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Priorix tetra – global experience and local evidence - Mohali march 2017

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Talk on GSK vaccine Priorix Tetra, MMRV, evidence-based use in India, recommendations as of March 2017

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Priorix tetra – global experience and local evidence - Mohali march 2017

  1. 1. Priorix Tetra – Global Experience & Local Evidence Dr Gaurav Gupta Mohali – 18th March, 2017
  2. 2. Conflict of Interest • Received grants from various vaccine manufacturers including
  3. 3. WIIFY • Combination vaccines – are they needed? • Is MMRV same as MMR + V? • Are 2 doses of CP helpful? • Is MMRV vaccine effective? Safe? • What is the link between MMRV & FS? • Best schedule?
  4. 4. • What is the recommended age of MMRV?
  5. 5. Combination Vaccines – Why? • Simplified Immunization Schedule • Less injections – Complications • Better Compliance • Lesser administration time/ costs/ space
  6. 6. Combination vaccines – Why not? • Adverse effects maybe more common • Reduced Immunogenicity • May have lesser shelf life • Technically difficult • Expensive
  7. 7. Priorix-Tetra: Lessons Learnt from an Established Vaccine > 23 million doses sold worldwide Registered in > 80 countries >10 years of global experience 51 Completed Clinical Trials 31 Countries in Clinical trials 66 Publications Cumulatively enrolled subjects Robust Clinical Evidence Data onfile 4.45 Lac
  8. 8. Composition – A Closer Look Minimum ViralTiter1 MEASLES MUMPS RUBELLA VARICELLA Strain Schwarz RIT 4385, Jeryl Lynn derived WistarRA 27/3 Oka Priorix ≥ 103.0 CCID50 ≥ 103.7 CCID50 ≥ 103.0 CCID50 Varilrix ≥ 103.3 PFU Priorix- Tetra ≥ 103.0 CCID50 ≥ 104.4 CCID50 ≥ 103.0 CCID50 ≥ 103.3 PFU Mumps strain:RIT 4385* Varicella strain:Oka Rubella strain: RA27/3 Measles strain: Schwarz Priorix™ Varilrix™ *Jeryl Lynn-derived mumps vaccines not associated with aseptic meningitis 1. Schuster V, et al. Pediatr Infect Dis J 2008;27:724-30. Priorix-Tetra™ is based on the same virus strains found in Priorix™ andVarilrix Developing a MMRV vaccine is more than just mixing MMR and V Lesson 1 Priorix-Tetra: Measles, Mumps, Rubella, Varicella Vaccine. Priorix: Measles, Mumps, Rubella Vaccine. Varilrix: Varicella Vaccine
  9. 9. Virus (assay, cut off) MMRV MMR + V N GMT N GMT Measles (ELISA, ≥150 mIU/ml) 2019 3184.5 509 1840.4 Mumps (PRNT, ≥28 ED50) 1741 147.0 444 143.1 Mumps (ELISA, ≥231 U/ml) 1963 976.7 495 927.6 Rubella (ELISA,≥4mIU/ml) 2022 62.2 507 79.7 Varicella (IFA, ≥4 dilution−1) 1934 97.5 494 97.9 Virus (assay, cut off) MMRV MMR + V N GMT N GMT Measles (ELISA, ≥150 mIU/ml) 1987 4828.6 505 2633.9 Mumps (PRNT, ≥28 ED50) 1709 478.4 440 410.2 Mumps (ELISA, ≥231 U/ml) 1982 1564.4 501 1465.1 Rubella (ELISA,≥4mIU/ml) 1989 119.7 504 130.4 Varicella (IFA, ≥4 dilution−1) 1908 2587.8 489 95.2 GMTs Post Dose1 GMTs Post Dose2 Czajka H, et al. Vaccine 2009;27:6504-6511. Randomized controlled trial (MMRV/MMRV or MMR+V/MMR). Dose 1 at 11-21m, dose 2 after 6-8 weeks. Developing a MMRV vaccine is more than just mixing MMR and V Lesson 1 Blood collected 42 days after dose. Per Protocol Population.
