Prioritise research on vaccines for pregnant and breastfeeding women

Abstract

Pregnant women, their fetuses, and infants are at increased risk of severe disease and death from many vaccine-preventable diseases, including COVID-19.1COVAX Maternal Immunization Working GroupAdvances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization?.https://media.tghn.org/medialibrary/2022/01/COVAX_MIWG_Webinar_Report_NOV2021_Final.pdfDate: 2021Date accessed: February 23, 2022Google Scholar, 2Kasehagen L Byers P Taylor K et al.COVID-19–associated deaths after SARS-CoV-2 infection during pregnancy—Mississippi, March 1, 2020–October 6, 2021.Morb Mortal Wkly Rep. 2021; 70: 1646-1648Google Scholar However, they are typically excluded from pre-implementation vaccine research aimed at generating robust data in support of evidence-informed decision making. This was initially the case with COVID-19 vaccines. In 2019, the PREVENT Working Group published 22 recommendations on how to include pregnant and breastfeeding women in vaccine research and implementation for emerging infections.3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar In February, 2021, the COVAX Maternal Immunization Working Group (MI-COVAX) developed guidance on responsible inclusion in the context of COVID-19 vaccination.4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar Nonetheless, responsible inclusion of pregnant and breastfeeding women in pre-implementation clinical trials has yet to become standard research practice. Nearly 30 years ago, law and ethics professor Rebecca Dresser advocated for ending research practices that normalised male bodies as quintessential research participants.5Dresser R Wanted single, white male for medical research.Hastings Cent Rep. 1992; 22: 24-29Google Scholar The resulting systematic exclusion of women from medical research, Dresser argued, meant that research done with primarily white male participants was less informative for women and people of colour. In subsequent decades, calls for the inclusion of women in research extended to pregnant and breastfeeding women on the grounds of equitable access to pharmaceuticals for maternal, fetal, and infant health.6Lyerly AD Little MO Faden R The second wave: toward responsible inclusion of pregnant women in research.Int J Fem Approaches Bioeth. 2008; 1: 5-22Google Scholar In the 2010s, international and US policy advisers removed the designation of pregnant women as “vulnerable” in oversight guidance, with the goal to improve their opportunities to consent to research participation and advance knowledge about pharmaceutical use in pregnancy.3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar Regulators developed guidance on how pregnant women could be included in clinical trials.7US Department of Health and Human ServicesUS Food and Drug AdministrationCenter for Drug Evaluation and ResearchCenter for Biologics Evaluation and ResearchPregnant women: scientific and ethical considerations for inclusion in clinical trials. April, 2018, p 1–11, clinical/medical, report no revision 1.https://www.fda.gov/media/112195/downloadDate accessed: February 23, 2022Google Scholar, 8Government of CanadaGuidance document: considerations for inclusion of women in clinical trials and analysis of sex differences.https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/clinical-trials/considerations-inclusion-women-clinical-trials-analysis-data-sex-differences.html#a23Date: May 2013Date accessed: February 23, 2022Google Scholar Yet, assumptions about vulnerability and related exclusion of pregnant and breastfeeding women in clinical trials persist.9Farrell R Michie M Pope R Pregnant women in trials of Covid-19: a critical time to consider ethical frameworks of inclusion in clinical trials.Ethics Hum Res. 2020; 42: 17-23Google Scholar Throughout COVID-19 vaccine development, researchers, clinicians, and regulators called for the inclusion of pregnant and breastfeeding women in vaccine trials.4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar, 9Farrell R Michie M Pope R Pregnant women in trials of Covid-19: a critical time to consider ethical frameworks of inclusion in clinical trials.Ethics Hum Res. 2020; 42: 17-23Google Scholar, 10Kweder S Thor S Vasisht K Yao L Everett D Global regulators envision paradigm shift toward inclusion of pregnant and breastfeeding women in clinical research for medicines and vaccines. US Food and Drug Administration, July 19, 2021https://www.fda.gov/news-events/fda-voices/global-regulators-envision-paradigm-shift-toward-inclusion-pregnant-and-breastfeeding-women-clinicalDate accessed: February 22, 2022Google Scholar, 11International Coalition of Medicines and Regulatory AuthoritiesICMRA pregnancy and lactation workshop.https://www.icmra.info/drupal/en/covid-19/9february2021Date: Feb 9, 2021Date accessed: February 22, 2022Google Scholar However, trials involving breastfeeding women were not