Effectiveness of influenza vaccination during pregnancy to prevent severe infection in children under 6 months of age,Spain, 2017–2019

IntroductionInfluenza vaccination is recommended to pregnant women in Spain to reduce the risk of influenza-related complications. Influenza related hospitalizations pose a significant disease burden in children every year. Although children below 6 months are too young to be vaccinated, they can receive protection against influenza through vaccination of their mothers during pregnancy. We estimated the effectiveness of maternal influenza vaccination to prevent influenza hospitalizations in infants under 6 months of age.MethodsThis is a retrospective pilot study, using data from the Severe Hospitalized Confirmed Influenza Cases (SHCIC) surveillance system in seasons 2017/18 and 2018/19 in Spain. Maternal vaccination status during pregnancy was collected for cases in children 6 months and younger hospitalized with confirmed influenza infection. Influenza vaccine effectiveness was estimated using the screening method, by comparing the proportion of children with vaccinated mothers during pregnancy (proportion of cases vaccinated, PCV), with the vaccination coverage among pregnant women in Spain (proportion of population vaccinated, PPV).ResultsFor all the study period, the PCV was 17% and the PPV was 35%. Influenza vaccination in mothers during pregnancy prevented influenza confirmed hospitalizations in infants aged 6 months and younger with a 61% (95%CI: 27–79%) effectiveness.ConclusionsIn line with evidence from other countries, influenza vaccination during pregnancy protects infants up to 6 months of age from influenza hospitalizations in Spain. These results support current recommendations of influenza vaccination in pregnant women, and more studies are needed in Spain to confirm the double protection of maternal vaccination in mothers and infants.     

Vaccination during pregnancy to protect infants against influenza: why and why not?

Influenza is a significant cause of morbidity and mortality for pregnant women and infants worldwide. Influenza vaccination during pregnancy has been shown to be safe and highly effective and should be recommended for all pregnant women before the influenza season. Despite existing recommendations, the vaccine is underused in most countries. Obstacles to immunization include insufficient awareness of the disease burden and of the importance and safety of immunization, fear of liability and the wish to minimize interventions during pregnancy. Therefore, educational interventions for the public and health care workers are necessary to increase protection of pregnant women and young infants from influenza related complications.     

Influenza epidemiology and immunization during pregnancy: Final report of a World Health Organization working group

From 2014 to 2017, the World Health Organization convened a working group to evaluate influenza disease burden and vaccine efficacy to inform estimates of maternal influenza immunization program impact. The group evaluated existing systematic reviews and relevant primary studies, and conducted four new systematic reviews. There was strong evidence that maternal influenza immunization prevented influenza illness in pregnant women and their infants, although data on severe illness prevention were lacking. The limited number of studies reporting influenza incidence in pregnant women and infants under six months had highly variable estimates and underrepresented low- and middle-income countries. The evidence that maternal influenza immunization reduces the risk of adverse birth outcomes was conflicting, and many observational studies were subject to substantial bias. The lack of scientific clarity regarding disease burden or magnitude of vaccine efficacy against severe illness poses challenges for robust estimation of the potential impact of maternal influenza immunization programs.     

Report of the WHO technical consultation on the effect of maternal influenza and influenza vaccination on the developing fetus: Montreal,Canada, September 30–October 1, 2015

In 2012, the World Health Organization (WHO) released a position paper on influenza vaccination recommending that pregnant women have the highest priority for seasonal vaccination in countries where the initiation or expansion of influenza immunization programs is under consideration. Although the primary goal of the WHO recommendation is to prevent influenza illness in pregnant women, the potential benefits of maternal immunization in protecting young infants are also recognized. The extent to which maternal influenza vaccination may prevent adverse birth outcomes such as preterm birth or small-for-gestational-age birth, however, is unclear as available studies are in disagreement.To inform WHO about the empirical evidence relating to possible benefits of influenza vaccination on birth outcomes, a consultation of experts was held in Montreal, Canada, September 30–October 1, 2015. Presentations and discussions covered a broad range of issues, including influenza virus infection during pregnancy and its effect on the health of the mother and the fetus, possible biological mechanisms for adverse birth outcomes following maternal influenza illness, evidence on birth outcomes following influenza illness during pregnancy, evidence from both observational studies and randomized controlled trials on birth outcomes following influenza vaccination of pregnant women, and methodological issues. This report provides an overview of the presentations, discussions and conclusions.     

