Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.


Maternal Pertussis Immunization Can It Help Infants? Natalia Jiménez-Truque, MSCI, PhD; Kathryn M. Edwards, MD

Pertussis (whooping cough) is a highly contagious and potentially fatal disease that is preventable by vaccination. However, the incidence of whooping cough has increased despite having high vaccine coverage rates in the United States.1 Infants Related article page 1760 younger than 12 months are especially susceptible to pertussis, and those younger than 2 months—too young to start their diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccination series—represent many of the pertussis cases, hospitalizations, and deaths.2 To protect infants from pertussis, the Advisory Committee on Immunization Practices (ACIP) recommended in 2008 that postpartum women and close contacts of the newborn receive a booster tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) injection to “cocoon” the infant from acquiring pertussis.3 Thisstrategyproveddifficulttoimplement,andin2011, the ACIP recommended that pregnant women receive Tdap if they had not been previously vaccinated.2 Given the rapid waning of the Tdap-elicited antibody response, in late 2012 the ACIP recommended that all pregnant women receive Tdap during the third trimester of every pregnancy, regardless of previous Tdap receipt,2 in an effort to provide adequate transplacental antibody titers to infants to protect them from disease. Since the first ACIP recommendation of administering Tdap to pregnant women, several concerns have been raised. The main concern has been the safety of both the mother and the infant. Although other vaccines have been routinely given to pregnant women without major safety concerns, such as poor fetal outcomes, extensive safety monitoring after Tdap administration had not occurred. Second, the vaccine must elicit an adequate immune response in the mother that would be transmitted transplacentally and ultimately be effective in protecting the infant from disease. Studies in adults suggest that Tdap is adequately immunogenic in women of childbearing age, with the peak antibody response noted as early as 14 days postvaccination.4 Third, although effective transplacental antibody transfer has been documented,5 a concern had been raised that high concentrations of maternally transferred antibodies can blunt the infant’s own immune response to vaccines.6 Although several studies have found no interference of maternal antibodies on the infant’s immune response,7 women in those studies were not vaccinated during gestation and thus might have lower antibody concentrations than if they had been vaccinated during pregnancy. Additionally, serologic interference attributable to maternal antibodies has been described with almost every infant vaccine administered, including measles, oral polio, influenza, and hepatitis A vaccines, among others.8 1736

The study by Munoz and colleagues in this issue of JAMA,9 which began before the latest ACIP recommendation of immunizing all pregnant women at every pregnancy, evaluated not only the safety and immunogenicity of Tdap administered during pregnancy compared with Tdap administered postpartum but also assessed the effect of maternally transferred antibodies on the infants’ serologic response to DTaP. With a solid methodology, this randomized, double-blind, placebo-controlled crossover study was conducted from October 2008 to May 2012 in 3 Vaccine and Treatment Evaluation Units (Houston, Durham, and Seattle) and included academic and private practice populations. Women received either Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks’ gestation, with crossover postpartum. Nonpregnant women (n = 32) also received Tdap and served as an additional control group. With regard to safety, no major concerns arose for infants or mothers. Minor injection site reactions were reported in 79% of pregnant and 80% of postpartum women, with injection site pain being the most commonly reported reaction. Systemic reactions were most common in postpartum women (73% vs 36% in pregnant women), with headache being most common. Although 22 participants reported serious adverse events such as fetal distress resulting in cesarean delivery, none were considered related to the vaccine and were often-reported complications of pregnancy and infancy. Infants born to both groups of mothers did not differ with regard to any of the safety measures assessed. The Tdap vaccine was also immunogenic in all women, and effective transplacental antibody transfer was demonstrated. Similar antibody concentrations were observed after vaccination in pregnant, postpartum, and nonpregnant women. A positive correlation between maternal and infant levels of antibodies was found, although infants born to mothers who received Tdap antepartum had statistically significantly higher antibody concentrations from birth through age 2 months when compared with infants born to women vaccinated postpartum. This high concentration of maternally derived antibodies in infants would suggest that, in accordance with the current ACIP recommendations, administration of Tdap during the third trimester of pregnancy results in effective transplacental antibody transfer. To assess whether high concentrations of maternally derived antibodies blunted the infants’ serologic response to DTaP, the authors measured the concentrations of antibodies in infants’ sera against diphtheria, tetanus, and pertussis antigens contained in the infant vaccine. Although only antibody titers for filamentous hemagglutinin at age 7 months were significantly lower in infants born to mothers vaccinated antepartum, no significant difference in antibody levels was seen at age 13 months for per-

