Takeda’s Dengue Vaccine Candidate · Dengue Fact Sheet, Australian Government Department of Health. Map adapted from Figure 2, Queensland Dengue Management Plan 2015-2020. The State

Joanne McCoubrie, PhD

Senior Medical Advisor Takeda Pharmaceuticals

Takeda’s Dengue Vaccine Candidate

• This presentation is solely for the purpose of responding to inquiries

about our vaccine candidates

• Nothing in this presentation is intended to, nor should be construed as

an offer to sell or to promote our vaccine candidates

• These candidates are under investigation and the information contained

herein is current only as of the date of this presentation

• New and additional information will be obtained through the investigation

process, potentially making the information in this presentation not

current

2

Disclaimer

1. Dengue disease

2. Dengue in Australia

3. Development of Takeda’s dengue vaccine candidate

4. Overview of ongoing and completed clinical studies

5. Summary of phase 1 trial findings

6. Phase 2 clinical trials:

– DEN-203 Antibody persistence

– DEN-204 Dose schedule selection for phase 3

– DEN-203 and DEN-204 Safety analysis

7. Phase 3 efficacy study design and progress

8. Conclusions

Overview of presentation

1. Dengue disease










8. Conclusions


Dengue virus: Background and structure

• Dengue is a flavivirus1

• There are more than 70 different

flaviviruses, including tick-borne

encephalitis virus, yellow fever

virus, Japanese encephalitis virus & Zika

virus1

• Many of these are arthropod-borne and

transmitted by either mosquitoes or ticks1

• There are four closely related dengue virus

serotypes: DENV-1, DENV-2, DENV-3

and DENV-42

• Each virus can cause infection and the

full spectrum of dengue disease symptoms2

5

C: capsid; E: envelope protein; M: membrane protein; prM: precursor-membrane; sE: soluble forms of E; TM: transmembrane

* Image reproduced from reference 1 with permission from Elsevier

1. Heinz, et al. Vaccine 2012;30:4301–6

2. Gubler, et al. Emerg Infect Dis 1995;1:55–7

Schematic model of a flavivirus particle

(both immature and mature stages)1*

Dengue vector: Aedes mosquitoes

Aedes aegypti

• Primary vector for the dengue virus1

• Lives in urban habitats and breeds in

man-made containers1

• Eggs can survive drying for long periods of

time, allowing distribution to new locations1

• The females bite people and are

daytime feeders1

Aedes albopictus

• Secondary vector in Asia, has

spread to Africa, North America and

Europe, in part due to the international

trade in used tires1

• Eggs can survive drying for long periods1

• Highly adaptive – can survive in cooler

temperate regions of Europe1

6

1. http://www.who.int/denguecontrol/mosquito/en/. Accessed 27/06/2016

2. https://commons.wikimedia.org/wiki/File:Aedes_aegypti_CDC-Gathany.jpg. Accessed 23/06/2016

3. https://commons.wikimedia.org/wiki/File:Aedes_Albopictus.jpg.Accessed 23/06/2016

Ae. aegypti mosquito2 Ae. albopictus mosquito3

http://www.who.int/denguecontrol/mosquito/en/

https://commons.wikimedia.org/wiki/File:Aedes_aegypti_CDC-Gathany.jpg



https://commons.wikimedia.org/wiki/File:Aedes_Albopictus.jpg

Dengue disease: Clinical presentation

Dengue fever1

• Severe, flu-like illness

• Should be suspected when

high fever (40°C/104°F) is accompanied

by two of the following symptoms: severe

headache, pain behind the eyes, muscle

and joint pains, nausea, vomiting, swollen

glands or rash

• Symptoms usually last for 2–7 days,

after incubation period of 4–10 days

after bite from infected mosquito

Severe dengue1

• A small proportion of patients progress to

severe disease

• Warning signs include: severe abdominal

pain, persistent vomiting, rapid breathing,

bleeding gums, fatigue, restlessness and

blood in vomit

• Above signs occur 3–7 days after the first

symptoms, in conjunction with a decrease

in temperature (below 38°C/100°F)

• Marks start of 24- to 48-hour critical

period - may lead to shock and death

7

After D. Vaughn

1. www.who.int/mediacentre/factsheets/fs117/en/. Accessed 27/06/2016

http://www.who.int/mediacentre/factsheets/fs117/en/

1. Dengue disease










8. Conclusions


More than 2,000 cases of dengue were confirmed in Australia in 2016.1

Dengue in Australia

9 1. Australian Government Department of Health.

