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Maternal Immunization

Thursday, 25th of May 2017 Print

Maternal Immunization

Saad B. Omer, M.B., B.S., M.P.H., Ph.D.

N Engl J Med 2017; 376:1256-1267March 30, 2017DOI: 10.1056/NEJMra1509044

Excerpts below. Full text is at http://www.nejm.org/doi/full/10.1056/NEJMra1509044


Vaccines have been one of the most useful tools for achieving substantial reductions in childhood mortality. However, progress in reducing deaths has been slower for infants too young to be vaccinated than for infants and children old enough to receive vaccines.1

Immunization schedules start when infants are 2 months of age in the United States and many other high- and middle-income countries and 6 weeks of age in most low-income countries. The primary immunization schedule is not complete until infants are 6 months of age in most high- and middle-income countries and 14 weeks of age in most low-income countries. Therefore, most childhood vaccines do not start providing adequate protection until the infant is several months old. This inability to use vaccines to prevent infections in neonates and young infants leaves an immunity gap that results in a higher proportion of infection-related hospitalizations and deaths in these age groups than in older children.

This vulnerability of infants who are too young to be vaccinated can be addressed by means of maternal vaccination. Moreover, several infections, such as influenza and hepatitis E, are considered to be associated with increased morbidity and mortality during pregnancy. Maternal vaccines, given their potential effect on maternal and infant morbidity and mortality, are the next frontier in vaccinology. This article synthesizes the evidence for current maternal immunization recommendations, reviews new developments in this rapidly evolving field, and outlines critical areas for future research that will provide a framework for a comprehensive maternal immunization platform.

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Influenza Vaccine

Influenza vaccine has been recommended for pregnant women in the United States since the 1960s.20 Currently, influenza vaccine is now recommended for all pregnant women (during each pregnancy). The vaccine can be administered in any trimester of pregnancy. Many other developed and middle-income countries now have recommendations for maternal influenza immunization. Similarly, in 2012, the World Health Organizations Strategic Advisory Group of Experts on Immunization recommended that countries considering the initiation or expansion of seasonal influenza vaccination programs give the highest priority to pregnant women.21 Despite this recommendation, few low-income countries regularly vaccinate pregnant women against influenza.

The justification for vaccinating pregnant women includes evidence, mainly from observational studies, suggesting that influenza results in more severe outcomes among pregnant women than among nonpregnant women. The evidence of more severe maternal and fetal outcomes after influenza is more consistent for pandemics22-26; nevertheless, a substantial burden of illness among pregnant women is attributable to seasonal influenza.27-32 Similarly, infants under 6 months of age have the highest burden of childhood complications and death associated with influenza.33However, no efficacious vaccines are licensed and available for infants younger than 6 months of age.34

Influenza vaccines are efficacious against influenza-like illness and laboratory-confirmed influenza in pregnant women and their infants.35 Four randomized, controlled trials, conducted in South Africa, Mali, Nepal, and Bangladesh, have evaluated the efficacy of inactivated influenza vaccine administered during pregnancy36,37 against laboratory-confirmed maternal and infant infection. In these trials, the efficacy in infants ranged from 30% in Nepal to 63% in Bangladesh (Figure 2FIGURE 2Estimated Efficacy of Influenza Vaccination during Pregnancy for Preventing Laboratory-Confirmed Influenza in Infants and Mothers.).18,37-39

Given the reported association between influenza during pregnancy and adverse birth outcomes, the potential protective effects of maternal influenza vaccination against adverse birth outcomes (e.g., low birth weight) have been explored. The evidence from clinical trials is characterized by subtle shades of meaning that require some interpretation. For example, in the Bangladeshi and Nepalese trials, maternal influenza immunization was associated with protection against low birth weight,39,40 whereas the South African and Malian trials did not show such an association. The Nepalese trial showed a 15% reduction in the incidence of low birth weight among newborns of vaccinated mothers as compared with newborns of unvaccinated mothers.39 This difference translated into a mean birth weight that was 43 g higher in newborns of the vaccinated mothers than in newborns of the women in the control group.39 Similarly, in the Bangladeshi trial, the mean birth weight was 193 g higher in the maternal-vaccination group than in the control group during the period of influenza virus circulation.40

