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

1. Priorix Tetra – Global Experience
& Local Evidence
Dr Gaurav Gupta
Mohali – 18th March, 2017

2. Conflict of Interest
• Received grants from various vaccine
manufacturers including

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. • What is the recommended age of MMRV?

5. Combination Vaccines – Why?
• Simplified Immunization Schedule
• Less injections – Complications
• Better Compliance
• Lesser administration time/ costs/ space

6. Combination vaccines – Why not?
• Adverse effects maybe more common
• Reduced Immunogenicity
• May have lesser shelf life
• Technically difficult
• Expensive

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. 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. 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. 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. Are 2 dose of Varicella really needed?

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. 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. 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. 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. What is the minimum gap between
doses of MMRV?

17. Is MMRV effective/ safe?

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

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. 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. 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. 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. 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. 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.

32. 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

33. 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

34. Missed something ?
Get the complete presentation
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Feedback: docgaurav@gmail.com
Acknowledgments:
• GSK Medical Affairs Team