Key words SARS-CoV-2 vaccine - pregnancy - booster shot - vertical immunity
Schlüsselwörter SARS-CoV-2-Impfung - Schwangerschaft - Auffrischimpfung - vertikale Immunität
Abbreviations
BMI:
body mass index
CDC:
Centres for Disease Control and Prevention
COVID-19:
coronavirus disease 2019
CRONOS study:
COVID-19-Related Obstetric and Neonatal Outcome Study
IgG:
immunoglobulin G
IQR:
interquartile range
mRNA:
messenger RNA
SARS-CoV-2:
severe acute respiratory syndrome coronavirus type 2
SPSS:
Statistical Package for the Social Sciences
Introduction
The COVID-19 pandemic which emerged at the end of 2019 is still ongoing [1 ]. Due to mechanical, physiological, and immunologic changes, pregnant women are
considered a vulnerable group and the risk of certain infections increases with
pregnancy [2 ]. Although pregnancy does not increase the risk of acquiring
SARS-CoV-2 infection, it appears to worsen the clinical course of SARS-CoV-2 infection
compared with non-pregnant women of the same age [3 ]. Due to this
circumstance, many international health organisations and professional societies
recommend vaccination during pregnancy, including the Center for Disease Control and
Prevention (CDC) of the
United States, the American College of Obstetricians and Gynecologists, the German
Society of Gynaecology and Obstetrics (DGGG), the German Society for Perinatal Medicine
(DGPM) and the
Standing Committee on Vaccination at the Robert Koch Institute (STIKO) [4 ], [5 ], [6 ], [7 ].
Newborn protection from infectious diseases is primarily dependent on innate neonatal
immune responses and maternally derived, transplacentally acquired antibodies. Recent
studies have
demonstrated the presence of SARS-CoV-2 antibodies in cord blood after maternal
SARS-CoV-2 infection; however, studies on antibody concentrations after vaccination
have been limited to small
sample sizes or to vaccination in the third trimester [8 ], [9 ], [10 ], [11 ], [12 ], [13 ], [14 ].
The concentration of maternally derived SARS-CoV-2 antibodies at birth is likely to
be an important factor in protecting the newborn against COVID-19. Yet, the optimal
time to vaccinate
during pregnancy in order to achieve high antibody levels in the newborn is not
known. This information can be important for counselling pregnant women and is a convincing
argument for
vaccination and/or booster vaccination during pregnancy.
We aimed to estimate vertically transmitted immunity after COVID-19 vaccination with
BNT162b2 (Comirnaty, BioNTech, Pfizer) or mRNA-1273 (Spikevax, Moderna) during all
trimesters of pregnancy
and to investigate the influence of maternal characteristics on antibody titres
in the umbilical cord at birth.
Methods
This prospective single centre study was designed in compliance with the Declaration
of Helsinki and in accordance with the institutional review board. The study was approved
by the ethics
committee of the medical association of Westfalen-Lippe and the Westphalian Wilhelms
University of Münster (WWU), reference number: 2020-292-b-S. Written informed consent
was obtained prior to
enrolment.
Recruitment and inclusion criteria
Women giving birth between March 2021 and November 2021 at the University Hospital
of Münster who were vaccinated against SARS-CoV-2 during pregnancy had the option
to participate in the
CRONOS Satellite, a subproject of the German Covid-19-Related Obstetric and Neonatal
Outcome Study (CRONOS) [15 ]. The primary aim of the prospective CRONOS
registry is to research the effects of an infection with the novel coronavirus
SARS-CoV-2 or the effects of vaccination against SARS-CoV-2 in pregnancy (CRONOS Satellite)
on the health of
mother and neonate.
In the subgroup who delivered at our hospital, we additionally assessed neonatal antibody
status from umbilical blood samples in a cohort of double-vaccinated women who participated
in
CRONOS Satellite and had singleton or twin live births. Written consent was obtained
during pregnancy and umbilical venous blood samples were examined directly after delivery.
The titre of
IgG to the receptor-binding domain of the SARS-CoV-2 spike protein was measured
using the chemiluminescent microparticle SARS-CoV-2 IgG II Quant immunoassay (Abbott
Diagnostics,
Germany).
