EPIDEMIOLOGY
The number of dengue cases reported annually to WHO has increased from 0.4 to 1.3 million in the decade 1996–2005, reaching 2.2 million in 2010 and 3.2 million in 2015. There is substantial under-reporting of dengue within health systems and to WHO.
Based on mathematical modelling, the global annual incidence has been estimated at about 50 million – 100 million symptomatic cases in recent years, predo-minantly in Asia, followed by Latin America and Africa, with clinical cases likely to represent about 25% of all dengue virus infections.
In 2013 dengue was estimated to be responsible for approximately 3.2 million severe cases and 9000 deaths, the majority occurring in lower middle income countries and for 1.1 million disability adjusted life years (DALYs) globally.
PATHOGEN
Dengue viruses are members of the genus Flavivirus, within the family Flaviviridae. There are 4 dengue virus serotypes (DEN-1, DEN-2, DEN-3 and DEN-4), all of which circulate globally, with most endemic countries reporting circulation of all 4 serotypes in recent years.
DISEASE
The majority of dengue virus infections are asymptomatic. For clinical cases the incubation period is usually 4–7 days but can be in the range 3–14 days. The most common presentation is the sudden onset of fever accompanied by headache, retro-orbital pain, generalized myalgia and arthralgia, flushing of the face, anorexia, abdominal pain and nausea. Rash is frequently seen on the trunk, on the medial aspect of the arms and thighs, and on plantar and palmar surfaces and can be macular, maculopapular, morbilli-form, scarlatiniform or petechial. Laboratory-detected abnormalities may include leukopenia and thrombocytopenia. Individuals infected multiple times with different dengue virus serotypes may experience multiple clinical episodes.
DIAGNOSIS, TREAT-MENT AND PREVENTION
Laboratory confirmation of dengue virus infection is usually done by serology [IgM antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA), IgG ELISA, plaque reduction and neutralization test (PRNT)], or by molecular methods [reverse transcriptase-polymerase chain reaction (RT-PCR) and detection of dengue non-structural protein 1 (NS1)]; virus isolation is used less commonly. Diagnosis by serology typically does not allow for serotyping the infecting virus (except by PRNT), and is susceptible to cross reactivity with other flaviviruses, variable sensitivity by timing of specimen collection, and the need for multiple samples (IgG acute and convalescent samples). RT-PCR and NS1 tests offer earlier and more specific diagnosis (80%–90% sensitivity if assessed 1–3 days after the onset of illness) and are considered virological proof of infection.
There is no specific anti-viral treatment for dengue illness. Clinical management is based on supportive therapy, primarily judicious monitoring of intravascular volume replacement. Improvements in case management have reduced the case fatality rate of hospitalized dengue illness to less than 1%, whereas historically it was as high as 20%. Until the recent vaccine licensure, the only approach to control or prevent the transmission of dengue virus was through interventions targeting the vector, for which WHO recommends integrated vector management.
VACCINES
One dengue vaccine has been registered in several countries (CYD-TDV); this is a live attenuated (recombinant) tetravalent vaccine. Several other dengue vaccine candidates are in clinical development. After CYD-TDV, the 2 most advanced candidates are also tetravalent live attenuated (recombinant) vaccines and are currently under evaluation in Phase 3 trials. WHO has developed recommendations to ensure the quality, safety, and efficacy of live attenuated tetravalent dengue vaccines. CYD-TDV has been evaluated in 2 parallel Phase 3 randomized clinical trials, known as CYD14 and CYD15. CYD14 was conducted at sites in 5 countries in Asia (Indonesia, Malaysia, Philippines, Thailand and Viet Nam), with 10 275 participants. CYD15 was conducted at sites in 5 countries in Latin America (Brazil, Colombia, Honduras, Mexico, and Puerto Rico (USA)), with 20869 participants. In each of these trials, participants were randomized to receive vaccine or placebo (0.9% solution of sodium chloride) in a 2:1 ratio.
VACCINE CHARAC-TERISTICS, CONTENT, DOSAGE, ADMINIS-TRATION, STORAGE
CYD-TDV is a pro-phylactic, tetravalent, live attenuated viral vaccine. The vaccination schedule consists of 3 injections of 0.5 mL administered at 6-month intervals. The indication from the first licenses is for the prevention of dengue illness caused by dengue virus serotypes 1, 2, 3, and 4 in individuals 9–45 years
or 9–60 years of age (depending on the license), living in dengue endemic areas. CYD-TDV is available in a single-dose vial or in a multidose (5-dose) vial. It is a freeze-dried product to be reconstituted before injection with either a sterile solution of 0.4% sodium chloride for the single-dose presentation or a sterile solution of 0.9% sodium chloride for the 5-dose presentation. After recons-titution, the 0.5 mL dose
is to be administered by the subcutaneous route. The diluent is provided as a pre-filled syringe for single-dose presentation. The CYD-TDV dengue vaccine contains no adjuvant or preservatives. The shelf-life of CYD-TDV is 36 months when stored between 2 °C and 8 °C.
