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Maternal Immunization Can Reduce Unnecessary Maternal and Newborn Deaths Abstract: Despite the indisputable successes of the United Nations Millennium Development Goals, which include goals on improving maternal health and reducing child mortality, millions of mothers and newborns still die tragically and unnecessarily each year. Many of these deaths result from vaccinepreventable diseases, where obstacles such as cost and accessibility have hampered efforts to deliver efficacious vaccines to those most in need. Additionally, many vaccines given to mothers and children under five are not suitable for newborns, since their maturing immune systems do not respond optimally during the first few months of life. Maternal immunization, the process by which a pregnant woman’s immune system is enhanced against a particular disease and the protection is then transferred to her unborn child, has emerged as a strategy to prevent many unnecessary maternal and newborn deaths. We review vaccines that are already used for maternal immunization, analyze vaccines under development that could be used for maternal immunization strategies in the future, and provide recommendations for policymakers to 1 utilize maternal immunization for improved maternal and newborn health. For the past fifteen years, the Millennium Development Goals (MDGs) have shaped the world’s response to glaring inequalities in health. These eight international development goals were established following the Millennium Summit of the United Nations in 2000 and focus on areas such as eradicating extreme poverty and hunger, improving education and environmental sustainability, and combating infectious diseases.(1) MDGs 4 and 5 focused specifically on reducing child mortality and improving maternal health, respectively.(2) Although impressive gains were made in both of these areas, millions of mothers and children still die from preventable causes each year. The mortality rate of children under five decreased by more than half between 1990 and 2015, from 90 deaths to 43 deaths per 1000 live births, but did not meet the initial target of a two-thirds reduction in child mortality.(3) In 2013, over 2.9 million newborns died, representing 44 percent of all deaths of children under 5.(4) As a consequence, achieving a reduction in neonatal mortality has remained a major focus of the global health agenda. Similarly, the global maternal mortality ratio (the ratio of the number of maternal deaths per 100,000 live births) decreased by nearly half since 1990, 2 but this fell far short of the goal of reducing the ratio by three quarters. In 2013, 289,000 women died during pregnancy, childbirth, or during the 42 days following delivery.(3) In September 2015, the Sustainable Development Goals (SDGs) replaced the MDGs as the United Nations’ strategy for combating health inequalities.(5) Maternal and child health again feature prominently in this global strategy to achieve health equality.(6) The majority of maternal and newborn deaths each year result from hemorrhage, hypertension, unsafe abortion, complications from preterm birth, among others.(7) However, vaccinepreventable diseases, including pertussis, tetanus, influenza, and others are also leading killers of mothers and newborns, despite widespread distribution of vaccines throughout much of the world in recent decades. Increased uptake of vaccines for these diseases, particularly in low- and middle-income countries, could save the lives of thousands of mothers and children each year.(8-10) The World Health Organization (WHO), through its Global Vaccine Action Plan, has deemed 2011-2020 the Decade of Vaccines. The Global Vaccine Action Plan framework aims to extend immunization to everyone by ensuring that adequate resources are provided for vaccines, health systems and 3 supportive infrastructure, and that more health workers are trained to reach remote and marginalized populations. The framework also advocates for the development of new vaccines and technologies to maximize the benefits of immunization around the world.(11) As the Decade of Vaccines passes its halfway point and the Sustainable Development Goals begin, maternal and newborn health must be kept at the forefront of global health policies, programming, and advocacy. In this article, we synthesize key information from the literature on vaccines that are currently used, or have the potential to be used, for maternal immunization. We utilize this information to provide policy recommendations for improving global maternal and newborn health. We first examine the mechanism by which maternal immunization protects women and newborns, and review maternal immunization for tetanus, influenza and pertussis. Mechanism of Maternal Immunization Immunization during pregnancy can serve two vitally important purposes: it can actively provide protection against the infectious disease to the mother and fetus during pregnancy; 4 and pass this protection on to the newborn through infancy. This occurs through placental transfer of antibodies, a natural phenomenon that occurs throughout gestation, primarily in the final four weeks of pregnancy, with protective antibody levels in the fetus sometimes reaching higher concentrations than those found in the mother.