Dengue Vaccine: Dengvaxia - PowerPoint Presentation

Slide1

Dengue Vaccine:

Dengvaxia

TM

The scientific issues to practical issues

รศ.ดร.พญ.เพณณินาท์ โอเบอร์ดอร์เฟอร์

หัวหน้าหน่วยโรคติดเชื้อ ภาคกุมารเวชศาสตร์

คณะแพทย์ศาสตร์ มหาวิทยาลัยเชียงใหม่

Slide2

THE CURRENTLY AVAILABLE DENGUE VACCINE :

Chimeric Yellow Fever 17D-Tetravalent Dengue Vaccine (CYD-TDV)

There are 4 genetic constructs, 1 for each serotype

.

The envelope and precursor membrane genes from each serotype were combined with the genes encoding the capsid and non-structural proteins from the yellow fever (YFV 17D) vaccine strain

.

Freeze-dried and contains no adjuvant or preservatives

.

3-dose schedule at 0, 6, 12 month

DENV-1 (strain PUO-359/TVP-1140, isolated in 1980 in Thailand)

DENV-2 (strain PUO-218, isolated in 1980 in Thailand)

DENV-3 (strain PaH881/88, isolated in 1988 in Thailand)

DENV-4 (strain 1228 (TVP-980), isolated in 1978 in Indonesia)

Guirakhoo

, 2001, J

Virol

. /

Guirakhoo

, 2000, J

Virol

. / Guy, 2011, Vaccine.

Slide3

Reduction

in

symptomatic dengue

65.6

%

(95% CI: 60.7–69.9)

Reduction in

hospitalized

dengue

80.8

%

(95% CI: 70.1–87.7)

SUMMARY: Efficacy Results in

>

9 years of age in CYD 14, CYD15 (Proposed age indication) at 25 months

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;

1

Full Analysis Set for Efficacy (FASE): all subjects who received at least one injection. †dengue hemorrhagic fever, IDMC criteria or 92.9% according to World Health Organization 1997 criteria. CI=confidence interval; DENV=dengue virus.

Reduction insevere dengue † 93.2% (95% CI: 77.3–98.0)

For each serotype:

DENV-1: 58%

(47.7–66.9

)

DENV-2: 47%

(31.3–59.2

)

DENV-3: 73%

(64.4–80.4)

DENV-4: 83%

(

76.2–88.2)

Slide4

Vaccine Side Effects

Vaccine Side Effects

Slide5

VE and 95% CI

CYD14

1

*

DENV

+

DENV–

CYD15

2†

DENV

+

DENV–

HIGHER VACCINE EFFICACY WITH AGE AND POSITIVE BASELINE SEROSTATUS DURING THE 25-MONTH OF THE LARGE-SCALE PHASE III EFFICACY STUDIES

35.7

86.6

-26.8

66.7

62.2

93.7

-61.5

80.0*Comparison made on ITT. RR=relative risk: incidence of VC dengue cases in CYD group vs control group.†Dengue+: baseline titer for at least 1 DENV serotype is ≥10 1/dil.DENV=dengue virus; ITT=intent to treat; VCD=virologically confirmed dengue; VE=vaccine efficacy; yo=years old. Capeding, 2014, LancetVillar, 2015, N Engl J Med.Baseline serostatus

VE Results by Baseline SerostatusIT SEEMS TO BE A GOOD BOOST TO NATURAL INFECTION

Slide6

Dengue anti-NS1 IgG ELISA Assay

Rationale

: NS1 protein in Dengue Virus is different from NS1 protein in Yellow Fever Virus.

The CYD Dengue Vaccine has gene encoding NS1 from Yellow Fever

The CYD Dengue Vaccine is unlikely to induce meaningful antibodies against the Dengue NS1 protein

Therefore, presence of Dengue NS1 antibodies may differentiate previous exposure to natural dengue infection from previous exposure to CYD vaccinationMethod developed at the University of Pittsburgh (CVR) The assay method was transferred to SP Global Clinical

Immunology (GCI) laboratory in Q1 2016Method Qualification completed as per internal SOP,

Jan/Feb-2017

Takes into account guidance from ICH, FDA,

EMA

, NCCLS, USP

Slide7

Dengue anti-NS1 IgG ELISA Assay

ROC Curves and Threshold Assessments : use cut off at 9

ROC Curves

Threshold Assessment

Unpublished data

Using samples from Group 1 and 2 as reference for Dengue unexposed and from Group 3, 4 and 5 as reference for Dengue exposed

False “Seronegative” Rate (misclassify Dengue exposed samples as seronegative by the assay) = 4.7%

False “Seronegative” Rate (misclassify Dengue exposed samples as seronegative by the assay) = 1%, when restricting the reference Dengue exposed to truly exposed samples (Groups 4 and 5).

