Experience with maternal pertussis and PCV13 immunisation in England

Experience with maternal pertussis and PCV13 immunisation in England Immunisation, Hepatitis & Blood Safety department Public Health England 5th RIVM Vaccine Preventable Diseases Research day 18 th November 2015

Total notifications Coverage (%) 200000 Notifications coverage by 2nd birthday 100 180000 90 160000 140000 120000 1957: routine infant DTwP introduced, completed by 6M 2001: Preschool DTaP booster at 3 ½ to 5 years 80 70 60 100000 50 80000 60000 40000 20000 0 1940 1943 1946 1949 1952 1955 1958 1961 1964 1967 1970 1973 1976 1979 1982 1990: accelerated infant DTwP at 2,3,4M Infant schedule at 3,5,11 months 1994: enhanced surveillance of lab confirmed pertussis 1985 1988 1991 1994 1997 2000 2003 2006 More sensitive diagnostic methods introduced from 2001 (serology, then PCR then oral fluid single high anti-pt titre 40 30 2004: 5 component DTaP at 2,3,4M 20 10 0

Annual age specific pertussis incidence rates, England, 1998-2012 Pertussis Immunisation in Pregnancy

Number of deaths from whooping cough in infants, England, 2001-2012 Sources: lab confirmed cases, certified deaths, Hospital episode statistics, GP registration details Pertussis Immunisation in Pregnancy

Onset age of laboratory confirmed pertussis cases in infants Pertussis Immunisation in Pregnancy

Pertussis Immunisation in Pregnancy Recommendation: From 1 st October 2012 Offer a single dose of Repevax (dtap 5 /IPV) ideally between 28-32 weeks pregnancy, up to 38 weeks Offer in every pregnancy Outbreak response measure Since July 2014, programme using Boostrix- IPV (dtap 3 /IPV) 6 Pertussis Immunisation in Pregnancy

Evaluation of pregnancy vaccination programme Vaccine coverage Vaccine effectiveness Programme impact Impact of passive antibodies on infant immune response 7 Pertussis Immunisation in Pregnancy

Vaccine Coverage January 2013- September 2015 Repevax (dtap 5 /IPV) Boostrix-IPV (dtap 3 /IPV)

Maternal vaccine coverage by week of birth, Week 40, 2012- Week 32, 2015 Source: Clinical Practice Research Datalink (CPRD)

Evaluation of pregnancy vaccination programme Vaccine coverage Vaccine effectiveness Programme impact Impact of passive antibodies on infant immune response 10 Pertussis Immunisation in Pregnancy

Pertussis programme effectiveness measured by two methods: (1)Amirthalingam G et al. Lancet 2014 (2)Dabrera G et al. Clinical Infectious Diseases 2014 Cases Coverage in Analysis vaccinated matched <2M age / total population Adjusted VE (95% CI) Case coverage method* (1) 11/81 (15%) 61% 90% (82% to 95%) Case-control study 10/58 39/55 93% (2) (17%) (71%) (81% to 97%) Vaccine effectiveness is calculated using the case coverage method where VE is one minus the odds of vaccination in cases (here mothers of cases) compared to the population. The expected coverage in the mother is determined for each confirmed case matched on the week of birth of the baby and the birth cohort of the mother (pre 1985,1985-89, 1990+).

Maternal pertussis vaccine effectiveness: Updated estimates to end September 2015 VE Analysis Cases vaccinated / total VE (95% CI) Vaccination 28 days before birth 31/229 91% 88% to 94%) Vaccination 7 to 27 days before birth Vaccination 0-6 days before or 1-13 days after birth 4/213 91% (80% to 96%) 3/179 43% (-35% to 76%)

Maternal Pertussis VE estimates by vaccine product Analysis Cases vaccinated / total VE* (95% CI) Repevax 20/172 93% (89%-95%) Boostrix-IPV 15/71 88% (79%-93%)