  10. 10. Fever in children aged 10–21 months (Priorix-Tetra as first dose of Measles Containing Vaccine) Schuster et al. Pediatr Infect Dis J 2008; 27: 724–30. ^Randomized controlled trial [MMRV/MMRV (N~735) or MMR+V/MMR (N~ 237)]. Dose 1: 10-21m. Dose 2 6 after 1st dose. For the Priorix™ + Varilrix™ group, only Priorix™ given as second dose. Fever: rectal temperature ≥38.0°C or axillary temperature ≥37.5°C. Subjects(%) Day Priorix-TetraTM PriorixTM +VarilrixTM Most cases of fever following vaccination occurred during the first 2 weeks of follow-up after dose 1 (a period of up to 42 days) Developing a MMRV vaccine is more than just mixing MMR and V Lesson 1 Priorix- MMR Vaccine - Measles, Mumps, Rubella Vaccine ; Varilrix- Varicella Vaccine; Priorix-Tetra – MMRV Vaccine - Measles, Mumps, Rubella , Varicella Vaccine Fever 0-15 days.P=0.023
  11. 11. Are 2 dose of Varicella really needed?
  12. 12. GMC, geometric mean concentration; GMT, geometric mean titre; VZV, varicella zoster virus. 1. Watson B. J Infect Dis 2008; 197 (suppl 2): S143–6; 2. Gershon AA, et al. Chapter 35 in, Vaccines, 5th Ed., Elsevier 2008; 3. Bonnani P, et al. Pediatr Infect Dis J 2013; 32:e305–13; 4. Watson B, et al. Clin Infect Dis 1995;20: 316–9;5. Wutzler P, et al. Dtsch Arztebl Int 2008;105: 567–72;6. Schuster et al. Pediatr Infect Dis J 2008;27: 724–30;7. Lalwani S et al. One dose of varicella vaccine mounts an incomplete immune response1–3 A second dose increases humoral and cell-mediated immune responses1 23.1 34.7 45 40 35 30 25 20 15 10 5 0 Meanstimulationindex after52weeks VZV-specific lymphocyteproliferation response is significantly higher after twodoses4 The booster effect of the second dose is atypical of live-attenuated vaccines5 2 doses of Varicella Vaccine provide better protection Lesson 2 0 500 1000 1500 2000 2500 GMT(mIU/mL) GMCs after one and two doses of Priorix-Tetra™6 0 1000 2000 3000 4000 5000 6000 GMCs after one and two doses of Priorix-Tetra™7 Dose 1 Dose 2 VZV-specificlymphocyte proliferation Dose 1 Dose 2 GMTs after Dose 1and Dose2 BMJ Open. 2015 Sep11;5(9):e007202 Dose 1 Dose 2 GMTs after Dose 1and Dose2
  13. 13. 99.594.9 95.3 98.4 100 90 80 70 60 50 40 30 20 10 0 Any varicella Moderate-to-severe varicella Vaccineefficacy (%±95%CI) 3 years follow-up 6 years follow-up 65.4 90.7 69.5 91.8100 90 80 70 60 50 40 30 20 10 0 Any varicella Moderate-to-severe varicella Vaccineefficacy (%±95%CI) Efficacy of one dose of GSK Oka™1,2 3 years follow-up 6 years follow-up One dose → high protection against moderate-to-severe disease Two doses → high protection against all varicella Efficacy of two doses of Priorix-Tetra™1,2 2 doses of Varicella Vaccine provide better protection Lesson 2 Available from: http://www.gsk-clinicalstudyregister.com/study/10399#rs [Accessed January 2016] 3 year attack rate ARR (person-years rate) for Any Varicella- 0.6 in MMRV, 0.128 in OKAH group respectively; Moderate to severe Varicella 0.0 in MMRV, 0.6 in OKAH group respectively; 6 year attack rate ARR (person-years rate) for Any Varicella- 0.1334 in MMRV, 0.128 in OKAH group respectively; Moderate to severe Varicella 0.469 in MMRV, 0.043 in OKAH group respectively. 1. Prymula R, et al. Lancet 2014; 383: 1313–24; 2. GSK clinical trial report on study number 100388 and subsequent extensions.
