Pertussis and influenza immunisation during pregnancy: a landscape review

doi:10.1016/S1473-3099(17)30190-1

The Lancet Infectious Diseases

Volume 17, Issue 7, July 2017, Pages e209-e222

https://doi.org/10.1016/S1473-3099(17)30190-1 Get rights and content

Summary

Immunisation during pregnancy is a relatively new strategy, and is currently limited to tetanus, pertussis, and influenza vaccines. None of these vaccines were developed specifically for use in pregnancy, but they provide an effective method of protecting mothers and young infants. In response to increases in pertussis morbidity and mortality among young infants, several countries have recommended universal tetanus, diphtheria, and acellular pertussis immunisation during pregnancy. Similarly, many countries recommend influenza immunisation during pregnancy to reduce the risk of disease for mother and infant. Although scientific evidence to support maternal immunisation against pertussis and influenza is rapidly accumulating, important knowledge gaps remain that need to be addressed by future research, which we have highlighted in this Series paper.

Introduction

Pertussis and inactivated influenza vaccines have been widely used for many decades, principally among the population groups at greatest risk of infection and severe outcomes. However, not all individuals at risk have been targeted for immunisation because of age-related concerns or safety considerations. Infants who are too young to complete a primary series of pertussis immunisations are at risk of severe and potentially fatal disease. Healthy pregnant women who contract influenza during pregnancy are at increased risk of severe complications, including admission to hospital or death,¹ but were not deemed safe candidates for vaccination until recently. However, perceptions about the safety and potential benefits of the administration of vaccines during pregnancy have evolved. Maternal tetanus immunisation in low-income countries to prevent neonatal disease proved to be safe, acceptable, and highly effective.² The resurgence of pertussis in some countries, such as the USA, combined with increased knowledge regarding the safety of tetanus, diphtheria, and acellular pertussis (Tdap) vaccines in adolescents and adults, led to recommendations to administer Tdap vaccines to pregnant women to protect their young offspring.³ Likewise, increased use of influenza immunisation during pregnancy, especially during the 2009 influenza A H1N1 pandemic, has favoured wider application and acceptance of this preventive measure.

In the case of both influenza and pertussis, nearly all women of childbearing age are assumed to have pre-existing humoral immunity from previous immunisations, natural infection, or both. However, specific antibody concentrations in pregnant women are often insufficient to provide passive protection to their offspring, but can be boosted with a single dose of vaccine, which increases the likelihood of maternal and infant protection.

Importantly, neither Tdap nor inactivated influenza vaccine was developed specifically for use in pregnancy and neither has this official indication. Several studies were required to support such use, assessing safety for mother and infant, immunogenicity, vaccine effectiveness, and best practice for immunisation. Unlike new vaccine development that is planned and coordinated by a manufacturer with guidance from regulatory agencies, the studies of Tdap and inactivated influenza vaccines in pregnancy were more ad hoc, involving a range of sponsors, investigators, study designs, and populations. In this Series paper we review the data about the immunogenicity, effectiveness, and safety of immunisation against pertussis and influenza during pregnancy, and identify gaps in knowledge that need to be addressed by future research (Panel 1, Panel 2). For the search strategy see the appendix of paper 1 in the Series.⁴

Section snippets

Disease burden

Despite high vaccination coverage against pertussis among children, outbreaks of Bordetella pertussis occurred in the USA between 2010 and 2012, with accompanying morbidity and mortality.5, 6 In the USA, infants during their first months of life have the highest rates of laboratory confirmed pertussis cases and nearly all fatalities occur in infants younger than 3 months.⁷ In low-income and middle-income countries (LMICs), accurate estimates of pertussis burden are not available because of

Immunity induced by immunisation during pregnancy

Most women have humoral immunity to pertussis from childhood immunisations with whole-cell vaccines or acellular vaccines, or from natural infection, but in each case serum antibody concentrations decrease to low or undetectable concentrations by early adulthood11, 12 and might be insufficient to passively protect their young offspring. A single dose of Tdap vaccine elicits a booster response, raising maternal antibody concentrations substantially¹³ and increasing the likelihood of passive

