Cost-Effectiveness of Alternative Uses of Polyvalent

Original Article

Medical Decision Making 2019, Vol. 39(5) 553–567 Ó The Author(s) 2019 Cost-Effectiveness of Alternative Uses Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0272989X19859899 of Polyvalent Meningococcal Vaccines journals.sagepub.com/home/mdm in Niger: An Agent-Based Transmission Modeling Study

S. M. Niaz Arifin, Christoph Zimmer, Caroline Trotter, Anaı¨s Colombini, Fati Sidikou, F. Marc LaForce, Ted Cohen, and Reza Yaesoubi

Background. Despite the introduction of an effective serogroup A conjugate vaccine (MenAfriVacä), sporadic epidemics of other Neisseria meningitidis serogroups remain a concern in Africa. Polyvalent meningococcal conjugate (PMC) vaccines may offer alternatives to current strategies that rely on routine infant vaccination with MenAfriVac plus, in the event of an epidemic, district-specific reactive campaigns using polyvalent meningococcal polysaccharide (PMP) vaccines. Methods. We developed an agent-based transmission model of N. meningitidis in Niger to compare the health effects and costs of current vaccination practice and 3 alternatives. Each alternative replaces MenAfriVac in the infant vaccination series with PMC and either replaces PMP with PMC for reactive campaigns or implements a one-time catch up campaign with PMC for children and young adults. Results. Over a 28-year period, replacement of MenAfriVac with PMC in the infant immunization series and of PMP in reactive campaigns would avert 63% of expected cases (95% prediction interval 49%–75%) if elimination of serogroup A is not followed by serogroup replacement. At a PMC price of $4/dose, this would cost $1412 ($81–$3510) per disability-adjusted life-year (DALY) averted. If serogroup replacement occurs, the cost-effectiveness of this strategy improves to $662 (cost-saving, $2473) per DALY averted. Sensitivity analyses accounting for incomplete laboratory confirmation suggest that a catch-up PMC campaign would also meet standard cost-effectiveness thresholds. Limitations. The assumption that polyvalent vaccines offer similar protection against all serogroups is simplifying. Conclusions. The use of PMC vaccines to replace MenAfriVac in routine infant immunization and in district-specific reactive campaigns would have important health benefits and is likely to be cost-effective in Niger. An additional PMC catch-up campaign would also be cost- effective if we account for incomplete laboratory reporting.

Keywords economic evaluation, meningitis, meningococcal, simulation, vaccine

Date received: June 29, 2018; accepted: June 4, 2019

The meningitis belt, a region in sub-Saharan Africa with epidemics in this region has relied on reactive vaccination an estimated population of 430 million people, is prone campaigns using polysaccharide vaccines in districts to sporadically occurring meningitis epidemics.1–3 These where the weekly meningitis incidence passes a critical epidemics place a heavy burden on national and local resources,4 resulting in substantial deaths and long-term 5 Corresponding Author disabling sequelae. The largest of these epidemics caused Reza Yaesoubi, Department of Health Policy and Management, Yale an estimated 250,000 cases with more than 25,000 deaths School of Public Health, 60 College Street, New Haven, CT 06510, 6,7 in 1996. For the past 30 years, control of meningitis USA ([email protected]). 554 Medical Decision Making 39(5) incidence threshold of 10/100,000 population.4,8,9 While with PMC vaccine and the addition of this vaccine to this strategy, when deployed early in an epidemic, could EPI (as a replacement for MenAfriVac) will likely be save lives, it has not reduced the frequency and magnitude cost-effective compared with the current World Health of epidemics because 1) polysaccharide vaccines induce Organization (WHO) strategy of reactive vaccination only short-term protection (especially in children)4,10,11 using PMP vaccines.33 Yet the evidence to inform the and 2) the successful implementation of reactive vaccina- best use of these novel polyvalent meningococcal vac- tion campaigns is hampered by significant delays between cines for other countries of the meningitis belt is lacking. outbreak identification and vaccination responses.12,13 Despite similarities in certain characteristics of meningo- The introduction of a Neisseria meningitidis serogroup A coccal epidemics across countries of meningitis belt,10,29 conjugate meningococcal vaccine (PsA-TT, MenAfriVacä) the difference in population sizes and structures, age dis- in the African meningitis belt in 2010 to 2011 has reduced tribution of meningococcal cases, and carriage prevalence meningitis A carriage and cases to an exceptionally low may affect the performance of vaccination strategies level.3,14–17 Despite the early success of MenAfriVac from one setting to another.17 in the prevention of meningitis A epidemics, other In this study, we describe a district-level, agent-based non-A serogroups continue to cause epidemics of menin- model (ABM) of meningococcal transmission in Niger. gitis.9,18–21 Examples include the N. meningitidis ser- While Niger has a similar total population size as ogroup W epidemic in Burkina Faso (2012)22;theN. Burkina Faso, the population density of Niger is consid- meningitidis serogroup X epidemics in Burkina Faso erably lower (with the largest concentrations of individu- (2010), Niger (2006), and Togo (2009)23,24; a recent severe als in southwestern districts), and Niger has experienced epidemic by a novel strain of N. meningitidis serogroup C less severe meningococcal epidemics since 2002. As vacci- (NmC) in Niger (2015)25,26; and the largest ever recorded nation programs may offer relatively smaller health gains epidemic of NmC in Nigeria (2017) with more than in settings with less severe meningococcal epidemics, the 14,000 suspected cases.26,27 evaluation of PMC vaccination strategies in Niger, and To combat the remaining threat from non-A meningo- comparison with previously reported results from coccal serogroups, polyvalent vaccines that target C, Y, W, Burkina Faso, will shed light on how the local epidemiol- and X serogroups (in addition to A) are being considered ogy of disease affects the projected health impact and for use in Africa.12,21,25,28,29 In contrast to the available costs associated with alternative vaccine strategies. polyvalent meningococcal polysaccharide (PMP) vaccines, polyvalent meningococcal conjugate (PMC) vaccines are Methods immunogenic in young children and induce longer-term (10–15 year) protection and, hence, can also be used in reac- An Agent-Based Model of Meningococcal tive and/or mass preventive vaccination campaigns2,30–32 as Transmission in Niger well as in the Expanded Program on Immunization (EPI). Our ABM is a stochastic, and spatially explicit model34–36 A recent cost-effectiveness analysis in Burkina Faso to describe the meningococcal transmission across 44 dis- suggests that a vaccination strategy that involves a catch- tricts of Niger (Figure 1 and Supplementary Figure S2). up nationwide vaccination campaign in young adults Meningitis epidemics in Niger (along with other countries of meningitis belt) occur sporadically and, when they do Department of Epidemiology of Microbial Diseases, Yale School of occur, are of greatly varying severity (Figure 2).21,37,38 Public Health, New Haven, CT, USA (SMNA, CZ, TC); Department This suggests that a stochastic model can best simulate of Veterinary Medicine, University of Cambridge, Cambridge, UK (CT); independent consultant, Madagascar (AC); Centre de Recherche the types of chance events that ultimately lead epidemic Medicale et Sanitaire (CERMES), Niamey, NE, Niger (FS); Serum takeoff or fade out after the appearance of meningitis Institute of India, Pune (FML); and Department of Health Policy and cases within a district. Management, Yale School of Public Health, New Haven, CT, USA Capturing meningococcal epidemics at the district (RY). The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. level is necessary to model reactive vaccination campaigns Financial support for this study was provided by a contract with that are triggered when districts exceed the WHO epi- 4 PATH (https://www.path.org/) and by awards 1K01AI119603 from the demic threshold of 10 per 100,000 population in a week. National Institute of Allergy and Infectious Diseases (https:// We employed a gravity model to approximate the age- www.niaid.nih.gov/), U54GM088558 from the National Institute of specific intensity of contacts among individuals within General Medical Sciences (www.nigms.nih.gov), and a scholarship from the German Research Foundation (DFG; http://www.dfg.de). The and between districts (see the Supplementary Appendix). funding agreement ensured the authors’ independence in designing the Our ABM is based on existing mathematical models study, interpreting the data, writing, and publishing the report. developed for different countries of the meningitis Arifin et al. 555

