Efficacy and Safety of Dengue Vaccine

Dengue vaccine is one of the latest vaccines that is expected to show benefits in dealing with dengue fever. However, the issue of withdrawing vaccines at the end of 2017 makes its safety questionable.

Dengvaxia®

Dengue vaccine (later patented by the name Dengvaxia®), is a combination of chimeric yellow fever and dengue viruses (DENV) 1, 2, 3, and 4. The preclinical vaccine development was carried out for 10 years by OraVax (Cambridge, MA) and then continued by Acambis Inc. In 2005 Sanofi Pasteur bought the company and took over and continued the development and research of the dengue vaccine, which was later patented under the name Dengvaxia®. The Dengue vaccine, Dengvaxia®, was declared safe and was received by Brazil, El Salvador, Mexico, and the Philippines in 2015.

Efficacy of Dengue Vaccine

Phase 3 research of the Dengvaxia® vaccine was conducted in five Asian countries (CYD14) and five Latin American countries (CYD15) involving more than 35,000 participants aged 2 to 16 years in total. Dengvaxia® vaccination carried out in three doses at the 0th, 6th, and 12th months.

Participants in five Asian countries (CYD14) were 2-14 years old at the time of the first vaccination. Participants in five Latin American countries (CYD15) were 9-16 years old at the time of the first vaccination. In each study, participants were randomly divided into two groups, namely the treatment group and the control group, with a ratio of 2: 1. Participants were actively followed up 1 year from the last dose of vaccination (25 months after the first dose of vaccination) and hospital-based follow-up for 4 years, which is still ongoing.

The results collected from the two studies (CYD14 and CYD15) showed that the efficacy of the Dengvaxia® vaccine against severe dengue cases was 79.1%. Vaccine efficacy varies, depending on serotype; vaccine efficacy was higher for serotypes 3 and 4 (71.6% and 76.9% respectively) when compared to serotypes 1 and 2 (54.7% and 43.0% respectively). The efficacy of vaccines also depends on the age and serotesting status at the time of vaccination (had been infected by dengue before).

Vaccine efficacy in severe cases of hospitalization and dengue was recorded in the 1st and 2nd year after the first dose. But in the 3rd year, there was an increase in the risk of severe cases of hospitalization and dengue in the group of participants aged 2-5 years in the CYD14 study in Asian countries. 15 cases were recorded in the treatment group and 1 case in the control group.

In the age group of 9 years and over, at 25 months after the first dose in the 3rd phase trial, there was a 93% reduction in severe dengue cases and an 81% reduction in hospitalization cases. Therefore, the age group below 9 years is not included in the Dengvaxia® vaccine indication.

Is Dengue Vaccine Safe?

The Dengvaxia® vaccine has been shown to provide good protection benefits to individuals with positive serotesting or who have previously been infected with dengue. Temporarily terminating the Dengvaxia® vaccine in the Philippines follows the results of exploratory studies that show that there is an increased risk of hospitalization and severe dengue in individuals with negative serotesting or who have never been infected with dengue before. 

WHO, through the Strategic Advisory Group of Experts (SAGE), which is the WHO advisory body in the field of vaccination, recommends seroprevalence thresholds as the best strategy at the population level. Based on mathematical calculations, optimal seroprevalence for the age group targeted by vaccination is in the range of ≥70%. WHO requested Sanofi Pasteur to conduct further research and provide data on the efficacy and safety of the Dengvaxia® vaccine to seronegative groups of individuals.

Further Research Regarding Dengue Vaccine

In the third phase of the Dengvaxia® vaccine study, Sanofi Pasteur did not collect blood samples to determine the serostatus before vaccination. Sanofi Pasteur conducted additional tests to collect the blood of all participants in the 13th month (1 month after the 3rd dose was received).

The blood sample is then tested with an assay that recognizes antibodies to the non-structural dengue protein code (NS1). Serostatus of participants before vaccination can still be determined (even though all participants have received the vaccination) because the non-structural protein code for Dengvaxia® is the Yellow Fever vaccine protein code.

Following the test results, Sanofi Pasteur re-analyzed to determine the safety and efficacy of the Dengvaxia® vaccine according to the seronegative or seropositive status of each individual before vaccination.

There are already five other dengue vaccine candidates, with 2 candidates (each developed by Butantan and Takeda) starting the third phase of research in early 2016. The dengue vaccine developed by Butantan and Takeda is significantly different from Dengvaxia®, so the benefits and safety of the two vaccines are not yet certain.

Source picture: https://doj.gov.ph/news_article.html?newsid=621

1. S.B. Halstead, The American Journal of Tropical Medicine and Hygiene, 2016; 95(4):741-745. Available on http://www.ajtmh.org/content/journals/10.4269/ajtmh.16-0222 - html_fulltext

2. Questions and Answers on Dengue Vaccines. Available on http://www.who.int/immunization/research/development/dengue_q_and_a/en/

3. Updated Questions and Answers Related to Information Presented in The Sanofi Pasteur Press Release on 30 November 2017 with Regards to the Dengue Vaccine Dengvaxia®. Available on http://www.who.int/immunization/diseases/dengue/q_and_a_dengue_vaccine_dengvaxia/en/