  14. 14. 100 90 80 70 60 50 40 30 20 10 0 %seroprevalence 1–5 6–10 11–15 16–20 21–30 31–40 Age group(years) Seroprevalence of antibodiesagainst varicella increased withage1 VZV, varicella zostervirus 1. Lokeshwar MR et al. Indian Pediatr 2000;37: 714–9;2. Beig FK et al. Int J Infect Dis 2010;14: e141–6;3. Jain P et al. Jpn J Infect Dis 2014;67: 197–203; Varicella is most common in adolescents and adults in tropicalregions4 Reports from South India showed that nearly 30% of adolescents >15 years of age may be susceptible to varicella5 Studies conducted in theUttar Pradeshregion:2,3 • 4.4–15.8% of patients hospitalised with acute viral encephalitis had anti-VZV antibodies Owing to the high disease burden in India, it’s important to protect against Varicella Study conducted across four sites across India (Kolkata, Lucknow, Mumbai, Bangalore):1 • Overall anti-VZV seroprevalence: 68.22% • Seroprevalence increased with age, with a significant proportion of adolescents susceptible to infection 4. World Health Organization. Wkly Epidemiol Rec 2014; 89: 265–87; 5. Verma R et al. Hum Vaccin 2011; 7:874–7.
  15. 15. 12 10 8 6 4 2 0 14 Meanvaricellavaccinations(MMRVor V)perpracticemonth Before change (Oct 10–Jun 11) MMRV After change (Oct 11–Jun 12) MMR+V Dose 1 Dose 2 Dose 1 Dose2 Munich Würzburg p=0.620 p<0.001 p=0.108 MMRV combination vaccines can improve varicella vaccine coverage Risk of FC must be balanced against coverage achieved with MMRV formulation The change in recommendations was in response to observations of increased FCs following a first dose of MMRV. FC, febrile convulsion. Mann-Whitney U-test. p=0.005 ↓12% ↓4% ↓19% ↓15% Varicella vaccination coverage decreased in some regions of Germany when it was recommended to use MMR+V instead of MMRV as the first dose Varicella vaccination before and after change in German recommendations Lesson 3 Streng A & Liese JG. Vaccine 2014; 32:897–900.
  16. 16. What is the minimum gap between doses of MMRV?
  17. 17. Is MMRV effective/ safe?
