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Sub-Saharan Africa has experienced epidemic cycles of Neisseria meningitidis group A (MenA) disease approximately every 5–10 years, with high disease incidence. One of the worst epidemics occurred in 1996, with greater than 250 000 recorded cases and 25 000 deaths [1]. The specific area of sub-Saharan Africa in which epidemics of MenA disease are frequent is termed the “meningitis belt” and was first described by Lapeyssonnie in 1963 [2] as spanning from Senegal in the west to Ethiopia in the east. Polysaccharide vaccines against MenA have been used in response to African outbreaks. These vaccines, however, are poorly immunogenic in children

Maternal and neonatal tetanus is still a significant, although vaccine-preventable, cause of morbidity and mortality in many developing countries. When tetanus develops, case-fatality rates are high and treatment is often limited by paucity of resources. The Maternal and Neonatal Tetanus Elimination Initiative, relaunched by the World Health Organization (WHO), United Nations Children's Fund, and United Nations Population Fund in 1999 following the initial launch in 1989, has made substantial progress in eliminating maternal and neonatal tetanus [1]. Although the number of deaths due to neonatal tetanus has fallen by 94%, from the estimated 787 000 in 1988 to 49 000 in 2013, further progress will require improved vaccination programs. WHO data indicate that sub-Saharan Africa remains one the highest-risk areas for neonatal and nonneonatal tetanus [1]. Maternal immunization with tetanus toxoid (TT)–containing vaccines has led to 82% of today's newborns being protected from tetanus [2]. For maternal protection, the degree and duration of immunity increase with the number of appropriately spaced TT doses administered. One dose of TT ensures little, if any, protection. Following a second dose, the mean antibody level usually exceeds the protective level of 0.01 IU/mL, although up to 10% may remain unprotected. Immunity declines over time, and after 1 year the percentage of those unprotected persons can be up to 20%. For this reason, a third dose of tetanus toxoid should be given during the subsequent pregnancy or 6–12 months after the initial 2 doses, giving a level of immunity that is high and which persists for at least 5 years. Even after the third dose, when given at yearly intervals, a fourth dose will give immunity for 10 years and a fifth dose immunity for at least 20 years [3]. In children, 3 primary doses of diphtheria-tetanus-pertussis (DTP) vaccine will induce a protective antibody level [4]. Glycoconjugate vaccines against Haemophilus influenzae type b (Hib) disease and various meningococcal and pneumococcal groups/types contain the specific bacterial poly/oligosaccharide conjugated to an immunogenic carrier protein, the most commonly utilized being either TT or the nontoxic mutant of diphtheria toxin (CRM197). These carrier proteins induce antibodies themselves, and for CRM197-induced antibodies, these have been shown to be functional [5]. During the development of PsA-TT, a choice of carrier protein had to be made. Discussions at the Meningitis Vaccine Project and its advisory bodies focused on published data on the efficacy of carrier proteins while asking whether there were public health advantages that could be attained with certain carrier molecules. Using TT as a carrier protein became an attractive option for 3 reasons: (1) Conjugate vaccines using TT as a carrier protein had been successfully developed; (2) both neonatal and nonneonatal tetanus were public health problems in sub-Saharan Africa; and (3) conjugate vaccines that were made with TT had shown an antitetanus serologic response when tested. Thus, PsA-TT was developed by the Serum Institute of India, Ltd, and following extensive immunogenicity and safety trials was prequalified by WHO in 2010. Rollout of this vaccine is now well under way across the meningitis belt of sub-Saharan Africa and, as of the end of 2014, >210 million Africans between the ages of 1 and 29 years will have received a dose of PsA-TT [6]. This conjugate vaccine contains 10–33 µg of TT per dose or 3–9 Lf (limit of flocculation). This paper reviews the tetanus serologic data that were obtained during the phase 1–3 clinical trials as well as reported cases of tetanus in African countries before and after introduction of PsA-TT in large campaigns aimed at 1- to 29-year-olds.

