Guidelines for Adult Immunisation

Upcoming Vaccines​

Dengue

Updated in November 2023

Introduction

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. 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. 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. 

In Malaysia in year 2020, the cumulative number of 90,304 dengue cases with 145 deaths has been reported. The cumulative number of 26,365 dengue cases (70.8% reduction from 2020) with 20 deaths has been reported in 2021(86.2% reduction from 2020). However, the numbers in 2023 are steadily going upwards. Dengue cases and deaths in Malaysia (2000-2021 is shown in Figure 20.1. Dengue cases reported weekly from 2022, 2023, and 5-year median in Malaysia is shown in Figure 20.2. 

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. Dengue outbreaks are associated with serotype shifts. Dengue cases and serotypes in Malaysia (2013-2021) is shown in Figure 20.3. A shift in dominance of DENV1 occurred in 2014-2015, followed by DENV2 dominance in 2017-2018. In year 2021 there was shift in dominance of DENV4 serotype in the country, which may account for the lower rates of death in comparison to the number of cases. 

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 serotypes. 

Clinical manifestations range from mild febrile illness to severe dengue manifested by plasma leakage, haemorrhagic tendencies, organ failure, shock, and 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 and as part of an integrated approach with strategies including vector control, environmental management, and best clinical practices.

 

Figure 20.1 Dengue cases and deaths for 2000-2021 in Malaysia

 

Figure 20.2 Dengue cases reported weekly from 2022, 2023 and median 2018-2022 in Malaysia

Figure 20.3 Dengue cases and serotypes in Malaysia (2013-2021)

Figure 20.4 Age-specific dengue incidence rate per 1000 population, Malaysia, Year 2013

 

Woon YL et al. “Estimating dengue incidence and hospitalization in Malaysia, 2001 to 2013.” BMC Public Health (2018). 2018;18(1):946.

 

Vaccines

 

Several DENV vaccines have been developed and are currently undergoing different phases of clinical trials (Table 20.3) or preclinical investigations. They are based on different platforms including live attenuated viruses, inactivated viruses, chimeric live attenuated viruses, DNA, and recombinant proteins. The three most advanced DENV vaccines (Dengvaxia®, TAK-003 and TV003/TV005) have reached phase III or have been licensed in different countries around the world. 

Effective dengue vaccines must induce strong and highly neutralising response against all four DENV serotypes, to avoid immunopathologic events. The three live attenuated dengue vaccines which have generated clinical endpoint efficacy data have all demonstrated:

  • higher efficacy in dengue immune recipients
  • higher efficacy against more severe clinical phenotypes
  • variance in DENV type-specific efficacy
  • the challenge of capturing data for all desired clinical endpoints (any dengue, severe dengue, hospitalized dengue), across all DENV-1–4 types, in both dengue immune and non-immune recipients.
  1. Dengvaxia® (CYD-TDV)
    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 made using recombinant DNA technology by replacing the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain vaccine with those from the four dengue serotypes. 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 licensed in more than 20 countries, thereafter, including neighbouring countries Singapore, Indonesia and Thailand. Dengvaxia® received EU marketing authorisation in December 2018, for people age 6-45 who have had a previous dengue infection. This followed European Medicines Agency’s (EMA) decision on the benefits being greater than the risks. In May 2019, FDA approved Dengvaxia® for the prevention of dengue disease caused by all dengue virus serotypes  in people ages 9 through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas.

  2. TAK-003 (DENVax, QDenga®)
    TAK-003 is a recombinant chimeric tetravalent vaccine originally developed in 1980s 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.

    The vaccine has already been approved as Qdenga® in August 2022 in Indonesia, where the disease is endemic, for the prevention of dengue disease by any of the four serotypes  in individuals six years to 45 years of age. Qdenga® also received a marketing authorisation valid throughout the EU in December 2022, for people age four and above. The approval follows the positive recommendation from the EMA’s Committee for Medicinal Products for Human Use (CHMP) in October 2022. TAK-003 has been generally well tolerated, with no evidence of disease enhancement in vaccine recipients, and no important safety risks have been identified, to date.

