Progress towards achieving and maintaining maternal and neonatal tetanus elimination in the African region

Despite the availability of effective tetanus prevention strategies, as of 2016, Maternal and Neonatal Tetanus Elimination (MNTE) has not yet been achieved in 18 countries globally. In this paper, we review the status of MNTE in the World Health Organization African Region (AFR),and provide recommendations for achieving and maintaining MNTE in AFR. As of November 2016, 37 (79%) AFR countries have achieved MNTE, with 10 (21%) countries remaining. DTP3 coverage increased from 52% in 2000 to 76% in 2015. In 2015, coverage with at least 2 doses of tetanus containing vaccine (TT2+) and proportion of newborns protected at birth (PAB) were 69% and 77%, compared with 44% and 62% in 2000, respectively. Since 1999, over 79 million women of reproductive age (WRA) have been vaccinated with TT2+ through supplementary immunization activities (SIAs). Despite the progress, only 54% of births were attended by skilled birth attendants (SBAs), 5 (11%) countries provided the 3 WHO-recommended booster doses to both sexes, and about 5.5 million WRA still need to be reached with SIAs. Coverage disparities still exist between countries that have achieved MNTE and those that have not. In 2015, coverage with DTP3 and PAB were higher in MNTE countries compared with those yet to achieve MNTE: 84% vs. 68% and 86% vs. 69%, respectively. Challenges to achieving MNTE in the remaining AFR countries include weak health systems, competing priorities, insufficient funding, insecurity, and sub-optimal neonatal tetanus (NT) surveillance. To achieve and maintain MNTE in AFR, increasing SBAs and tetanus vaccination coverage, integrating tetanus vaccination with other opportunities (e.g., polio and measles campaigns, mother and child health days), and providing appropriately spaced booster doses are needed. Strengthening NT surveillance and conducting serosurveys would ensure appropriate targeting of MNTE activities and high-quality information for validating the achievement and maintenance of elimination.


Introduction
Tetanus is a non-communicable vaccine-preventable disease caused by the bacterium Clostridium tetani (C. tetani). The disease cannot be eradicated because C. tetani spores exist in the environment [1]. Although tetanus can occur in all age-groups, neonates and women with recent pregnancies are most at risk, particularly when childbirths (or terminations of pregnancies) take place under unhygienic conditions [2]. Neonatal tetanus (NT) occurs during the first 28 days of life and maternal tetanus occurs during or within the first 6 weeks after pregnancy. Casefatality rates from tetanus in resource-limited settings can be up to 100%, though with adequate medical care rates can be reduced to 10-20% [3].
Tetanus toxoid containing vaccine (TTCV) is one of the most effective, safe, heat-stable, and inexpensive vaccines ever developed [4]. TTCV can be given safely during pregnancy to protect both mothers and newborns [5]. Vaccines containing tetanus for infants and pregnant women have been part of the WHO Expanded Program on Immunizations since its inception. WHO recommends a 6 dose schedule of TTCV including 3 doses in infancy and 3 booster doses, 1 each during the second year of life, childhood (4-7 years), and adolescence (9-15 years), to provide long-term protection against tetanus in all ages [3]. For previously non-immunized adolescents and adults, a total of 5 TTCV doses are recommended [3]. In countries where maternal and neonatal tetanus (MNT) is still a problem, pregnant women whose tetanus vaccination history is unknown or inadequate are recommended to receive 2 TTCV doses during their first pregnancy, with the first dose provided at first contact with health services and the second dose provided at least 4 weeks later and at least 2 weeks before delivery [3]. The third dose can be given at least 6 months after the second, and 2 boosters are provided during subsequent pregnancies or at least 1 year later. This schedule has been shown to reduce neonatal mortality from tetanus by 94% [5].
In industrialized countries, MNT was generally eliminated before vaccine introduction through clean birth practices [6]. Deliveries assisted by skilled birth attendants (SBA), who can ensure clean delivery practices and education on hygienic umbilical cord practices, has been shown to be an effective intervention to prevent MNT and to reduce neonatal mortality due to tetanus by 50-70% [6][7][8][9].