VE of a maternal dose at least 7 days before birth in infants who have started primary immunisation Primary dose Vaccinated mother/ total cases VE (95% CI) Exactly 1 Dose 11/43 (26%) 82% (65% to 91%) Exactly 2 Doses 5/12 (41.7%) 69% (8% to 90%) Exactly 3 Doses 10/18 29% (-112% to 76%) *VE calculated based on matched coverage on each individual not using average matched coverage 14 Pertussis Immunisation in Pregnancy

Evaluation of pregnancy vaccination programme Vaccine coverage Vaccine effectiveness Programme impact Impact of passive antibodies on infant immune response 15 Pertussis Immunisation in Pregnancy

Annual age specific laboratory confirmed pertussis incidence rates, 1998 2014, England Introduction of temporary vaccination programme for pregnant women 16 Pertussis Immunisation in Pregnancy

Proportionate changes in laboratory confirmed cases for Jan-Sept 2011-2015 compared with Jan Sept 2010 17 Pertussis Immunisation in Pregnancy

Reconciled deaths from pertussis in infants, England 16 14 <3M <3M mum vaccinated <3M mum not vaccinated 3-5M 6-11M 12 10 8 6 4 2 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015* Sources: lab confirmed cases, certified deaths, Hospital episode statistics, GP registration details, HPZone *reported by 21/9/2015

Reconciled deaths from pertussis in infants, England 16 14 12 <3M <3M mum vaccinated <3M mum not vaccinated 3-5M 6-11M additional expected deaths 10 8 6 4 2 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015* Sources: lab confirmed cases, certified deaths, Hospital episode statistics, GP registration details, HPZone *reported by 21/9/2015

Evaluation of pregnancy vaccination programme Vaccine coverage Vaccine effectiveness Programme impact Impact of passive antibodies on infant immune response 20 Pertussis Immunisation in Pregnancy

Immunising Mothers against Pertussis (imap) Ladhani et al. Clinical Infectious Diseases, 2015 Clinical service evaluation to monitor immune responses of infants to their primary vaccination following introduction of pregnancy vaccination programme Recruitment of women during antenatal period across 3 English regions Blood samples from infants of vaccinated mothers at 2 months (pre-immunisation) & 5 months (post primary immunisation) Antibody levels to all routine antigens measured and compared with historical controls (P13UK, Sched1)) 21 Pertussis Immunisation in Pregnancy

Comparing pertussis and concomitant vaccine responses with previous UK studies Ladhani et al. Clinical Infectious Disease,2015 imap1 at 2 months imap1 at 5 months P13UK/Sched1 at 5 months Fold difference PT 11.2 (9.6-13.1) 28.8 (25.7-32.4) 43.2 (39.4-47.2) 0.67 (0.58-0.77) FHA 46 (39.8-53.1) 25.5 (23.0-28.3) 41.1 (37.5-45.1) 0.62 (0.54-0.71) FIM 123.2 (92.7-163.5) 113.9 (99.0-131.1) 224.9 (196.1-258.0) 0.51 (0.42-0.62) Tet (IU/mL) 3.28 (2.87-3.74) 1.36 (1.24-1.50 ) 1.11 (0.99-1.25) 1.24 (1.05-1.46) Hib-TT 0.14 (0.12-0.17) 4.92 (3.71-6.51 ) 2.17 (1.71-2.77) 2.30 (1.59-3.34) MenC-TT 569.6 (316.2-1026) 115.1 (78.7 168.4) 5.2 Dip (IU/mL) 0.30 (0.25-0.37) 0.55 (0.47-0.63 ) 1.00 (0.89-1.12) 0.55 (0.45-0.66) MenC-CRM 43.9 (25.8-74.4 ) 68.8 (49.7 95.3) 0.64 22 Vaccination in Pregnancy in