Outbreaks of dengue occur each year in

North Queensland and there is the risk of

local spread in areas where Aedes aegypti is

present.

Aedes aegypti is currently limited to parts of

Northern, Central and Southwest

Queensland.

The Aedes albopictus mosquito only occurs

in the Torres Strait Islands.1

In most parts of Australia, there is no risk of

dengue being spread by mosquitoes

because most areas of Australia do not have

the Aedes aegypti or Aedes

albopictus mosquitoes

Dengue outbreaks in Australia

10 1. Dengue Fact Sheet, Australian Government Department of Health.

Map adapted from Figure 2, Queensland Dengue Management Plan 2015-2020. The State of Queensland (Queensland Health. V1 21Sept2016.

Impact of international travel on geographic expansion

of dengue

• Marked increase in dengue since 1980s associated with increasing

international travel1

1.Kilpatrick, et al. Lancet 2012;380:1946–55 11

The global aviation network1*

Lines show direct links between airports

Color indicates passenger capacity in people per day:

Red – thousands

Yellow – hundreds

Blue – tens

Dengue fever distribution

12 https://wwwnc.cdc.gov/travel/images/map3-2-dengue-eastern-hemisphere-large.jpg

https://wwwnc.cdc.gov/travel/images/map3-1-dengue-western-hemisphere-large.jpg

https://wwwnc.cdc.gov/travel/images/map3-2-dengue-eastern-hemisphere-large.jpg











Most common destinations for returned travellers with

dengue 2007–2011

1. Leder, et al. Ann Intern Med 2013;158:456–68

Data collected from

GeoSentinel sites:

• N. America – 21 sites

• Europe – 17 sites

• Australasia - 10 sites

• Latin America – 3 sites

• Southern Africa – 1 site

• Middle East – 1 site

Number of dengue cases: n=1473

13

Top identified specific causes for illnesses among travellers

returning to Australia, New Zealand and Oceania

14 1. Leder, et al. Ann Intern Med 2013;158:456–68

Fly-in-fly-out workers affected by dengue

15

1. Dengue disease










8. Conclusions


Relevant vaccine history

17

1. World Health Organization. Weekly epidemiological record. 2011;86:241–56

2. Messina, et al. Trends Microbiol 2014;22:138–46

3. Bhamarapravati, et al. Bull World Health Organ 1987;65:189–95

4. Huang, et al. J Virol 2003;77:11436–47

5. Frierson. Yale J Biol Med 2010;83:77–85

1940–1950

Four dengue virus

serotypes identified2

1990 2000 1940

1986

DEN-2 PDK-53 virus

vaccine developed at

Mahidol University,

Bangkok3 2000–2003

Chimeric viruses developed

for DENV-1, DENV-3 and

DENV-4 on the PDK-53

background4

1980 1950

May 2010

First Phase 1

clinical trial

(DEN-101)

Nov 2011

Phase 2 age

de-escalation trial in

endemic countries

(DEN-203)

Dec 2014

Phase 2 trial using

established final

formulation

and schedule

(DEN-204)

Sep 2016

First

Phase 3

trial

(DEN-301)

1946

Takeda open facility in Hikari

for vaccine manufacturing

2010

Jan 2012

Takeda launch

Global Vaccine

Business Division

May 2013

Takeda acquire Inviragen

(including dengue

vaccine candidate)

1947–2013

Takeda develop 10 vaccines

(including three co-marketing products)

1937

First human flavivirus vaccine developed (tick-borne encephalitis

inactivated mouse brain vaccine)1

Takeda

1937–1939

Yellow fever (17D) LAV-vaccine developed (embryonated eggs)5

Dengue

Other flavivirus vaccines

• To develop an effective, live-attenuated dengue vaccine with an acceptable

safety profile based on the dengue virus 2 backbone that:

– Elicits a serotype-specific neutralizing humoral immune response to all four dengue

virus serotypes and a multifunctional cellular immune response to dengue antigens in

flavivirus-naïve and exposed individuals

– Protects against infection with all four dengue virus serotypes and all severities

of dengue disease

– Provides durable protection to all individuals, regardless of pre-existing

dengue virus antibody status

Takeda: dengue vaccine development objectives

18

Takeda’s live-attenuated tetravalent dengue vaccine

candidate (TDV) is a DENV-2*-based recombinant vaccine1

• Induces antibody responses to all four serotypes in dengue-naïve and dengue-exposed children and adults2-6