A few factors should be considered in comparing the results of the four trials. First, whereas all four trials were of high quality, the Nepalese trial was the only one that included a birth outcome (low birth weight) as one of the primary outcomes. Therefore, unlike the other trials, the Nepalese trial was specifically powered to detect a difference in low birth weight between the study groups, reducing the likelihood of a type II error.

Second, the women in the Malian, Bangladeshi, and South African trials were vaccinated in the third trimester, whereas the women in the Nepalese trial received the vaccine between 17 weeks and 34 weeks of gestation.36,37 Early vaccination may have provided a longer period to influence fetal growth and weight gain. Moreover, assessment of gestational age can be inaccurate for women presenting late in pregnancy. For example, in the otherwise well-conducted Malian trial, the investigators used the New Ballard Score to assess gestational age but were able to validate Ballard Score–based gestational age with ultrasonography in approximately 13% of the women participating in the study. In this subset, there was a correlation of only 0.4 between ultrasound-based and Ballard Score–based gestational age.18

Third, the baseline birth weight was lower in the Nepalese study populations than in the South African and Malian study populations.36 Hence, maternal influenza vaccine may be more useful as protection against adverse birth outcomes in vulnerable populations, particularly if it is given late in the second trimester or early in the third trimester.

Influenza infection is associated with an increased risk of subsequent bacterial infection — particularly, pneumococcal infection and disease.41 In fact, a substantial proportion of deaths during the 1918 influenza pandemic were probably due to Streptococcus pneumoniae.42 This potential synergy between influenza virus and S. pneumoniae can be leveraged for young infants through maternal influenza immunization. For example, in the Bangladeshi trial, a 2×2 factorial analysis was performed to determine the antenatal efficacy of influenza vaccination in mothers plus pneumococcal conjugate vaccination in their infants in providing protection against respiratory illness during early infancy.43 As compared with the administration of either inactivated influenza vaccine in mothers or pneumococcal conjugate vaccination (7-valent) in infants alone, the combination of maternal and infant vaccination had higher efficacy against respiratory illness with fever and medically attended acute respiratory illness in infants.43 Similarly, in a study conducted in a U.S.-based managed-care organization, the efficacy of pneumococcal conjugate vaccination was higher for protection against otitis media in infants if their mothers had received inactivated influenza vaccine during pregnancy.44

Vaccination to Prevent Pertussis

The primary indication for pertussis vaccination during pregnancy, most often administered as the combined Tdap vaccine, is for the prevention of pertussis in young infants, who have a disproportionately high burden of severe pertussis. Since 2012, pertussis vaccination has been recommended in the United States and the United Kingdom for every pregnancy. These recommendations allow for pertussis vaccination in any trimester of pregnancy but with a preference for late pregnancy: a gestational age of 27 to 36 weeks in the United States and 20 to 32 weeks in the United Kingdom.45-47 Other countries, such as Australia, New Zealand, Belgium, Argentina, and Brazil, also recommend pertussis vaccination during pregnancy.

The recommendations to administer Tdap vaccine to pregnant women evolved in response to large national or subnational pertussis outbreaks. In fact, the current recommendations in the United Kingdom are the result of a temporary vaccination program that was subsequently extended.47 The genesis of these recommendations has erected ethical barriers to the conduct of phase 3 trials of Tdap vaccination in countries that recommend maternal pertussis vaccination. Hence, most of the data on the effectiveness and safety of maternal pertussis vaccination come from observational studies.

