Overview of varicella disease and role of vaccination - - PowerPoint PPT Presentation

“Overview of varicella disease and role of vaccination”

BD/VAR/0002/18

“Overview of varicella disease and role of vaccination”

• Dr. Raunak Parikh.

MBBS, MD (Micro.), Dip. Pharm. Med.

Senior Medical Advisor (Vaccines) GSK Pharmaceuticals India.

The varicella-zoster virus (VZV) causes varicella and HZ

Varicella-zoster virions Varicella (chicken pox)

Without vaccination,

HZ (shingles)

Secondary disease that Without vaccination, >90% of children are seropositive by adolescence in temperate countries1,2 Secondary disease that

• ccurs when dormant

VZV reactivates in previously infected individuals3

Varicella: a substantial burden of disease

The WHO estimated that 4.2 million severe complications

• f varicella worldwide result in hospitalisation and

4200 deaths per year1 Hospitalisation rates in children aged <17 years range from 0.82–22.7 per 100,000 across Europe2,3 from 0.82–22.7 per 100,000 across Europe2,3 Economic cost of varicella can be substantial,4-8 due to both societal costs and direct medical costs4,7,8*

WHO, World Health Organization. *Societal costs include work hours lost due to care of sick children; Direct costs include visits to primary care physicians, hospitalisations, medication costs and diagnostic examinations.

• 1. World Health Organization. Wkly Epidemiol Rec 2014; 89: 265–87; 2. Cameron JC et al. Arch Dis Child 2007; 92: 1062–6; 3. Bonsignori F et al. Infection

2007; 35: 444–50; 4. Banz K et al. Eur J Health Econ 2004; 5: 46–53; 5. Carapetis JR et al. Vaccine 2004; 23: 755–61; 6. Edgar BL et al. Can Commun Dis Rep 2007; 33: 1–15; 7. Somekh E et al. J Infect 2002; 45: 233–6; 8. Vally H et al. Aust N Z J Public Health 2007; 31: 113–9.

Chickenpox (Varicella)

– Primary infection with Varicella-zoster virus – Benign, self-limiting disease in children – Severe disease more likely in neonates, infants, pregnant women, adults, and immunocompromised persons – Fever, malaise, and a generalized vesicular rash – Fever, malaise, and a generalized vesicular rash [especially concentrated on the head and trunk] – Highly transmissible by the airborne route – infecting virus coming predominately from vesicular skin lesions

5

• 1. Varicella and herpes zoster vaccines: WHO position paper, June 2014. Weekly epidemiological record 2014;89:265-288

Varicella Rash

Starting on face and trunk, and spread to extremities in a so-called “centripetal spread.” New batches of lesions appear every few days for 5-7 days.2 Vesicles at various stages of evolution are

pruritic erythematous macules papular stage

hrs2

Vesicles at various stages of evolution are found on the skin.2 Varicella lesions are superficial and crusts fall

• ff after 1–2 weeks.3

Spots of hypopigmentation that can remain for several months or leave persistent scars.3

6

clear, fluid-filled vesicles Crusting of the lesions

24-48 hr

• 1. Leonid I, et al. J Clin Aesthet Dermatol. 2009 Aug; 2(8): 36–38. 2. Varicella and herpes zoster vaccines: WHO position paper, June 2014. Weekly

epidemiological record 2014;89:265-288. Heininger U, et al. Lancet 2006;368:1365-76.

Complications

– Vast majority of complications occur in healthy individuals.1 – Cannot predict which patients will experience complications.1 – Central nervous system:2 – Cerebellar ataxia (1 in ~4000 cases) – Encephalitis (1 in 33 000–50 000 cases) – Vasculitis, stroke (most frequently in children) – Vasculitis, stroke (most frequently in children) – Secondary bacterial infections:2 – most common complication in children – group A β-haemolytic streptococci or Staphylococcus aureus – Usually affect skin and underlying soft tissue – Invasive infections (pneumonia, arthritis, osteomyelitis, necrotizing fasciitis, and sepsis) – Pneumonia; usually viral (most common complication in adults).2

7

• 1. Bonanni P, et al. BMC Med. 2009 May 28;7:26. 2. Varicella and herpes zoster vaccines: WHO position paper, June 2014. Weekly epidemiological

record 2014;89:265-288

Bacterial superinfec tion/scarri ng Other complicati

• n

Complications

Comparative incidence of varicella complications Estimates, Germany

Bacterial superinfec tion/scarri ng Acute neurologic al disorder Other complicati

• n

Complications requiring hospitalization

Pneumoni a/bronchiti s Acute neurologic al disorder Otitis media Pneumoni a/bronchiti s

• n

Model estimates based on input data mainly from a retrospective epidemiological survey of 1,334 varicella cases in Germany. Base case analysis the model predicted approx.740,000 varicella cases per year with 39,700 complications and 5,740 hospitalization and 22 deaths. 1. Banz K, et al. Eur J Health Econom 2004;5:46–53.

