TM The scientific issues to practical issues รศดรพญเพณณนาท โอเบอรดอรเฟอร หวหนาหนวยโรคตดเชอ ภาคกมารเวชศาสตร ID: 933038
Download Presentation The PPT/PDF document "Dengue Vaccine: Dengvaxia" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Dengue Vaccine:
Dengvaxia
TM
The scientific issues to practical issues
รศ.ดร.พญ.เพณณินาท์ โอเบอร์ดอร์เฟอร์
หัวหน้าหน่วยโรคติดเชื้อ ภาคกุมารเวชศาสตร์
คณะแพทย์ศาสตร์ มหาวิทยาลัยเชียงใหม่
Slide2THE 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.
Slide3Reduction
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)
Slide4Vaccine Side Effects
Vaccine Side Effects
Slide5VE 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
Slide6Dengue 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
Slide7Dengue 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
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
Slide9Multiple 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
Slide10Time to Hospitalized VCD – MI (M0
up to
M66~) pooled
Age 9-16 years in
Seropositive
Subjects
Unpublished data
XXX
evelique nonecto
XXX
Slide11Time to Hospitalized VCD – MI (M0
up to
M66~) pooled
Age 9-16 years in
Seronegative
Subjects
Unpublished data XXX
evelique nonecto
XX %
XXX
Slide12Seronegative
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
Slide13Seronegative
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
Slide14Hospitalized
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
Slide15The 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/
Slide16Likely process of dengue infection/vaccination
Slide17Antibody-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)
Slide18Updated WHO Position, December 2017
Updated WHO Position, December 2017
Slide19Considerations When Vaccinating Children
Considerations When Vaccinating Children
Slide20Updated 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.
Slide21Several
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.
Slide22Updated 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.
Slide23Updated 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.
Slide24Updated 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.
Slide25วัคซีนไข้เลือดออก 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
Slide26Subjects seropositive at baseline from CYD14 (Thailand only) and CYD23
Slide27PRNT: 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
Slide28Dengvaxia
should be promoted as adult vaccine to help protect community against dengue
Slide29IgG
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.
Slide30PRNT50
: 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
Slide31Neutralizing Dengue Antibody in Pregnant
Thai Women (age 15 – 41) at
Ratchaburi
(PRNT
50)
Kriangsak
K.
PLoSNTD
2016
Slide32การแก้ไขทำเตือนของวัคซีนป้องกันไข้เลือดออก
(
Dengvaxia
)
Slide33CYD 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.
Slide34Dengue 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
Slide35Immunogenicity 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
Slide36Immunogenicity 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.
Slide37Thank you