In 1988, NT was estimated to cause over 787,000 deaths per year [10]. To address the global burden of NT, in 1989, The World Health Assembly called for the elimination of NT by 1995, defined as an incidence of <1 NT case per 1,000 live births in every district annually [11]. Maternal tetanus elimination was added in 1999, and the goal was relaunched through a partnership with World Health Organization (WHO), United Nations Children's Fund (UNICEF), and United Nations Population Fund (UNFPA) as the Maternal and Neonatal Tetanus Elimination (MNTE) Initiative, focusing on 59 priority countries (including the addition of Timor Leste and South Sudan) that had not yet achieved elimination as of 2000 [7,12]. The strategies recommended by the UN agency partnership to achieve MNTE are 1) routine immunization of women during pregnancy with TTCV, 2) immunization of all women of reproductive age (WRA) living in high risk areas with 3 doses of TTCV, 3) delivery by SBA to ensure clean delivery practices, and 4) surveillance for NT cases [7]. High-risk districts for MNT are defined as those reporting clean delivery coverage of < 70% and coverage with at least 2 TTCV doses <80% during the past 5 years among pregnant women or WRA [12]. All WRA living in high-risk areas are provided 3 doses of TTCV irrespective of their previous vaccination status, through appropriately spaced supplementary immunization activity (SIA) rounds [12]. As a result of MNTE efforts, the estimated number of NT deaths has been reduced by 94% (49,000 estimated deaths) in 2013, compared to 1988 [13]. However, the target date for MNTE has been repeatedly missed and extended; the most recent target date was 2015 [7]. As of October 2016, 41 (69%) of the 59 priority countries identified have achieved MNTE [14].
Beyond MNTE, a goal of tetanus vaccination is to prevent tetanus in all ages [3].The Global Vaccine Action Plan (GVAP) set a target of 90% coverage with three doses of diphtheria, tetanus, and pertussis containing vaccine (DTP3/Penta) among children aged <12 months nationally, and 80% in every district by 2015 [15]. GVAP objectives also emphasize equitable provision of vaccines to underserved areas and marginalized groups, as well as introducing strategies to provide vaccinations to all ages ("life course approach"). High vaccination coverage and provision of tetanus booster doses throughout the lifespan would raise population immunity and sustain achievements of the MNTE Initiative.
The World Health Organization (WHO) African Region (AFR) consists of 47 countries in Sub-Saharan Africa that carry a substantial burden of the remaining MNT cases. In this paper, we describe the current status of progress towards MNTE in AFR, discuss the challenges and barriers to reaching elimination, and make recommendations for reaching and maintaining elimination in the region.

Methods
For each country in AFR, we reviewed national vaccination schedules, vaccination coverage estimates and reported NT cases from the WHO-UNICEF joint reporting form available on the WHO website [16][17][18][19][20][21]. WHO-UNICEF coverage estimates were reviewed to determine coverage of the third dose of Diphtheria Tetanus and Pertussis vaccine (DTP3)/ Pentavalent vaccine (Penta 3) among children aged <12 months and the proportion of births in a given year that can be considered as having been protected against tetanus (protected at birth, PAB) as a result of maternal immunization [19,20]. WHO-UNICEF estimates of PAB were calculated on the basis of mathematical modeling [22], whereas PAB is usually defined as having received 2 tetanus toxoid (TT) doses during the last birth, ≥2 TT doses with the last dose ≥ 3 years prior to the last birth, ≥3 doses with the last dose ≤ 5 years prior, ≥4 doses with the last dose ≤10 years prior, or ≥ 5 prior doses [23]. Official country administrative coverage figures reported to WHO-UNICEF were reviewed for the proportion of women who have received their second or subsequent dose of TTCV during pregnancy (TT2+) [21]. Administrative TT2+ coverage is calculated by dividing the number of pregnant women who received the second or subsequent dose of TT by the estimated number of live births for the year [24]. 2005, 2010, and 2011-2015 averages forDTP3/ Penta3, TT2+, and PAB coverage were calculated for countries yet to achieve MNTE and those that have achieved MNTE using the formula: (sum of (coverage x target population)) / sum of target populations). NT incidence rates were calculated for each country based on the number of reported cases divided by the number of births. Population denominators are from the United Nations Population Division [25].