EFFICACY
Vaccine efficacy against virologically-confirmed dengue illness was assessed during the active phase of surveillance (25 months post-enrolment) in CYD14 and CYD15. Per protocol vaccine efficacy against virolo-gically confirmed sympto-matic dengue illness of any serotype was 56.5% (95% CI 43.8%–66.4%)
in CYD14, and 60.8% (95% CI 52.0%–68.0%) in CYD15 (from one month post dose 3 for 12 months). In both trials, vaccine efficacy was lower against serotypes 1 (50.2%, 95% CI 35.6%– 61.5%) and 2 (39.6%, 95% CI 18.7%–55.2%) than against serotypes 3 (74.9%, 95% CI 65.1%–82.0%) and 4 (76.6%, 95% CI 65.0%–84.4%). Vaccine efficacy estimates were similar in the 2 Phase 3 trials despite variable epidemiological settings and ages at vaccination (2–14 years in CYD14 and 9–16 years in CYD15).
Vaccine efficacy estimates against virologically confirmed dengue illness for all serotypes were similar in the per protocol analysis cited above and in the intent-to-treat (ITT) analyses starting from the first dose. The over-
all pooled estimate for CYD14 and CYD15 combined for virologically-confirmed dengue illness of any serotype in the 25 months post-dose 1 (ITT) was 60.3%.The summary vaccine efficacy estimates reported above have included children of all ages in the Phase 3 trials, including those <9 years of age who are
not included in the currently indicated age ranges.
A post-hoc pooled analysis limited to those >9 years of age in CYD14 and CYD15 was carried out. Pooled efficacy estimates in the 25 months following dose 1 limited to partici-pants aged =9 years are similar to those for the full trial population. Vaccine efficacy was 65.6% (95% CI 60.7%–69.9%) against virologically-confirmed dengue illness of any serotype in the >9 years population and in the
subset for which baseline serostatus was assessed the efficacy was 81.9% (95% CI 67.2%–90.0%) in those seropositive at baseline and 52.5% (95% CI 5.9%–76.1%) in those seronegative at baseline.
Vaccine efficacy varied by country, with efficacy ranging from 31.3% (95% CI 1.3%–51.9%) in Mexico to 79.0% (95% CI 52.3%–91.5%) in Malaysia. This variability in efficacy likely reflects at least in part the baseline seropositivity and circulating serotypes, both of which affect the per-formance of the vaccine.
Vaccine efficacies against virologically-confirmed dengue illness resulting in hospitalization or non-hospitalized severe dengue illness were higher in the 25 months following dose 1 than for virologically confirmed dengue illness of any severity. Pooled vaccine efficacies against hospitalized dengue illness were 72.7% and 80.8% among participants of all ages and those = 9 years, respectively. The corresponding pooled efficacy estimates against virologically-confirmed severe dengue illness were 79.1% and 93.2% (95% CI 77.3%–98.0%) among participants of all ages and those = 9 years, respectively.
DURATION OF PROTECTION
Vaccine efficacy against virologically-confirmed dengue illness of any severity has been measured in the first and second years post dose 1. Active surveillance is currently being re-initiated, so that vaccine efficacy 5–6 years post dose 1 can be evaluated. Data on hospitalized dengue illness have been collected throughout the trials, though with different surveillance systems in different phases of the trial. These data were reviewed for assessment of protection during the duration of the Phase 3 trials. For hospitalized dengue illness in ages included in the indication (9–16 years), the estimated yearly RR of hospitalized dengue illness typically remained below 1, suggesting a sustained protective effect. In all age groups, the RR of severe dengue illness among vaccinated compared to controls was lower during the first 2 years of the trials than during the later years. These data may reflect potential waning of protection among all age groups.
VACCINE SAFETY
Local and systemic adverse reactions following CYD-TDV are comparable to those recorded for other live attenuated vaccines. Safety data across multiple clinical trials that used the final formulation and final vaccination schedule have been pooled for the age range of 9–60 years, both in endemic and non-endemic areas. Solicited systemic reactions occurred in 66.5% of CYD-TDV recipients compared to 59% of placebo recipients. The most common solicited systemic reactions were headache (>50%), malaise (>40%), and myalgia (>40%). Fever occurred in 5% and 16% of participants in the CYD-TDV recipients aged 18–60 years and 9–17 years, respectively.
Approximately 10% of solicited systemic reactions were Grade 3, mostly related to headache and fever. Solicited injection-site reactions occurred in 49.6% of CYD-TDV recipients compared to 38.5% of placebo recipients. Among solicited injection site reactions, the most common was pain, reported by 45.2% of CYD-TDV recipients aged 18–60 years and 49.2% in those aged 9–17 years. Of all solicited injection site reactions, <1% were Grade 3. In the Phase 3 trials, the number of serious adverse events was similar in the CYD and placebo groups (respectively 5% and 6% in CYD14, and 4.1% and 4.4% in CYD15). There is a hypothetical
risk of acute viscerotropic or neurotropic disease due to the YF 17D back-bone, but no cases have
been detected to date.