  18. 18. Immunogenicity in unprimed children % Seroconversion Rates Post Dose 2 (95% CI) Measles Mumps Rubella Varicella 100 % (97.6–100) 100 % (97.6–100) 100 % (97.6–100) 100 % (97.4–100) 150 children received 2 doses of MMRV at 9 and 15months India1 Measles Mumps Rubella Varicella 156 MMR primed children received MMRV at 15 months6 Study sites: Bangalore, Chennai, Goa, Kolkata, Pune(2) 100 % (97.6–100) 100 % (97.6–100) 100 % (97.6–100) 98.6 % (95.0–99.8) Note: Above study was a Phase III pre-registration study in India. Priorix Tetra has been subsequently approved in India for use in children 12 months to 12 years only. GSK does not recommend use of Priorix Tetra in children less than 1 year age. ELISA cut-off values of 150 mIU/mL (measles), 231 U/mL (mumps) and 4 IU/mL (rubella) and IFA cut-off value of 4/dilution for Varicella Randomized controlled trial [2:2:1 to MMRV/MMRV group or MMR/MMRV or MMR/MMR (control) at 9,15 months respectively]. Blood collected 43 days after dose. ATP Cohort for immunogenicity. 1. Lalwani S, et al. BMJ Open 2015;5:e007202. Immunogenicity in MMR primed children % Seroconversion Rates Post MMRV (95% CI) Indian immunogenicity of Priorix-Tetra consistent with global experience Lesson 5 Priorix-Tetra- Measles, Mumps, Rubella and Varicella Vaccine; Priorix- MMR Vaccine - Measles, Mumps, Rubella Vaccine ;Varilrix- Varicella Vaccine
  19. 19. Rubella Measles Mumps 1.83 X higher GMTs with MMRV (4828.6 vs.2633.9) Comparable rubella immuneresponse between MMRV and separate MMR and varicellavaccination India2 MMRV/MMRV (N=148) MMR/MMR +V(N=72) Dosesat 9 & 15months GMTs Post Dose2 Europe1 MMRV/MMRV (N=1987) MMR+V/MMR (N=505) Children aged 11-21 months. Doses given 6-8 weeks apart GMTs Post Dose2 1.79 X higher GMTs with MMRV (4471.3 vs.2495.0) 1.06 X higher GMTs with MMRV (1564.4 vs.1465.1) 1.30 X higher GMTs with MMRV (6428.0 vs.4925.3) Statistical significance of difference not tested. GMT, geometric mean titre. ELISA cut-off values of 150 mIU/mL (measles). ^; Randomized controlled trial (MMRV/MMRV or MMR+V/MMR). Blood collected 42 days after dose. Per Protocol Population. *; Randomized controlled trial [2:2:1 to MMRV/MMRV group or MMR/MMRV or MMR/MMR (control) at 9 and 15 months respectively]. Blood collected 43 days after dose. ATP GMTs vs. Separate MMR+V Lesson 6 Priorix-Tetra demonstrated Higher/Comparable Cohort for immunogenicity. 1. Czajka H, et al. Vaccine 2009;27:6504-6511. 2. Lalwani S, et al. BMJ Open 2015;5:e007202. Priorix-Tetra- Measles, Mumps, Rubella and Varicella Vaccine; Priorix- MMR Vaccine - Measles, Mumps, Rubella Vaccine ;Varilrix- Varicella Vaccine
  20. 20. Dose1 (Priorix-Tetra as first doseof Measles ContainingVaccine) Dose2 (Priorix-Tetra as second doseof Measles ContainingVaccine) Fever in children aged 10–21months Most cases of fever following vaccination occurred during the first 2 weeks of follow-up with MMRV as first dose of measles vaccine 40 30 20 10 0 Subjects(%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Day Priorix-TetraTM PriorixTM +VarilrixTM 40 30 20 10 0 Subjects(%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Day Priorix-TetraTM PriorixTM +VarilrixTM MMRV vaccines show increased fever (and FC) compared to MMR/MMR+V if given as 1st measles containing vaccine Lesson 7 For the Priorix™ + Varilrix™ group, only Priorix™ given as second dose. Fever: rectal temperature ≥38.0°C or axillary temperature ≥37.5°C. Priorix- MMR Vaccine - Measles, Mumps, Rubella Vaccine ; Varilrix- Varicella Vaccine; Priorix-Tetra – MMRV Vaccine - Measles, Mumps, Rubella , Varicella Vaccine Schuster et al. Pediatr Infect Dis J 2008; 27: 724–30. ^Randomized controlled trial [MMRV/MMRV (N~735) or MMR+V/MMR (N~ 237)]. Dose 1: 10-21m. Dose 2 6 after 1st dose. Fever 0-15 days.P=0.023