initiated, while trials involving pregnant women began after emergency use authorisation of the vaccines was granted and were not completed due to low recruitment.1COVAX Maternal Immunization Working GroupAdvances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization?.https://media.tghn.org/medialibrary/2022/01/COVAX_MIWG_Webinar_Report_NOV2021_Final.pdfDate: 2021Date accessed: February 23, 2022Google Scholar Despite the absence of clinical trial data, some countries, including Brazil, Canada, Israel, and the USA recommended that pregnant and breastfeeding women may receive COVID-19 vaccination early in the roll-out on the basis of previously developed standards and enhanced post-implementation vaccine safety monitoring.3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar, 4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar Post-implementation surveillance and research generated reassuring observational evidence of vaccine safety,12Shimabukuro TT Kim SY Myers TR et al.Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons.N Engl J Med. 2021; 384: 2273-2282Google Scholar vaccine effectiveness among pregnant and breastfeeding women, and placental and breastmilk antibody transfer to offspring.13Gray KJ Bordt EA Atyeo C et al.COVID-19 vaccine response in pregnant and lactating women: a cohort study.Am J Obstet Gynecol. 2021; 225: 303.e1-303.e17Google Scholar However, the UK, India, and many African and Latin American countries initially advised against COVID-19 vaccination for most pregnant women4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar or restricted early access to vaccines.14Berman Institute of Bioethics and Center for Immunization ResearchJohns Hopkins UniversityCOVID-19 Maternal Immunization Tracker (COMIT).http://www.comitglobal.org/Date: 2021Date accessed: February 22, 2022Google Scholar Eventually, many countries updated policies to recommend COVID-19 vaccination during pregnancy and breastfeeding14Berman Institute of Bioethics and Center for Immunization ResearchJohns Hopkins UniversityCOVID-19 Maternal Immunization Tracker (COMIT).http://www.comitglobal.org/Date: 2021Date accessed: February 22, 2022Google Scholar on the basis of post-implementation data generated by countries with robust surveillance systems and mounting evidence of severe COVID-19 outcomes in pregnancy.2Kasehagen L Byers P Taylor K et al.COVID-19–associated deaths after SARS-CoV-2 infection during pregnancy—Mississippi, March 1, 2020–October 6, 2021.Morb Mortal Wkly Rep. 2021; 70: 1646-1648Google Scholar, 12Shimabukuro TT Kim SY Myers TR et al.Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons.N Engl J Med. 2021; 384: 2273-2282Google Scholar, 13Gray KJ Bordt EA Atyeo C et al.COVID-19 vaccine response in pregnant and lactating women: a cohort study.Am J Obstet Gynecol. 2021; 225: 303.e1-303.e17Google Scholar, 15DeSisto CL Wallace B Simeone RM et al.Risk for stillbirth among women with and without COVID-19 at delivery hospitalization—United States, March 2020–September 2021.Morb Mortal Wkly Rep. 2021; 70: 1640-1645Google Scholar Yet, some health-care providers and women hesitate to accept these recommendations. Responsible inclusion of pregnant women from the outset would have improved acceptance and benefited women in all countries, including low-income and middle-income countries, where there were delays in vaccine procurement and production. Wide-ranging changes are needed to ensure responsible inclusion of pregnant and breastfeeding women in research (panel). To inform responsible inclusion and decisions about prioritisation for early vaccine access, data about disease risks in pregnant and breastfeeding women, fetuses, and infants must be collected at the onset of disease outbreaks. Adaptable, robust surveillance systems should be developed in obstetric and perinatal care that can be scaled up during disease outbreaks to collect data on disease burden, and monitor vaccine safety and effectiveness in these high-risk populations.PanelBarriers and countermeasures to ensure responsible inclusion of pregnant and breastfeeding women in vaccine researchBarriers to responsible inclusion•Erroneous assumptions about vulnerability•Gaps in evidence about disease burden•Normalised practices of systematic exclusion•Disincentives (eg, increased cost, liability concerns, and potential for trial delays)16Price N Sachs R Sherkow JS Larrimore Ouellette L How does pregnancy factor into COVID-19 innovation?.https://writtendescription.blogspot.com/2021/12/how-does-pregnancy-factor-into-covid-19.html?m=1Date: Dec 6, 2021Date accessed: February 22, 2022Google Scholar•Pragmatic challenges (eg, potential trial delays, public trust, and recruitment)Examples of countermeasures•Revise and enforce research guidelines and regulations to promote responsible inclusion•Develop training materials for students, staff, faculty, grant applicants, reviewers, safety committee members, and