safety profiles of cyd-tdv vaccinenvi.go.th/uploads/default/files/national-vaccine... · cyd14...

Safety Overview of

CYD-TDV Dengue Vaccine:

Pooled Analysis of Data from

18 Clinical Trials

Dr. Tawee Chotpitayasunondh,MD

20 July 2017, National Vaccine Institute

| 2

Reduction in

symptomatic dengue

65.6% (95% CI: 60.7–69.9)

Reduction in

hospitalized dengue

80.8% (95% CI: 70.1–87.7)

CONSISTENT EFFICACY PROFILE OF CYD 14 & CYD 15 STUDIES

IN SUBJECTS 9–16 YEARS OF AGE DURING ACTIVE PHASE

1.Hadinegoro, 2015, N Engl J Med.

Key Efficacy Results 25-month active phase* Pooled efficacy analyses‡1

*Data come from the 2 pivotal, phase III, large-scale efficacy trials CYD14 and CYD15, which were designed to fully assess efficacy; postdose 1; 1Full Analysis Set

for Efficacy (FASE): all subjects who received at least one injection. †dengue hemorrhagic fever, Severe Dengue, IDMC criteria. CI=confidence interval;

DENV=dengue virus.

Reduction in

severe dengue †

93.2% (95% CI: 77.3–98.0)

For each serotype:

DENV-1: 58.4% (95% CI: 47.7–66.9)

DENV-2: 47.1% (95% CI: 31.3–59.2)

DENV-3: 73.6% (95% CI: 64.4–80.4)

DENV-4: 83.2% (95% CI: 76.2–88.2)

By dengue serostatus:

Seropositive: 81.9% (95% CI: 67.2–90.0)

Seronegative: 52.5% (95% CI: 5.9–76.1)

PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0004821 July 14, 2016

Pooled analysis of safety data from

18 clinical trials

| 7

Integrated safety analyses performed in 9 to 60 yo population create significant size of safety

database

13 Clinical trials with final immunization schedule from phase II to phase III were included

in the pooled safety analyses

20,667 subjects of 9 to 60 years

~19,700 received all 3 doses

Allowing to detect very common, common, and uncommon adverse events (AEs) that

occur with an incidence ≥ 0.1%, in accordance with WHO guidelines

*Integrated safety analysis pooling data from 13 studies that used the final formulation and final vaccination schedule (CYD12, 13, 22, 24, 28, 30, 47, 23, 17, 32, 14, 15, 51).

AE=adverse event; AR=adverse reaction.

METHODOLOGY:- INTEGRATED SAFETY ANALYSES FROM CLINICAL TRIALS STUDIES

CONDUCTED ENROLLING INDIVIDUALS UP TO 60 YEARS OF AGE


Criteria of safety assessment

• Solicited* (local vs systemic reactions)

• Injection-site reactions : pain, erythema and swelling (monitored for 7 days after vaccination)

• Systemic reactions : fever, headache, myalgia, asthenia,

malaise (monitored for 14 days after vaccination)

• Unsolicited** (monitored for 28 days after vaccination)

• Immediate AE : AEs occurring within 30 minutes of

an injection

• Adverse event of special interest (AESI)

*considered as being vaccine-related (adverse reactions)

**relatedness was assessed by the investigators (can be considered as

adverse events or adverse reactions)


Overall safety profile (stratified by age groups)

Results showed that the overall reactogenicity and safety profile for the CYD-TDV vaccine was comparable to placebo

across all age groups (2–8 years; 9–60 years) with similar reported rates and nature of events.


