Haemophilus influenzae type b (Hib) seroprevalence in France: impact of vaccination schedules.

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.

Evidence for Multi-Organ Infection During Experimental Meningococcal Sepsis due to ST-11 Isolates in Human Transferrin-Transgenic Mice.

The description of invasive meningococcal disease that is provoked by Neisseria meningitidis (Nm) is frequently restricted to meningitis. However, a wide panel of clinical presentations can be encountered including severe forms with intense inflammatory reaction leading to multi-organ failure. Several human factors are involved in the development of invasive infections such as transferrin, factor H or CEACAM1. In this study, we used an experimental meningococcal infection in transgenic mice expressing the human transferrin to show multi-organ infection. Mice were infected by an intraperitoneal injection of bacterial suspension (1.5 × 107 colony-forming unit/mouse) of a bioluminescent serogroup C strain belonging to the clonal complex ST-11. Dynamic imaging and histological analysis were performed. The results showed invasion of tissues by Nm with bacteria observed, outside blood vessels, in the kidneys, the heart and the brain as well as skin involvement. These data further support the systemic aspect of invasive meningococcal disease with involvement of several organs including skin as in humans. Thus, our model can be used to study severe forms of meningococcal invasive infections with multi-organ failure.

Analysis of the impact of corticosteroids adjuvant treatment during experimental invasive meningococcal infection in mice.

Invasive meningococcal disease (IMD) is usually associated with intense inflammatory response that is correlated with severe infection. Corticosteroids may regulate this inflammatory response through an early but transient induction of IL-10 that is suggested to improve the outcome of IMD. We explored the mechanism of action of corticosteroids as an adjuvant treatment to antibiotics. Transgenic mice expressing the human transferrin were infected by a hyperinvasive meningococcal strain and transcriptomic analysis were then performed in the blood for all conditions of infection and treatment. Infected untreated mice, infected antibiotic-treated mice and infected amoxicillin and dexamethasone-treated mice were compared. Treatment using both corticosteroids and antibiotics was associated with differential gene expression in the blood especially in Monocytes-Macrophages pathways. Depletion of these cells in infected mice was associated with a more severe bacterial infection and uncontrolled production of both pro-inflammatory and anti-inflammatory cytokines. Accordingly, children suffering from severe IMD had low counts of monocytes at admission. Our data are in favor of a role of corticosteroids in enhancing a polarization from pro-inflammatory to anti-inflammatory phenotypes of Monocytes-Macrophages axis that may help controlling meningococcal invasive infections.

Differential expression of hemoglobin receptor, HmbR, between carriage and invasive isolates of Neisseria meningitidis contributes to virulence: lessons from a clonal outbreak.

Carriage and invasion balance in the pathogenesis of Neisseria meningitidis was analyzed during a recent clonal outbreak of meningococcal B in Normandy, France, that offered the opportunity to compare six isolates undistinguable by conventional typing (B:14:P1.7,16:F3-3/ST-32) isolated from invasive disease or pharyngeal asymptomatic carriage. Data from animal model (transgenic mice rendered susceptible to N. meningitidis infection) showed an absence of virulence for two non-capsulated carriage isolates, an intermediate virulence for two capsulated carriage isolates and a marked virulence for two capsulated invasive isolates. This differential pathogenesis well correlated with whole genome sequencing analysis that clustered both isolates of each group together, forming their own arm within the Norman cluster. Gene-by-gene analysis specified that genes involved in iron acquisition were among the elements differentially represented in cluster of invasive isolates compared to cluster of capsulated carriage isolates. The hemoglobin receptor encoding gene hmbR was in an ON-phase in the capsulated invasive isolates while carriage capsulated isolates were in an OFF-phase. An ON-phase variant of a capsulated carriage isolate showed enhanced virulence. These data underline the role of phase variation (ON/OFF) of HmbR in the balance between disease isolates/carriage isolates.

Clonal replacement and expansion among invasive meningococcal isolates of serogroup W in France.

BACKGROUND: Neisseria meningitidis group W (NmW) belonging to the clonal complex ST-11 (NmW/cc11) spread in Europe and in France in 2000 and declined thereafter. In France, invasive meningococcal disease (IMD) due to NmW increased again in 2012 and thereafter since 2015. Several sub-lineages of NmW/cc11 are circulating worldwide with successive epidemic waves. We aimed to describe recent epidemiological trends of NmW in France and to explore the microbiological and epidemiological characteristics associated with different NmW/cc11 sub-lineages. METHODS: The epidemiology of NmW was described based on data collected through mandatory notification of IMD and strain typing data for culture-confirmed and PCR-confirmed cases for the period 2000-2016. All culture-confirmed cases due to NmW from the period 2010-2016 were characterised by whole genome sequencing (WGS). A detailed epidemiological analysis was performed for culture-confirmed cases on the basis of WGS data. FINDINGS: During the period 2010-2016, genotyping was obtained for 148 cases including all the 132 culture-confirmed cases, among which 127 were matched with epidemiological data, and 16 PCR-confirmed cases (out of a total of 47 PCR-confirmed cases). An increase in IMD was observed in 2012 and was linked to isolates belonging to the "Anglo-French-Hajj" sub-lineage. These isolates have decreased significantly since 2013 and have been replaced by NmW/cc11 isolates related to the "South American - UK" sub-lineage which caused a marked increase in the number of cases of NmW in 2016. In this sub-lineage, the "original UK strain" was first detected in 2012 and increased thereafter, followed by the recently described "UK 2013-strain". Isolates related to the "South American-UK" sub-lineage represented 45% of all NmW cultured isolates from the whole period 2010-2016 but were the most frequent isolates in 2016, representing 76% of the total NmW typed isolates and 94% of the typed NmW/cc11 isolates. A changing pattern in the epidemiology of NmW has been observed in 2015-2016 in relation to the spread of the "UK 2013-strain" with a sharp increase in the number of cases among persons aged 15 years and over and a high case fatality rate (CFR). Among cases due to the "UK 2013-strain", 94% of cases were aged 15 years and over and the CFR was 28%. INTERPRETATION: Our data suggest a recent clonal replacement among NmW/cc11 isolates with the expansion of the "South American-UK" sub-lineage in France and particularly the "UK 2013-strain" which was predominant in 2015 and 2016. A shift in the age-distribution of IMD due to NmW to older ages and the high CFR are consistent with the expansion of a new virulent clone in a naive population. These data may have an impact on tailoring vaccination strategies against NmW.