Immunity during varicella infection

VZV-specific T cells: Essential to terminate viremic phase and enable recovery Severity of infection inversely correlated with T - cell response Innate and adaptive immune responses VZV reactivation: Attributed to declining T cell, rather than humoral immunity After resolution of initial infection, VZV establishes latency in sensory ganglia, where it persists lifelong VZV-specific antibodies: Not associated with reduced clinical severity of infection May prevent a second infection if immune individual exposed to virus

9

Warren-Gash C, et al. Expert Review of Vaccines, 16:12 1191-1201

Varicella vaccines development

1970s: early development of OKA strain Development of first marketed vaccine Further development

PFU, plaque-forming units; Virus image courtesy of the CDC.

• 1. Takahashi M. Infect Dis Clin North Am 1996; 10: 469–88; 2. GlaxoSmithKline. Varilrix Summary of product

characteristics 2016; 3. Kreth HW et al. BioDrugs 2008; 22: 387–402; .

strain

• Varicella virus isolated1
• Attenuated using three

cell lines to create the Oka strain1

• Varilrix: lyophilised

formula not less than 103.3 PFU (≥~1995 PFU); launched by GSK in 19842,3

• New stabiliser added to

Varilrix in 1994 to allow storage at 2–8°C2

• Merck Varicella vaccines

launched in 1995

• Combined MMRV

vaccines launched in 2000s

Question related to varicella vaccination??

Timing of first 1 vs. 2 doses ?

11

Timing of first dose? Vaccinate against varicella?

Vaccination can reduce incidence of OPD visits related to varicalla

Uruguay: varicella URV for 1‒2 year olds introduced in 1999

100 1000 ricella cases / tion (log scale)

2005 vs. 1997-9 87% decline (all age groups) [p<0.001]

Varicella vaccination introduced end of 1999 for children aged 12 months. Estimated to exceed 90%. Information on medical consultations for varicella was collected from two private health insurance systems. Ambulatory visits for varicella compared between 1999 and 2005 and 1997 and 1999 Quian J et al. Arch Dis Child 2008; 93: 845‒50.

12

1 10 1997 1998 1999 2000 2001 2002 2003 2004 2005 Number of varic 1000 populatio Year <1 1–4 5–9 10–14

Rate Number Hospitalisation rates declined by 21.4% per annum

Vaccination can reduce varicella related hospitalization

alisation rate population ual number pitalisations 7 6 5 4 1200 1000 800

Principal or any coded varicella or HZ hospitalizations were retrieved from the national hospital morbidity database from 1998 to 2010. Incidence rate ratios (IRR) were calculated between periods before and after implementation of immunization programme funding. Varicella vaccine coverage ~ 75% in children aged 24 months and> 80% in children aged 60 months. Heywood AE et al. Bull World Health Organ 2014; 92: 593–604.

13

Annual hospitali per 100,000 po Annua

• f hospi

Pre-vaccine (before 1999) Vaccine licensed (2000–2003) Vaccine recommended (2004–2005) Vaccine funded (2006–2010) 4 3 2 1 600 400 200

Vaccination can reduce varicella related mortality

80 100 120

aths per year

Pre-vaccine period Implementation of a two-dose schedule Implementation of a

• ne-dose schedule

Annual varicella-related deaths in the USA, national vital statistics system data, 1990–20112

Data on varicella deaths for 2008–2011 using the Mortality Multiple Cause-of Death public use records from the National Center for Health Statistics and and calculated rates to compare with the prevaccine and mature 1-dose varicella vaccination program eras Leung J, et al. Hum Vaccin Immunother 2015; 11: 662–8.

20 40 60 80 1990–1994 2005–2007 2008–2011

Average number of deat

Varicella listed as underlying cause of death Varicella listed as contributing cause of death

Optimal age for 1st varicella vaccination

– Knowledge of kinetics of maternal antibodies is important in order to properly estimate the optimal age of vaccination. – When live attenuated vaccines are injected, the presence

• f maternal IgG antibodies may neutralize vaccine

viruses, thereby inhibiting the vaccine-specific immune viruses, thereby inhibiting the vaccine-specific immune response.

