Correction: Identifying Optimal Vaccination Strategies for Serogroup A Neisseria meningitidis Conjugate Vaccine in the African Meningitis Belt.

[This corrects the article DOI: 10.1371/journal.pone.0063605.].

Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey.

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.

Long-term safety of icatibant treatment of patients with angioedema in real-world clinical practice.

The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real-world setting. We analyzed safety data from 3025 icatibant-treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off-label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on-label vs off-label icatibant users.

Triggers and prodromal symptoms of angioedema attacks in patients with hereditary angioedema

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Introduction and Rollout of a New Group A Meningococcal Conjugate Vaccine (PsA-TT) in African Meningitis Belt Countries, 2010-2014.

BACKGROUND: A group A meningococcal conjugate vaccine (PsA-TT) was developed specifically for the African "meningitis belt" and was prequalified by the World Health Organization (WHO) in June 2010. The vaccine was first used widely in Burkina Faso, Mali, and Niger in December 2010 with great success. The remaining 23 meningitis belt countries wished to use this new vaccine. METHODS: With the help of African countries, WHO developed a prioritization scheme and used or adapted existing immunization guidelines to mount PsA-TT vaccination campaigns. Vaccine requirements were harmonized with the Serum Institute of India, Ltd. RESULTS: Burkina Faso was the first country to fully immunize its 1- to 29-year-old population in December 2010. Over the next 4 years, vaccine coverage was extended to 217 million Africans living in 15 meningitis belt countries. CONCLUSIONS: The new group A meningococcal conjugate vaccine was well received, with country coverage rates ranging from 85% to 95%. The rollout proceeded smoothly because countries at highest risk were immunized first while attention was paid to geographic contiguity to maximize herd protection. Community participation was exemplary.

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 vaccine's 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.

Lessons Learned From Enhancing Vaccine Pharmacovigilance Activities During PsA-TT Introduction in African Countries, 2010-2013.

BACKGROUND: The rollout of the group A meningococcal vaccine, PsA-TT, in Africa's meningitis belt countries represented the first introduction of a vaccine specifically designed for this part of the world. During the first year alone, the number of people who received the vaccine through mass vaccination campaigns was several hundredfold higher than that of subjects who participated in the closely monitored clinical trials. Implementation of a system to identify rare but potentially serious vaccine reactions was therefore a high priority in the design and implementation of those campaigns. METHODS: National authorities and their technical partners set up effective vaccine pharmacovigilance systems, including conducting active surveillance projects. RESULTS: Implementation of national expert advisory groups to review serious adverse events following immunization in all countries and active monitoring of conditions of interest in 3 early-adopter countries did not identify particular concerns with the safety profile of PsA-TT, which had already provided tremendous public health benefits. CONCLUSIONS: Lessons learned from this experience will help to improve preparations for future vaccine introductions in resource-poor settings and capitalize on such efforts to advance vaccine safety systems in the future.

Active Surveillance for Adverse Events After a Mass Vaccination Campaign With a Group A Meningococcal Conjugate Vaccine (PsA-TT) in Mali.

BACKGROUND: The monovalent meningococcal A conjugate vaccine (PsA-TT, MenAfriVac) was developed for use in the "meningitis belt" of sub-Saharan Africa. Mali was 1 of 3 countries selected for early introduction. As this is a new vaccine, postlicensure surveillance is particularly important to identify and characterize possible safety issues. METHODS: The national vaccination campaign was phased from September 2010 to November 2011. We conducted postlicensure safety surveillance for PsA-TT in 40 government clinics from southern Mali serving approximately 400 000 people 1-29 years of age. We conducted analyses with individual-level data and population-level data, and we calculated rates of adverse events using the conditional exact test, a modified vaccine cohort risk interval method, and a modified self-controlled case series method for each outcome of interest, including 18 prespecified adverse events and 18 syndromic categories. RESULTS: An increased rate of clinic visits for fever within 3 days after vaccination was found using multiple methods for all age groups. Although other signals were found with some methods, complete assessment of all other prespecified outcomes and syndromic categories did not reveal that PsA-TT was consistently associated with any other health problem. CONCLUSIONS: No new safety concerns were identified in this study. These results are consistent with prelicensure data and other studies indicating that PsA-TT is safe. The approach presented could serve as a model for future active postlicensure vaccine safety monitoring associated with large-scale immunization campaigns in low-income countries.

Neisseria meningitidis serogroup W, Burkina Faso, 2012.

In 2010, Burkina Faso became the first country to introduce meningococcal serogroup A conjugate vaccine (PsA-TT). During 2012, Burkina Faso reported increases in Neisseria meningitidis serogroup W, raising questions about whether these cases were a natural increase in disease or resulted from serogroup replacement after PsA-TT introduction. We analyzed national surveillance data to describe the epidemiology of serogroup W and genotyped 61 serogroup W isolates. In 2012, a total of 5,807 meningitis cases were reported through enhanced surveillance, of which 2,353 (41%) were laboratory confirmed. The predominant organism identified was N. meningitidis serogroup W (62%), and all serogroup W isolates characterized belonged to clonal complex 11. Although additional years of data are needed before we can understand the epidemiology of serogroup W after PsA-TT introduction, these data suggest that serogroup W will remain a major cause of sporadic disease and has epidemic potential, underscoring the need to maintain high-quality case-based meningitis surveillance after PsA-TT introduction.

