According to a WHO 2019 statement, Dengue fever is considered one of the top 10 threats to health in the world. Dengue fever is a painful, debilitating mosquito-borne disease caused by any of the four closely related dengue viruses (DENV1-4). The existence of four DENV serotypes means a person can be infected four times in his/her lifetime, with the disease thought to spread by several species of female mosquitoes of the Aedes genus i.e. Aedes aegypti.
According to WHO estimates, around half of the world’s population is at risk and an estimated 100-400 million infections occur every year. The majority of the cases happen in tropical and sub-tropical areas including the Indian subcontinent, Southeast Asia, Southern China, Taiwan, The Pacific Islands, The Caribbean (except Cuba and the Cayman Islands), Mexico, Africa, and Central and South America (except Chile, Paraguay, and Argentina).
To date, there is no medicine available for the treatment of Dengue. Only symptoms associated with it can be treated. However, medical professionals and organizations have suggested various preventive therapies. One of the key approaches is to protect someone from mosquito bites by using insect repellent and wearing clothes with long sleeves. Another less famous but emerging therapy is having a vaccination.
Right now, there is only one commercially available vaccine in the world: Dengvaxia, a live recombinant tetravalent dengue vaccine, developed by Sanofi Pasteur. It is approved for patients aged 9 to 45 years old in a 3-dose series regimen: a 0/6/12 month schedule. More so, it is a suspension for injection (supplied as a lyophilized powder to be reconstituted with its supplied diluent). The single dose, after reconstitution, is 0.5 ml. Dengvaxia was initially approved in Mexico in 2015, then in the EU in 2018, and the US in 2019. Following these approvals, it also got licensed in another 20 countries.
However, in 2018, a big controversy surrounded Dengvaxia. In the Philippines, Dengvaxia was shown to increase the risk of disease severity for some people who had received it. A vaccination program had been run by the Philippine Department of Health (DOH) who had administered Sanofi Pasteur’s Dengvaxia to schoolchildren. The program was stopped when Sanofi Pasteur advised the government that the vaccine could put previously uninfected people at a somewhat higher risk of a severe case of dengue fever. A political controversy erupted over whether the program was run with sufficient care and who should be held responsible for the alleged harm to the vaccinated children. In late November 2017, the DOH suspended the school-based vaccination program. The DOH subsequently banned the vaccine’s use and sale in the Philippines. The scare, however, caused by the controversy, has been suggested as a factor in the country’s loss of confidence in vaccines and low immunization rates, resulting in an infectious disease crisis in the country in 2019, including a measles outbreak.
Following this controversy, the WHO recommended various updates for using Dengvaxia in the future. According to their recommendation, it can only be given to patients who have been previously been infected with the virus (seropositive patients) because if given to patients who were not previously infected (seronegative patients) it is thought to be able to cause risks of severe dengue.
Currently, the biggest challenge for upcoming vaccines is to be equally effective in both seropositive and seronegative patients. Some of the molecules in the pipeline are working on the same aspect as well. Some late-phase molecules include:
- TAK-003:
- Developed by Takeda
- TAK-003, a tetravalent dengue vaccine, is based on a live-attenuated dengue serotype 2 virus, which provides the genetic “backbone” for all four vaccine viruses,
- TAK-003 was found equally effective in seronegative patients as well as in seropositive patients (one of the biggest flaws of Dengvaxia). Another advantage over Dengvaxia is the dosing schedule of TAK-003: two-dose schedule (0 and 3 months) vs. Dengvaxia’s three-dose schedule (0, 6, 12 months) and the wider target age range (4-16 years), which will address the unmet need of providing an immunization strategy for younger children.
- Recently, the EMA accepted the company’s filing package and is also due to conduct the first-ever parallel assessment of Takeda’s Dengue Vaccine Candidate (TAK-003); for use in the EU; countries outside of the EU through the EU-M4all (Previously Article 58) Procedure.
- Takeda also intends to submit regulatory filings in Argentina, Brazil, Colombia, Indonesia, Malaysia, Mexico, Singapore, Sri Lanka, and Thailand during 2021.
- TV003/TV005 (or TetraVax-DV):
- TV003/005 was initially developed by the US National Institute of Allergy and Infectious Diseases (NIAID). Later licensed to:
- The Butantan Institute in Brazil, where it is in Phase III trials
- Merck & Co in the US, Canada, China, Europe and Japan, and
- Various other developers in India (e.g. Serum Institute and Panacea Biotech), the Middle East and Asia-Pacific markets, with the goal of ensuring market access by facilitating cheaper domestic production in key dengue-endemic regions
- Phase III trial in Brazil is expected to be completed in H2 2021.
- Expectations from TV003/005 to beat TAK-003 and Dengvaxia
- Better efficacy results and a strong response against DEV-3 where TAK-003 did not show good efficacy
- Another advantage with TV003/005 is its single dosing schedule compared to the two dosing regimens of TAK 003 and three dosing regimen of Dengvaxia.
- TV003/005 was initially developed by the US National Institute of Allergy and Infectious Diseases (NIAID). Later licensed to:
There are other vaccine candidates as well in the early phases of development. However, the upcoming vaccines are trying to cover the flaws of the previous vaccines. Still, there other significant unmet needs and challenges when it comes to Dengue treatment:
- Inefficient diagnostics
- Inefficient clinical monitoring
- No availability of therapeutics
- Improved real-time molecular characterization of dengue viruses
- Lack of wearable technology to measure vitals during dengue treatment
Whether a vaccine will be able to cover the majority of the listed unmet needs is still a question in everybody’s mind. But as we say ‘precaution is better than cure’; the scientific and medical communities continue to hope that upcoming vaccines will be able to provide a shield to a larger part of the population.
#dengue #vaccines #infectiousdiseases
Sources
https://www.mayoclinic.org/diseases-conditions/dengue-fever/symptoms-causes/syc-20353078
https://www.cdc.gov/dengue/symptoms/index.htm