2023-06-08 21:10:47
The commercialization of a vaccine against dengue in Belgium (Qdenga®) led to one advice from the Supreme Health Council (SHC).
The SHC recommends vaccination against dengue in those who travel for more than 4 weeks or frequently to high-risk areas, but only for those who have had dengue in the past. This target group was chosen because the risk of serious dengue progression is greater with a secondary infection. In addition, the effectiveness of the vaccine is less good in people who have not yet come into contact with dengue and the safety is also less clear. The vaccination schedule must be completed before departure.
A number of uncertainties remain, including the real-life protection for travelers from non-endemic areas and the exact duration of protection against the different dengue serotypes. History and risk of previous exposure provide some guidance in the decision to vaccinate the traveller, but the lack of a reliable serological test is a disadvantage.
The mosquito repellent measures also remain important for vaccinees.
Of Supreme Health Council (SHC) published an opinion on this in April 2023 vaccination against dengue (dengue fever) in the context of travel: Advice 9739 (April 2023).1 It Institute of Tropical Medicine already included the recommendations in its travel advice: Wanda for doctors > Dengue (English) in Wanda for travelers > Dengue vaccination.2
The advice of the SHC follows the commercialization in March 2023 of Qdenga®the first dengue vaccine in Belgium, with als indication the prevention of dengue from the age of 4 years. Qdenga® is a live attenuated vaccine containing the 4 strains (serotypes) of the dengue virus (DENV1,2,3 and 4) [zie Repertorium 12.1.1.16.].
Dengue: course and epidemiology
The virus responsible for dengue becomes transferred by Aedesmosquitoes, which mainly bite during the day. Dengue occurs in (sub)tropical areas (especially Asia, followed by Latin America and Africa3). The 4 serotypes can co-circulate, and many countries are hyper-endemic for multiple subtypes. The incidence has increased sharply in recent decades (400% increase from 2000 to 20133). In 2019, 5.2 million cases were reported to the US World Health Organisation (WHO). According to the WHO, this is a significant underreporting as most cases are asymptomatic. It is estimated that approximately 25% of infections are accompanied by clinical symptoms, in most cases mild to moderate flu-like symptoms. A serious course (progressing to severe bleeding and organ failure) is rare (2–5% of dengue cases, depending on sources4,5), and occurs mainly in a secondary infection, i.e. an infection with a different dengue virus serotype than in the first infection, and in children in an endemic setting. Dengue occasionally occurs travellers, the risk of life-threatening complications is very small. The travel-related infection rate in European travelers in the period 2015-2019 was estimated at 2.8 cases per 100 000 travelers globally and 6.1 cases per 100 000 travelers from Asia6. All cases in Belgium are import cases (202 reported cases in Belgium in 2019, mainly due to serotypes DENV1 and DENV2, and mainly after infection in Asia, see Sciensano). There is no specific antiviral treatment for dengue.
Of mosquito repellent measures also remain important for vaccinees. (See wanda for travelers > mosquito repellent measures) in wanda for travelers > insect repellents (repellents)).
Target groups for vaccination against dengue
The SHC recommends vaccination with Qdenga® in persons from the age of 4 years who travel for more than 4 weeks or frequently to high-risk areas*, I comply with the following criteria:
The person has had a dengue infection in the past. According to the SHC, the evaluation is mainly based on anamnesis and risk of previous exposure (previous travel to or stay in an endemic area). The SHC does not recommend generalized serological screening (insufficient specificity due to cross-reactivity with other flaviviruses). In case of doubt, the SHC recommends consulting an infectious disease specialist.
The vaccination schedule is completed before departure. The schedule consists of 2 subcutaneous injections (preferably in the upper arm near the deltoid muscle) with an interval of 3 months. There is no minimum time span stated between the 2of dose and departure. There are no data on protection or safety when only 1 dose was administered.
* Wanda.be > Dengue defines the areas for which vaccination should be considered, as the darkest red colored countries on the dengue global consensus map.
The advice emphasizes that the expected benefits and the potential undesirable effects of Qdenga® and the uncertainties should be considered discussed with the traveler (see further).
Of price for 1 dose is € 89.70 (not refundedsituation on 01/06/23).
About efficacy and safety and the uncertainties
The efficacy and risks of Qdenga® were briefly discussed in “Novelties” in Folia March 2023. We provide here some details about efficacy, safety and the uncertainties.7-11
The efficacy of Qdenga® was investigated in a double-blind, randomized, placebo-controlled study in children and adolescents in endemic areas (Latin America, Asia/Pacific; children aged 4 to 16 years; n= 19 021; approximately 70% were seropositive at time of vaccination). In this population, the vaccine gives a 80.2% protection against symptomatic infection* (from 1 month to 12 months after 2of dose, primary endpoint) and of 90.4% against dengue hospitalization (from 1 month to 18 months after 2of dose, secondary endpoint). The protection decreases with time, although the protection against hospitalization in the 3of years after vaccination still about 70%. The need for a booster vaccination is currently being investigated.