(8, 9, 12-16) Without this transfer of immune protection from the mother, newborns would be even more vulnerable to infectious diseases. Newborns have to adjust from the tolerogenic in utero environment to cope with numerous external influences after birth. Newborns often do not respond well to vaccines and require multiple doses of vaccines appropriately spaced apart in time in order to prime their immune system to deal effectively with a specific infection. Conversely, a single dose can often immunize a pregnant woman who has already received a priming course of immunizations in her youth or has “seen” the disease previously. Most vaccines are not used in newborns under 6 weeks old, therefore maternal immunization, which has been shown to passively protect the baby for the first several months of its life, can limit the amount of time a newborn lacks immune protection from numerous infectious diseases.(17, 18) As most pregnant women routinely seek prenatal care, patient accessibility makes maternal 5 immunization not only a good medical option, but also a feasible and cost-saving intervention for mutual benefit.(19) Vaccines Recommended for Use During Pregnancy Tetanus Tetanus is caused by the spores of the bacterium Clostridium tetani, which exists in ubiquitous quantities in soil and animal intestinal tracts to the extent that it contaminates numerous surfaces and substances and can never be fully eradicated. While tetanus can affect people of all ages, newborns and their mothers are particularly at high risk for infection if childbirth occurs under unhygienic conditions. Eliminating tetanus infections therefore requires immunization and high quality health services that are universally accessible.(20, 21). Over 1 million people died from tetanus each year in the 1980s, despite the fact that an effective vaccine, tetanus toxoid (TT), had been available for decades.(22, 23) As late as 1988, the WHO estimated that 787,000 of these deaths were from neonatal tetanus, defined as tetanus in the first 28 days of life.(21) To decrease the impact of tetanus, in 1989, the 6 42nd World Health Assembly made a global commitment to eliminate neonatal tetanus, defined as fewer than one case per 1000 live births in all districts.(24) This commitment was updated in 1999 to include maternal tetanus and renamed the Maternal and Neonatal Tetanus Elimination Initiative.(21) As shown in Exhibit 1, by 1994, neonatal tetanus deaths had decreased to 490,000 per year, and in 2000 had decreased further to 200,000. The latest data, from 2013, shows that 49,000 neonatal tetanus deaths still occur each year.(20) As of May 2015, maternal and neonatal tetanus has been eliminated in all but 22 countries, and overall deaths from tetanus have been reduced by 94 percent since 1988.(9, 25) This reduction in tetanus infection was achieved through four key strategies: delivery of infants by skilled birth attendants to ensure clean delivery practices; maternal immunization with tetanus toxoid-containing vaccines; immunization of women of reproductive age with tetanus toxoidcontaining vaccines in high-risk areas; and surveillance for neonatal tetanus.(20) Maintaining this decline in infections and ultimately eliminating deaths due to tetanus will require sustained commitment from the international community. Maternal immunization has played a key role in the progress toward 7 eliminating maternal and newborn tetanus thus far, and continuing to use it as a strategy will be critical to saving at-risk maternal and newborn lives. It also provides a powerful example for the success of the concept of maternal immunization, which could be applicable to other vaccinepreventable infectious diseases. Influenza Pregnant women, new mothers, and newborns are also vulnerable to influenza infection, which can result in hospitalization, prematurity, stillbirth, and in rare cases the mother or newborn’s death.(26-28) Influenza vaccines given during pregnancy have been shown to produce an immune response during pregnancy that is passed on to the newborn (29-32) and to reduce confirmed cases of influenza by up to 63 percent.(17) As the risk of influenza infection is substantial for pregnant women, fetuses, and newborns, influenza immunization is recommended at the beginning of the seasonal influenza epidemic, independent of the stage of the pregnancy.(33) Protecting newborns from influenza infection with maternal immunization is especially important, as influenza vaccination is not recommended for children younger than 6 months.(34) 8 The effectiveness of maternal immunization, paired with epidemiological data showing that breastfeeding can protect against influenza infection in newborns,(35) led the WHO to recommend in 2005 that all pregnant women be immunized against influenza.