Transplacental transfer of immunity and timing of immunisation

Transplacental transfer of pertussis-specific antibodies has been shown for pertussis toxin,13, 15, 16, 17, 18, 19, 20, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 filamentous haemagglutinin,13, 15, 16, 17, 18, 19, 20, 49, 50, 51, 52, 53, 54, 55, 56 pertactin,13, 15, 16, 17, 18, 49, 55, 56, 57 and fimbriae.13, 16, 17, 18, 51, 54, 57 Several studies have shown higher concentrations of pertussis-specific antibodies in cord serum samples than in maternal serum samples when women were given Tdap

Effect of breastmilk on immunity

Pertussis antibodies, which are transferred into breastmilk, have an antibacterial effect on B pertussis in vitro and in animal models.24, 70, 71, 72, 73, 74 Pertussis-specific IgA is detectable in the breastmilk of women vaccinated with Tdap after delivery, declining 14–28 days after immunisation.²⁴ Pertussis antigen-specific IgA antibodies in the breastmilk remain detectable up to 8–9 weeks post partum in women immunised with Tdap before or during pregnancy or immediately post partum.70, 71

Effectiveness of immunisation during pregnancy

Protection of infants against pertussis after Tdap immunisation during pregnancy is the combined result of direct protection from maternally derived pertussis antibodies and indirect protection resulting from reduced risk of B pertussis infection in the mother and infant exposure.

In response to an increase in the number of infant deaths from pertussis, the UK Department of Health issued a temporary recommendation in September, 2012, for the vaccination of all women with Tdap between 28 and 32

Interference with vaccine responses in infants and effect on neonatal immune system

Several studies done in the 1990s and recent data suggest that high maternally derived antibody titres (pre-existing or boosted by Tdap immunisation before or during pregnancy) can have a suppressive effect on infant responses to primary immunisation against pertussis, although the clinical significance of this observation has not been evaluated (table 2).13, 18, 19, 20, 60, 85, 86, 87, 88, 89, 90 Interference with active immunisation against pertussis was not only affected by the

Safety of vaccination in pregnancy

Safety is an important determinant in a woman's decision about whether or not to receive a vaccine during pregnancy. The amount of literature regarding the safety of maternal pertussis immunisation (table 3) is increasing; available evidence does not suggest an increase in adverse events in mothers or infants associated with Tdap during pregnancy.13, 98, 99, 100, 101, 102, 103, 104, 105, 106

Donegan and colleagues¹⁰² reported data from a large cohort of women vaccinated with Tdap during

Future directions

On the basis of the literature review and subsequent broad consultation with experts, as detailed in the first paper of this Series by Marchant and colleagues,⁴ several gaps in knowledge were identified and require future studies (Panel 1, Panel 2).

Although evidence on vaccine efficacy after acellular pertussis administration during pregnancy is promising, the precise mechanism that leads to clinical protection from disease is not well established. Little is known about which transplacental

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While reported coverage of both influenza and pertussis vaccine in birthing women in NSW has increased over time, disparities in coverage exist and they highlight areas where evidence-based interventions to improve maternal vaccination could be targeted.
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Adverse pregnancy outcomes including maternal mortality, stillbirth, preterm birth, intrauterine growth restriction cause millions of deaths each year. More effective interventions are urgently needed. Maternal immunization could be one such intervention protecting the mother and newborn from infection through its pathogen-specific effects. However, many adverse pregnancy outcomes are not directly linked to the infectious pathogens targeted by existing maternal vaccines but rather are linked to pathological inflammation unfolding during pregnancy. The underlying pathogenesis driving such unfavourable outcomes have only partially been elucidated but appear to relate to altered immune regulation by innate as well as adaptive immune responses, ultimately leading to aberrant maternal immune activation. Maternal immunization, like all immunization, impacts the immune system beyond pathogen-specific immunity. This raises the possibility that maternal vaccination could potentially be utilised as a pathogen-agnostic immune modulatory intervention to redirect abnormal immune trajectories towards a more favourable phenotype providing pregnancy protection. In this review we describe the epidemiological evidence surrounding this hypothesis, along with the mechanistic plausibility and present a possible path forward to accelerate addressing the urgent need of adverse pregnancy outcomes.
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Sixty-seven mother-infant dyads were enrolled; nine of those did not meet the eligibility criteria. Of the 58 mother-infant dyads included, 6-month follow-up data were available for 57 mother-infant dyads. The mean ± standard deviation log SARS-CoV-2 anti-spike antibody level at delivery was lower among infants who were COVID-19 positive versus negative during follow-up (3.41 ± 0.74 AU/mL, n = 12; vs. 3.87 ± 0.84 AU/mL, n = 46; p 0.036); a log titre of ≥4.07 AU/mL (11 750) at delivery was associated with a significantly lower likelihood of infant infection (1/26 vs. 11/32 in infants with antibody level of <4.07 log AU/mL, OR = 0.076 [95% CI, 0.076, 0.64], p 0.018). A spline curve model showed a linear decrease in antibody levels when the last dose was administered at ≤30 weeks of gestation (50 days before delivery), after which the antibody levels increased (R² = 0.50). In multivariate analysis, more vaccine doses, prior maternal infection, and last administered dose at ≥31 weeks of gestation were associated with higher antibody levels at delivery.
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Initial studies on COVID-19 in pregnancy have demonstrated a range of neutralizing activity, but little has been published on the full profile of SARS CoV-2 related antibodies in maternal and cordblood.
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This was a prospective cohort study of delivering patients at Thomas Jefferson University Hospital from April 2020 to February 2021. The primary objective was to describe unique maternal and fetal antibody epitope titers and specificity in patients with COVID-19 history. Serologic profile was assessed with a multiplex platform. Antigens used were hemagglutinin trimer influenza A (Hong Kong H3); spike trimers for SARS-CoV-2, SARS-CoV-1, Middle East respiratory syndrome coronavirus, and betacoronaviruses HKU-1 and OC43; and spike N-terminal domain, spike receptor-binding domain, and nucleocapsid protein (full length) for SARS-CoV-2.
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View all citing articles on Scopus

