Maternal benefits of immunization during pregnancy

The US Centers for Disease Control & Prevention currently recommend routine immunization to prevent 17 vaccine-preventable diseases that occur in infants, children, adolescents, or adults. Pregnant women are at particularly high risk for morbidity and mortality related to several vaccine-preventable diseases. Furthermore, such illnesses are also associated with adverse pregnancy outcomes such as spontaneous abortion, congenital anomalies, preterm birth, and low birthweight. In addition to directly preventing maternal infection, vaccination during pregnancy may offer fetal and infant benefit through passive immunization. Several vaccines aimed at providing passive immunity to neonates are either currently recommended or in development. This article specifically addresses maternal benefits of maternal immunization following (1) vaccines recommended for all pregnant women; (2) vaccines recommended for pregnant women with particular risk factors; and (3) novel vaccines currently under development that primarily aim to at reduce infant morbidity and mortality.     

Maternal immunization against Group B streptococcus: World Health Organization research and development technological roadmap and preferred product characteristics

Group B streptococcus, found in the vagina or lower gastrointestinal tract of about 10–40% of women of reproductive age, is a leading cause of early life invasive bacterial disease, potentially amenable to prevention through maternal immunization during pregnancy. Following a consultation process with global stakeholders, the World Health Organization is herein proposing priority research and development pathways and preferred product characteristics for GBS vaccines, with the aim to facilitate and accelerate vaccine licensure, policy recommendation for wide scale use and implementation.     

Impact of a maternal immunization program against pertussis in a developing country

BackgroundPertussis disease is a growing concern for developing countries. In Argentina, rates of illness and death peaked in 2011. More than 50% of fatalities due to pertussis occurred in infants younger than two months of age, too young for vaccination. In 2012, the government offered immunization with a vaccine containing Tdap to all pregnant women after 20 weeks of gestation with the intent of reducing morbidity and mortality in young infants.MethodsMaternal acellular pertussis vaccine impact on reducing infant disease burden was estimated based on data from the Argentinean Health Surveillance System. We divided Argentinean states in two groups experiencing high (>50) and low (⩽50) Tdap vaccine coverage and compared these two groups using a Bayesian structural time-series model. Low coverage regions were used as a control group, and the time series were compared before and after the implementation of the Tdap program.FindingsWe observed a relative reduction of 51% (95% CI [−67%, −35%]; p = 0.001) in pertussis cases in high coverage states in comparison with the low coverage areas. Analysis of infants between two and six months showed a 44% (95% CI [−66%, −24%]; p = 0.001) reduction in illness. Number of deaths was highest in 2011 with 76 fatalities, for an incidence rate of 2.9 per 100,000. Comparing with 2011, rates decreased by 87% to 10 subjects, or 0.9 per 100,000 in 2013.InterpretationWe show an age-dependent protective effect of maternal Tdap immunization in a developing country for infants younger than six months.     

Maternal immunization with RSV fusion glycoprotein vaccine and substantial protection of neonatal baboons against respiratory syncytial virus pulmonary challenge

Globally, human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infection in infants and young children. There are no licensed vaccines despite the high worldwide disease burden. RSV fusion (F) glycoprotein vaccine is the most advanced candidate for maternal immunization. In this report, a baboon maternal immunization model was used to assess the immunogenicity and protection of infants against pulmonary challenge with human RSV/A. Vaccination in the third trimester produced high anti-RSV F IgG titers and virus-neutralizing antibodies. Infants born to immunized females had high levels of serum RSV antibodies that were comparable to maternal levels at birth and persisted for over 50 days with a half-life of 14–24 days. Furthermore, infants from immunized females and challenged with RSV/A were healthy, developed less severe disease, and had only mild pulmonary inflammatory changes whereas infants born to non-vaccinated females developed more severe disease with marked to moderate interstitial pneumonia, pulmonary edema, and bronchiolar obstruction. These results support the further development of the RSV F vaccine for maternal immunization.     

Maternal immunization – Promises and concerns

In this issue of Vaccine, the maternal immunization platform as an approach to protect mothers and infants against diverse pathogens is presented. Potential vaccine targets and the safety, science, trial designs, ethical considerations, and international perspectives focusing on low and middle income countries (LMIC) are discussed. This information provides a timely update because maternal immunization is increasingly being considered as an intervention to prevent maternal and/or neonatal disease. Prioritization of vaccine targets for maternal immunization by researchers, public health officials and health care workers needs to begin now.     