Influenza vaccine for pregnant women in resource-constrained countries: a review of the evidence to inform policy decisions

Seasonal influenza is responsible for three to five million severe cases of disease annually, and up to 500,000 deaths worldwide. Pregnant women and infants suffer disproportionately from severe outcomes of influenza. The excellent safety profile and reliable immunogenicity of inactivated influenza vaccine support WHO recommendations that pregnant women be vaccinated to decrease complications of influenza disease during pregnancy. Nevertheless, influenza vaccine is not routinely used in most low-and middle-income countries and is not widely used in pregnant women worldwide.Two recent prospective, controlled trials of maternal influenza vaccination in Bangladesh and US Native American reservations demonstrated that inactivated influenza vaccine given to pregnant women can decrease laboratory-confirmed influenza virus infection in their newborn children. These studies support consideration of the feasibility of targeted influenza vaccine programs in resource-constrained countries.Platforms exist for the delivery of influenza vaccine to pregnant women worldwide. Even in the least developed countries, an estimated 70% of women receive antenatal care, providing an opportunity for targeted influenza vaccination. Challenges to the introduction of maternal influenza vaccination in resource-constrained countries exist, including issues regarding vaccine formulation, availability, and cost. Nonetheless, maternal influenza vaccination remains an important and potentially cost-effective approach to decrease influenza morbidity in two high-risk groups - pregnant women and young infants.     

Maternal immunization: US FDA regulatory considerations

Vaccination of pregnant women provides important health benefits to both, mother and infant, and has been an important disease prevention strategy in these two groups. While most vaccines currently licensed in the US are not indicated for use during pregnancy, depending on the vaccine, vaccination programs do frequently include pregnant women. In addition, recent emphasis has been placed on maternal immunization strategies to protect young infants from severe infections. Currently, unless the vaccine is specifically indicated four maternal immunization, no data are collected regarding the vaccine's safety in pregnant women prior to licensure. However, more females of childbearing age participate in clinical trials and a broad range of novel vaccine products are in development indicated for adolescents and adults. Thus, there is increasing concern for the unintentional exposure of an embryo/fetus before information is available regarding the potential risk versus benefit of the vaccine. Since pregnant women are usually excluded from participation in clinical trials, conclusions regarding developmental risk at the time of licensure are frequently based solely on data derived from developmental toxicity studies in animal models. This paper will review regulatory, preclinical and clinical issues as they pertain to development programs for vaccines intended for vaccination during pregnancy.     

Interventions to increase the uptake of seasonal influenza vaccination among pregnant women: A systematic review

BackgroundPregnant women and their infants under 6 months of age infected with influenza have a high risk of serious morbidity and mortality. Influenza vaccine during pregnancy offers 3-for-1 benefits to pregnant women, fetuses and newborn infants. Current vaccination uptake rates during pregnancy, however, are often lower than other high-risk groups and the general population.MethodsWe systematically reviewed evidence on the effectiveness of interventions to improve influenza vaccination coverage in pregnant women. Risk differences (RDs) were calculated from the included studies.ResultsEleven studies were included in the review, of which four were randomized controlled trials (RCTs). Three cohort studies assessed provider-focused interventions while four RCTs and one cohort study evaluated pregnant women-focused interventions. Two cohort studies and a prospective intervention study assessed the effectiveness of bundled interventions. No study solely assessed the effectiveness of interventions to enhance access to influenza vaccination. One moderate quality RCT showed that an influenza pamphlet, with or without a verbalized benefit statement, improved the vaccination rate (RD = 0.26; RD = 0.39). The other reviewed RCTs showed discordant results, with RDs ranging from −0.15 to 0.03. Although all observational studies significantly improved vaccination rates (RDs ranged from 0.03 to 0.44), the quality of the evidence varied.ConclusionsThere is a lack of effective interventions to increase the influenza vaccination rate in pregnant women. Based on the existing research, we recommend that clinicians provide influenza pamphlets to pregnant women with a verbalized statement about the benefits of influenza vaccine to newborns. Further high-quality RCTs are needed to develop successful maternal influenza vaccination programs. Increased clarity in reporting the content of interventions would help to improve the comparability and generalizability of the published studies.     