In our ABM, individuals are assumed to be in 1 of 4 health states at any given time: susceptible, carrier, meningitis, and immune (Figure 1). Susceptible individuals are at dynamic, age-specific risk of infection with N. meningitidis that is proportional to the prevalence of invasive meningitis and carriage. Infected individuals move to an asymptomatic but infectious state (‘‘carrier’’), where they may develop invasive meningitis disease (‘‘meningitis’’) or lose their carriage status and develop immunity (‘‘immune’’). The rate of progression to the active disease is highest at the time of infection and decreases gradually over time such that only a small por- tion (about 1%) of carriers eventually develop meningitis. Individuals who lose their carriage state or recover from meningitis will develop immunity against reinfec- tion. The duration of this immunity is assumed to be shorter for those who acquired their immunity through the loss of carriage state compared with those who Figure 1 Model structure depicting health states (ovals) and become immune after recovering from meningitis dis- health events (rectangles) for our agent-based model of ease. We also assume that the probability of superinfec- meningococcal epidemics. Natural death may occur in any tion while in the carriage state is negligible. Further state. details about the model assumptions and parameters as well as the demographics of Niger are provided in the Supplementary Appendix.

Data Sources To parameterize our model, we used an anonymized data set of all documented clinical meningitis cases in Niger from 2002 to mid-2015 (provided by the Ministry of Health, Niger). The data set contains sample date, district, age, and the final clinical diagnosis for 29,349 clinical cases. To use this data set to calibrate our simulation model, we categorized each reported meningitis case into 1 of 6 mutually exclusive groups based on the final clinical diagnosis (Table 1). For reported cases in which Figure 2 Weekly confirmed meningococcal cases in Niger laboratory typing was not completed (n=5089), we use reported between 2002 and mid-2015, associated with empirical distributions of the serogroup distribution of serogroups A, C, W, and X (blue curve) and with serogroups each epidemic season to assign a meningitis type, assum- C, W, and X (red curve). ing that these case designations were missing at random. Using this data set, we estimated the weekly N. meningitidis cases by serogroup and age group within districts of belt20,33,39–41 but allows for additional flexibility to repre- Niger, which was then used to calibrate our model (see sent complex vaccination strategies and the sequential below). timing of events experienced by individuals. In contrast Analyzing this data set shows that in districts where to compartmental models in which the change in size of epidemics were detected between 2002 and 2015, the each compartment is tracked over time, ABMs track each majority of reported cases did not have a conclusive population member separately. For our study, this allows bacteriological diagnosis and were recorded as bacterio- us to 1) model the variation in cost and health outcome logically negative (Supplementary Figure S6 in the across individuals and 2) more accurately describe the Appendix). Given the imperfect sensitivity of diagnostics, individual-level impact and population-level implementa- there is likely to be underreporting of meningococcal tion of vaccine strategies (as described below). cases in this data set, as most meningitis cases (.79%) in 556 Medical Decision Making 39(5)

Table 1 Bacteriologic Results from Cerebrospinal Fluid (CSF) replacement,’’ which assumes that the future will be simi- Specimens from Cases of Suspected Meningitis, Niger 2002– lar to the past with serogroup A excluded. These 2 2015a extreme scenarios bound the performance of vaccination strategies and allow us to investigate how robust the Category Cases cost-effectiveness of vaccination strategies is with respect N. meningitidis to the possibility of future strain A replacement. Group A 3077 Non-A 2650 Grouping not done 2771 Model Calibration Other bacteriab 1777 Positive (but not typed) 5089 We calibrated our ABM to capture the key characteris- Negative (no conclusive diagnosis) 13,985 tics of meningococcal epidemics under both strain Total CSF tested 29,349 replacement scenarios, including the age distribution of meningococcal incidence (Figure 3A), average carriage a. Data from the Centre de Recherche Medicale et Saniteire prevalence among different age groups (Figure 3B), and (CERMES) and the Ministry of Health, Niger. b. Streptococcus pneumoniae, Haemophilus influenzae b, Haemophilus weekly average incidence of meningococcal cases (Figure influenzae non-b, Salmonellae, Micrococcus, Staphylococcus aureus, 3C) between 2002 and mid-2015 (the full duration of the Staphylococcus epidermidis, Acinetobacter spp, Bacillus spp. available time series). We used the cosine of the angle (u) between the vectors of Fourier amplitude for observed and simulated time series of weekly meningococcal cases epidemic years 2006 to 2008 were caused by N. meningiti- to measure how well the simulated trajectories match the 18 dis. Our projections of the cost-effectiveness of menin- periodicity of past meningococcal epidemics in Niger gococcal vaccination strategies could underestimate the (Figure 3D). Figure 4 displays the time series of menin- health benefits from vaccination programs if bacteriolo- gococcal cases from 3 simulated trajectories over 30 gically confirmed cases significantly undercount the true years produced by the calibrated model in comparison burden of meningococcal meningitis. To account for this with the meningococcal time series observed in Niger possibility, we consider 2 scenarios: 1) a conservative sce- during 2002 to 2015. We emphasize that our goal is not nario that assumes all meningococcal cases occurred in to fit to the timing of past epidemics but instead to cali- Niger from 2002 to mid-2015 are reported in our data brate the model against the periodicity of past epidemics set and correctly categorized and 2) an alternative sce- in additional to calibration targets depicted in Figure 3. nario that assumes meningitis cases confirmed as N. Details of our calibration approach are described in the meningitidis in our data set represent only half of all Supplementary Appendix. meningococcal cases occurring in Niger during this Figure 5 suggests that our model behavior is consis- period. We report the results of our cost-effectiveness tent with the observed data on the N. meningitidis cases analysis under both scenarios. for all districts of Niger between 2002 and mid-2015. Reactive campaigns are launched in districts where weekly Strain-Replacement Scenarios clinical meningitis incidence (which include not only confirmed meningococcal cases but also suspect cases While the introduction of MenAfriVac has dramatically of Haemophilus influenzae types b and non-b, and lowered the incidence of serogroup A in Niger,14,17,42 the Streptococcus pneumoniae) exceeds the WHO epidemic possibility of serogroup A being replaced by other ser- threshold of 10 per 100,000 population.12,33 Supplementary ogroups in the future still exists,18,19,21 as evidenced by Figure S9 in the Appendix confirms that our model’s beha- yearly outbreaks and a severe epidemic caused by a novel vior at the district level is consistent with the observed data strain of serogroup C (NmC) in Nigeria in 2013 to 2015 of clinical meningitis cases on the number of years from and the largest ever recorded epidemic of NmC in 2002 to mid-2015, where each Niger district passes the Nigeria in 2017.26 As such, consistent with a similar cost- WHO epidemic threshold. effectiveness study conducted for Burkina Faso,33 we consider 2 extreme scenarios to quantify the impact of serogroup A replacement on the performance of vaccina- Modeling the Impact of Vaccination tion strategies (Figure 2): 1) ‘‘complete strain replace- In our simulation model, we track the vaccination status ment,’’ which assumes that future epidemics will occur of each individual by agent-level attributes. If individuals with similar frequency and magnitude as observed in are vaccinated in the susceptible state, their susceptibility Niger between 2002 and mid-2015, and (2) ‘‘no strain to infection is reduced according to the effectiveness of Arifin et al. 557

