priorix tetra – global experience and local evidence - mohali march 2017

Priorix Tetra – Global Experience & Local Evidence

Dr Gaurav Gupta

Mohali – 18th March, 2017

Conflict of Interest

• Received grants from various vaccine manufacturers including

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?

• What is the recommended age of MMRV?

Combination Vaccines – Why?

• Simplified Immunization Schedule

• Less injections – Complications

• Better Compliance

• Lesser administration time/ costs/ space

Combination vaccines – Why not?

• Adverse effects maybe more common

• Reduced Immunogenicity

• May have lesser shelf life

• Technically difficult

• Expensive

Priorix-Tetra: Lessons Learnt from an Established Vaccine

> 23 million doses sold worldwide

Registered in

> 80countries

>10 years of global

experience

51Completed

Clinical Trials

31Countries

in Clinical trials

66

Publications Cumulativelyenrolled subjects

Robust Clinical Evidence

Data onfile

4.45Lac

Composition – A Closer LookMinimum ViralTiter1

MEASLES MUMPS RUBELLA VARICELLA

Strain Schwarz

RIT 4385,Jeryl Lynn

derivedWistar RA

27/3Oka

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

Rubellastrain: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™ and Varilrix

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

Virus (assay, cut off) MMRV MMR + V

N GMT N GMTMeasles (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 GMTMeasles (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 Dose 1

GMTs Post Dose 2

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.


Lesson 1

Blood collected 42 days after dose. Per Protocol Population.

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.

Su

bje

cts

(%)

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)


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

Are 2 dose of Varicella really needed?

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

34.745

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VZV-specific lymphocyte proliferation response is significantly higher after

two doses4

The booster effect of the second dose is atypical of live-attenuated vaccines5

2 doses of Varicella Vaccine provide betterprotection

Lesson 2

0

500

1000

1500

2000

2500

GM

T(m

IU/m

L)

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-specific lymphocyte proliferation

Dose 1 Dose 2

GMTs after Dose 1 andDose 2

BMJ Open. 2015 Sep11;5(9):e007202

Dose 1 Dose 2

GMTs after Dose 1 and Dose 2

99.594.9 95.3 98.4100908070605040302010

0

Any varicella Moderate-to-severe

varicella

Vacc

ine

effi

cacy

(% ±

95%

CI)

3 years follow-up 6 years follow-up

65.4

90.7

69.5

91.8100908070605040302010

0

Any varicella Moderate-to-severe varicella

Vacc

ine

effi

cacy

(% ±

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 betterprotection

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.

http://www.gsk-clinicalstudyregister.com/study/10399

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%sero

pre

vale

nce

1–5 6–10 11–15 16–20 21–30 31–40

Age group (years)

Seroprevalence of antibodiesagainst varicella increased with age1

VZV, varicella zoster virus1. 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 tropical regions4

Reports from South India showed that nearly30% of adolescents >15 years of age may besusceptible to varicella5

Studies conducted in the Uttar Pradesh region: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 ofadolescents 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.

12

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4

2

0

14

Mea

nva

rice

llava

ccin

atio

ns

(MM

RV

or

V)

per

pra

ctic

e m

ont

h Before change (Oct 10–Jun 11) MMRV

After change (Oct 11–Jun 12) MMR+V

Dose 1 Dose 2 Dose 1 Dose 2

Munich Würzburg

p=0.620p<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.

What is the minimum gap between doses of MMRV?

Is MMRV effective/ safe?

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 15 months

India1Measles

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 9,15months 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

Rubella

Measles

Mumps

1.83 Xhigher GMTs with

MMRV(4828.6 vs.2633.9)

Comparable rubella immuneresponsebetween MMRV and separate MMR and varicellavaccination

India2MMRV/MMRV (N=148) MMR/MMR +V(N=72)Doses at 9 & 15 months

GMTs Post Dose2

Europe1

MMRV/MMRV (N=1987) MMR+V/MMR (N=505)Children aged 11-21 months.Doses given 6-8 weeks apartGMTs Post Dose2


MMRV(4471.3 vs.2495.0)


MMRV(1564.4 vs.1465.1)


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 daysafter 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+VLesson 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

Dose 1(Priorix-Tetra as first dose of Measles ContainingVaccine)

Dose 2(Priorix-Tetra as second dose of

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

Subje

cts

(%)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Day


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cts

(%)

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MMRV vaccines show increased fever (and FC) comparedto 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.


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.


Germany, MMRV vaccination schedule includes dose 1 at 11-14 months and dose 2 is at 15-23 months

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 per 10,0001 additional case per

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) comparedto MMR/MMR+V if given as 1st measles containing vaccine

Dose 1(Priorix-Tetra as first dose of Measles ContainingVaccine)

Dose 2(Priorix-Tetra as second dose of

Measles ContainingVaccine)

Fever in children aged 10–21 months

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30

20

10

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cts

(%)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Day


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ubje

cts

(%)

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Day


MMRV vaccine show NO increase in fever (and FC) comparedto MMR/MMR+V if given as 2nd measles containing vaccine

Lesson 8


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.


Germany, MMRV vaccination schedule includes dose 1 at 11-14 months and dose 2 is at 15-23 months

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) comparedto 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 per 10,000

1. Data onFile

Most fevers and febrile seizures after administration of a measles-containing vaccine occur _________ days after vaccination with the FIRST dose.

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Incidence of solicited injection site reactionsduringthe 4-day post-vaccination periods

Injection site pain was the most common solicited local symptom during the4-day post-dose follow-up periods

Redness

Postdose 1

Redness

Postdose 2

Vaccination regimen:

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 :e007202Randomized controlled trial [2:2:1 to MMRV/MMRV group or MMR/MMRV or MMR/MMR (control) at 9 and 15 months respectively].

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

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Post Dose 1 Post Dose 1 Post Dose 2 Post Dose 2

%o

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ver

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ast

on

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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

USA1

Age 12--47 MonthsEither MMR+V vaccine or MMRV vaccine maybe

used. (Preference for separate injections)

At any age (15 months--12 years)Use of MMRV vaccine generally is preferred

over separate injections of its equivalent

component vaccines

CANADA2

Up to 47 monthsEither MMR+Vvaccine or MMRV vaccine may be

used. (Preference for separate injections)

15 months-12 yearsMMRV

GERMANY4

11 to 14 monthsMMR+V

15 to 23 monthsMMRV/MMR+V

MMRV vaccines can be and are being used very flexibly across the world

FIRST DOSE SECOND DOSE

Lesson10

AUSTRALIA5

12 monthsMMR

18 monthsMMRV

ITALY3

12 to 15 monthsMMRV/ MMR+V

5 to 6 yearsMMRV/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

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.pdf

http://www.rki.de/EN/Content/infections/Vaccination/recommandations/34_2015_engl.pdf

http://www.health.gov.au/internet/immunise/publishing.nsf/content/IT0167-cnt

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.

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.

IAP response – Personal communication with Dr VipinVashishta, 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.

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 availablecomponents

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

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

Missed something ?

Get the complete presentation www.slideshare.net/gauravg

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Acknowledgments:• GSK Medical Affairs Team

http://www.slideshare.net/gauravg

mailto:[email protected]

priorix tetra – global experience and local evidence - mohali march 2017

Health & Medicine