Implementation of maternal influenza immunization in El Salvador: Experiences and lessons learned from a mixed-methods study

IntroductionThe World Health Organization (WHO) recommends that countries prioritize pregnant women for influenza vaccination, yet few low- or middle-income countries (LMICs) have implemented maternal influenza immunization programs. To inform vaccine decision-making and operational planning in LMICs, there is a need to document and share experiences from countries that provide seasonal influenza vaccine to pregnant women, particularly those with high coverage, like El Salvador.MethodsIn 2015 and 2016, PATH and country researchers conducted a mixed-methods study to document the experience and lessons learned from maternal influenza immunization delivery and acceptance in El Salvador as part of a collaborative effort between WHO and PATH. Researchers conducted focus group discussions, semi-structured interviews, antenatal clinic exit interviews, and key informant interviews with 326 participants from two municipalities in each of the country’s three regions. Respondents included pregnant and recently pregnant women, family members, community leaders, health personnel, public health managers and partners, and policymakers.ResultsFactors perceived as positively influencing maternal influenza immunization delivery and acceptance in El Salvador include the use of multiple vaccine delivery strategies, targeted education and community engagement efforts, and a high degree of trust between the community and health care providers. Influenza vaccine acceptance by pregnant women is high and has improved over time, largely attributed to education targeting health care advisors. Perceived challenges to pregnant women receiving health care and vaccination include the need for permission to attend services and limited access to health services in insecure areas related to the presence of criminal gang activity.ConclusionsWe identified approaches and barriers perceived to affect maternal influenza vaccine delivery in El Salvador. This information will be useful to public health decision-makers and implementers in El Salvador and other countries considering introduction of new maternal vaccines or striving to increase coverage of vaccines currently provided.     

The effectiveness of influenza vaccination in pregnancy in relation to child health outcomes: Systematic review and meta-analysis

ObjectivesTo determine the effectiveness of influenza vaccination during pregnancy on child health outcomes.DesignSystematic review/meta-analysis.Data sourcesClinical Trials.gov, Cochrane Library, EMBASE, Medline, Medline in process, PubMed and Web of Science, from 1st January 1996 to 29th June 2018. An updated Medline search was performed 30th June 2018 to 31st October 2019.MethodsRandomised controlled trials (RCTs) and observational studies reporting health outcomes of infants and children born to women who received inactivated influenza vaccine during pregnancy. The primary outcome was infant laboratory confirmed influenza (LCI). Secondary outcomes included influenza-like illness (ILI), other respiratory illnesses, primary care, clinic visit or hospitalisations due to influenza illness and long-term respiratory childhood outcomes.Results19 studies were included; 15 observational studies and 4 primary RCTs with an additional 3 papers reporting secondary outcomes of these RCTs. In a random effects meta-analysis of 2 RCTs including 5742 participants, maternal influenza vaccination was associated with an overall reduction of LCI in infants of 34% (95% confidence interval 15–50%). However, there was no effect of maternal influenza vaccination on ILI in infants ≤6 months old. Two RCTs were excluded from the meta-analysis for the outcome of LCI in infants (different controls used). Both of these studies showed a protective effect for infants from LCI, with a vaccine efficacy of up to 70%.Overall observational studies showed an inverse (protective) association between maternal influenza vaccination and infant LCI, hospitalisation and clinic visits due to LCI or ILI in infants and other respiratory illness in infants ≤6 months old.ConclusionsThis systematic review supports maternal influenza vaccination as a strategy to reduce LCI and influenza-related hospitalisations in young infants. Communicating these benefits to pregnant women may support their decision to accept influenza vaccination in pregnancy and increase vaccine coverage in pregnant women.RegistrationPROSPERO CRD42018102776.     

