Expert Review of Vaccines

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierv20

Immune interference (blunting) in the context

of maternal immunization with Tdap-containing
vaccines: is it a class effect?

Walid Kandeil , Miloje Savic , Maria Angeles Ceregido , Adrienne Guignard ,

Anastasia Kuznetsova & Piyali Mukherjee

To cite this article: Walid Kandeil , Miloje Savic , Maria Angeles Ceregido , Adrienne Guignard ,
Anastasia Kuznetsova & Piyali Mukherjee (2020) Immune interference (blunting) in the context
of maternal immunization with Tdap-containing vaccines: is it a class effect?, Expert Review of
Vaccines, 19:4, 341-352, DOI: 10.1080/14760584.2020.1749597

To link to this article: https://doi.org/10.1080/14760584.2020.1749597

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EXPERT REVIEW OF VACCINES
2020, VOL. 19, NO. 4, 341–352
https://doi.org/10.1080/14760584.2020.1749597

REVIEW

Immune interference (blunting) in the context of maternal immunization with

Tdap-containing vaccines: is it a class effect?
Walid Kandeil †*, Miloje Savic *, Maria Angeles Ceregido, Adrienne Guignard, Anastasia Kuznetsova
and Piyali Mukherjee
Vaccines, GSK, Wavre, Belgium

ABSTRACT ARTICLE HISTORY

Introduction: Maternal immunization with reduced antigen content tetanus-diphtheria-acellular pertussis Received 6 November 2019
(Tdap)-containing vaccines has been recommended to prevent infant pertussis. However, maternal antibodies Accepted 27 March 2020
may interfere with infant responses to routine immunization with diphtheria-tetanus-acellular pertussis (DTaP)- KEYWORDS
containing vaccines, raising concerns of suboptimal protection after infant vaccination. We performed a Blunting; class effect; infant
narrative literature review to assess whether blunting occurs regardless of the manufacturer of maternal and immunization; maternal
infant vaccines. Because internationally agreed correlates of protection are lacking, the clinical significance of immunization; pertussis;
blunting is not yet fully understood. We have reviewed the evidence available to date. Tdap vaccine
Areas Covered: Thirteen studies that evaluated blunting after maternal immunization and infant
primary/booster series were identified. Blunting was observed with various combinations of Tdap-
and DTaP-containing vaccines for maternal and pediatric immunization. Studies assessing the effec-
tiveness of maternal Tdap immunization beyond the primary infant immunization series in England and
in the United States suggested no evidence of a clinically relevant blunting effect so far.
Expert commentary: This review indicates that the phenomenon of blunting does not depend on the
manufacturer/brand of the pertussis-containing vaccines used for immunizing mothers or children.
Currently, there is no epidemiological evidence that children whose mothers received Tdap are at
increased risk of pertussis after pediatric vaccinations, although longer follow-up is required.

Plain Language Summary

What Is the Context?

● Pertussis, also known as whooping cough, is a highly infectious respiratory disease. Although it can
affect all ages, the number of complications and deaths from infection are highest in infants who are
too young to mount protective antibody responses after vaccination (<2-3 months).
● Immunizing pregnant women with tetanus-diphtheria-acellular pertussis (Tdap) vaccine protects
children against pertussis in early infancy . Antibodies are transferred from the mothers to the fetus
through the placenta and infants are protected before they receive their primary vaccination of a
pertussis-containing vaccine.
● The presence of maternal antibodies may interfere with the infant immune response to routine
pertussis combination vaccines in early life. It can lead to a lower responsiveness of infants whose
mothers have been vaccinated. This immunological interference is called blunting.

What is new?

● We reviewed the available data in the published literature on blunting following maternal immunization
with pertussis containing combination vaccines. We found that: The blunting of the infant response
● The impact on children’s health of blunting for pertussis remains unknown. However, there has
been no increase in pertussis disease in countries with a universal maternal immunization program
● Despite this success, pneumococcal diseases still pose an important health issue and efforts are
needed to tackle this.

What is the impact?

● Surveillance of pertussis epidemiology in various settings using different combinations of maternal

and pediatric vaccines is needed to assess the clinical impact of blunting

CONTACT Piyali Mukherjee piyali.x.mukherjee@gsk.com; Miloje Savic miloje.x.savic@gsk.com GSK, Avenue Fleming 20, Wavre B-1300, Belgium
†
*
Co-authorship Present affiliation: Takeda Pharmaceuticals International AG, Zurich, Switzerland
Supplemental data for this article can be accessed here.
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
342 W. KANDEIL ET AL.
1. Introduction
Pertussis, also known as whooping cough, is a highly contagious
respiratory disease caused by Bordetella pertussis. Although it can
affect all ages, the number of complications and deaths from
infection are highest in young infants under 2–3 months of age
[1]. Maternal immunization with reduced antigen content tetanus-
diphtheria-acellular pertussis (Tdap) vaccines has demonstrated to
be a safe, effective, and successful strategy in preventing infant
pertussis disease, since it can offer protection through transpla-
cental transfer of maternal antibodies before the infants receive
their primary vaccination [2–5]. At least 40 countries are currently
recommending maternal immunization as part of their routine
immunization schedules [6,7], including the United States (US)
and the United Kingdom (UK) [8,9].
There are concerns that antibodies produced following Tdap
vaccination during pregnancy and transferred to the fetus could
interfere with the immune responses of infants to primary and
booster vaccination with pertussis-containing vaccines, which is a
phenomenon referred to as immune interference or blunting of
immune responses [2,10]. The interference of maternal antibodies
with immune responses following infant vaccination has also been
described for other infant vaccines (such as measles, hepatitis A and
B, mumps) [11]. The mechanism behind blunting is not well under-
stood and currently a topic of debate [12]. Although various coun-
tries are using Tdap- and pediatric diphtheria-tetanus-acellular
pertussis (DTaP)-containing vaccines during pregnancy and child-
hood, respectively, from different manufacturers, which are admi-
nistered according to different schedules, all pertussis-containing
vaccines show comparable protection against targeted diseases
[13,14]. It is unclear whether blunting in this context occurs with
specific Tdap- or DTaP-containing vaccines or whether this effect
can occur within the entire class of available Tdap- and/or DTaP-
containing vaccines irrespective of the brand. The clinical relevance
of blunting is also not clear and especially difficult to establish for
pertussis, in the absence of an agreed immunological correlate of
protection [12].
The main objective of this review was to examine available data
in the published literature and from 2 GSK-sponsored randomized
clinical trials on blunting of the infant response to diphtheria, teta-
nus, and pertussis antigens in primary and booster vaccination series
following maternal immunization with Tdap-containing vaccines,
and to assess whether blunting is a product- or class-specific effect.
In addition, we evaluated the blunting of the infant response to the
other antigens included in DTaP-combination vaccines. We also
discuss the available evidence on the clinical relevance of blunting
for pertussis.
2. Methods
The search strategy for relevant peer-reviewed publications was
conducted in PubMed using the search terms: ‘(maternal immuniza-
tion AND pertussis AND blunting)’. Eligible studies were either
randomized clinical trials or observational studies published in the
English language until 1 March 2019, and describing antibody titers
post-primary DTaP vaccination in infants born to women vaccinated
with Tdap during pregnancy and in infants born to women who
were not exposed to Tdap during pregnancy.
Article Highlights
● Immune interference (or blunting) of maternally transferred antibo-
dies on infant immune responses to childhood vaccination has been
observed for maternal antibodies acquired after natural infection but
also for maternal antibodies induced after vaccination. The exact
biological mechanism of blunting is not yet fully understood.
● For childhood diseases with well-established correlates of protection,
there is no clinical relevance of the infant’s blunted immune
responses since most infants reach seroprotective levels after the
primary and/or booster vaccination series.
● In the case of pertussis disease, for which no agreed correlates of
protection exist, close monitoring of the impact of the maternal Tdap
immunization program is needed.
● Epidemiological and clinical data to date highlight that maternal
immunization is a successful additional strategy in reducing the
burden of pertussis disease in infants too young to mount protective
antibody responses after vaccination.
● The interference of maternal antibodies with infant immune
responses to DTPa-containing vaccines can occur regardless of the
Tdap- or DTPa-containing vaccine brand used. Thus, blunting can be
considered as a class effect for Tdap- and/or DTPa-containing
vaccines.
The retrieved literature list (9 publications) was cross-com-
pared with a recent systematic literature review on maternal
immunization [2] and two additional publications were identi-
fied from the reference lists of selected publications. In addi-
tion to the literature search, data from two randomized clinical
trials conducted by GSK were included which were not pub-
lished at the time of the search (www.clinicaltrials.gov:
NCT02096263 [15–17] and NCT02422264 [18]).
We defined blunting as reported statistically significant
lower GMC levels (based on non-overlapping 95% confidence
intervals (CI) or p-values) against antigens included in DTaP-
containing vaccines when comparing immunogenicity in
infants born to mothers who were vaccinated with Tdap-con-
taining vaccines during pregnancy to a control group (infants
born to mothers not exposed to Tdap during pregnancy) after
primary immunization and/or booster dose. Of note, several
papers reported significant p-values (p < 0.05) with overlap-
ping 95% CI [19–25]. We adopted the approach to consider
these papers as reporting statistically significant lower GMC
levels between the two groups and provided point estimates
and 95% CI (Table 2) for readers to make their own assessment
whether the reported statistical significance refers to a real
difference in GMC levels or haphazard reporting. Study quality
was also assessed for each study using the checklist by Downs
and Black [26] and studies were scored as: low (0–10 points),
medium (11–20 points), or high (21–30 points).
We consider blunting as a class effect when blunting is
observed regardless of the vaccine brands used.
3. Results – Class effect of Tdap vaccines
administered during pregnancy in blunting the
infant immune response to DTaP primary/booster
immunization
Up to 1 March 2019, 13 studies in total were identified and
reviewed, which were conducted in different settings and
included different Tdap-containing vaccines for maternal