The regional average for DTP3/Penta3 coverage has increased from 52% in 2000 to 76% in 2015 overall, though coverage in several countries has not improved during this time period [19,30]. In 2015, DTP3/Penta3 coverage among countries that had achieved MNTE was 84% compared with 68% among countries that had not yet achieved MNTE ( Figure  2). Of the AFR countries that have achieved elimination, 16 (43%) had ≥90% DTP3/Penta3 coverage in 2015 (Table 1). Of the 10 countries that have not achieved MNTE, Kenya is the only country that has ever reached ≥90% DTP3/Penta3 coverage though not in every year since 2010 ( Table 2). Ebola-affected countries (Guinea, Liberia, and Sierra Leone) experienced decreases in DTP3/Penta3 coverage rates during and following the outbreak in 2014 and 2015. Over the same time period, Angola and South Sudan had decreases in DTP3/Penta3 coverage, likely due to insecurity. Notably, DTP3/Penta3 coverage has been consistently low (<65%) in Equatorial Guinea which achieved elimination in 2016; such coverage may prove a challenge for maintaining elimination.
Both TT2+ and PAB coverage are estimates of tetanus immunity among pregnant women. The percentage of pregnant women covered with TT2+ among all countries in the AFR region increased from 44% in 2000 to 69% in 2015; PAB increased from 62% to 77% during the same time period [30]. In countries that have achieved MNTE, the average PAB and TT2+ coverage for 2015 was 86% and 64%, respectively ( Figure 2), with ≥ 80% TT2+ or PAB coverage in all but Equatorial Guinea, Madagascar, and Zimbabwe (Table 3). Of the AFR countries that have not yet achieved MNTE, the average PAB and TT2+ coverage in 2015 was 69% and 64%, respectively ( Figure 2); among these countries, ≥80% TT2+ or PAB coverage was achieved in Chad, DRC, Ethiopia, Guinea, Kenya, and Mali (Table 4). Guinea and Liberia, which were affected by the 2014 Ebola outbreak, had lower TT2+ coverage in 2014 and 2015 relative to other years, but PAB remained stable. However, Sierra Leone, also affected by the Ebola outbreak, did not have a drop in TT2+ or PAB coverage.TT2+ coverage can underestimate true protection from tetanus, especially in countries with well-established vaccination programs (e.g. Botswana, Cabo Verde, and Comoros), because it excludes women unvaccinated during pregnancy but already protected through previous vaccination or who received one dose in pregnancy and had undocumented previous doses (Table 3) [23,24].
During 1999 to the end of 2016, over 79 million WRA were vaccinated with at least 2 TTCV doses during SIAs in AFR countries, but by the end of 2016 about 5.5 million WRA in AFR countries still need to be reached. Only a limited number of districts are assessed as high-risk in the 10 countries remaining to achieve MNTE (e.g., in DRC only 11 of the 514 health zones are high-risk). The total number of TTSIA phases completed as of April 2016 and number of TT2+ doses provided through SIAs are reported for countries yet to achieve MNTE in Table 5. Most of the required funds are available to support Angola, Chad, DRC, Ethiopia, Guinea, Kenya, and South Sudan to complete all their planned and final TTCV SIAs; these countries are on course to achieve elimination by 2018 [31]. However, most of the funding for TTCV SIAs in CAR, Mali, and Nigeria is still lacking [31].

Clean delivery and cord care
In addition to vaccination, clean delivery and cord care are essential interventions to prevent and eliminate MNT. The proportion of births delivered by SBAs is a key indicator for monitoring progress towards MNTE. In AFR, the percentage of births attended by SBAs was 54% in 2013 [32].

Surveillance
Sensitive NT surveillance is important for conducting epidemiologic analysis of cases, planning targeted interventions, and evaluating program effectiveness. WHO recommends routine monthly surveillance of NT, including zero reporting, active surveillance, and retrospective record review at major health facilities at least once a year to identify previously unreported NT cases [33]. During 2015, the number of NT cases reported from countries that have not achieved MNTE ranged from 0 in South Sudan to 330 in the DRC, with a respective reported national incidence of 0 to 0.59 NT cases per 1,000 live births (Table 5).However, underreporting of NT surveillance is common, with the efficiency of notification for NT cases globally estimated at less than 11% [2]. Likely causes of NT underreporting include the general occurrence of NT cases in remote and underserved areas, NT deaths occurring in the community without being seen by a health worker, and lack of a robust system of active NT surveillance in most countries.
