Development of dengue

vaccines
Ching-Len Liao
National Institute of Infectious Diseases and Vaccinology (NIIDV)
National Health Research Institute (NHRI)
Mioali County, Taiwan ROC
2015-12-07

1. A brief update of current status of dengue vaccine

candidates under clinical trials.
2. A short introduction of lipidated subunit vaccine using
the domain III of dengue E protein developed by
NIIDV in NHRI Taiwan.
3. Brief discussion of weighting the possibility to conduct
clinical trials in Taiwan especially for the elders.

2015/12/8

1. Dengue is a mosquito-borne flavivirus disease

that has spread to most tropical and many
subtropical areas.
2. The disease is caused by four closely related
viruses, the Dengue viruses 1-4.
3. Since there are no specific dengue therapeutics,
prevention is currently dependent merely on
vector control measures.
4. A dengue vaccine would therefore represent a
major advance in the control of the disease

The growing global epidemic of dengue is of

mounting concern, and in addition to vector
control, a safe and effective vaccine is urgently
needed. Vaccines are expected to be an
integrated part of the Global dengue
prevention and control strategy campaigned by
WHO (2012-2020).

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2.
3.
4.

Challenges to vaccine development

Infection by one of the four dengue virus serotypes has been
shown to confer lasting protection against homotypic reinfection, but not against a secondary heterotypic infection.
Moreover, secondary heterotypic infection is associated with
an increased risk of severe disease, likely via mechanism of
immune enhancement.
Due to these dengue-specific complexities, vaccine development
focuses on the generation of a tetravalent vaccine aimed at
providing long-term protection against all virus serotypes.
Additional challenges are posed by the lack of an appropriate
animal disease models and the resulting uncertainty makes
difficult to predict protection efficacy and to understand
dengue pathogenesis.

Status of vaccine development

Nat Biotech 2014

Require three doses (0-6-12 month) of immunization protocol.

Overall efficacy is 56.5% in Asia and 60.8% in Latin America.
The serotype specific efficacy for dengue-2 (43%) was not significant high enough as expected.
6
However, CYD-TVD were overall not toxic and the hospital-visit rates in general were significantly lower for vaccinated groups.

(NEJM 2015)

Unanswered paradoxes about CYD-TDV

1. Unlike other live attenuated vaccines in use, it is
currently unknown why Sanofi CYD-TDV needs multiple
immunization protocol.
2. The high neutralizing capability tested in-vitro from
CYD-TDV-immunized participants does not correlate
well to vaccine efficacy.
3. It is unclear why CYD-TDV were less effective for
nave participants than re-infected vaccinee.

Key considerations of a licensed dengue vaccine include vaccine

safety, vaccine efficacy, disease burden, suitable vaccination
program, including dose scheduling, and cost-effectiveness.
It is important to conduct an integrated efficacy analysis and
interim long-term follow up for the given vaccine candidates
through carefully planned phase III trials.

A safe, effective and affordable dengue

vaccine for the disease control could be an
important tool for reaching the WHO goal of
reducing dengue morbidity by at least 25% and
mortality by at least 50% by 2020.

What are the implications for

future vaccine candidates?
We do not clearly understand the relationship between vaccine-induced
immune response, individual characteristics, and disease risk, so it is
therefore unknown whether similar safety and efficacy profiles of Sanofi
CYD-TDV would be seen with other candidate dengue vaccines, currently
none of which have yet been evaluated in Phase III trials.
Clinical trials of future dengue vaccine candidates will also need to
carefully monitor efficacy and safety over time among different subsets of
the trial population. Continued efforts for dengue vaccine development are
needed to address the growing burden of dengue globally.

Subunit dengue vaccines with intrinsic adjuvant activity by lipidation

platform technology developed by NHRI, Taiwan

Subunit vaccine (recombinant lipidated dengue envelope protein domain III).

No live components of pathogens.
Exogenous adjuvant-independent.
Reducing the potential risk of antibody-dependent enhancement of infection

 Dengue infections cause more severe DHF for the elderly (median age
76) and patients with underlined chronic diseases (co-morbidity) in
Taiwan.
It may be worth to address whether a preventive intervention by
using any given vaccine candidates has a beneficial effect for such
high-risk populations in Taiwan.
It needs to investigate whether the previous infection for the elders
during 1942 endemic in Taiwan plays a role in high-risk dengue caused
death.
On the other hand, in Taiwan whether this elder population (age > 70) is
more suitable to be enrolled for vaccine clinical trial should be carefully
addressed.

Thank you!