0.2

74

49.6

66.5

44.3

0

64.1

36.5

59

39

0 10 20 30 40 50 60 70 80 90 100

Immediate unsolicited AR

Solicited AR

Solicited injection site reaction

Solicited systemic reaction

Unsolicited non-serious AE

Placebo (n=1780)

CYD vaccine (n=4615)

Percentage of subjects presenting with at least 1 reaction or event



Gailhardou et al, PLoSNTD, 2016

RESULTS:- SAFETY OVERVIEW AFTER ANY DENGUE VACCINE OR PLACEBO DOSE –

SUBJECTS AGED 9–60 YEARS SAFETY POOLED ANALYSIS*

| 14

%, 95% CI

Solicited

injection site

reaction

Adults aged 18–60 years

Subjects aged 9–17 years

Grade 3

solicited

injection site

reaction



Pain



Erythema



Swelling



RESULTS OVERVIEW OF SAFETY : SOLICITED INJECTION SITE

REACTIONS1 (AGE 9–60 YEARS) - SAFETY POOLED ANALYSIS*

46.9

51.0

0.7

1.5

45.2

49.2

7.9

8.4

2.4

6.9

-5 15 35 55

44.3 49.4

49.2 52.8

0.4 1.3

1.1 2.0

42.7 47.7

47.5 51.0

6.6 9.3

7.4 9.4

1.7 3.3

6.0 7.8



• Pain was the most common in all age groups

• Most solicited injection site reaction were grade 1 severity


| 15

RESULTS OVERVIEW OF SAFETY : SOLICITED SYSTEMIC REACTIONS1

(AGE 9–60 YEARS) - SAFETY POOLED ANALYSIS*

%, 95% CI

Solicited

systemic

reaction



Grade 3 Adults aged 18–60 years


Fever Adults aged 18–60 years


Headache Adults aged 18–60 years


Malaise Adults aged 18–60 years


Myalgia Adults aged 18–60 years


Asthenia Adults aged 18–60 years


65.6

67.0

10.8

11.1

4.9

16.4

51.4

54.1

44.3

40.9

42.2

42.0

28.3

34.2

0 20 40 60

63.1 67.9

65.3 68.7

9.2 12.4

10.0 12.2

3.9 6.1

15.1 17.8

48.9 54.0

52.3 55.9

41.8 46.8

39.2 42.7

39.7 44.7

40.2 43.8

26.1 30.7

32.5 35.9




Headache, malaise, myalgia were most frequently reported in both groups

• Rates were similar between the age groups except for fever.

• (more frequent in children and adolescents than adults)

Results : Serious Adverse Events

• Frequency and nature of SAEs observed up to 28 days post injection and between day >28 and 6 months post injection of any dose were similar in both groups and were common medical conditions that could be expected as a function of age

• No safety concern observed in the review of SAEs during longer-term follow up (up to year-3 post dose 1)

• Six (CYD) and eight(Placebo) deaths* reported within 6 months after any injection in the CYD-TDV and placebo groups in participants aged 2-60 years; all were assessed as not related

*In the CYD-TDV group the deaths were due to road traffic accidents (n = 3), tracheal injury (n = 1), deliberate poisoning (n = 1) and accidental asphyxia by strangulation (n = 1). In the placebo group the deaths were due to drowning (n = 2), T-cell lymphoma (n = 1), road traffic accident (n = 1), bronchoscopic aspiration (n = 1), head injury (n = 1), lupus nephritis (n = 1) and metastatic osteosarcoma (n = 1).


Results : AESI (1)

Allergic reactions and anaphylaxis (within 7 days of vaccination)

• Non-serious potential allergic reactions (mainly rashes) among participants aged 9–60 years in the main trials were found within 7 days after any injection

• 46 (0.7%) in the CYD-TDV

• 15 (0.5%) in the placebo groups

• Similar profile observed in participants aged 2-8 years

• Overall, no severe or serious immediate anaphylactic reactions

were reported in any age group

Viscerotropic or neurotropic events* (within 30 days of vaccination)

• No confirmed cases of viscerotropic or neurotropic disease were reported.

*Viscerotropic and neurotropic diseases are very rare events that have been reported for YFV vaccines such as Stamaril [37]. The event rate after vaccination with a licensed YFV vaccine has been reported to be 0.4/100,000 doses for viscerotropic events and 0.8/100,000 doses for neurotropic events [38].


Safety profiles after each dose

Rates were lower after the second or third dose than the first dose.