Serosurveys can help monitor progress towards achieving or maintaining MNTE, especially in countries or areas where TT2+ or PAB coverage may not be accurate. In Burundi in 1989, a national serosurvey among women giving birth in the previous year reported 73% PAB coverage and 67% seroprotection [34]. More recently, a national serosurvey in CAR in 1995 reported 74% PAB and 89% seroprotection among women giving birth in the past year [35]. In Cambodia in 2012, seroprotection was 88% for WRA overall, while parous women had 83% PAB and 97% seroprotection [23]. PAB coverage can be underestimated due to residual immunity from infant doses in some adult women, booster doses provided outside routine services, misclassification of PAB status due to poor availability of documentation, and recall bias [23]. Serosurveys can help estimate population immunity, which contributes to validation of MNTE, and identify areas at high risk for MNT [36]. Integration of tetanus testing in serosurveys for other antigens (e.g., rubella) using multiplex testing may reduce the cost and resources required [23].

Challenges and recommendations for AFR countries that have not yet achieved MNTE
A number of challenges exist among the countries that have not yet achieved MNTE. In all the countries that have not yet achieved elimination, weak health systems affect their ability to effectively implement the four MNTE strategies. In most countries, sub-optimal routine immunization is evidenced by low rates of DTP3/Penta3 and TT2+/PAB coverage. The proportion of safe deliveries occurring in health facilities or at home with skilled birth attendants also remains low. Insecurity and unrest in CAR, Nigeria, Mali, and some areas of other countries result in WRAs living in high-risk areas being inaccessible. These countries also have challenges with funding the remaining TTCV SIAs needed to achieve MNTE. Vaccine controversy issues related to targeted vaccination of WRA have also occurred, resulting in varying extents of vaccine hesitancy. In Kenya, the national Conference of Catholic Bishops made public allegations that tetanus vaccine could cause sterility in women, which has delayed the country's timeline for MNTE [37]. Furthermore, AFR countries face competing priorities both within the EPI program, such as polio eradication (e.g., Nigeria) and measles elimination activities (i.e., throughout AFR), response campaigns to meningitis serogroup A and yellow fever outbreaks, and with other health programs (e.g., Ebola, HIV, TB, malaria).
Despite these challenges, MNTE is achievable in the remaining 10 AFR  g. Reported NT incidences are national and do not represent district level data used to determine elimination status (<1 NT case per 1000 live births in every district annually). Underreporting of NT cases is common, with the efficiency of notification for NT cases globally estimated at less than 11% by Khan et al [2]. h. TT2+ doses are missing for phases 11 and 12 because round-wise coverage was reported instead of individual level coverage for receipt of multiple doses.
countries if there is strong national commitment, timely availability of resources, high quality micro plans, well implemented activities with monitoring and supervision, active community engagement, and adequate coordination with and implementation of maternal and child health services [31]. The methods to approach the MNTE strategies to reach elimination vary by country.
Efforts to strengthen the health care system of AFR countries yet to achieve MNTE could result in increased vaccination of pregnant women through routine services along with improving rates of clean deliveries. Eritrea, Rwanda, South Africa, and Zimbabwe were successful at eliminating MNT through efforts to strengthen the health system, without conducting any TTCV SIAs [31]. To achieve MNTE, Eritrea and Liberia promoted clean deliveries through additional training of traditional birth attendants [38,39]. Liberia also encouraged facility births with distribution of free kits for mothers, including baby articles and bed nets [39]. Burundi constructed and staffed rural health facilities with trained health workers to provide free health care for mothers and children, in addition to conducting catchup vaccination during mother and child health weeks [40]. Immunization programs should encourage using every opportunity to provide TTCV to women (e.g., child health days, outreach immunization sessions, periodic intensification of routine immunization, antenatal care visits, family planning visits) to improve coverage. Providing TTCV booster doses in the routine immunization schedule (e.g., in the second year of life with MCV2, or in school) can ensure women are protected, or need fewer booster doses to be protected, by the time they reach reproductive age.