Figure 3 The proposed agent-based model matches the key characteristics of meningococcal epidemics in Niger between 2002 and mid-2015 under the assumption of complete strain replacement. (A) Age distribution of meningococcal meningitis cases in Niger versus the age distribution of cases generated by the model. (B) Estimated meningococcal carriage prevalence in different age groups from carriage survey studies in the African meningitis belt19 versus the age-specific average carriage prevalence obtained from the model. (C) Average of confirmed weekly meningococcal cases observed from 2002 to mid-2015 versus those produced by the model. (D) Cosine of the angle (u) between the vectors of Fourier amplitude for observed and simulated meningitis time series; a cosine of 1 indicates a total match in periodicity, and a cosine of 0 indicates no overlap between the significant periods of the 2 time series. See Supplementary Figure S8 in the Appendix for the fit of the model under the no-strain-replacement scenario. the administered vaccine (Table 2). Vaccinated carriers (MenAfriVac, PMP, and PMC), the targeted age groups, are assumed to remain infectious but are protected from and the vaccination programs (routine, reactive, and pre- progression to the invasive disease for the duration of ventive) to immunize the population (Table 2). These immunity offered by the vaccine. For those vaccinated policies are consistent with those considered in a recent while in the immune state, if the natural immunity wanes cost-effectiveness study conducted for Burkina Faso.33 sooner than the vaccine immunity, they proceed to the The Base strategy represents the current WHO strategy of susceptible state but remain partially protected against using PMP vaccines in reactive campaigns in districts in infection as long as the vaccine immunity lasts. We fur- which the weekly meningitis incidence passes the thresh- ther assume that individuals with active meningitis are old of 10 cases per 100,000 population. As PMC vaccines not eligible for vaccination, those vaccinated with PMP offer protection against multiple serogroups (as opposed will become reeligible for vaccination at the beginning of to MenAfriVac that induces immunity only against ser- the next epidemic season, and those vaccinated with ogroup A) and have better immunogenicity properties PMC will become vaccine eligible 10 years after the time compared with PMP (Table 3), the Base strategy can be of vaccination. improved by replacing MenAfriVac in routine EPIs and PMP in reactive campaigns with PMC vaccines. This cor- responds to the Base Prime strategy in Table 3. Alternative Vaccination Strategies Prevention 1 and 2 strategies immunize younger We estimate the cost and health outcomes of 4 vaccina- adults through mass nationwide immunization cam- tion strategies that differ by the types of vaccines used paigns in addition to using PMC vaccines in EPI. We 558 Medical Decision Making 39(5)

Figure 4 Comparing the time series of meningococcal cases observed between 2002 and 2015 in Niger (black curve) with 3 simulated trajectories produced by the calibrated model (blue, green, and red curves) under the with-strain-replacement scenario. The periodicity at which simulated epidemics are occurring matches the periodicity of observed epidemics. Figure 3, Figure 5, and Supplementary Figure S9 show that trajectories generated by our model also match other key properties of meningococcal epidemics in Niger (e.g., age distribution of cases, age-specific carriage prevalence, average weekly meningococcal incidence at the national and district level, and number of districts in each year between 2002 and 2015 in which the threshold of 10 meningitis cases per 100,000 population is exceeded). note that while the Base Prime strategy attempts to con- For reactive campaigns in Base and Base Prime stra- trol district-level outbreaks, the 2 prevention strategies tegies, once an epidemic is declared in a district, the use nationwide campaigns to reduce the risk of infection time until the initiation of a reactive campaign is and to potentially achieve herd immunity. We assume assumed to follow a discrete uniform distribution of [2, that preventive campaigns occur in November of the first 10] weeks.33 Once triggered, reactive campaigns are simulation year and are completed before the start of the assumed to continue until the end of the current season next epidemic season. (although the majority of the district’s population will Arifin et al. 559

Figure 5 Average weekly N. meningitidis cases in Niger’s districts produced by our model and observed in the data for the complete-strain-replacement scenario. See Supplementary Figure S10 in the Appendix for the fit of the model under the scenario of no strain replacement.