The studies conducted in the United Kingdom have shown high effectiveness of maternal pertussis vaccination. For example, the effectiveness for preventing pertussis in young infants was 91% (95% confidence interval [CI], 84 to 95) in a study that used the screening method (which involves the use of readily available administrative and surveillance data), and 93% (95% CI, 81 to 97) in a case–control study.48,49

Similarly, the results of studies evaluating the safety of maternal pertussis vaccination have been reassuring overall. A large study conducted in a network of U.S.-based managed-care organizations showed no increase in adverse birth or pregnancy outcomes, with the exception of a 20% higher adjusted rate of a chorioamnionitis diagnosis among women who received Tdap vaccine during pregnancy (6.1%, vs. 5.5% among women who did not receive Tdap vaccine).50 However, on chart review, only half the patients could be confirmed as having a clinical presentation consistent with chorioamnionitis.50 This finding supports the interpretation that, in the United States, perhaps because of litigation concerns, many fevers during the third trimester are labeled as chorioamnionitis. Notably, in this study, there was no increase in the risk of preterm birth, which was the main clinical outcome of concern associated with chorioamnionitis.50

In another study in the United States, there was no increase in risk associated with concomitant administration of influenza and Tdap vaccines during pregnancy.51 Similarly, there was no increase in acute events (local reactions, fever, or allergy) or in adverse birth outcomes (preterm delivery, small size for gestational age, or low birth weight) associated with the time since previous receipt of tetanus-containing vaccine.52

Maternal pertussis immunization results in increased concentrations of pertussis antibodies in infants,53 and there is a theoretical concern that these vaccine-induced maternal antibodies might reduce the immunogenicity of infant diphtheria–tetanus–pertussis (DTP) vaccine. Studies evaluating the attenuation of infant DTP responses by infection-derived maternal antibodies have had heterogeneous findings. Overall, however, there was greater attenuation of immunogenicity in infants who received DTP vaccine containing whole-cell pertussis (DTwP) than in those who received DTP vaccine containing acellular pertussis (DTaP).54

There are emerging data on the effect of vaccine-induced maternal pertussis antibodies on infant DTaP responses, whereas apparently no studies have assessed such responses in infants receiving DTwP, the version of pertussis vaccine used in most developing countries. Small trials in the United States14 and Canada55 showed lower antibody responses to DTaP among infants whose mothers received Tdap during pregnancy than among the infants of unvaccinated women. In a small trial in Vietnam (where infants also received DTaP), antibodies against pertactin (an immunogenic virulence factor of Bordetella pertussis) but not against pertussis toxin and filamentous hemagglutinin, two other pertussis antigens, were lower in the infants of mothers who received Tdap during pregnancy.55,56

The clinical relevance of studies showing attenuation of vaccine responses in infants is uncertain, since there is no broadly accepted immunologic correlate of protection for pertussis. Nevertheless, these findings warrant monitoring of age-specific pertussis trends in populations with maternal pertussis immunization in order to detect any shifting of the disease burden from infants who are younger than 6 months of age to infants who are 6 months of age or older, as well as to children and adolescents.

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Maternal vaccines have the potential to provide clinically significant protection for mothers and infants. However, realizing the full potential of maternal vaccines will require rigorous evaluation of these vaccines in preventing adverse birth outcomes, as well as infant hospitalization and death. Moreover, the immunization delivery system in the United States and globally has traditionally focused on childhood vaccines. Incorporating maternal vaccines into antenatal care has been a challenge in many locations. For example, maternal vaccination in the United States is estimated to be approximately 50% for influenza nationally and 10% for Tdap in 16 states that have data on maternal Tdap vaccination.77,78 Evidence-based interventions are needed at the practice, provider, and patient levels to ensure high maternal vaccination.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

I thank Varun Phadke and Rachael Porter of Emory University for assistance in the preparation of an earlier version of the manuscript.


From the Departments of Global Health and Epidemiology, Rollins School of Public Health, Emory University, and the Department of Pediatrics, Emory University School of Medicine — both in Atlanta.

Address reprint requests to Dr. Omer at 1518 Clifton Rd. NE, CNR Bldg., Atlanta, GA 30322, or at somer@emory.edu.

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