immunization and different DTaP-containing vaccines for
infant primary/booster vaccination series. The list of studies
and study details including gestational week of maternal vac-
cination and vaccine brands used, pediatric immunization
schedule and vaccines used are summarized in Table 1,
along with the quality assessment of the studies. Details on
the measured geometric mean antibody concentration (GMC)
levels and the percentage of seroprotected (defined by inter-
nationally agreed correlates of protection) or seropositive
infants are summarized in Table 2 and Supplementary Table
1. A schematic summary of the antibodies evaluated in the
reviewed studies is provided in Supplementary Table 2. Four
studies evaluated immune responses after primary and boos-
ter vaccination [15–17,20,25,27], 7 after primary vaccination
[21–24,28–30] and 2 after booster vaccination [19,31]. Of
note, the primary and booster vaccination results of two stu-
dies (in Belgium [19,28] and Vietnam [24,31]) are described in
separate publications. For one of the GSK-sponsored clinical
trials, the included results are from an exploratory analysis of a
multicenter randomized clinical trial and are unpublished but
a link is provided to the primary publication [16], abstract [15]
and full clinical study report publicly available on the GSK
study register [17].
3.1. Pertussis antigens (PT, FHA, PRN)
Nine (out of 11) studies reported significantly lower responses
to one or more pertussis antigens after completion of the
primary vaccination series in infants whose mothers received
Tdap during pregnancy compared to infants whose mothers
received no vaccine, placebo, or a non-pertussis-containing
vaccine during pregnancy (Table 2). Seven studies reported
significantly lower anti-pertussis toxoid (PT) GMC levels [15–
17,20–22,27,28,30], six studies reported significantly lower
anti-filamentous hemagglutinin (FHA) GMC levels [15–
17,20,21,23,27,30] and five studies reported significantly
lower anti-pertactin (PRN) GMC levels [20,22,24,27,30] after
primary vaccination. One randomized controlled trial (RCT)
from Mexico reported lower responses to PT, after maternal
immunization with Adacel (Sanofi Pasteur) and primary vacci-
nation with Pentaxim (Sanofi Pasteur) [22]. The same study
reported declining levels of anti-PRN antibodies until 6 months
of age which were higher in infants born to Tdap-vaccinated
mothers compared to infants born to mothers who received a
placebo. These antibodies were maternally transferred and not
elicited by pediatric vaccination, as Pentaxim does not con-
tain PRN.
The blunting of immune responses to pertussis antigens
was observed in different types of studies (observational or
RCT) and with different vaccine brands used for maternal and
infant immunization. For example, blunting was observed
when Boostrix (GSK) and Infanrix hexa vaccines (GSK) were
used [28,30], as well as when other vaccines, including
Adacel/Repevax (Sanofi Pasteur) and Pediacel/Pentaxim (Sanofi
Pasteur), were used for maternal and primary vaccination,
respectively [20–22].
After completion of the booster vaccination, there was no
evidence of the blunting effect on pertussis responses in most
of the reviewed studies [25,27,31], except in a large RCT from
EXPERT REVIEW OF VACCINES 343
Canada (anti-PT and anti-FHA) [20], in a small, observational
study from Belgium (anti-PT) [19] and in an exploratory analy-
sis of a multicenter RCT (anti-FHA) [15, 16, GSK Study Register:
GSK Study ID 117,119, #107].
3.2. Diphtheria and tetanus antigens (D, T)
3.2.1. Diphtheria toxoid (D)
After completion of the primary vaccination series, seven stu-
dies reported significantly lower anti-D GMC levels in infants
born to Tdap-vaccinated mothers compared to infants born to
mothers who were not vaccinated or vaccinated with placebo
(Table 2) [15–17,21,23,24,27,28,30]. Blunting was observed in
both observational studies and RCTs and after the use of
different vaccine combinations for maternal and primary vac-
cination. In these studies, at least 98% of children in the Tdap
groups reached anti-D antibody concentrations above sero-
protection levels post-primary vaccination, except in the study
by Rice et al. (85%; estimated from figure) [29] and in the study
by Hardy-Fairbanks et al. (not assessed) [27]. In the exploratory
analysis of a multicenter RCT [15–17], blunting was observed
in the arms receiving either Boostrix or Adacel for maternal
immunization and Infanrix hexa or Pentacel (Sanofi Pasteur) for
infant primary immunization.
After booster vaccination, blunting was maintained in the
exploratory analysis in the infants who received Infanrix hexa
[15–17] and in the Hardy-Fairbanks study [27] but no blunting
was observed in the other studies.
3.2.2. Tetanus toxoid (T)
None of the studies reported blunting of the infant immune
responses to tetanus antigens after primary vaccination (Table 2).
One RCT reported a statistically significant increase in anti-T GMC
levels in infants vaccinated with Infanrix hexa whose mothers
received Adacel compared to those whose mothers received a
tetanus only vaccine [24].
However, after booster vaccination, the same RCT reported
statistically significant lower anti-T GMC levels. Another RCT
conducted in the US reported statistically significant higher
anti-T antibody GMC levels after booster vaccination with
Pentacel in children whose mothers received Adacel during
pregnancy compared to children whose mothers received
Adacel post-partum [25].
3.3. Other antigens (Hib, Polio, Hep B)
Five studies evaluated the impact of maternal Tdap vaccine on
infant’s responses to Haemophilus influenzae type b (Hib),
poliomyelitis (Polio) and/or hepatitis B (Hep B) antigens
included in DTaP-containing vaccines (Supplementary Table
1). Available data from two studies indicate no impact of
Tdap maternal vaccination on GMT/GMC levels or on the
rate of infants achieving seroprotective levels for Polio and
Hep B [15–17,30]. In one study [27], antibody titers against
Polio and antibody concentrations against Hep B were
reported to be lower in the Tdap group versus control after
primary and booster vaccination [20,21,27]. While the seropro-
tection rates for Hib were not impacted by maternal Tdap
vaccination in any of the studies, anti-PRP GMCs were
 344

Table 1. Summary of the literature review.