Background. Yellow fever (YF) is still a major public health problem in endemic regions of Africa and South America. In Africa, one of the main control strategies is routine vaccination within the Expanded Programme on Immunization (EPI). A new meningococcal A conjugate vaccine (PsA-TT) is about to be introduced in the EPI of countries in the African meningitis belt, and this study reports on the immunogenicity of the YF-17D vaccines in infants when administered concomitantly with measles vaccine and PsA-TT. Methods. Two clinical studies were conducted in Ghana and in Mali among infants who received PsA-TT concomitantly with measles and YF vaccines at 9 months of age. YF neutralizing antibody titers were measured using a microneutralization assay. Results. In both studies, the PsA-TT did not adversely affect the immune response to the concomitantly administered YF vaccine at the age of 9 months. The magnitude of the immune response was different between the 2 studies, with higher seroconversion and seroprotection rates found in Mali vs Ghana. Conclusions. Immunogenicity to YF vaccine is unaffected when coadministered with PsA-TT at 9 months of age. Further studies are warranted to better understand the determinants of the immune response to YF vaccine in infancy. Clinical Trials Registration. ISRCTN82484612 (PsA-TT-004); PACTR201110000328305 (PsA-TT-007).

Efforts to prevent the large-scale outbreaks of meningococcal disease that have led to significant morbidity and mortality in the African meningitis belt, a region stretching from Senegal to Ethiopia, changed dramatically in 2010 when a newly developed group A meningococcal polysaccharide–tetanus toxoid protein conjugate vaccine, PsA-TT or MenAfriVac, was introduced in the first-ever preventive mass vaccination campaign in Burkina Faso, Mali, and Niger [1–4]. Developed by the Meningitis Vaccine Project, a partnership between the World Health Organization (WHO) and PATH with funding from the Bill & Melinda Gates Foundation, PsA-TT transformed the reactive vaccination strategy in place in the Meningitis Belt since the 1970s, which utilized polysaccharide meningococcal vaccines to respond to meningococcal disease outbreaks, into a preventive campaign that is implementing mass vaccination of individuals aged 1–29 years in >25 countries in Africa [5]. Evidence has indicated that PsA-TT is highly immunogenic; the vaccine was licensed based on immunogenicity alone [2, 6–8]. By the end of 2014, >217 million people in 15 countries had been vaccinated with PsA-TT [9]. The introduction of PsA-TT has dramatically altered the epidemiology of meningococcal disease in Africa, and significant reductions in the incidence of meningococcal A disease [10, 11] and meningococcal A carriage [12, 13] have been achieved in countries where the vaccine has been introduced. As with all recently developed and newly introduced vaccines, questions remain about the duration of protection provided by PsA-TT. Assessing the duration of protection has been identified as a priority for the prevention and control of meningitis in Africa [14]. Evaluating antibody persistence both in the context of clinical trials and in population-based epidemiologic studies is an important component of investigating the impact conjugate meningococcal A vaccination has had on immunity in this region. Meningococcal conjugate vaccines including PsA-TT join together polysaccharides from the outer membrane of Neisseria meningitidis to a protein carrier such as tetanus toxoid. Conjugate vaccines elicit a more robust immune response than polysaccharide-only vaccines, which are limited in that immunity wanes after 3–5 years and in that they are not immunogenic in very young children [15–17]. Although conjugate meningococcal C and ACWY vaccines provide a longer duration of immunity than comparable polysaccharide vaccines, antibody levels have been shown to wane rapidly following vaccination [18, 19]. Booster doses have been added to vaccination schedules in both the United States, where meningococcal ACWY conjugate vaccine is recommended for 11- and 12-year-olds with a booster dose at age 16 years [20], and the United Kingdom, where meningococcal C conjugate vaccine is recommended for infants and booster doses are given at 12 months and around 14 years [21]. Booster doses for these meningococcal conjugate vaccines have been recommended due to concerns about waning immunity during periods of high risk [18, 22–24], further emphasizing the need to understand the duration of immunity following PsA-TT introduction has been introduced in areas where meningococcal disease is highly endemic. To assess the duration of protection and changes in population-level immunity over time following the 2010 introduction of PsA-TT, we established a cohort in 2012 among residents of Bamako, Mali. Here we report the results of the first seroprevalence survey undertaken in the cohort, 2 years after the PsA-TT mass vaccination campaign.