Meeting report: CEPI consultation on accelerating access to novel vaccines against emerging infectious diseases for pregnant and lactating women,London, 12–13 February 2020

Infectious diseases may cause serious morbidity and mortality in pregnant women, their foetuses, and infants; the risk associated with any newly emerging infectious disease (EID) is likely unknown at the time of its emergence. While the ongoing SARS-CoV-2 pandemic shows that the development of vaccines against new pathogens can be considerably accelerated, the immunization of pregnant women generally lags behind the general population. Guided by the priority pathogen list for WHO’s R&D Blueprint for Action to Prevent Epidemics, this workshop sought to define the evidence needed for use of vaccines against EIDs in pregnant and lactating women, using Lassa fever as a model. Close to 60 maternal immunization (MI) and vaccine safety experts, regulators, vaccine developers, Lassa fever experts, and investigators from Lassa-affected countries examined the critical steps for vaccine development and immunization decisions for pregnant and lactating women. This paper reports on key themes and recommendations from the workshop.Current practice still assumes the exclusion of pregnant women from early vaccine trials. A shift in paradigm is needed to progress towards initial inclusion of pregnant women in Phase 2 and 3 trials. Several practical avenues were delineated. Participants agreed that vaccine platforms should be assessed early for their suitability for maternal immunization. It was noted that, in some cases, nonclinical data derived from assessing a given platform using other antigens may be adequate evidence to proceed to a first clinical evaluation and that concurrence from regulators may be sought with supporting rationale. For clinical trials, essential prerequisites such as documenting the disease burden in pregnant women, study site infrastructure, capabilities, and staff experience were noted. Early and sustained communication with the local community was considered paramount in any program for the conduct of MI trials and planned vaccine introduction.     

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.     

Obstetrics risk Assessment: Evaluation of selection criteria for vaccine research studies in pregnant women

Vaccines designed for use in pregnancy and vaccine trials specifically involving pregnant women are rapidly expanding. One of the key challenges in designing maternal immunization trials is that developing exclusion criteria requires understanding and quantifying the background risk for adverse pregnancy outcomes in the pregnancy being studied, which can occur independent of any intervention and be unrelated to vaccine administration.The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project has developed and published case definitions and guidelines for data collection, analysis, and evaluation of maternal immunization safety in trials involving pregnant women. Complementing this work, we sought to understand how to best assess obstetric risk of adverse outcomes and differentiate it from the assessment of vaccine safety. Quantification of obstetric risk is based on prior and current obstetric, and maternal medical history. We developed a step-wise approach to evaluate and quantify obstetric and maternal risk factors in pregnancy based on review of published literature and guidelines, and critically assessed these factors in the context of designing inclusion and exclusion criteria for maternal vaccine studies. We anticipate this risk assessment evaluation may assist clinical trialists with study design decisions, including selection of exclusion criteria for vaccine trials involving pregnant women, consideration of sub-group classification, such as high or low risk subjects, or schedule considerations, such as preferred trimester of gestation for an intervention during pregnancy. Additionally, this tool may be utilized in data stratification at time of study analyses.     

Effectiveness of seasonal trivalent influenza vaccination against hospital-attended acute respiratory infections in pregnant women: A retrospective cohort study

BackgroundPregnant women are at risk of serious influenza infection. Although previous studies indicate maternal influenza vaccination can prevent hospitalisation in young infants, there is limited evidence of the effect in mothers.MethodsA cohort of 34,701 pregnant women delivering between 1 April 2012 and 31 December 2013 was created using birth records. Principal diagnosis codes from hospital emergency department (ED) and inpatient records were used to identify episodes of acute respiratory illness (ARI) during the 2012 and 2013 southern hemisphere influenza seasons. Cox regression models were used to calculate adjusted hazard ratios (aHRs) by maternal vaccination status, controlling for Indigenous status, socioeconomic level, medical conditions, and week of delivery.Results3,007 (8.7%) women received a seasonal influenza vaccine during pregnancy. Vaccinated women were less likely to visit an ED during pregnancy for an ARI (9.7 visits per 10,000 person-days vs. 35.5 visits per 10,000 person-days; aHR: 0.19, 95% CI: 0.05−0.68). Vaccinated women were also less likely to be hospitalised with an ARI compared to unvaccinated women (16.2 hospitalisations per 10,000 person-days vs. 34.0 hospitalisations per 10,000 person-days; aHR: 0.35, 95% CI: 0.13−0.97).ConclusionsInfluenza vaccination during pregnancy was associated with significantly fewer hospital attendances for ARI in pregnant women.     