• TDV elicits multifunctional and cross-reactive T cell-mediated responses to dengue structural and non-structural proteins7-8

1, Osorio, et al. Expert Rev Vaccines 2016;15(4):497–508 | 2. George, et al. J Infect Dis 2015;212:1032–41 | 3. Osorio, et al. Lancet Infect Dis 2014;14(9):830–8 | 4. Rupp, et al. Vaccine

2015;33(46):6351–9 | 5. Sirivichayakul, et al. J Infect Dis 2016;213(10):1562–72 | 6. Sáez-Llorens , et al. Lancet Infect Dis 2017; http://dx.doi.org/10.1016/S1473-3099(17)30166-4

|7. Ambuel, et al. Front Immunol 2014;5:263 | 8. Chu, et al. J Infect Dis 2015;212(10):1618–28| 9. Butrapet , et al., Journal of Virology 2000; 74 (7): 3011-3019

TDV-2

(DENV-2 backbone)

TDV-1

TDV-3

TDV-4

C, capsid; E, envelope; NS, non-structural; prM, pre-membrane

Site of

mutation9

5’-

5’-

5’-

5’-

–3’

–3’

–3’

–3’

C prM E NS1 2A 2B NS3 4A 4B NS5




DENV-2, dengue virus 2

Figure © Elsevier B.V., reproduced with permission.

*In this presentation, DENV denotes wild type dengue virus

1. Dengue disease










8. Conclusions


‡The illustration of the phase 1 and 2 studies in non-endemic populations does not depict the end date of

each study.

http://clinicaltrials.gov/

2017 2010 2011 2012 2013 2014 2015 2016

DEN-102 (Colombia) n=96

DEN-101

(US) n= 72

DEN-103

(US) n=67

DEN-104

(US) n=136

DEN-106

(US) n =996

Non-endemic: Phase 1 and 2 (flavivirus-naïve adults)‡

Includes

children Ongoing

Endemic:

Phase 2

and 3

DEN-203: Adults and children n=360

(in dengue endemic: Puerto Rico, Colombia, Singapore, Thailand)

DEN-204: Children only n=1794

(Philippines, Panama, Dominican Republic)

DEN-205: Adults only

n=351 (Singapore)

DEN-301: Children only

N=20,100 (Brazil, Colombia,

Dominican Republic, Nicaragua, Panama,

Philippines, Sri Lanka, Thailand)

More than 17,000 participants have received at least one

dose of TDV in phase 1, 2 and 3 studies, including almost

15,000 children

Ongoing and completed clinical studies

DEN-313: CMI:

Children only

n=200 (Panama,

Philippines)

Phase 1 studies (flavivirus-naïve adults) :

• DEN-101 (US)1,2, DEN-102 (Colombia)3,4: Different dose levels and routes of

administration: intradermal (ID) and subcutaneous (SC)

• DEN-103 (US): ID needle vs needle-free ID administration5,6

• DEN-104 (US): Different dose levels and schedules7,8

TDV: Phase 1 studies

22

ID: intradermal; SC: subcutaneous; TDV: tetravalent dengue vaccine

1. George, et al. J Infect Dis 2015;212:1032–41

2. https://clinicaltrials.gov/show/NCT01110551. Accessed 24/02/2016

3. Osorio, et al. Lancet Infect Dis 2014;14:830–8


5. Chu, et al. J Infect Dis 2015;212:1618–28


7. Rupp, et al. Vaccine 2015;33:6351–9


https://clinicaltrials.gov/show/NCT01110551



https://clinicaltrials.gov/show/NCT01542632. Accessed 24/02/2016

Phase 2 study (flavivirus-naïve adults):

• DEN-106 (US): Two dose schedule of SC lyophilized vs liquid formulation1

Phase 2 studies (dengue-endemic regions):

• DEN-203: Safety, tolerability and immunogenicity in healthy adults and

children (SC)2,3 – Part 1: Age de-escalation

– Part 2: Expansion phase (age 1.5 -11 years)

• DEN-204: Safety and immunogenicity (S&I) of different schedules in healthy

children (SC)4–6

– Comparison of two dose and one dose schedules & evaluation of booster at

12 months

• DEN-205: S&I of two different serotype 2 potencies of TDV in adults (SC)7

• DEN-313: Cell-mediated immunity & safety in healthy children aged 4-16 years

(SC)8

TDV:Phase 2 studies

23

SC: subcutaneous; S&I: safety and immunogenicity;

