During pregnancy and infancy, individuals are more susceptible to infections. Maternal vaccination plays a crucial role in safeguarding both the mother and the infant from vaccine-preventable diseases. It not only protects pregnant women from infections but also provides an immune defense to the fetus during pregnancy and the infant during the early stages of life.

The significance of maternal vaccination in providing immune protection to infants was first recognized in 1879 against smallpox. Maternal vaccination against influenza was introduced in the United States in the 1950s–1960s and was recommended routinely in pregnancy by the Centers for Disease Control and Prevention in the late 1990s. Australia and United Kingdom took similar measures following the H1N1 pandemic of 2009. In 1999, recommendations by the World Health Organization led to the introduction of maternal vaccination against tetanus in low-income countries. In high-income countries where tetanus has been eliminated, combination vaccines including tetanus, diphtheria and acellular pertussis have been routinely recommended in pregnancy for protection against infant pertussis. More recently, in response to the pandemic, COVID-19 vaccines have been included in maternal vaccination recommendations.

Maintaining high vaccine uptake rates and ensuring continued adherence to vaccination schedules are crucial to fully realize the benefits of routine vaccination during pregnancy for both mothers and infants.

This review will provide an overview of current vaccine recommendations during pregnancy, including pertussis and influenza vaccines. It will also discuss new vaccine recommendations, COVID-19 vaccines and the future prospects for vaccines targeting group B streptococcus (GBS), respiratory syncytial virus (RSV) and cytomegalovirus (CMV).

CURRENT VACCINES

Table 1 lists current vaccines that are routinely recommended and those that are contraindicated or may be considered in special situations in pregnancy.

Table 1. - Vaccines in Pregnancy Indication Vaccine Platform Recommended in pregnancy  Influenza Inactivated virus  Pertussis Acellular (Tdap/Tdap IPV)  COVID-19 mRNA, viral vector, protein subunit, inactivated whole virus  RSV Protein subunit Contraindicated in pregnancy  Measles, mumps, rubella Live attenuated virus  Varicella/Zoster Live attenuated virus  BCG Live attenuated mycobacterium  HPV* Recombinant virus-like particle  Zoster* Recombinant glycoprotein Special Considerations in Pregnancy Vaccine Platform Considerations Hepatitis B Recombinant subunit If high risk of contracting hepatitis B virus Neisseria meningitidis Polysaccharide-protein conjugate or protein-based Consider only if high risk of disease or in an outbreak Polio Inactivated virus Routinely offered in some countries in combination with Tdap vaccine Anthrax Recombinant antigen For postexposure prophylaxis Cholera Inactivated bacterium If high risk of disease Haemophilus influenza type b Polysaccharide-protein conjugate Considered if protection is necessary Hepatitis A Inactivated virus If high risk of exposure Japanese encephalitis virus Inactivated virus If high risk of exposure Rabies Inactivated virus Considered for preexposure prophylaxis Streptococcus pneumoniae Polysaccharide-protein conjugate Considered if protection is necessary Tick-borne encephalitis virus Inactivated virus Considered where benefits outweigh risks Typhoid Polysaccharide Considered where benefits outweigh risks Yellow fever Live attenuated virus Considered where risks of infection outweigh possible risks of vaccination

*No safety data currently available to support use in pregnancy.

BCG indicates Bacillus Calmette-Guérin; HPV, Human papilloma virus; Tdap IPV, tetanus, diphtheria, acellular pertussis, inactivated poliovirus vaccine.

Pertussis

Maternal vaccination with a pertussis-containing vaccine has been adopted in numerous countries to protect infants against this disease. Available vaccines that are widely used include those containing tetanus, diphtheria, acellular pertussis (Tdap) and Tdap combined with inactivated polio (Tdap/IPV), which is given as a single dose, and available throughout the year. There is currently no consensus on the optimal timing for the pertussis vaccine during pregnancy with different guidelines available; for example, the US recommendation is for 27–36 weeks’ gestation while the UK recommendation is for 16–32 weeks. A recent study reported equivalent concentrations of IgG antibodies in infants born to mothers who received the pertussis vaccine at 3 different time intervals in pregnancy, supporting a broader interval of 16–32 weeks.1 Safety evaluations of the Tdap vaccine have not revealed any significant concerns associated with its use during pregnancy. Maternal vaccination with a pertussis-containing vaccine leads to elevated antibody levels in newborns, which persist for at least 2–3 months. Additionally, women who receive the pertussis vaccine while pregnant exhibit significant levels of pertussis-specific IgA antibodies in their colostrum, which can be detected in breastmilk for up to 8 weeks after delivery.2

