Dengue and Dengue Vaccines

Anna P Durbin

Johns Hopkins Bloomberg School of

Public Health

Pathogen, disease and unmet

medical need

• Dengue is a member of the Flavivirus family – Dengue, Yellow fever virus, Japanese

encephalitis virus

• Four dengue serotypes

• Endemic in all tropical and subtropical regions of the world

• Mosquito-borne disease – Dengue is the most important arboviral

infection world-wide

– Aedes species are the primary vector

Pathogen, disease and unmet

medical need

• Nearly 4 billion people at risk

– 400 million infections annually

• ~ 100 million are symptomatic

• ~ 500,000 severe cases

• Mortality rate ranges <1% - >10%

Messina et al, Nature Reviews, Vol 13 2015

Pathogen, disease and unmet

medical need

• Treatment for dengue is supportive only

– No antiviral agents

• Currently there is no licensed vaccine

– The first dengue vaccine will likely be

registered very soon

• Prevention of dengue is primarily

vector control centered around

outbreaks

Pathogen, disease and unmet

medical need

• Although dengue cases can occur year-round in endemic areas, outbreaks are seasonal

• Large outbreaks occur every few years in endemic areas

• Dengue outbreaks overwhelm health care systems

• Great pressure in endemic areas for a dengue vaccine

Pathogen, disease and unmet

medical need • Target population for a dengue vaccine may differ

by region

• In areas that have had multiple serotypes circulating for generations (Asia), the target group is children ~ 1 year of age

• In areas that have more recently become hyper-endemic (Latin America), adults bear a significant amount of disease burden

• The burden of disease may vary by region within a country (Brazil)

• Most countries will want to target children for vaccination

Vaccine development: background

• Four DENV serotypes all capable of causing the full spectrum

of disease (need for a tetravalent vaccine)

• Life-long homotypic protection afforded after infection but

only short term (months) heterotypic protection is afforded

• Secondary infection with a different serotype is strongly associated with severe disease

– Antibody-mediated enhancement of infection

Vaccine development: background

• Humans, some NHP, and mosquitoes are the only natural hosts – DENV replicates in NHP but does not cause

disease

• Immunodeficient mouse models exist but do not fully replicate human disease – AG129 (IFN𝛼/𝛽 and IFN𝛾 receptor deficient)

– Humanized NOD/SCID mouse

• DENV generally need to be adapted to replicate in mice

Vaccine development: background

• The plaque reduction neutralization titer (PRNT) assay has been the gold standard for measuring the immune response to dengue/dengue vaccines

• Primary human monocytes or immortalized cell lines (K562, U936) have been used to detect enhancing antibody

• Currently no single assay that measures both neutralizing and enhancing antibody

• The role of cellular immunity in protection against severity of illness is being studied

Vaccine development: background

• Correlates of protection currently do not exist

– Neutralizing antibody thought to be a correlate

but a Phase 2b efficacy trial of a dengue

candidate vaccine demonstrated no efficacy

against DENV-2 despite the presence of

neutralizing antibody

– The PRNT assay is currently performed in cells

that do not express the Fc𝛾R and therefore do

not measure enhancing antibody

Vaccine development: background

• Endpoint for licensure is demonstrated

efficacy against symptomatic dengue of any severity

– Efficacy against each of the four serotypes

is not required

– All four serotypes do not circulate in the

same place at the same time with high

enough frequency to power a study for this

outcome

Vaccine development: background

• Risk of enhanced disease as vaccine

induced immunity wanes is a great

safety concern for dengue vaccines

– Antibody-dependent enhancement

• Longer-term safety follow-up of

subjects enrolled in dengue vaccine

trials is required (3 – 5 years at least,

the longer the better)

Vaccine development: pipeline

• Live attenuated tetravalent vaccines

– CYD-TDV (Sanofi-Pasteur)

– TV003/TV005 (U.S. NIH)

– TDV (Takeda)

• Purified inactivated tetravalent vaccine

– WRAIR, GSK

• Sub-unit protein vaccine (V180)

CYD-TDV

• Live attenuated tetravalent chimeric

vaccine

• Administered as 3 doses on a 0/6/12

month schedule

NS proteins are from YFV 17D

DENV-1

DENV-2

DENV-3

DENV-4

YFV

CYD-TDV

• Completed a Phase 2b trial – Thailand (CYD23)

