Pregnant women's perceptions of risks and benefits when considering participation in vaccine trials

IntroductionDespite historical exclusion, there has been recent recognition of the need to address the health of pregnant women in research on vaccines against emerging pathogens. However, pregnant women’s views and decision-making processes about vaccine research participation during infectious disease outbreaks remain underexplored. This study aims to examine women’s decision-making processes around vaccine research participation during infectious disease outbreaks.MethodsWe conducted qualitative semi-structured in-depth interviews with pregnant and recently pregnant women (n = 13), eliciting their views on four hypothetical Zika Virus vaccine research scenarios and probing their decision-making processes around participation. After recorded interviews were transcribed, thematic analysis was conducted based on a priori and emergent themes.ResultsMost women interviewed were accepting of vaccine research scenarios. Three broad themes—evidence, risk, and trust—characterized women’s decision-making processes. Women varied in how different types and levels of evidence impacted their considerations, which risks were most salient to their decision-making processes, and from whom they trusted recommendations about vaccine research participation. Exemplary quotes from each theme are presented, and lessons for vaccine development during the current COVID-19 pandemic and future outbreaks are discussed.ConclusionSome pregnant women are accepting of participation in vaccine research during infectious disease outbreaks. Incorporating their priorities into trial design may facilitate their participation and generation of evidence for this important population.     

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.     

Prophylaxis and treatment of pregnant women for emerging infections and bioterrorism emergencies

Emerging infectious disease outbreaks and bioterrorism attacks warrant urgent public health and medical responses. Response plans for these events may include use of medications and vaccines for which the effects on pregnant women and fetuses are unknown. Healthcare providers must be able to discuss the benefits and risks of these interventions with their pregnant patients. Recent experiences with outbreaks of severe acute respiratory syndrome, monkeypox, and anthrax, as well as response planning for bioterrorism and pandemic influenza, illustrate the challenges of making recommendations about treatment and prophylaxis for pregnant women. Understanding the physiology of pregnancy, the factors that influence the teratogenic potential of medications and vaccines, and the infection control measures that may stop an outbreak will aid planners in making recommendations for care of pregnant women during large-scale infectious disease emergencies.     

Development of orphan vaccines: an industry perspective

The development of vaccines against rare emerging infectious diseases is hampered by many disincentives. In the face of growing in-house expenditures associated with research and development projects in a complex legal and regulatory environment, most pharmaceutical companies prioritize their projects and streamline their product portfolio. Nevertheless, for humanitarian reasons, there is a need to develop niche vaccines for rare diseases not preventable or curable by other means. The U.S. Orphan Drug Act of 1983 and a similar proposal from the European Commission (currently under legislative approval) provide financial and practical incentives for the research and development of drugs to treat rare diseases. In addition, updated epidemiologic information from experts in the field of emerging diseases; increased disease awareness among health professionals, patients, and the general public; a list of priority vaccines; emergence of a dedicated organization with strong leadership; and the long-term pharmacoeconomic viability of orphan products will be key factors in overcoming the complexity of orphan status and the limited need for vaccine.     

Quality vaccines for all people: Report on the 16th annual general meeting of the Developing Countries Vaccine Manufacturers' Network, 05–07th October 2015, Bangkok,Thailand

The Developing Countries Vaccine Manufacturers Network (DCVMN) assembled high-profile leaders from global health organisations and vaccine manufactures for its 16th Annual General Meeting to work towards a common goal: providing quality vaccines for all people.Vaccines contribute to a healthy community and robust health system; the Ebola outbreak has raised awareness of the threat and damage one single infectious disease can make, and it is clear that the world was not prepared. However, more research to better understand emerging infectious agents might lead to suitable vaccines which help prevent future outbreaks.DCVMN members presented their progress in developing novel vaccines against Dengue, HPV, Chikungunya, Cholera, cell-based influenza and other vaccines, demonstrating the commitment towards eliminating and eradicating preventable diseases worldwide through global collaboration and technology transfer. The successful introduction of novel Sabin-IPV and Oral Cholera vaccine in China and Korea respectively in 2015 was highlighted.In order to achieve global immunisation, local authorities and community leaders play an important role in the decision-making in vaccine introduction and uptake, based on the ability of vaccines to protect vaccinated people and protect non-vaccinated in the community through herd immunity. Reducing the risk of vaccine shortages can also be achieved by increasing regulatory convergence at regional and international levels. Combatting preventable diseases remains challenging, and collective efforts for improving multi-centre clinical trials, creating regional vaccine security strategies, fostering developing vaccine markets and procurement, and building trust in vaccines were discussed.     