Infants born to vaccinated mothers may have a reduced antibody response to their own pertussis, polio and diphtheria vaccinations due to the presence of high maternal antibody levels. In the case of pertussis, this reduction does not appear to be clinically significant, and antibody levels typically return to normal after booster vaccinations.3 For polio, however, infants may be insufficiently protected and consideration should be given to the timing of a polio-containing booster in infants or to the removal of the IPV component from the maternal vaccine.4

Influenza

Pregnant women are at risk of severe disease and mortality from seasonal influenza compared to nonpregnant women. Inactivated influenza virus vaccines (3 strains, trivalent or 4 strains, quadrivalent influenza vaccines) are recommended during pregnancy. The intranasal live attenuated influenza vaccine is contraindicated in pregnancy due to the theoretical risk of transplacental transfer of the live virus.5

Pregnant women can receive the influenza vaccine at any stage of pregnancy, including the first, second or third trimesters. This recommendation emphasizes the safety and benefits of the influenza vaccine for pregnant individuals, regardless of the specific gestational period. Additional protection may be offered to the infant by maternal vaccination, as a result of the placental transfer of IgG antibodies and potentially, the IgG/A antibodies present in breast milk; these may be detected for up to 6 months after birth.6,7

NEW VACCINES COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant morbidity and mortality worldwide, including in pregnant women. Although more than half of infections in pregnant women are asymptomatic, infection during pregnancy is associated with higher risks compared to noninfected pregnant individuals. These risks include an increased likelihood of preterm birth, stillbirth, maternal mortality and need for admission to the intensive care unit. Infants born to infected mothers also have an elevated risk of neonatal intensive care unit admission, mainly secondary to prematurity.8

During the pandemic, vaccine trials were conducted rapidly to assess the efficacy and safety of COVID-19 vaccines in adults. However, pregnant individuals were excluded from these trials due to perceived safety concerns. As safety data became available, largely from inadvertent pregnancies among trial participants and postauthorization surveillance studies, various health organizations revised their recommendations to allow vaccination during pregnancy based initially on an individual risk assessment but ultimately recommending widespread vaccination.

Importantly, a systematic review of studies of COVID-19 vaccines in pregnancy showed a reduced risk of stillbirth in vaccinees and no evidence of a higher risk of miscarriage, preterm delivery, placental abruption, pulmonary embolism, postpartum hemorrhage, maternal death, low birthweight, intensive care unit or neonatal intensive care unit admission.9 A large observational study undertaken during the Omicron period showed that there was a high risk of severe maternal morbidity and mortality over the first 6 months, particularly among unvaccinated women. Women who had received a complete or boosted series of vaccines had a lower risk of severe symptoms, complications and death.10 Studies have also demonstrated the placental transfer of SARS-CoV-2 IgG antibodies and the detection of SARS-CoV-2 IgA and IgG antibodies in the breastmilk of women who were vaccinated during pregnancy. There is now clear evidence of protection of infants born to vaccinated women for up to 4–6 months after birth.11,12 Additional data is needed to guide further recommendations for vaccine administration in pregnancy but current recommendations by the World Health Organization include an additional booster dose in those previously vaccinated. An ongoing study in the United Kingdom is assessing the optimal schedule of COVID-19 vaccination in pregnancy (https://doi.org/10.1186/ISRCTN15279830).