Cost-effectiveness of seasonal inactivated influenza vaccination among pregnant women

ObjectiveTo evaluate the cost-effectiveness of seasonal inactivated influenza vaccination among pregnant women using data from three recent influenza seasons in the United States.Design, setting, and participantsWe developed a decision-analytic model following a cohort of 5.2 million pregnant women and their infants aged <6 months to evaluate the cost-effectiveness of vaccinating women against seasonal influenza during pregnancy from a societal perspective. The main outcome measures were quality-adjusted life-year (QALY) gained and cost-effectiveness ratios. Data sources included surveillance data, epidemiological studies, and published vaccine cost data. Sensitivity analyses were also performed. All costs and outcomes were discounted at 3% annually.Main outcome measuresTotal costs (direct and indirect), effects (QALY gains, averted case numbers), and incremental cost-effectiveness of seasonal inactivated influenza vaccination among pregnant women (cost per QALY gained).ResultsUsing a recent benchmark of 52.2% vaccination coverage among pregnant women, we studied a hypothetical cohort of 2,753,015 vaccinated pregnant women. With an estimated vaccine effectiveness of 73% among pregnant women and 63% among infants <6 months, QALY gains for each season were 305 (2010–2011), 123 (2011–2012), and 610 (2012–2013). Compared with no vaccination, seasonal influenza vaccination during pregnancy was cost-saving when using data from the 2010–2011 and 2012–2013 influenza seasons. The cost-effectiveness ratio was greater than $100,000/QALY with the 2011–2012 influenza season data, when CDC reported a low attack rate compared to other recent seasons.ConclusionsInfluenza vaccination for pregnant women can reduce morbidity from influenza in both pregnant women and their infants aged <6 months. Seasonal influenza vaccination during pregnancy is cost-saving during moderate to severe influenza seasons.     

Maternal immunization efforts of the National Institutes of Health

Over the last 35 years, efforts at the National Institutes of Health (NIH) to protect mothers and their infants against infectious diseases have involved a bench-to-bedside approach. Basic and translational research that provided a foundation for clinical trials of vaccines in pregnancy include natural history and vaccine antigen identification studies. Development of laboratory assays and reagents have been funded by NIAID; these are critical for the advancement of vaccine candidates through the preclinical and clinical steps along the maternal immunization research pathway to support vaccine efficacy. Animal models of maternal immunization have been developed to evaluate efficacy of vaccine candidates. Clinical studies required development of maternal immunization protocols to address specific pregnancy related issues, for enrollment and safety assessment of mothers and their infants. NIH has organized and participated in meetings, workshops and other collaborative efforts with partners have advanced maternal immunization efforts. Partners have included many institutes and offices at NIH as well as other Department of Health and Human Services agencies and offices (Food and Drug Administration, Centers for Disease Control and Prevention, National Vaccine Program Office), World Health Organization, academic investigators, Biotech and pharmaceutical companies, and nonprofit organizations such as the Bill and Melinda Gates Foundation. These research and development partnership are essential for advancing maternal immunization. Continued efforts are needed to promote maternal immunization to protect pregnant women and their infants against vaccine-preventable infectious disease, especially in resource-limited settings where the burden of infections is high.     

Translating vaccine policy into action: A report from the Bill & Melinda Gates Foundation Consultation on the prevention of maternal and early infant influenza in resource-limited settings

Immunization of pregnant women against influenza is a promising strategy to protect the mother, fetus, and young infant from influenza-related diseases. The burden of influenza during pregnancy, the vaccine immunogenicity during this period, and the robust influenza vaccine safety database underpin recommendations that all pregnant women receive the vaccine to decrease complications of influenza disease during their pregnancies. Recent data also support maternal immunization for the additional purpose of preventing disease in the infant during the first six months of life.     

Does influenza vaccination improve pregnancy outcome? Methodological issues and research needs