No influence of Baseline dengue sero-status on safety


Dengue Vaccine Viremia • From pooled analysis of viremia data available, <6.0% (38/683) had

detectable vaccine viremia after dose 1 or 2 of the CYD-TDV vaccine, but with low level (34 after dose 1, 4 after dose 2)

• None of Participants with viremia experienced immediate AEs, post-vaccination dengue-like syndrome, AEs leading to trial discontinuation, AESIs, or SAEs

• Rate of all adverse reactions or events were similar between viremic and non-viremic participants

• No safety concerns were identified in participants with vaccine viremia


This participant did not have virologically-confirmed dengue disease and had no reports of safety outcomes.

Focusing on Dengue hospitalization and severe dengue after vaccination

*CYD14 was conducted in Asia-Pacific in subjects 2–14 years of age. †Efficacy surveillance phase year 1=day 0 to dose 3; year 2=dose 3 to month 25; cumulative results=day 0 to year 5.

RR=relative risk; VCD=virologically confirmed dengue.

CYD14 - OVERALL RESULTS BY STUDY YEAR - HOSPITALIZED

VCD (ANY SEVERITY) IN SUBJECTS ≥ 9 YOA

0.39

(0.12, 1.17) 0.08

(0.01, 0.25)

0.57

(0.18;1.86) 0.42

(0.28, 0.62)

25-Month Active Phase + Year 31 + Year 42 + Year 53

Vaccine Group Control Group

RR

(95% CI)

0.73

(0.34, 1.61)

0.2 <0.1 0.3

0.6

0.4 0.3 0.5

1.1

0.5

0.8 0.7 0.7

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Year 1 Year 2 Year 3 Year 4 Year 5 Cumulative Results

Ann

ua

l In

cid

ence R

ate

(%

)

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0.54

(0.23, 1.30)

Active Phase Surveillance† Long Term Safety Follow-up Period

Database cleaned, not locked

1. Hadinegoro SR, et al N Engl J Med 2015; 373:1195-1206

2. Hadinegoro SR, et.al. Long-Term Safety of the CYD-TDV Dengue Vaccine in Asia-Pacific Dengue Endemic Countries.

Poster presented at: 5th Pan American Dengue Research Network Meeting. 2016 Apr 20-23 Panama, Panama.

3. Capeding et al - ACVR, April 24-26, 2017, US

| 27

CYD14 RESULTS: KAPLAN-MEIER FOR HOSPITALIZED VCD DUE TO ANY SEROTYPE IN

CYD14 STUDY IN ≥9 YEARS OF AGE GROUP

No at risk:

Vaccine group

Control group

(≥9 yo)

3315

1657

3297

1644

3285

1619

3263

1606

413

220

3215

1580

This still show reduce against hospitalized VCD in vaccinees ≥9 years of age over

the 5-year study period.

9-14y CYD

9-14y Control

*CYD14 was conducted in Asia-Pacific in subjects 2–14 years of age. †Efficacy surveillance phase ;year 1=day 0 to dose 3; year 2=dose 3 to month 25; cumulative results=day 0 to year 5.


CYD14 - OVERALL RESULTS BY STUDY YEAR - HOSPITALIZED

VCD (ANY SEVERITY) IN SUBJECTS < 9 YOA

0.36

(0.16, 0.78) 0.53

(0.25, 1.12)

1.58

(0.61, 4.83) 0.85

(0.63, 1.16)

25-Month Active Phase + Year 31 + Year 42 + Year 53


RR

(95% CI)

1.19

(0.65, 2.28)

0.4 0.4 0.6

1.1

1.0

0.7

1

0.8

0.4

0.9 0.9 0.8

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Year 1 Year 2 Year 3 Year 4 Year 5 Cumulative Results

Ann

ua

l In

cid

ence R

ate

(%

)

| 28

1.09

(0.59, 2.11)

Active Phase Surveillance† Long Term Safety Follow-up Period

Database cleaned, not locked

1. Hadinegoro SR, et al N Engl J Med 2015; 373:1195-1206

2. Hadinegoro SR, et.al. Long-Term Safety of the CYD-TDV Dengue Vaccine in Asia-Pacific Dengue Endemic Countries.

Poster presented at: 5th Pan American Dengue Research Network Meeting. 2016 Apr 20-23 Panama, Panama.