Maternal intervention Pediatric intervention
Study Country, Study
Ref design year Timing# Tdap (N) Control (N) Schedule Primary (N) Booster (N) Findings* quality¥
1b
[27] OBS USA Tdap: 1a Tdap [Adacel] (16) No vaccine 2,4,6 + DTaP-HBV-IPV DTaP [Infanrix] PP: observed lower PT, FHA, Low
2006 Control:/ (54) 12–18 mo [Pediarix] (80%) PRN, and higher FIM 2 and 3
W. KANDEIL ET AL.

(Tdap) (16) DTaP-HBV-IPV PB: observed lower FIM 2 and

2008– [Pediarix] 3
2009 (15%)
(Control) DTaP-Hib
[TriHIBit] (5%)
[28] OBS Belgium Tdap: 28.6 (2.8) Tdap [Boostrix] No vaccine 8,12,16 wks DTaP-HBV-IPV/Hib / PP: observed lower PT and D Medium
2012– Control:/ (57) (42) [Infanrix hexa] (55)
2014
[19] Belgium 15 mo / DTaP-HBV-IPV/Hib PB: observed lower PT Medium
2015 [Infanrix hexa]
(55)
[24] RCT Vietnam Tdap: 25.8 (2.2) Tdap [Adacel] (52) TT-Vac [IVAC] (51) 2,3,4 mo DTaP-HBV-IPV/Hib / PP: observed lower PRN, D and Medium
2012– Control: 24.9 (3) [Infanrix hexa] (51) higher T
2013
[31] Vietnam 18 mo2 / DTaP-HBV-IPV/Hib PB: observed lower T Medium
2015 [Infanrix hexa]
(30)
[25] RCT USA Tdap: 30–32 Tdap [Adacel] (pre- Placebo 2,4,6 DTaP-IPV-Hib DTaP-IPV-Hib PB: observed higher T Medium
2008– Control: 30–32 partum) (pre-partum) + 12 mo [Pentacel] [Pentacel]
2012 (33) and (33) (33)
Tdap [Adacel]
(post-partum)
(15)
[21] OBS UK Tdap: 3 Tdap-IPV [Repevax] No vaccine 2,3,4 mo DTaP-IPV-Hib / PP: observed lower PT, FHA and Medium
2012– Control:/ (141) (246) [Pediacel] D and higher PRN
2014 (141)
[20] RCT Canada Tdap: 34.5 (0.4) Tdap [Adacel] Td 2,4,6 DTaP-IPV-Hib DTaP-IPV-Hib PP: observed lower PT, FHA and High
2007– Control: 34.5 (135) (138) + 12 mo [Pediacel] [Pediacel] PRN
2014 (0.5) (134) (134) PB: observed lower PT, FHA
and FIM
[23] RCT§ UK Tdap: 28.5 Tdap-IPV [Repevax] No vaccine 2,3,4 mo DTaP-IPV-Hib / PP: observed lower FHA and D Low
2012– Control:/ (31) (121) [Pediacel]
2014 (31)
[22] RCT Mexico Tdap: 28–30 Tdap [Adacel] Placebo 2,4,6 mo DTaP-IPV-Hib / PP**: observed lower PT and Medium
2011– Control: 28–30 (90) (81) [Pentaxim] higher PRN
2014 (90)
[29] OBS UK Tdap: 31.4 (24–37) Tdap-IPV [Repevax] (2) or No vaccine 8,12,16 wks DTaP-IPV-Hib / PP: No differences Low
2014– Control:/ Tdap-IPV [Boostrix-IPV] (15) [Pediacel] or DTaP-
2016 (14) IPV/Hib
[Infanrix-IPV/Hib]
(16)
(Continued )
Table 1. (Continued).
Maternal intervention Pediatric intervention
Study Country, Study
Ref design year Timing# Tdap (N) Control (N) Schedule Primary (N) Booster (N) Findings* quality¥
[15–17] RCT United Tdap: 4 Tdap [Adacel] or Tdap No vaccine 2,4,6 DTaP-HBV-IPV/Hib DTaP-HBV-IPV/Hib PP: observed lower FHA /(exploratory
States Control:/ [Boostrix]4 (170) + 15–18 mo [Infanrix hexa] [Infanrix hexa] analysis)
2014– (294) (102) (90)
2015 DTaP-HBV-IPV DTaP-HBV-IPV PP: observed lower FHA
[Pediarix] + [Pediarix] + PB: observed lower PT and
Hib [ActHIB] Hib [ActHIB] FHA
(94) (85)
DTaP-IPV-Hib DTaP-IPV-Hib PP: observed lower PT, FHA and
[Pentacel] + [Pentacel] + D
HBV [Engerix-B] HBV [Engerix-B] PB: observed lower FHA
(98) (82)
[30] RCT Multicountry Tdap: 27–36 Tdap [Boostrix] Placebo 2,4,6/ DTaP-HBV-IPV/Hib / PP: observed lower PT, FHA, PRN /(unpublished at
2016– Control: 27–36 (pre-partum) (pre-partum) 2,3,4 or [Infanrix hexa] and D time of
2018 (341) and Tdap 2,4/2,5 mo (296) search)
[Boostrix]
(post-partum-
(346)
1a
In this study, the Tdap group consisted of 16 pregnant women of which 4 were vaccinated during the first trimester, 8 in the second and 4 in the third trimester of pregnancy.
1b
Statistical analyses were descriptive and no p-values or 95% confidence intervals are listed.
2
Actual mean age was 22.18 months due to delays in study approval.
3
The median interval (interquartile range [IQR]) between antenatal vaccination and infant birth in this study was 9.9 (IQR, 8.0–11.1) weeks.
4
This was an exploratory analysis. Tdap vaccination status was not part of the study design nor defined as an inclusion/exclusion criterion or randomization factor, and therefore no data was available on the timing of maternal
immunization and on how many mothers received Adacel vs Boostrix.
#
Time of maternal immunization expressed in mean weeks’ gestation or range (Standard deviation).
§
Observational substudy of a larger multicenter, randomized controlled vaccination trial in premature infants.
*Described as a statistically significant difference in GMC levels in infants when comparing Tdap to control group.
**Timing of blood sample collection was 6 months of age, prior to administration of the third dose. Of note, anti-PRN antibodies were measured but PRN is not included in Pentaxim.
¥
Study quality was assessed using the checklist by Downs and Black [26]; studies were scored as: low (0–10 points), medium (11–20 points), or high (21–30 points).
D, diphtheria toxoid; FHA, filamentous hemagglutinin; N, number of enrolled mothers (Tdap, Control) or infants born to Tdap-vaccinated mothers (the number of evaluated infants may be lower as not all samples were
collected at each time point nor all collected samples provided meaningful read-outs in each study); OBS, observational; PB, post-booster; PP, post-primary; PRN, pertactin; PT, pertussis toxoid; RCT, randomized controlled
study; Ref, reference; T, tetanus toxoid; wks, weeks; mo, months; y, years; /, not applicable or information not provided.
EXPERT REVIEW OF VACCINES
345
 346