A socio-ecological exploration to identify factors influencing the COVID-19 vaccine decision-making process among pregnant and lactating women: Findings from Kenya

The vaccine decision-making process of pregnant and lactating women is complex. Regarding COVID-19, pregnant women are at increased risk for severe disease and poor health outcomes. While pregnant and lactating women were excluded from COVID-19 vaccine trials, available evidence suggests that COVID-19 vaccines are safe and protective during pregnancy. In this study, we used a socio-ecological approach to explore factors influencing the decision-making process for COVID-19 vaccines in pregnant and lactating women in Kenya, for the purpose of informing demand generation strategies. As pregnant and lactating women are influenced by many factors, we conducted 84 in-depth interviews with a variety of stakeholders, including 31 pregnant or lactating women, 20 healthcare workers such as nurses, midwives, doctors, and frontline workers, 25 male family members of pregnant or lactating women, and 8 gatekeepers such as community leaders and faith-based leaders. These individuals were recruited from six communities in Kenya: three urban, and three rural. We applied a grounded theory approach to identify emerging themes and organized emerging themes using the SAGE Vaccine Hesitancy model, which includes three categories of determinants of vaccine acceptance, including contextual influences, individual and group influences, and vaccine and vaccination specific issues. Myths, interpersonal norms, and religion emerged as themes related to contextual influences. Safety, risk perception, and the role of the healthcare worker emerged as themes related to individual and group influences. For vaccine and vaccination specific issues, emerging themes included availability, accessibility, and eligibility. While maternal immunization can substantially reduce the effect of infectious diseases in mothers and infants, vaccine acceptance is critical. However, vaccines do not save lives; vaccination does. We hope the results of this study can be used to tailor communication efforts to increase vaccine demand among pregnant and lactating women.     

Vaccines for emerging infections

Emerging infectious diseases represent a grave threat to animal and human populations in terms of their impact on global health, agriculture and the economy. Vaccines developed for emerging infections in animals can protect animal health and prevent transmission of zoonotic diseases to humans. Examples in this paper illustrate how industry and public health can collaborate to develop a vaccine to prevent an emerging disease in horses (West Nile virus vaccine), how poultry vaccination can protect animals and prevent transmission to people (avian influenza vaccine), how regulatory changes can pave the way for vaccines that will control the carrier state in animals and thus prevent infection in humans (Bartonella henselae vaccine in cats) and how novel technologies could be applied to vaccinate wildlife reservoir species for rabies. Stemming from the realisation that zoonotic diseases are the predominant source of human emerging infectious diseases, it behoves academic, public health, and animal health agencies to consider creative constructive approaches to combat serious public health challenges. Vaccination of vector/reservoir species, when efficacious vaccines are available, offers significant advantages to combating zoonotic human disease.     

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.     

Gonococcal vaccines: Public health value and preferred product characteristics; report of a WHO global stakeholder consultation,January 2019

Renewed interest in developing vaccines against Neisseria gonorrhoeae has been sparked by the increasing threat of gonococcal antimicrobial resistance (AMR) and growing optimism that gonococcal vaccines are biologically feasible. Evidence suggests serogroup B Neisseria meningitidis vaccines might provide some cross-protection against N. gonorrhoeae, and new gonococcal vaccine candidates based on several approaches are currently in preclinical development. To further stimulate investment and accelerate development of gonococcal vaccines, greater understanding is needed regarding the overall value that gonococcal vaccines might have in addressing public health and societal goals in low-, middle-, and high-income country contexts and how future gonococcal vaccines might be accepted and used, if available. In January 2019, the World Health Organization (WHO) convened a multidisciplinary international group of experts to lay the groundwork for understanding the potential health, economic, and societal value of gonococcal vaccines and their likely acceptance and use, and for developing gonococcal vaccine preferred product characteristics (PPCs). WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper describes the main discussion points and conclusions from the January 2019 meeting of experts. Participants emphasized the need for vaccines to control N. gonorrhoeae infections with the ultimate goals of preventing adverse sexual and reproductive health outcomes (e.g., infertility) and reducing the impact of gonococcal AMR. Meeting participants also discussed important PPC considerations (e.g., vaccine indications, target populations, and potential immunization strategies) and highlighted crucial research and data needs for guiding the value assessment and PPCs for gonococcal vaccines and advancing gonococcal vaccine development.     

Safety of immunization during pregnancy: A review of the evidence of selected inactivated and live attenuated vaccines

Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus.This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines.     