– Reduce the gap of immunity between the disappearance of transmitted maternal antibodies and the age of initiation of active immunization can decrease burden of varicella disease in infants

15

Pinquier D, et al. Clin Vaccine Immunol. 2009 Apr; 16(4): 484–487.

200 250 300 350 400 50 60 70 80 90 100

mIU/ml ( - line) sitivity (%)

France

Potential immunity gap in infants

Seroprevalence in infants

250 300 350 400 450 500 50 60 70 80 90 100

r mIU/ml ( - line) s Title

Switzerland (N=253)

50 100 150 200 10 20 30 40 50 0-3 months 3-6 months 6-9 months 9-12 months >=12 months

Antibody Titer m Seropositi

16

50 100 150 200 250 10 20 30 40 50 0-3 months 3-6 months 6-9 months 9-12 months

Antibody Titer m Axis T

*; Prospective multicenter study 2005-7 in seven hospitals in France with 345 infants. 37% mothers had history of varicella. seropositive = antibody titre ≥150 mIU/ml by a time-resolved fluorescence immunoassay (TRFIA). ^; Serum specimens of children aged 0–16 months hospitalized at University Children’s Hospital Basel 1994-9. 253 serum specimens from 240 patients were analyzed. >100 mIU/ml were considered positive by ELISA. 1. Pinquier D, et al. Clin Vaccine Immunol. 2009 Apr; 16(4): 484–487. 2. Heininger U, et al. Vaccine 2006; 24:3258-2380.

N=48 N=44 N=94 N=114 N=45 N=57 N=47 N=47 N=48

97.1 60 70 80 90 100

ersion (%)

Turkish study1^

Varicella vaccines are immunogenic at 9 months

Study with GSK oka containing vaccine

94.2 100 60 70 80 90 100

ersion (%)

Indian study2#

99.1 100 100 100 60 70 80 90 100

ersion (%)

Singapore study3*

10 20 30 40 50 Post dose 1 [9 months]

Seroconvers

17

10 20 30 40 50 Post dose 1 [9 months] Post dose 2 [15 months]

Seroconvers

10 20 30 40 50 Post dose 1 [9 months] Post dose 2 [12 months]

Seroconvers

N=111 N=126 N=118 N=133

*; randomized, controlled study. Vaccines administered 2 dose of MMRV or MMR+V at 9 and 12 months age. Antibody assessment 42 days post dose with indirect IFA with cut-off of 4 dilution–1.^; prospective controlled study with 143 infants 9 months given V vaccine. Antibody assessment 42 days post dose with indirect IFA with cut-off of 4 dilution–1. #; randomised, non-inferiority study. 9-10m received MMRV/MMRV at 9,15m or MMR/MMRV or MMR/MMR+V. Antibody titres against varicella 42 days post dose with IFA. 1. Kanra G, et al. Pediatr Int 2000;42(6):674-7. 2. Lalwani S, et al. BMJ Open 2015 Sep 11;5(9):e007202. 3. Goh P, et al. Infection 2007;35:326-333.

N=138 N=138 N=105 Monovalent varicella vaccine MMRV vaccine

Boosting effect with 2nd dose of varicella vaccination

– Several studies have evaluated 2nd dose in children with months to 6 years between doses – Seroconversion rate increased after two doses in comparison to

• ne dose

5318.5 4000 5000 6000

la GMT

Increase in antibody titres after 2nd dose.2^

18

• ne dose

– Geometric mean titre (GMT) increased – Dramatic boosting of immune response indicates primary immune response after one dose was inadequate

120.5 1000 2000 3000 Dose 1 Dose 2

Anti-varicella G

^randomised, non-inferiority study. 9-10m received MMRV/MMRV at 9,15m or MMR/MMRV or MMR/MMR+V. Antibody titres against varicella 42 days post dose with IFA

• 1. WHO. The immunological basis for immunization Series. Module 10: Varicella-zoster vaccine.
• 2. Lalwani S, et al. BMJ Open 2015 Sep 11;5(9):e007202.

MMRV vaccine N=138 N=138

Sustained high antibody titres following two doses

• f GSK oka in 2nd year of life

1200 1400 1600 1800 2000 D42 D84 Y1 Y2 Y4 Y6 Y8 Y10

19

200 400 600 800 1000

GMTs

10 years

Randomized controlled trial in ten European countries with endemic varicella. Healthy children aged 12-22 months received 3:3:1 MMRV/MMRV or MMR/V or MMR/MMR. Subjects in ATP-immunogenicity persistence cohort followed up for 10 years with periodic serum analysis. Varicella ELISA cut-off: 25 mIU/mL. Available at: GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result-Summary.pdf

