Boostrix: An Update on Tdap Vaccine in Pregnancy

Why is immunisation important in pregnancy?

1. An Update on Maternal Immunisation with Tdap Vaccine Dr Nupur Gupta

2. Maternal Immunization To protect the newborn in 6-8 weeks after birth To protect both mother and foetus during pregnancy Vaccination to boost maternal antibodies , aiming to

3. Maternal immunization: benefits to mother, foetus & young infants Inactivated influenza, Tetanus toxoid, Tdap ( acellular pertussis vaccines ) Chu HY & Englund JA. Clin Infect Dis 2014;59:560 –56 8

4. Tetanus, Diphtheria & pertussis are very serious diseases Tdap vaccine can protect against all of these Before vaccines , almost 2 lac cases of diphtheria & tetanus were reported in US each year Post vaccination , cases reduced by about 99% for diphtheria & 80% for pertussis Why Get Vaccinated?

5. Pertussis (Whooping Cough) Highly contagious respiratory infection Gram-negative bacterium Bordetella pertussis It affects people of all ages (adults – mild, baby not vaccinated – life threatening) Transmission: airborne droplets or direct contact with nasopharyngeal discharges from an infected person Humans are the only reservoirs

6. Severe bouts of coughing “Whooping” sound is heard when they try to breathe & gasp for air Whooping Cough

7. Pertussis has been seen highest in the period between birth and 6–8 weeks of age 2,4 > 90% of infants under 2months with pertussis infection are hospitalized 3 76% of pertussis related deaths occur in infants aged under 2 months 4 1.Berti E, et al. Acta Paediatr 2014;103:846–9.) 2. Meulen et al,CID,2016 3. Hong JY. Update on pertussis and pertussis immunization. Korean J Pediatr 2010;53(5):629–633 . 4. Healy CM et al Hum Vac Imm 2016 Prevalence of the Disease

8. Pertussis Trends 8 January 2016

9. Pertussis incidence is increasing in adolescents across the world Since 2005, there has been an increase in pertussis incidence in the 10–14 year age group 2010: 80% in ≥ 10 year olds 1998: 29% in ≥ 10 year olds Pertussis is not just a childhood disease 1 . Adolescents account for an increasing proportion of pertussis cases Pertussis cases increased by around 50% England and Wales 3 1 USA 5 Europe 1,4

10. is caused by a bacterium often found in soil. Once it enters the body it releases a toxin that attacks the  nervous system , causing  muscle spasms & death if left untreated. Tetanus or Lockjaw

11. D iphtheria a respiratory disease that can cause  breathing problems, paralysis,  heart failure, & death . It is highly contagious & is spread by  coughing & sneezing

12. Without vaccination – 50 infants born in a hospital will become sick every yr (40 will need hospitalisation ) With vaccination - Only 4 babies will get whooping cough How effective is vaccination in pregnancy ( pertussis )?

13. Adolescents 11 – 12 years (if missed, asap ) Td booster every 10 years In every pregnancy Contraindications – H/o life threatening allergic reaction or coma or long repeated seizures to any component of DTP Caution – if seizures or GBS Tdap Vaccine

14. Pain, redness, swelling at injection site Fever, headache or tiredness Nausea, vomiting, diarrhoea or stomach ache Chills, bodyache , swelling of the arm Allergic reaction – hives, swelling of face, difficulty in breathing, palpitation, dizziness or weakness Risks

15. Childhood vaccination helps prevent complications and deaths in infants 1 Pertussis in adolescents is characterized by Long-lasting , non-specific , mostly misdiagnosed cough 1 However, vaccination does not confer lifelong immunity. It wanes off 4-12 years after vaccination 2 Immunity against pertussis wanes over time Adolescent and pre school booster vaccination helps protect them against pertussis 1 4-6 years Zepp et al. Lancet Infect Dis 2011;11(7):557–570 Wendelboe et al. Pediatr Infect Dis J 2005:24;S58–61

16. Tdap in Pregnancy & Adolescents Inactivated non infectious bacterial products Boostrix (GSK)

17. Adacel ( Sanofi Pasteur) Tdap in Adolescents

18. Optimal Timing 27 to 36 weeks (To take advantage of naturally occurring process of antibody transfer) (Also to achieve higher antibody concentration in the fetus) Or at least 2 weeks prior to delivery Protection of infant is up to 6 months of delivery till their routine course is completed

19. Postpartum Tdap is not protective It takes 2 weeks after administration that protective antibodies are formed So does not provide immunity to infant Women who have received a Tdap as adolescents or adults but not in pregnancy, should not receive the vaccine postpartum.

