Dengue virus (DENV), a member of the genus Flavivirus, is the causative agent of dengue fever and the more severe and potentially life-threatening dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). DENV is endemic in South and Central America, Southeast Asia and Sub-Saharan Africa, and is one of the World Health Organization’s top ten threats to global health in 2019. Approximately half of the world is at risk of dengue, which is estimated to cause 390 million infections and 20,000 deaths globally each year.
In Malaysia, in year 2020, the cumulative number of 90,304 dengue cases with 145 deaths has been reported. The cumulative number of 130,101 dengue cases with 182 deaths has been reported in 2019. Dengue cases and deaths in Malaysia (2000 – 2019) is shown below in Figure 21.4.1. Dengue cases reported weekly in 2019 and 2020 is shown below in Figure 21.4.2.
Dengue is spread by Aedes aegypti and Aedes albopictus mosquitoes. There are 4 genetically and immunologically distinct serotypes: dengue-1 virus (DENV1), dengue-2 virus (DENV2), dengue-3 virus (DENV3) and dengue-4 virus (DENV4). The prevalence of individual serotypes varies across different regions, countries, seasons and over time. Recovery from infection by one serotype provides lifelong immunity against only that serotype, and subsequent infections by heterologous serotypes give rise to the potential immunopathology of severe dengue due to antibody-dependent enhancement. Patients with a second dengue infection with a different serotype are at increased risk for severe dengue. One of the challenges to the development of a dengue vaccine is that it must induce immunity to all 4 serotype.
Clinical manifestations range from mild febrile illness to severe dengue manifested by plasma leakage, haemorrhagic tendencies, organ failure, shock, and possibly death. Fatality rates are around 0.1% to 1% in hospitalised cases. Prevention and control are based on mosquito vector control programmes and treatment is limited to supportive care. Vaccination represents a major opportunity to control dengue. Vaccination would be a part of an integrated approach in the fight against dengue, with strategies including vector control, environmental management and best clinical practices.
The majority of people living in high endemic areas have been infected by dengue by the time they reach adolescence. About 75% of dengue infections could be asymptomatic so most people may not know they had a previous dengue infection. For people who have had a previous dengue infection, vaccination should confer strong and persistent protection against dengue hospitalisations and severe disease.
Currently there are no WHO pre-qualified vaccines against dengue.
Dengue Cases and Deaths in Malaysia (2000-2019)
Figure 20.4.1 Dengue cases and deaths in Malaysia (2000-2019)
Figure 20.4.2 Dengue cases reported weekly in 2019 and 2020, Ministry of Health, Malaysia
Figure 20.4.3 Age-specific dengue incidence rate per 1000 population, Malaysia, Year 2013
Source: Woon YL et al. “Estimating dengue incidence and hospitalization in Malaysia, 2001 to 2013.” BMC Public Health (2018). 2018;18(1):946.
A dengue vaccine, Dengvaxia®. (CYD-TDV), was developed by Sanofi Pasteur. CYD-TDV is a tetravalent live recombinant chimeric dengue vaccine, based on the yellow fever 17D backbone. It is given as a 3-dose series on a 0, 6 and 12 months schedule for individuals 9-45 years of age living in endemic areas. It was first licensed in Mexico in December 2015, and is now licensed in some countries for people age 9-45 years old, including neighbouring countries Singapore, Indonesia, and Thailand.
A retrospective analysis of data from clinical trials using a newly developed NS1-based antibody assay, became available in November 2017. The findings showed that the vaccine raises the risk for severe dengue and hospitalisation in people with no prior exposure to the virus (seronegative vaccine recipients) compared to seronegative non-vaccinated individuals, while confirming long-term protection in seropositive individuals. The relative risk of getting severe dengue from a mosquito bite post-vaccination for a study participant 9 years of age or older who had no prior infection was similar to that seen in an unvaccinated person who gets a secondary infection. The findings also confirm the vaccine’s population-level benefit and potential to prevent dengue, particularly severe dengue (84%) and hospitalisations due to dengue (80%) for the 5-year follow-up period of the study in individuals 9 years of age or older who have had a prior dengue infection. An update to the prescribing information was issued for the vaccine, recommending use in individuals with prior dengue infection and warning against vaccination of those without prior infection.
The Philippines is among the countries, including Mexico, El Salvador, Brazil, Singapore and Costa Rica, where CYD-TDV has been approved for marketing. Philippines had vaccinated more than 800,000 children with CYD-TDV since 2016 when it became the first country to start using it on a mass scale. CYD-TDV has been granted priority review by the FDA. In May 2019, FDA approved Dengvaxia®. CYD-TDV for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas.