N= 674 2209 2019 1869 1362 1292 1146 1146

– D1 – D2

Sustained seropositivity following two doses of GSK oka in 2nd year of life

99.6 60 70 80 90 100

vity (%)

D42 D84 Y1 Y2 Y4 Y6 Y8 Y10 – D1

20

10 20 30 40 50

Seropositivity

N= 674 2209 2019 1869 1362 1292 1146 1146

Randomized controlled trial in ten European countries with endemic varicella. Healthy children aged 12-22 months received 3:3:1 MMRV/MMRV or MMR/V or MMR/MMR. Subjects in ATP-immunogenicity persistence cohort followed up for 10 years with periodic serum analysis. Varicella ELISA cut-off: 25 mIU/mL. GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result-Summary.pdf

– D1

Efficacy of 1 dose varicella vaccine vs 2 doses varicella vaccine

OKA-H 179-182: observer-blind, randomised, controlled study (Europe)

Healthy children 12–22 months old

MMR MMRV MMR V MMRV MMR R

Day 0 Day 42

3 3 1

10Yr

Group N (randomised) N (completed 10 yr) Number V doses Day 0 Day 42 MMRV 2489 1415 2 MMRV MMRV MMR+V 2487 1415 1 MMR V MMR 827 468 Control MMR MMR 5803

The 1 dose group is identified as MMR+V. After completion of the first phase of the trial, the MMR+V group was offered a second dose of MMR in accordance with local immunisation recommendations. MMRV, measles-mumps-rubella-varicella combined vaccine; MMR+V, measles-mumps-rubella combined vaccine plus monovalent varicella vaccine; V, monovalent varicella vaccine.

. GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result- Summary.pdf

50.0 60.0 70.0 80.0 90.0 100.0

centage

Attack rate

Vaccine efficacy – Confirmed Moderate-Severe Varicella

90.7 99.5 89.5 99.1 60 70 80 90 100

ntage

Vaccine Efficacy

1.6 0.1 15.7 3.0 0.3 23.7 0.0 10.0 20.0 30.0 40.0 50.0 1 Dose Vx 2 Dose Vx No Varicella Vx

Percen

0-3 years 3-10 years

22

10 20 30 40 50 1 Dose Vx 2 Dose Vx

Percent

0-3 years 3-10 years 1 Dose Vx = MMR/V, 2 Dose Vx = MMRV/MMRV, No Varicella Vx = MMR/MMR

Randomized controlled trial in ten European countries with endemic varicella. Healthy children aged 12-22 months received 3:3:1 MMRV/MMRV or MMR/V or MMR/MMR. Absolute Risk Reduction [in person-year rate] vs. No vaccine: Any severity: 1 Dose: 0.066, 2 Doses = 0.098. Moderate-Severe: 1 Dose = 0.051, 2 Doses = 0.057. GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result- Summary.pdf

50.0 60.0 70.0 80.0 90.0 100.0

rcentage

Attack rate

Vaccine efficacy – Confirmed Varicella [any severity]

65.4 94.4 69.8 95.9 50 60 70 80 90 100

entage

Vaccine Efficacy

10.7 1.2 27.1

14.1 2.1 37.6 0.0 10.0 20.0 30.0 40.0 50.0 1 Dose Vx 2 Dose Vx No Varicella Vx

Perce

0-3 years 3-10 years

23

10 20 30 40 50 1 Dose Vx 2 Dose Vx

Percen

0-3 years 3-10 years 1 Dose Vx = MMR/V, 2 Dose Vx = MMRV/MMRV, No Varicella Vx = MMR/MMR

Randomized controlled trial in ten European countries with endemic varicella. Healthy children aged 12-22 months received 3:3:1 MMRV/MMRV or MMR/V or MMR/MMR. Absolute Risk Reduction [in person-year rate] vs. No vaccine: Any severity: 1 Dose: 0.066, 2 Doses = 0.098. Moderate-Severe: 1 Dose = 0.051, 2 Doses = 0.057. GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result- Summary.pdf

Varicella Vaccine Effectiveness

81.8 65.3 98.2 94.4 89.3 99.5 60 70 80 90 100

ctiveness (%)

Germany, 2006–2015 (n = 1,449,411) > 0.5 to 8.0 years since vaccination

p < 0.0001 p < 0.0001 p < 0.0001

10 20 30 40 50 Overall No complication All complication

Vaccine Effectiv

1 Dose 2 Doses

24 Immunisation information system based on countrywide health insurance claims data to analyse vaccine effectiveness (VE). Out of 1.4 million children 29,404 varicella cases over a follow-up of 8 years post-vaccination [V or MMRV]. Vaccine effectiveness within 1 dose and 2 doses and between 1 dose and 2 doses difference significant (all p < 0.0001). Rieck T, et al. Euro Surveill. 2017 Apr 27; 22(17): 30521

