Overcoming challenges with maternal vaccine trials

Childhood vaccines have proven to be one of the most effective public health interventions to reduce infant and child mortality. Vaccines prevent more than 2.5 million child deaths worldwide each year and, with greater access to vaccines in the developing world, have the potential to prevent another two million child deaths. Vaccine programmes protect the wider population also, through herd immunisation. This has led to the eradication of diseases such as smallpox, and the elimination of diseases such as polio and diphtheria.

Vaccines during pregnancy can benefit the pregnant person, developing foetus, and newborn infant. During pregnancy, the body’s response to pathogens changes, including cardiorespiratory adaptions. These changes protect the baby from immunological rejection and leave the pregnant person at increased risk of severe diseases. Pregnancy can also reduce lung capacity and put the cardiovascular system under additional pressure.¹

Throughout history, women have been disproportionately impacted by influenza, pneumonia, and COVID. A study from Chicago in 1918 found that the mortality rate was 45% in pregnant women admitted to hospital with influenza, complicated by pneumonia, compared to 32% in non-pregnant women with the same illness.² Influenza was also the leading cause of death during pregnancy during the 1957 influenza pandemic, at 20%. Half of the women of reproductive age who died of influenza were pregnant.³

Pregnant women, their foetuses, and newborn infants have much to gain from vaccination. However, pregnant women are severely underrepresented in clinical trials. Data from Clintrial.gov reveals that, between 2018 and 2023, 400 Phase 3 and 4 studies were conducted. Of those, just 22 (or 6%) were designed for, or included, pregnant women. Only seven of these studies were maternal studies with the intent of protecting the foetus.⁴

With so few clinical trials including pregnant women, it’s vital to ensure that those studies are executed with the utmost attention to detail. Given the unique challenges involved, designing these trials comes with additional steps.

Challenges

Vaccine hesitancy 

Vaccine hesitancy has increased overall since COVID, with even higher hesitancy among pregnant women. There are many reasons for this, including: a lack of confidence in the safety and efficacy of vaccines; mistrust of healthcare providers, especially among Black and Hispanic women; some pregnant women’s desire for an “all natural” pregnancy; a belief that the vaccine will make them sick; or concern that the child will develop autism. 

Consent

Another area which adds complexity to maternal vaccine studies is the issue of consent. Depending on regulations, consent may be required from both parents on behalf of the newborn infant. In the case of underage pregnancies, consent from the pregnant mothers’ parent or guardian may be necessary. 

Collaboration and data collection

During the trial, in addition to the principal investigator (PI), there may be further collaborators, such as post-partum physicians, delivery facilities, and a paediatrician. Related to this are the additional burdens associated with data collection and management from these collaborators. There may be more than one site involved, especially if follow up of the baby is required; for example, with paediatric services. 

Solutions

During study set up and planning, each one of these factors must be built in from the start. At enrolment, the regulations of the host country and literacy of participants must be considered. Poorer literacy rates will impact enrolment and translation services may also be required. Selecting a regional site and deciding on the most appropriate PI, whether that should be the mother’s OB-GYN or principal care physician, must be taken into account. Because this may be considered a paediatric study as well as a maternal one, additional approvals may be required from Institutional Review Boards or Ethics Committees. Inexperienced sites may need extra support during planning prior to the start of the study. 

Site set-up and processes

During enrolment, enable early discussions with the participant to allay any fears, answer questions, and ensure that they understand their involvement in the trial. The timing of other vaccinations during the gestation period should be mapped out at this point. The PI will need to ensure that they have access to medical charts and they may need to provide suggestions for affiliated delivery facilities. Delivery staff will need instructions about the study, along with site contact information and a lab kit where required. The investigator will need access to the medical records from the delivery hospitals, as well as from the paediatricians when the baby’s health is being tracked. All of this must be factored into the processes’ development ahead of enrolment. For seasonal vaccine studies, communication process consideration needs to be given to the start and end of season and end point visits tracking.

Data considerations

Data entry may be delayed due to obtaining medical information, especially when it comes to delivery of the baby and non-affiliated networks. Putting a dedicated team in place to track illness visits and other endpoint data collection can mitigate against these delays. Ambiguities can be reduced with precise conversations about expectation requirements. This can help to eliminate any misinterpretations. It may be necessary to use dummy data where data points are not permitted by regulations; for example, dates of birth. The retention of paediatric participants and their data can be supported by frequent communication between the PI and paediatrician. 

Communication

Given the complexity of maternal vaccine studies, a clearly defined communication plan is an essential component for success. Communication channels may include sponsors, CRO partners, participants, fathers, parents/guardians, OBGYN, paediatrician, and delivery hospital teams. The number of people, and the nature of their involvement, necessitates carefully crafted messaging and an appropriate central point of contact. 

Conclusion

While maternal vaccine trials pose unique challenges, they are not insurmountable. Careful planning and execution by researchers can overcome these challenges throughout the trial process. When those challenges are addressed, there are potential health benefits to pregnant mothers, infants, and the wider community.

About the authors

Dinah Knotts is VP of project management in vaccines and infectious diseases at ICON plc. She has been working in the clinical research industry for over 25 years. Her last role was VP for Accellacare Site Network (wholly owned by ICON). Knotts has been at ICON for over 12 years and has held many leadership roles across multiple therapeutic areas, including vaccines, oncology, cardiovascular, rare disease, dermatology, CNS, and gastrointestinal.  She has experience leading and overseeing the operational delivery of large pharma partnerships with the largest having over 75 active studies. Knotts led the operational delivery of the first Pfizer COVID-19 vaccine study with over 48,000 subjects enrolled, receiving Emergency Use Authorization in an unprecedented 247 days and full FDA approval in record time.

Mitsu Rana is senior director of project management at ICON. Rana has over 31 years of experience in the clinical research industry, beginning her career as a study coordinator.  She has worked at the site, pharma, and CRO levels. Over the past 22 years, she has been with ICON in various roles. The last 14 years of her career have been dedicated to vaccine research. Her current portfolio of studies relates to COVID-19 and RSV vaccine studies, including being the project director responsible for the landmark Pfizer COVID-19 trial and most recently leading the operational delivery of an RSV adult trial of >37,000 participants. She is the recipient of the 2021 PharmaTimes Clinical Research Hero award and the 2022 Clinical Researcher of the Year - Americas - Global Project Team bronze award.