Threshold selection was driven by the goal of maximizing chances of unbiased estimate in

seronegatives

, accepting potential penalty in sensitivity

AUC ≥0.85 to ≥0.95

Slide8

Expanded Case-cohort design

Addressing sub-cohort representativeness and M0-M13 gaps

Using “expanded” sub-cohort randomly selected from entire study populations

XXX

evelique nonecto

Icaborporae mo mint

Lo icaborporae raXX %

XXX

Unpublished Data

Slide9

Multiple Imputation Analysis

Using logistic regression were used to impute missing baseline PRNT

serostatus

.

The variables in the logistic regression model were:

- baseline

serostatus - M13 anti-NS1 titers - vaccine group, age, sex, country,

- indicator of whether subject had VCD in M0 -M13

Ten iterations of modified Cox regression model

(

Prentice’s

method) were performed

Slide10

Time to Hospitalized VCD – MI (M0

up to

M66~) pooled

Age 9-16 years in

Seropositive

Subjects

Unpublished data

XXX

evelique nonecto

XXX

Slide11

Time to Hospitalized VCD – MI (M0

up to

M66~) pooled

Age 9-16 years in

Seronegative

Subjects

Unpublished data XXX

evelique nonecto

XX %

XXX

Slide12

 

Seronegative

Vaccine

group

Seronegative

Control group

Relative Risk

(95% CI)

Number VCD episodes, N

56

20

 

Duration of clinical symptoms, days

 

 

 

    

Median

(min-max)

8 (3-29)

7.5 (4-14)

 

Duration of fever, days

 

 

 

     Median (min-max)

5 (1-10)5 (2-8) Hospitalized VCD serotypes     Serotype 1, n249 

     Serotype 2, n195      Serotype 3, n116      Serotype 4, n32 Median duration of hospitalization, days (min-max)4 (1-8)4 (2-6)

 

Any hemmorrhage

22/56 (39.3)

9/20 (45.0)

0.873 (0.39; 2.15)

Any visceral manifestation

0/56 (0.0)

1/20 (5.0)

0.000 (0.00; 13.93)

Plasma Leakage

 

 

 

    

Any

20/56 (35.7)

2/20 (10.0)

3.571 (0.87; 31.51)

    

With

clinical signs

2/56 (3.6)

0/20 (0.0)

 

    

Hematocrit

increase>=20%

20/56 (35.7)

2/20 (10.0)

3.571 (0.87; 31.51)

Thrombocytopenia

 

 

 

    

Platelet

count <= 50x10^9/L

23/56 (41.1)

3/20 (15.0)

2.738 (0.83; 14.25)

    

Platelet

count <= 100x10^9/L

43/56 (76.8)

14/20 (70.0)

1.097 (0.59; 2.17)

Shock

0/56 (0.0)

0/20 (0.0)

 

Clinical signs and symptoms of all

hospitalized VCD

episodes after M13

Age

>

9 years at enrollment -

CYD14/15/57 - NS1 IgG Th9 (E-SAP)

Unpublished data

Slide13

 

Seronegative

Vaccine

group

Seropositive

Control group

Relative Risk

(95% CI)

Number VCD episodes, N

45

64

 

Duration of clinical symptoms, days

 

 

 

    

Median

(min-max)

9 (3-29)

8 (4-18)

 

Duration of fever, days

 

 

 

     Median (min-max)

5 (2-10)5 (1-14) Hospitalized VCD serotypes     Serotype 1, n1918 

     Serotype 2, n1425      Serotype 3, n1010      Serotype 4, n212 Median duration of hospitalization, days (min-max)4 (1-7)4 (2-12)

 

Any hemmorrhage

20/45 (44.4)

26/64 (40.6)

1.094 (0.58; 2.04)

Any visceral manifestation

0/45 (0.0)

2/64 (3.1)

0.000 (0.00; 7.57)

Plasma Leakage

 

 

 

    

Any

16/45 (35.6)

26/64 (40.6)

0.875 (0.44; 1.69)

    