(36) The Surgeon General of the United States recommended maternal immunization for influenza as far back as 1960,(37) yet low rates of influenza immunization during pregnancy have persisted. In 2001-2002, a telephone survey found that only 11.2 percent of pregnant women in the United States were vaccinated against influenza, although this steadily increased each year for three years but then plateaued for three years, reaching 26.9 percent in 20072008.(38) The 2009 influenza A (H1N1) pandemic saw an upsurge in coverage, and increase has been seen every year since, leading to a 52.2 percent coverage rate by 2013-2014, and a decrease in death rate from influenza and pneumonia over this period, as shown in Exhibit 2.(39) Given the seasonality of influenza demonstrated in many resource-rich settings, it is now important to gather epidemiological data from resource-poor settings through influenza surveillance to predict the best time to administer the vaccine during pregnancy, especially as vaccination rates are often significantly lower in resource-poor settings.(31) 9 However, recent studies suggest that more data is required to determine the true disease burden of influenza on pregnant women and newborns. New evidence has shown little to no impact of maternal influenza virus infection on birth outcomes in South Africa, whilst it had appeared beneficial in earlier clinical trials in Bangladesh. The potential impact of maternal immunization on mortality or severe disease is currently unclear.(40) Despite this, preventing hospitalization through maternal immunization is still an important public health outcome, and increasing vaccination rates in all settings should remain an international priority. Pertussis From the 1920s until the widespread adoption of the diphtheria, pertussis, and tetanus (DPT) vaccine in the 1950s, between 100,000 and over 250,000 cases of pertussis were reported in the United States each year. From 1970 until the early 2000s, pertussis cases dwindled to less than 5,000 per year typically. However, in the past decade, pertussis cases have increased, peaking in 2012 with over 48,277 cases reported, and over 28,000 cases reported in 2013 and 2014.(41) (Exhibit 3) 10 Similarly, in the United Kingdom, fewer than 1,000 cases were reported in 2000, but 9367 cases were reported in 2012, followed by 4621 cases in 2013 and 3388 cases in 2014.(42) (Exhibit 4) In both the United Kingdom and the United States, the majority of hospitalizations and deaths occurred in children under 2 months old, the period when newborns are most vulnerable to pertussis infection, as the routine immunization schedule only commences by 2 months of age.(8, 9) In response to these outbreaks of pertussis, both the United States and United Kingdom recently updated their recommendations regarding pertussis vaccinations. The UK’s Department of Health recommended in September 2012 that all pregnant women should be offered the pertussis vaccination in the third trimester of each pregnancy.(43) Since July 2014, Boostrix IPV, a vaccine against pertussis, polio, diphtheria, and tetanus, has been given in the United Kingdom, replacing a similar vaccine, Repevax.(44) Similarly, the Advisory Committee on Immunization Practices in the United States recommended in October 2012 that all pregnant women of 27-36 weeks gestation receive Tdap, an updated vaccination against tetanus, diphtheria, and pertussis, during each pregnancy to maximize the transfer of protective antibody from mother to fetus.(45) However, questions remain as to whether repeated doses of Tdap are safe 11 and effective for pregnant women, and large-scale studies are currently underway to provide more data on its safety and immunogenicity.(46) Additionally, immunity can wane over time using the Tdap vaccine, which is acellular, meaning that the vaccine only contains purified components of B. pertussis, compared to previously used whole-cell vaccines, decreasing effectiveness and with it the potential for herd immunity.(47, 48) Although pertussis can affect mothers, newborns are more vulnerable to severe reactions to infection, including death. The primary objective in administering the vaccine during pregnancy is therefore to protect the newborn rather than the mother, as it will prevent spread of the pertussis organism from mother to baby.(49) In 2008, an estimated 16 million cases of pertussis and 195,000 deaths from pertussis occurred globally in children, making the size and scale of the recent outbreaks in the United States and United Kingdom pale in comparison.(50) Deaths in settings where maternal vaccination programs have been introduced have dropped dramatically. Of the seven deaths in the United Kingdom in newborn infants in 2013 due to pertussis, six occurred in infants of unvaccinated mothers, and the seventh infant’s mother was immunized too late in pregnancy.(41) Higher rates of maternal immunization worldwide 12 could dramatically decreases the number of cases and deaths from pertussis. Safety of Maternal Immunization Maternal immunization has been used as a strategy to protect mothers and newborns for decades(51), and numerous studies have confirmed the safety of vaccines for this purpose.