Maternal immunisation

Elke Leuridan, MD, PhD

Center for the Evaluation of Vaccination

Vaccine & Infectious Diseases Institute

Outline of the talk

1.General introduction

2. Pertussis vaccination in pregnancy

a) Safety

b) Immunogenicity

c) Interference/blunting

d) Effectiveness

3. Influenza vaccination in pregnancy

a) Safety

b) Effectiveness

4. Conclusion

1. General introduction

Vaccination during pregnancy: triple goal

• Protection of the pregnant woman (influenza)

• Protection of the foetus (influenza, CMV)

• Protection of the newborn (tetanus, pertussis, influenza, GBS, RSV)

• Newborns have an increased susceptibility to infectiousdiseases

• Augmenting the amount of maternal antibodiestransported towards the foetus

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Advantages of vaccination usually outweigh the potential risk of a side effect.

Every woman should start a pregnancy in a perfectly protectedstatus: pre-conceptional consult (food- folic acid- vaccinationstatus- serological status- irregular antibodies…)

Vaccines containing inactivated material do not appear to beharmful to foetus or pregnant women. Attenuated vaccines are contra-indicated in pregnant women(1 mo anticonception in fertile aged women)

A few general rules

• Pregnant □ Control

Effect of ’pregnancy’ on humoral immune responses

Huygen et al Vaccine 2015

1. Maternal titer• Time since contact

vaccine/pathogen• Vaccination versus

disease• Dilution blood

volume in pregnancy

2. Placenta: • FcRn receptor• Disease of the

placenta

Faucette A N et al. Hum. Reprod. Update

3. Gestational age• Placental function

Malek 1996

Determinants of the amount of maternal antibodies in infants

PERTUSSIS vaccination in pregnancy

Infants: 3 doses at 8-12-16 weeks + booster dose at 15 months(aP)

Children: 1 dose at 4-6 years (aP)

Adolescents: 1 dose at 14-16 years (since 2009) (aP)

Adults: 1 dose dTpa:

• For adults who did not receive the booster at 14-16 years

• Pregnant women every pregnancy between 24-32 weeks of gestation (since 2013)

• Adults in regular contact with infants (< 12 months)

Future parents

Grandparents

Personel in nurseries

Heatlh care personel

HGR-CSS: Belgium pertussis vaccination policy

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National Reference Laboratory forPertussis

General introduction

Source: https://www.wiv-isp.be/pedisurv/AnnualReports/CurrentReport/jaarverslag_nl.pdf

UK: - N= 17.560 women: FU until 28 days post

vaccination- N= 6.185 women: FU until 44 weeks post-last

day menstruation- Risk assessment: stillbirth, maternal or

neonatal death, (pre-) eclampsia, haemorrhage, fetal distress, uterine rupture, placenta (vasa) praevia, C section, low birthweight, neonatal kidney failure, other severe diseases Donegan BMJ 2014

Safety

US, 2 California VSD sites (Tdap): Kharbanda Jama 2014

- Risk assessment: sga, prematurity, hypertensive disorders, chorioamnionitis

- N= 123.494 women- RR chorioamnionitis 1.19- 50% confirmed after revision of charts; no preterm birth association

VAERS chorioamnionitis (Tdap): Datwani Vaccine 2015

- Chorioamnionitis was found to be uncommonly reported, representing 1% (N=31) of pregnancy reports to VAERS

- No clear risk factor

Review (general): - No evidence for increased risk- Benefit> risk- Importance of background incidence rates- Surveillance necessary

Keller Stanlowski Vaccine 2014

Muñoz et al JAMA 2014

Immunogenicity

Maertens & Leuridan et al, accepted, Vaccine 2016

Prospective study

Vaccine group (Boostrix): N= 57 women, 55 infants

Control group (no vaccine): N=42 women, 26 infants

Infants received Infanrix hexa

Interference/ blunting by maternal antibodies

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- Blunting by high titers of maternal antibodies for tetanus and pneumococcal responses, yet not for aP responses (p0.14) (Jones et al Vaccine 2014)

- Interference of maternal antibodies has been described with infant immune responses to wP vaccines (Sako W TW Jama 1945; Provenzano NEJM 1965; Englund JA, Pediatrics 1995)

RCT USA: prospective double blind placebo controlled

Muñoz et al JAMA 2014

Pre- iMap: at 2 months before primary immunisationPost-iMap: at 5 months (one month after primary immunisation)Post P13-UK: at 5 months for historical cohort of infants whose mothers did not receive pertussis vaccine in pregnancyIMAP cohort: N= 141 infantsHistorical control: N= 203 infants

Ladhani et al CID 2015

Conclusion: high pre-immunization antibody concentrations, but blunting of subsequentresponses to pertussis toxinEffect on other components of infant vaccination schedule- CRM conjugated vaccines: less good

responses- MCC-TT and Hib-TT enhanced response

Study UK: prospective, historically controlled

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Pregnancy 1 monthpostvacc

At delivery Cord Prevacc Postvacc Preboost Postboost

An

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/mL)

Anti-PT antibodies

PT Vaccine group

PT Control group

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100,00

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Pregnancy 1 monthpostvacc

At delivery Cord Prevacc Postvacc Preboost Postboost

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Anti-FHA antibodies

FHA Vaccine group

FHA Control group

0,00

100,00

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Pregnancy 1 monthpostvacc

At delivery Cord Prevacc Postvacc Preboost Postboost

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U/m

L)

Anti-Prn antibodies

Prn Vaccine group

Prn Control group

Light colour: Vaccine group

Dark colour: Control group

Star mark: Statistically significant

Maertens et al. Vaccine. Accepted for publication.

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0,00

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Pregnancy 1 monthpostvacc

At delivery Cord Prevacc Postvacc Preboost PostboostAn

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(IU

/mL)

Anti-TT antibodies

TT Vaccine group

TT Control group

0,00

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Pregnancy 1 monthpostvacc

At delivery Cord Prevacc Postvacc Preboost PostboostAn

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/mL)

Anti-DT antibodies

DT Vaccine group

DT Control group

Light colour: Vaccine group

Dark colour: Control group

Star mark: Statistically significant

Maertens et al. Vaccine. Accepted for publication.

Effectiveness

Historical data on maternal PT vaccinationwith wP vaccines

http://www.who.int/immunization/sage/meetings/2014/april/3_SAGE_April_Pertussis_Miller_Strategies.pdf?ua=1

Effectiveness on hospitalisation, caused by pertussis disease among young infants

Amirthalingam et al Lancet 2015

Maertens et al, 2016, BJOG in revision

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INFLUENZA vaccination in pregnancy

Groep 1: personen met risico voor complicaties, d.w.z.:

1. zwangere vrouwen die in het tweede of derde trimester van hun

zwangerschap zijn op het ogenblik van het griepseizoen. Zij worden gevaccineerd

vanaf het tweede trimester van de zwangerschap

2. alle patiënten vanaf de leeftijd van 6 maanden die lijden aan een

onderliggende chronische aandoening, ook indien gestabiliseerd, van de longen

(inclusief ernstig astma), het hart (uitgezonderd hypertensie), de lever, de nieren,

aan metabole aandoeningen (inclusief diabetes), aan neuromusculaire

aandoeningen of aan immuniteitsstoornissen (natuurlijk of geïnduceerd)

3. alle personen vanaf 65 jaar

4. alle personen die in een instelling opgenomen zijn

5. kinderen tussen 6 maanden en 18 jaar die een langdurige aspirinetherapie

ondergaan.

Groep 2: alle personen werkzaam in de gezondheidssector

Groep 3: personen die onder hetzelfde dak wonen als

1.de risicopersonen van groep 1

2.kinderen jonger dan 6 maanden.

Reasons for vaccination: - Higher susceptibility for influenza (Th1-Th2 shift And

physionomic: higher diaphragm, faster breathing frequencyand more superficial respiration)

- Pandemic flu: higher risk for hospitalisation on ICU, mechanical ventilation and mortality (up to 26% of allhospitalisations on ICU) (Siston JAMA 2010; Knight BJOG 2011)

- Postpartal still higher risk for severe disease (Mertz BMJ 2013)

- Congenital anomalies and IUGR, prematurity, missedabortions, stillbirths, spina bifida, split lip, limb reduction

Timing:- in USA all trimesters,

in BE only 2e/ 3e trimester- H1N1 study CH: N=188, at least 14 days before delivery(Blanchard Rohner PIDJ 2013)(Dubar PLoS One. 2010 )

- All considered safe except for the live attenuated vaccines

- Adjuvanted pandemic A/H1N1 2009 influenza vaccine: Denmark: N=54.585 pregnancies, no increased risk on fetal death, spontaneousabortion, stillbirth (Pasternak BMJ 2012)

- Seasonal vaccine: meta analysis: no increased risk on fetal death, spontaneous abortion, congenital malformation, but first trimester data are lacking (McMillan Vaccine 2015)

Safety

EffectivenessPregnant women:

- Bangladesh: 36% drop in respiratory infections (Zaman New Engl J

Med 2008)

- S Africa: 50% effectiveness against influenza , less in hiv + (Mahdi NEJM 2014)

- US: 50% reduction respiratory infections among vaccinatedpregnant women (Thompson CID 2013)

Foetus: positive effect on SGA and prematurity, more benefit for higherrisk profile (african american and lower SE situation) (Omer Saad Plos Medicine

2011) (Adedinsewo Vaccine 2013)

Neonate:

positive effect: protection from disease(Zaman N Engl J Med. 2008) (Eick Arch Ped Adolesc Med 2011) (benowitz CID 2010) (Galvao, ISRN Prev Med2013)

Overview: vaccinate safely?

Polio YES Haemophilus YES

Rubella Contraindicated Hepatitis YES

Measles Contraindicated Pneumococcus YES

Mumps Contraindicated Yellow fever Contraindicated

Tetanus/d YES Pertussis YES

Influenza YES Varicella Contraindicated

And more vaccines…

Rabies YES 100% lethal infection, vaccinate if necessary

Tick Borne Encephalitis

YES Seasonality: high risk in Eastern Europe

Japaneseencephalitis

YES Prevention mosquitos!

Meningococcus YES Seasonality! Men-afrivac recommendation in meningitis belt (WER 2011 jan)

Cholera Yes/No 50% immunogenicity, no obligation to immunize

TBC Yes/No Skintest/RX. Treatment treats fœtus!

Small pox No malformations

Anthrax No data

- No vaccine has ever been proven to have embryotoxic or teratogeniceffects

- Theoretically avoid live attenuated vaccine in pregnancy

- Accidental exposure to attenuated vaccines: no indication fordiscontinuation

- Adequate humoral immune response during pregnancy

- Active transplacental transport of maternal antibodies

- Pertussis vaccination during pregnancy

- offers increased antibody titers at birth which last at least until the infant’s first vaccination, thus closing the susceptibility gap

- minor blunting is noticed after infant vaccination

- Influenza vaccination increases the protection against ILI in pregnant women and has a positive effect on the infants’ protection

Take home messages

Acknowledgements

All collaborators at CEV and WIV

All participating women and their lovely children