Data collection
Data were collected from internal electronic medical records and a specifically developed
electronic case report file at CASTOR EDC (castoredc.com, Amsterdam, NL) [15 ]. These contained the full medical history of the mother (BMI, smoking status, gravidity,
parity, concomitant diseases), demographic characteristics (ethnicity, age), gestational
week at the time of delivery and vaccination history, including pregnancy week
at the time of first and second vaccination, type of vaccine, reason for vaccination,
and symptoms after
vaccination. A follow-up with a structured phone interview 4 – 6 weeks after
delivery collected data on maternal and neonatal well-being, adverse outcomes or child
malformation.
Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences
(SPSS) software, version 28 (IBM Corporation, New York, NY, USA). Descriptive statistics
were used
to characterise the study population. Normally and non-normally distributed parameters
are shown as median and interquartile range. All examined parameters except maternal
age were
non-normally distributed and were analysed as such. All inferential statistics
are intended to be exploratory (hypothesis generating), not confirmatory, and are
interpreted accordingly.
Therefore, no power calculation was performed. The p-values are considered significant
if p ≤ 0.05. Correlations between variables were assessed using Spearmanʼs rank correlation
coefficient
ρ (rho). Correlations between antibody concentration in umbilical cord blood
samples and variables of interest, including time of first or second vaccination, mean interval between
first or second vaccination and delivery in weeks, maternal age and BMI were examined. The correlation between antibody concentrations and gestational week
at vaccination
and time between vaccination and birth was additionally analysed by simple linear
regression analysis. A graphical illustration of regression analyses was performed
with GraphPad Prism
Version 9.3.1 (350), December 7, 2021.
All data was entered by medical residents of the Obstetrics Department of the University
of Münster after a personal medical interview, aside from follow-up data, which was
collected by
phone interview. Validation controls were regularly performed by the study organisation
team of the CRONOS study [15 ].
Results
Study population
Of the 103 women participating in the CRONOS Satellite, 70 women and their 74 newborns
(4 twin pregnancies) were included in the final evaluation ([Fig. 1 ]).
The demographic characteristics and full medical history of the study population
are displayed in [Table 1 ]. The median age (interquartile range/IQR) of
participants was 33.5 (32.0 – 37.0) years, and in 51% of the cases (n = 36/70)
the mother had a pre-existing or concomitant medical condition ([Table 1 ]).
Pregnancy was the single most common reason why women decided to get vaccinated
(74.3%, n = 52/70). The majority of women (89%, n = 62/70) were vaccinated with BNT162b2
and all but one (99%,
n = 69/70) with an mRNA vaccine. All women were double-vaccinated at the time
of birth, and the longest interval between last vaccination and delivery was 36 weeks.
However, the exact week
of gestation at second vaccination was documented in only 80% (n = 56/70) of
the cases. No severe side effects were reported, and only 9% of women reported medium
side effects (e.g., fever
or headache lasting a maximum of 48 h). The vaccination history of the study
population is displayed in [Table 2 ].
Fig. 1 Flow diagram describing patient inclusion.
Table 1 Demographic and medical data of the study population.
Parameter
Value
* Abbreviation: IQR, interquartile range
** Percentages of different organ systems do not add up to the total percentage of
concomitant disease as some women had more than one comorbidity. ‘Other’ includes
neurological,
gastrointestinal, endocrinological, pulmonary system or pre-existing diabetes
mellitus.
Median maternal age (IQR*)
33.5 (32.0 – 37.0)
Ethnic
92.9% (65/70)
2.9% (2/70)
2.9% (2/70)
1.4% (1/70)
BMI (kg/m2 )
23.5 (22.0 – 28.0)
61.5% (43/70)
21.5% (15/70)
17.0% (12/70)
Smoking status
96.0% (67/70)
4.0% (3/70)
Gravida (IQR*)
2.0 (1 – 3)
Parity (IQR*)
1.0 (0 – 1)
Pregnancy
94.0% (66/70)
6.0% (4/70)
Median pregnancy week at delivery (IQR*)
40.0 (39 – 41)
Concomitant disease
49.0% (34/70)
51.0%** (36/70)
8.6%** (6/70)
15.7%** (11/70)
11.4%** (8/70)
22.9%** (16/70)
Table 2 Vaccination history of the study population.