Table 2. Summary of anti-pertussis, -diphtheria, and -tetanus geometric mean antibody concentrations (95%CI) and seroprotection or seropositivity rates (95%CI) in infants post-primary and post-booster vaccination.
Vaccines PT FHA PRN D T
GMC % GMC % GMC % GMC % GMC %
Ref MI PI PS Period¥ Group (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
1
[27] Tdap [Adacel] DTaP-HBV-IPV 2,4,6 + 12–18 mo PP Tdap 56.8 100 61.4 100 34.1 93.3 0.0 - 0.8 -
[Pediarix] + Control 75.2 100 83.6 100 50.7 93.9 0.2 - 0.9 -
DTaP [Infanrix] PB Tdap 64.0 92.3 86.9 100 100.2 92.3 1.5 - 2.6 -
or DTaP-HBV- Control 75.1 100 93.2 100 105.2 92.3 2.2 - 2.5 -
IPV [Pediarix]
W. KANDEIL ET AL.

or DTaP-Hib
[TriHIBit]
[28] Tdap [Boostrix] DTaP-HBV-IPV/Hib 8,12,16 wks PP Tdap 29 - 65 - 68 - 2.1 - 1.7 -
[Infanrix hexa] (25–35) (56–75) (56–84) (1.9–2.2) (1.7–1.8)
Control 54 - 54 - 87 - 2.6 - 1.9 -
(42–69) (41–70) (62–121) (2.4–2.9) (1.7–2.1)
[19] 15 mo PB Tdap 36.3 - 100.9 - 92.7 - 3.3 - 3.8 -
(31–43) (85–120) (67–128) (2.9–3.7) (3.4–4.3)
Control 56.6 - 139.4 - 81.2 - 3.9 - 3.4 -
(42–76) (113–173) (58–113) (3.4–4.3) (2.7–4.3)
[24] Tdap [Adacel] DTaP-HBV-IPV/Hib 2,3,4 mo PP Tdap 70 - 77 - 83 - 2.0 - 1.5 -
[Infanrix hexa] (58–84) (66–90) (65–104) (1.6–2.3) (1.3–1.8)
Control 67 - 66.6 - 132.6 - 2.8 - 1.0 -
(53–84) (56–78) (104–168) (2.5–3.1) (0.8–1.2)
[31] 18 mo PB Tdap 129.0 - 161.3 - 159.0 - 2.0 - 2.7 -
(98–171) (134–194) (141–179) (1.6–2.4) (2.4–3.1)
Control 133.7 (107–168) - 181.7 - 187.1 - 2.3 - 4.2 -
(160–206) (164–214) (2.1–2.6) (3.7–4.7)
[25] Tdap [Adacel] DTaP-IPV-Hib 2,4,6 + 12 mo PP Tdap 64.9 - 40.6 - 72.3 - 0.6 100 1.9 100
[Pentacel] (54–78) (31–54) (49–107) (0.4–0.9) (87–100) (1.4–2.5) (87–100)
Control 96.6 - 78.6 - 77.9 - 1.1 100 1.3 100
(57–165) (53–117) (39–153) (0.6–2.0) (77–100) (0.7–2.2) (77–100)
PB Tdap 80.1 - 69.9 - 203.3 - 5.3 92 6.8 100
(57–112) (50–99) (122–340) (3.1–8.9) (74–99) (4.7–9.9) (87–100)
Control 83.9 - 108.9 - 115.2 - 7.7 92 2.7 92
(50–141) (78–152) (55–242) (3.0–19) (62–100) (1.5–4.8) (62–100)
[21] Tdap-IPV DTaP-IPV-Hib 2,3,4 mo PP Tdap 28.8 - 25.5 - - - 0.6 97.7 1.4 100
[Repevax] [Pediacel] (26–32) (23–28) (0.5–0.6) (94–100) (1.2–1.5) (97–100)
Control 43.2 - 41.1 - - - 1.0 100 1.1 100
(39–47) (38–45) (0.9–1.1) (98–100) (1.0–1.2) (98–100)
[20] Tdap [Adacel] DTaP-IPV-Hib 2,4,6 PP Tdap 56.9 - 50.8 - 40.0 - 0.2 - 1.5 -
[Pediacel] + 12 mo (50–65) (44–59) (33–49) (0.1–0.2) (1.3–1.7)
Control 77.3 - 84.0 - 67.9 - 0.2 - 1.4 -
(67–89) (73–96) (58–80) (0.1–0.2) (1.2–1.6)
PB Tdap 55.6 - 69.3 - 114.2 - 2.9 - 5.2 -
(48–64) (59–81) (92–142) (2.3–3.6) (4.4–6.2)
Control 70.2 - 101.8 - 101.7 - 2.6 - 4.8 -
(62–80) (90–116) (87–118) (2.0–3.2 (4.1–5.6)
[23] Tdap-IPV DTaP-IPV-Hib 2,3,4 mo PP Tdap 37.2 - 23.0 - - - 0.6 - 1.8 -
[Repevax] [Pediacel] (26–53) (16–33) (0.3–1.0) (1.1–2.7)
Control 44.1 - 45.6 - - - 1.1 - 1.4 -
(38–51) (38–55) (0.9–1.3) (1.2–1.7)
[22] Tdap f[Adacel] DTaP-IPV-Hib 2,4,6 mo PP* Tdap 49.1 - - - 16.8 - - - - -
[Pentaxim] (41–59) (13–22)
Control 69.1 - - - 4.5 - - - - -
(59–81) (3.8–5.4)
(Continued )
Table 2. (Continued).
Vaccines PT FHA PRN D T
GMC % GMC % GMC % GMC % GMC %
Ref MI PI PS Period¥ Group (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
[29]2 Tdap-IPV DTaP-IPV-Hib 8,12,16 wks PP Tdap 47.9 ~80 34.4 ~70 87.3 ~90 0.2 ~85 1.2 ~100
[Repevax] or [Pediacel] or (22–74) (22–47) (47–127) (0.1–0.3) (0.9–1.5)
Tdap-IPV DTaP-IPV/Hib Control 51.2 ~90 60.7 ~88 194.5 ~88 0.6 ~70 2.0 ~100
[Boostrix-IPV] [Infanrix-IPV/ (29–73) (23–99) (41–348) (0.2–1.0) (0.3–3.7)
Hib]
[15–17] Tdap DTaP-HBV-IPV/Hib 2,4,6 PP Tdap 37.7 100 94.3 100 48.8 100 1.4 100 2.4 100
[Adacel] or [Infanrix hexa] + 15–18 mo (32–45) (96–100) (80–111) (96–100) (40–59) (96–100) (1.2–1.7) (95–100) (2.1–2.8) (96–100)
Tdap Control 51.2 100 136.0 100 71.2 100 2.4 100 2.6 100
[Boostrix] (42–63) (91–100) (112–166) (91–100) (55–92) (92–100) (2.0–2.9) (92–100) (2.0–3.2) (91–100)
PB Tdap 61.1 100 172.7 100 199.2 98.7 7.3 100 10.3 100
(51–73) (95–100) (146–205) (95–100) (154–257) (93–100) (6.3–8.4) (95–100) (8.5–13) (95–100)
Control 95.2 100 234.0 100 253.9 100 10.8 100 9.0 100
(72–126) (90–100) (184–298) (90–100) (185–349) (89–100) (9.0–13) (90–100) (6.6–12) (90–100)
DTaP-HBV-IPV PP Tdap 41.2 100 108.6 100 34.4 100 1.4 100 2.7 100
[Pediarix] + (36–48) (95–100) (94–124) (95–100) (28–42) (95–100) (1.2–1.7) (95–100) (2.3–3.3) (95–100)
Hib [ActHIB] Control 59.8 97.6 166.3 100 55.2 97.6 1.8 100 2.3 100
(46–79) (87–100) (134–207) (92–100) (38–80) (87–100) (1.3–2.3) (91–100) (1.8–3.0) (92–100)
PB Tdap 76.6 100 172.7 100 192.4 100 7.4 100 9.9 98.6
(64–92) (95–100) (146–205) (95–100) (143–260) (95–100) (6.2–8.9) (95–100) (8.3–12) (93–100)
Control 126.8 (102–158) 100 349.2 100 258.4 100 8.1 100 7.5 94.1
(90–100) (291–420) (90–100) (184–363) (90–100) (6.3–10) (90–100) (5.2–11) (80–99)
DTaP-IPV-Hib PP Tdap 19.0 98.7 45.7 100 27.7 98.7 1.0 100 2.2 98.7
[Pentacel] + (16–22) (93–100) (38–55) (95–100) (22–35) (93–100) (0.8–1.2) (95–100) (1.8–2.6) (93–100)
HBV [Engerix-B] Control 34.9 100 95.9 100 36.8 100 1.7 100 1.9 100
(27–45) (92–100) (78–118) (92–100) (27–51) (92–100) (1.3–2.1) (92–100) (1.5–2.4) (92–100)
PB Tdap 47.9 100 82.7 100 146.4 98.6 9.0 100 8.2 98.6
(39–59) (95–100) (67–102) (95–100) (111–193) (93–100) (7.6–11) (95–100) (6.6–10) (93–100)
Control 68.6 100 147.0 100 109.9 100 9.1 100 5.9 100
(50–93) (91–100) (113–191) (91–100) (74–163) (91–100) (7.2–11) (91–100) (4.6–7.6) (91–100)
[30] Tdap [Boostrix] DTaP-HBV-IPV/Hib 2,4,6/2,3,4 or 2,4/3,5 mo PP Tdap 32.7 100 68.5 100 60.5 100 1.7 100 2.3 100
[Infanrix hexa] (30–35) (99–100) (64–74) (99–100) (54–68) (99–100) (1.6–1.9) (99–100) (2.1–2.6) (99–100)