About five other dengue vaccine candidates are in clinical development, with two candidates (developed by Takeda and NIH/Butantan) now in Phase 3 trials. The candidate dengue vaccines in development include recombinant, live attenuated, inactivated, DNA and viral-vector vaccines.
- TAK-003 or DENVax
TAK-003 or DENVax is a recombinant chimeric tetravalent vaccine originally developed at Mahidol University in Bangkok and now funded by Takeda (TAK-003) and Inviragen (DENVax). TAK-003 is based on a live-attenuated DENV2 PDK53 (dengue virus type 2, passaged 53 times in primary dog kidney cells), which provides the genetic “backbone” for all four vaccine viruses, i.e. chimeric DENV1, DENV3 and DENV4 components on DENV2 backbone.
Phase 1 and 2 trials were conducted in the United States, Colombia, Puerto Rico, Singapore and Thailand. Based on 18-month data published earlier, TAK-003 produced sustained antibody responses against all four dengue serotypes, regardless of previous dengue exposure (both seropositive and seronegative participants) and dosing schedule. In the phase 2 randomized, placebo-controlled trial published in July 2020, TAK-003 was reported to be safe and well tolerated, and persistence of neutralizing antibody titers were demonstrated over 3 years in children and adults living in dengue-endemic countries. Seropositivity rates were 97.3%, 98.7%, 88% and 56% for DENV-1, -2, -3 and -4, respectively.
In January 2019, Takeda announced TAK-003 had met the primary endpoint in a pivotal Phase 3 clinical trial being conducted in Latin America (Brazil, Colombia, Dominican Republic, Nicaragua and Panama) and Asia (Philippines, Sri Lanka and Thailand). TAK-003 was found to be efficacious in children and adolescents living in dengue-endemic countries, in preventing symptomatic dengue of any severity caused by any of the four dengue virus serotypes up to 15 months after administration of the first vaccine dose. TAK-003 is not yet licensed anywhere in the world.
TDENV PIV is a tetravalent purified inactivated vaccine undergoing phase I trials as part of a collaboration between GSK and the Walter Reed Army Institute of Research (WRAIR). A prime-boost strategy (synergistic formulation with another live attenuated candidate vaccine) is under evaluation in a phase II trial. In prime-boosting, one type of vaccine is followed by a boost with another type in an attempt to improve immunogenicity.
V180 is a recombinant subunit vaccines by Merck, expressed in Drosophila S2 cells. Studies are in phase I stage in 2015.
The Naval Medical Research Center (NMRC) developed a monovalent plasmid DNA vaccine, D1ME100, but results in phase 1 proof-of-concept trial showed it to be only moderately immunogenic.
TetraVax-DV is a live attenuated (recombinant) tetravalent vaccines, admixture of monovalent vaccines developed by the National Institute of Allergy and Infectious Diseases, National Institues of Health (NIAID). Several monovalent vaccines were tested separately for safety and immunogenicity. TV003 and TV005 candidate vaccines completed phase 1 trials and are being tested in phase 2 studies in Thailand and Brazil. In Brazil, the phase 2 studies are being done in collaboration with the Butantan Institute.
Other vaccines by manufacturers in India and Vietnam
Panacea Biotec and Biological E. Limited have vaccine candidates in the earliest stages of development. A company in Vietnam (Vabiotech) is conducting safety tests and developing a clinical trial plan. All three companies are involved in studies of a TetraVax-DV vaccine in conjunction with the National Institutes of Health (NIH).
Vaccines Available in Malaysia
There are no dengue vaccines available currently. In Malaysia, Dengvaxia®. (CYD-TDV) was approved for conditional registration in April 2017, for a postregistration (Phase IV) clinical study for two years involving volunteers aged 9-45. These followed evaluation results in two Phase 3 clinical trials (CYD14 in five countries in Asia and CYD15 in five countries in Latin America).
The approval was given for the vaccine to be used in Phase IV clinical trials to get more information on vaccine safety, in which Sanofi Pasteur has to meet seven conditions before the product can be registered in Malaysia. However, the product did not fulfil all the stipulated conditions within the conditional registration period and hence, the registration was not continued.
Mode of Administration
- CYD-TDV is recommended as a 3-dose series given over a 12-month period (months 0, 6 and 12), by subcutaneous administration.
- Should a vaccine dose be delayed for any reason, it is not necessary to restart the course and the next dose in the series should be administered as soon as possible.
Contraindications and Adverse Effects
The manufacturer stipulates that vaccination is contraindicated in:
» individuals with a history of severe allergic reaction to any component of the dengue vaccine or after prior administration of the dengue vaccine or a vaccine containing the same components.