Review of prescribing information for influenza vaccines for pregnant and lactating women

Information provided by most influenza vaccine manufacturers do not reflect the recommendations of WHO and/or national public health advisory groups with regard to the use of influenza vaccines in pregnant or lactating women. The majority of vaccines contain precautionary language which could discourage use in pregnant women and some include stronger language discouraging or contradicting use in pregnant or lactating women. Regulators and manufacturers should regularly assess the language of pregnancy and lactation sections in product information for vaccines and include information from national public health advisory groups regarding use by pregnant or lactating women and data from relevant studies.     

COVID-19 vaccine decision-making among pregnant and lactating women in Bangladesh

Pregnant and lactating women’s vaccine decision-making process is influenced by many factors. Pregnant women were at increased risk for severe disease and poor health outcomes from COVID-19 at various time points during the pandemic. COVID-19 vaccines have been found to be safe and protective during pregnancy and while breastfeeding. In this study, we sought to examine key factors that informed the decision-making process among pregnant and lactating women in Bangladesh. We conducted 24 in-depth interviews, with 12 pregnant and 12 lactating women. These women were from three communities in Bangladesh: one urban community, and two rural communities. We used a grounded theory approach to identify emerging themes and organized emerging themes using a socio-ecological model. The socio-ecological model suggests that individuals are influenced by many levels, including individual-level influences, interpersonal-level influences, health care system-level influences, and policy-level influences. We found key factors at each socio-ecological level that influenced the decision-making process of pregnant and lactating women, including perceived benefits of vaccines and vaccine safety (individual-level), the influence of husbands and peers (interpersonal-level), health care provider recommendations and vaccine eligibility (health care system-level), and vaccine mandates (policy-level). As vaccination can reduce the effect of COVID-19 disease in mothers, infants, and unborn children, targeting critical factors that inform the decision-making process is paramount for improving vaccine acceptance. We hope the results of this study will inform vaccine acceptance efforts to ensure that pregnant and lactating women take advantage of this life-saving intervention.     

The concept of "tailor-made", protein-based, outer membrane vesicle vaccines against meningococcal disease

Protein-based, outer membrane vesicle (OMV) vaccines have previously proven to be efficacious against serogroup B meningococcal disease in Norway and Cuba. Currently, a public health intervention is going on in order to control a serogroup B epidemic in New Zealand. The scale-up and standardization of vaccine production required for controlling the New Zealand epidemic has allowed the establishment of large-scale GMP manufacturing for OMV vaccines. The outcome of this will be licensing of the vaccine in New Zealand and possibly other countries. The availability of licensed OMV vaccines raises the question of whether such vaccines may provide the opportunity to control other outbreaks and epidemics. For instance, such a vaccine could control a localised outbreak of group B meningococci in Normandy, France. "Tailor-made" vaccines, focusing on the sub-capsular antigens may also be considered for use in sub-Saharan Africa for the prevention of the recurrent outbreaks by serogroups A and W135 meningococci. This assumption is based on the epidemiological observation that meningococcal outbreaks in Africa are clonal and are strikingly stable regarding their phenotypic characteristics.     

新型冠状病毒疫苗:现状与展望

 新型冠状病毒肺炎的大流行严重威胁人类健康和发展,为应对这一全球性公共卫生事件,多种技术路线的新型冠状病毒疫苗（新冠疫苗）被投入紧急使用。本文介绍了新冠疫苗技术路线,并就新冠疫苗应对多种突变毒株的效力和在高危人群中的使用进行了梳理,发现现有疫苗对突变毒株效力出现了不同程度的下降,提示应关注突变毒株的影响。现有疫苗对高龄,孕妇等高风险人群缺乏足够的临床数据,应尽快开展针对高风险人群接种疫苗的相关研究。     

The repeated setbacks of HIV vaccine development laid the groundwork for SARS-CoV-2 vaccines

The decades-long effort to produce a workable HIV vaccine has hardly been a waste of public and private resources. To the contrary, the scientific know-how acquired along the way has served as the critical foundation for the development of vaccines against the novel, pandemic SARS-CoV-2 virus. We retell the real-world story of HIV vaccine research – with all its false leads and missteps – in a way that sheds light on the current state of the art of antiviral vaccines. We find that HIV-related R&D had more than a general spillover effect. In fact, the repeated failures of phase 2 and 3 clinical trials of HIV vaccine candidates have served as a critical stimulus to the development of successful vaccine technologies today. We rebut the counterargument that HIV vaccine development has been no more than a blind alley, and that recently developed vaccines against COVID-19 are really descendants of successful vaccines against Ebola, MERS, and SARS. These successful vaccines likewise owe much to the vicissitudes of HIV vaccine development. We then discuss how the failures of HIV vaccine development have taught us how adapt SARS-CoV-2 vaccines to immune escape from emerging variants. Finally, we inquire whether recent advances in the development of vaccines against SARS-CoV-2 might in turn further the development of an HIV vaccine - what we describe as a reverse spillover effect.     