Control 54.7 100 103.5 100 92.0 100 2.7 100 2.3 100
(51–59) (99–100) (96–112) (99–100) (82–104) (98–100) (2.5–3.0) (99–100) (2.1–2.5) (99–100)
CI, confidence interval; D, diphtheria toxoid; FHA, filamentous hemagglutinin; GMC, geometric mean antibody concentration; MI, maternal immunization; mo, months; PB, post-booster; PI, pediatric immunization; PP, post-primary;
PRN, pertactin; PS, pediatric schedule; PT, pertussis toxoid; %, percentage of seroprotected or seropositive infants; T, tetanus toxoid; wks, weeks; y, years; -, not assessed.
Values were rounded up to 1 decimal except if no decimals were reported and CIs were rounded to no decimals except for values below 10. Bolded values represent reported statistically significant differences in GMCs between Tdap
and control groups.
Seroprotection for diphtheria and tetanus was defined as an antibody concentration ≥0.1 IU/ml for post-primary and ≥1.0 IU/ml for post-booster. Seropositivity for pertussis was defined as antibody concentrations above the assay
cutoffs.
1
Bolded values are reported as different from control group but no p-values or 95% CI are listed in the article.
2
% seroprotected: exact % not provided in the article and approximation was derived from Figure 1 of the article.
* anti-PRN antibodies were measured but PRN is not included in Pentaxim.
¥
Post-primary blood samples were taken 1 month post-primary vaccination except in the study by Villarreal-Perez [22] (prior to administration of the third dose at 6 months of age); post-booster vaccination blood samples were
taken 1 month post-booster vaccination.
EXPERT REVIEW OF VACCINES
347
348 W. KANDEIL ET AL.
Figure 1. Plain Language Summary.
observed to be higher in infants from Tdap-vaccinated
mothers after primary vaccination in several studies [15–
17,21,27]. This effect was not noticeable after booster
vaccination.
4. Clinical relevance of blunting
As described above, there is current evidence documenting
the interference of maternal antibodies with the immune
response of infants to their primary and/or booster vaccination
series. For diphtheria, tetanus, Polio, Hep B, and Hib diseases,
immunological correlates of protection exist. Since the vacci-
nated children in the reviewed studies reached the seropro-
tective levels for these antigens (when assessed) after the
primary and/or booster dose, the observed blunting after
primary and booster infant immunization is of lesser clinical
concern for these diseases. It is more difficult to assess the
clinical impact on pertussis disease because of the lack of
internationally agreed correlates of protection [2,32]. If anti-
body levels after the primary vaccination series are lower in
infants of women immunized with Tdap during pregnancy,
this could potentially lead to an increased burden of pertussis
disease in the second half of the first year of life or afterward
[2]. Through a transmission model, Bento et al. predicted a
potential increase of pertussis incidence in older children if
maternal antibodies lead to blunting [33]. However, the mor-
bidity and mortality following a pertussis infection in children
older than 6 months of age who have a more mature immune
system is much lower than in newborns [34]. The benefits of
protecting newborns during their most susceptible months of
life outweigh the potential risks of blunting later in life [35]. So
far, no evidence of a clinically significant blunting effect has
been found in the US and the UK where maternal Tdap
vaccination has been implemented since 2011 (US) and 2012
(UK). This was based on epidemiological studies of infant
disease up to 2 years of age after primary infant vaccination
[36–38]. One study in the UK evaluated vaccine effectiveness
(VE) of maternal Tdap immunization against infant pertussis
disease following primary infant immunization with the
screening method in children up to 23 months of age and
found an effectiveness of 82% (95% CI: 65–91%) in infants
after the first primary dose of DTaP, 69% (95% CI: 8–90%)
after two doses and 29% (95% CI: −112–76%) after the third
dose [36]. Although maternal immunization did not demon-
strate additional protection on top of the protection provided
by the primary immunization after the third infant dose, the
point estimates are positive, meaning there was no evidence
of an increased risk of pertussis disease after primary vaccina-
tion in the infants born to mothers vaccinated with Tdap
during pregnancy. In a large, retrospective cohort study from
the US in 148,981 infants based on commercial insurance
claims data, the additional protection from maternal vaccina-
tion was estimated to continue in infants who had protection
from 3 DTaP doses through the first year of life (65.9% VE [95%
CI: 4.5–87.8%]) [37]. Another retrospective cohort study in the
US using commercial insurance claims data found no differ-
ences in pertussis rates (hazard ratio: 0.69 [95% CI: 0.26–1.86])
or inpatient-only pertussis rates (hazard ratio: 2.60 [95% CI:
0.15–46.2]) between 6 and 18 months of life in children whose
mothers received prenatal Tdap compared to children of
unimmunized mothers after adjusting for DTaP receipt in the
infants [38].
5. Discussion
Most of the studies identified in this review show evidence of
maternal antibodies interfering with the immune responses to
one or more pertussis antigens following primary vaccination
in infants born to mothers who received Tdap compared to
infants born to mothers who receive no vaccine/placebo or a
control vaccine. This blunting effect on pertussis responses
disappeared in a number of studies after booster vaccination;

