Dengue Vaccines Development

Prof.DR Dr.Hindra Irawan Satari,Sp.A(K),MTropPaed

Development of Dengue Vaccines
Vaccination against dengue

The first dengue vaccine, Dengvaxia® (CYD-TDV) developed by Sanofi Pasteur was
licensed in December 2015 and has now been approved by regulatory authorities
in ~20 countries.
In November 2017, the results of an additional analysis to retrospectively
determine serostatus at the time of vaccination were released. The analysis
showed that the subset of trial participants who were inferred to be seronegative
at time of first vaccination had a higher risk of more severe dengue and
hospitalizations from dengue compared to unvaccinated participants.
As such, use of the CYD-TDV vaccine is targeted for persons living in endemic areas,
9-45 years of age, who have had at least 1 episode of dengue virus infection in the
past. Several additional dengue vaccine candidates are under evaluation.
 Explanatory hypothesis for excess cases in seronegative trial participants:
“Silent infection” mode of action

Ferguson et al., Science 2016; Flasche et al., PLoS Med. 2016

WHO position on the CYD-TDV vaccine[26]

• As described in the WHO position paper on the Dengvaxia vaccine (September

2018)[26] the live attenuated dengue vaccine CYD-TDV has been shown in clinical trials
to be efficacious and safe in persons who have had a previous dengue virus infection
(seropositive individuals).
• For countries considering vaccination
Ferguson et al., as Flasche
Science 2016; part ofettheir dengue
al., PLoS control programme, pre-
Med. 2016
vaccination screening is the recommended strategy. With this strategy, only persons
with evidence of a past dengue infection would be vaccinated (based on an antibody
test, or on a documented laboratory confirmed dengue infection in the past). Decisions
about implementing a pre-vaccination screening strategy will require careful
assessment at the country level, including consideration of the sensitivity and specificity
of available tests and of local priorities, dengue epidemiology, country-specific dengue
hospitalization rates, and affordability of both CYD-TDV and screening tests.
 Benefit-risk assessment
Incidence rates (IRs) and attributable risks (ARs) in
<9y and 9+y age groups (MI method)
WHO position on the CYD-TDV vaccine
 Countries need to consider local factors

• Decisions about implementing a “pre-vaccination screening” strategy

with the currently available tests will require careful assessment at
the country level, including consideration of:
• • the sensitivity and specificity of available tests
• local priorities
• dengue epidemiology
• country-specific dengue hospitalization rates
• affordability of both CYD-TDV and screening tests.
WHO position (continued)

• If pre-vaccination screening is not feasible, vaccination without

individual screening could be considered in areas with recent
documentation of seroprevalence rates of at least 80% by age 9 years.
• Decisions about implementing a seroprevalence criterion-based
vaccination strategy without individual screening will require
population serosurveys at high resolution, i.e. at district and sub-
district level.
• Careful assessment is required with regard to the feasibility and cost
of population seroprevalence studies.
• Communication needs to ensure appropriate and full disclosure of the
risks of vaccination of persons with unknown serostatus.
Development of live attenuated vaccines (1/2)
CYD-TDV

Pinheiro-Michelsen JR, Souza RdSO, Santana IVR, da Silva PdS, Mendez EC, Luiz WB and Amorim JH (2020) Anti-dengue Vaccines: From Development to Clinical Trials.
Front. Immunol. 11:1252. doi: 10.3389/fimmu.2020.01252
Development of live attenuated vaccines (2/2)

Pinheiro-Michelsen JR, Souza RdSO, Santana IVR, da Silva PdS, Mendez EC, Luiz WB and Amorim JH (2020) Anti-dengue Vaccines: From Development to Clinical Trials.
Front. Immunol. 11:1252. doi: 10.3389/fimmu.2020.01252
The World Health Organization (WHO) has highlighted the development of a safe and effective
vaccine against the four serotypes of DENV as a priority. However, the vaccine development is
challenging because of a limited understanding of the viral pathogenesis.

Worldwide distribution of clinical trials of anti-dengue vaccines.

World map with the representation of areas in which dengue is
endemic and countries in which clinical trials registered at
ClinicalTrials.gov were carried out or are being carried out.
Pinheiro-Michelsen JR, Souza RdSO, Santana IVR, da Silva PdS, Mendez EC, Luiz WB and Amorim JH (2020) Anti-dengue Vaccines: From Development to Clinical Trials.
Front. Immunol. 11:1252. doi: 10.3389/fimmu.2020.01252
Dengue vaccine candidates in use or in clinical trials
 Dengue vaccine candidates in use or in clinical trials.

