Post on 22-Jan-2018
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?
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.
Developing a MMRV vaccine is more than just mixing MMR and V
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)
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
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
40
35
30
25
20
15
10
5
0
Me
an
stim
ula
tion
ind
ex
aft
er
52
we
eks
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.
100
90
80
70
60
50
40
30
20
10
0
%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
10
8
6
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.
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
1.79 Xhigher GMTs with
MMRV(4471.3 vs.2495.0)
1.06 Xhigher GMTs with
MMRV(1564.4 vs.1465.1)
1.30 Xhigher 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 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
Priorix-TetraTM PriorixTM +VarilrixTM
40
30
20
10
0
Subje
cts
(%)
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) 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.
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
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
40
30
20
10
0
Subje
cts
(%)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Day
Priorix-TetraTM PriorixTM +VarilrixTM
40
30
20
10
0S
ubje
cts
(%)
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) comparedto 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
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.
50
45
40
35
30
25
20
15
10
5
0Pain Swelling Pain Swelling
%ch
ildre
nre
po
rtin
g at
leas
to
nce
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
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
%o
fch
ildre
nre
po
rtin
gfe
ver
atle
ast
on
ce
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
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 ?
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Acknowledgments:• GSK Medical Affairs Team