    Takeda filed for FDA approval of TAK-003 for the prevention of dengue disease caused by any dengue virus serotype in individuals aged four through 60 and continues to progress regulatory filings in other dengue-endemic countries in Asia and Latin America, and non-endemic countries.

  3. TV003/TV005
    TV003/TV005 (LATV) is a live attenuated (recombinant) tetravalent vaccine, admixture of monovalent vaccines developed by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIAID). Several monovalent vaccines were tested separately for safety and immunogenicity. Following several Phase I trials on monovalent formulations, six monovalent candidates were selected for further clinical evaluations formulated as five tetravalent mixtures (TV001-TV005). TV003 and TV005 were further selected after showing the most balanced neutralizing antibody responses against the four DENV. TV003 and TV005 candidate vaccines passed phase I trials and phase II studies in the US, Thailand, Bangladesh, India, and Brazil and are being tested in phase 2 studies in Thailand and Brazil.

    The US National Institutes of Health (NIH) has conducted phase I and phase II studies in over 1000 participants in the US. NIH has licensed their technology for further development and commercial scale manufacturing to Panacea Biotec, Serum Institute of India, Instituto Butantan, Vabiotech (Vietnam), Merck and Medigen.

    In Brazil, phase III studies are being conducted by Instituto Butantan in collaboration with NIH. Panacea Biotec has conducted phase II clinical studies in India. Vabiotech in Vietnam is conducting safety tests and developing a clinical trial plan. All these companies are involved in studies of this vaccine in conjunction with the NIH.
 
Other vaccine candidates 

Several other DENV vaccines developed and currently undergoing different phases of clinical trials, shown in Table 20.3.

Table 20.3 Candidate dengue vaccines in phase I or phase II clinical trials

TDENV-PIV 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 heterologous prime-boost strategy with TDENV-PIV and TDENV-LAV (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. 

D1ME100 
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. 

V180
V180 is an investigational recombinant subunit vaccine by Merck, expressed in Drosophila S2 cells. It consists of truncated dengue envelope proteins (DEN-80E) for all 4 serotypes. Studies are in phase I stage in 2015, and results of Phase I trial were published in 2019. 

DENV-1-LVHC 
The newly derived DENV-1-live virus human challenge (DENV-1-LVHC) strain 45AZ5, was manufactured at the WRAIR Pilot Bioproduction Facility, US. The objective was to assess safety as defined by clinical and laboratory parameters. The secondary objectives were to characterize the clinical, immunologic, and virologic responses following inoculation and to assess its performance in eliciting an uncomplicated dengue-like illness. 

Other vaccines by manufacturers in India and Vietnam
Panacea Biotec India, DengiAIl is a single-dose live-attenuated tetravalent vaccine. Completion of the Phase I/II trial concluded that it induced robust, balanced neutralizing antibody responses against all the four dengue virus serotypes, and the vaccine has been found to be safe and well-tolerated with no serious adverse effects. After a single-dose, more than 80% of the participants showed more than a Tri-valent response and nearly 95% showed a multivalent response.

 

Vaccines Available in Malaysia

 

There are no dengue vaccines available currently. 

Dengvaxia® (CYD-TDV) was approved for conditional registration in Malaysia in April 2017, for a post-registration (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. 

Takeda submitted for NPRA approval of Qdenga® in Malaysia and is currently under review.

Mode of Administration

 
  • CYD-TDV (Dengvaxia®) 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.
  • TAK-003 (QDenga®) is given as 0.5 mL dose at a two-dose (0 and 3 months) schedule, by subcutaneous administration preferably in the upper arm in the region of deltoid.

Contraindications and Adverse Effects

 
  • The manufacturers stipulate 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 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.

  • Vaccination 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.

     

  • Vaccination is contraindicated in immunocompromised individuals due to lack of data.

Current Status

 
  • The Strategic Advisory Group of Experts (SAGE) on Immunization issued an updated recommendation on Dengvaxia®, the first licenced 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.