3. Capeding et al - ACVR, April 24-26, 2017, US

| 29

CYD14 RESULTS: KAPLAN-MEIER FOR HOSPITALIZED VCD DUE TO ANY SEROTYPE IN

CYD14 STUDY IN <9 YEARS OF AGE GROUP

No at risk:

Vaccine group

Control group

(< 9 yo)

3533

1767

3498

1735

3476

1712

3438

1698

562

262

3377

1673

This still show reduce against hospitalized VCD in vaccinees <9 years of age

over the 5-year study period.

2-8y CYD

2-8y Control

Annual incidence=cases among M * 100 converted to annual rate; cases=number of participants with at least 1 hospitalized symptomatic VCD episode.


| 31

RR (%)

(95% CI)


0.166

(0.05, 0.48)

0.214

(0.10, 0.43) 0.533

(0.25, 1.16)

0.334

(0.10, 1.05)

<0,1 <0,1 0.1 <0,1 <0,1

0.2

0.4

0.2

0.1

0.2

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Y1 (AP) Y2 (AP) Y3 (Y1 of HP) Y4 (Y2 of HP) Entire Study

Ann

ua

l In

cid

ence R

ate

(%

)

0.291

(0.19, 0.44)

Cortes et al – ASTMH, 2016

CYD15: RESULTS BY STUDY YEAR HOSPITALIZED VCD (ANY SEVERITY)

Active Phase: from D0 to the end of the Active Phase Hospital Phase: from the end of the Active until the cut off date Aug. 13th 2015

9-16yrs (CYD)

9-16yrs (Control)

CYD15 - CUMULATIVE HOSPITALIZED CASES (NON-SEVERE & SEVERE)

DUE TO ANY SEROTYPE FROM Post Dose1 UP TO 50 MONTHS

| 32

1. Cortes M, et al. Poster presentation at the 65th Annual Meeting of the ASTMH, 13–17 Nov 2016, Atlanta, Georgia, USA.

CYD23/57 - KAPLAN-MEIER CURVES FOR HOSPITALIZED OR SEVERE DENGUE IN ≥9 YEARS SUBJECTS IN THE ENTIRE STUDIES FOR CYD57

9-11y CYD

9-11y Control

There is greater protection, that appears to be stable, against hospitalized or severe VCD in subjects ≥9 years of age observed over time.

1. Limkittikul et al, Presentation at ACPID2016, 7-10 Nov 2016, Bangkok - Thailand

Y6

No difference in the clinical pattern of hospitalized cases and severe cases***

In the hospital phase compared to the active phase

In vaccinees compared to controls

No clinically relevant difference of frequency and duration of signs and symptoms

HOSPITALIZED VCD: NO DIFFERENCES IN THE CLINICAL / VIROLOGICAL OR IMMUNOLOGICAL PROFILE BETWEEN VACCINEES AND PLACEBO RECIPIENTS

Clinical Profile

Non-serotype specific dengue case viraemia*

*Among hospitalized VCD cases of any severity, any serotype no difference. Quantified viremia ≥LLOQ (log10 PFU/mL); median (Q1, Q3); at any time. The time to collect acute sample was calculated between start date of fever and date of acute sample taken. LLOQ=lower limit of quantification; VCD=virologically confirmed dengue. **A panel of 38 cytokines/chemokines associated with inflammatory of immunosuppressive responses were tested in the sera of hospitalized/severe cases *** Severe case - WHO classification: All DHF Grade I and Grade II, except 2 DHF III in CYD57 (CYD Group, less than 9 years, year 1 of LTFU)

Immune profile: 38 panel cytokines/chemokines**

1. Hadinegoro SR, et al. N Engl J Med 2015;373(13):1195–1206. 2. Harenberg A, et al. PLoS Negl Trop Dis 2016;10(7): e0004830.