CYD-TDV: the live attenuated chimeric yellow fever 17D virus-tetravalent dengue vaccine; DENVax: the live attenuated tetravalent dengue vaccine;
PIV: the purified formalin-inactivated virus vaccine; TVDV: the tetravalent DNA vaccine; TLAV: the tetra-live attenuated virus vaccine.
Deng S-Q, Yang X, Wei Y, et al. A Review on Dengue Vaccine Development. Vaccines 2020, 8, 63; doi:10.3390/vaccines8010063
Structure of TAK-003 vaccine candidate

Osorio, et al. Expert Rev Vaccines 2016;15:497–508; 2. Butrapet, et al. J Virol 2000;74:3011–19

• Tetravalent dengue vaccine candidate TAK-003

• Based on a live attenuated DENV-2 virus, provides the genetic backbone
for all four of the viruses in the vaccine
• The other three virus strains (TDV-1, TDV-3, TDV-4) are chimeras
generated by replacing the pre-membrane and envelope genes of TDV-3
with those from wild-type DENV-1, DENV-3, and DENV-4 strains.
Biswal S, et al. Lancet 2020; 395: 1423–1433
TIDES (Tetravalent Immunization
against Dengue Efficacy Study):
TAK-003 Clinical Study
TIDES : Tetravalent Immunisation against Dengue Efficacy Study
26 site location from 8 country

• 20,099 participants randomized; 20,071 received at least one injection

• 97.3% of vaccine and 97.4% of placebo recipients completed part 1
• Similar baseline characteristics in the two treatment group
• Mean age of the participants in the per-protocol population: 9.6 years
• 27.7% of participants were seronegative at baseline
• Balanced enrollment between Asia-Pacific (46.5%) and Latin America (53.5%)
Biswal, et al. N Engl J Med 2019; 381: 2009-19
 TIDES : Tetravalent Immunisation against Dengue Efficacy Study
Primary endpoint: (30 days after second vaccination to end of Part 1)
Vaccine efficacy of two doses of TAK-003 in preventing VCD fever induced by any dengue serotype

Secondary efficacy endpoints: (30 days after second vaccination to end of Part 2)
Vaccine efficacy of two doses of TAK-003 in preventing:
• Hospitalization due to VCD (any serotype) – a key secondary endpoint
• VCD (any serotype) in baseline seronegative or seropositive participants
• VCD in each serotype
• Severe VCD (any serotype)

Other secondary objectives: (Parts 1, 2 and 3)

• Safety (all participants)
• Reactogenicity (subset of participants)
• Immunogenicity (subset of participants)

Exploratory endpoints included: (30 days after second vaccination to end of Part 2)
Vaccine efficacy of two doses of TAK-003 in seropositive and seronegative individuals according to:
• Age (4–5, 6–11 and 12–16 years)
• Serotype (DENV 1, 2, 3 or 4)

Exploratory endpoints also included: (Cumulative efficacy since first dose; efficacy in the 12 months after Part 1)
Long-term efficacy and safety 24 months after two-dose TAK-003 vaccination in both seropositive and seronegative individuals, in terms of:
• Vaccine efficacy against VCD (overall and by serotype, age, and region)
• Preventing hospitalization due to VCD
• Preventing DHF

Biswal, et al. N Engl J Med 2019; 381: 2009-19

López-Medina, et al. J Infect Dis 2020;jiaa761. doi:10.1093/infdis/jiaa761
 TIDES primary and secondary endpoint
Primary endpoint : 80.2% overall efficacy against virologically confirmed dengue (12 months after 2nd dose)

Biswal, et al. N Engl J Med 2019; 381: 2009-19

Key secondary endpoint : 90.4% efficacy against VCD requiring hospitalization (18 months after 2nd dose)

Biswal S, et al. Lancet 2020; 395: 1423–1433

 TIDES secondary endpoint
Secondary endpoint: VE by serostatus and serotype (18 months after second dose)

Secondary VE endpoints were met for DENV1–3 but continued to be variable.

VE remained inconclusive against DENV-4 due to low case counts.