Monovalent varicella vaccine is well tolerated and has non-inferior immunogenicity with other childhood vaccines1

DTaP DTaP- IPV MMR

Varicella vaccine is frequently co-administered with Measles containing vaccine1,2

Varicella vaccine

influenza (LAIV) Hib Hib- HepB

25

• 1. Varicella and herpes zoster vaccines: WHO position paper, June 2014. Weekly epidemiological record 2014;89:265-288. 2. Rieck T, et al. Euro Surveill. 2017 Apr 27; 22(17): 30521

Monovalent varicella vaccine is well tolerated and has non-inferior immunogenicity with other childhood vaccines1

Varicella vaccine is frequently co-administered with Measles containing vaccine1,2

Vaccine Effectiveness 1 dose Vaccine Effectiveness 2 doses 2nd dose 1–27 days 2nd dose same day

26

days day

• r > 27 days

1st dose 1–27 days 32.2 (10.4–48.6) No meaningful estimate 92.8 (84.8–96.6) 1st dose same day

• r > 27 days

80.9 (80.2–81.5) 95.3 (66.6–99.3) 94.1 (93.9–94.3) Optimal protection against varicella with simultaneous administration of MCV and varicella vaccine or a time interval > 27 days between these vaccinations2*

*;Immunisation information system based on countrywide health insurance claims data to analyse vaccine effectiveness (VE). Out of 1.4 million children 29,404 varicella cases over a follow-up of 8 years post-vaccination [V or MMRV]. Vaccine effectiveness within 1 dose and 2 doses and between 1 dose and 2 doses difference significant (all p < 0.0001).

• 1. Varicella and herpes zoster vaccines: WHO position paper, June 2014. Weekly epidemiological record 2014;89:265-288 2. Rieck T, et al. Euro Surveill. 2017 Apr 27; 22(17): 30521

• Varilrix is a vaccine for immunisation against varicella
• Live attenuated Oka varicella strain

– Lyophilised preparation ≥103.3 plaque-forming units/dose

• Meets the WHO requirements
• Storage at 2‒8°C

Varilrix monovalent varicella vaccine

• Storage at 2‒8°C
• No. of studies = 42
• No. of publications = 47
• Registered in 87 countries
• 47 million doses distributed since 1994

Local Varilrix prescribing information- GDS12/IPI013/Date of issue: 14/09/2016. Kreth et al. Biodrugs 2008; 22: 387–402

Full prescribing information is available on request

Varilrix is indicated for active immunisation against varicella of

• healthy subjects (from the age of 9 months).
• patients at high risk of severe varicella

Posology

• Healthy children 9 months up to and including 12 years: 2 doses

– second dose at least 6 weeks after the first dose but in no circumstances less than 4 weeks.

Varilrix Indications, posology and administration

• Healthy adolescents and adults from 13 years of age and above: 2 doses

– second dose at least 6 weeks after the first dose but in no circumstances less than 4 weeks.

• The same schedule described for healthy subjects should be applied for high-risk

patients.

• In these patients, periodic measurement of varicella antibodies after vaccination may be

indicated in order to identify those who may benefit from re-vaccination.

Administration

Varilrix is for subcutaneous administration in the deltoid region or in the anterolateral area of the thigh.

Local Varilrix prescribing information- GDS12/IPI013/Date of issue: 14/09/2016.

Full prescribing information is available on request

Varilrix is supported by sustained long term seropositivity data with GSK oka strain

99.6 60 70 80 90 100

vity (%)

D42 D84 Y1 Y2 Y4 Y6 Y8 Y10 – D1

29

10 20 30 40 50

Seropositivity

N= 674 2209 2019 1869 1362 1292 1146 1146

Randomized controlled trial in ten European countries with endemic varicella. Healthy children aged 12-22 months received 3:3:1 MMRV/MMRV or MMR/V or MMR/MMR. Subjects in ATP-immunogenicity persistence cohort followed up for 10 years with periodic serum analysis. Varicella ELISA cut-off: 25 mIU/mL. GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result-Summary.pdf

– D1

Varilrix is supported by sustained long term efficacy data with GSK oka strain

90.7 99.5 89.5 99.1 60 70 80 90 100

fficacy (%)

Varicella [moderate-severe]

65.4 94.4 69.8 95.9 50 60 70 80 90 100

Efficacy (%)

Varicella [any severity]

