seroepidemiological study using 166 normal sera collected between 2016 and 2024. Anti-Neisseria meningitidis IgG levels were quantified by ELISA using purified capsular polysaccharides for serogroups B, C, W, Y, and X. Samples were categorized into three periods: pre-NPIs (n = 72), during NPIs (n = 33), and post-NPIs (n = 61). Statistical comparisons were performed using Kruskal–Wallis tests for non-parametric data. Results: Our results show a significant decline in anti-serogroup B IgG antibody levels after the lifting of NPIs (p < 0.0001) in line with reduced circulation. Anti-serogroup C IgG antibody levels increased incrementally (p = 0.0003), particularly in those aged 1–4 years, likely reflecting a catch-up in anti-meningococcal C vaccination coverage. Anti-serogroup W IgG antibody levels remained stable, suggesting sustained circulation, but shifted to young children in the post-NPI period, potentially due to a genotypic shift. Anti-serogroup Y IgG antibody levels transiently increased significantly (p < 0.0001) during the NPI period but then decreased back after their lifting. Anti-serogroup X IgG antibody levels remained stable, consistent with its low prevalence and the absence of targeted vaccination.

Serum bactericidal assay (SBA) is a functional assay that evaluates infection- and vaccine-induced neutralizing antibodies representing the serological correlate of protection against Neisseria meningitidis. However, it is time consuming due to its readout using the enumeration of colony-forming units (CFUs), making this conventional SBA (C-SBA) difficult for large-scale use. We developed a new SBA method that takes advantage of a bioluminescence N. meningitidis serogroup B (BioLux-SBA). The assay development steps involved the human complement source validation, the setup of the optimal incubation time, and the assessment of intra-day and inter-day variability. BioLux-SBA was then compared to C-SBA using a serum collection of Norman children vaccinated in 2011 with MenBvac, an OMV meningococcal vaccine. While a conventional approach requests 48 h of work to test 24 sera per day, BioLux-SBA takes only 5 h to test 96 sera per day. The SBA titers (n = 10) correlated with R2 of 0.98 (p-value < 0.0001). The deposition of terminal complement components (C5b-C9) measured by flow cytometry on the bacterial surface well correlated with BioLux SBA titers. This high-throughput method to evaluate the immunogenicity of meningococcal vaccines appears to be a reliable method for an OMV meningococcal B vaccine and requires further assessment in other laboratories and against other meningococcal vaccines.