Identifying optimal vaccination strategies for serogroup A Neisseria meningitidis conjugate vaccine in the African meningitis belt.

OBJECTIVE: The optimal long-term vaccination strategies to provide population-level protection against serogroup A Neisseria meningitidis (MenA) are unknown. We developed an age-structured mathematical model of MenA transmission, colonization, and disease in the African meningitis belt, and used this model to explore the impact of various vaccination strategies. METHODS: The model stratifies the simulated population into groups based on age, infection status, and MenA antibody levels. We defined the model parameters (such as birth and death rates, age-specific incidence rates, and age-specific duration of protection) using published data and maximum likelihood estimation. We assessed the validity of the model by comparing simulated incidence of invasive MenA and prevalence of MenA carriage to observed incidence and carriage data. RESULTS: The model fit well to observed age- and season-specific prevalence of carriage (mean pseudo-R2 0.84) and incidence of invasive disease (mean R2 0.89). The model is able to reproduce the observed dynamics of MenA epidemics in the African meningitis belt, including seasonal increases in incidence, with large epidemics occurring every eight to twelve years. Following a mass vaccination campaign of all persons 1-29 years of age, the most effective modeled vaccination strategy is to conduct mass vaccination campaigns every 5 years for children 1-5 years of age. Less frequent campaigns covering broader age groups would also be effective, although somewhat less so. Introducing conjugate MenA vaccine into the EPI vaccination schedule at 9 months of age results in higher predicted incidence than periodic mass campaigns. DISCUSSION: We have developed the first mathematical model of MenA in Africa to incorporate age structures and progressively waning protection over time. Our model accurately reproduces key features of MenA epidemiology in the African meningitis belt. This model can help policy makers consider vaccine program effectiveness when determining the feasibility and benefits of MenA vaccination strategies.

Adverse events following immunization during mass vaccination campaigns at first introduction of a meningococcal A conjugate vaccine in Burkina Faso, 2010.

MenAfriVac™ is a new meningococcal A conjugate vaccine developed to prevent meningitis outbreaks in Africa. It was first introduced during the last quarter of 2010 in three West African countries. We report on the monitoring of adverse events following immunization (AEFI) in Burkina Faso where more than 11 million people aged 1-29 years were vaccinated. Vaccine pharmacovigilance relied on stimulated passive AEFI surveillance countrywide and active surveillance for 12 clinical conditions in one sentinel district (Ziniaré) with 97,715 people eligible for vaccination. All AEFI occurring during the 10 days of mass campaign or the 42 subsequent days were to be notified. Serious AEFI were submitted to a national expert committee (NEC) for causality assessment. A total of 11,466,950 people were vaccinated with 1471 vaccinees reported to have experienced at least one AEFI (12.83 cases per 100,000). 1444 AEFI were minor; the most common of which were fever, headache, gastro-intestinal disorders and local reactions (2-7 cases per 100,000). Of 27 serious AEFI reported, four cases were classified by the NEC as related to vaccine (1 case per 3 million vaccinated) including one case each of exanthematous pustulosis, angioedema, bronchospasm and severe vomiting. Active surveillance identified 71 cases of the 12 conditions of interest. Convulsions, urticaria and bronchospasm were more frequently reported. Attack rates for those conditions were similar to the baseline rates recorded in the same population, over the same time period, a year earlier. With the exception of convulsions in the days following vaccination the distribution of time intervals between vaccination and the occurrence of symptoms did not reveal any temporal clustering. The monitoring of AEFI of MenAfriVac™ in Burkina Faso did not suggest special concern regarding the vaccine safety. However, reported possible hypersensitivity reactions to vaccine components would require further review to rule out any anaphylactic reaction.

The most efficient use of resources to identify those in need of antiretroviral treatment in Africa: empirical data from Côte d'Ivoire's Drug Access Initiative.