30

10 20 30 40 50 1 Dose Vx 2 Dose Vx

Vaccine Effic

0-3 years 3-10 years

Randomized controlled trial in ten European countries with endemic varicella. Healthy children aged 12-22 months received 3:3:1 MMRV/MMRV or MMR/V or MMR/MMR. Absolute Risk Reduction [in person-year rate] vs. No vaccine: Any severity: 1 Dose: 0.066, 2 Doses = 0.098. Moderate-Severe: 1 Dose = 0.051, 2 Doses = 0.057. GSK clinical trial report on study number 100388 and subsequent extensions. Available at: https://www.gsk-clinicalstudyregister.com/files2/100388%20-%20Clinical-Study-Result- Summary.pdf

1 Dose Vx = MMR/V, 2 Dose Vx = MMRV/MMRV, No Varicella Vx = MMR/MMR 10 20 30 40 50 1 Dose Vx 2 Dose Vx

Vaccine Ef

0-3 years 3-10 years

Varilrix is supported by effectiveness data showing reduction in varicella disease

Uruguay: varicella URV for 1‒2 year olds introduced in 1999

100 1000 ricella cases / tion (log scale)

2005 vs. 1997-9 87% decline (all age groups) [p<0.001]

Varicella vaccination introduced end of 1999 for children aged 12 months. Estimated to exceed 90%. Information on medical consultations for varicella was collected from two private health insurance systems. Ambulatory visits for varicella compared between 1999 and 2005 and 1997 and 1999 Quian J et al. Arch Dis Child 2008; 93: 845‒50.

31

1 10 1997 1998 1999 2000 2001 2002 2003 2004 2005 Number of varic 1000 populatio Year <1 1–4 5–9 10–14

Rate Number Hospitalisation rates declined by 21.4% per annum

Varilrix is supported by impact data showing reduction in varicella hospitalization

alisation rate population ual number pitalisations 7 6 5 4 1200 1000 800

Principal or any coded varicella or HZ hospitalizations were retrieved from the national hospital morbidity database from 1998 to 2010. Incidence rate ratios (IRR) were calculated between periods before and after implementation of immunization programme funding. Varicella vaccine coverage ~ 75% in children aged 24 months and> 80% in children aged 60 months. Heywood AE et al. Bull World Health Organ 2014; 92: 593–604.

32

Annual hospitali per 100,000 po Annua

• f hospi

Pre-vaccine (before 1999) Vaccine licensed (2000–2003) Vaccine recommended (2004–2005) Vaccine funded (2006–2010) 4 3 2 1 600 400 200

Varilrix is well tolerated in children and adults

3.5 2.5 3 3.5 4 ce (%) Children aged <13 years (n=2811) Adolescents and adults aged ≥13 years (n=151) 0.5 1 0.4 1.9 2 0.7 1.3 2 0.7 0.5 1 1.5 2 2.5 Fever Rash Redness Swelling Pain Other Incidence (

Kreth et al. BioDrugs 2008; 22: 387−402

Important Safety information: 1

• As with other vaccines, the administration of Varilrix should be postponed in

subjects suffering from acute severe febrile illness. In healthy subjects the presence of a minor infection, however, is not a contra-indication for immunisation.

• Varilrix is contraindicated in pregnant women. Pregnancy should be avoided for
• ne month after vaccination.
• Should a measles containing vaccine not be given at the same time as Varilrix, it

is recommended that an interval of at least one month should be respected since is recommended that an interval of at least one month should be respected since it is recognised that measles vaccination may lead to short lived suppression of the cell mediated immune response.Varilrix should not be administered intradermally.

• Varilrix must under no circumstances be administered intravenously.
• 1. Varilrix GDS12/IPI013/Date of issue: 14/09/2016.

Full prescribing information is available on request

Patient safety is the fundamental principle for GSK, ahead of commercial or other interests. We conduct our clinical trials according to high standards of ethics and safety, and we are committed to transparency

• n the benefits and risks of all our medicines in all
• n the benefits and risks of all our medicines in all

communications with patients, prescribers, payers and regulators.

