DENGUE VACCINES

January 8, 2019

Dengue Vaccines: Vaccine development, ongoing challenges and current status.

Written By: Maria Imran Ali (PUCP)

Summary:       

Dengue is among the most important and prevalent arbovirus disease of humans. In order to effectively control this disease, control of the vector mosquitoes and a safe and efficacious vaccine are critical. Despite considerable efforts, the development of a successful vaccine is still elusive.

Multi factors have complicated the creation of successful vaccines. Despite the multiple impediments, there are currently many promising vaccine candidates in pre-clinic and clinical development.

BACKGROUND:

Dengue Virus (DENV) causes a self-limited illness, dengue fever, and a less common syndrome manifested variably by:

  • Organ failure
  • Hemorrhage
  • Capillary leakage
  • Shock & death

DENV is a globally important pathogen. Roughly 2/5 of the world’s population lives in areas that are at risk for DENV transmission. According to WHO:

“In 2012, dengue ranks as the most important mosquito-borne viral disease with an epidemic potential in the world. There has been a 30 fold increase in dengue incidence during the past 50 years, and its human and economic costs are staggering.”

Dengue Vaccine Research:

The disease is caused by four closely related viruses, the dengue viruses 1-4. There is no specific dengue therapeutics and prevention is currently limited to vector control measures. A dengue vaccine, therefore, represents a major advance in the control of the disease.

Status of Vaccine Development:

The first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was first registered in Mexico in December 2015. CYD-TDV is a live recombinant tetravalent dengue vaccine that has been evaluated as a 3-dose series on a 0/6/12 month schedule in Phase III clinical studies. It has been registered for use in individuals 9-45 years of age living in endemic areas.

There are approximately five additional candidates under evaluation in clinical trials, including other live attenuated vaccines, as well as a sub-unit, DNA and purified inactivated vaccine candidates. Additional technological approaches, such as virus-vectored and VLP-based vaccines, are under evaluation in pre-clinical studies.

The growing global epidemic of dengue is of mounting concern, and a safe and effective vaccine is urgently needed. WHO expects vaccines to be an integrated part of the Global Dengue prevention and control strategy (2012-2020).

“-WHO report: global strategy for dengue prevention and control, 2012-2020”

Challenges to Vaccine Development:

Infection by one of the four dengue virus serotypes has been shown to confer lasting protection against homotypic re-infection, but only transient protection against secondary heterotypic infection. Moreover, secondary heterotypic infection is associated with an increased risk of severe disease. This and other observations suggest an immunopathological component in dengue pathogenesis, which is referred to as immune enhancement of disease. 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.

Figure:

Potential mechanisms for the immune-mediated enhancement of DENV infection. A) Immune responses following primary DENV infection include infection of monocytes and other antigen presenting cells which produce cytokines/chemokines and present antigen to lymphocytes. Type-specific and cross-reactive B and T lymphocytes are activated. B lymphocytes produce serotype-specific, neutralizing antibodies as well as cross-reactive, weakly or non-neutralizing antibodies. B) Following secondary heterogonous infection, uptake of DENV is facilitated through binding of cross-reactive, non-neutralizing antibodies from a previous infection (or maternally derived antibodies in the case of primary infection in infants). Additionally, there is activation of cross-reactive T cells that produce skewed cytokine responses and demonstrate decreased cytotoxicity for DENV infected cells. Massive quantities of pro-inflammatory cytokines (“cytokine storm”) result in increased vascular permeability and plasma leakage. Furthermore, expression or release of DENV-NS1 by infected cells may mediate complement activation resulting in increased vascular permeability.

 

Additional challenges are posed by the lack of an adequate animal disease model and the resulting uncertainty around correlates of protection.

In spite of these challenges, vaccines development has made remarkable progress in recent years, and the current dengue vaccine pipeline is advanced, diverse and overall promising.

The impediments can be briefly listed as follows:

  1. The epidemiology of the four DENV serotypes.
  2. The complex and incompletely understood immune-protective and/or immune-pathogenic responses following natural infection or vaccination.
  3. A lack of validated animal models of disease.