Table 2 Vaccination Parameters

Parameter Vaccine/Vaccination Campaign Range/Value Reference Sources

Relative susceptibility to infection PMP 0%–15% 29, 43–45 compared with unvaccinateda PMC 0%–10% 46, 47 Duration of protectiona PMP Age 1–4 years 1–3 years 45, 48 Age 5+ years 3–5 years 29, 49 PMC 10–20 years 39, 47 Delay between administration of vaccine PMP or PMC 2 weeks 50 and the establishment of immunity Vaccine uptake Routineb 80%–90% 51 Reactive and preventive 90%–100% 52–54 (within 10 days)

PMC, polyvalent meningococcal conjugate; PMP, polyvalent meningococcal polysaccharide. a. These parameters are sampled for each individual in a simulated trajectory. All other parameters are sampled once per simulated trajectory. b. Vaccine uptake for routine vaccination is assumed to be equal to the 9-month measles coverage.51 get vaccinated within a few weeks after the vaccines are respect to the Base strategy (Table 3) and are discounted delivered). at an annual rate of 3% to 2016. Assumptions and details for health, financial outcomes, and DALY calculations are provided in the Supplementary Appendix. Health and Financial Outcomes We followed the Consolidated Health Economic We use disability-adjusted life-years (DALY) to measure Evaluation Reporting Standards (CHEERS)55 to report the the health outcomes associated with vaccination strate- results of our cost-effectivenessanalysisstudy.CHEERS gies. To measure the financial outcomes (presented in US was developed by the ISPOR Health Economic Evaluation dollars), we consider disease-related costs incurred due to Publication Guidelines Good Reporting Practices Task meningitis case management and care for patients who Force with the objective of optimizing the reporting of experience sequelae as well as costs of implementing vac- health economic evaluation studies. We present all estimates cination campaigns. As the government and donors pri- from the model as the average and 95% prediction intervals marily bear the vaccination program costs in Niger, we (the 2.5th and 97.5th percentiles) of 200 trajectories simu- adopt the payer’s perspective in conducting cost- lated over a 28-year period. We found that obtaining addi- effectiveness analysis. All health and financial outcomes tional trajectories does not meaningfully change the bounds of alternative vaccination strategies are presented with of the prediction intervals (see Supplementary Figure S11). 560 Medical Decision Making 39(5)

Table 3 Alternative Vaccination Strategies for Employing Meningococcal Vaccines (Adopted from ref. 33)

Vaccination Program/Campaign Strategy Routine (EPI) Reactive Preventive

Base MenAfriVac at 9 months PMP vaccine for 1–29 years old — Base prime PMC vaccine at 9 months PMC vaccine for 1–29 years old — Prevention 1a PMC vaccine at 9 months — PMC vaccine for 1–18 years old Prevention 2a PMC vaccine at 9 months — PMC vaccine for 1–29 years old

EPI, Expanded Program on Immunization; PMC, polyvalent meningococcal conjugate; PMP, polyvalent meningococcal polysaccharide. a. If the district-level epidemic threshold is exceeded, a reactive campaign using PMC vaccines would be initiated in the district.

6). This improvement is associated with superior immunogenicity of PMC vaccines compared with PMP vaccines (Table 2). Both Base and Base Prime strategies rely on reactive campaigns to respond to epidemics, and hence their performance would be impaired by logistical delays in the launch of these campaigns once the epidemic threshold is passed in a district. Our model shows that proactive strategies (i.e., Prevention 1 and 2) that aim to immunize young adults in mass vaccination campaigns avert the largest number of meningococcal cases: Prevention 1 averts 74% (54%–99%) and 74% (58%–99%) of cases, and Prevention 2 averts 79% (57%–99%) and 79% (60%–99%) of cases with respect to the Base strategy under complete-strain-replacement and no-strain-replacement scenarios. Our model suggests that none of these strategies results in elimination of N. meningitidis, and the meningococcal epidemics may recur if reintroduction occurs after Figure 6 Expected percentage reduction in annual meningococcal cases over a 28-year simulation period for the the herd immunity achieved through mass vaccination vaccination strategies described in Table 3 compared with the campaigns wanes. Base strategy. Bars represent the 95% prediction intervals. Figure 7 shows the expected number of vaccines required for each vaccination strategy. Base and the Base Prime strategies have the highest and the lowest Role of the Funding Source expected annual consumption of total vaccine doses, respectively, under both strain-replacement scenarios. The sponsors of the study had no role in study design, data For the Base strategy, the wide prediction intervals of collection, data analysis, data interpretation, or writing of the estimated number of PMP vaccines used are due to the report. The corresponding author had full access to all the sporadic district-level outbreaks that may trigger the data in the study, and all authors had final responsibil- reactive campaigns in the affected districts. Since routine ity for the decision to submit for publication. programs target 9-month-old infants, extending the vaccination projection horizon does not affect the estimated Results annual consumption of MenAfriVac, PMP, or PMC vaccines in routine programs. However, the extended hori- Replacing both MenAfriVac in routine EPIs and PMP in zon reduces the estimated annual consumption of PMC reactive campaigns with PMC vaccines (Base Prime strat- vaccines in reactive and preventive campaigns. This is egy) results in a 62% (46%–77%) and 63% (49%–75%) because preventive campaigns are implemented only reduction in the annual meningococcal cases expected once at the beginning of the projection period. under the Base strategy for complete-strain-replacement We estimate the incremental cost-effectiveness ratio and no-strain-replacement scenarios, respectively (Figure (ICER) of the Base Prime strategy with respect to the Arifin et al. 561

Figure 7 Expected number of vaccines used per year (over a 28-year simulation period). (A) Complete-strain-replacement scenario. B) No-strain-replacement scenario. We note that preventive campaigns are implemented only once at the beginning of the projection period. Error bars represent 95% projection intervals (error bars that are shorter than the width of symbols are not shown). PMP, polyvalent meningococcal polysaccharide; PMC, polyvalent meningococcal conjugate.

Table 4 Cost-Effectiveness of Alternative Vaccination Strategies for Both Strain Replacement Scenarios

Expected Expected Expected Incremental Incremental ICER (in US$) Annual Cost Expected Annual Cost Annual DALYs per DALY (in Million US$) Annual DALYs (in Million US$) Averted Averted

Complete strain replacement Base 3.64 (0.97, 7.66) 4139 (2240, 6344) — — — Base Prime 5.39 (5.01, 5.84) 1499 (536, 2874) 1.75 (21.94, 4.37) 2639 (1642, 3768) 662 (Cost-saving, 2473) Prevention 1 6.81 (6.47, 7.11) 917 (11, 2083) 1.42 (1.05, 1.76) 582 (169, 1428) 2437 (696, 6643) Prevention 2 7.3 (6.97, 7.73) 748 (7, 2134) 0.49 (0.18, 0.84) 169 (240, 980) 2900a No strain replacement Base 2.5 (0.86, 5.12) 3097 (1779, 5048) — — — Base Prime 5.32 (4.99, 5.61) 1099 (456, 2189) 2.82 (0.21, 4.57) 1997 (1200, 3062) 1412 (81, 3510) Prevention 1 6.78 (6.47, 7.05) 691 (20, 1573) 1.46 (1.28, 1.75) 408 (136, 1017) 3569 (1343, 11,594) Prevention 2 7.27 (6.97, 7.54) 570 (7, 1505) 0.49 (0.21, 0.66) 121 (243, 715) 4048a

DALY, disability-adjusted life-year; ICER, incremental cost-effectiveness ratio. Numbers in parentheses show 95% prediction intervals. For each vaccination strategy, expected incremental annual cost, DALYs, and ICERs are calculated with respect to the left-hand side strategy on the cost-effectiveness frontier shown in Figure 8 (i.e., Base Prime compared with Base; Prevention 1 compared with Base Prime; Prevention 2 compared with Prevention 1). a. The 95% prediction intervals were unstable because the incremental annual DALYs averted were small for some trajectories.