Adverse event on GSK products should be reported to – GlaxoSmithKline Bangladesh Ltd. Phone-029858870 Or 09678333475 (24hours) E-mail: bd.adverse-event@gsk.com

API

Name of the Product: Varilrix (Varicella vaccine) Qualitative and quantitative composition: Varilrix is a lyophilised preparation of the live attenuated Oka strain of varicella-zoster virus, obtained by propagation of the virus in MRC-5 human diploid cell culture. Each dose of the reconstituted vaccine contains not less than 103.3 plaque-forming units (PFU) of the attenuated varicella-zoster virus. Pharmaceutical form: Powder and solvent for solution for injection. Indications: Healthy subjects: Varilrix is indicated for active immunisation against varicella of healthy subjects from the age of 9 months onwards. Vaccination of susceptible healthy close contacts of subjects at risk of severe varicella is recommended, in order to reduce the risk of transmission of wild-type virus to these

• patients. Close contacts include parents and siblings of high-risk patients, and medical and paramedical personnel. Patients at high risk of severe varicella: Patients suffering from leukaemia, patients

under immunosuppressive treatment (including corticosteroid therapy) for malignant solid tumour, for serious chronic diseases (such as chronic renal failure, auto-immune diseases, collagen diseases, severe bronchial asthma) or following organ transplantation, are predisposed to severe natural varicella. Vaccination with the Oka-strain has been shown to reduce the complications of varicella in these patients. There is only limited data from clinical trials available for Varilrix in patients at high risk of severe varicella; should vaccination be considered, it is advised that a) maintenance chemotherapy should be withheld one week before and one week after immunisation of patients in the acute phase of leukaemia. Patients under radiotherapy should normally not be vaccinated during the treatment phase. Generally patients are immunised when they are in complete haematological remission from the disease. b) the total lymphocyte count should be at least 1,200 per mm3 or no other evidence of lack of cellular immune competence exists. c) vaccination should be carried out a few weeks before the administration of the immunosuppressive treatment for patients undergoing organ transplantation (e.g. kidney transplant). Dosage and Administration: 0.5 ml of reconstituted vaccine contains one immunising dose. Posology: Healthy subjects: Children 9 months up to and including 12 years of age: Children from the age of 9 months up to and including 12 years of age should receive 2 doses of Varilrix to ensure optimal protection against varicella. It is preferable to administer the second dose at least 6 weeks after the first dose but in no circumstances less than 4 weeks. Adolescents and adults from 13 years of age and above: From 13 years of age and above: 2 doses. It is preferable to administer the second dose at least 6 weeks after the first dose but in no circumstances less than 4 weeks. High risk patients: The same schedule described for healthy subjects should be applied for high-risk patients. In these patients, periodic measurement of varicella antibodies after vaccination may be indicated in order to identify those who may benefit from re-vaccination. Method of administration: Varilrix is for subcutaneous administration in the deltoid region or in the anterolateral area of the thigh. Contraindications: As with other vaccines, the administration of Varilrix should be postponed in subjects suffering from acute severe febrile illness. In healthy subjects the presence of a minor infection, however, is not a contra- indication for immunisation. Varilrix is contraindicated in subjects with severe humoral or cellular immunodeficiency such as; subjects with primary or acquired immunodeficiency states with a total lymphocyte count less than 1,200 per mm3; subjects presenting other evidence of lack of cellular immune competence (e.g. subjects with leukaemias, lymphomas, blood dyscrasias, clinically manifest HIV infection); subjects receiving immunosuppressive therapy including high dose of corticosteroids. Varilrix is contraindicated in subjects with known hypersensitivity to neomycin or to any other component of the vaccine. A history of contact dermatitis to neomycin is not a contraindication. Varilrix is contraindicated in subjects having shown signs of hypersensitivity after previous component of the vaccine. A history of contact dermatitis to neomycin is not a contraindication. Varilrix is contraindicated in subjects having shown signs of hypersensitivity after previous administration of varicella vaccine. Warnings and Precautions: Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. It is important that procedures are in place to avoid injury from faints. Alcohol and other disinfecting agents must be allowed to evaporate from the skin before injection of the vaccine since they can inactivate the attenuated viruses in the vaccine. Limited protection against varicella may be obtained by vaccination up to 72 hours after exposure to natural disease. As with any vaccine, a protective immune response may not be elicited in all vaccinees. As for other varicella vaccines, cases of varicella disease have been shown to occur in persons who have previously received Varilrix™. These breakthrough cases are usually mild, with a fewer number of lesions and less fever as compared to cases in unvaccinated individuals. Transmission of the Oka vaccine virus has been shown to occur at a very low rate in seronegative contacts of vaccinees with rash. Transmission of the Oka vaccine from a vaccinee who does not develop a rash to seronegative contacts cannot be excluded. As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine. For this reason, the vaccinee should remain under medical supervision for 30 minutes after immunisation. There is limited data on the use of Varilrix in immunocompromised subjects, therefore vaccination should be considered with caution and only when, in the opinion of the physician, the benefits outweigh the risks. Immunocompromised subjects who have no contraindication for this vaccination may not respond as well as immunocompetent subjects, therefore some of these subjects may acquire varicella despite appropriate vaccine administration. Immunocompromised subjects should be monitored carefully for signs of varicella. Very few reports exist on disseminated varicella with internal organ involvement following vaccination with Oka varicella vaccine strain mainly in immunocompromised