^†: Joint first authors

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SeriesPertussis and influenza immunisation during pregnancy: a landscape review

Summary

Introduction

Section snippets

Disease burden

Immunity induced by immunisation during pregnancy

Transplacental transfer of immunity and timing of immunisation

Effect of breastmilk on immunity

Effectiveness of immunisation during pregnancy

Interference with vaccine responses in infants and effect on neonatal immune system

Safety of vaccination in pregnancy

Future directions

Lancet

J Pediatr

J Obstet Gynaecol Can

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Vaccine

Lancet Infect Dis

J Comp Pathol

Vaccine

Vaccine

Vaccine

Vaccine

Lancet

Vaccine

Am J Obstet Gynecol

Vaccine

Lancet

Vaccine

Vaccine

Vaccine

Vaccine

Am J Obstet Gynecol

Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women

Am J Epidemiol

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

Maternal immunisation: a worldwide landscape analysis

Lancet Infect Dis

Pertussis epidemic—Washington, 2012

MMWR Morb Mortal Wkly Rep

Pertussis epidemic—California, 2014

MMWR Morb Mortal Wkly Rep

Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States

JAMA

Pregnancy and infection

N Engl J Med

Prevalence of antibody to Bordetella pertussis antigens in serum specimens obtained from 1793 adolescents and adults

Clin Infect Dis

Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial

JAMA

Pertussis disease burden in the household: how to protect young infants

Clin Infect Dis

Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels

Am J Obstet Gynecol

Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants

Clin Infect Dis

Immune responses in infants whose mothers received Tdap vaccine during pregnancy

Pediatr Infect Dis J

Antibody responses to pertussis toxin display different kinetics after clinical Bordetella pertussis infection than after vaccination with an acellular pertussis vaccine

J Med Microbiol

Kinetics of the antibody response to tetanus-diphtheria-acellular pertussis vaccine in women of childbearing age and postpartum women

Clin Infect Dis

The decline of pertussis-specific antibodies after tetanus, diphtheria, and acellular pertussis immunization in late pregnancy

J Infect Dis

Influenza vaccination given at least 2 weeks before delivery to pregnant women facilitates transmission of seroprotective influenza-specific antibodies to the newborn

Pediatr Infect Dis J

The safety and immunogenicity of trivalent inactivated influenza vaccination: a study of maternal-cord blood pairs in Taiwan

PLoS One

Multi-centre observational study of transplacental transmission of influenza antibodies following vaccination with AS03(A)-adjuvanted H1N1 2009 vaccine

PLoS One

Pandemic influenza A H1N1 2009 infection versus vaccination: a cohort study comparing immune responses in pregnancy

Series
Pertussis and influenza immunisation during pregnancy: a landscape review