Figure 6.1. Proposed framework for promoting the early and optimal inclusion of pregnant and lactating women in prelicensure TB vaccine trials:

For the early and optimal inclusion of pregnant and lactating women in prelicensure TB vaccine trials, the proposed framework in Figure 6.1 suggests the following:

1. Engage women of childbearing potential throughout the research process, from research question identification, through study design, participant recruitment, conduction of research, and result dissemination.
2. Conduct non-clinical DART studies earlier in the vaccine development process, and prior to phase 3 clinical trials, for all new TB vaccine candidates.
3. Women who become pregnant while on vaccine trials should remain on trial with collection of opportunistic maternal and infant immunogenicity and safety data as early as phase 2a registrational trials. Any additional non-live vaccine doses should be deferred until the DART study data are sufficient and acceptable. Additional live vaccine doses should not be provided.
4. For non-live vaccine trials, if sufficient and acceptable safety data are available in non-pregnant women and from DART studies, pregnant women may be included as early as phase 2b studies or studies specifically designed to enrol pregnant participants.
5. In all phase 2, 3 and 4 non-live vaccine trials, lactating women should be allowed to participate, with informed consent. In live vaccine trials, where there are reassuring safety data available for that vaccine in infants, lactating women should be included (e.g. MTBVAC) (1). Where no safety data in infants exist, live vaccine trials evaluating transfer of vaccine components to the breastmilk, and the impact on infant safety and immunity should be considered.
6. Strengthening and expanding comprehensive, rigorous active safety surveillance to enable timely and reliable detection of adverse birth outcomes and rare events, such as birth defects, associated with exposure to TB therapeutics and vaccines during pregnancy and lactation. This should include a systematic review of vaccine components, including adjuvants where these are used, to be routinely conducted for TB vaccine candidates, to inform a risk–benefit assessment for pregnant women; the review should consider evidence from non-TB vaccines that may be applicable when data from TB-specific vaccine candidates are not available (e.g. vaccine platform data).

Specific considerations for protocols

The risk–benefit profile for vaccination differs for pregnancy and lactation and should be considered distinctly; it may also vary by vaccine platform. Important components of the evaluation are epidemiological TB burden among pregnant and lactating women, safety of vaccine components (including adjuvants) in the mother and infant, and likelihood of inducing protective immunity if a TB vaccine candidate is administered during pregnancy or postpartum. TB prevention products and trials could provide a conceptual framework for risk/benefit assessment, as well as pre-exposure prophylaxis during pregnancy/lactation in high-HIV-burden settings.

Lactating women

In current TB vaccine studies, lactation is a standard exclusion criterion. However, anticipated risk if the mother is vaccinated during lactation is expected to be low for both the mother and infant. Little or no vaccine particle transfer should occur through breastfeeding, and it is likely that immunity in the infant would be enhanced rather than negatively impacted. However, consideration for such studies is important to accelerate inclusion of lactating women in vaccine studies, where potential safety concerns exist. Therefore, although no increased risk with lactation and TB vaccine receipt is expected, exclusion of lactating women from clinical vaccine trials, resulting in no available data is likely to affect licensing indications and recommendations for use in this group.

Considerations for inclusion of lactating women in vaccine trials:

• Non-live vaccine studies: no exclusions for clinical trial enrolment should be present for lactating women.
• Live vaccine studies where the vaccine has already been evaluated in infants and safety data are reassuring: no exclusions for clinical trial enrolment should be present for lactating women.
• Live vaccine studies where the vaccine has not yet been evaluated in infants and no safety data in infants exist: trials should consider evaluating transfer of vaccine components to the breastmilk, and the impact on infant safety and immunity should be considered

Generation of safety data for administration during lactation could inform lactation-specific product labelling and policy recommendations made by national, regional and global immunization technical advisory groups.

Incident pregnancy

In current TB vaccine studies, contraceptive requirements are in place at vaccination and a few months post vaccination for women of childbearing potential. It is, however, expected that pregnancies will occur during follow up in these studies. Potential theoretical concerns regarding TB vaccine administration in pregnancy include increased adverse events (local and systemic, including fever) increased adverse outcomes common in pregnancy (e.g. gestational hypertension, stillbirth, prematurity, congenital anomalies etc.) which may be considered related to the vaccine components or to the adjuvant used. Counselling and contraceptive choice support are important for women participating in clinical trials regardless of whether pregnant populations are included in the study or not. As studies move towards evaluating TB vaccines in pregnant populations, these considerations will be essential as the participant navigates participation.