    >> Following the observed safety signal for Dengvaxia® reported in 2017, 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.  In order to utilise the currently available Dengvaxia® to maximise the public health impact, two main strategies are to be recommended 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. Population seroprevalence criteria for mass vaccination without individual pre-vaccination screening. Subnational or national mass vaccination strategy for areas of high dengue burden i.e. areas with recent documentation of seroprevalence rates of at least 80% by age 9 years.

     

  • In December 2021, CDC US published Advisory Committee on Immunization Practices (ACIP) recommendation on vaccination with Dengvaxia® for children aged 9–16 having evidence of a previous dengue infection and living in areas where dengue is endemic. Evidence of previous dengue infection, such as detection of anti-DENV immunoglobulin G with a highly specific serodiagnostic test, will be required for eligible children before vaccination.
  • 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.
  • Research to be prioritised on the development of highly sensitive and specific, rapid screening tests to determine serostatus.
  • There are currently no guidelines for dengue vaccination in travellers.
  • 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.
  • 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. Longer-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 long-term safety assessments of dengue vaccines.

 

Dengvaxia® by Sanofi Pasteur 

 

  • Findings of the first phase 2b efficacy study in Thailand, 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%). 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. 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%.
  • A newly developed NS1-based antibody assay became available in 2017, which could distinguish prior vaccination from prior infection. 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.

    >> This retrospective analysis confirmed the vaccine’s favourable 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.

    >> 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.

    >> The findings showed that the 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 seronegative non-vaccinated individuals, while confirming long-term protection in seropositive individuals.

    >> 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.

     

  • In November 2017, Sanofi Pasteur announced these results to better describe the benefit-risk in seronegative individuals. An update to the prescribing information was issued, recommending use in individuals with prior dengue infection and contraindications against vaccination of those without prior infection. 
  • Further data from Phase IV trials on CYD-TDV will provide information on long-term duration of protection, vaccine safety and impact on dengue transmission, among others.
 

Qdenga® by Takeda

  • Takeda’s TAK-003 vaccine 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 elicited sustained antibody responses against all four serotypes, which persisted to 48 months post-vaccination, regardless of baseline serostatus and dosing schedule. Vaccine efficacy varied by serotype. The phase 2 randomised, placebo-controlled trial was published in the Lancet in March 2020. The results provide a long-term safety database and support further assessment of the vaccine in the phase 3 efficacy study. 
  • In the clinical 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.
  • The vaccine was assessed in a double-blind, randomised and placebo-controlled Phase 3 trial, Tetravalent Immunisation against Dengue Efficacy Study (TIDES), to evaluate the efficacy, safety and immunogenicity of two doses of the vaccine. It is conducted in Latin America (Brazil, Colombia, Dominican Republic, Nicaragua and Panama) and Asia (Philippines, Sri Lanka and Thailand). The vaccine 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. The study comprised of 5 parts.
  • 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.
  • In January 2019, Takeda announced TAK-003 had met the primary endpoint in the TIDES trial, which 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). 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%]. Results were consistent with previously reported safety, immunogenicity, and efficacy data.
  • Overall Phase 1, 2 and 3 trials with more than 28,000 children and adults, including four and a half years of follow-up data from the global TIDES trial. The TIDES trial met its primary endpoint of overall vaccine efficacy (VE) by preventing 80.2% of symptomatic dengue cases 12 months after vaccination. In addition, TAK-003 met its key secondary endpoint by preventing 90.4% of hospitalizations 18 months after vaccination. Efficacy varied by serotype (DENV-1 – 4). The TIDES exploratory analyses showed that throughout the 4.5-year study follow-up, TAK-003 prevented 84% of hospitalized dengue cases and 61% of symptomatic dengue cases in the overall population, including both seropositive and seronegative individuals. TAK-003 has been generally well tolerated, with no evidence of disease enhancement in vaccine recipients, and no important safety risks have been identified to date. 
  • Approval from the EU at the end of 2022 was supported by results across these Phase 1, 2 and 3 trials, with more than 28,000 children and adults, including four and a half years of follow-up data from the TIDES trial.

 

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