Maternal pertussis (Tdap) vaccination and its effects on the immune response of the newborn up to 12 months of age.

Pertussis, *Whooping cough* caused by the Bordetella pertussis bacterium, is a
highly contagious potentially life-threatening respiratory illness especially
in infants less than 6 months of age. Recently there has been a considerable
increase in pertussis activity with a sharp increase in incidence rate in
infants < 2months of age who are too young to be protected through routine
vaccination but with the highest risk of complications and death. A possible
alternative way to protect these very young infants is by indirect protection,
either through a cocooning strategy, i.e. vaccinating primary caregivers of
new-borns, or by passive transfer of maternal antibodies induced by maternal
vaccination. The purpose of this trial is to evaluate the possibility to
provide initial immunological protection of newborn babies against pertussis
infection by passively acquired maternal IgGs after vaccination of pregnant
women. Pregnant woman will receive a single dose of a combination vaccine
including reduced dose acellular pertussis, tetanus toxoid and reduced dose
diphtheria toxoid (Tdap) between week 30 and 32 of pregnancy. The control group
will consist of pregnant women who will be vaccinated with the same Tdap
vaccine postpartum. All infants, born of pregnant women of both groups, will
then be vaccinated with the routine vaccines of the national immunisation
program (NIP) DtaP-IPV-Hib-Hep and PCV10 at the age of 3, 5 and 11 months
instead of the standard schedule of 2, 3, 4, and 11 months. Experience in other
countries and our own research has shown that vaccinations at age 3 and 5
months, followed by a booster dose will result in equal clinical effectiveness
in protection against Hib, pneumococcus, diphtheria, tetanus and polio compared
with a schedule which starts at 2 months of age. Infants will probably, up to 3
months of age, be protected through the presence of maternal pertussis
antibodies (group 1) or by reducing the risk that new-borns will be infected by
their parents by vaccinating their mother and partner or other primary
caregivers (cocooning strategy, group 2). In this way the total number of
vaccines each child gets can be reduced.

Primary objective;
Confirm superiority of IgG antibody levels against pertussis toxin (Ptx),
present in the acellular vaccines, in infants at the age of 3 months of mothers
having received a pertussis vaccine during pregnancy versus infants of mothers
who have been vaccinated postpartum.

Secondary objectives:
- Determine the effect of the presence of maternal antibodies in the infant on
the infant's immune response to active immunization with pertussis vaccine
- Compare serum IgA levels against pertussis antigens of infants of both groups
at the age of 2, 3, 6, 11, 12, 24, 46 en 47 months
- Determine the rate of maternal antibody decline in infants between birth and
at 2 and 3 months of age before the first infant pertussis vaccination
- Determine levels of pertussis IgG antibodies transferred from the mother to
the neonate relative to the interval from immunization to delivery, if possible
depending on the variation in interval;
- Determine whether maternal immunization during pregnancy interferes with
active antibody production following routine DTaP-IPV-Hib-Hep and PCV10
vaccination in infants at 3, 6, 11, 12, 24, 46 en 47 months of age
- Assess cellular immune response (Plasma B cells and memory B cells)
immediately before and 7-9 days after the booster dose at 11-months of age
- Assess cellular immune response (Plasma B cells and memory B cells)
immediately before and 28-35 days after the booster dose of around 4 years of
age
- Safety evaluation after Boostrix (Tdap) vaccination during pregnancy
- Assess pertussis IgG antibody levels in mothers of both groups,
pre-vaccination, at delivery (=pre-vaccination for control group) and at 6, 12,
24 and 47 months post-delivery;
- Compare IgA levels against pertussis antigens in breast milk of both groups
at the infants age of 7-10 days and 3 and 6 months of age
- Compare infants pain response and maternal response to infant blood
collection by heel stick and venipuncture

Randomised, controlled intervention trial

Pregnant woman in group 1 will receives a single dose of Boostrix vaccine
between week 30 and 32 of pregnancy and pregnant woman in group 2 will receive
a single dose of Boostrix vaccine postpartum.
All partners or other caregivers will receive a single dose of Boostrix within
28 hours after birth.

Available data on the use of Tdap in pregnant women does not suggest any
elevated frequency or unusual patterns of adverse events in pregnant women who
received Tdap.

Group 1a and 2a; 7 heel/finger stick blood collections of 250 µl will be
performed, the 11 months sample will be taken from the 4 ml sample.
Group 1b and 2b: 8 heel/finger stick blood collections of 250 µl will be
performed.
The burden and risk is considered low.
One cord blood sample will be collected from all participating infants at
birth.

One 8 ml blood sample will be collected from all infants, either immediately
before vaccination at the age of 11 months or 7-9 days after the 11 months of
age vaccination.
Optional: One 10 ml blood sample will be collected from infants, either
immediately before vaccination at the age of 4 years or 28-35 days after
vaccination of around 4 years of age. The burden and risk is considered low. It
might be painful but only for a few seconds. Blood collection could result in a
small bruise at the needle stick location, which will disappear within a few
days.

To reduce the burden of 11-12 visits, home visits will be performed.

Mothers will be asked to collect 10 ml of breastmilk at 3 timepoints during the
studie
The burden and risk is considered low.