Multi-tiered intervention to increase maternal immunization coverage: A randomized,controlled trial

ObjectiveTo evaluate the impact of a multi-component intervention package of maternal immunization uptake in obstetric care clinics.MethodsIn a multi-level, cluster- and individually-randomized controlled trial we implemented an evidence-based intervention that targeted practice-, provider- and patient-level barriers to vaccine uptake. Obstetric practices were randomized to receive the practice and provider-level interventions or continue their normal standard of care. We enrolled pregnant women at practices in Georgia and Colorado and randomized women into patient-level intervention and control groups, resulting in four study arms. The primary outcomes were receipt of the influenza and tetanus, diphtheria and acellular pertussis (Tdap) vaccines during pregnancy. A sample size of 550 women per arm (2200 total) was planned and enrolled to compare the intervention between the four study arms.ResultsBetween June 2017 and July 2018, 4907 women were screened and 2200 women were randomized, 550 to each of the four study arms. We were unable to follow-up with 108 women, for a final sample size of 2092. Sample characteristics and sample size were similar among study arms. There was no significant increase in Tdap or influenza vaccine uptake overall. Among women who had no intention of or were unsure about receiving the influenza vaccine during pregnancy, those who received just the patient-level intervention were 61% more likely to receive the influenza vaccine than those in the control arm (Relative risk: 1.61; 95% Confidence Interval: 1.18–2.21). There was no significant difference in vaccine uptake for either influenza or tetanus, diphtheria and acellular pertussis between the four arms of the study.ConclusionsThis trial highlights the need for more targeted interventions to improve vaccine uptake. Future work should focus on clinics with low baseline vaccine uptake and the patient-level intervention should be expanded and targeted towards women with low vaccine confidence.     

Maternal immunization with pneumococcal 9-valent conjugate vaccine and early infant otitis media

A randomized trial of an investigational 9-valent pneumococcal conjugate vaccine (PCV-9) or placebo given to pregnant women during the last trimester to prevent early infant otitis media (OM) was conducted. All infants received Prevnar^® at 2, 4, 6, and 12 months. Clinic and adverse event records were reviewed to identify OM. Variables significantly related to acute OM by age 6 months (p < 0.05) were: vaccine group (9 valent or placebo), sibling history of tympanostomy tubes, upper respiratory infection, and number of clinic visits by 6 months. Infant OM rates were similar between 6 and 12 months (58% and 56%). Results suggested that immunizing pregnant women with PCV-9 increased infants’ risk of acute OM in the first 6 months of life, and this correlated with decreased infant antibody responses to their infant Streptococcus pneumoniae vaccine serotypes, but did not influence antibody responses to 3 other serotypes two of which were in maternal vaccine (types 1 and 5) and one was a control (type 7F). Explanations for these results include dampening of infant antibody production by high levels of passively acquired maternal pneumococcal antibodies and/or altered B lymphocyte immune responses in infants exposed to these specific polysaccharide antigens in utero.     

A systematic review of adverse events following immunization during pregnancy and the newborn period

In 2013, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) requested WHO to develop a process and a plan to move the maternal immunization agenda forward in support of an increased alignment of data safety evidence, public health needs, and regulatory processes. A key challenge identified was the continued need for harmonization of maternal adverse event following immunization (AEFI) research and surveillance efforts within developing and developed country contexts. We conducted a systematic review as a preliminary step in the development of standardized AEFI definitions for use in maternal and neonatal clinical trials, post-licensure surveillance, and other vaccine studies. We documented the current extent and nature of variability in AEFI definitions and adverse event reporting among 74 maternal immunization studies, which reported a total of 240 different types of adverse events. Forty-nine studies provided explicit AEFI case definitions describing 35 separate types of AEFIs. We identified variability in how AEFIs were determined to be present, in how AEFI definitions were applied, and in the ways that AEFIs were reported. Definitions for key maternal/neonatal AEFIs differed on four discrete attributes: overall level of detail, physiological and temporal boundaries and cut-offs, severity strata, and standards used. Our findings suggest that investigators may proactively address these inconsistencies through comprehensive and consistent reporting of AEFI definitions and outcomes in future publications. In addition, efforts to develop standardized AEFI definitions should generate definitions of sufficient detail and consistency of language to avoid the ambiguities we identified in reviewed articles, while remaining practically applicable given the constraints of low-resource contexts such as limited diagnostic capacity and high patient throughput.     