  21. 21. Germany, MMRV vaccination schedule includes dose 1 at 11-14 months and dose 2 is at 15-23months Febrile convulsions with MMRV vaccine when administered as first dose of Measles vaccine.1 MMRV vs. MMR matched cohort N = 74,734 MMRV vs. MMR+V matched cohort N = 32,180 MMRV vs. MMR/MMR+V matched cohort N = 82,561 Odds Ratio 2.3 (1.4–3.9) 1.5 (0.8–2.9) 2.4 (1.5–3.9) FC (Jacobsen) with corresponding 95% CIs for the main risk periods (5–12 days following vaccination 6.19 vs. 2.55 per10,000 1 additional caseper 2747 subject Lesson 7 Schink T, et al. Risk of febrile convulsions after MMRV vaccination in comparison to MMR or MMR+V vaccination. Vaccine 2014;32:645-650. MMRV vaccines show increased fever (and FC) compared to MMR/MMR+V if given as 1st measles containing vaccine
  22. 22. Dose1 (Priorix-Tetra as first doseof Measles ContainingVaccine) Dose2 (Priorix-Tetra as second doseof Measles ContainingVaccine) Fever in children aged 10–21 months 40 30 20 10 0 Subjects(%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Day Priorix-TetraTM PriorixTM +VarilrixTM 40 30 20 10 0 Subjects(%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Day Priorix-TetraTM PriorixTM +VarilrixTM MMRV vaccine show NO increase in fever (and FC) compared to MMR/MMR+V if given as 2nd measles containing vaccine Lesson 8 Priorix- MMR Vaccine - Measles, Mumps, Rubella Vaccine ; Varilrix- Varicella Vaccine; Priorix-Tetra – MMRV Vaccine - Measles, Mumps, Rubella , Varicella Vaccine Schuster et al. Pediatr Infect Dis J 2008; 27: 724–30. ^Randomized controlled trial [MMRV/MMRV (N~735) or MMR+V/MMR (N~ 237)]. Dose 1: 10-21m. Dose 2 6 after 1st dose. For the Priorix™ + Varilrix™ group, only Priorix™ given as second dose. Fever: rectal temperature ≥38.0°C or axillary temperature ≥37.5°C. Fever 0-15 days.P=0.023
  23. 23. Germany, MMRV vaccination schedule includes dose 1 at 11-14 months and dose 2 is at 15-23months FC (Jacobsen) with corresponding 95% CIs for the main risk periods (5–12 days following vaccination) Lesson 8 MMRV vaccine show NO increase in fever (and FC) compared to MMR/MMR+V if given as 2nd measles containing vaccine Febrile convulsions with MMRV when administered as second dose of Measles vaccine1 MMRV vs. MMR N = 96,626 MMRV vs. MMR+V N = 20,382 MMRV vs. MMR/MMR+V N = 99,066 Odds Ratio 0.36 (0.12–1.14) NA 0.40 (0.13-1.28) 0.8 vs. 2.0 per10,000 1. Data onFile
  24. 24. Most fevers and febrile seizures after administration of a measles-containing vaccine occur _________ days after vaccination with the FIRST dose.
  25. 25. 50 45 40 35 30 25 20 15 10 5 0 Pain Swelling Pain Swelling %childrenreportingatleastonce Incidence of solicited injection site reactionsduring the 4-day post-vaccinationperiods Injection site pain was the most common solicited local symptom during the 4-day post-dose follow-upperiods Redness Postdose1 Redness Postdose2 Vaccinationregimen: Dose 1: MMRV (N=174) Dose 2: MMRV (N=155) Dose 1: MMR (N=172) Dose 2: MMRV (N=159) Dose 1: MMR (N=84) Dose 2: MMR+V (N=79) Priorix-Tetra is generally well-tolerated in Indian children Lesson 9 Lalwani S et al. BMJ Open 2015; 5:e007202 Randomized controlled trial [2:2:1 to MMRV/MMRV group or MMR/MMRV or MMR/MMR (control) at 9 and 15 months respectively].