(52-57) Despite overwhelming data supporting safety of these vaccines, many pregnant women still refuse to accept maternal immunization as a preventive strategy against infectious disease due to fears about safety. Other reasons for refusing immunization include a perceived low risk of exposure to particular diseases and a lack of trust in the information about the vaccine.(58) The lack of encouragement or knowledge about maternal immunization by health care workers and the lack of infrastructure to store and distribute vaccines, particularly in low-resource settings, also contribute to poor uptake of maternal immunization.(8) This evidence suggests that a more comprehensive strategy is required to eliminate misinformation about immunization safety and efficacy in pregnancy, train health care workers about the benefits of maternal immunization, and develop the 13 infrastructure required to implement maternal immunization worldwide. High-level policy documents such as the WHO’s Global Vaccine Safety Blueprint are helpful in promoting top-down approaches in reassuring the public about vaccine safety(59), but more must be done from the bottom-up to translate policy into action. The Future of Maternal Immunization A number of other vaccines have been used safely and effectively in adults and children for many years and should be tested for use in pregnant women, including vaccines against pneumococcus, Hemophilus influenza Type b, and meningococcus.(9) Uptake of these vaccines in areas where these types of infections are endemic could be strategically advantageous. Clinical trials for the use of the 23 valent pneumococcal vaccines during pregnancy have been completed, although results thus far have been inconclusive.(60) Continuing to test these vaccines for safety and efficacy should remain a priority. There are also several new vaccines in the pipeline that have the potential to be used for maternal immunization. A vaccine against group B Streptococcus (GBS), the most common cause of 14 bacterial sepsis and meningitis in newborns in high-income countries and a common cause in low- and middle-income countries, could be used to prevent infection in newborns when given to the pregnant woman. (61) Safety and immunogenicity data are already available from field trials, but more studies are needed to evaluate the effectiveness of the vaccines.(6264) Similarly, vaccines under development for respiratory syncytial virus,(65) herpes simplex virus,(66, 67) and cytomegalovirus(68) could be transformative for worldwide maternal and child health, if proven to be safe and effective for pregnant mothers and their offspring. Maintaining momentum in developing these vaccines will be paramount to their successful approval, as it can often take more than 10 years to develop a fully licensed vaccine, with costs between $200 million and $500 million.(69) Continued focus on preventing these types of infections should remain a high priority as the Sustainable Development Goals gain momentum. In order to further support the prioritization of maternal and newborn health, we propose the following recommendations to be considered by policymakers when developing national and global strategies for saving the lives of women and children. 15 Policy Recommendations The MDGs have led to decreases in deaths of mothers and children worldwide, yet too few countries have reached the specified targets of MDGs 4 and 5. As a significant proportion of these deaths are preventable, policymakers should continue prioritizing the lives of vulnerable mothers and infants in particular. Global frameworks such as Strategies Toward Ending Preventable Maternal Mortality (70) and the Every Newborn Action Plan (4) recommend human rights-based strategies and set specific targets for reducing national maternal mortality ratios and ending preventable newborn deaths and stillbirths. Focusing on essential care during labor, birth, and the first day and week of life; and integrating maternal and newborn care are two strategies that could have significant impact. In addition, vaccines against tetanus, influenza, and pertussis have been proven to be safe and effective in preventing infections in mothers and newborns, particularly in high-income countries such as the United States and the United Kingdom. Providing these vaccines to pregnant women in lowand middle-income countries should be a priority. The strategy set out by the Global Vaccine Action Plan should be updated to emphasize the importance of maternal immunization and set specific targets for immunization coverage rates in areas where tetanus, influenza, and pertussis infection are endemic. 