National immunization advisory committees of the World Health Organization's European Region

This study sought to understand the prevalence, structure and decision-making process of national immunization advisory committees (IACs) among the 53 member countries of the World Health Organization (WHO)’s European region. Of the 47 countries responding to the electronically administered questionnaire, 37 (72%) have an IAC. The majority of committees have a legislative basis while just over half have formal terms of reference. Fewer than half have experts in health economics. The vast majority of countries do not allow the public to attend committee meetings nor distribute publicly the minutes of their meetings. Countries should partner with financial experts early in the process of immunization policy decision-making and should examine their policies regarding conflicts of interest and public access to meetings, as financial strategy and public trust are essential to the successful implementation of new vaccines.     

Maternal determinants of complete child immunization among children aged 12-23 months in a southern district of Nigeria

This study was conducted to identify determinants of complete immunization status among children aged 12-23 months in a southern district of Nigeria. The World Health Organization cluster survey was used to evaluate immunization coverage of infants. Mothers of 525 children selected by the two-stage sampling method and interviewed using an adapted questionnaire responded. Completion of the immunization schedule was verified by an immunization card or by reported history indicating that the child had received full doses of four of the antigens included in the Nigeria routine immunization schedule. Multivariate logistic regression was used to identify factors associated with completion of immunization. Only 32.4% of children had completed the immunization schedule. Determinants of complete immunization status included a maternal age less than 30 years (AOR = 2.26, 95% CI:1.27-4.03), availability of an immunization card at first contact (AOR = 7.72, 95% CI:4.43-13.44), fewer than three children (AOR = 2.22, 95% CI:11.1-4.42), completion of post secondary education (AOR = 2.34, 95% CI:1.12-4.47) and maternal unemployment (AOR = 1.71, 95% CI:1.01-2.89). Identifying mothers whose children are at risk of not completing the immunization schedule and educating them is an important strategy to improve antigen coverage and prevent early childhood deaths from diseases like tuberculosis, poliomyelitis, tetanus, diphtheria, pertussis and measles.     

Maternal immunization in Malawi: A mixed methods study of community perceptions,programmatic considerations,and recommendations for future planning

BackgroundSafe, effective vaccines are given to pregnant women to protect their infants and/or themselves against certain infectious agents; however, apart from tetanus vaccination, maternal immunization in low- and middle-income countries (LMICs) remains low. Tetanus toxoid vaccine is integrated into antenatal care services in Malawi with high coverage and provides an opportunity to identify factors that facilitate successful immunization delivery to pregnant women in LMICs.MethodsPATH and the University of Malawi’s Centre for Social Research conducted a mixed-methods study in 2015 to document community perceptions of maternal immunization, using tetanus vaccine as an example, and to identify factors perceived to be important to successfully introducing other maternal vaccines, such as influenza vaccine, in Malawi. We conducted 18 focus group discussions with pregnant and recently pregnant women and their family members and 76 semi-structured interviews with pregnant and recently pregnant women, community leaders, health workers, public health program managers, non-governmental partners, and policy makers.ResultsWe identified factors perceived to support the introduction of new maternal vaccines, including strong maternal vaccine acceptance in the community, an existing strategy for maternal tetanus vaccine delivery, and positive health workers’ views about the introduction of additional maternal vaccines. Potential challenges to adoption and acceptance included identifying and tracking the target population and monitoring adverse events, and the need to ensure operational capacity of the health system to support the introduction and wide-scale use of an additional vaccine. For influenza vaccine specifically, additional challenges included limited awareness of influenza disease and its low prioritization among health needs.ConclusionsLessons from the successful delivery of maternal tetanus immunization in Malawi may be informative for similar countries considering new vaccines for pregnant women or striving to optimize the delivery of those currently provided.     