With

clinical signs

2/45 (4.4)

11/64 (17.2)

0.259 (0.03; 1.18)

    

Hematocrit

increase>=20%

16/45 (35.6)

21/64 (32.8)

1.084 (0.53; 2.18)

Thrombocytopenia

 

 

 

    

Platelet

count <= 50x10^9/L

17/45 (37.8)

37/64 (57.8)

0.653 (0.35; 1.19)

    

Platelet

count <= 100x10^9/L

35/45 (77.8)

57/64 (89.1)

0.873 (0.56; 1.35)

Shock

0/45 (0.0)

2/63 (3.2)

0.000 (0.00; 7.45)

Clinical signs and symptoms of all

hospitalized VCD

episodes after M25

(E-SAP)

Age

>

9 years at enrollment

–

Hospital Phase/SEP - CYD14/15/57 - NS1 IgG Th9

Unpublished data

Slide14

Hospitalized

and

Severe

VCD cases

among

1,000 vaccinated or 1,000 not

vaccinated

seronegative

or

seropositive

individuals

in 5

yearsVaccinatedNot vaccinatedDifference

Vaccinated

– Not

vaccinated

Seropositives

Hospitalized

cases419- 15Severe Cases15- 4SeronegativesHospitalized cases1611+ 5Severe Cases42+2 Over 5 years of follow-up, in the epidemiological context of the Phase IIb and Phase III efficacy studies, among 1,000 individuals, either vaccinated or not: Results are based on the incidence and seroprevalence observed in the clinical trials in 9-16 years old (pooled studies), cumulative over the first 5 years following dose 1

Unpublished data

Slide15

The 5-year risk of severe dengue in

>

9 year-old: Data from the new analysis

Baseline serostatus

Estimated risk of hospitalized VCD in 5 yearvaccinated seronegative

4 per 1,000unvaccinated seropositive 4.8 per 1,000

unvaccinated seronegative 1.7 per 1,000

vaccinated seropositive

<1 per 1,000

WHO:http

://www.who.int/immunization/diseases/dengue/q_and_a_dengue_vaccine_dengvaxia_use/en/

Slide16

Likely process of dengue infection/vaccination

Slide17

Antibody-dependent enhancement of severe dengue disease in

humans:

a pediatric

cohort in

Nicaragua

Katzelnick

LC. Science. 2017 17;358(6365):929-932.

That risk of severe dengue disease is highest

within a narrow range of preexisting anti-DENV antibody titers

(inhibition

enzymelinked

immunosorbent

assay;

iELISA) 1:10-1:80protection from all symptomatic dengue disease at high antibody titers (>1:320)

Slide18

Updated WHO Position, December 2017

Updated WHO Position, December 2017

Slide19

Considerations When Vaccinating Children

Considerations When Vaccinating Children

Slide20

Updated SAGE recommendations on the use of CYD-TDV (

Dengvaxia

®) 20 April 2018

There are 2 options to

be further used in public programs:(1) Subnational or national mass vaccination strategy based on population seroprevalence

(2) Pre-vaccination screening and vaccinating only those testing seropositive.

Slide21

Several

major challenges of a

seroprevalence

-based strategy warrant consideration:

S

eroprevalence required for predicted benefit in seronegative recipients within

10 years:At age 9 years = 80%. At

age 16

years

=

86

%.

No available data on the risk in seronegative individuals beyond 5-6 years after vaccination (1) To minimize harm in seronegatives, high seroprevalence thresholds of SP9 of 80% is required.(2) Very few locations have seroprevalence > 80% in 9 year olds(3) The spatiotemporal heterogeneity >> necessitate large scale serosurveys >> complexity and cost to any public vaccination programme.(4) National coverage rates would be low >> limited public health impact.(5) A technically identifiable subpopulation of seronegative persons would be put at increased risk of severe dengue, at least for a period of time.(6) Communication around a strategy >> undermine vaccine confidence in general.

Slide22

Updated SAGE recommendations on the use of

CYD-TDV

(

Dengvaxia

®) 20 April 2018

At this stage, “pre-vaccination screening strategy” would be the preferred optionConventional serological testing for dengue virus IgG (e.g. dengue IgG ELISA) could be used to identify persons who have had previous dengue infections.

Sensitivity and specificity should be assessed in a local context, and will depend on the prevalence of other flaviviruses, and past use of flavivirus

vaccines (such as Japanese encephalitis and yellow fever vaccines).