16 Vaccines and other drugs often face excessive hurdles during the path from research to market. When proven to be safe and effective, vaccines that are given accelerated approval and market protection could be transformative in saving the lives of women and newborns in maternal immunization programs. Innovative strategies that could be implemented to expedite development and increase uptake include developing publicprivate partnerships for research and development, committing to advance contracts, patent buyouts or extensions, and tax credits for vaccine sales, among others. A number of vaccine candidates exist that could be useful for maternal immunization. Priority should be given to vaccines against diseases that weigh considerably in the global burden of disease and where the potential benefits are high. Accompanying research and ongoing surveillance should be supported. However, increasing overall funding for research and development is only the first step to increased uptake. Innovative strategies such as diversifying sources of funding for new vaccines, advocating governments to invest in immunization in incremental levels according to their ability to pay, and utilizing differential pricing approaches to pay for vaccines that are available are all potential pathways to increased development and uptake of maternal immunization. 17 Conclusion Maternal immunization has proven to be a safe and effective strategy for preventing specific infections for many years and has saved many lives of mothers and newborns. The disease burden of tetanus, influenza, and pertussis has been minimized in many countries through maternal immunization, but wider applications of this strategy are now needed. Millions of mothers and newborns still die each year from infectious diseases, particularly in low- and middle-income countries where vaccines are not as widely distributed or recommended in maternal immunization programs, or where access to prenatal care is considerably difficult to achieve. In addition, a number of other vaccines in the pipeline could potentially be used in pregnant women, provided they are found to be safe and effective. As we enter the second half of the Decade of Vaccines and usher in the Sustainable Development Goals, maintaining a long-term focus on saving the lives of the most vulnerable should be the global health community’s primary focus. Maternal immunization should be a cornerstone of this strategy. 18 Notes 1. Dodd R, Cassels A. 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Geneva (Switzerland): WHO, 2015 [cited 2015 Dec 10]. Available from: http://apps.who.int/iris/bitstream/10665/153544/1/978924150848 3_eng.pdf?ua=1 31 Exhibit List Exhibit 1 (figure) Caption: Estimated number of deaths worldwide due to neonatal tetanus, and global coverage with tetanus toxoid vaccine, 1980-2014 Source: Authors’ analysis of data from the sources listed in the notes below. Notes: Notes: Numbers of estimated number of deaths due to neonatal tetanus are denoted by the blue bars and relate to the left-hand y-axis. Coverage with at least two doses of tetanus toxoid is denoted by the orange line and relate to the right-hand y-axis. Estimated number of deaths were retrieved from the following sources: (1) Roper et al. (Reference 21 in text) for 1980-1994. (2) Khan et al. (Reference 20 in text) for 2000-2013. Tetanus toxoid coverage data was retrieved from the following sources: (1) For 1980-2009: World Health Organization. WHO vaccine-preventable diseases: monitoring system. 2010 global summary. Available from: http://apps.who.int/iris/bitstream/10665/70535/1/WHO_IVB_2010_ eng.pdf (cited 2015 Aug 28). (2) For 2010-2014: World Health Organization. Global and regional immunization profile. 2015. Available from: http://www.who.int/immunization/monitoring_surveillance/data/g s_gloprofile.pdf?ua=1 (cited 2015 Aug 28). 32 Exhibit 2 (figure) Influenza immunization rate among pregnant women and death rate per 100,000 from influenza and pneumonia in the United States, 2001-2013 Source: Authors’ analysis of data from items listed in the notes below. Notes: Influenza immunization rate is denoted by the blue line and relates to the left hand y-axis. Death rate per 100,000 population from influenza and pneumonia for children under 1 year old is denoted by the orange line and relates to the right hand y-axis. Influenza immunization rate data was retrieved from the following sources: (1) Kennedy et al. (Reference 38 in text) for 2001-2010. (2) Ding et al. (Reference 39 in text) for 2011-2013. Death rate from influenza and pneumonia data was retrieved from the Centers for Disease Control and Prevention. Mortality Multiple Causeof-Death. Available from: http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_02.pdf (cited 2015 Nov 4). Exhibit 3 (figure) Caption: Number of pertussis cases in the United States, 19222014 33 Source: Author’s analysis of data from items listed in the notes below. Notes: Number of pertussis cases in the United States from 1922-2014 is denoted by the blue bars and relates to the left hand y-axis. Data was retrieved from Centers for Disease Control and Prevention. Pertussis Cases by Year (1922-2014). Available from: http://www.cdc.gov/pertussis/survreporting/cases-by-year.html (cited 2015 Nov 4). Exhibit 4 (figure) Caption: Number of pertussis cases in the United Kingdom, 1922-2014 Source: Author’s analysis of data from items listed in the notes below. Notes: Number of pertussis cases in the United Kingdom from 1974-2014 is denoted by the blue bars and relates to the left hand y-axis. Data was retrieved from World Health Organization. Global Health Observatory Data Repository. Available from: http://apps.who.int/gho/data/view.main.1540_43?lang=en (cited 2015 Nov 6). 34