Maternal immunization with respiratory syncytial virus fusion protein formulated with a novel combination adjuvant provides protection from RSV in newborn lambs

Respiratory syncytial virus (RSV) is the causative agent of serious upper and lower respiratory tract infections in newborns and infants. Protection from RSV is crucial for neonates, and maternal immunization is one approach that holds promise for providing immediate protection to young infants against severe RSV infection. We previously reported efficacy of a subunit vaccine consisting of the fusion (F) protein formulated with a novel adjuvant (ΔF/TriAdj) in neonates. The goal of the current study was to evaluate the ΔF/TriAdj as a maternal vaccine. Pregnant ewes were vaccinated intramuscularly with ΔF/TriAdj or PBS six weeks prior to lambing, and re-vaccinated four weeks later, which resulted in transfer of maternal antibodies (MatAbs) to the newborn lambs through the colostrum. Significantly higher levels of RSV ΔF-specific serum IgG were detected in vaccinated pregnant ewes and their lambs when compared to control animals, which revealed that MatAbs were passively transferred to the offspring. All newborn lambs were challenged with RSV at three days of age. After RSV challenge, virus production and lung pathology were significantly lower in lambs that had received passively transferred antibodies than in control animals. These results indicate that maternal immunization with ΔF/TriAdj might be an alternative, safe and effective approach to provide protection against RSV in newborn and young infants.     

Evaluating the cost-effectiveness of maternal pertussis immunization in low- and middle-income countries: A review of lessons learnt

This issue of Vaccine is devoted to papers from a research project that developed two types of simulation models, static and dynamic transmission, to evaluate the cost-effectiveness of maternal immunization to prevent pertussis in infants in low- and middle-income countries (LMICs). The research was conducted by a multinational team of investigators and funded by the Bill & Melinda Gates Foundation to gain an understanding of when and where maternal immunization might be a good public health investment for LMICs. Here we review the project’s central lessons for vaccine policy and research. Models require a lot of data. As most LMICs lack good data, the models were built using pertussis disease burden data from Brazil, a middle-income country with three long-established, independent information systems (disease surveillance, hospitalization, and mortality), on the hypothesis that the disease process is similar across countries. Values for key parameters, particularly infant mortality, infant vaccine coverage, and costs of vaccination and treatment, were then varied to represent other LMICs. The results show that coverage levels of infant whole cell pertussis (wP) vaccine are key to the cost-effectiveness of maternal pertussis immunization. In settings where infant wP coverage is below the threshold thought necessary to eliminate pertussis in the population, 90–95%, maternal immunization is cost-effective, even cost-saving. By contrast, it is very expensive in countries capable of maintaining infant vaccination in or above the threshold range. The research also suggests that, while static models may serve to explore an intervention’s cost-effectiveness initially, dynamic transmission models are essential for more accurate estimates. These findings can help guide policies toward maternal pertussis immunization, but also show that developing better data on neonatal pertussis mortality burden and infant vaccine coverage in LMICs, and on the duration of immunity of currently available pertussis vaccines, are key priorities to support better vaccine policy.     

乙型肝炎疫苗预防接种与疑似不良反应

乙型肝炎(乙肝)是严重危害我国人群健康的传染病，按照2006年全国乙肝血清流行病学调查结果估算，我国总人群中有34％的人感染过HBV，其中HBsAg携带者约为9 300万，每年有大约26万人由于感染HBV导致肝硬化和原发性肝癌死亡?。HBV可通过母婴、血液和性接触三种途径传播，目前尚无有效治愈乙肝的药物，因此接种疫苗成为控制乙肝的关键。     

Application of Rapid Investigation in Research of Poliomyelitis Intensification immunization rate

采用快速调查法对重点人群口服脊髓质炎疫苗 (Opv)强化免疫接种状况进行调查 ,发现人口流动是导致脊灰疫苗漏报的主要原因 ,漏服与儿童流入该地区的时间长短及家长素质有关。快速调查法是对儿童免疫状况进行督导和采取补救措施的一种好方法。     

中国首部疫苗管理法:用最严制度维护人民身体健康

作为我国第一部关于疫苗管理工作集大成的法律,《中华人民共和国疫苗管理法》具有里程碑式意义。从该法出台的背景与意义,对基层预防接种单位工作的要求等方面进行解读,分析比较该法的条款与既往法律法规的承袭与创新,强调日常接种行为需时刻遵法守法。通过关键内容解读,便于基层预防接种工作人员对该法有个初步认识。在开展免疫规划工作中尽量避免违法行为的发生,最终确保预防接种服务的安全、规范、科学,从而保障和促进公众健康。