Jean-Marc Collard

The Diversity of Meningococcal Carriage Across the African Meningitis Belt and the Impact of Vaccination With a Group A Meningococcal Conjugate Vaccine

Background. Study of meningococcal carriage is essential to understanding the epidemiology of Neisseria meningitidis infection. Methods. Twenty cross-sectional carriage surveys were conducted in 7 countries in the African meningitis belt; 5 surveys were conducted after introduction of a new serogroup A meningococcal conjugate vaccine (MenAfriVac). Pharyngeal swab specimens were collected, and Neisseria species were identified by microbiological and molecular techniques. Results. A total of 1687 of 48 490 participants (3.4%; 95% confidence interval [CI], 3.2%–3.6%) carried meningococci. Carriage was more frequent in individuals aged 5–14 years, relative to those aged 15–29 years (adjusted odds ratio [OR], 1.41; 95% CI, 1.25–1.60); in males, relative to females (adjusted OR, 1.17; 95% CI, 1.10–1.24); in individuals in rural areas, relative to those in urban areas (adjusted OR, 1.44; 95% CI, 1.28–1.63); and in the dry season, relative to the rainy season (adjusted OR, 1.54; 95% CI, 1.37–1.75). Forty-eight percent of isolates had genes encoding disease-associated polysaccharide capsules; genogroup W predominated, and genogroup A was rare. Strain diversity was lower in countries in the center of the meningitis belt than in Senegal or Ethiopia. The prevalence of genogroup A fell from 0.7% to 0.02% in Chad following mass vaccination with MenAfriVac. Conclusions. The prevalence of meningococcal carriage in the African meningitis belt is lower than in industrialized countries and is very diverse and dynamic, even in the absence of vaccination.

Airborne dust and high temperatures are risk factors for invasive bacterial disease

Background: The Sahel region of West Africa has the highest bacterial meningitis attack and case fatality rate in the world. The effect of climatic factors on patterns of invasive respiratory bacterial disease is not well documented. Objective: We aimed to assess the link between climatic factors and occurrence of invasive respiratory bacterial disease in a Sahel region of Niger. Methods: We conducted daily disease surveillance and climatic monitoring over an 8‐year period between January 1, 2003, and December 31, 2010, in Niamey, Niger, to determine risk factors for bacterial meningitis and invasive bacterial disease. We investigated the mechanistic effects of these factors on Streptococcus pneumoniae infection in mice. Results: High temperatures and low visibility (resulting from high concentrations of airborne dust) were identified as significant risk factors for bacterial meningitis. Dust inhalation or exposure to high temperatures promoted progression of stable asymptomatic pneumococcal nasopharyngeal carriage to pneumonia and invasive disease. Dust exposure significantly reduced phagocyte‐mediated bacterial killing, and exposure to high temperatures increased release of the key pneumococcal toxin pneumolysin through increased bacterial autolysis. Conclusion: Our findings show that climatic factors can have a substantial influence on infectious disease patterns, altering density of pneumococcal nasopharyngeal carriage, reducing phagocytic killing, and resulting in increased inflammation and tissue damage and consequent invasiveness. Climatic surveillance should be used to forecast invasive bacterial disease epidemics, and simple control measures to reduce particulate inhalation might reduce the incidence of invasive bacterial disease in regions of the world exposed to high temperatures and increased airborne dust.

Public Health Impact After the Introduction of PsA-TT: The First 4 Years.

Background. During the first introduction of a group A meningococcal vaccine (PsA-TT) in 2010–2011 and its rollout from 2011 to 2013, >150 million eligible people, representing 12 hyperendemic meningitis countries, have been vaccinated. Methods. The new vaccine effectiveness evaluation framework was established by the World Health Organization and partners. Meningitis case-based surveillance was strengthened in PsA-TT first-introducer countries, and several evaluation studies were conducted to estimate the vaccination coverage and to measure the impact of vaccine introduction on meningococcal carriage and disease incidence. Results. PsA-TT implementation achieved high vaccination coverage, and results from studies conducted showed significant decrease of disease incidence as well as significant reduction of oropharyngeal carriage of group A meningococci in vaccinated and unvaccinated individuals, demonstrating the vaccines ability to generate herd protection and prevent group A epidemics. Conclusions. Lessons learned from this experience provide useful insights in how to guide and better prepare for future new vaccine introductions in resource-limited settings.