however, post-booster blunting persisted in five studies,
including the large RCT from Canada, which has the most
robust post-booster data to date with a total of 239 samples
of infant sera assessed at the booster dose [20]. Blunting of
diphtheria responses was also seen after primary vaccination
in some studies, while the effect on tetanus responses was
inconsistent between studies. Based on our review of the 13
studies on maternal immunization, there is no evidence that
the observed blunting is product-specific or is related to the
vaccine combinations used for maternal and childhood
immunization.
To the authors’ knowledge, this is the first review examin-
ing whether blunting of infant pertussis immune responses
following exposure to Tdap vaccine in utero is a class effect.
However, due to the low sample size of most studies, except
for the two large RCTs specifically designed to evaluate blunt-
ing [20,30], we are unable to comment on the statistical sig-
nificance of these findings. Therefore, we presented a
narrative review, as a more appropriate approach given the
large heterogeneity of the included studies (observational vs
RCT), distinct primary/booster vaccination schedules, different
laboratory testing, and the existence of potential confounders
between the populations investigated in these studies which
were not accounted for (e.g. different demographic composi-
tion of the study population, different disease-specific epide-
miological background, different vaccination history, etc.).
The blunting of the immune response to infant immunization
with DTaP-containing vaccines has also been described in the
absence of maternal immunization during pregnancy. One study
reported blunting of antibody responses to PT, FHA, and PRN after
Tdap vaccination or natural infection of the mother less than
5 years before delivery [39]. However, due to the limited sample
size of the subgroups, these results should be interpreted with
caution. Additionally, a meta-analysis of data from 7630 infants
from 32 studies in 17 countries showed blunting of infant immune
responses by preexisting maternal antibodies for 20 of the 21
measured antigens included in global immunization programs
without maternal vaccination, up to the age of 24 months [40].
This meta-analysis reported a correlation between the level of
maternal antibodies and the magnitude of the blunting effect.
Another study reported an association between preexisting mater-
nal antibody concentrations and blunting of infant immune
responses to pertussis toxin after whole-cell pertussis vaccination
but not after DTap vaccination, while no adverse effects on other
antibodies were observed after either whole-cell or acellular per-
tussis vaccines [41]. Further studies are needed to understand
whether blunting also occurs after primary vaccination with
whole-cell pertussis vaccines and possible consequences.
Blunting of the infant immune response has also been observed
for other vaccines outside the context of maternal immunization,
including the measles vaccine as the best studied example, but
also rotavirus, pneumococcal, mumps, and other vaccines [11].
This confirms blunting as a natural phenomenon that occurs
regardless of the source of maternal antibodies (i.e. natural infec-
tion or vaccination).
The clinical significance of blunting is not yet completely under-
stood for pertussis due to the lack of agreed immunological corre-
lates of protection. Based on three epidemiological studies that
EXPERT REVIEW OF VACCINES 349
assessed the effectiveness of maternal immunization, no evidence
of a clinically significant blunting effect has been found so far in
England and in the US [36–38]. After the maternal pertussis immu-
nization program in England was put in place in 2012, the Joint
Committee on Vaccination and Immunization noted that, for the
first time after 1993, no infant deaths were reported in 2017, and
that the rates of disease in young infants are the lowest since 1998
[42]. Based on the growing evidence on the safety and effective-
ness of maternal immunization, the World Health Organization
concluded in 2015 that maternal immunization was likely to be
the most cost-effective additional strategy to protect young infants
from disease [43].
Although the blunting effect of maternal pertussis immu-
nization has not shown clinical significance, it remains an
interesting area for further assessment through long-term
immunogenicity and effectiveness studies. An interesting
question was whether delaying the timing of infant primary
vaccination would reduce blunting. A recently published RCT
by Barug et al. in the Netherlands compared the effect of
maternal pertussis immunization on infant immune
responses after a delayed (at 3 months of age instead of
2 months) and reduced primary 2 + 1 (instead of 3 + 1)
dose vaccination schedule [44]. Antibody concentrations
against pertussis antigens at age 3 months in the maternal
Tdap group were well above the GMCs of infants aged
2 months without maternal vaccination. With delay of the
first dose and reduced primary vaccination doses, the blunt-
ing effect was still present, but substantial antibody titers
were achieved after the booster dose [44,45]. Therefore,
Barug et al. proposed that the timing of infant vaccination
schedules after maternal pertussis vaccination should be
reconsidered when coverage of maternal pertussis vaccina-
tion is high to optimize the efficacy of infant vaccinations and
reduce the magnitude of interference of maternal antibodies
with infant immune responses. The effect of a delayed sche-
dule on antibody responses to other antigens included in
hexavalent vaccines remains unknown and should be care-
fully monitored. The Health Council of the Netherlands
Committee recently recommended to replace the existing
primary vaccination schedule for infants by two schedules
after the introduction of maternal pertussis vaccination: a 3,5-
month schedule for children whose mother has been vacci-
nated and a 2,3,5-month schedule for children whose mother
has not been vaccinated or who belong to another group at
greater risk [46].
The mechanism behind blunting is not well understood
and is a topic of debate. Several mechanisms for an impact
on the infant humoral antibody responses are postulated to
be involved, including antibody feedback mechanisms invol-
ving inhibition of B cell responses through epitope masking by
maternal antibodies, or inhibition of B cell activation by bind-
ing of IgG to the Fcγ-receptor IIB [47]. In addition, removal of
the vaccine antigens by macrophages and neutralization of
the vaccine antigens by maternal antibodies have been
hypothesized to play a role [47]. The evidence for an effect
of maternal antibodies on cell-mediated immunity develop-
ment before and after infant DTaP vaccination is very limited
and suggests that the infant T cell responses usually remain
350 W. KANDEIL ET AL.
unaffected by maternal antibodies [47,48]. We cannot exclude
that conjugated carrier proteins in the combination vaccines
play also a role in the mechanism of blunting since they could
be immunogenic. Further investigations are needed to eluci-
date the mechanism.
6. Conclusion
In this paper, we reviewed the available evidence on blunting
following maternal immunization with Tdap-containing vaccines
to determine if this is a class-effect. Blunting of the infant
immune responses against the antigens included in the DTaP-
containing vaccines was observed regardless of the vaccine
manufacturer or the vaccine combinations used for maternal
and childhood vaccination. Considering that Tdap- and DTaP-
containing vaccines from different manufacturers are used
across the globe and are showing similar protection against the
targeted diseases, and according to the available literature, there
is currently no evidence to indicate that blunting is a product-
specific phenomenon. Moreover, it is a natural phenomenon that
occurs in the absence of maternal immunization.
Due to the absence of an agreed correlate of protection for
pertussis antigens, blunting could raise concerns about a
potential increase in pertussis incidence in children.
However, studies assessing the effectiveness of Tdap maternal
immunization beyond the primary infant immunization series
in England and in the US found no evidence so far of a
clinically relevant blunting effect for pertussis.
7. Expert opinion
Based on review of the 13 studies on maternal immunization
and blunting of the infant immune responses, we conclude
that blunting occurs irrespective of the maternal and infant
vaccines used. The fact that blunting is not a vaccine-specific
related effect warrants a class effect perception, meaning that
available Tdap- and DTaP-containing vaccines which share
similar respective antigens and are being used to protect
against the same diseases through a similar mechanism of
action, induce similar effects following primary and/or booster
infant vaccinations in children whose mothers were immu-
nized with a Tdap-containing vaccine during pregnancy,
regardless of the vaccine brands used.
Clinical risks of disease are relatively straightforward to
assess when established humoral correlates of protection
exist (e.g. diphtheria and tetanus). However, in the case of
pertussis disease risk in infants, an open question remains due
to lack of agreed correlates of protection. To truly interpret the
clinical impact of blunting, it is therefore important to not only
take into account immunogenicity results from clinical trials
but also epidemiological data. To do this, more long-term
follow-up data on pertussis disease are necessary from coun-
tries with substantial immunization coverage and with good
surveillance systems in place. One of the strategies investi-
gated to reduce the potential impact of blunting is delaying
the first infant pertussis vaccine dose as recently implemented
in the infant immunization program in the Netherlands
[44,46]. Additional research on the establishment of correlates
of protection for pertussis, and on current and future pertussis
vaccine development should be pursued.
A second research avenue of special interest is cell-
mediated immunity in the background of maternal immuniza-
tion. In this respect, we do not know if there are qualitative
differences in B cells and anti-pertussis antibodies produced
by children with blunted immune response compared to chil-
dren born to non-immunized mothers. Current literature
focuses on quantifying the amount of produced antibodies
via GMC measurement; however, antibody characteristics, like
avidity and neutralization potential, or effects on memory B
cells have not been assessed. In addition, any potential long-
term effects of blunting are unknown and require longer
observation time and analyses (at preferably several time
points) of the immune system of affected children.
Another relevant question concerns any effects on T cell-
mediated immunity and T cell development in children born
to Tdap-immunized mothers. The importance of T cells in
providing immunity against pertussis infection, clearance of
invading pathogen and reducing symptom severity and
sequelae, formation of vaccine-induced long-term memory T
cells, and the role of cell-mediated immunity in pertussis
carriage and transmission are still open questions and very
exciting research is ahead of us.
Better understanding of humoral and cell-mediated immu-
nity development under blunting conditions, in addition to
the benefit and risk assessment of maternal immunization,
would better inform immunization policy makers and decide
on the most optimal timing for maternal immunization (e.g.
second vs third trimester) and start of the infant immunization
program.
Acknowledgments
The authors would like to thank Elke Leuridan (Centre for the Evaluation of
Vaccination, University of Antwerp, Belgium) and Gayatri Amirthalingham
(Immunisation and Countermeasures Division, National Infection Service,
Public Health England) for their independent review on the GSK position
paper. No financial reimbursement has been received.
The authors thank Kristel Vercauteren (Modis c/o GSK) for writing
support and Fabienne Danhier (Modis c/o GSK) for publication
coordination.
Funding
This work was supported by GlaxoSmithKline Biologicals SA which was
involved in all stages of this work and paid for all costs associated with the
development and publication of this manuscript.
Declaration of interest
M. Savic, M. A. Ceregido, A. Guignard, A. Kuznetsova, and P. Mukherjee are
employed by the GlaxoSmithKline group of companies. W. Kandeil was an
employee of GlaxoSmithKline at the time of the study. M. Savic, A.
Guignard, and P. Mukherjee hold shares in the GlaxoSmithKline group of
companies. Writing assistance was utilized in the production of this manu-
script: writing support was provided by Kristel Vercauteren (Modis c/o
GSK) and publication coordination was provided by Fabienne Danhier
(Modis c/o GSK), and funded by GlaxoSmithKline. The authors have no
other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject

matter or materials discussed in the manuscript apart from those
disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Trademarks
Boostrix, Boostrix-IPV, Infanrix, Infanrix hexa, Infanrix-IPV/Hib, Engerix-B,
and Pediarix are trademarks of the GSK group of companies.
Adacel, Pentacel, Repevax, Pediacel, ActHIB, TriHIBit, and Pentaxim are
trademarks of Sanofi Pasteur.
ORCID
Walid Kandeil http://orcid.org/0000-0002-3781-7431
Miloje Savic http://orcid.org/0000-0002-7376-4568
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and
clinical manifestations of respiratory infections due to Bordetella
pertussis and other Bordetella subspecies. Clin Microbiol Rev.
2005;18(2):326–382.
2. Campbell H, Gupta S, Dolan GP, et al. Review of vaccination in
pregnancy to prevent pertussis in early infancy. J Med Microbiol.
2018;67(10):1426–1456.
3. Furuta M, Sin J, Ng ESW, et al. Efficacy and safety of pertussis
vaccination for pregnant women - a systematic review of rando-
mised controlled trials and observational studies. BMC Pregnancy
Childbirth. 2017;17(1):390.
4. Gkentzi D, Katsakiori P, Marangos M, et al. Maternal vaccination
against pertussis: a systematic review of the recent literature. Arch
Dis Child Fetal Neonatal Ed. 2017;102(5):F456–F463.
5. Healy CM. Pertussis vaccination in pregnancy. Hum Vaccin
Immunother. 2016;12(8):1972–1981.
6. Pertussis: recommended vaccinations. Available from: https://vac
cine-schedule.ecdc.europa.eu/Scheduler/ByDisease?
SelectedDiseaseId=3&SelectedCountryIdByDisease=−1
7. World Health Organization (WHO). WHO vaccine-preventable dis-
eases: monitoring system. 2019 Global summary. Available from:
http://apps.who.int/immunization_monitoring/globalsummary
8. Centers for Disease Control and Prevention. Updated recommen-
dations 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.
9. Public Health England (PHE)-National Health Service (NHS). Timing
of pertussis vaccine in pregnancy. Available from: https://www.
england.nhs.uk/south/wp-content/uploads/sites/6/2016/07/pertus
sis-brief-june16.pdf
10. Forsyth K, Plotkin S, Tan T, et al. Strategies to decrease pertussis
transmission to infants. Pediatrics. 2015;135(6):e1475–1482.
11. Edwards KM. Maternal antibodies and infant immune responses to
vaccines. Vaccine. 2015;33(47):6469–6472.
12. Leuridan E. Pertussis vaccination in pregnancy: state of the art.
Vaccine. 2017;35(35 Pt A):4453–4456.
13. ECDC Guidance. Scientific panel on childhood immunisation sche-
dule: diphtheria-tetanus-pertussis (DTP) vaccination. Available from:
https://www.ecdc.europa.eu/en/publications-data/expert-opinion-
childhood-immunisation-schedule-diphtheria-tetanus-pertussis-dtp.
EXPERT REVIEW OF VACCINES 351
14. Liang JL, Tiwari T, Moro P, et al. Prevention of pertussis, tetanus,
and diphtheria with vaccines in the United States: recommenda-
tions of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2018;67(2):1–44.
15. Klein N, Abu-Elyazeed R, Cheuvart B, et al. The response to pertus-
sis-containing combination vaccines in infants after maternal
immunization with reduced antigen content tetanus-diphtheria-
acellular pertussis vaccine. 5th International Neonatal & Maternal
Immunization Symposium; 2019; Vancouver, BC, Canada.
16. Klein NP, Abu-Elyazeed R, Cheuvart B, et al. Immunogenicity and
safety following primary and booster vaccination with a hexavalent
diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated
poliovirus and Haemophilus influenzae type b vaccine: a rando-
mized trial in the United States. Hum Vaccin Immunother. 2019;15
(4):809–821.
17. GSK Study Register. GSK Study ID 117119. Study to determine the
immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals;
Infanrix hexa at 2, 4 and 6 months of age in healthy infants. Available
from: https://www.gsk-studyregister.com/en/trial-details/?id=117119.
18. Perrett KP, Halperin SA, Nolan T, et al. Immunogenicity, transpla-
cental transfer of pertussis antibodies and safety following pertus-
sis immunization during pregnancy: evidence from a randomized,
placebo-controlled trial. Vaccine. 2020 Feb 18;38(8):2095-2104.
19. Maertens K, Cabore RN, Huygen K, et al., Pertussis vaccination
during pregnancy in Belgium: follow-up of infants until 1 month
after the fourth infant pertussis vaccination at 15 months of age.
Vaccine. 2016;34(31): 3613–3619. .
• A follow-up study on immune interference in Belgium after the
booster dose that showed blunted immune response against
pertussis toxin after the booster dose.
20. Halperin SA, Langley JM, Ye L, et al., A randomized controlled trial of
the safety and immunogenicity of tetanus, diphtheria, and acellular
pertussis vaccine immunization during pregnancy and subsequent
infant immune response. Clin Infect Dis. 2018;67(7): 1063–1071. .
•• The largest RCT included in this literature review that assessed
immune interference after the primary and booster vaccina-
tion. The blunting of anti-pertussis antigens was observed
after the primary schedule, and it persisted after the booster
dose.
21. Ladhani SN, Andrews NJ, Southern J, et al. Antibody responses after
primary immunization in infants born to women receiving a per-
tussis-containing vaccine during pregnancy: single arm observa-
tional study with a historical comparator. Clin Infect Dis. 2015;61
(11):1637–1644.
22. Villarreal Perez JZ, Ramirez Aranda JM, de la OCM, et al.
Randomized clinical trial of the safety and immunogenicity of the
Tdap vaccine in pregnant Mexican women. Hum Vaccin
Immunother. 2017;13(1):128–135.
23. Kent A, Ladhani SN, Andrews NJ, et al. Pertussis antibody concen-