  26. 26. Vaccination regimen: Dose 1: MMR (N=172) Dose 2: MMRV(N=159) Dose 1: MMR (N=84) Dose 2: MMR+V(N=79) Incidence of any fever* during the 15-day post-vaccination period1 15 10 5 0 20 25 30 35 40 45 60 55 50 Post Dose 1 Post Dose 1 Post Dose 2 Post Dose 2 %ofchildrenreportingfeveratleastonce MMR MMR MMRV MMR+V Priorix-Tetra is generally well-tolerated in Indian children Lesson 9 Randomized controlled trial [2:2:1 to MMRV/MMRV group or MMR/MMRV or MMR/MMR (control) at 9 and 15 months respectively]. Lalwani S et al. BMJ Open 2015; 5:e007202
  27. 27. USA1 Age 12--47 Months Either MMR+V vaccine or MMRV vaccine maybe used. (Preference for separateinjections) At any age (15 months--12 years) Use of MMRV vaccine generally ispreferred over separate injections of its equivalent component vaccines CANADA2 Up to 47 months Either MMR+Vvaccine or MMRV vaccine may be used. (Preference for separateinjections) 15 months-12 years MMRV GERMANY4 11 to 14 months MMR+V 15 to 23 months MMRV/MMR+V MMRV vaccines can be and are being used very flexibly across the world FIRST DOSE SECOND DOSE Lesson10 AUSTRALIA5 12 months MMR 18 months MMRV ITALY3 12 to 15 months MMRV/ MMR+V 5 to 6 years MMRV/MMR+V 1. MMWR, 2010/ 59(RR03);112;2. http://healthycanadians.gc.ca/publications/healthy-living-vie-saine/vaccine-measles-mumps-rubella-varicella-seizures-2016-vaccin-rougeole- rubeole-oreillons-varicelle-convulsions/alt/pub1-eng.pdfAssessed on September, 2016; 3. Bechini et al. Human Vaccines & It is well acknowledged that there is a reduced risk of fever and febrile convulsions in children when MMRV is administered as the second dose of MMR-containing vaccine.5 mmunotherapeutics;2015,11:1,6371;4.http://www.rki.de/EN/Content/infections/Vaccination/recommandations/34_2015_engl.pdf? blob=publicationFile, September, 2016; 5. http://www.health.gov.au/internet/immunise/publishing.nsf/content/IT0167-cnt, Assessed on September, 2016 Assessed on
  28. 28. Overall, the risk of fever, and the subsequent risk of febrile convulsion in children is greatly reduced by having a schedule with the first vaccine dose as MMR at 12 months and the second vaccine dose as MMRV at 18 months.
  29. 29. For the second dose of MMRV vaccines at any age (15 months--12 years) and for the first dose at age ≥48 months, use of MMRV vaccine generally is preferred over separate injections of its equivalent component vaccines.
  30. 30. IAP response – Personal communication with Dr Vipin Vashishta, Chairperson ACVIP, Sept 2016 We have purposely not recommended MMRV at the time of 1st or 2nd dose of MMR since the Indian data was not adequately powered to look the association of FS with MMRV. We need more data particularly, a large PMS study to rule out this association with the vaccine before offering any recommendation in this regard.
  31. 31. Conclusion Priorix-Tetra is a new vaccine for India but there is a huge experience available from other countries and regions Development of MMRV vaccines requires more than just mixing of the available components Priorix-Tetra shows strong immunogenicity against all 4 components No increased fever rate (or febrile convulsion) was observed with Priorix-Tetra when given in in second year of life in children already primed with MMR Local Indian data consistent the learning from use of Priorix-Tetra worldwide Priorix-Tetra fits excellently in the new Indian Vaccination schedule
  32. 32. Call to action • Start using MMRV • FS is not an issue since MMR is given at 9 months • 15 months is a good time to give MMRV • Second dose of MMRV can be planned at 5 years / ? earlier
  33. 33. Missed something ? Get the complete presentation www.slideshare.net/gauravg Feedback: docgaurav@gmail.com Acknowledgments: • GSK Medical Affairs Team

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