Base strategy to be $662 (Cost-saving to $2473) and $1412 be above this cost-effectiveness threshold (Table 4). ($81 to $3510) for scenarios with and without strain A Prevention 1, however, remains a viable alternative as it is replacement. Per WHO recommendations, strategies that expected to cost $984 (Cost-saving to $2964) and $1779 avert 1 DALY for less than 3 times the per capita gross ($516 to $4007) per DALY averted with respect to the domestic product are considered cost-effective.56 Hence, at Base strategy under with and without strain A replace- the cost-effectiveness threshold of $1077, 3 per capita gross ment scenarios (Figure 8A, B). domestic product of Niger in 2015,57 the Base Prime strat- Figure 8C, D compare the impact of vaccination stra- egy is expected to be cost-effective with respect to the Base tegies on the population’s net monetary benefit (NMB) strategy under the complete-strain-replacement scenario. for varying values of the cost-effectiveness threshold (v). The ICER of Prevention 1 and 2 strategies is estimated to The expected gain in NMB for a strategy with respect to 562 Medical Decision Making 39(5)

Figure 8 Economic evaluation of vaccination strategies described in Table 3 for the complete-strain-replacement scenario (A, C) and the no-strain-replacement scenario (B, D). The price of the polyvalent meningococcal polysaccharide and polyvalent meningococcal conjugate vaccines is $4 per dose (see the Supplementary Appendix for sensitivity analysis to the vaccine prices). In C and D, the expected gain in net monetary benefit of a strategy is calculated with respect to the Base strategy. The dashed line in these figures represents the cost-effectiveness threshold of 3 per capita gross domestic product of Niger, which was estimated to be 1077 USD in 2015.57 the Base strategy is calculated as: v 3 (additional meningococcal cases that occurred from 2002 to mid- DALYs averted by the strategy) – (additional cost of the 2015 in Niger are reported and correctly diagnosed in strategy). Prevention 1 and 2 demonstrate similar perfor- the patient-level data set we used to calibrate our model. mance under both strain-replacement scenarios and the As demonstrated in Supplementary Figure S6, this is a incremental benefit from all strategies are slightly larger very conservative assumption and could lead to substan- when strain A elimination is followed by complete strain tial underestimation of health benefits from meningococ- replacement (Figure 8 and Table 4). cal vaccination strategies. Under an alternative scenario The cost-effectiveness analysis results presented above that only 50% of cases caused by N. meningitidis are (and in Figure 8 and Table 4) assume that all correctly diagnosed in our data set (Supplementary Arifin et al. 563

Figure 9 Economic evaluation of vaccination strategies described in Table 3 for the complete-strain-replacement scenario (A, C) and the no-strain-replacement scenario (B, D) for the scenario in which only 50% of meningococcal cases are reported and correctly categorized. The price of polyvalent meningococcal polysaccharide and polyvalent meningococcal conjugate vaccines are $4 per dose. In C and D, the expected gain in net monetary benefit of a strategy is calculated with respect to the Base strategy. The dashed line in these figures represents the cost-effectiveness threshold of 3 per capita gross domestic product of Niger, which is estimated to be $1077 USD in 2015.57

Figure S6), we estimate the cost-effectiveness ratios for Additional sensitivity analysis shows that the cost- Base Prime, Prevention 1, and Prevention 2 strategies effectiveness of Base Prime and Prevention 1 and 2 strate- with respect to the Base strategy at $395 (Cost-saving to gies diminishes as the price of the PMC vaccine increases $1237), $563 (Cost-saving to $1482), and $611 (Cost-saving (Supplementary Figure S14). If the PMC vaccine price is to $1537) under complete strain replacement and at $795 $10 per dose, we estimate the cost-effectiveness ratios for ($41 to $1755), $986 ($258 to $2003), and $1046 ($317 to Base Prime, Prevention 1, and Prevention 2 strategies $2159) under no strain replacement (Figure 9). As expected, with respect to the Base strategy at $3539 ($1631–$6430), under this scenario, the cost-effectiveness of the preventive $3988 ($1932–$7455), and $4139 ($2139–$7677) under catch-up vaccination strategies improves. complete strain replacement and at $5208 ($2570–$9326), 564 Medical Decision Making 39(5)

$5809 ($3010–$10,272), and $6017 ($3223–$10,608) characterize serogroup competition.40 As polyvalent vac- under no strain replacement. cines offer protection against all meningococcal serogroups, our model describes only the circulation of one vaccine serogroup. This simplification may undermine the Discussion robustness of our model’s results and its ability to project the frequency and magnitude of future meningitis epi- The current WHO-recommended strategy for meningitis demics, especially in the event that there is differential, control in sub-Saharan Africa relies on using serogroup-specific effectiveness of vaccines or complex MenAfriVac in the EPI and PMP vaccines in districts between-serogroup interactions. where the epidemic threshold is passed. Our results indi- The vaccination strategies considered here can be cate that once affordable PMC vaccines become avail- compared with those we previously evaluated in a cost- able for Africa, this currently recommended strategy effectiveness study of polyvalent meningococcal vaccines could be improved by alternative policies that rely on in Burkina Faso.33 This previous study concluded that using PMC vaccines. A strategy that uses PMC vaccines for Burkina Faso, vaccination strategies that rely on the in the EPI and in reactive vaccination programs could use of PMC vaccines in EPI and also within catch-up offer a substantial improvement in reducing the menin- prevention vaccination campaigns can be cost-effective gococcal epidemics burden and is likely to be cost- (with respect to the current WHO strategy). The general- effective at the PMC vaccine price of $4 or lower per izability of this conclusion to other settings of the menin- dose. This strategy, however, still leaves the district at gitis belt, however, was unclear. The findings presented risk of sporadic outbreaks. Augmenting this strategy here confirm that the conclusion that PMC vaccines can with the addition of nationwide mass vaccination cam- be used within vaccination strategies in a cost-effective paigns to immunize 1- to 18-year-olds with PMC vac- manner when compared with the current WHO- cines could avert the majority of meningococcal cases. recommended strategy also appears to be the case in The cost-effectiveness of vaccination strategies that use Niger. However, in contrast to the situation in Burkina the PMC vaccine is improved if elimination of serogroup Faso, we note that preventive strategies (i.e., Prevention A is followed by a strain replacement. Accounting for 1 and 2) were found to cost more per DALY averted incomplete laboratory confirmation also improves the with respect to the status quo in Niger (Table 4) than cost-effectiveness of PMC vaccination, including catch- with respect to the status quo in Burkina Faso.33 While up campaigns. there are differences in the modeling approach between A major strength of our study was the availability of these analyses, we believe that the driving reason for the a rich, individual-level data set of more than 29,000 difference in the conclusion about the cost-effectiveness reported meningitis cases in Niger between 2002 and of the use of PMC in catch-up campaigns is that meningi- mid-2015. The availability of age, district, and final diag- tis has been responsible for a far larger burden of disease nosis (due to N. meningitidis serogroups as well as H. in Burkina Faso (notifications of approximately 91,000 influenzae type b and S. pneumoniae) for reported cases cases between 2005 and 2015) than in Niger (notifications allowed us to calibrate our model against key properties of approximately 37,000 cases in this time period).62 of meningococcal epidemics in Niger. Our model demon- The results of these cost-effectiveness analyses in strates the ability to accurately describe the age distribu- Niger and Burkina Faso indicate a need to revisit the cur- tion of meningococcal cases and carriage prevalence as rent WHO strategy for meningitis control in sub-Saharan well as the discrete-level magnitude and frequency of Africa, which relies on reactive campaigns using PMP meningitis activity. Moreover, while our model shares a vaccines, once affordable PMC vaccines are available. similar structure to the existing compartmental models The cost-effectiveness of strategies to inform the use of of African meningitis,20,33,39,40,58 the use of an ABM PMC vaccines (e.g., to be employed in reactive v. preven- approach allowed for more accurate representation of tive campaigns) will differ across the countries of the disease natural history and evaluation of different vacci- meningitis belt depending on the population distribution nation strategies. and the expected severity of meningococcal epidemics. One of the limitations of our study stems from the assumption that polyvalent vaccines offer the same degree of protection against all serogroups. This assump- Acknowledgments tion is consistent with existing models that aggregate ser- The authors gratefully acknowledge the generous assistance 33,40,59–61 ogroups into ‘‘vaccine’’ and ‘‘nonvaccine’’ type provided by Dr. Idrissa Maiga, Secretary General, and Dr. and is also necessitated by the lack of data to Kadade Goumbia, Director, Surveillance et la Epidemic Arifin et al. 565