» individuals with congenital or acquired immune deficiency that impairs cell-mediated immunity.
» individuals with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function.
» pregnant or breastfeeding women.
CYD-TDV is not recommended in pregnant and lactating women because insufficient data are available on the use in pregnancy and lactation. However, no evidence of increased adverse pregnancy outcomes has been identified in the limited data generated from inadvertent vaccination of pregnant women that occurred during clinical trials.
- CYD-TDV is contraindicated in immunocompromised individuals due to lack of data.
The Strategic Advisory Group of Experts (SAGE) on Immunization issued an updated recommendation on Dengvaxia®. vaccine in April 2018, and the WHO Position Paper was published in September 2018, for countries considering vaccination as part of dengue control strategy.
Dengue vaccination should be considered as part of an integrated strategy for dengue prevention and control. In countries or areas with high burden disease, vaccination should only be recommended when the potential benefits outweigh the potential risks, and between population-level benefit versus individual-level risk.
- The likelihood of prior dengue infection in an individual before vaccination needs to be evaluated, and measures to minimise the risks among seronegative persons, where seronegative persons should not be vaccinated.
The challenge is how to use the currently available CYD-TDV to maximise the public health impact, minimize harm and restore public confidence in dengue vaccines. Two main strategies are to be recommended for the vaccine to be further used in public programs:
i. Pre-vaccination screening and vaccinating only those tested seropositive based on a screening test, or in some cases based on a documented laboratory-confirmed dengue infection in the past. This strategy is the preferred option, and may also be considered in low to moderate transmission settings, or
ii. Subnational or national mass vaccination strategy based on population seroprevalence criteria, without individual pre-vaccination screening, for areas of high dengue burden i.e. areas with recent documentation of seroprevalence rates of at least 80% by age 9 years.
These two approaches have limitations, for different reasons and with different implications, and achieving high population protection from dengue remains a challenge.
i. Implementation of a pre-vaccination screening strategy with the currently available tests will require careful assessment, including consideration of the sensitivity and specificity of the tests and dengue epidemiology, country-specific dengue hospitalization rates, logistics issues and affordability of both screening tests and CYD-TDV.
ii. Screening tests would need to be highly specific to avoid vaccinating truly seronegative persons and to have high sensitivity to ensure that a high proportion of seropositive persons are vaccinated.
iii. Implementation of a seroprevalence criterion without individual screening will require serological surveys and mapping at high resolution, i.e. at district and sub-district level, to identify subnational areas with high disease burden or high seropositivity rates.
iv. Communication needs to ensure appropriate and full disclosure of:
• the limitations of the screening test to those offered vaccination.• the risks of vaccination of persons with unknown serostatus.
The optimal age group to be targeted is the age before severe dengue disease incidence is highest, which can be assessed from data such as the national and subnational routine hospital laboratory-confirmed surveillance data.
Catch-up immunisation for other age-groups in areas with high disease burden may be necessary to control dengue. Disease-reporting data would be required to determine immunisation strategies and identify age groups for catch-up immunisations.
There are currently no guidelines for dengue vaccination in travelers.HCWs are not at increased risk for dengue and they should follow the vaccine recommendations for adults based on age or other relevant risk factors.
Research to be prioritised on the development of highly sensitive and specific, rapid screening tests to determine serostatus.
- Assessment of simplified immunization schedules and the need for booster doses should also be prioritized. There is currently no recommendation for a booster dose.
Evidence of Effectiveness
- Candidate vaccines in clinical trials appear to have acceptable short-term safety profiles. However, their long-term safety and duration of protection are yet to be confirmed. Severe disease due to vaccine failure and vaccine-induced immune enhancement of disease may be indistinguishable in individual vaccinees and benefit-risk assessments will have to rely on epidemiological studies. Both human host and viral factors could theoretically influence vaccine safety and merit careful evaluation in longterm safety assessments of dengue vaccines.
- Findings of the first phase 2b efficacy study in Thailand, of the Sanofi Pasteur CYD TDV was a major milestone which showed acceptable safety and neutralising antibody immunogenicity profile.
- The Asian Phase III trial (CYD14) evaluated the efficacy and safety of Sanofi’s CYD TDV in 10,275 healthy children aged 2-14 years in Malaysia, Indonesia, the Philippines, Thailand and Vietnam. Results reported in July 2014 showed efficacy of 56.5% against virologically confirmed dengue as observed during 25 months of active surveillance. The data showed good serotype-specific protection, with better protection shown against DENV3 and DENV4 (75%). However, it showed less protection against DENV1 (50%) and least to DENV2 (35%). It is 88% effective against dengue haemorrhagic fever. Vaccine efficacy was statistically significant for all serotypes except DENV2 and vaccine safety was reassuring. The results also provided new insights in exploratory analyses, showing an increase in vaccine efficacy with age and a reduction of risk of severe disease in vaccinated children.