Mozambique provides TTCV to WRA during routine EPI sessions and also in secondary schools and workplaces; in addition, children of both sexes are provided TTCV in the first and second grade resulting in continued seroprotection of older children and adolescents [41,42].
Many countries conduct multiple polio and measles SIAs, with many targeting hard-to-reach, inaccessible or previously inaccessible areas (i.e., conflict affected). Integrated campaigns that include TTCV could be an opportunity to reach WRA in high-risk areas. For countries with inaccessible areas or insecurity, innovative approaches such as use of TT-Uniject™ (a heat-stable prefilled injection device) could help reach these populations and improve TTCV coverage for WRA. An evaluation in Mali, where there are a limited number of health workers, showed that community-based volunteers could safely administer TT-Uniject™, communities were accepting of the practice, and previously inaccessible populations were reached [43]. Use of TT-Uniject™ during campaigns would allow unskilled vaccinators to provide vaccine, similar to polio SIAs.
India achieved MNTE in 2015 by employing a combination of approaches that may be applicable for some AFR countries. India faced similar challenges to the AFR region including a history of unsafe birth practices during home deliveries and suboptimal TTCV coverage [44]. Some of the approaches used in India to achieve MNTE included addition of TTCV booster doses to the childhood immunization schedule, immunization of pregnant women during antenatal care visits, implementation of SIAs in high-risk areas, and extension of outreach services to include vaccination of children, adolescent, and pregnant women with TTCV. India also promoted institutional deliveries through the provision of conditional cash transfers, communication with communities on clean cord care practices, and distribution of clean delivery kits to SBAs [44,45].
As mentioned above, sensitive NT surveillance is a challenge for countries trying to achieve MNTE. Developing standardized NT surveillance guidelines with performance indicators similar to those used for acute flaccid paralysis (AFP for polio) and measles-rubella (MR) surveillance are needed to improve NT surveillance; such guidelines and indictors already exist for the Region of the Americas and could be adapted to other regions. Active surveillance for NT cases has been successfully integrated into existing active case-based surveillance activities for AFP and MR in many countries, resulting in more robust NT reporting. For example in Nepal, NT surveillance was integrated into the AFP surveillance system, which uses a network of surveillance medical officers reporting weekly from 413 sentinel surveillance sites (10% of government health facilities), and investigating suspected NT cases using a standard case-investigation form [46]. Since many neonatal deaths occur at home, it is important to supplement health facility-based surveillance with community based surveillance. In addition, sensitivity of NT surveillance may be improved through investigation of neonatal deaths reported through vital registration and reporting [31].

Sustaining elimination
Because tetanus cannot be eradicated from the environment, countries need to have a plan for sustaining MNTE. Attention to MNT will likely decrease after elimination along with resources. However, efforts to ensure clean deliveries, maintain high immunization coverage of pregnant women, and strengthen NT surveillance should be continued through integration with routine programs. Countries with weak health systems that achieved elimination through SIAs need to have employed additional strategies for reaching women beyond routine services, which may include continued SIAs in high risk areas and outreach activities during child health days or antenatal care, to ensure population immunity does not lapse after MNTE validation [7].
Providing TTCV booster doses during the second year of life, childhood, and adolescence in the routine schedule will help ensure individuals of all ages and both sexes are adequately protected without relying on SIAs [3]. As school attendance has increased in the African region, schoolbased immunizations platforms are increasingly attractive platforms for administering booster doses during childhood and adolescence. In 2012, 24% of AFR countries reported providing vaccinations in school [47]. Opportunities to provide TTCV boosters increasingly exist as AFR countries, many with funding assistance from GAVI, the Vaccine Alliance, introduce vaccinations given beyond the first year of life, including a second dose of measles containing vaccine (MCV2) in the second year of life (2YL) and human papillomavirus vaccine in early adolescence [48]. As of September 2016, 25 (53%) AFR countries provided MCV2, most during the 2YL [16]. Additionally, booster doses would address tetanus immunity gaps in older children and adult men in the region [42,49]. Attention was brought to the seriousness of this issue after cases of tetanus were reported following voluntary medical male circumcision in Eastern and Southern African countries [49,50]. When countries develop plans to maintain MNTE, it is important to include booster doses for both sexes to improve equity, ensure long-term protection and decrease the burden of tetanus in all ages.