Response, Ministry of Health, Government of Niger, Niamey, 13. Sow SO, Okoko BJ, Diallo A, et al. Immunogenicity and Niger; Dr. Jean-Paul Moulia-Pelat, Centre de Recherche Medicale safety of a meningococcal A conjugate vaccine in Africans. et Sanitaire (CERMES), Niamey, Niger; Dr. Assinawe Pana, N Engl J Med. 2011;364:2293–304. WHO/WR, Niger, Clement Lingani, InterCountry Meningitis 14. World Health Organization. Meningococcal disease control Unit, WHO/AFRO, Ouagadougou; and Dr. Olivier Ronveaux, in countries of the African meningitis belt, 2014. Wkly Epi- WHO/HQ, Geneva. demiol Rec. 2015;90:123–31. 15. Kristiansen PA, Diomande F, Ba AK, et al. Impact of the serogroup A meningococcal conjugate vaccine, MenAfri- ORCID iD Vac, on carriage and herd immunity. Clin Infect Dis. Reza Yaesoubi https://orcid.org/0000-0002-9276-5750 2013;56:354–63. 16. Frasch C, Preziosi M-P, LaForce FM. Development of a Supplementary Material group A meningococcal conjugate vaccine, MenAfriVacä. Supplementary material for this article is available on the Hum Vaccin Immunother. 2012;8:715–24. Medical Decision Making Web site at http://journals.sagepub 17. Marc LaForce F, Ravenscroft N, Djingarey M, Viviani S. .com/home/mdm. Epidemic meningitis due to group A Neisseria meningitidis in the African meningitis belt: a persistent problem with an imminent solution. Vaccine. 2009;27(Suppl 2):B13–9. References 18. LaForce FM, Djingarey M, Viviani S, Preziosi M-P. Suc- 1. Greenwood B. Priorities for research on meningococcal cessful African introduction of a new group A meningo- disease and the impact of serogroup A vaccination in the coccal conjugate vaccine: future challenges and next steps. African meningitis belt. Vaccine. 2013;31:1453–7. Hum Vaccin Immunother. 2018;14:1098–102. 2. Rondy M, Issifou D, Ibrahim AS, et al. Vaccine effective- 19. MenAfriCar Consortium. The diversity of meningococcal ness of polysaccharide vaccines against clinical meningitis— carriage across the African meningitis belt and the impact Niamey, Niger, June 2015. PLoS Curr. 2016;8:ecurrents of vaccination with a group A meningococcal conjugate .outbreaks.5d6e9c1d071a2088109c242771b68886. vaccine. J Infect Dis. 2015;212:1298–307. 3. Novak RT, Kambou JL, Diomande FV, et al. Serogroup 20. Gamougam K, Daugla DM, Toralta J, et al. Continuing A meningococcal conjugate vaccination in Burkina Faso: effectiveness of serogroup A meningococcal conjugate vac- analysis of national surveillance data. Lancet Infect Dis. cine, Chad, 2013. Emerg Infect Dis. 2015;21:115–8. 2012;12:757–64. 21. Sidikou F, Zaneidou M, Alkassoum I, et al. Emergence of 4. World Health Organization. Meningitis outbreak response epidemic Neisseria meningitidis serogroup C in Niger, 2015: in sub-Saharan Africa: WHO guideline. Report No. an analysis of national surveillance data. Lancet Infect Dis. WHO/HSE/PED/CED/14.5. 2014. Available from: https:// 2016;16:1288–94. apps.who.int/iris/handle/10665/144727 22. MacNeil JR, Medah I, Koussoube´D, et al. Neisseria 5. McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. meningitidis serogroup W, Burkina Faso, 2012. Emerg Effect of vaccines on bacterial meningitis worldwide. Lan- Infect Dis. 2014;20:394–9. cet. 2012;380:1703–11. 23. Boisier P, Nicolas P, Djibo S, et al. Meningococcal menin- 6. World Health Organization. Epidemic meningitis in gitis: unprecedented incidence of serogroup X—related Africa, 1997. Wkly Epidemiol Rec. 1997;72:313–5. cases in 2006 in Niger. Clin Infect Dis. 2007;44:657–63. 7. Roberts L. An ill wind, bringing meningitis. Science. 24. Delrieu I, Yaro S, Tamekloe´TA, et al. Emergence of epi- 2008;320:1710–5. demic Neisseria meningitidis serogroup X meningitis in 8. World Health Organization. Detecting meningococcal Togo and Burkina Faso. PloS One. 2011;6:e19513. meningitis epidemics in highly-endemic African countries. 25. Maı¨nassara HB, Oumarou GI, Issaka B, et al. Evaluation Wkly Epidemiol Rec. 2000;38:306–9. of response strategies against epidemics due to Neisseria 9. Ali O, Aseffa A, Bedru A, et al. Meningococcal carriage in meningitidis C in Niger. Trop Med Int Health. 2017;22: the African meningitis belt. Trop Med Int Health. 2013;18: 196–204. 968–78. 26. Brynildsrud OB, Eldholm V, Bohlin J, Uadiale K, Obaro 10. Trotter CL, Greenwood BM. Meningococcal carriage in S, Caugant DA. Acquisition of virulence genes by a carrier the African meningitis belt. Lancet Infect Dis. 2007;7: strain gave rise to the ongoing epidemics of meningococcal 797–803. disease in West Africa. Proc Natl Acad Sci U S A. 2018;115: 11. Hassan-King MK, Wall RA, Greenwood BM. Meningo- 5510–5. coccal carriage, meningococcal disease and vaccination. J 27. Nnadi C, Oladejo J, Yennan S, et al. Large outbreak of Infect. 1998;16:55–9. Neisseria meningitidis serogroup C—Nigeria, December 12. Aguado MT, Jodar L, Granoff D, Rabinovich R, Ceccar- 2016–June 2017. Morb Mortal Wkly Rep. 2017;66:1352. ini C, Perkin GW. From epidemic meningitis vaccines for 28. Girard MP, Preziosi MP, Aguado MT, Kieny MP. A Africa to the Meningitis Vaccine Project. Clin Infect Dis. review of vaccine research and development: meningococ- 2015;61(Suppl 5):S391–5. cal disease. Vaccine. 2006;24:4692–700. 566 Medical Decision Making 39(5)

29. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic of the Advisory Committee on Immunization Practices meningitis, meningococcaemia, and Neisseria meningitidis. (ACIP). Morb Mortal Wkly Rep. 1997;46:11–21. Lancet. 2007;369:2196–210. 46. Campbell JD, Edelman R, King JC Jr, Papa R, Ryall R, 30. Frasch CE, Kapre SV, Lee C-H, Pre´aud J-M. Technical Rennels MB. Safety, reactogenicity, and immunogenicity development of a new meningococcal conjugate vaccine. of a tetravalent meningococcal polysaccharide-diphtheria Clin Infect Dis. 2015;61:S404–9. toxoid conjugate vaccine given to healthy adults. J Infect 31. Borrow R. Advances with vaccination against Neisseria Dis. 2002;186:1848–51. meningitidis. Trop Med Int Health. 2012;17:1478–91. 47. Shepard CW, Ortega-Sanchez IR, Scott RD II, Rosenstein 32. Daugla DM, Gami JP, Gamougam K, et al. Effect of a ser- NE, Team AB. Cost-effectiveness of conjugate meningo- ogroup A meningococcal conjugate vaccine (PsA–TT) on coccal vaccination strategies in the United States. Pedia- serogroup A meningococcal meningitis and carriage in trics. 2005;115:1220–32. Chad: a community study. Lancet. 2013;383:40–7. 48. Reingold AL, Broome CV, Hightower AW, et al. Age- 33. Yaesoubi R, Trotter C, Colijn C, et al. The cost- specific differences in duration of clinical protection after effectiveness of alternative uses of polyvalent meningococ- vaccination with meningococcal polysaccharide A vaccine. cal vaccines in Burkina Faso: a transmission dynamic mod- Lancet. 1985;2:114–8. eling study. PLoS Med. 2018;15:e1002495. 49. Welte R, Trotter CL, Edmunds WJ, Postma MJ, Beutels P. 34. Bonabeau E. Agent-based modeling: methods and tech- The role of economic evaluation in vaccine decision mak- niques for simulating human systems. Proc Natl Acad Sci ing: focus on meningococcal group C conjugate vaccine. USA. 2002;99:7280–7. Pharmacoeconomics. 2005;23:855–74. 35. Gilbert GN. Agent-Based Models. Thousand Oaks, CA: 50. de Voer RM, van der Klis FR, Engels CW, et al. Kinetics Sage; 2008. of antibody responses after primary immunization with 36. De Marchi S, Page SE. Agent-based models. Annu Rev Pol meningococcal serogroup C conjugate vaccine or second- Sci. 2014;17:1–20. ary immunization with either conjugate or polysaccharide 37. Oluwole OS. Climate regimes, El Nino-southern oscilla- vaccine in adults. Vaccine. 2009;27:6974–82. tion, and meningococcal meningitis epidemics. Front Public 51. World Health Organization. Immunization Surveillance, Health. 2015;3:187. Assessment and Monitory—Measles (MCV) Immunization 38. Paireau J, Mainassara HB, Jusot JF, et al. Spatio- Coverage among 1-Year Olds, 1980-2013. September 2015. temporal factors associated with meningococcal meningitis Available from: http://gamapserver.who.int/gho/interacti- annual incidence at the health centre level in Niger, 2004- ve_charts/immunization/mcv/atlas.html 2010. PLoS Negl Trop Dis. 2014;8:e2899. 52. Meyer SA, Kambou JL, Cohn A, et al. Serogroup A 39. Karachaliou A, Conlan AJ, Preziosi M-P, Trotter CL. meningococcal conjugate (PsA-TT) vaccine coverage and Modeling long-term vaccination strategies with MenAfri- measles vaccine coverage in Burkina Faso—implications Vac in the African meningitis belt. Clin Infect Dis. 2015;61: for introduction of PsA-TT into the Expanded Programme S594–600. on Immunization. Vaccine. 2015;33:1492–8. 40. Trotter CL, Gay NJ, Edmunds WJ. Dynamic models of 53. Centers for Disease Control and Prevention. Serogroup A meningococcal carriage, disease, and the impact of ser- meningococcal conjugate vaccine coverage after the first ogroup C conjugate vaccination. Am J Epidemiol. national mass immunization campaign—Burkina Faso, 2005;162:89–100. 2011. Morb Mortal Wkly Rep. 2012;61:1022–4. 41. Irving TJ, Blyuss KB, Colijn C, Trotter CL. Modelling 54. Djingarey MH, Barry R, Bonkoungou M, et al. Effectively meningococcal meningitis in the African meningitis belt. introducing a new meningococcal A conjugate vaccine Epidemiol Infect. 2012;140:897–905. in Africa: the Burkina Faso experience. Vaccine. 2012; 42. LaForce FM, Konde K, Viviani S, Pr’eziosi M-P. The 30(Suppl 2):B40–5. Meningitis Vaccine Project. Vaccine. 2007;25:A97–100. 55. Husereau D, Drummond M, Petrou S, et al. Consolidated 43. Soriano-Gabarro M, Toe L, Tiendrebeogo SR, et al. Effec- Health Economic Evaluation Reporting Standards tiveness of a trivalent serogroup A/C/W135 meningococcal (CHEERS)—explanation and elaboration: a report of the polysaccharide vaccine in Burkina Faso, 2003. Vaccine. ISPOR Health Economic Evaluation Publication Guide- 2007;25(Suppl 1):A92–6. lines Good Reporting Practices Task Force. Value Health. 44. Pinner RW, Onyango F, Perkins BA, et al. Epidemic 2013;16:231–50. meningococcal disease in Nairobi, Kenya, 1989. The 56. Hutubessy R, Chisholm D, Edejer TT-T. Generalized cost- Kenya/Centers for Disease Control (CDC) Meningitis effectiveness analysis for national-level priority-setting in Study Group. J Infect Dis. 1992;166:359–64. the health sector. Cost Eff Resour Alloc. 2003;1:8. 45. Centers for Disease Control and Prevention. Control and 57. T.W.B. Group. World Development Indicators—Niger. prevention of serogroup C meningococcal disease: evaluation May 31, 2017. Available from: http://databank.worldbank and management of suspected outbreaks: recommendations .org/data/reports.aspx?Code=NY.GDP.MKTP.CD&id= Arifin et al. 567