Evidence that influenza vaccination during pregnancy is safe and effective at preventing influenza disease in women and their children through the first months of life is increasing. Several reports of reduced risk of adverse outcomes associated with influenza vaccination have generated interest in its potential for improving pregnancy outcome. Gavi, the Vaccine Alliance, estimates maternal influenza immunization programs in low-income countries would have a relatively modest impact on mortality compared to other new or under-utilized vaccines, however the impact would be substantially greater if reported vaccine effects on improved pregnancy outcomes were accurate. Here, we examine the available evidence and methodological issues bearing on the relationship between influenza vaccination and pregnancy outcome, particularly preterm birth and fetal growth restriction, and summarize research needs. Evidence for absence of harm associated with vaccination at a point in time is not symmetric with evidence of benefit, given the scenario in which vaccination reduces risk of influenza disease and, in turn, risk of adverse pregnancy outcome. The empirical evidence for vaccination preventing influenza in pregnant women is strong, but the evidence that influenza itself causes adverse pregnancy outcomes is inconsistent and limited in quality. Studies of vaccination and pregnancy outcome have produced mixed evidence of potential benefit but are limited in terms of influenza disease assessment and control of confounding, and their analytic methods often fail to fully address the longitudinal nature of pregnancy and influenza prevalence. We recommend making full use of results of randomized trials, re-analysis of existing observational studies to account for confounding and time-related factors, and quantitative assessment of the potential benefits of vaccination in improving pregnancy outcome, all of which should be informed by the collective engagement of experts in influenza, vaccines, and perinatal health.     

Racial disparities in influenza immunization during pregnancy in the United States: A narrative review of the evidence for disparities and potential interventions

Objective: The objectives of this review were to summarize existing data on racial disparities in maternal immunization for influenza in the U.S. and to review the literature on interventions to improve the uptake of the influenza vaccine among Black pregnant women.Data Sources: U.S. survey data on maternal influenza immunization by racial and ethnic group were summarized in narrative form. To review intervention studies, PubMed, CINAHL, EMBASE, and the Cochrane Library databases were searched for English language articles published 2017 to 2021, in addition to studies identified by a previous systematic review.Study Eligibility Criteria: Peer-reviewed studies conducted in the U.S. and reporting interventions designed to increase the uptake of the influenza vaccine in pregnancy with study populations including at least 20% of participants identifying as Black were included.Study Appraisal and Synthesis Methods: Studies were grouped and reviewed in a narrative manner according to whether they were conducted in predominantly Black populations or in more racially diverse populations, and whether they tested multicomponent or single-component interventions.Results: A decade of survey data show that Black women in the U.S. consistently have the lowest rate of influenza immunization in pregnancy. Black women report a lower rate of being recommended or offered the vaccine, and provider recommendation is associated with greater vaccine uptake. Intervention studies to increase influenza immunization among Black pregnant women have reported mixed results. Successful interventions include multicomponent practice-based interventions, group prenatal care, and culturally competent patient educational messages.Conclusions: Racial disparities in maternal uptake of the influenza vaccine are long-standing, but not intractable. More research is needed to test interventions to address this disparity, with a focus on increasing provider recommendation and offer of the vaccine, addressing patients’ concerns about vaccine safety and efficacy, improving providers’ cultural competence, and building trust between providers and patients.     

Malaria vaccine trials in pregnant women: An imperative without precedent

Pregnant women are highly susceptible to Plasmodium falciparum malaria, leading to substantial maternal, perinatal, and infant mortality. While malaria vaccine development has made significant progress in recent years, no trials of malaria vaccines have ever been conducted in pregnant women. In December 2016, an expert meeting was convened at NIAID, NIH, in Rockville, Maryland to deliberate on the rationale and design of malaria vaccine trials in pregnant women. The discussions highlighted the progress made over recent years in the field of maternal immunization for other infectious diseases, and the evolving regulatory and ethical environment, all of which support a new emphasis on testing malaria vaccines that offer direct benefits to pregnant women. Initial safety and immunogenicity studies of malaria vaccines will be conducted in non-pregnant adult volunteers. Subsequently, efficacy trials involving pregnant women will likely be conducted in malaria-endemic and often resource-poor environments where sufficiently high malaria incidence will allow vaccine activity to be measured. Such trials will need to meet all international standards to ensure the safety of mother and offspring, under oversight of appropriate ethical and regulatory bodies. The convened experts drafted a clinical development plan to test a malaria vaccine product during pregnancy, using as a case study PfSPZ Vaccine being developed by Sanaria Inc. that is currently in phase 2 testing. Following the expert recommendations, a pregnancy registry has been initiated in Ouelessebougou, Mali, to provide baseline information on maternal and fetal outcomes as a context for evaluating PfSPZ Vaccine safety in the future, and new regimens are being assessed that will be suitable for evaluation in pregnant women.