* Symptomatic infection: Fever or other clinical symptoms deemed by the investigator to be due to dengue, in combination with a positive serotype-specific RT-PCR test.The protection depends on the serotype, with the highest protection against the DENV-2 strain. There are insufficient data to confirm its efficacy against the DENV-4 strain to evaluate.
The protection also depends on the serostatus at the time of vaccination. In the persons who HIV positive at the time of vaccination (i.e. persons who have already had a dengue infection at the time of vaccination) protection is overall higher than in those who were seronegative at the time of vaccination (ie, those who have not had a dengue infection at the time of vaccination). In the seronegatives, there was no protection against the DENV-3 strain. There were even slightly more hospitalizations and severe dengue cases due to DENV-3 in the seronegative vaccinees than in the placebo group, although the difference was not statistically significant (small numbers). However, this signal must be followed. Indeed, with another vaccine against dengue (Dengvaxia®, authorized but not commercialized in the European Union) in the 3of years after vaccination, an increased risk of severe dengue was found when the person was seronegative at the time of vaccination.
The efficacy of Qdenga® in individuals over 16 years of age has been derived from an immunogenicity study in seronegative subjects aged 18 to 60 years in non-endemic areas: the immune response (measured 6 months after the 2of dose) was non-inferior to the immune response in the children and adolescents from the randomized study mentioned above.7 There are no studies in people over 60 years of age.
Unwanted effects are mainly local reactions at the injection site, as well as headache, muscle pain, feeling generally unwell, feeling weak, fever.
Contraindications for vaccination with Qdenga® are persons with immunodeficiency and immunosuppression, pregnant women in women who are breastfeeding (SKP). Also see Directory 12.1. Vaccines > rubric Special precautions > Immunodeficiency or immunosuppression and vaccination. As with other live vaccines, women should not become pregnant in the month following vaccination (see Directory 12.1. Vaccines > rubric Pregnancy and breastfeeding).
Qdenga® can be administered at the same time (but at a different site) as the vaccine against hepatitis A and the yellow fever vaccine. In the co-administration study with the yellow fever vaccine, the immune response to the dengue vaccine was reduced, but the clinical significance of this is not clear.
Conclusion related to the uncertainties
There are no data yet on protection in travellers, nor on protection against symptomatic infection, nor on protection against hospitalization due to dengue.
The exact duration of protection against the different dengue serotypes and the need for a booster vaccination have yet to be determined.
Anamnesis and risk of previous exposure provide some guidance in the decision to vaccinate the traveller, but the lack of a reliable serological test is a disadvantage.
Specialty Names
Sources
1 Superior Health Council. Advice 9739 – Vaccination against Dengue (only available in English). Publication date: 06/04/23
2 Wanda for doctors > Dengue (last update 19/04/2023). Wanda for travelers > Dengue (last update 19/04/2023). Wanda for travelers > Dengue vaccination (last update 19/04/2023).
3 Wilder-Smith A, Ooi EE, Horstick O and Wills B. Dengue. Seminar. Lancet 2019;393:350-63 (doi: https://doi.org/10.1016/S0140-6736(18)32560-1)
4 CDC. Dengue. For Healthcare providers > Clinical presentation (last reviewed: 13/04/23)
5 Halstead S en Wilder-Smith A. Severe dengue in travellers: pathogenesis, risk and clinical management. Journal of Travel Medicine 2019;26:1-15 (doi: 10.1093/jtm/taz062)
6 Gossner CM, Fournet N et al. Dengue virus infections among European travellers, 2015 to 2019. Euro Surveill. 2022;27(2):pii=2001937. https://doi.org/10.2807/1560-7917.ES.2022.27.2.2001937
7 Biswal S, Reynales H, Saez-Lorenz X et al. Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents. N Engl J Med 2019;381:2009–19. 10.1056/NEJMoa1903869)
8 Biswal S, Borja-Tabora C, Vargas LM et al. Efficacy of a tetravalent dengue vaccine in healthy children aged 4–16 years: a randomised, placebo-controlled, phase 3 trial. Lancet 2020; 395: 1423–33 (doi: https://doi.org/10.1016/S0140-6736(20)30414-1)
9 Wilder-Smith A. Comment. Evaluation of a tetravalent dengue vaccine by serostatus and serotype. Lancet 2020;395: 1402-1404 (doi: https://doi.org/10.1016/S0140-6736(20)30603-6)
10 Rivera L, Biswel S, Sáez-Llorens X et al. Three-year Efficacy and Safety of Takeda’s Dengue Vaccine Candidate (TAK-003). Clin Infect Dis 2022;75:107-117 (doi: https://doi.org/10.1093/cid/ciab864)
11 European Medicines Agency. EPAR Qdenga®
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