Currently available rapid diagnostic tests - despite their lower sensitivity and

specificity-

could be considered in high transmission settings until better tests are available.

In settings with high dengue transmission, a test with lower specificity might be acceptable.

But some

truly seronegative individuals may be vaccinated due to a false positive test result.

Slide23

Updated SAGE recommendations on the use

of

CYD-TDV (

Dengvaxia

®): cont’

Although the efficacy against dengue infections in seropositive individuals is high, it is still not

complete, need to be clearly communicated. Need to adhere to other disease preventive

measures and vector control

Seek

prompt medical care in the event of dengue-like symptoms, regardless of whether vaccinated or not.

Decisions

about implementing a “pre-vaccination screening” strategy

will

require careful assessment at the country level: …local priorities, dengue epidemiology, country-specific dengue hospitalization rates, and affordability of both CYD-TDV and screening tests.

Slide24

Updated SAGE recommendations on the use

of

CYD-TDV (

Dengvaxia

®): cont’

Age…………NOT CHANGE

The age to target for vaccination depends on the dengue transmission intensity in a given country, and will be lower in countries with high transmission, and higher in countries with low transmission. Schedule…NOT CHANGE

In the absence of data on vaccine efficacy and safety with fewer than three doses, CYD-TDV is recommended as a three dose series given 6 months apart.

Booster…..NOT CHANGE

There are currently no data on the use of booster doses. Additional studies to are under way.

Slide25

วัคซีนไข้เลือดออก ควรแนะนำในผู้ใหญ่ และวัยรุ่นตอนปลาย

ให้

ฉีดมากๆ เพื่อให้เกิด

herd immunity

ในชุมชน

คำแนะนำการฉีดวัคซีนไข้เลือดออกในเด็ก

(9 – 18

ปี

)

ในผู้ที่ยังไม่เริ่มฉีดวัคซีน

อธิบายถึง

benefit-risk

ของการฉีดวัคซีน

ไข้เลือดออก หากมีประวัติเคยเป็นโรคไข้เลือดออก หรือคนในบ้าน ชุมชน รับความเสี่ยงได้

ฉีดวัคซีนได้

เลย ไม่ต้องตรวจเลือด

หากไม่เคยมี

ประวัติ



ใช้ข้อมูลระบาดวิทยา หรือ

seroprevalence พิจารณาฉีดหลังอายุ 15 ปีในผู้ที่ฉีดวัคซีนมาแล้วแต่ยังไม่ครบยังไม่มีข้อมูล benefit-risk ของการได้รับวัคซีนเพียง 1 หรือ 2 เข็มเนื่องจากเป็น live vaccine ฉีด 1 เข็มก็ถือว่า prime แล้ว จึงน่าจะฉีดให้ครบจะดีกว่าข้อระวัง-ฉีดแล้วก็ยังเป็นโรคได้ โดย severity ไม่ต่างจากไม่ฉีดและเป็นโรค-ฉีดแล้วยังต้องป้องกันยุงกัด

Slide26

Subjects seropositive at baseline from CYD14 (Thailand only) and CYD23

Slide27

PRNT: Dengue seroprevalence observed at CYD14 baseline, Thailand

By age 9, 80% seropositive

Data from CYD14 clinical trial. Summarized in:

L’Azou et al., N Engl J Med. 2016;374(12):1155–66

341 samples tested

Slide28

Dengvaxia

should be promoted as adult vaccine to help protect community against dengue

Slide29

IgG

และ

IgM

dengue

ในอาสาสมัครผู้มาบริจาคโลหิตที่ศูนย์รับบริจาคโลหิตในกรุงเทพมหานคร และจังหวัดชลบุรี รวมทั้งสิ้นจำนวน

1,200

คน

พบว่าไม่มีความแตกต่างอย่างมีนัยสำคัญในแต่ละช่วงอายุ

(p > 0.05)

แต่พบว่าเพิ่มขึ้นตามอายุ

IgG

-negative

Past Infection

Recent or acute infection

Total

(n=1,200)

17-29 yrs

35.3%

63.7%

0.8%

60030-42 yrs31.5%67.5%

1%

40043-55 yrs27.5%70.5%

1.5%

200total32.8%66.1%

1%2%= no conclusion

Dengue IgG seroprevalence among healthy adults in ThailandPiyada Udomchaisakul, et al. In: Proceedings of the 7th Asian Congress of Pediatric Infectious Diseases, Beijing, China, October 12-15, 2014.

