PROJECT SUMMARY/ABSTRACT Meningitis epidemics, primarily caused by N. meningitidis serogroup A, occur annually during the dry season in the African meningitis belt, leading to significant morbidity and mortality among the 450 million people living in this region. The introduction of MenAfriVac, a newly developed conjugate meningococcal serogroup A vaccine, in Burkina Faso, Mali, and Niger in December 2010 was the first ever population-based, preventive mass-vaccination campaign against meningococcal meningitis in the meningitis belt and the first- ever nationwide use of this vaccine. While clinical trials have demonstrated that MenAfriVac induces a stronger immune response than polysaccharide meningococcal serogroup A vaccines, the duration of protection provided by MenAfriVac is currently unknown. The persistence of the serogroup A-specific serum bactericidal antibody (SBA) response and the IgG response, both accepted correlates of protection against invasive disease, are key determinants of whether the MenAfriVac mass-vaccination campaign will successfully prevent the deadly epidemics of meningitis that have occurred in the region for the past century. Our goal is to address a critical barrier to progress in the field by evaluating the impact of the MenAfriVac mass-vaccination campaign. Specifically, we will assess the duration of protection provided by the vaccine up to five years after the population-based, mass-vaccination campaign targeted to all individuals aged 1-29 years in Bamako, Mali. We will determine when, if at all, population-level immunity begins to wane up to five years after mass- vaccination. Additionally, we will determine the most effective vaccination strategy, which can then be implemented both in Mali and other countries of the African meningitis belt in the future. We will evaluate the antibody persistence following the MenAfriVac mass-vaccination campaign by collecting prospective immunogenicity data from a random sample of 800 residents of Bamako, Mali, aged 1- 29 years at 18 months, 36 months, and 54 months after mass vaccination. Specifically, we aim to: 1.) determine the proportion of individuals with protective levels of serogroup A-specific SBA and IgG both overall and by age at each of the three post-vaccination time points, 2.) evaluate the significance of temporal changes in serogroup A-specific SBA and IgG titers both overall and by age up to five years post-vaccination, and 3.) assess potential risk factors, such as age at vaccination, prior polysaccharide meningococcal vaccination, nutritional status, and socioeconomic status, for low SBA and IgG titers at each of the three post-vaccination time points. Statistical methods will be used to provide evidence for the degree of vaccine-induced antibody persistence and to evaluate risk factors for low antibody response. The results will be used to develop and implement the most effective vaccination strategy in the countries of the African meningitis belt, to determine if there is a need for additional booster doses of vaccine in any age group after five years, and to increase our understanding of the mechanism by which MenAfriVac provides protection against invasive disease.

PROJECT NARRATIVE Seasonal meningitis outbreaks caused primarily by Neisseria meningitidis serogroup A are responsible for significant morbidity and mortality among the nearly 450 million people living in the African meningitis belt. In December 2010, the first-ever preventive meningitis mass-vaccination campaign using a newly developed conjugate meningococcal serogroup A vaccine was launched in this region. We aim to evaluate the persistence of the protective antibody response generated by this vaccine in Bamako, Mali, for up to five years post-vaccination. Our goal is to determine the most effective vaccination strategy capable of maintaining protective levels of immunity in the population and ending the devastating epidemics of meningitis. __SpecificAimsTextDelimiter__ SPECIFIC AIMS For more than a century, seasonal meningitis epidemics caused by the bacterial pathogen Neisseria meningitidis have occurred throughout the African meningitis belt. With no viable strategy for prevention, meningitis epidemics have been controlled after they are identified by reactive vaccination with polysaccharide meningococcal vaccine. This approach has many limitations due to the short-term protection provided by polysaccharide vaccines. In December 2010, the first preventive mass-vaccination campaign against N. meningitidis serogroup A was launched in the meningitis belt using a new conjugate meningococcal serogroup A vaccine (MenAfriVac) specifically designed to address this significant public health problem. The MenAfriVac campaign targeted those aged 1-29 years in Burkina Faso, Mali, and Niger. The introduction of this new vaccine provides the first opportunity to evaluate its population-level impact in the African meningitis belt. While MenAfriVac clinical trials have demonstrated a strong vaccine-induced immune response lasting at least one year, the duration of protection provided by the vaccine is not known. Serogroup-A specific serum bactericidal antibody (SBA) titers and serogroup-A specific IgG titers are accepted surrogates of protection against invasive disease. Persistence of antibody titers at the population level are one of the key factors determining if the MenAfriVac campaign will successfully reduce the deadly epidemics of meningitis caused by N. meningitidis serogroup A. Our overall objective is to evaluate the impact of the MenAfriVac mass-vaccination campaign in Bamako, Mali, to determine the most effective population-based vaccination strategy and to assess whether there is a need for additional booster doses of vaccine in any age group after initial mass-vaccination. Our goal is to address three critical barriers to progress in the field of epidemic meningitis prevention. We will assess 1.) the persistence of antibody against invasive meningococcal disease produced by MenAfriVac, 2.) population- level changes in antibody persistence over time, and 3.) risk factors for poor antibody persistence. To accomplish these goals, we will collect and analyze prospective immunogenicity data from 800 participants to determine antibody persistence at each of three time points (18 months, 36 months, and 54 months post-mass vaccination). An age stratified (age groups 1-<2 years, 2-10 years, 11-17 years, and 18-29 years), random sample of those who were eligible for the MenAfriVac campaign launched in Bamako in December 2010 will be drawn. Participants will be asked to provide a blood sample to determine serogroup A-specific SBA and IgG titers and answers to a detailed questionnaire. Based on the results of a small-scale demonstration campaign in Mali earlier in 2010, vaccination coverage is expected to reach nearly 100% of the targeted age groups. Specifically, we aim to: AIM 1: Determine the proportion of individuals 1-29 years old with protective levels of serogroup A-specific serum bactericidal antibody titers and serogroup A-specific IgG antibody titers against invasive disease caused by N. meningitidis overall and by age group at 18 months, 36 months, and 54 months after the preventive MenAfriVac mass vaccination campaign in Bamako, Mali. AIM 2: Evaluate the statistical and clinical significance of temporal, population-level changes in serogroup A- specific serum bactericidal antibody titers and serogroup A-specific IgG antibody titers at 18 months, 36 months, and 54 months post-mass vaccination with MenAfriVac overall and by age group. AIM 3: Assess potential risk factors for low serogroup A-specific serum bactericidal antibody titers and low serogroup A-specific IgG antibody titers at 18 months, 36 months, and 54 months post-introduction of MenAfriVac, including age at vaccination, prior polysaccharide meningococcal vaccination, history of meningococcal disease, nutritional status, and socioeconomic status. This study will be undertaken in partnership with the Centre pour le D¿veloppement des Vaccins (CVD- Mali) in Bamako where all data collection will take place, the Health Protection Agency (HPA) in the United Kingdom where all serum samples will be analyzed, and the University of Washington in Seattle where the PI will design the study and analyze the data. By accomplishing these aims, we will be able to assess the duration of protection against invasive disease in the population targeted for vaccination up to five years after the MenAfriVac campaign. Currently, it is not known if repeated mass vaccination or boosting will be needed to maintain population-level immunity. Our proposal addresses a significant need to evaluate the persistence of protective antibody levels against N. meningitidis serogroup A. The mechanism of vaccine-induced protection must be evaluated carefully to determine the success of the MenAfriVac campaign, and to establish the most effective vaccination strategy for the benefit of the entire African meningitis belt.