• Enrolled 4002 children between 4-11

• Completed two pivotal Phase 3 trials – Asia (CYD14)

• Enrolled 10,275 children between 2 – 14

• Thailand, Indonesia, Malaysia, Philippines, and Viet Nam

– Latin America (CYD15) • Enrolled 20,869 children between 9 – 16

• Colombia, Brazil, Mexico, Puerto Rico, and Honduras

CYD-TDV efficacy trials

• All studies randomized 2:1

vaccine:placebo

• Primary efficacy endpoint was

prevention of symptomatic dengue of

any severity

• Efficacy was determined from 28 days

following the third dose of vaccine to

month 25 (12 month period)

Efficacy and long-term follow-up

periods

Hadinegoro et al, NEJM, 2015

Efficacy1 of CYD-TDV

Trial Region

Vaccine recipients enrolled Age

Overall Efficacy (95%

CI)

Efficacy in seropositive at baseline

Efficacy in seronegative at baseline

CYD232 Thailand 2,669 4-11 30.2

(-13.4-56.6) Not

reported Not

reported

CYD143 SE Asia 6,851 2-14 56.5

(43.8-66.4) 74.3

(53.2-86.3) 35.5

(-26.8-66.7)

CYD154 Latin America 13,920 9-16 60.8

(52.0-68.0) 83.7

(62.2-93.7) 43.2

(-61.5-80)

1. Per protocol analysis. Period of primary efficacy evaluation was > 28 days after the third dose to month 25 (12 month period)

2. Sabchareon, The Lancet, 2012 3. Capeding et al, The Lancet, 2014 4. Villar et al, NEJM, 2014

Efficacy1 of CYD-TDV by serotype

Study Overall Efficacy DENV-1 DENV-2 DENV-3 DENV-4

CYD23 30.2

(-13.4-56.6) 55.6%

(-21.6 - 84) 9.2%

(-75 – 51.3) 75.3%

(-37.5 – 99.6) 100%

(24.8 – 100)

CYD14 56.5

(43.8-66.4) 50.0%

(24.6 – 61.0) 35.0%

(-9.2 – 61.0) 78.4%

(52.9 – 90.8) 75.3%

(54.5 – 87.0)

CYD15 60.8

(52.0-68.0) 50.3%

(29.1 – 65.2) 42.3%

(14.0 – 61.1) 74.0%

(61.9 – 82.4) 77.7%

(60.2 – 88.0)

1. Per Protocol analysis 2. Sabchareon, The Lancet, 2012 3. Capeding et al, The Lancet, 2014 4. Villar et al, NEJM, 2014

Efficacy of CYD-TDV by age

(CYD14)

Age / Serostatus Vaccine efficacy % (95% CI)

2 – 5 years 33.7 (11.7; 50.0)

6 - 11 years 59.5 (48.9; 68.0)

12 -14 years 74.4 (59.2; 84.3)

Seropositive 74.3 (53.2; 86.3)

Seronegative 35.5 (-26.8; 66.7)

Efficacy CYD-TDV summary

• Efficacy varied by:

– Region

– Serotype

– Serostatus at baseline

– Age

• Post-hoc analysis demonstrated

efficacy against hospitalized dengue

(67.2% CYD14, 80.3% CYD15)

CYD long-term safety follow-up

• Re-enrolled participants from CYD23 for longer-term safety follow-up (CYD57) – Data available for 3203/4002 (80%)

• Follow-up data available for 99% of CYD14 and 95% CYD15 participants

• Long-term safety analyses based on data collected during year 3 of CYD14 & CYD15 and years 3 and 4 of CYD23/57

Incidence of hospitalization in first

year of long-term follow-up Vaccine Group Control Group

Trial Cases

dengue Total

subjects Cases of dengue

Total subjects

Relative risk (95% CI)

CYD14

All subjects 27 6,778 13 3,387 1.01 (0.52-2.19)

2-5 yr 15 1,636 1 813 7.45 (1.15-313.8)

6-11 yr 10 3,598 8 1,806 0.63 (0.22-1.83)

12-14 yr 2 1,544 4 768 0.25 (0.02-1.74)

< 9 yr 19 3,493 6 1,741 1.58 (0.61-4.83)

≥ 9yr 8 3,285 7 1,646 0.57 (0.18-1.86)