• subjects. Varilrix must not be administered intravascularly or intradermally. Interactions: If tuberculin testing has to be done it should be carried out before or simultaneously with vaccination since it

has been reported that live viral vaccines may cause a temporary depression of tuberculin skin sensitivity. As this anergy may last up to a maximum of 6 weeks, tuberculin testing should not be performed within that period after vaccination to avoid false negative results. In subjects who have received immune globulins or a blood transfusion, immunisation should be delayed for at least three months because of the likelihood of vaccine failure due to passively acquired varicella antibodies. Salicylates should be avoided for 6 weeks after varicella vaccination as Reye’s Syndrome has been reported following the use of salicylates during natural varicella infection. Healthy subjects: Varilrix™ can be administered at the same time as any other vaccines. Different injectable vaccines should always be administered at different injection sites. Inactivated vaccines can be administered in any temporal relationship to Varilrix. Should a measles containing vaccine not be given at the same time as Varilrix, it is recommended that an interval of at least one month should be respected since it is recognised that measles vaccination may lead to short lived suppression of the cell mediated immune response. High-risk patients: Varilrix should not be administered at the same time as other live attenuated vaccines. Inactivated vaccines may be administered in any temporal relationship to Varilrix, given that no specific contraindication has been established. Pregnancy and Lactation: Pregnant women must not be vaccinated with Varilrix. Pregnancy should be avoided for one month after vaccination. Women who intend to become pregnant should be advised to delay pregnancy. Lactation: There are no data regarding use in nursing women. Adverse Reactions: Very common: pain, redness, Common: rash, Uncommon: upper respiratory tract infection, pharyngitis lymphadenopathy, irritability, headache, somnolence, cough, rhinitis, nausea, vomiting, nausea, vomiting, varicella-like rash, pruritus, arthralgia, myalgia, fever (oral/axillary temperature > 39.0°C or rectal temperature > 39.5°C), fatigue, malaise, Rare: conjunctivitis, abdominal pain, diarrhoea, urticarial. Swelling at the injection site and fever were reported very commonly in studies conducted in adolescents and adults. Swelling was also reported very commonly after the second dose in children under 13 years of age. A trend for higher incidence of pain, redness and swelling after the second dose was observed as compared to the first dose. Shelf Life: It has been demonstrated that the reconstituted vaccine may be kept for up to 90 minutes at room temperature (25°C) and up to 8 hours in the refrigerator (2°C-8°C). Special Precautions for Storage: The lyophilised vaccine should be stored in a refrigerator between +2°C and +8°C and protected from light. Version number: GDS12/IPI013/Date of issue: 14/09/2016.

Summery :

“Overview of varicella disease and role of vaccination”

Varicella, although a frequently benign childhood disease, nevertheless represents a considerable health burden. WHO recommends including varicella vaccines in universal routine vaccination programs, and maintaining coverage >80%. Many countries have successfully introduced varicella vaccination and have benefited from lower disease burden, but many others have not adopted the vaccine. Reasons include cost commitment for a ‘mild childhood disease’ or concerns that vaccination will shift varicella to older age groups or increase herpes zoster incidence. The main burden of varicella disease is economic due to the high number of cases and the need for parents and caregivers to look after their children. Non-complicated cases tend to last for up to 2 weeks during which time affected children will not be able to attend day care or school. The indirect costs associated with parents taking time off from work make a significant but potentially underestimated contribution to the economic impact of VZV infection. Varicella vaccines are immunogenic with acceptable safety profiles. Varicella dosing recommendations from supranational authorities consider two doses for best acceptable safety profiles. Varicella dosing recommendations from supranational authorities consider two doses for best effectiveness and prevention of outbreaks, separated by a long or short dosing interval. The dosage schedule comprises

• f two doses. A first dose can be given at any day from 9 months followed by a second dose preferably at least 6 weeks

after the first dose, but in no circumstances less than 4 weeks. Although it is assumed that a shorter interval may be

• ptimal in terms of epidemiologic impact, pragmatically some countries retain longer intervals to better fit with their

childhood vaccination programs. Countries implementation programs have shown both one and two dose schedules are highly effective against varicella and large reductions in disease incidence, particularly moderate-severe disease, have been widely reported. In conclusion, varicella vaccination easily fits into existing immunization programs and significantly reduces the often underestimated burden of varicella.