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Editorial Opinion

tussis antigens, indicating no evidence of serologic interference. Infants of women immunized during pregnancy actually had significantly higher antibody concentrations against tetanus antigens at age 13 months than infants of women immunized postpartum. Earlier studies also found no serologic interference of infants’ immune responses to DTaP by preexisting antibodies against pertussis toxin, although serologic interference was observed in recipients of whole-cell pertussis vaccine.7 Nonetheless, potential interference was recently shown in infants born to Tdap-immunized pregnant women.10 Whether antepartum Tdap immunization has an effect on infants’ response to other vaccine antigens administered early in life remains unknown. Although the study design and methodology are strong and the findings add valuable information to the field of pertussis prevention, the main limitation of the study by Munoz and colleagues is the small sample size, which lacks the statistical power to detect potential differences between groups for safety and immunogenicity. Whether a larger sample size might enable detection of a significant difference in infants’ antibody concentrations to DTaP antigens at age 13 months remains unknown. Also, though no cases of prolonged cough were observed, the actual efficacy of administering Tdap during pregnancy vs postpartum to prevent infant pertussis disease could not be assessed. Nonetheless, with an incidence of infant pertussis of nearly 7 per 100 000 in the United States in 2013,11 studies to assess efficacy of such a strategy would need to follow thousands of maternal-infant dyads. The United Kingdom instituted a Tdap immunization program for pregnant women in response to a pertussis outbreak in 2012, when almost 10 000 cases of disease were diagnosed, ARTICLE INFORMATION Author Affiliations: Vanderbilt Vaccine Research Program, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. Corresponding Author: Kathryn M. Edwards, MD, Department of Pediatrics, Vanderbilt Vaccine Research Program, Vanderbilt University, 1161 21st Ave S, S-2323 MCN, Nashville, TN 37232 ([email protected]). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Vitek CR, Pascual FB, Baughman AL, Murphy TV. Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis J. 2003;22(7):628-634. 2. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2013;62(7):131-135. 3. Murphy TV, Slade BA, Broder KR, et al; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of pertussis, tetanus, and diphtheria among pregnant and postpartum women and their infants recommendations of the Advisory

the highest incidence in more than a decade.12 Although the efficacy of this strategy has not yet been published, it has been reported to be approximately 90%, and pertussis cases reportedly decreased in 2013.13 One problem with this approach, however, might be if it were contemplated in developing countries, where acellular vaccines are not licensed; it is unclear whether whole-cell vaccine would have similar safety and immunogenicity, though older studies suggest this to be the case.14 Another limitation is that the study evaluated only the Adacel (Tdap)-Pentacel (DTaP) combination of maternal-infant vaccines. Whether similar results would be observed with different vaccine combinations remains unknown, although a major difference in results would be unexpected. Although Tdap has an excellent safety record,13,15 future cohort or surveillance studies must continue to assess safety, immunogenicity, and serologic interference of Tdap immunization during pregnancy on infant responses. Networks such as the Vaccines and Medications in Pregnancy Surveillance System, Vaccine Adverse Events Reporting System, and PostLicensure Rapid Immunization Safety Monitoring and Vaccine Safety Datalink will be important in capturing vaccine safety data. Continued reporting of pertussis cases will also be necessary to assess the effectiveness of administering Tdap during pregnancy. In addition, the assessment of potential interference with DTaP and other vaccine antigens administered during infancy will require large prospective studies. Last, future research must address the safety and immunogenicity of repeated doses of Tdap during each pregnancy, because frequent immunization might lead to a blunted antibody response.

Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2008;57(RR-4):1-51. 4. Halperin BA, Morris A, Mackinnon-Cameron D, et al. Kinetics of the antibody response to tetanus-diphtheria-acellular pertussis vaccine in women of childbearing age and postpartum women. Clin Infect Dis. 2011;53(9):885-892. 5. Shakib JH, Ralston S, Raissy HH, Stoddard GJ, Edwards KM, Byington CL. Pertussis antibodies in postpartum women and their newborns. J Perinatol. 2010;30(2):93-97.

10. Hardy-Fairbanks AJ, Pan SJ, Decker MD, et al. Immune responses in infants whose mothers received Tdap vaccine during pregnancy. Pediatr Infect Dis J. 2013;32(11):1257-1260. 11. 2013 Provisional Pertussis Surveillance Report. Centers for Disease Control and Prevention website. http://www.cdc.gov/pertussis/downloads /Pertussis-Surveillance-Report.pdf. 2014. Accessed March 22, 2014.

6. Polewicz M, Gracia A, Buchanan R, et al. Influence of maternal antibodies on active pertussis toxoid immunization of neonatal mice and piglets. Vaccine. 2011;29(44):7718-7726.

12. Enhanced Pertussis Surveillance. Table 1: Laboratory Confirmed Cases of Pertussis Infection, England and Wales, by Laboratory Method and Quarter 2002-2012. Public Health England website. http://www.hpa.org.uk/webc/HPAwebFile/HPAweb _C/1317133571358. 2013. Accessed March 19, 2014.

7. Englund JA, Anderson EL, Reed GF, et al. The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics. 1995;96(3, pt 2):580-584.

13. Salisbury D. Maternal Tdap and cocooning: the UK experience. Presented at: Meeting of the Advisory Committee on Immunization Practices; June 19-20, 2013; Atlanta, Ga. Centers for Disease Control and Prevention website. http://www.cdc .gov/vaccines/acip/meetings/downloads/minarchive/min-jun13.pdf. Accessed March 29, 2014.

8. Siegrist CA. Mechanisms by which maternal antibodies influence infant vaccine responses: review of hypotheses and definition of main determinants. Vaccine. 2003;21(24):3406-3412.

14. Cohen P, Scadron SJ. The effects of active immunization of the mother upon the offspring. J Pediatr. 1946;29(5):609-619.

9. Munoz FM, Bond NH, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA. doi:10.1001/jama.2014.3633.

15. Centers for Disease Control and Prevention; American Academy of Pediatrics Committee on Infectious Diseases. Additional recommendations for use of tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis vaccine (Tdap). Pediatrics. 2011;128(4):809-812.


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Maternal pertussis immunization: can it help infants?

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