research ethics committee members•Collect data about disease risks in pregnant and breastfeeding women, fetuses, and infants•Prioritise development and reproductive toxicology (DART) studies when pertinent3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar•Require inclusion of pregnant and breastfeeding women in pre-implementation vaccine trials when appropriate•Continue trials in non-pregnant populations concurrently with DART studies and trials in pregnancy and breastfeeding•Require active surveillance4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar and develop programmes that can quickly scale up to monitor vaccine safety and effectiveness for pregnant and breastfeeding women1COVAX Maternal Immunization Working GroupAdvances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization?.https://media.tghn.org/medialibrary/2022/01/COVAX_MIWG_Webinar_Report_NOV2021_Final.pdfDate: 2021Date accessed: February 23, 2022Google Scholar•Fund research into outcomes for pregnant and breastfeeding women and their offspring•Require regulatory and ethics approval requirements for responsible inclusion•Provide no fault national and global compensation programmes•Include post-vaccination adverse pregnancy and neonatal events in national and global no-fault vaccine compensation programmes3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar•Invest in public education about potential benefits of research participation•Normalise practices from successful non-pandemic vaccine development among pregnant and breastfeeding women3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar Barriers to responsible inclusion •Erroneous assumptions about vulnerability•Gaps in evidence about disease burden•Normalised practices of systematic exclusion•Disincentives (eg, increased cost, liability concerns, and potential for trial delays)16Price N Sachs R Sherkow JS Larrimore Ouellette L How does pregnancy factor into COVID-19 innovation?.https://writtendescription.blogspot.com/2021/12/how-does-pregnancy-factor-into-covid-19.html?m=1Date: Dec 6, 2021Date accessed: February 22, 2022Google Scholar•Pragmatic challenges (eg, potential trial delays, public trust, and recruitment) Examples of countermeasures •Revise and enforce research guidelines and regulations to promote responsible inclusion•Develop training materials for students, staff, faculty, grant applicants, reviewers, safety committee members, and research ethics committee members•Collect data about disease risks in pregnant and breastfeeding women, fetuses, and infants•Prioritise development and reproductive toxicology (DART) studies when pertinent3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar•Require inclusion of pregnant and breastfeeding women in pre-implementation vaccine trials when appropriate•Continue trials in non-pregnant populations concurrently with DART studies and trials in pregnancy and breastfeeding•Require active surveillance4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar and develop programmes that can quickly scale up to monitor vaccine safety and effectiveness for pregnant and breastfeeding women1COVAX Maternal Immunization Working GroupAdvances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization?.https://media.tghn.org/medialibrary/2022/01/COVAX_MIWG_Webinar_Report_NOV2021_Final.pdfDate: 2021Date accessed: February 23, 2022Google Scholar•Fund research into outcomes for pregnant and breastfeeding women and their offspring•Require regulatory and ethics approval requirements for responsible inclusion•Provide no fault national and global compensation programmes•Include post-vaccination adverse pregnancy and neonatal events in national and global no-fault vaccine compensation programmes3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar•Invest in public education about potential benefits of research participation•Normalise practices from successful non-pandemic vaccine development among pregnant and breastfeeding women3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar Responsible inclusion has yet to be required in vaccine development. Clinical development plans for new vaccines must incorporate responsible inclusion of pregnant and breastfeeding women, with maximum diversity across age, ethnicity, and other social stratifiers in all aspects of research, from epidemiological and surveillance studies to interventional trials. Research funders, research ethics committees, and regulators must require and enforce responsible inclusion for funding, ethics approval, trial authorisation, design, and conduct unless exclusion is justified. Academic and research institutions should develop or improve training materials about responsible inclusion for researchers, ethics committees, and data safety monitoring boards on the basis of the PREVENT and MI-COVAX guidelines.3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar, 4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar Regulatory agencies require minimum data to support vaccine trials in pregnancy, which may include developmental and reproductive toxicity studies in animals and demonstration of safety and immunogenicity with potential for efficacy in phase 1 and 2 trials of non-pregnant populations.4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar Collection of these data must be prioritised early in the development pathway3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar so that phase 1 and 2 trials in pregnant and breastfeeding women can be initiated after phase 1 and 2 studies in non-pregnant populations or concurrently with phase 3 trials in the general population.17Baylis F Halperin S Research involving pregnant women: trials and tribulations.Clin Investig. 2012; 2: 139-146Google Scholar During vaccine roll-out, regulators must require inclusion of pregnant and breastfeeding women and infants in phase 4 studies and pregnancy registries to carefully monitor vaccine effectiveness and safety, with attention to differences among groups of women on the basis of age, ethnicity, and diverse intersectional identities.4COVAX Maternal Immunization Working GroupConsiderations for the evaluation of COVID-19 vaccines in pregnant and lactating women.https://epi.tghn.org/covax-overview/clinical-science/maternal-immunization/reports-mi/Date: 2021Date accessed: February 23, 2022Google Scholar Public health should strengthen and expand passive and active surveillance systems to capture adverse pregnancy and neonatal outcomes after vaccination with scalability to respond to new epidemic threats.1COVAX Maternal Immunization Working GroupAdvances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization?.https://media.tghn.org/medialibrary/2022/01/COVAX_MIWG_Webinar_Report_NOV2021_Final.pdfDate: 2021Date accessed: February 23, 2022Google Scholar Support is needed to remove real and perceived barriers to responsible inclusion (eg, increased cost, liability, safety concerns).16Price N Sachs R Sherkow JS Larrimore Ouellette L How does pregnancy factor into COVID-19 innovation?.https://writtendescription.blogspot.com/2021/12/how-does-pregnancy-factor-into-covid-19.html?m=1Date: Dec 6, 2021Date accessed: February 22, 2022Google Scholar Such supports include mechanisms to prioritise regulatory review of trials involving pregnant women and the establishment of national and global no-fault compensation programmes that include adverse pregnancy and neonatal outcomes.3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar Funding is needed for the additional costs of evaluating vaccine safety and efficacy during and after pregnancy in women, their fetuses, and infants.1COVAX Maternal Immunization Working GroupAdvances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization?.https://media.tghn.org/medialibrary/2022/01/COVAX_MIWG_Webinar_Report_NOV2021_Final.pdfDate: 2021Date accessed: February 23, 2022Google Scholar Prelicensure trials of respiratory syncytial virus and group B streptococcus vaccines designed specifically for pregnant women are examples of successful participant recruitment and trial progression, while maintaining public confidence.3Krubiner CB Faden RR Karron RA et al.Pregnant women and vaccines against emerging epidemic threats: ethics guidance for preparedness, research, and response.Vaccine. 2021; 39: 85-120Google Scholar With time and public education about the potential benefits of research participation, responsible inclusion should become a prerequisite for vaccine research. All groups of women deserve equitable access to life-saving vaccines and therapeutics when these become available to the general population and priority access when appropriate (eg, during pregnancy). The actions we propose here need to be adopted to change the status quo and provide policy makers and women with timely, robust evidence to inform their decisions about vaccination. KAT has received grants from GlaxoSmithKline to her institution for work related to vaccines that could be given to pregnant women. FMM is a member of the Data and Safety Monitoring Boards for vaccines manufactured by Pfizer (respiratory syncytial virus [RSV]), Moderna (RSV, human metapneumovirus, parainfluenza, SARS-CoV-2, influenza), Virometix (RSV), and Meissa (RSV vaccines). FMM is an investigator in research supported by Pfizer (SARS-CoV-2 vaccines), Gilead (remdesivir), the US National Institutes of Health (safety of vaccines in pregnancy, Zika virus), and the US Centers for Disease Control and Prevention (respiratory virus epidemiology) for work directly or indirectly related to vaccines that could be given to pregnant women. TM has received funding from an IWK Health Centre postdoctoral fellowship grant and is funded by the Public Health Agency of Canada and Canadian Institutes of Health Research through a Canadian Immunization Research Network postdoctoral grant. FB declares no competing interests.