Dengue viremia in CYD VS Control group

4.15

2.55

4.53

3.35

0

1

2

3

4

5

6

7

Active Phase HospitalPhase (Y3)

4.84

3.3 3.84 3.21

0

1

2

3

4

5

6

7

Active Phase Hospital Phase(Y3)

Qu

anti

fied

vir

emia

log1

0 p

fu/m

L

VACCINE EFFICACY ACCORDING TO AGE AS A CONTINUOUS VARIABLE active phase CYD14 and CYD15

*Using kernel smoothing

VE against symptomatic virologically-confirmed dengue cases during the whole Active Phase due to any of the 4 serotypes according to age using kernel smoothing - FASE - CYD14 & CYD15 (2-16 years)

Solid line corresponds to point estimate and the dotted lines represent the 95% CI

Vac

cin

e Ef

fica

cy (

%)

Age in Years (CYD14+CYD15) Thisyakorn et al, 8th Asian Congress of Pediatric Infectious

Diseases (ACPID) - 7-9 November 2016, Bangkok, Thailand

What is ADE theory ??

• Primary dengue infection confers life- long homotypic protective

immunity.

• Secondary infection (Heterotypic antibody)

: Antibody from 1ry infection with DENV , are not sufficient

to neutralize 2nd infection by different DENV serotype.

• ADE has been demonstrated in vitro and animal model.

• Heterotypic immunity will protect new serotype for 6 months.

• If ADE occur , it should be 12 month after 1ry infection.

(Nature Communications 8, Article number: 15674 (23 June,2017)doi:10.1038/ncomms15674)

49

Antibody-dependent enhancement of dengue infection

(ADE Theory)

It will happen in sequential dengue infection.

Investigations on disease outcome and immune profile

| 50

● The pattern of hospitalized cases, including severe disease, remains similar to that observed in the control group during the active phase.

● No increased breakthrough Dengue viremia in vaccinee VS placebo1

1. Hadinegoro SR, et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N Engl J Med 2015;373:1195–206.

4.15

2.55

4.53

3.35

0

1

2

3

4

5

6

7

Active Phase Hospital Phase (Y3)

CYD

Control

4.84

3.3 3.84

3.21

0

1

2

3

4

5

6

7

Active Phase Hospital Phase (Y3)

Qu

anti

fied

vir

emia

log1

0 p

fu/m

L

51

Infection-ending T-cell responses misdirected by

original antigenic sin (ADE Theory)

| 52

● No differences in immune profiles between hospitalized vaccinees and placebos , no excess of deleterious cytokines, which would rule out excess ADE activity in vaccines versus placebos1

1. Harenberg A, et al. Cytokine Profile of Children Hospitalized with Virologically-Confirmed Dengue during Two Phase III Vaccine Efficacy Trials. PLoS Negl Trop Dis. 2016;10(7):e0004830.

● The few differences at the individual cytokine level support a positive effect of the vaccine

• IL-1Ra, at higher levels in severe dengue, is also significantly higher in the placebo group

• On the other hand, sCD40L, at higher levels in non-severe cases is higher in the vaccine group

Investigations on disease outcome and immune profile

NO EVIDENCE OF DISEASE ENHANCEMENT WAS OBSERVED IN PHASE IIb TRIAL (CYD23/57)

• Clinical characteristics of dengue episodes were similar between the vaccine group and the control/placebo group, irrespective of serotype.

• No SAE related to vaccine was observed after 2 years of follow-up after the first injection, in the presence of nonprotective immune responses to DENV-2.

– There was also no observed increase in DENV-2 dengue cases due to vaccination.

• In line with the WHO guidelines, participants will be followed for safety for 4 years post–dose 3.

WHO, 2011, Dengue Vaccine Guidelines. Sabchareon, 2012, Lancet.

VIREMIA AND IMMUNE PATTERN

Similar levels of viremia observed in vaccine vs control groups (CYD14 and CYD15).

No cytokine/chemokine pattern associated with increased disease enhancement in vaccine vs placebo.

CLINICAL, VIROLOGICAL AND IMMUNOLOGICAL PRESENTATION INSIGHTS: NO IMPORTANT DIFFERENCE IN CLINICAL SIGNS, SYMPTOMS & BIOLOGY DURING

ONGOING LTFU VERSUS ACTIVE PHASE & PLACEBO GROUP IN SUBJECTS 2–16 YEARS OF AGE (IN CYD14 & CYD15) 1

LTFU=long-term follow-up; VCD=virologically confirmed dengue.

LENGTH OF HOSPITALIZATION

Similar for both the 25-month active phase and the ongoing LTFU phase in CYD14, CYD15, and CYD23/57.