The final landmark Phase III study (CYD15) conducted on 20,875 children aged 9-16 across 5 countries in Latin America – Brazil, Columbia, Honduras, Mexico and Puerta Rico was reported in September 2014. It confirmed that the vaccine was safe and provided high protection against dengue haemorrhagic fever. There was 80.3% lower risk of hospitalisation for dengue. Overall vaccine efficacy was 60.8%, and efficacy was observed against each of the 4 dengue serotypes. Efficacy was 42.3% against DENV2 compared to 35% in the Asian trial. As in the Asian trial, the vaccine was more effective in people previously exposed to dengue, making the vaccine particularly useful in endemic areas.
- Together, these CYD14 and CYD15 trials included over 35,000 participants aged 2 to 16 years. Vaccine efficacy against confirmed dengue pooled across both trials was 59.2% in the year following the primary series (per protocol analysis). During this initial time period, pooled vaccine efficacy against severe dengue was 79.1%. Efficacy varied by serotype: vaccine efficacy was higher against serotypes 3 and 4 (71.6% and 76.9%, respectively) than for serotypes 1 and 2 (54.7% and 43.0%). Vaccine efficacy varied by age, dengue serotype, disease severity, and whether or not individuals had a previous natural dengue infection at vaccination. Vaccine efficacy against virologically confirmed dengue, over 25 month period from the first dose among 9-16 year-olds was 65.6% and in this age group severe dengue was reduced by 93% and hospitalisations with dengue by 82%.
- On 29 November 2017, Sanofi Pasteur announced the results of additional studies conducted to better describe the benefit-risk in seronegative individuals. A newly developed NS1-based antibody assay, which could distinguish prior vaccination from prior infection, was applied to serum samples taken 13 months after vaccination. This enabled the serostatus prior to vaccination to be inferred retrospectively, and enabled estimation of the efficacy and long-term safety of the vaccine by serostatus.» Overall population level benefit is favourable
» CYD-TDV was found to perform differently in seropositive versus seronegative individuals. Vaccine efficacy (VE) against virologically-confirmed symptomatic dengue was high among inferred baseline seropositive participants aged 9 years or older: 76%, but much lower among baseline seronegative participants: 38.8% in the first 25 months after the first dose of vaccine.
» In the approximate 5 year follow-up period after the first dose of vaccine, an overall higher risk of severe dengue and hospitalizations from dengue was observed in vaccinated seronegative trial participants of all ages compared to unvaccinated seronegative trial participants.
» Clinical manifestations and relative risk of severe dengue were similar in vaccinated seronegative persons compared to unvaccinated seropositive persons, consistent with the working hypothesis that CYD-TDV mimics a primary-like infection.
- Further data from Phase IV trials on CYD-TDV will provide further information for long-term duration of protection, vaccine safety and impact on dengue transmission, among other concerns.
- Takeda’s TAK-003 vaccine was assessed in a double-blind, randomised and placebo-controlled Phase 3 trial, Tetravalent Immunisation against Dengue Efficacy Study (TIDES). This trial was designed to evaluate the efficacy, safety and immunogenicity of two doses of the vaccine. It is given subcutaneously three months apart in over 20,000 children and adolescents aged 4 to 16 years (both dengue exposed and naive individuals) living in dengue-endemic areas, in Latin America and Asia.
» The pivotal Phase 3 TIDES trial includes analysis on overall vaccine efficacy and assessment of secondary efficacy endpoints by serotype, baseline serostatus and disease severity (18 months after the second dose, which was administered three months after the first dose). Results demonstrated protection against virologically confirmed dengue (VCD) in children ages four to 16 years (overall efficacy was 73.3% [95% confidence interval (CI): 66.5% to 78.8%]. TAK-003 was generally well tolerated, and results were consistent with previously reported safety, immunogenicity and efficacy data for TAK-003.
» Results of DEN-204 study, the phase 2 randomised, placebo-controlled trial of TAK-003 tetravalent dengue vaccine was published in the Lancet in March 2020. TAK-003 elicited antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus. The results provide a long-term safety database and support further assessment of the vaccine in the ongoing phase 3 efficacy study. Further findings will help determine the potential utility of the Takeda vaccine as a tool in dengue prevention and form the basis for filing for licensure.
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