Methods for Identifying Neisseria meningitidis Carriers: A Multi-Center Study in the African Meningitis Belt.

Objective Detection of meningococcal carriers is key to understanding the epidemiology of Neisseria meningitidis, yet no gold standard has been established. Here, we directly compare two methods for collecting pharyngeal swabs to identify meningococcal carriers. Methods We conducted cross-sectional surveys of schoolchildren at multiple sites in Africa to compare swabbing the posterior pharynx behind the uvula (U) to swabbing the posterior pharynx behind the uvula plus one tonsil (T). Swabs were cultured immediately and analyzed using molecular methods. Results One thousand and six paired swab samples collected from schoolchildren in four countries were analyzed. Prevalence of meningococcal carriage was 6.9% (95% CI: 5.4-8.6%) based on the results from both swabs, but the observed prevalence was lower based on one swab type alone. Prevalence based on the T swab or the U swab alone was similar (5.2% (95% CI: 3.8-6.7%) versus 4.9% (95% CI: 3.6-6.4%) respectively (p=0.6)). The concordance between the two methods was 96.3% and the kappa was 0.61 (95% CI: 0.50-0.73), indicating good agreement. Conclusions These two commonly used methods for collecting pharyngeal swabs provide consistent estimates of the prevalence of carriage, but both methods misclassified carriers to some degree, leading to underestimates of the prevalence.

Region-specific diversification of the highly virulent serotype 1 Streptococcus pneumoniae.

Serotype 1 Streptococcus pneumoniae is a leading cause of invasive pneumococcal disease (IPD) worldwide, with the highest burden in developing countries. We report the whole-genome sequencing analysis of 448 serotype 1 isolates from 27 countries worldwide (including 11 in Africa). The global serotype 1 population shows a strong phylogeographic structure at the continental level, and within Africa there is further region-specific structure. Our results demonstrate that region-specific diversification within Africa has been driven by limited cross-region transfer events, genetic recombination and antimicrobial selective pressure. Clonal replacement of the dominant serotype 1 clones circulating within regions is uncommon; however, here we report on the accessory gene content that has contributed to a rare clonal replacement event of ST3081 with ST618 as the dominant cause of IPD in the Gambia.

Household transmission of Neisseria meningitidis in the African meningitis belt: a longitudinal cohort study

BACKGROUND Information on transmission of meningococcal infection in the African meningitis belt is scarce. We aimed to describe transmission patterns of Neisseria meningitidis (meningococcus) in households in the African meningitis belt. METHODS Cross-sectional carriage surveys were done in seven African meningitis belt countries (Chad, Ethiopia, Ghana, Mali, Niger, Nigeria, and Senegal) between Aug 1, 2010, and Oct 15, 2012. Meningococcal carriers identified in these surveys and all available people in their households were recruited into this longitudinal cohort study. We took pharyngeal swabs at first visit and took further swabs twice a month for 2 months and then monthly for a further 4 months. We used conventional bacteriological and molecular techniques to identify and characterise meningococci. We estimated the rates of carriage acquisition and recovery using a multi-state Markov model. FINDINGS Meningococci were isolated from 241 (25%) of 980 members of 133 households in which a carrier had been identified in the cross-sectional survey or at the first household visit. Carriage was detected subsequently in another household member who was not an index carrier in 75 households. Transmission within a household, suggested by detection of a further carrier with the same strain as the index carrier, was found in 52 of these 75 households. Children younger than 5 years were the group that most frequently acquired carriage from other household members. The overall individual acquisition rate was 2·4% (95% CI 1·6-4·0) per month, varying by age and household carriage status. The mean duration of carriage was 3·4 months (95% CI 2·7-4·4). INTERPRETATION In the African meningitis belt, transmission of meningococci within households is important, particularly for young children, and periods of carriage are usually of short duration. FUNDING Bill & Melinda Gates Foundation, Wellcome Trust.