20. Cocooning may not be effective It means vaccinating anyone who comes in close contact with the infant It is hard to implement It is costly too

21. Tdap should not be offered as part of preconception care Because protection does not last long Even if given, has to be repeated in pregnancy (rapid waning of antibody levels)

22. Tdap can be given in early pregnancy also For wound care or during a community outbreak Should not be repeated between 27 to 36 weeks pregnancy (only one dose is recommended) Considered safe at any gestation if indicated

23. Despite high DTP coverage, pertussis cases reported Global distribution - 1,39,535 pertussis cases WHO in 2016

24. Pertussis cases in India (2000-2016) 24 > 30,000 reported cases each year India is the top country by pertussis cases in the world 1

25. Pertussis is under estimated The true incidence of pertussis is likely to be higher in both developed & developing countries due to under-diagnosing & under-reporting

26. Who is at risk of Pertussis ? Infants Adolescents Adults Recommendation to vaccinate is since 2006

27. Pertussis : C omplications in young infants Hong . Korean J Pediatr 2010;53(5):629–633 < 2 months of age Complication Rate, % Hospitalisation >90 Pneumonia 15 – 25 Seizures 2–4 Encephalopathy 0.5 – 1 Death 0.5 – 1

28. Mothers: MC source of pertussis for newborns Percentage of total source contacts with pertussis 37.3 17.6 26.8 4.2 14.9 Main source of infection Sources of infant pertussis cases by contact category (%) Wiley KE, et al. Vaccine 2013; 31:618–625.

29. Adolescents Adults Children Waning immunity 1,4 Vaccine-induced protection 1,4 Limited immunity 1,4 Transmission Elderly Complications & death 5 Older individuals represent a reservoir of infection, potentially transmitting disease to unvaccinated or partially vaccinated infants Young infants As per current practice, only children are vaccinated with DTP, starting at 6 weeks What happens when only children are vaccinated

30. Highly effective in protecting infants from pertussis 4 Vaccination strategies that may help protect young infants from pertussis Adolescent & Adult booster vaccination Cocooning Maternal immunisation

31. What is Tdap vaccine ?

32. Boostrix Prescribing Inform.Version BTX/PI/IN/2017/01 dated 04 Apr 2017 Posology and method of administration A single 0.5 ml dose recommended IM preferably in the deltoid region Boostrix has shown no vaccine related adverse effect on pregnancy or on the health of the foetus in the 3rd & 2nd trimester/newborn child It also doesn’t harm the foetus at any trimester of pregnancy

33. Argentina (safety data > 1.2 Million Doses) Maternal Vaccination coverage (%) National Immunization program 2012 to 2014 Objective: Maternal & infant outcomes 20 adverse events ( rate:1.59/100,000 ) 7 were mild ( 2 episodes of rash & 5 had local pain , redness & swelling ) There were no serious or fatal events reported 1

34. Public Health England (PHE), 2014 A national pertussis outbreak was declared in April 2012 by the Health Protection Agency in the UK Vaccination was recommended for pregnant women from 28 to 32 weeks of pregnancy , to ensure that high levels of antibodies against pertussis cross the placenta from the mother to passively protect the baby when it is born There are no safety concerns at any stage of pregnancy

35. Immunogenicity of Tdap vaccine in Maternal Immunisation Showed efficient transplacental transfer of pertussis specific antibodies Results in high infant antibody concentrations Was associated with the highest umbilical cord antibody when Tdap was administered between 27~31 weeks of gestation

36. Lakshmi Sukumaran et al, JAMA. 2015;314(15): 1581-1587 Morgan JL, et al, Obstet Gynecol. 2015 Jun;125(6): 1433-8 United States (What if freq vaccination?) Among women who received Tdap during pregnancy, No increased risk of acute adverse events or adverse birth outcomes for those who had been previously vaccinated < 2 yrs before or 2 to 5 yrs before compared with those who had been vaccinated > 5 yrs before. These findings suggest that relatively recent receipt of a prior tetanus-containing vaccination does not increase risk after Tdap in pregnancy.

37. 37 Thailand: reactogenicity in Tdap vaccinated pregnant women with prior TT vaccine A prospective randomized controlled study involved healthy Thai pregnant women (631 screened, 370 were enrolled) aged 18–45 year who were offered Boostrix between 26-36 weeks of gestation It did not increase the incidence and severity of any solicited Adverse Events nor resulted in prolonged duration of the symptoms. There was no premature delivery 98 women received in addition to Boostrix at least one extra dose of TT containing vaccine during the same pregnancy (1 dose in 37 women, 2 doses in 60 women,3 doses in 1 woman). N . Wanlapakorn et al. / Vaccine 36 (2018) 1453–1459