FUTURE VACCINES Respiratory Syncytial Virus (RSV)

RSV is a significant contributor to acute lower respiratory tract infections in infants and young children across the globe. While the primary approach to managing RSV infection is supportive care, there are several prevention strategies becoming available. Until now, an effective humanized monoclonal antibody (mAb, palivizumab) has been largely reserved for those at high risk but is expensive and requires multiple monthly doses over the RSV season. New, long-acting mAb are in advanced clinical trials and the first of these, nirsevimab, has recently been approved for use in Europe. Maternal vaccination is an alternative strategy and a recent phase 3 trial evaluating the effectiveness of the Pfizer bivalent fusion protein vaccine, administered between 24 and 36 weeks of gestation, has demonstrated efficacy against medically significant lower respiratory tract infections associated with RSV during the first 90 days of life.13 The optimal strategy to prevent RSV in infants, maternal vaccine or infant mAb, or both, seasonal or year-round, is not yet clear and may be different in different settings.

Group B Streptococcus (GBS)

GBS is a significant global cause of neonatal sepsis and meningitis. Maternal rectovaginal GBS colonization has also been associated with an increased risk of preterm delivery and stillbirth. To protect the fetus and provide passive immunity to the infant, there is a need for an effective maternal GBS vaccine. Capsular polysaccharide–protein conjugate vaccines and protein-based vaccines are the leading candidates. Although there are 10 capsular serotypes, 6 serotypes cause most invasive disease and are included in a candidate conjugate vaccine; while of the family of 6 membrane proteins (alpha-like proteins), 4 cause most disease and are included in a candidate protein vaccine. These vaccine candidates are currently in phase 2 trials in pregnant women (ClinicalTrials.gov: NCT04596878, NCT03765073), with phase 3 trials imminent. These initiatives represent hugely important steps towards preventing GBS in newborns.

Cytomegalovirus (CMV)

CMV is a common infection that typically results in a mild and self-limiting illness among healthy individuals. However, it is of particular concern as a cause of congenital infection. CMV is the most common congenital infection and a leading cause of hearing loss in newborns worldwide, emphasizing the importance of the development of a vaccine.

Congenital CMV can occur in pregnant women who have never been infected with CMV and acquire the infection during pregnancy (primary infection). It can also occur in women who had previous CMV infection and experience reactivation or are infected with a different CMV strain during pregnancy (secondary infection). The highest risk of congenital infection occurs in infants born to mothers with primary CMV infection. The various modes of infection, along with our limited understanding of the precise mechanisms through which maternal immunity protects the fetus, have made the development of a CMV vaccine complex. However, there has been recent progress in the development of CMV vaccine candidates, with several in advanced stages of development. These include a replication-defective pentameric vaccine, an adjuvanted glycoprotein B-based vaccine, viral vector vaccines, RNA vaccines and a DNA plasmid vaccine. Moderna, for example, has completed enrollment into a phase 2 study of their mRNA vaccine (mRNA-1647) in men and women of childbearing age in March 2020 (ClinicalTrials.gov identifier: NCT04232280). Enrollment into the phase 3 study has begun (ClinicalTrials.gov identifier: NCT05085366), marking significant progress in the development of a CMV vaccine.

CONCLUSIONS

The value of antenatal immunization is increasingly being acknowledged, emphasizing the importance of including pregnant women in vaccine trials. To ensure the successful implementation of antenatal vaccination programs, it is crucial to understand the concerns and issues surrounding vaccine uptake in this population. Normalizing and promoting routine antenatal vaccines is essential, and strategies to aid acceptance should be prioritized.

Coadministration of routine vaccines, when safety has been carefully assessed, can contribute to acceptance. Additionally, the development of combination vaccines can simplify the immunization process for pregnant women. Aligning vaccine administration with routine antenatal visits can further facilitate uptake and integration into prenatal care.

To support healthcare professionals in their practice, clear guidance on antenatal vaccination is needed. This guidance should provide information on vaccine safety and administration protocols and address any specific considerations related to maternal health.

Overall, recognizing the value of antenatal immunization, ensuring inclusion in trials, addressing concerns, promoting acceptance and providing guidance for healthcare professionals are crucial steps toward optimizing vaccine uptake and protecting the health of pregnant women and their infants.

ACKNOWLEDGMENTS

We acknowledge Vanessa Greening, research midwife, for her critical review of the manuscript.

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