Biswal S, et al. Lancet 2020; 395: 1423–1433

TIDES: 36 months data (exploratory endpoints)
Overall Efficacy against VCD and Hospitalized VCD: 36 months data
Vaccine efficacy (95% CI) of TAK-003 in preventing virologically-confirmed dengue (VCD) and hospitalized
VCD from the first dose to three years after the second dose (approximately Month 39 after first dose;
safety set data) by baseline serostatus.

Data under the placebo and TAK-003 groups are presented as number of VCD or hospitalized VCD /number of evaluable participants
(number of VCD cases per 100 person years at risk)

Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
Cumulative VCD incidence until 36 months after second dose
Subgroup analysis based on baseline serostatus (safety set)

Per 100,000 vaccinated, prevention of

• 4664 cases in baseline seropositives
• 3977 cases in baseline seronegatives

Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
 Cumulative incidence hospitalized VCD until 36 months after second dose
Subgroup analysis based on baseline serostatus (safety set)

Per 100,000 vaccinated, prevention of

• 1606 cases in baseline seropositives
• 1480 cases in baseline seronegatives

Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
 Vaccine efficacy during year 3 after second dose
Vaccine efficacy (95% CI) of TAK-003 in preventing virologically-confirmed dengue (VCD)
and hospitalized VCD during Year 3 after the second dose (per-protocol set data).

Efficacy against VCD during the third year declined to 44.7% (32.5–54.7), whereas
efficacy against hospitalized VCD was sustained at 70.8% (49.6–83.0).
Data under the placebo and TAK-003 groups are presented as number of VCD or hospitalized VCD /number of evaluable participants
(number of VCD cases per 100 person years at risk)
Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
 Vaccine Efficacy to Severe Dengue
First dose until 36 months after second dose (safety set)

Placebo TAK-003 VE
Subgroup
(n=6687) (n=13380) (95% CI)
VCD (-100 person per year) –based on severity
Severe dengue (DCAC) 5 (<0,1) 3 (<0,1) 70,2 (−24,7, 92,9)
DHF (WHO 1997 criteria) 13 (<0,1) 9 (<0,1) 65,4 (19,0, 85,2)
Case that fulfill both criteria 1 2

Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
Immunogenicity and Safety
 Imunogenicity of seronegative baseline participant

• Average of Geometric Mean Titer (GMTs) still

above baseline
• Tetravalent seropositivity: 80,5% on 36 months
after second dose
• Stabilized GMT for DENV-1, DENV-3 and DENV-4
since 9 months after first dose

Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
 Local reaction at injection
site and systemic reaction
Summary of diary reported injection site
reactions up to 7 days and systemic
adverse events up to 14 days after any
vaccination (subset of safety set data).

Frequency of injection site reactions

and solicited systemic events were
similar in both groups (12 months)

Data are presented as number of participants with events / number of evaluated

participants in the analysis set (% of evaluated participants with events)

Biswal, et al. N Engl J Med 2019;281:2009–19

 Overview of safety set data until end of part 2
(Until 18 moths, safety set)

Total incidence of unsolicited adverse events were similar for both group

Biswal, et al. Lancet 2020;395:1423–33

 Serious Adverse Events (month 19 to 36 after second dose)

Numbers (%) of participants experiencing serious adverse events during first half of Part 3
(approximately Month 22 to Month 39 after the first dose/Month 19 to 36 after the second dose; safety set
data)

aAsassessed by the sponsor or by the investigator (blinded).

bCauses of death were adenocarcinoma of colon, road traffic accident, wound by sharp element, traumatic lung injury secondary to drowning, completed suicide,
multiple organ dysfunction secondary to suicide attempt, and traumatic brain injury.

SAEs were reported by 2.9% of TAK-003 recipients and 3.5% of placebo recipients in the first half of part 3.
None of the SAEs were considered related to the study vaccine.
No important safety risks have been identified during the study.

Rivera L, Biswal S, Saez-Llorens X, et al. Clinical Infectious Diseases, 2001; ciab864, https://doi.org/10.1093/cid/ciab864
 Summary
• Todate, there is no specific treatment in dengue. Therefore,
urgent to develop vaccines is needed.
• There were candidates of dengue vaccines, and TAK-003 vaccine
candidate showed good protection to symptomatic dengue
through 3 years, for 4-16 years children with seronegative or
seropositive baseline
• The efficacy, which was variable by serotype, declined over time
but remained durable against hospitalized dengue
• No serious safety risk identified until 3 years after second dose

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