CYD15

All subjects 16 13,268 15 6,630 0.53 (0.25-1.16)

9 - 11 10 6,029 9 3,005 0.55 (0.2-1.54)

12 - 16 6 7,239 6 3,625 0.50 (0.13-1.87)

Efficacy against hospitalization

over time Trial Cases M Cases M RR (95% CI)

CYD14-All participants

Year 1 (Day 0 – Dose 3) 20 6,848 26 3,424 0.38 (0.20; 0.72)

Year 2 (Dose 3 – month 25) 20 6,812 35 3,407 0.29 (0.16; 0.51)

Year 3 27 6,778 13 3,387 1.04 (0.52; 2.19)

Day 0 – Year 3 67 6,813 73 3,406 0.46 (0.32; 0.65)

CYD15-All participants

Year 1 (Day 0 – Dose 3) 5 13,915 15 6,939 0.17 (0.05; 0.48)

Year 2 (Dose 3 – month 25 12 13,522 28 6,749 0.21 (0.10; 0.43)

Year 3 16 13,268 15 6,630 0.53 (0.25; 1.16)

Day 0 – Year 3 33 13, 568 58 6,773 0.25 (0.18; 0.44)

Summary of long-term follow-up

data

• In the CYD14 trial, the pre-specified age-specific analysis showed a clear trend toward a high RR for hospitalization for virologically confirmed dengue among young children

– RR if age <9 = 1.58 (0.61; 4.83)

– RR if age ≥ 9 = 0.57 (0.18; 1.86)

• This trend was not apparent in CYD15 (all participants were ≥ 9)

– RR = 0.53 (0.25; 1.16)

Summary of CYD-TDV

• 3 Doses of vaccine given over 12 months (0/6/12)

• Variable efficacy based on region, serotype, age at vaccination, serostatus at vaccination

• RR of hospitalization increased over time for vaccine recipients who were < 9 at time of vaccination

• Licensure being sought for those ≥ 9 years of age

NIH dengue vaccine TV003/TV005

• Live attenuated tetravalent vaccine given as a

single dose

• Primary attenuation mutation is 30 nt deletion in

3´ UTR

• One component is a chimeric virus

TV003/TV005

Dose of each component (log10PFU) DENV-1 DEN-2 DEN-3 DENV-4

TV003 3,3,3,3 rDEN1Δ30 rDEN2/4Δ30 rDEN3Δ30/31 rDEN4Δ30

TV005 3,4,3,3 rDEN1Δ30 rDEN2/4Δ30 rDEN3Δ30/31 rDEN4Δ30

rDEN1Δ30

rDEN2/4Δ30

rDEN3∆30/31

rDEN4Δ30

DENV-1

DENV-2

DENV-3

DENV-4

TV003/TV005

• Evaluated in numerous Phase I trials in the U.S.

– Safety profile acceptable; most common vaccine-associated AE is transient rash (correlated with tetravalent response)

• Single dose induces tetravalent responses in 74-92% (TV003) and 90% (TV005) of flavivirus-naïve adult subjects

• Protective efficacy of TV003 against DENV-2 evaluated in challenge study

Multivalent responses to single

dose of TV003 or TV005 % vaccinees with multivalent response (cumulative)

Formulation N Tetra Tri Bi Mono

TV0031 38 74 (74) 18 (92) 8 (100) 0

TV0032 37 86 (86) 11 (97) 3 (100) 0

TV0033 38 87 (87) 10 (97) 0 (97) 3 (100)

TV0031 24 92 (92) 8 (100) 0 0

TV0051 39 90 (90) 8 (98) 0 (98) 2 (100)

1. Flavivirus-naïve adults U.S. 2. Flavivirus unscreened adults U.S. 3. Flavivirus-experienced adults U.S.

TV003 affords complete protection

against DENV-2 challenge

Outcome TV003 (n=21) Placebo (n=20) p (2-sided)

Viremia 0% 100%1 < 0.0001

Rash 0% 80% < 0.0001

Neutropenia 0% 20% 0.048

Fever 0% 0% n/a

1. Mean peak titer of recovered virus = 2.3 log10 PFU/mL. All but one placebo recipient who was challenged was viremic on multiple days

TV003/TV005

• Phase 2 trials on-going in Thailand (TV005) and Brazil (TV003, Instituto Butantan)

• TV003/TV005 has been licensed to Instituto Butantan (Brazil), Vabiotech (Viet Nam), Panacea Biotech & Serum Institute (India) for in-country manufacture

– Instituto Butantan planning Phase 3 trial for Q4/2015

• TV003/TV005 has been licensed exclusively to Merck & Co. in the U.S.