Vaccines: Shaping global health

The Developing Countries Vaccine Manufacturers’ Network (DCVMN) gathered leaders in immunization programs, vaccine manufacturing, representatives of the Argentinean Health Authorities and Pan American Health Organization, among other global health stakeholders, for its 17th Annual General Meeting in Buenos Aires, to reflect on how vaccines are shaping global health. Polio eradication and elimination of measles and rubella from the Americas is a result of successful collaboration, made possible by timely supply of affordable vaccines. After decades of intense competition for high-value markets, collaboration with developing countries has become critical, and involvement of multiple manufacturers as well as public- and private-sector investments are essential, for developing new vaccines against emerging infectious diseases. The recent Zika virus outbreak and the accelerated Ebola vaccine development exemplify the need for international partnerships to combat infectious diseases. A new player, Coalition for Epidemic Preparedness Innovations (CEPI) has made its entrance in the global health community, aiming to stimulate research preparedness against emerging infections. Face-to-face panel discussions facilitated the dialogue around challenges, such as risks of viability to vaccine development and regulatory convergence, to improve access to sustainable vaccine supply. It was discussed that joint efforts to optimizing regulatory pathways in developing countries, reducing registration time by up to 50%, are required. Outbreaks of emerging infections and the global Polio eradication and containment challenges are reminders of the importance of vaccines’ access, and of the importance of new public-private partnerships.     

Aggregating human judgment probabilistic predictions of the safety,efficacy, and timing of a COVID-19 vaccine

Safe, efficacious vaccines were developed to reduce the transmission of SARS-CoV-2 during the COVID-19 pandemic. But in the middle of 2020, vaccine effectiveness, safety, and the timeline for when a vaccine would be approved and distributed to the public was uncertain. To support public health decision making, we solicited trained forecasters and experts in vaccinology and infectious disease to provide monthly probabilistic predictions from July to September of 2020 of the efficacy, safety, timing, and delivery of a COVID-19 vaccine. We found, that despite sparse historical data, a linear pool—a combination of human judgment probabilistic predictions—can quantify the uncertainty in clinical significance and timing of a potential vaccine. The linear pool underestimated how fast a therapy would show a survival benefit and the high efficacy of approved COVID-19 vaccines. However, the linear pool did make an accurate prediction for when a vaccine would be approved by the FDA. Compared to individual forecasters, the linear pool was consistently above the median of the most accurate forecasts. A linear pool is a fast and versatile method to build probabilistic predictions of a developing vaccine that is robust to poor individual predictions. Though experts and trained forecasters did underestimate the speed of development and the high efficacy of a SARS-CoV-2 vaccine, linear pool predictions can improve situational awareness for public health officials and for the public make clearer the risks, rewards, and timing of a vaccine.     

海湾国家公共卫生安全风险、治理体系和治理能力分析

海湾国家是中国重要的战略合作伙伴,面临双重疾病负担。近年来,海湾国家新发和再发传染病频发,对中国公共卫生安全构成威胁。此次全球新冠病毒肺炎大流行充分暴露出,海湾国家的公共卫生体系建设和治理能力仍存在诸多挑战。本文就海湾国家公共卫生安全风险与治理能力展开分析,并建议中国与海湾国家在完善疾病监测系统、卫生应急能力提升、公共卫生人才培养,以及疫苗、药物及诊疗技术研发等方面开展合作。     

Introduction of new vaccines for immunization in pregnancy – Programmatic,regulatory, safety and ethical considerations

Immunizing pregnant women is a promising strategy to reduce infectious disease-related morbidity and mortality in pregnant women and their infants. Important pre-requisites for the successful introduction of new vaccines for immunization in pregnancy include political commitment and adequate financial resources: trained, committed and sufficient numbers of healthcare workers to deliver the vaccines; close integration of immunization programs with antenatal care and Maternal and Child Health services; adequate access to antenatal care by pregnant women in the country (especially in low and middle-income countries (LMIC)); and a high proportion of births occurring in health facilities (to ensure maternal and neonatal follow-up can be done). The framework needed to advance a vaccine program from product licensure to successful country-level implementation includes establishing and organizing evidence for anticipated vaccine program impact, developing supportive policies, and translating policies into local action. International and national coordination efforts, proactive planning from conception to implementation of the programs (including country-level policy making, planning, and implementation, regulatory guidance, pharmacovigilance) and country-specific and cultural factors must be taken into account during the vaccines introduction.