38. Safety of Boostrix + FLU vaccinations in pregnancy Sukumaran L,et al. Obstet Gynecol 2015 Vol. 126, NO. 5, Nov 2015 Concomitant group - No statistically significant increased risk of fever or any other Adverse Effect Both groups - No difference in preterm delivery, LBW, or small for gestational age neonates 36,844 pregnancies - Tdap & Flu vaccines concomitantly in 8,464 (23%) pregnancies sequentially in 28,380 (77%) pregnancies Retrospective, cohort study of pregnant women using the Vaccine Safety Datalink from 2007 to 2015

39. No increased risks for any pre-specified maternal safety outcomes within 42 days of vaccination More evidence: generally well tolerated profile Kharbanda EO Vaccine. 2016;34(7):968-73 ; Morgan et al. Obstet Gynecol 2015;125:1433–8) Vizzotti C et al. Vaccine 2015;33:6413-19 Tdap vaccines safety cohort included 53,885 vaccinated pregnant women

40. FOGSI Recommendation Tetanus diphtheria acellular pertussis ( Tdap ) vaccination can be considered instead of the second dose of tetanus toxoid(TT) to offer protection against diphtheria and pertussis in addition to tetanus FOGSI Good Clinical Practice Recommendations on PRECONCEPTION CARE - 2016 " Tdap should be administered during pregnancy in order to provide optimal protection to the baby during its first months of life

41. ACOG Recommendations(Sep 2017) ACOG UPDATE ON Immunization & Pregnancy Sep 2017(718) Administer Tdap vaccine to all pregnant woman as early as 27–36 weeks Pregnant women should be counseled that Tdap during each pregnancy is safe and important to make sure that newborn protected against pertussis at birth If not administered during pregnancy, the Tdap vaccine be given immediately postpartum if the woman has never received a prior dose of Tdap as an adolescent, adult, or during a previous pregnancy

42. IAP recommendation “One dose of Tdap vaccine between 27 to 36 wks gestation regardless of number of years from prior Td or Tdap vaccination ” ACVIP (Advisory Committee on Vaccines and Immunization Practices)

43. VACCINE EFFECTIVENESS STUDIES

44. Australia A 1:1 matched case-control study 16.8.15 to 17.8.16 at New South Wales Vaccine effectiveness (VE) against hospitalization was 94% (95% CI 59–99%)

45. United States California , Connecticut, Minnesota, New Mexico & New York The Vaccine Effectiveness was 90.5% ( 95% CI: 65.2- 97.4) against preventing infant p ertussis h ospitalization A case–control study 1 January 2011 and December 2014.

46. Vizzotti C, et al. Vaccine. 2015 Nov 25;33(47):6413-9 - Reduction in mortality : 87% Overall fatality rate : 69.9% 10 20 30 40 50 60 70 80 2011 2012 2013 0.5 1 1.5 2 2.5 3 0.9 1.7 2.6 10 32 76 Years Number of deaths No. of deaths Fatality rate Fatality rate Infants <2 months of age Argentina (2011- 2013)

47. Spain The adjusted Vaccine effectiveness (VE) was 90.9% (95%CI- 56.6 to 98.1) in protecting newborns against laboratory confirmed pertussis infection A matched case control study was undertaken in the period between 1.3.15 to 29.2.16

48. Countries that implement or recommend pertussis booster vaccine in Maternal Immunisation Country with maternal immunisation recommendation Country without maternal immunisation recommendation > 31 countries have Recommendation/implementation UK S Korea India Australia New Zealand Italy Taiwan Greece Qatar Colombia Suriname Switzerland USA Canada Spain # Belgium Israel Ireland El Salvador Panama Brazil Argentina Paraguay Costa Rica 1.Ivo Vojtek et al. Annals of Medicine,2018:1-16-MI: where are we now & how to move forward 2.Data on file-1

49. 27−30+6 weeks 31−36 weeks or >36 weeks Timing: Which is better?

50. Efficient transplacental transfer of pertussis specific antibodies Antibody responses to pertussis antigens in umbilical cord sera Tdap b/w 27–30 +6 wks was associated with the highest umbilical cord IgG GMCs to PT & FHA compared with immunisation beyond 31 wks of gestation Abu Raya B et al. Vaccine 2014;32(44):5787–5793 GMC, geometric mean concentration; PT, pertussis toxin; FHA, filamentous haemagglutinin ; PRN, pertactin

51. To Summarise The use of Tdap may be considered during the third trimester of pregnancy Tdap in the 3 rd trimester have shown no vaccine related adverse effect on pregnancy or on the health of the fetus/newborn child

52. Boost their immunity with Boostrix Children due for their second DTP booster at 4- 6 years of age Children aged 10 years + due for their adolescent booster 4- 6 years 10 years +

53. Future Research Long-term impact of maternal vaccination in pregnancy on vaccine effectiveness in children & adults Safety & impact of repeated Tdap in subsequent pregnancies; Safety of immunization earlier in pregnancy; Cost-effectiveness of maternal pertussis immunization in pregnancy Development of more effective infant pertussis vaccines