trations in infants born prematurely to mothers vaccinated in
pregnancy. Pediatrics. 2016;138(1):e20153854-e20153854.
24. Hoang HT, Leuridan E, Maertens K, et al. Pertussis vaccination
during pregnancy in Vietnam: results of a randomized controlled
trial Pertussis vaccination during pregnancy. Vaccine. 2016;34
(1):151–159.
25. 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. 2014;311(17):1760–1769.
26. Downs SH, Black N. The feasibility of creating a checklist for the
assessment of the methodological quality both of randomised and
non-randomised studies of health care interventions. J Epidemiol
Community Health. 1998;52(6):377–384.
27. 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.
28. Maertens K, Cabore RN, Huygen K, et al., Pertussis vaccination
during pregnancy in Belgium: results of a prospective controlled
cohort study. Vaccine. 2016;34(1): 142–150. .
352 W. KANDEIL ET AL.
• A controlled cohort study on immune interference following
primary immunization schedule in Belgium that showed the
blunting effect for antibodies against diphtheria and pertussis
toxoid.
29. Rice TF, Diavatopoulos DA, Smits GP, et al. Antibody responses to
Bordetella pertussis and other childhood vaccines in infants born
to mothers who received pertussis vaccine in pregnancy - a pro-
spective, observational cohort study from the United Kingdom. Clin
Exp Immunol. 2019;197(1):1–10.
30. Perrett KP, Halperin SA, Nolan T, et al. Impact of tetanus-diphtheria-
acellular pertussis immunization during pregnancy on subsequent
infant immunization seroresponses: follow-up from a large rando-
mized placebo-controlled trial. Vaccine. 2020.Feb 18;38(8):2105-2114.
31. Maertens K, Hoang TT, Nguyen TD, et al. The effect of maternal
pertussis immunization on infant vaccine responses to a booster
pertussis-containing vaccine in Vietnam. Clin Infect Dis. 2016;63
(suppl 4):S197–S204.
32. Plotkin SA. Correlates of protection induced by vaccination. Clin
Vaccine Immunol. 2010;17(7):1055–1065.
33. Bento AI, Rohani P. Forecasting epidemiological consequences of
maternal immunization. Clin Infect Dis. 2016;63(suppl 4):S205–
S212.
34. Black S. Epidemiology of pertussis. Pediatr Infect Dis J. 1997;16(4):
S85–S89.
35. Centers for Disease Control and Prevention. Pregnancy and whoop-
ing cough for healthcare professionals: vaccine effectiveness.
Available from: https://www.cdc.gov/pertussis/pregnant/hcp/vac
cine-effectiveness.html.
36. Amirthalingam G, Campbell H, Ribeiro S, et al., Sustained effective-
ness of the maternal pertussis immunization program in England 3
years following introduction. Clin Infect Dis. 2016;63(suppl 4):
S236–S243. .
• A study assessing the effectiveness of maternal Tdap immuni-
zation program in the UK after 3 years of implementation
showed that maternal immunization is effective in preventing
pertussis diseases in infants too young to mount protective
antibody responses after vaccination.
37. Baxter R, Bartlett J, Fireman B, et al. Effectiveness of vaccination
during pregnancy to prevent infant pertussis. Pediatrics. 2017;139
(5):e20164091.
38. Becker-Dreps S, Butler AM, McGrath LJ, et al., Effectiveness of
prenatal tetanus, diphtheria, acellular pertussis vaccination in the
prevention of infant pertussis in the U.S. . Am J Prev Med. 2018;55
(2): 159–166. .
• A study assessing the effectiveness of the maternal Tdap
immunization program in the US showed that maternal immu-
nization is effective in preventing pertussis diseases in infants
too young to mount protective antibody responses after
vaccination.
39. Wood N, Nolan T, Marshall H, et al. Immunogenicity and safety of
monovalent acellular pertussis vaccine at birth: a randomized clin-
ical trial. JAMA Pediatr. 2018;172(11):1045–1052.
40. Voysey M, Kelly DF, Fanshawe TR, et al., The influence of maternally
derived antibody and infant age at vaccination on infant vaccine
responses: an individual participant meta-analysis. JAMA Pediatr.
2017;171(7): 637–646. .
•• A meta-analysis of 32 randomized clinical trials to assess the
influence of pre-existing maternal antibody concentrations
(none of the studies implemented maternal vaccination) and
infant age at first vaccination on infant’s vaccine responses.
This study described immune interference (blunting) as a nat-
ural phenomenon that happens in the absence of maternal
immunization.
41. 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.
42. Joint Committee on Vaccination and Immunisation. Minute of the
meeting held on 2019 June 05. Available from: https://app.box.
com/s/iddfb4ppwkmtjusir2tc
43. World Health Organization (WHO). Pertussis vaccines: WHO posi-
tion paper - September 2015. Wkly Epidemiol Rec. 2015;90
(35):433–458.
44. Barug D, Pronk I, van Houten MA, et al. Maternal pertussis vaccina-
tion and its effects on the immune response of infants aged up to
12 months in the Netherlands: an open-label, parallel, randomised
controlled trial. Lancet Infect Dis. 2019;19(4):392–401.
45. Maertens K, Leuridan E. Maternal pertussis immunisation as the first
infant dose. Lancet Infect Dis. 2019;19(4):342–344.
46. Health Council of the Netherlands. Vaccination schedule for infants
after maternal pertussis vaccination - executive summary.
47. Niewiesk S. Maternal antibodies: clinical significance, mechanism of
interference with immune responses, and possible vaccination
strategies. Front Immunol. 2014;5:446.
48. Orije MRP, Maertens K, Corbiere V, et al. The effect of maternal
antibodies on the cellular immune response after infant vaccina-
tion: a review. Vaccine. 2020;38(1):20–28.