Background. Mass vaccination campaigns of the population aged 1–29 years with 1 dose of group A meningococcal (MenA) conjugate vaccine (PsA-TT, MenAfriVac) in African meningitis belt countries has resulted in the near-disappearance of MenA. The vaccine was tested in clinical trials in Africa and in India and found to be safe and highly immunogenic compared with the group A component of the licensed quadrivalent polysaccharide vaccine (PsACWY). Antibody persistence in Africa and in India was investigated. Methods. A total of 900 subjects aged 2–29 years were followed up for 4 years in Senegal, Mali, and The Gambia (study A). A total of 340 subjects aged 2–10 years were followed up for 1 year in India (study B). In study A, subjects were randomized in a 2:1 ratio, and in study B a 1:1 ratio to receive either PsA-TT or PsACWY. Immunogenicity was evaluated by measuring MenA serum bactericidal antibody (SBA) with rabbit complement and by a group A–specific immunoglobulin G (IgG) enzyme-linked immunosorbent assay. Results. In both studies, substantial SBA decay was observed at 6 months postvaccination in both vaccine groups, although more marked in the PsACWY group. At 1 year and 4 years (only for study A) postvaccination, SBA titers were relatively sustained in the PsA-TT group, whereas a slight increasing trend, more pronounced among the youngest, was observed in the participants aged

Background. A meningococcal group A conjugate vaccine, PsA-TT (MenAfriVac), developed through the Meningitis Vaccine Project and manufactured by the Serum Institute of India, Ltd, was tested in multiple clinical trials conducted mainly in Africa. The impact of age at which subjects were vaccinated on immune response and persistence postimmunization with PsA-TT was the main focus of the current analysis. Methods. Subjects who were vaccinated with a single dose of 10 µg of PsA-TT at 12–23 months or 22–33 months of age in study A conducted in Mali and The Gambia; at 2–10 years, 11–17 years, or 18–29 years of age in study B conducted in Mali, The Gambia, and Senegal; and at 14–18 weeks, 9–12 months, or 12–18 months of age in study C conducted in Ghana are included in the current analysis. Immunogenicity was measured by group A serum bactericidal antibody (SBA) titer with baby rabbit complement. Results. Significant differences in SBA titers were found among the age groups in studies B and C both 28 days and 1 year postimmunization. A significant difference in SBA titers between age groups 12–23 months and 22–33 months was only observed 1 year postimmunization in study A. Antibody titers remained at similar levels from 1 to 2 years postimmunization for subjects vaccinated at 12–23 months in study A and at 9–12 months or 12–18 months of age in study C. Conclusions. Subjects immunized at different ages had different postimmunization immune responses as measured by SBA titers. Toddlers tended to have higher immune responses than infants. This pattern persisted at least 1 year postimmunization. Clinical Trials Registration. ISRCTN78147026 (study A), ISRCTN87739946 (study B), and ISRCTN82484612 (study C).

The “meningitis belt” of sub-Saharan Africa runs across the continent from Senegal to Ethiopia, and this region is prone to major epidemics of meningococcal meningitis, with a high case fatality rate and serious sequelae. Until recently, most epidemics were due to group A Neisseria meningitidis (MenA). The observed reduction in meningococcal meningitis due to MenA has been due to the development of an affordable group A meningococcal vaccine, PsA-TT (MenAfriVac, Serum Institute of India, Ltd). The Meningitis Vaccine Project, a partnership between the World Health Organization (WHO) and PATH, coordinated the development, testing, licensure, and introduction of this vaccine with the aim of eliminating epidemic meningitis attributable to MenA [1–4]. Since 2010, PsA-TT has been introduced into countries across the meningitis belt through mass campaigns [5, 6]. PsA-TT is expected to confer both longer-lasting individual protection and herd protection than MenA polysaccharide vaccines. Ongoing surveillance shows that no cases of MenA meningococcal disease have occurred in vaccinated individuals [6], but the longevity of this protective immune response is not known. Prior to the introduction of PsA-TT into the African countries of the meningitis belt, multiple clinical trials assessed the safety and immunogenicity of PsA-TT. A trial conducted in children aged 12–23 months demonstrated that this vaccine was immunogenic and induced immune memory. However, antibody persistence is key in maintaining direct and indirect protection [7, 8]. We report here on the persistence of MenA-specific antibodies in individuals vaccinated with PsA-TT in early childhood.