TDV: tetravalent dengue vaccine


2. Sirivichayakul, et al. J Infect Dis. 2016;213:1562–72


4. Biswal. Presented at Asia Dengue Summit; Session 1; Jan 13, 2016


6. Sáez-Llorens, et al. Lancet Infect Dis 2017;DOI:10.1016/S1473-3099(17)30166-4


8. https://clinicaltrials.gov/show/ NCT02948829 Accessed August 2017





1. Dengue disease










8. Conclusions


• Takeda’s TDV candidate is generally well tolerated in flavivirus-naïve

volunteers1,2

• TDV induced neutralizing antibodies to all four DENV serotypes1,2

– GMTs for both administration routes and TDV formulations:1

DENV-2 > DENV-1 > DENV-3 > DENV-4

• SC administration may be favoured over ID administration1,3

– Both TDV formulations (via either SC or ID administration) induced neutralizing

antibodies to all four DENV serotypes1,3

Summary of Phase 1 findings

25

DENV: dengue virus; ID: intradermal; SC: subcutaneous; TDV: tetravalent dengue vaccine

1. Osorio, et al. Lancet Infect Dis 2014;14:830–8

2. Osorio, et al. Vaccine 2015;33:7112–20

3. Chu, et al. J Infect Dis 2015;212:1618–28

1. Dengue disease










8. Conclusions


TDV: DEN-203 – Phase 2 trial in dengue-endemic countries


1. Sirivichayakul, et al. J Infect Dis. 2016;213:1562–72

2. https://clinicaltrials.gov/show/NCT01511250 Accessed 24/02/2016

Primary objective 2:1,2

To assess the immunogenicity of TDV against all four

dengue serotypes in healthy adults and children

Primary objective 1:1,2

To evaluate the safety and tolerability of a subcutaneously

administered TDV in healthy adults and children (1.5–45 years old)

27


DEN-203 study design1: randomized, double blind,

placebo-controlled Phase 2 study

Part 2

(expansion)

+

28

0 7 14 28 90 97 104 120 180 360 720 1080

Group 2

12–20 yrs.

n = 36

+

28

Group 3

6–11 yrs.

n = 38

Group 1

21–45 yrs.

n = 38 Randomization 2:1

vaccine to placebo

+

28

Group 4

1.5–5 yrs.

n = 36

+

Key:

Dose

Safety review (N ≥ 12)

Viremia + safety samples

Immunogenicity sample

+

Part 1 (age-descending)

Enrolled, n = 148

n=212

1.5-11 yrs

Randomization 3:1

vaccine to placebo

ClinicalTrials.gov identifier: NCT01511250

1Sirivichayakul et al., 2016J Infect Dis. 2016;213(10):1562-72. doi:

10.1093/infdis/jiv762. Epub 2015 Dec 23

The same

vaccination

and sample

schedule

was used for

each group

DEN-203: Neutralizing antibody response – 2 year interim

data

• TDV elicited neutralizing antibody responses that persist through Day 720 in children and adults,

irrespective of initial immune status

MNT positive to ≥1

DENV at baseline

MNT negative to all

4 DENV at baseline

×

DENV-1

DENV-2

DENV-3

DENV-4

Ge

om

etr

ic m

ea

n M

NT

50

Ge

om

etr

ic m

ea

n M

NT

50

Study day Study day

= Vaccination

FAS, full analysis set, Part 1

Day 28, n=133

Day 90, n=131

Day 120, n=130

Day 180, n=39

Day 360, n=38

Day 720, n=40

Day 0, n=116

Day 28, n=115

Day 90, n=115

Day 120, n=115

Day 180, n=45

Day 360, n=44

Day 720, n=50

Takeda: Data on file

MNT- Micro Neutralization Test

TDV: DEN-204 – Safety and immunogenicity of different

schedules in healthy children1-3

30

1.Biswal. Presented at Asia Dengue Summit; Session 1; Jan 13, 2016

2.https://clinicaltrials.gov/show/NCT02302066. Accessed 10/02/2016

3.Sáez-Llorens, et al. Lancet Infect Dis 2017;DOI:10.1016/S1473-

3099(17)30166-4

Key objective:1-3

Comparison of two dose and one dose schedules & evaluation of booster at

12 months

1800 children age 2 to <18 years in Panama, the

Dominican Republic and the Philippines

Enrolment completed February 2015


• Descriptive comparison of two-dose and one-dose schedules, and an assessment of a

booster-dose at 12 months

• First use of the new formulation of TDV (which has 10-fold lower potency of TDV-2 than the

previous formulation)