Pneumococcal imap GMC IU/mL Control GMC IU/mL Geometric Mean fold ratio serotype 95% CI 95% CI imap: control 1 1.35 (1.18-1.54) 1.84 (1.63-2.07) 0.74 (0.61-0.89) 3 0.56 (0.51-0.63) 1.65 (1.49-1.82) 0.34 (0.29-0.40) 4 1.08 (0.96-1.22) 1.55 (1.41-1.70) 0.70 (0.60-0.82) 5 0.57 (0.50-0.65) 0.96 (0.87-1.08) 0.59 (0.50-0.70) 6A 0.90 (0.75-1.07) 1.56 (1.35-1.80) 0.58 (0.46-0.73) 6B 0.36 (0.31-0.42) 0.32 (0.29-0.36) 1.11 (0.92-1.33) 7F 2.04 (1.80-2.32) 2.63 (2.37-2.93) 0.78 (0.65-0.93) 9V 0.72 (0.61-0.85) 0.93 (0.83-1.04) 0.78 (0.64-0.95) 14 4.76 (3.94-5.76) 5.28 (4.54-6.13) 0.90 (0.71-1.15) 18C 1.08 (0.92-1.26) 1.19 (1.06-1.34) 0.91 (0.74-1.11) 19A 1.27 (1.06-1.51) 1.56 (1.38-1.77) 0.81 (0.66-1.01) 19F 4.01 (3.48-4.64) 4.57 (4.04-5.16) 0.88 (0.73-1.07) 23 23F 0.64 (0.54-0.78) 0.69 (0.60-0.79) 0.94 (0.74-1.19)

Key remaining questions 1. How do we improve maternal vaccine coverage and ensure vaccines are delivered at the optimal stage in pregnancy? 2. Are there any differences in terms of effectiveness and potential blunting of the infant immune response between the two currently available vaccines? 3. Will blunting require addition of toddler booster? 4. Should the programme for pregnant women in England become routine? Introduced without CEA as a temporary outbreak control measure. a. If it is to be continued as a routine vaccination then must be shown to be cost effective b. If not, under what circumstances can the programme be stopped? 24 Pertussis Immunisation in Pregnancy

Cost effectiveness: factors affecting the cost per QALY gained (van Hoek AJ, Miller E submitted) Cost per QALY gained should be between 20,000 to 30,000 to be considered cost effective in UK but this will vary with: Vaccine price Time horizon less cost effective the longer the time horizon (5-200 years investigated) For short time horizons, whether started in epidemic or non-epidemic year Discount rate for costs and benefits Future incidence of pertussis in first 3 months of life (unknown) but predicted by modelling to continue at an elevated level Under many of the scenarios investigated maternal immunisation would not be cost-effective but would any policy maker (or politician) withdraw the programme on this criterion? 25 Pertussis Immunisation in Pregnancy

Acknowledgements PHE colleagues: Gayatri Armirthalingam, Helen Campbell, Nick Andrews, Sonia Ribeiro, Local PHE Health Protection Teams that provide information on cases in their areas London School Hygiene and Tropical Medicine Dr. Albert Jan van Hoek Pertussis Immunisation in Pregnancy

Impact of 13V pneumococcal vaccine on invasive pneumococcal disease in the UK

Evolution of Pneumococcal Vaccination Policy: E&W 1992 PPV23 (23 valent pneumococcal polysaccharide vaccine) for 2 years of age at increased risk of IPD. 2002 PCV7 for children < 2 years of age at increased risk of IPD. 2003 PPV23 for 80 years of age. 2004 PPV23 for 75 years of age. 2005 PPV23 for 65 years of age. 2006 From September, PCV7 as a 2 + 1 schedule in infant immunisation schedule. Catch- up to 2 years of age. 2010 From April, PCV13 replaced PCV7, no catch-up.

PHE Enhanced Surveillance of IPD S pneumoniae cultures sent for serotyping to reference lab at Colindale All microbiology Labs in England and Wales Reports of S. pneumoniae isolates sent to Colindale electronically into national database Real time data from serotyped isolates on PHE website Joint data set held in Immunisation department reconciled annually 6 months after end of epi year (July to June) to generate incidence rates

Direct and herd immunity impact of PCV7 offset by serotype replacement: From Miller et al Lancet ID 2011 Age years Type of IPD Incidence rate ratio (95% CI) 2009-10 vs 2000-2006 % reduction <2 Vaccine Type 0.02 (0.01-0.05) 98% reduction Non PCV7 1.68 (1.37-2.06) All IPD 0.44 (0.39-0.49) 56% reduction 65 Vaccine Type 0.19 (0.14-0.25) 81% reduction Non PCV7 1.48 (1.32-1.65) All IPD 0.81 (0.75-0.88) 19% reduction 30