1ff4a498&report_name=Popular-Indicators&populartype 2011 and the impact of vaccination. BMC Infect Dis. =series&ispopular=y 2013;13:576. 58. Mueller JE, Gessner BD. A hypothetical explanatory 73. MenAfriCar Consortium. The diversity of meningococcal model for meningococcal meningitis in the African menin- carriage across the African meningitis belt and the impact gitis belt. Int J Infect Dis. 2010;14:e553–9. of vaccination with a group A meningococcal conjugate 59. Christensen H, Hickman M, Edmunds WJ, Trotter CL. vaccine. J Infect Dis. 2015;212:1298–307. Introducing vaccination against serogroup B meningococ- 74. Mossong J, Hens N, Jit M, et al. Social contacts and mix- cal disease: an economic and mathematical modelling study ing patterns relevant to the spread of infectious diseases. of potential impact. Vaccine. 2013;31:2638–46. PLoS Med. 2008;5:e74. 60. Trotter CL, Edmunds WJ. Reassessing the cost- 75. Prem K, Cook AR, Jit M. Projecting social contact effectiveness of meningococcal serogroup C conjugate matrices in 152 countries using contact surveys and demo- (MCC) vaccines using a transmission dynamic model. Med graphic data. PLOS Comput Biol. 2017;13:1–21. Decis Making. 2006;26:38–47. 76. Tzeng YL, Stephens DS. Epidemiology and pathogenesis 61. Tartof S, Cohn A, Tarbangdo F, et al. Identifying optimal of Neisseria meningitidis. Microbes Infect. 2000;2:687–700. vaccination strategies for serogroup A Neisseria meningiti- 77. Blakebrough IS, Greenwood BM, Whittle HC, Bradley dis conjugate vaccine in the African meningitis belt. PloS AK, Gilles HM. The epidemiology of infections due to One. 2013;8:e63605. Neisseria meningitidis and Neisseria lactamica in a northern 62. Trotter CL, Lingani C, Fernandez K, et al. Impact of Nigerian community. J Infect Dis. 1982;146:626–37. MenAfriVac in nine countries of the African meningitis 78. Irving TJ, Blyuss KB, Colijn C, Trotter CL. Modelling belt, 2010-15: an analysis of surveillance data. Lancet Infect meningococcal meningitis in the African meningitis belt. Dis. 2017;17:867–72. Epidemiol Infect. 2012;140:897–905. 63. Apache. Apache Commons Math: Data Generation. 2017. 79. Trotter CL, Gay NJ, Edmunds WJ. The natural history of Available from: http://commons.apache.org/proper/com meningococcal carriage and disease. Epidemiol Infect. mons-math/userguide/random.html 2006;134:556–66. 64. Central Intelligence Agency. The World Factbook: Niger. 80. World Health Organization. Control of epidemic meningo- 2017. Available from: https://www.cia.gov/library/publica coccal disease: WHO practical guidelines. Report No. tions/the-world-factbook/geos/ng.html WHO/EMC/BAC/98.3. 1998. Available from: https:// 65. G. Van Brummelen. Heavenly Mathematics: The Forgotten apps.who.int/iris/handle/10665/64467 Art of Spherical Trigonometry. Princeton, NJ: Princeton 81. Duhamel P, Vetterli M. Fast Fourier-transforms: a tutorial University Press; 2013. review and a state-of-the-art. Signal Process. 1990;19:259–99. 66. Ministry of Public Health. Niger. Available from: http:// 82. Wehrens R, Putter H, Buydens LMC. The bootstrap: a www.msp.ne/ tutorial. Chemometr Intell Lab Syst. 2000;54:35–52. 67. World Health Organization. World Health Organization: 83. Colombini A, Trotter C, Madrid Y, Karachaliou A, Pre- life tables by country: Niger. 2016. ziosi M-P. Costs of Neisseria meningitidis group A disease 68. Sultan B, Labadi K, Gue´gan J-F, Janicot S. Climate drives and economic impact of vaccination in Burkina Faso. Clin the meningitis epidemics onset in West Africa. PLoS Med. Infect Dis. 2015;61:S473–82. 2005;2:e6. 84. Colombini A, Bationo F, Zongo S, et al. Costs for house- 69. Agier L, Deroubaix A, Martiny N, Yaka P, Djibo A, Brou- holds and community perception of meningitis epidemics in tin H. Seasonality of meningitis in Africa and climate for- Burkina Faso. Clin Infect Dis. 2009;49:1520–5. cing: aerosols stand out. J R Soc Interf. 2013;10:20120814. 85. Colombini A, Badolo O, Gessner BD, Jaillard P, Seini E, 70. Christensen H, May M, Bowen L, Hickman M, Trotter Da Silva A. Costs and impact of meningitis epidemics for CL. Meningococcal carriage by age: a systematic review the public health system in Burkina Faso. Vaccine. 2011;29: and meta-analysis. Lancet Infect Dis. 2010;10:853–61. 5474–80. 71. Campagne G, Schuchat A, Djibo S, Ousseini A, Cisse L, 86. Bovier PA, Wyss K, Au HJ. A cost-effectiveness analysis Chippaux JP. Epidemiology of bacterial meningitis in Nia- of vaccination strategies against N. meningitidis meningitis mey, Niger, 1981-96. Bull World Health Organ. 1999;77: in sub-Saharan African countries. Soc Sci Med. 1999;48: 499–508. 1205–20. 72. Collard JM, Issaka B, Zaneidou M, et al. Epidemiological 87. UNICEF. UNICEF meningococcal vaccine price data. changes in meningococcal meningitis in Niger from 2008 to November 19, 2017.