Slide30

PRNT50

: Dengue

seroprevalence

in HCW in QSNICH

by age group (n = 400)Seropositive : PRNT50 ≥ 10, Seropositive : PRNT50 < 10

Age (year)

n=400 n=28 n=59 n=58 n=50 n=51 n=38 n=63 n=49 n=4

400 HCW age 21-60 year old, (13.2% men, 86.8% Woman women)

High dengue

seroprevalenmce

in study population,

95% (380/400) have PRNT50>10 for at least one serotypes (Seropositive by PRNT50)

5% (20/400) has PRNT50 < 10 for all serotypesThe dengue seroprevalence in HCWs in QSNICH is more than 90% in all age group Vandepitte WP, et al. In: Proceedings of the Joint International Tropical Medicine Meeting, Bangkok, Thailand, December 6-8, 2017.

21-24

Slide31

Neutralizing Dengue Antibody in Pregnant

Thai Women (age 15 – 41) at

Ratchaburi

(PRNT

50)

Kriangsak

K.

PLoSNTD

2016

Slide32

การแก้ไขทำเตือนของวัคซีนป้องกันไข้เลือดออก

(

Dengvaxia

)

Slide33

CYD Tetravalent Dengue Vaccine Reduces Symptomatic and Asymptomatic Dengue Virus Infections in Healthy Children Aged 2–16 Years in Asia and Latin America (N=3,736)

Efficacy against asymptomatic infection reduce transmission

of all dengue

infections are asymptomatic

1

Olivera-Botello

G. JID 2016;214:994-1000.

% VE

NS

NS

NS

NS= Non significant

The annual incidence of asymptomatic vs symptomatic = 14.8% vs 3.4% (4.4 times)

Efficacy against symptomatic

and asymptomatic

infections

in

9–16

Yo

80%

Asymptomatic individuals are significantly more infectious to mosquitoes than people with symptomatic infections. Duong V et al. PNAS 2015; 112(47):14688–93.

Slide34

Dengue Vaccines in active human clinical trials

The Dengue Vaccine Landscape

In-Kyu Yoon, MD. Director, Dengue Vaccine Initiative International Vaccine Institute Seoul, Korea

Category

Sponsor

Vaccine name

Approach

Phase

Live

attenuated with or without chimera

Sanofi

Pasteur

CYD-TDV

Yellow fever 17D backbone and YF-DENV chimeraIII License

Takeda

TDV

DENV-2 PDK-53 backbone

and DENV-DENV chimera

II; soon

III

US NIH, Butantan, Vabiotech, Panacea, Serum Institute of India, MerckTV003/TV005Direct mutagenesis DEN-1,3,4 and DENV-2/4 chimeraPreclin II, IIIProtein subunitMerckV180DENV 80% E protein recombinant+adjIInactivated whole virusGSK/ Fiocruz/ US ArmyDPIVFormalin inactivated-adjPreclin IDNAUS NavyTVDVPlasmid DNA+adjIHeterologous prime-boostUS ArmyTDENV-LAV+TDENV-PIVLive attenuated/inactivated wholeI

Slide35

Immunogenicity and safety of Takeda tetravalent dengue vaccine in healthy children aged 2-17 years in Asia and Latin America: phase 2,

randomised

, placebo-controlled

study

Sáez-Llorens

X.

Lancet Infect Dis 2018;18(2):162-170.

1 dose 0,3 M 0,12 M Placebo

Symptomatic,

virologically

confirmed dengue= 21/1569 (1·3%) TDV vs 9/198 (4·5%) placebo

Slide36

Immunogenicity and safety

of Takeda

tetravalent dengue vaccine in healthy children aged

2-17

years in Asia and Latin America:

phase 2, randomised

, placebo-controlled study

G1=1 dose; G2= 0,3 M; G3= 0,12 M; G4=Placebo

Sáez-Llorens

X.

Lancet Infect

Dis

 2018;18(2):162-170.

Serotype-specific GMTs (per-protocol set)Upper plots are for all participants, middle plots are for those who were seronegative at baseline, and lower plots are for those who were seropositive at baseline. Datapoints are GMTs and error bars denote 95% CIs. DENV=dengue virus. GMT=geometric mean titre.In baseline-seronegative participants, a 1-year booster clearly increased GMTs.

Slide37

Thank you