• Has contributed to a large safety database of the endemic paediatric population

DEN-204: A randomized, controlled phase 2 endemic

paediatric study

ClinicalTrials.gov Identifier: NCT02302066

Enrolment

Injection Month 6

Interim Analysis

Month 12

Month 48

Month 3 Month 0

V = vaccine

P = placebo Group 1 V V P N=200

Group 2 V P P N=400

Group 3 V N=1000

Group 4 P P P N=200

Immunogenicity

subset

V P

100

200

200

100

2 doses

1 dose

Saez-Llorens et al. Lancet ID Volume 17, No. 6, p615–625, June 2017

DEN-204: Summary of immunogenicity data at 6 months

• High GMTs and seropositivity rates

against all the dengue serotypes were

observed in all participants including

those seronegative at baseline

• At 6 months in participants who were

seronegative at baseline:

– One dose resulted in 67.5% tetravalent

seropositivity

– Two doses resulted in 85% tetravalent

seropositivity

• 18 month data to be presented at ASTMH

November 2017

Takeaway: Test a two-dose regimen 3 months apart in the phase 3 efficacy trial to

maximize vaccine take in participants who are seronegative at baseline

Multivalent seropositivity rates at Month 6 in all

participants and those seronegative at baseline

All participants Sero(-) at baseline

GMT, geometric mean titer

Saez-Llorens et al. Lancet ID Volume 17, No. 6, p615–625, June 2017 ClinicalTrials.gov Identifier: NCT02302066

1. Solicited AEs

– Pain (mostly mild and transient) was the most common local adverse event, with the

highest rate (31%) seen in children 6-17 years of age

– Swelling and redness occurred in approximately 5% of vaccinees in this analysis

– Fever, headache and myalgia were commonly reported in both studies and were

observed at similar rates in placebo recipients and vaccinees

2. Unsolicited AEs

– In both studies, the majority of unsolicited AEs were infections common to children in

these age groups (e.g., laryngitis and tonsillitis). Overall, there were no major or

consistent differences in unsolicited AEs between TDV and placebo

– There were no major differences in unsolicited AEs following Dose 1 or Dose 2 observed

in the TDV versus placebo groups. The majority of unsolicited AEs were assessed as

unrelated to the study vaccine

– After Dose 1 and Dose 2, SAEs were reported in fewer than 2% of participants in the TDV

and placebo groups; all SAEs were assessed as unrelated to the study vaccine

DEN-203/204: Integrated safety analysis1

– Summary of AEs in paediatric participants

Takeda: Data on file; AE, adverse event 1Papadimitriou et al., 2016 ,E-poster presented at 8th Asian Congress of Paediatric Diseases, Bangkok, Thailand (post hoc analysis)

• TDV was well tolerated in children and adults, across multiple formulations and

vaccination schedules

• No vaccine-related SAEs were reported

• No safety concerns were identified based on local or systemic reactogenicity

or unsolicited AEs

TDV: pooled analysis of DEN-203 and DEN-204

Summary1

34

AE: adverse event; SAE: serious adverse event; TDV: tetravalent dengue vaccine

1. Papadimitriou, et al. Presented at 8th Asian Congress of Pediatric Infectious Diseases, Thailand, November 2016. Registered at:

https://clinicaltrials.gov/show/NCT01511250 and https://clinicaltrials.gov/ct2/show/NCT02302066 Accessed 09/12/2016



https://clinicaltrials.gov/ct2/show/NCT02302066

https://clinicaltrials.gov/ct2/show/NCT02302066

Key clinical findings supporting phase 3 start of TDV


Over 3500 subjects have received TDV including over 1800 children living in

dengue endemic countries in 8 completed or ongoing Phase 1 or 2 trials

Acceptable safety profile in these phase 1 and phase 2 trials

Sustained antibody responses to all four dengue serotypes, in both naïve and

previously-exposed subjects

T cell-mediated responses to dengue structural and non-structural proteins

Five formulations evaluated, with varying potency of individual serotypes

Lyophilized presentation evaluated in late phase 2 studies, enabling storage

at 5oC.