Pharyngeal carriage of Neisseria species in the African meningitis belt

Summary Objectives Neisseria meningitidis, together with the non-pathogenic Neisseria species (NPNs), are members of the complex microbiota of the human pharynx. This paper investigates the influence of NPNs on the epidemiology of meningococcal infection. Methods Neisseria isolates were collected during 18 surveys conducted in six countries in the African meningitis belt between 2010 and 2012 and characterized at the rplF locus to determine species and at the variable region of the fetA antigen gene. Prevalence and risk factors for carriage were analyzed. Results A total of 4694 isolates of Neisseria were obtained from 46,034 pharyngeal swabs, a carriage prevalence of 10.2% (95% CI, 9.8–10.5). Five Neisseria species were identified, the most prevalent NPN being Neisseria lactamica. Six hundred and thirty-six combinations of rplF/fetA_VR alleles were identified, each defined as a Neisseria strain type. There was an inverse relationship between carriage of N. meningitidis and of NPNs by age group, gender and season, whereas carriage of both N. meningitidis and NPNs was negatively associated with a recent history of meningococcal vaccination. Conclusion Variations in the prevalence of NPNs by time, place and genetic type may contribute to the particular epidemiology of meningococcal disease in the African meningitis belt.

The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1

Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype.

A Seroepidemiological study of Serogroup A meningococcal infection in the African meningitis belt

The pattern of epidemic meningococcal disease in the African meningitis belt may be influenced by the background level of population immunity but this has been measured infrequently. A standardised enzyme-linked immunosorbent assay (ELISA) for measuring meningococcal serogroup A IgG antibodies was established at five centres within the meningitis belt. Antibody concentrations were then measured in 3930 individuals stratified by age and residence from six countries. Seroprevalence by age was used in a catalytic model to determine the force of infection. Meningococcal serogroup A IgG antibody concentrations were high in each country but showed heterogeneity across the meningitis belt. The geometric mean concentration (GMC) was highest in Ghana (9.09 μg/mL [95% CI 8.29, 9.97]) and lowest in Ethiopia (1.43 μg/mL [95% CI 1.31, 1.57]) on the margins of the belt. The force of infection was lowest in Ethiopia (λ = 0.028). Variables associated with a concentration above the putative protective level of 2 μg/mL were age, urban residence and a history of recent vaccination with a meningococcal vaccine. Prior to vaccination with the serogroup A meningococcal conjugate vaccine, meningococcal serogroup A IgG antibody concentrations were high across the African meningitis belt and yet the region remained susceptible to epidemics.

Investigation of correlates of protection against pharyngeal carriage of Neisseria meningitidis genogroups W and Y in the African meningitis belt

Background Serum bactericidal antibody titres that correlate with protection against invasive meningococcal disease have been characterised. However, titres that are associated with protection against acquisition of pharyngeal carriage of Neisseria meningitidis are not known. Methods Sera were obtained from the members of a household in seven countries of the African meningitis belt in which a pharyngeal carrier of N. meningitidis had been identified during a cross-sectional survey. Serum bactericidal antibody titres at baseline were compared between individuals in the household of the carrier who became a carrier of a meningococcus of the same genogroup during six months of subsequent follow-up and household members who did not become a carrier of a meningococcus of this genogroup during this period. Results Serum bacterial antibody titres were significantly higher in carriers of a serogroup W or Y meningococcus at the time of recruitment than in those who were not a carrier of N. meningitidis of the same genogroup. Serum bactericidal antibody titres to a strain of N. meningitis of the same genogroup as the index cases were no different in individuals who acquired carriage with a meningococcus of the same genogroup as the index case than in those who did not become a carrier during six months of follow-up. Conclusion Serum bacterial antibody titres to N. meningitidis of genogroup W or Y in the range of those acquired by natural exposure to meningococci of these genogroups, or with cross-reactive bacteria, are not associated with protection against acquisition of carriage with meningococci of either of these genogroups.