PCV7 was replaced by PCV13 in April 2010 with no catch up

Vaccine effectiveness estimates to December 2014: additional PCV13 serotypes: 2 dose under 12m or 1 dose aged 12+m Serotype Cases vaccinated : unvaccinated Controls* vaccinated : unvaccinated Adjusted VE (95% CI) 1 14:31 486:93 77.6 (47.1-90.5) 3 41:23 486:93 33.5 (-38.5-68.1) 6A 1:7 486:93 97.2 (60.4-99.8) 7F 6:41 486:93 93.8 (81.0-98.0) 19A 39:56 486:93 70.7 (43.7-84.7) Controls are age matched IPD cases infected with a non-vaccine serotype

2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 2013/2014 Impact of PCV13 on vaccine type IPD children <5 years to June 2014 from Waight et al Lancet ID 2015 <2 PCV7 Corrected IPD incidence per 10 5 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 2013/2014 2 to 4 45 40 35 30 25 20 15 10 5 PCV7 PCV13 PCV13 only Corrected IPD incidence per 10 5 14 12 10 8 6 4 2 PCV7 PCV13 0 0

2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 2013/2014 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 2013/2014 Impact of PCV13 on vaccine type IPD adults aged 45+ years to June 2014 45 to 64 65 9 8 PCV7 PCV13 20 18 PCV7 PCV13 Corrected IPD incidence per 10 5 7 6 5 4 3 2 Corrected IPD incidence per 10 5 16 14 12 10 8 6 4 1 2 0 0

Data to Sept 2015

Cumulative Number of Reports Cumulative weekly number of reports of Invasive Pneumococcal Disease due to serotype 19A: Children aged <2 years in England and Wales by epidemiological year July-June (2006 to Sept 2015) 80 70 06/07 07/08 08/09 09/10 10/11 11/12 12/13 13/14 14/15 15/16 Introduction of Prevenar13 RUST LINE Week 13 2010 60 50 40 30 20 Introduction of Prevenar GREEN LINE Week 36 2006 10 0 26 28 30 32 34 36 38 40 42 44 46 48 Week 50 52 01 03 05 07 09 11 13 15 17 19 21 23 25

Data to Sept 2015

Cumulative Number of Reports Cumulative weekly number of reports of Invasive Pneumococcal Disease due to serotype 19A : Persons aged 65 years in England and Wales by epidemiological year July-June (2006 - to Sept 2015) 350 06/07 07/08 08/09 09/10 10/11 11/12 12/13 13/14 14/15 15/16 300 Introduction of Prevenar13 RUST LINE Week 13 2010 250 200 150 100 Introduction of Prevenar GREEN LINE Week 36 2006 50 0 26 28 30 32 34 36 38 40 42 44 46 48 50 52 01 03 05 07 09 11 13 15 17 19 21 23 25 Week

Predicting serotype replacement with PCV13 Post PCV13 carriage study in 2012/13 showed full serotype replacement in the nasopharynx (van Hoek Vaccine 2014) Impact on overall IPD depends on whether replacing serotypes are more or less invasive than the vaccine types (case:carrier ratio) Carriage study from 2008/09 (Flasche et al PLoS Med 2011) together with IPD surveillance allowed estimation of average invasiveness of PCV13 VT and NVT 2008/2009 Carriage IPD PCV13 27.6% 63.6% Rest 72.4% 36.4% Non PCV13 serotypes overall appear less invasive less potential for replacement disease predicted despite full serotype replacement in carriage