Considerations around handling incident pregnancy occurring during vaccine trial follow up:

• Measure maternal and infant safety:
  • Guidance for the participant must be framed within ethical principles, particularly where potential safety risks exist, allowing autonomy for decision making. For example, whether to continue on study or access contraception rather than risk pregnancy.
  • A comprehensive standard minimal dataset to evaluate relevant maternal, pregnancy, and infant clinical outcomes should be used to evaluate safety during the pregnancy and postpartum period.
  • This dataset should be adapted using the Global Alignment of Immunization safety Assessment in pregnancy (GAIA) consortium (2).
• Measure immunogenicity
  • Maternal immunogenicity data should be collected in pregnancy and postpartum to evaluate potential differences in the magnitude of cellular and humoral immunity compared with non-pregnant individuals.
  • Exclusion of pregnant and postpartum women from immunogenicity assessments is only warranted if there is a relevant medical contraindication (e.g. anemia).
  • TB vaccine protocols should include clear delineation of how incident pregnancy will be managed in the trial. Women of reproductive age should be informed at enrolment about expectations regarding study visits, data and sample collection if she becomes pregnant on study.
  • Additional informed consent will be needed for procedures or study visits that are conducted only for women during pregnancy and postpartum.
  • Where correlates of protection are well established, this, at minimum, should be the immunological readout/s. Where a correlate of protection is unknown as is the case for TB, and where BCG vaccine is provided soon after birth, immunogenicity assessments should include assessment of reduced or non-inferiority to the standard practice.

Pregnant women (3, 4)

In current TB vaccine studies, pregnancy is a standard exclusion criterion. Risk may differ depending on vaccine type and adjuvant. Some potential concerns raised include vaccine particle transfer to the infant, increased inflammation post-vaccine, and time taken for optimal cell-mediated immunity to develop post TB-vaccine (around two months). Risks of known vaccines during pregnancy include pregnancy complications (hypertension, prematurity, stillbirth), fetal harm, legal liability, and distorted perceptions of risk, which have led to significant knowledge gaps. Potential benefits to the mother and infant include passive antibody transfer to the fetus/infant, prevention of TB disease and associated morbidity and mortality in pregnant and lactating women, and the associated impact on the infant and family in these circumstances. Therefore, while there is some uncertainty around risk that may depend on vaccine type, exclusion of pregnant women from all clinical vaccine trials results in a lack of available data to inform licensing indications and recommendations for use in this group. Data describing the background rates of these adverse events in pregnant women from similar geographic and socio-economic backgrounds where the vaccine studies are conducted are helpful to understand any additional burden of adverse events that could be misattributed to vaccine. Direct comparison to a non-exposed control group, however, is most accurate.

• Non-live vaccine candidates where preclinical DART data are reassuring: phase 2 trials in pregnant women should be conducted in parallel with phase 3 trials of non-pregnant populations, OR there should be targeted enrolment of pregnant women in late phase 3 clinical trials.
• Live vaccine candidates should not be evaluated in pregnant women until DART studies have been conducted, sufficient safety data are available in non-pregnant women and in women who have become pregnant while on study, and no safety signals are apparent.

Comprehensive standard minimal dataset to evaluate maternal and infant endpoints

A comprehensive standard minimal dataset to evaluate relevant maternal and infant clinical endpoints should be used to more adequately analyse safety across individuals and different vaccine platforms; this dataset should be adapted from the Global Alignment of Immunization safety Assessment in pregnancy (GAIA) consortium, who in 2014, developed a harmonized approach to actively monitor the safety of vaccines in pregnancy. Standardized definitions to classify adverse events can be found here (5).

Access the vaccine knowledge portal toolkit—a practical resource hub grounded in WHO guidance, regulatory frameworks, and emerging evidence to advance the safe and equitable inclusion of pregnant and lactating women across vaccine R&D, evaluation, and delivery.

Coalition for Epidemic Preparedness Innovations (CEPI) is working to include pregnant women in vaccine trials (e.g. mpox vaccine MVA-BN®), recognizing pregnant and lactating women and their infants are high-risk groups needing protection. They have created a template tool for the evaluation of vaccines for emerging pathogens to be used for pregnant and breast-feeding women.  

COVAX Maternal immunization working group. Advances in maternal immunization science and implementation in times of COVID-19—how has the COVID-19 pandemic impacted the future of maternal immunization. 2021.  

References

1. Tameris M, Rozot V, Imbratta C, Geldenhuys H, Mendelsohn SC, Kany Luabeya AK et al. Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting. eBioMedicine. 2025;114. doi:10.1016/j.ebiom.2025.105628

2. Davies HG, Bowman C, Watson G, Dodd C, Jones CE, Munoz FM et al. Standardizing case definitions for monitoring the safety of maternal vaccines globally: GAIA definitions, a review of progress to date. Int J Gynecol Obstet. 2023;162(1):29–38 https://doi.org/10.1002/ijgo.14843.

3. Beigi RH, Goldkind SF, Jevaji I. Research on vaccines and antimicrobials during pregnancy: challenges and opportunities. Vaccine. 2013;31(40):4261–3. doi:10.1016/j.vaccine.2013.05.060

4. Munoz FM. The challenges of pregnancy in clinical trials for vaccines. Clin Invest. 2014;4(2):103–5 (https://www.openaccessjournals.com/articles/the-challenges-of-pregnancy-in-clinical-trials-for-vaccines.pdf, accessed 22 February 2026).

5. Munoz FM, Eckert LO, Katz MA, Lambach P, Ortiz JR, Bauwens J et al. Key terms for the assessment of the safety of vaccines in pregnancy: Results of a global consultative process to initiate harmonization of adverse event definitions. Vaccine. 2015;33(47):6441–52. doi:10.1016/j.vaccine.2015.07.112