Parameter
Value
* Abbreviation: IQR, interquartile range
Vaccine type
89.0% (62/70)
10.0% (7/70)
1.0% (1/70)
Vaccination in
10.0% (7/70)
30.0% (21/70)
60.0% (42/70)
Median week of gestation at
28.5 (23.0 – 33.0)
32.0 (28.0 – 35.8)
Median time interval in weeks between
11.0 (7 – 16)
7.0 (4 – 11)
Reason for vaccination
74.3% (52/70)
5.7% (4/70)
17.1% (12/70)
2.9% (2/70)
Symptoms after vaccination/
21.0% (15/70)
56.0% (39/70)
9.0% (6/70)
0.0% (0/70)
14.0% (10/70)
Presence of IgG antibodies to the receptor-binding domain of the SARS-CoV-2 spike
protein and exploratory data analysis
IgG antibodies to the receptor-binding domain of SARS-CoV-2 spike protein were detected
in all specimens (n = 74/74, among them 2 pairs of twins). Twin pregnancies were represented
as one
newborn in exploratory data analysis to avoid bias (n = 70). The titre concentration
between twins did not differ strongly (values from dichorionic diamniotic pregnancies:
11 197.9
AU/ml /11 836.4 AU/ml, 21 211.5 AU/ml /20 474 AU/ml, 6548.7 AU/ml /no blood sample, values from monochorionic diamniotic pregnancy: 3151.6 AU/ml /2984.6 AU/ml). The
highest value in italics was considered in the statistical analysis. None of the parameters of interest (week
of gestation at vaccination, time interval between vaccination and birth,
maternal age and BMI) showed a meaningful correlation to cord blood antibody
concentrations ([Table 3 ]). Regression analysis demonstrates no meaningful
correlation of antibody concentrations with time of vaccination during pregnancy
or interval between vaccination and birth ([Fig. 2 a ] and [b ]).
Table 3 Spearman correlation coefficient analysis of SARS-CoV-2 IgG antibodies to the receptor-binding
domain of the SARS-CoV-2 spike protein after vaccination
(n = 70).
Variable
Correlation coefficient (ρ)*
P-value**
* Positive or negative ρ values imply a positive or negative association, respectively.
Value spectrum: ± 0.6 – 0.8 (strong association), ± 0.4 – 0.6 (moderate association),
± 0.2 – 0.4 (weak association), ± 0 – 0.2 (very weak association).
** p ≤ 0.05 was considered significant.
Week of gestation at
0.060
0.620
0.247
0.066
Mean time interval in weeks between
− 0.026
0.832
− 0.202
0.136
Maternal age
− 0.118
0.331
BMI
0.118
0.332
Fig. 2 SARS-CoV-2 antibody concentration in cord blood at birth a as a function of week of gestation at vaccination and b as a function of time interval between
vaccination and birth.
Follow-up
More than three quarters of the women (81%, n = 57/70) participated in the follow-up
4 – 6 weeks after delivery. In 5% (n = 3/70) no valid phone number was documented,
and 14% (n = 10) had
not yet completed the follow-up at the time of data evaluation.
In follow-up surveys no adverse drug events were reported during the postpartum period
of 46 weeks. No malformations in children have been reported in association with the
vaccine.
Discussion
Transplacental transfer of maternal SARS-CoV-2-specific antibodies after infection
in pregnancy has been proven [8 ] – [11 ]. Data
on transplacental transfer after SARS-CoV-2 vaccination is insufficient and is
limited to case series of women vaccinated with BNT162b2 in the third trimester of
pregnancy [9 ], [13 ] and two case reports [10 ], [12 ], [13 ], [14 ]. Most importantly, in this study we were able to demonstrate transplacental passage
of antibodies to the receptor-binding domain of the
SARS-CoV-2 spike protein after vaccination in pregnancy in all cases. Moreover,
antibody concentrations were not dependent on gestational week at vaccination. No
adverse outcome, including
foetal malformation, was reported, even after vaccination in the first trimester.
Antibodies in newborns after maternal SARS-CoV-2 infection during pregnancy have been
detected in 63 – 87% of cases [8 ], [9 ], [11 ]. In our cohort the detection rate after vaccination was 100%. This fact is relevant
for patients who are hesitant regarding vaccination in
pregnancy, as vaccination during pregnancy not only protects against a severe
maternal course of COVID-19 but also provides the newborn with antibodies. These can
potentially shield them from
postnatal SARS-CoV-2 infection. As SARS-CoV-2 antibodies in adults after vaccination
decrease over time [19 ], [20 ], one would
expect fewer antibodies in umbilical cord blood after vaccination in early pregnancy
and a longer interval between vaccination and delivery. In the present study, however,
regression analysis
showed no significant dependence of antibody titres on the above variables and
Spearmanʼs rank correlation coefficient showed only a weak or very weak correlation.
A possible explanation is
that decreasing antibody concentration in maternal plasma over the course of time
is counteracted by a higher transplacental transfer rate in the later weeks of pregnancy,
resulting in an
increase in the fetomaternal antibody ratio [11 ]. Nevertheless, the uneven distribution of gestational age at vaccination with underrepresentation
of
vaccination in the first trimester of pregnancy does not allow a final conclusion.
It is furthermore remarkable that vertically transferred antibodies could be detected
36 weeks after the last vaccination, proving that maternal humoral immunity can last
longer than
6 months. From this information, it can be inferred that a vaccination at any
point in pregnancy will help confer passive immunisation on the newborn.
Recommendations on booster vaccination during pregnancy vary. The CDC and ACOG suggest
that pregnant women may receive a COVID-19 vaccine booster shot in pregnancy [5 ], [21 ]. The Standing Committee on Vaccination at the Robert Koch Institute in Germany (STIKO)
recommends a booster vaccination during pregnancy from
the 2nd trimester onward and the German Society of Gynaecology and Obstetrics
(DGGG) recommends a booster vaccination at least three months after the last dose
[22 ]. Our data supports the general recommendation in regard to potential neonatal immunity
through maternally derived, transplacentally acquired antibodies. A booster vaccination
at
any time during pregnancy could increase neonatal antibody titres.
Although SARS-CoV-2 infection is not known to be widespread in newborns and infants,
this paediatric population is particularly vulnerable to severe disease following
SARS-CoV-2 infection
[23 ], highlighting the urgency of understanding the factors that contribute to neonatal
SARS-CoV-2 immunity.
The main limitation of our work is the small sample size in which specific subgroups
were not sufficiently represented, such as women vaccinated early in pregnancy or
vaccinated with
mRNA-1273. Although this is one of the largest cohorts on the topic, it is possibly
too small to detect clinical variables that influence neonatal SARS-CoV-2 IgG antibody
concentrations. A
maternal SARS-CoV-2 infection before or during pregnancy, which could influence
neonatal IgG levels, was excluded only by medical history. Moreover, the study is
limited by an inability to
assess persistent immunity and antibody transfer ratios, as well as the exclusive
focus on antibody titres rather than neutralising antibodies.
The strengths of this work include high data security and quality, as our project
was part of the centrally designed CRONOS study. Moreover, participants were recruited
after personal medical
interview, which ensures correct data collection. The unanimous detection of IgG
antibodies to the receptor-binding domain of the SARS-CoV-2 spike protein in all umbilical
cord blood samples,
irrespective of maternal medical or vaccination history, allows the definitive
statement that after vaccination in pregnancy maternal antibodies do vertically transfer
to the newborn.
Future studies with larger patient cohorts and longer follow-up times for mother and
child, including regular determination of antibody levels of both, could give an insight
into placental
transfer ratios after COVID-19 vaccination during pregnancy. Moreover, determination
of neutralising antibodies may enhance our ability to understand whether and to what
extent vertically
transferred immunity after vaccination protects the newborn from SARS-CoV-2 virus.
Future studies should also define the optimal window for primary immunisation or booster
immunisation to
ensure neonatal immunity. Moreover, data collection on vaccination in the first
trimester is necessary, as postponement of vaccination or booster vaccination during
the ongoing pandemic poses
a health risk for vulnerable populations, e.g., women with relevant concomitant
diseases.
In conclusion, our data provides evidence for the presence of antibodies against SARS-CoV-2
in all analysed umbilical cord blood samples after maternal vaccination at any time
during
pregnancy. This is an additional argument when counselling women to get vaccinated
during pregnancy.
Clinical trial identification number: DRKS00021208
URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021208