From Waight et al LID 2015 to end June 2014

Change from pre-pcv7 baseline by end Age Serotype 2000-06 June 2014 incidence per 10 5 2013/14 incidence per 10 5 IRR 2013/14: 2000-6 95% CI * <2 All 51.81 12.03 0.23 0.46-0.59 PCV7 39.05 0.38 0.01 0.00-0.03 PCV13only 7.49 1.43 0.19 0.10-0.37 NVT 5.27 10.23 1.94 1.42-2.63 65 All 34.13 20.58 0.60 0.56-0.64 PCV7 17.89 0.53 0.03 0.02-0.04 PCV13only 7.02 3.72 0.53 0.43-0.61 NVT 9.22 16.33 1.77 1.62-1.95 All ages All 15.63 6.85 0.44 (56% reduction) 0.43-0.47 PCV7 7.73 0.20 0.03 0.02-0.04 PCV13only 3.80 1.40 0.37 0.33-0.41 NVT 4.10 5.25 1.28 1.20-1.35

Data to end September 2015

Cumulative Number of Reports Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the serotypes NOT in Prevenar13 : Persons aged 65 years in England and Wales by epidemiological year July-June (2006 - to date) 06/07 07/08 08/09 09/10 10/11 2000 11/12 12/13 13/14 14/15 15/16 1800 1600 Introduction of Prevenar13 RUST LINE Week 13 2010 1400 1200 1000 800 600 400 Introduction of Prevenar GREEN LINE Week 36 2006 200 0 26 28 30 32 34 36 38 40 42 44 46 48 50 52 01 03 05 07 09 11 13 15 17 19 21 23 25 Week

Proportion of non-pcv13 IPD cases 100 Distribution of NVT IPD serotypes 2014/15 90 80 70 60 50 40 30 20 10 0 Serotype 44

PCV impact on CAP Rodrigo et al. Eur Respir J. 2015 Jun;45(6):1632-41. Prospective cohort study of CAP admissions in 16 yr olds to two teaching hospitals in Nottingham over 5 years from September 2008 to August 2013 Surveillance case definition: 1 LRTI symptom [breathlessness, cough, sputum, fever] + new infiltrates on CXR + clinical diagnosis CAP) Exclusion criteria: aspiration pneumonia, obstructive pneumonia from lung cancer, active TB, prior CAP admission within 10 days Lab confirmation of PCV13 type CAP - Blood culture or PCV13 type identified by urinary Bioplex (PHE) Participants: 2702 eligible, 2321 consented, excluded 16 not CAP and 76 no urine sample, final # 2229 (82%) Mean annual CAP incidence 79.9 per 10 5 Median age 71 years (IQR 55.1-80.5) 653 (29%) lab confirmed as any pneumococcal CAP (566 non-invasive) 30 day case fatality: pneumococcal cases 6.2%

Impact of PCV 7 and PCV13 on VT CAP (from table 2) versus VT IPD Incidence per 100,000 of PCV13 attributable CAP (assuming any 6A/C, 7A/F or 18 is a VT) 2008/9* 2012/13 IRR-CAP IRR-IPD for 65yrs** PCV7 65-74 26.7 7.1 0.27 0.20 75-84 39.1 5.6 0.14 0.15 85 177.1 31.2 0.18 0.17 PCV13 only 65-74 23.2 12.5 0.54 0.56 75-84 44.7 22.3 0.50 0.62 85 104.2 20.8 0.20 0.62 * From Sept 2008 to August 2009 ** From July 2008 to June 2010

Conclusions PCV7 and 13 have had profound impacts on the incidence and serotype distribution of IPD in England and Wales Herd immunity impact on PCV-atttributable CAP similar to IPD By end June 2014 there was an overall reduction in IPD compared with pre PCV7 baseline of 56%. However this reduction is now being eroded by progressive increases in non-pcv13 serotypes and a recent increase in 19A A variety of non-pcv13 are increasing with 22F and 33F (15 valent candidates) covering less than 20% of NVTs Do we need even higher valency PCVs or a new type of vaccine?

PHE Colleagues: Immunisation Department: Acknowledgements Sarah Collins, Nick Andrews, Shamez Ladhani, Pauline Kaye (nee Waight), Rashmi Malkani Respiratory and Vaccine Preventable Bacteria Reference Unit: Carmen Sheppard, David Litt, Norman Fry Microbiology Laboratories who send isolates for serotyping and electronic reports of IPD cases Risk of narcolepsy after GPs who provide clinical information and vaccination histories for AS03 their adjuvanted patients pandemic A/H1N1 2009 influenza