Most countries in the African meningitis belt have or will introduce the meningococcal serogroup A polysaccharide TT-conjugate vaccine (MenAfriVac) by conducting SIAs targeting persons aged 1-29 years, followed by introduction into the routine immunization schedule during the first or second year of life [16]. Results from a serosurvey conducted in Mali before and after the MenAfriVac campaign showed significant increases in tetanus immunity 2 years after the SIA [51]. A 25% reduction in NT cases was observed after MenAfriVac SIAs in 5 African countries, compared with before the SIA [52]. Therefore, MenAfriVac introduction in AFR countries in the meningitis belt could help boost tetanus immunity in those populations and support MNTE.
Effective NT surveillance, including sensitive and timely identification of NT cases, targeted implementation of control strategies, and effective monitoring and evaluation of the impact of these strategies, will be critical to sustaining MNTE. In addition to improving NT surveillance as mentioned above, annual reviews of data should be done to identify districts that could be at high-risk for MNT resurgence and need to implement additional control strategies to sustain MNTE [31]. In countries that have achieved MNTE, tetanus serosurveys of tetanus immunity in countries that have achieved MNTE can help supplement district level data reviews by identifying immunity gaps, which can provide evidence for the need for booster doses, including optimal schedules, and the need for targeted vaccination [31,36].

Conclusion
Though MNTE was not achieved in AFR by the target date of 2015, significant progress has been made in the region where 37 (79%) of 47 countries have achieved elimination as of November 2016. Table 6 summarizes the key findings of the MNTE strategies in the AFR region.
In 2015, PAB and TT2+ coverage increased to 77% and 69% compared to 62% and 44% in 2000, respectively. Nevertheless, the region has 10 (56%) of the 18 countries worldwide that are yet to achieve MNTE. The majority of these countries are challenged with insecurity, weak health systems, competing priorities, and/or insufficient funding. In countries with insecurity, use of pre-filled injection devices, and integration of TTCV SIAs with polio and/or measles vaccination SIAs, or post-conflict campaigns, could help ensure tetanus protection among WRA in highrisk areas. To achieve and maintain MNTE, programs should use every available opportunity to provide TTCV to pregnant women, including in antenatal clinics, outreach, and during child health days. Providing the WHO-recommended TTCV booster doses to both sexes, e.g., in the 2YL, childhood (4-7 years), and adolescence (9-15 years), would help ensure women are protected before pregnancy and reduce the tetanus burden across the whole population. Case-based NT surveillance could be strengthened by development of standardized performance indicators and integration with active surveillance for AFP and MR. Countries that have achieved MNTE should develop plans to maintain elimination, including efforts to ensure high-quality NT surveillance and high tetanus immunity among WRA. Serosurveys may provide important information on tetanus population immunity for countries that have yet to achieve, as well as those that have already achieved MNTE.

What is known about this topic
• Maternal and neonatal tetanus is preventable through appropriate vaccination of pregnant women and implementation of clean delivery and umbilical cord practices; • Because of efforts towards maternal and neonatal tetanus elimination (MNTE), neonatal mortality from tetanus has declined an estimated 94% between 1988 and 2013; • Worldwide, 41 (69%) of 59 priority countries have achieved MNTE, with 18 countries yet to achieve elimination, including 10 countries in the African region.

What this study adds
• As of November 2016, over 79 millions women of reproductive age in countries in the African region (AFR) have been reached with at least 2 doses of tetanus-toxoid containing vaccines through supplemental immunization activities; • Challenges to achieving MNTE in AFR countries include insecurity, weak health systems, competing priorities, and insufficient funding, but 7 of 10 AFR countries are on track to achieve MNTE by 2018; • Only 5 (11%) AFR countries currently provide the 3 WHOrecommended tetanus booster doses during childhood, adolescence, and early adulthood to provide long-term protection against tetanus and assist with sustaining MNTE.