OBJECTIVE: To describe the cost and outcome associated with the use of CD4 cell count and viral load tests as part of screening strategies to identify persons eligible for subsidized antiretroviral therapy (ART) in Côte d'Ivoire. METHODS: Empirical data from the Drug Access Initiative in Côte d'Ivoire (DAI-CI) were used to describe the laboratory cost of patient screening using sequential clinical staging, CD4 cell count, and viral load and the proportion of screened patients identified as eligible for ART. We also estimated costs modelling a parallel screening algorithm, across a range of laboratory costs and with current international recommendations to assess treatment eligibility. Benefit was defined as being found eligible for ART. RESULTS: Of the 2138 HIV-positive, ART-naive, adults who presented to the DAI-CI between July 1998 and July 2000, median CD4 cell count was 172 x 10(6) cells/microl. DAI-CI criteria identified 2057 (96%) of these persons eligible for antiretroviral treatment. In a serial screening algorithm, 75% were eligible by CDC clinical stage B or C; 18% by CD4 cell count less than 500 x 10(6) cells/microl; and an estimated 3.9% by a viral load greater than 10 000 copies/ml. Use of the current US recommendations and a serial algorithm would have resulted in 1977 (92%) persons eligible for ART: 75% by CDC clinical stage B or C; 15% by CD4 cell count less than 350 x 10(6) cells/microl (including 8% < 200 x 10(6) cells/microl); and an estimated 3.6% due to viral load greater than 55 000 copies/ml. Using DAI-CI criteria and heavily subsidized laboratory test costs, the addition of CD4 cell count to clinical criteria cost US dollar 50 (serial algorithm) and US dollar 203 (parallel algorithm) to identify each additional eligible person. Modelling current recommendations with a serial algorithm, CD4 cell count cost an average US dollar 62/eligible person (US recommendations) and US dollar 109 (WHO recommendations). The addition of viral load cost between US dollar 108 (serial algorithm DAI) to US dollar 1700 (parallel algorithm DAI) to identify each additional eligible person. CONCLUSION: In the African context of scarce resources and the huge unmet demands for voluntary HIV testing and for ART, simple screening strategies are needed to identify those most in need of ART. Health personnel should be trained to identify and refer clinically symptomatic persons. Viral load testing is of high cost and dubious benefit and should not be part of screening algorithms for initiating ART.

Use of the generalised linear model with Poisson distribution to compare caries indices.

In dental epidemiological studies, an analysis of variance assuming a normal distribution is commonly used to compare caries indices, which are often not normally distributed. As these indices represent discontinuous data, it would be preferable to use the negative binomial or the Poisson distribution. In this study, in order to compare the DMFS indices of adults working in the confectionery manufacturing industry in France, the results of the generalised linear model obtained using the normal and the Poisson distribution with identity or log built-in link function were compared. The negative binomial distribution was not used because it is very often unavailable in the most used statistical software. Analysis of the caries indices showed that the use of the normal distribution could lead to an incorrect interpretation of the data. Therefore it is concluded that the generalised linear model with Poisson distribution and over dispersion is to be preferred when comparing caries levels.

Nail changes in patients infected with human immunodeficiency virus. A prospective controlled study.

OBJECTIVES: To study the frequency of nail changes in a population of human immunodeficiency virus (HIV)-infected patients and to evaluate the specificity of these findings by comparison with HIV-negative control subjects. DESIGN: Prospective controlled study. Nail changes were recorded by a standardized clinical examination (curvature, nail plate, color, onychomycosis). In case of clinical diagnosis of onychomycosis, mycological culture was performed. SETTING: Primary care university hospital. PATIENTS: A total of 155 HIV-1-positive patients and 103 healthy HIV-negative control subjects of comparable age and sex ratio. INTERVENTION: None. MAIN OUTCOME MEASURE: Clinical examination findings. RESULTS: Nail symptoms were present in 67.7% of HIV-positive patients vs 34.0% of controls (P << .001). The following symptoms were significantly more frequent in the HIV group: clubbing (5.8%) (P < .05), transverse lines (7.1%) (P < .01), onychoschizia (7.1%) (P < .05), leukonychia (14.3%) (P < .001), and longitudinal melanonychia (14.8%) (P < .01). The main finding was onychomycosis in 30.3% of patients vs 12.6% of controls (P < .001). Trichophyton rubrum was present in 48% of onychomycoses and unusual Candida species were also recorded. Multiple fungi were frequently cultured in a single patient. The mean CD4+ cell count was lower in patients with onychomycosis and the frequency of onychomycosis increased in advanced stages of HIV disease. Acquired total leukonychia of the 20 nails was present in 4% of patients. CONCLUSION: Nail symptoms are much more frequent in patients with HIV than in healthy controls, and some of them could be linked to the level of immunosuppression.

Caries prevalence and salt fluoridation among 9-year-old schoolchildren in Strasbourg, France.

The 9-year-old group (236 children) of an epidemiological study carried out in 1991 in Strasbourg on children aged 6 to 15 years was selected with the aim of determining if the caries prevalence reduction observed could be related to the use of salt fluoridation (FS) introduced in France in 1987. From these 236 children, 143 answered a questionnaire which showed that 36 of them were fluoridated salt users and 107 were not. The dft index was significantly lower in the FS consumers which showed 35.5% dft reduction compared to the non-FS-consuming children. When using the Generalized Linear Model, this reduction was significant (P = 0.03). Although lower in the FS group, the DMFT and DMFS indices showed no statistical significant difference. It appeared that 72.2% of the users took simultaneously fluoride tablets but no dental fluorosis was observed. The use of fluoride tablets had a significant effect on the DMFS (P = 10(-2)). The children who consumed FS used more frequently fluoridated mouthrinses (P = 10(-3)) and had more frequent professional application of fluoridated gel and varnishes than non-consumers (P = 0.02). The DMFS index increased with the number of meals (P = 10(-6)), which was the most significant variable entered into the Generalized Linear Model. The children who brushed their teeth once a day had a DMFS value 2.6 times higher than those who brushed regularly three times a day (P = 10(-3)). The DMFS value was 4.4 times higher among the children who brushed their teeth irregularly when compared with those who brushed three times a day (P = 10(-2)).