TDV - Takeda

• LATV chimeric dengue vaccine based

on DENV-2

• Two doses given 3 months apart (single

dose being considered)

DENV-1

DENV-2

DENV-3

DENV-4

TDV - Takeda

• Different formulations and routes of

administration have been evaluated

– SQ & ID

– Low dose & high dose

• Evaluated in flavivirus-naïve healthy

adults in Colombia and U.S.

– Safety profile acceptable

• DENV-2 component dominant

Mulitvalent response to TDV Formulation N Tetra Tri Bi Mono None

ID - Low

Dose 1 12 25 17 (42) 25 (67) 17 (84) 16 (100)

Dose 2 9 44 11 (55) 33 (88) 12 (100) 0

SQ Low

Dose 1 12 58 17 (75) (17 (92) 0 (92) 8 (100)

Dose 2 9 78 11 (89) 11 (100) 0 0

ID High

Dose 1 12 67 25 (92) 8 (100) 0 0

Dose 2 10 80 20 (100) 0 0 0

SQ High

Dose 1 12 50 50 (100) 0 0 0

Dose 2 11 62 23 (85) 13 (98) 2 (100) 0

George, et al; JID 2015

TDV - Takeda

• Phase 2 trial in subjects 2 – <18 in Asia and Latin America – 2 doses 90 days apart (current schedule)

– 1 dose (placebo at day 90)

– 1 dose with booster at 1 year

– Placebo comparator

– Estimated enrollment: 1800

• Phase 2 trial in Singapore evaluated a single dose of high or low dose formulation – Adults age 21 – 45, unscreened dengue status

– Estimated enrollment: 400

GSK - PIDV

• Purified inactivated tetravalent dengue vaccine

• Evaluating different adjuvants – Alum

– AS03B

– AS01E

• Evaluating 2 doses given 28 days apart

• Phase 1 trials in U.S. and Puerto Rico

Sub-unit protein vaccine - Merck

• Sub-unit protein vaccine comprised of

truncated envelope protein (E) from each of

the 4 DENV serotypes (V180)

• Phase 1 trial in Australia

– 3 doses given at 1 month apart (0,1,2)

– Evaluated with Alum or ISCOMATRIX™

• Phase 1 trial evaluating booster effect of

V180 on recipients of TV003 or TV005

Vaccine development: pipeline

• Pathway to licensure will be Phase 3

efficacy trials

– No correlate of protection as yet

– Licensure of the first DENV vaccine may

complicate the pathway for others

• Long term safety follow-up will be

important for ALL dengue candidate

vaccines

Vaccine development: pipeline

• CYD will likely be registered in ≥1

country 2015/2016

• TV003/TV005: licensure in Brazil 2017

• Linking of pharmacovigilence and

dengue surveillance systems important

for long-term safety follow-up

Role of WHO

• WHO has been instrumental in

development of dengue manufacturing

and clinical evaluation guidelines

• WHO can lead development of long-

term safety study strategies, regulatory

pathway for licensure of new dengue

vaccines

• SAGE review of CYD to occur in 2016

Efficacy against hospitalization

over time Trial Cases M Cases M RR (95% CI)

CYD14-All participants

Year 1 (Day 0 – Dose 3) 20 6,848 26 3,424 0.38 (0.2; 0.72)

Year 2 (Dose 3 – month 25) 20 6,812 35 3,407 0.29 (0.16; 0.51)

Year 3 27 6,778 13 3,387 1.04 (0.52; 2.19)

Day 0 – Year 3 67 6,813 73 3,406 0.46 (0.32; 0.65)

CYD15-All participants

Year 1 (Day 0 – Dose 3) 5 13,915 15 6,939 0.17 (0.05; 0.48)

Year 2 (Dose 3 – month 25 12 13,522 28 6,749 0.21 (0.10; 0.43)

Year 3 16 13,268 15 6,630 0.53 (0.25; 1.16)

Day 0 – Year 3 33 13, 568 58 6,773 0.25 (0.18; 0.44)