A two-dose schedule at Months 0 and 3 selected to maximize seropositivity in

subjects seronegative at baseline

35

1. Dengue disease










8. Conclusions


• Phase III, Double-Blind, Randomized, Placebo-Controlled Trial to

Investigate the Efficacy, Safety and Immunogenicity of TDV Administered

Subcutaneously in Healthy Children Aged 4 - 16 Years Old


1. https://clinicaltrials.gov/show/NNCT02747927Accessed August 2017

37

Key objective:1

To evaluate the efficacy of 2 doses of TDV in preventing

symptomatic dengue fever of any severity and due to any of the

four dengue virus serotypes in 4 to 16 year old participants

Efficacy, Safety and Immunogenicity of Takeda's Tetravalent

Dengue Vaccine (TDV) in Healthy Children (TIDES)

• 20,100 subjects from Brazil, Colombia, Dominican Republic,

Nicaragua, Panama, Philippines, Sri Lanka, Thailand

TIDES (DEN-301): Overall study design and objectives

Part 1

120 cases of dengue

Minimum 12 months post-

vaccination for each subject

Efficacy against dengue of

any severity and due to any

of the 4 serotypes

Efficacy against dengue by exposure status at baseline,

serotype, severity (Hospitalized and Severe dengue) Long term safety and efficacy

Reactogenicity (post vaccination period) and Immunogenicity in a subset

Optional dry-run part for up to 10 months prior to Part 1 to commence and test febrile

surveillance methodology (Not mandatory for all sites or all subjects)

Part 2

6 months Part 3

3 years

Active surveillance and collection of all SAEs

Modified active surveillance and

collection of related/relevant SAEs

Time points of planned analysis and reporting


TIDES (DEN-301): randomization, vaccination, and

sampling

Part 1 120 cases of dengue

+ 12 months post 2nd dose

Part 2 6 months

Part 3 3 years

Modified active surveillance (Part 3)

Placebo - 6,700 subjects, stratified by region and age range (4-5, 6-11 and 12-16 years)

Time in Months 0 1 3 4 15 27 39 51 9

All subjects- 0 and 4 months

Subset (4000 subjects)- All time points Immunogenicity

sample

Dose

Active surveillance (Part 1 & 2)

TDV - 13,400 subjects, stratified by region and age range ( 4-5, 6-11 and 12-16 years)


20,100


• DEN-301 vaccination began in September 2016

• Recruitment is complete:

• 20,100 subjects 4-16 years recruited in 7 months in 26 clinical trial sites in 8

countries

• All subjects have been vaccinated

• First results expected in late 2018

Status update: Takeda’s candidate dengue vaccine pivotal

efficacy trial TIDES (NCT02747927)

1. Dengue disease










8. Conclusions


Conclusions

• More than 17,000 subjects including almost 15,000 children have received

at least one dose of TDV in 10 completed and ongoing phase1, 2 and 3

clinical studies

• In phase 1 and 2 clinical studies, the vaccine candidate was immunogenic

and showed acceptable reactogenicity in children, adolescents and adults1-6

• In DEN-203 and DEN-204, no vaccine-related Serious Adverse Events

occurred5,6

• A vaccination schedule comprising two doses three months apart was

selected for phase 3 because DEN-204 6-month interim results showed that

a second dose improved tetravalent seropositivity in children who were

dengue seronegative before vaccination

• Takeda’s pivotal phase 3 study DEN-301 began in September 2016,

recruitment and vaccination are complete, and the first results are expected

in 2018

1. Osorio, et al. Expert Rev Vaccines 2016;15(4):497–508 | 2. George, et al. J Infect Dis 2015;212:1032–41 | 3. Osorio, et al. Lancet Infect Dis 2014;14(9):830–8 | 4. Rupp, et

al. Vaccine 2015;33(46):6351–9 | 5. Sirivichayakul, et al. J Infect Dis 2016;213(10):1562–72 | 6. Sáez-Llorens , et al. Lancet Infect Dis 2017;

http://dx.doi.org/10.1016/S1473-3099(17)30166-4

Thank you

Documents

Takeda’s Dengue Vaccine Candidate · Dengue Fact Sheet, Australian Government Department of Health. Map adapted from Figure 2, Queensland Dengue Management Plan 2015-2020. The State