The African meningitis belt suffers from frequent large epidemics of meningococcal meningitis. A novel vaccine against Neisseria meningitidis group A (MenA), the major cause of epidemic meningitis, was developed through the Meningitis Vaccine Project (MVP), manufactured by the Serum Institute of India, Ltd [1]. The vaccine, known as MenAfriVac, was first introduced into Burkina Faso, Mali, and Niger in 2010 in mass immunization campaigns targeting 1- to 29-year-olds. MenAfriVac continues to be rolled out across the region, and >217 million individuals have been immunized to date. These campaigns have been remarkably successful in the short term in reducing the incidence of meningitis and the prevalence of MenA carriage, as shown in Burkina Faso [2, 3] and Chad [4]. To ensure that this success continues, long-term immunization strategies are required to maintain population protection. Computational models have become an important tool for vaccine policy makers. By simulating the impact of a vaccine in silico, a wide range of vaccine strategies can be explored and the sensitivity of their predicted impact to structural and parameter uncertainty can be understood. Transmission dynamic models are essential to quantify both the direct and indirect (herd protection) effects of vaccination programs. For meningococcal infection, most transmission occurs between asymptomatic carriers, so any model attempting to capture the transmission dynamics of meningococci must essentially include the carrier state. This is especially relevant when considering the impact of MenAfriVac, given the evidence that MenA carriage is much reduced following MenAfriVac introduction [2, 4]. This is likely to give rise to large indirect vaccine effects, as seen with other conjugate vaccines [5]. Other key features of the epidemiology of MenA in the African meningitis belt must also be incorporated, which include the periodic but irregular nature of epidemics of varying size; the seasonality of meningitis with epidemics occurring in the dry season and dying out with the onset of the rains [6]; and the variation in disease risk [7] and carriage prevalence [8] by age. A range of transmission models for meningococcal infection has been developed [9–11]. Only 2 have specifically examined MenA in the African meningitis belt. Irving et al [12] explored the potential mechanisms underlying the striking epidemiology in this region, showing that the complex and irregular timing of epidemics could be explained by the interaction of temporary immunity conferred by carriage of the bacteria together with seasonal changes in the transmissibility of infection. Tartof et al [13] used a transmission model to investigate different strategies using MenAfriVac. Here we extend the transmission models of Irving et al [12] by addressing some of the limitations (such as the lack of age structure and wide parameter space considered), and incorporating vaccination. We utilize recently available MenA/MenAfriVac specific parameters and apply the model to investigate appropriate policy options for the sustained use of MenAfriVac.

International audience; BACKGROUND:A group A meningococcal (MenA) conjugate vaccine, PsA-TT (MenAfriVac), was introduced in Burkina Faso via mass campaigns between September and December 2010, targeting the 1- to 29-year-old population. This study describes specific antibody titers in the general population 11 months later and compares them to preintroduction data obtained during 2008 using the same protocol.METHODS:During October-November 2011, we recruited a representative sample of the population of urban Bobo-Dioulasso aged 6 months to 29 years, who underwent standardized interviews and blood draws. We assessed anti-MenA immunoglobulin G (IgG) concentrations (n = 200) and, using rabbit complement, serum bactericidal antibody (SBA) titers against 2 group A strains: reference strain F8238 (SBAref) (n = 562) and strain 3125 (SBA3125) (n = 200).RESULTS:Among the 562 participants, 481 (86%) were aged ≥23 months and had been eligible for the PsA-TT campaign. Among them, vaccine coverage was 86.3% (95% confidence interval [CI], 82.7%-89.9%). Prevalence of putatively protective antibodies among vaccine-eligible age groups was 97.3% (95% CI, 95.9%-98.7%) for SBAref titers ≥128, 83.6% (95% CI, 77.6%-89.7%) for SBA3125 ≥128, and 84.2% (95% CI, 78.7%-89.7%) for anti-MenA IgG ≥2 µg/mL. Compared to the population aged 23 months to 29 years during 2008, geometric mean titers of SBAref were 7.59-fold higher during 2011, 51.88-fold for SBA3125, and 10.56-fold for IgG.CONCLUSIONS:This study shows high seroprevalence against group A meningococci in Burkina Faso following MenAfriVac introduction. Follow-up surveys will provide evidence on the persistence of population-level immunity and the optimal vaccination strategy for long-term control of MenA meningitis in the African meningitis belt.

Clinical Infectious Diseases, 61, ISSN:1058-4838, ISSN:1537-6591

Clinical Infectious Diseases, 61, ISSN:1058-4838, ISSN:1537-6591

Background. In 2010, mass vaccination with a then-new meningococcal A polysaccharide–tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1- to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying age- and sex-specific immunity prior to and 2 years after introduction. Methods. Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels ≥0.1 IU/mL (indicating short-term protection) and ≥1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. Results. Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre–PsA-TT, significantly higher GMCs in all age–sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6–36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7–43.3; P < .0001) pre- and postvaccination. Conclusions. Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity.