The effectiveness and safety of vaccinating pregnant women Helen Petousis-Harris, PhD Director of Immunisation Research and Vaccinology April 2018

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1 Friday, 20 April 2018 The effectiveness and safety of vaccinating pregnant women Helen Petousis-Harris, PhD Director of Immunisation Research and Vaccinology April 2018

2 Mechanism and effectivess for maternal immunisation Optimal timing of pertussis vaccination Safety of maternal vaccination 2

3 Primary mechanism for maternal immunisation (natures little gift) is active transport across placenta Mechanism Concentrates in fetus IgG, active transport Complemented by IgA in colostrum and breast milk Begins around 13 weeks By 33 weeks maternal and fetal level equivalent By 40 weeks fetal IgG concentration higher than maternal Maternally acquired antibody provides short term passive immunity

4 Maternal Tdap is >90% effective when given at least 7 days before birth, and sustained Amirthalingam, Gayatri, Nick Andrews, Helen Campbell, Sonia Ribeiro, Edna Kara, Katherine Donegan, Norman K. Fry, Elizabeth Miller, and Mary Ramsay. "Effectiveness of maternal pertussis vaccination in England: an observational study." The Lancet (2014).

5 Vaccine Effectiveness of maternal Tdap in preventing pertussis in 148,981 new born s first year of life Effectiveness of maternal pertussis vaccine when given >8 days prior to birth for first 12 months of life 69.0% ( , p=<.001) Baxter, Roger, Joan Bartlett, Bruce Fireman, Edwin Lewis, and Nicola P. Klein. "Effectiveness of vaccination during pregnancy to prevent infant pertussis." Pediatrics (2017): e /04/2018 5

6 Optimal timing? Higher cord sera at weeks compared with weeks Evidence that second trimester results in higher birth anti-pt titres in neonates Bahaa Abu Raya, et al. The effect of timing of maternal tetanus, diphtheria, and acellular pertussis (Tdap) immunization during pregnancy on newborn pertussis antibody levels A prospective study (2014), Vaccine, 32;44: , Madison A. Naidu, et al. The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study. American Journal of Obstetrics and Gynecology (2015) Christiane S. Eberhardt, Geraldine Blanchard-Rohner, Barbara Lemaître, Christophe Combescure, Véronique Othenin-Girard, Antonina Chilin, Jean Petre, Begoña Martinez de Tejada, Claire-Anne Siegrist; Pertussis Antibody Transfer to Preterm Neonates After Second- Versus Third-Trimester Maternal Immunization, Clinical Infectious Diseases, Volume 64, Issue 8, 15 April 2017, Pages /04/2018 6

7 In summary Immunising mum against whooping cough induces protective antibodies preventing whooping cough in 9/10 babies before they can be immunised themselves 9/10

8 Maternal influenza vaccination offers reasonable protection to the baby after birth - WHO recommends, regardless of trimester Good immune response Protects mum Good transfer of antibody to fetus similar to non pregnant women Prevents 67% (51-78%) of serologically confirmed influenza non pregnant healthy adults 28% efficacy against any febrile illness in pregnant women Half life days Protective in baby for around 8 weeks (61%) Mak TK, Mangtani P, Leese J, Watson JM, Pfeifer D. Influenza vaccination in pregnancy: current evidence and selected national policies. The Lancet Infectious Diseases 2008;8(1): Jefferson TO, Rivetti D, Di Pietrantonj C, Rivetti A, Demicheli V. Vaccines for preventing influenza in healthy adults.[update of Cochrane Database Syst Rev. 2004;(3):CD001269; PMID: ]. Cochrane Database of Systematic Reviews 2007(2):CD Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, et al. Effectiveness of Maternal Influenza Immunization in Mothers and Infants. N Engl J Med 2008 October 9, 2008;359(15):

9 Flu vaccination in pregnancy works 245,386 women and 249,387 infants in Utah 23,383 vaccinated Infants born to women reporting influenza immunisation during pregnancy had: Risk reductions of 64% for ILI, 70% reductions for laboratoryconfirmed influenza, and 81% reductions for influenza hospitalisations in their first 6 months. Shakib, J. H., Korgenski, K., Presson, A. P., Sheng, X., Varner, M. W., Pavia, A. T., & Byington, C. L. (2016). Influenza in Infants Born to Women Vaccinated During Pregnancy. Pediatrics, e /04/2018 9

10 Maternal influenza vaccine associated with improved birth outcomes in flu season No difference in flu off-season for outcomes Flu-like illness 25% in vaccinated v 44.8% in unvaccinated SGA 3.7 per 100 person months compared with 7.2 per 100 Mean BW 3178g in vaccinated v 2978g in unvaccinated Steinhoff, M. C., Omer, S. B., Roy, E., El Arifeen, S., Raqib, R., Dodd, C.,... & Zaman, K. (2012). Neonatal outcomes after influenza immunization during pregnancy: a randomized controlled trial. Canadian Medical Association Journal, 184(6), /04/

11 Safety of maternal immunisation How safe? Biological first principals How tested? Prospective trials Observational studies Examples of studies LBW, Still birth, congenital NZ PIPS active surveillance Cohort study. 11

12 Most vaccines have been, and can be, used safely in pregnant women Live attenuated Killed/Inactivated Sub unit and toxoid Viral Measles Mumps Rubella Varicella Zoster Rotavirus Yellow fever Bacterial BCG Killed refer to bacterial wpertussis Inactivated refers to viral Polio HepA Influenza Excreted toxin Tetanus Diphtheria ap toxin Selected antigens HepB Hib Pneumococcal apertussis HPV Meningococcal Images Dow AgroSciences LLC

13 What is in a vaccine 1. The immunogen! 2. Sometimes an adjuvant (immune enhancer), usually aluminium salt 3. Sometimes a preservative (2- phenoxyethanol) 4. Buffer, stabiliser, tonicity. Usually table salt, gelatin, polysorbate 5. Residuals (measured in nanograms or ppb) Quantities are very small and not harmful, very rare allergic reactions can occur 13

14 Biological mechanisms 20/04/

15 Live vs. non-live vaccines Non-live vaccines, transported To local lymph node, local immune response Live vaccines induce a systemic response Vaccines are digested and removed from the body. They do not persist.

16 How vaccines are assessed for safety 20/04/

17 Vaccine safety is monitored at many levels globally Also: FDA CDC EMA MedSafe Etc NIPs WHO and SAGE Provide advice WHO Global Advisory Committee on Vaccine Safety 14 multidisciplinary members Nominated by Director of WHO Department of Essential Medicines and Health Products Determine causal relationships Ad hoc task forces incl. urgent matters Provide recommendations to assist WHO, governments and international organisations Basic sciences Epidemiology Collaboration with experts

18 Vaccine safety is monitored at many levels globally Basic science Epidemiology WHO GACVS WHO SAGE Expert collaboration 14 multidisciplinary members Nominated by Director of WHO Department of Essential Medicines and Health Products Determine causal relationships Ad hoc task forces incl. urgent matters Provide recommendations to assist WHO, governments and international organisations NIPs FDA CSC EMA MedSafe Etc 20/04/

19 Vaccine safety modern approaches to studies Through life of product Multiple methodologies Evidence as a whole Biological Clinical studies Observational studies Clinical trials Passive safety surveillance Vaccine safety Large linked databases Clinical centres 20/04/

20 Passive surveillance hypothesis generating 125 national pharmacovigilance centres collecting spontaneous reports CAEFISS VAESCO VAERS China NCADRM NPCs Singapo re VCB TGA Centre for Adverse Reaction Monitoring (CARM)

21 Example of passive safety surveillance - US Vaccine Adverse Event Reporting System Found no unusual patters of pregnancy complications of fetal outcomes 20/04/

22 Active surveillance Usually large observational studies using data-linkage Some countries are able to produce large observational studies with very low risk of bias. 22

23 Maternal pertussis vaccination safety studies no safety concerns VAERS 3389 pregnancy reports VAERS Enhanced surveillance 000,000s US, VSD, 26,229/12 3,494 US Single centre 7152/7378 US/VSD enhanced surveillanc e 53,885/ 438,487 Datwani H, Moro PL, Harrington T, Broder KR. Chorioamnionitis following vaccination in the Vaccine Adverse Event Reporting System. Vaccine 2015;33: Morgan JL, Baggari SR, McIntire DD, Sheffield JS. Pregnancy Outcomes After Antepartum Tetanus, Diphtheria, and Acellular Pertussis Vaccination. Obstetrics & Gynecology 2015;125: Donegan K, King B, Bryan P. Safety of pertussis vaccination in pregnant women in UK: observational study. BMJ 2014;349:g4219 Kharbanda EO, Vazquez-Benitez G, Lipkind HS, et al. Evaluation of the Association of Maternal Pertussis Vaccination With Obstetric Events and Birth Outcomes. JAMA. 2014;312(18): doi: /jama Moro PL, Cragan J, Tepper N, Zheteyeva Y, Museru O, Lewis P, et al. Enhanced surveillance of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines in pregnancy in the Vaccine Adverse Event Reporting System (VAERS), Vaccine. 2016;34(20): Kharbanda, E. O., Vazquez-Benitez, G., Lipkind, H. S., Klein, N. P., Cheetham, T. C., Naleway, A. L.,... & McCarthy, N. (2016). Maternal Tdap vaccination: Coverage and acute safety outcomes in the vaccine safety datalink, Vaccine, 34(7), UK, 20,074 vaccinate d + matched controls No safety concerns 2017 Systematic review 21 studies

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25 We have the ability to test hypotheses when they arise No increased risk for microcephaly. Structural defects similar in each group. DeSilva M, Vazquez-Benitez G, Nordin JD, et al. Tdap vaccination during pregnancy and microcephaly and other structural birth defects in offspring. JAMA. 2016;316(17): /04/

26 From down under: Three studies to explore safety of pertussis vaccine in pregnancy (PIPS) Study 1 Cohort study (data-linkage) Studies 2&3 - Active Safety Surveillance Diaries, phone interviews PHO Enrollment Collection Practice Manageme nt Systems NHI database Data linked by individual NHI National Minimum Dataset EpiSurv notificatio ns database School Based Vaccinatio n System National Immunisat ion Register 20/04/

27 2-3 per 100 pregnant NZ women have severe injection site pain after Tdap injection PAIN (N = 793) n (%) None 146 (18.4) Mild, still able to move arm normally 347 (43.8) Moderate, hurts to move arm normally or to touch 279 (35.2) Severe, unable to move arm 21 (2.7) Onset of pain after injection, n = hours 543 (83.9) hours 103 (15.9) hours 1 (0.2) Resolution of pain, n = hours 161 (25.1) hours 227 (35.4) >49 hours 253 (39.5) Petousis-Harris H, Walls T, Watson D, Paynter J, Graham P, Turner N. Safety of Tdap vaccine in pregnant women: an observational study. BMJ open. 2016;6(4):e /04/

28 Systemic events are uncommon in NZ pregnant women receiving Tdap. SYSTEMIC Onset within 24 Co-administered flu vaccine EVENTS hrs n (%) of sample n (%) of sample (N=793) n (%) n (%) 31 (3.9) 27 (87) Headache/Dizzy 22 (2.8) 19 (86) Nausea/Vomiting 67 (8.4) 58 (86) Fatigue 24 (3.0) 21 (88) Myalgia/Arthralgia experiencing event 13 (42) 5 (23) 17 (25) 6 (25) with 24-hour onset 11 (41) 5 (26) 13 (22) 6 (29) Petousis-Harris H, Walls T, Watson D, Paynter J, Graham P, Turner N. Safety of Tdap vaccine in pregnant women: an observational study. BMJ open. 2016;6(4):e /04/

29 No serious events in 793 pregnant NZ women causally related to Tdap within four weeks Participant Event SAE definition Onset post Tdap Gestation (weeks) 1 PV bleeding Required hospitalisation 11d 30/40 2 Hypertension in Required hospitalisation 28d 40+/40 pregnancy 3 Pelvic pain, bacterial Required hospitalisation 9d 34/40 vaginitis 4 Fetal death (trisomy 11q) Resulted in death 8d 36/40 5 Cellulitis Required hospitalisation 7d 38/40 6 Hypertension in Required hospitalisation 7w 39+/40 pregnancy 7 Threatened labour and Group A strep infection Required hospitalisation 20d 31/40 8 Maternal tachycardia Required hospitalisation 16d 34/40 9 Gestational diabetes and Required hospitalisation 30d 34/40 antenatal partum haemorrhage 10 Preterm labour Required hospitalisation 1d 35/40 11 Preeclampsia Required hospitalisation 6d 34/40 12 Preterm labour Required hospitalisation 7d 33/40 13 Preeclampsia Required hospitalisation 7d 36/40 14 Preterm labour Required hospitalisation 16d 35/40 15 Perinatal death Resulted in death 52d 40/40 16 Vaginal bleeding Required hospitalisation 28d 35/40 17 Preterm labour Required hospitalisation 9d 35/40 18 Infection Required hospitalisation 1d 33/40 20/04/2018 Petousis-Harris H, Walls T, Watson D, Paynter J, Graham P, Turner N. Safety of Tdap vaccine in pregnant women: an observational study. BMJ open. 2016;6(4):e

30 NZ cohort study using data-linking: No safety concerns 350,041 women contributed pregnancy person-time from Restricted cohort of 68,550 women eligible to receive funded Tdap vaccination antenatally from 28 to 38 weeks gestation during 2013, 8,178 (11.9%) received Tdap vaccine and 60,372 (88.1%) did not. Decreased risk No effect Increased risk pre-eclampsia with severe features, antenatal bleeding, preterm labour, premature rupture of membranes, pre-term delivery, hyperemesis gravidarum, urinary tract infections, rhesus isoimmunisation, other fetal problems, placenta previa, and false labour moderate to late preterm birth, low birth weight and small for gestational age (SGA) gestational hypertension, preeclampsia, gestational diabetes mellitus, fetal growth restriction, placental abruption, chorioamnionitis, premature rupture of membranes, labour dysfunction, first-stage labour dysfunction, second-stage labour dysfunction, fetal distress, post-partum haemorrhage, maternal fever during labour, C-section delivery, maternal sepsis, maternal fever after labour, anaemia, neurologic disorders and hyperemesis gravidarum. stillbirth, infant Apgar score at 5 minutes after birth, microcephaly, asphyxia, sepsis or infection, hypoxic ischemic encephalopathy lactation disorders and perineal laceration during delivery ankyloglossia and neonatal erythema toxicum 20/04/ Petousis-Harris, Griffin, Jiang, Yu, Howe, Watson, Turner, Walls. unpublished data,

31 Nutshell: The are no particular concerns about vaccinating pregnant women, research demonstrates safety for both mum and baby Vaccines are given to the mother and do not pass to the fetus, only mum s antibody does There are no biologically plausible risks that place mother or baby at greater risk for vaccine associated event Ongoing research supports the safety of vaccines for pregnant women and their babies An absence of evidence of harm Biological plausibility No signal detection Significant evidence of safety