FREQUENCIES OF SIGNS AND SYMPTOMS

No clinically important differences observed for the frequencies of various signs and symptoms during the 25-month efficacy phase and the ongoing LTFU phase in CYD14, CYD15, and CYD23/57.

DURATION OF FEVER AND CLINICAL SYMPTOMS

Similar for both the 25-month efficacy phase and the ongoing LTFU phase in CYD14, CYD15, and CYD23/57.

1. Hadinegoro SR, et al. N Engl J Med 2015;373(13):1195–1206. 2. Harenberg A, et al. PLoS Negl Trop Dis 2016;10(7): e0004830.

ADE of Zika infection in Dengue primed

Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus (No ADE)

• DENV-immune serum, has been shown in vitro that antibody-dependent

enhancement (ADE) of ZIKV infection can occur.

• in vivo study, two cohorts of rhesus macaques (N=8) infect with ZIKV;

- one cohort (N=4) has been exposed to DENV 2.8 years earlier ,

- second control cohort (N=4) is naïve to flaviviral infection.

• Results,

- pre-existing DENV immunity does not result in more severe ZIKV disease.

- But results show a reduction in the number of days of ZIKV viremia in

DENV immune comparing to naïve macaques group.

- No ADE of ZIKV pathogenesis in DENV immune macaques.

(Nature Communications 8, Article number: 15674 (23 June,2017)doi:10.1038/ncomms15674)

Viral load and cytokine response profile does not support

ADE in dengue-primed Zika-infected patients: Brazil 2016.

• The mechanism of severe Dengue disease is poorly understood.

• Most studies focus on the process of antibody-dependent

enhancement (ADE) as a primary risk factor.

• ZIKV in DENV-endemic areas, Zika outcomes remains unknown.

• Neither dengue nor Zika viremia was higher in 65 Brazilian

patients with prior DENV infection, and measure 10 cytokines.

• Conclusion: No signs of ADE were observed in vivo in patients

with acute ZIKV infection who had prior exposure to DENV.

(Clin Infect Dis , 20 June 2017. DOI:https://doi.org/10.1093/cid/cix558)

https://doi.org/10.1093/cid/cix558

https://doi.org/10.1093/cid/cix558

Safety data from Dose 1 School-Based EPI Implementation in Philippines (Phase IV)

Round 1 Dengue Vaccine School-based Immunization Coverage Report by Region

Region Total no.

of Schools

Total no. of Grade 4 enrolled

pupils (Masterlist)

Tot. no. of pupils w/ approved parental consent

Total no. of pupils

vaccinated

Vaccination

Acceptance Rate

Uptake Rate

NCR 524 203,631 118,968 104,412 58% 88%

3 2,963 232,707 205,058 205,058 91% 97%

4A 2,680 292,772 209,120 182,520 71% 87%

Total 6,167 729,110 539,549 491,990 74% 91%

J. Lecciones, PIDSP, Feb2017, Philippines

Top 10 AEFI** rates experienced among minor AEFI cases Dengue SBI Round1


Top 10 AEFI** rates experienced among minor AEFI cases Dengue SBI Round2


Take Home Message

• The vaccine showed an acceptable safety profile with no related deaths in the CYD dengue vaccine group reported during the entire study.

• No clinically important differences noted in the frequencies of various signs and symptoms during the entire long-term follow-up between CYD and control groups for any age group.

เราจะเลอืกเช่ืออะไรระหว่าง Evidence based กบั Personal opinion

Eupatorium pertoliatum 200C ใช้ในการป้องกนัไข้เลอืดออกของ กรมพฒันาแพทย์แผนไทยและแพทย์ทางเลอืก กระทรวงสาธารณสุข

Brazil (Public Programme)

Philippines (Public Programme)

Mexico

El Salvador

Paraguay

Costa Rica

Guatemala

Peru

Indonesia

Ongoing regulatory submission in other endemic countries.

Thailand

Bolivia

Singapore

Dengvaxia® approved in 17 countries

Cambodia

Venezuela

Malaysia

Argentina

Honduras

ขอบคุณครับ

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