CO-ADMINISTRATION
Co-administration studies previously conducted in children outside the indicated age range, in which CYD-TDV was co-administered with YF vaccine, DTaP-IPV/ Hib, and MMR, did not identify any safety con-
cerns (data were comparable when vaccines were co-administered or given alone), and that the immunogenicity profiles were satisfactory both for CYD-TDV and for co-administered vaccines.
WHO POSITION
Countries should consider introduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological data indicate a high burden of disease. In defining populations to be targeted for vaccination, prior infection with dengue virus of any serotype, as measured by sero-prevalence, should be approximately 70% or greater in the age group targeted for vaccination in order to maximize public health impact and cost effectiveness. Vaccination of populations with seroprevalence bet-
ween 50% and 70% is acceptable but the impact of the vaccination programme may be lower.
Dengue vaccine intro-duction should be a part of a comprehensive dengue control strategy, including wellexecuted and sustained vector control, evidence-based best practices for clinical care for all patients with dengue illness, and strong dengue surveillance. Vaccine introduction must be accompanied by a targeted communication strategy. Decisions about introduction require careful assessment at the country level, including consi-deration of local priorities, national and subnational dengue epidemiology, predicted impact and cost-effectiveness with country-specific inputs, affordability and budget impact. At the time of introduction, countries are encouraged to have a functional pharmacovigilance system with at least minimal capacity to monitor and manage adverse events following immunization. Countries considering vaccination should also have a dengue surveillance system able to detect and report hospitalized and severe dengue cases consistently over time.
If CYD-TDV is introduced, it should be administered as a 3-dose series given on a 0/6/12 month schedule.
However, additional evidence is needed to determine whether simplified schedules may elicit equivalent or better protection. Should a vaccine dose be delayed for any reason, the vaccine course should be resumed (not restarted), maintaining the 6-month interval between subsequent doses. Because of the 12-month duration of the immunization schedule and to enable better vaccine monitoring, countries should have systems in place for tracking vaccination. Because of the association of CYD-TDV with increased risk of hospitalized and severe dengue illness in the 2–5 year age group, CYD-TDV is not recommended for use in children under 9 years of age, consistent with current labelling. The target age for routine vaccination should be defined by each country, based on maximizing vaccination impact and programmatic feasibility of targeting specific age groups. Some countries may experience the highest incidence of dengue illness among adults and may consider vaccinating populations up to 45 years of age in routine prog-rammes. Introduction of a routine CYD-TDV vacci-nation programme at 9 years of age in settings meeting the criteria outlined above is expected to result in a 10%–30% reduction in symptomatic and hospitalized dengue illness over 30 years. Catch-up campaigns targeting older age groups may be considered if additional impact is desired and the additional costs can be met, although
most models predicted that a one-off catch-up campaign for children aged 9–17 years prevented a similar number of symptomatic and hospi-talized dengue cases per dose of vaccine delivered as in a routine vaccination programme at 9 years of age. Because the risk of immunological inter-ference due to co-administration of live with non-live vaccines is considered small, co-administration is permissible with these and other non-live attenuated vaccines. Co-administration may be desirable to reduce programmatic costs associated with school-based vaccination programmes.
CYD-TDV has not been studied as an intervention for dengue outbreak control. Although the 3-dose vaccine may be introduced during an outbreak as part of an overall dengue control strategy, vaccination is not expected to have a significant impact on the course of the ongoing outbreak. Any deployment of the vaccine in the context of an outbreak should only be done in areas that meet the recommended seropre-valence criteria for introduction of dengue vaccine in routine programmes.
There is presently no recommendation concerning CYD-TDV in pregnant and lactating women due to lack of sufficient data in this population. However, the limited data collected during the clinical trials on inadvertent immunization of pregnant women have yielded no evidence of harm to the fetus or pregnant woman. Women of child-bearing age who are targeted for vaccination do not need to be tested for pregnancy. Until data become available from forthcoming studies in HIV-infected individuals or other persons with immune deficiency, there is no recommendation concerning the use of CYD-TDV in HIV-infected or immuno-compromised individuals. There is no recommedation for vaccination of travellers or health-care workers at this time.
Dengue surveillance should be strengthened, particularly in the context of emerging infections with clinical similarities to dengue and in areas of the world for which data are scarce or absent. Use of standardized case definitions is encouraged to enhance data sharing and comparability across regions. With the increase in false-positive results from serological testing of CYD-TDV vaccinated individuals, diagnostic testing should move to virological confirmation whenever possible.
Important research and implementation questions remain for CYD-TDV. Research on reduced or shorter interval dosing schedules and safety in pregnant women are high priorities. An approach to evaluate epidemiologic data based on high-quality age-stratified surveillance is needed to infer likely seroprevalence by age in order to target vaccination efforts where seroprevalence data are not available. As the vaccine is introduced in endemic countries, determination of vaccine effectiveness by dose and duration of protection and long-term impact of vaccine programmes will be research priorities. However, it should be noted that using surveillance data to monitor population impact of a vaccination programme may be challenging as the year-to-year variability in dengue virus transmission may be greater than the expected vaccine impact on dengue illness. Special studies should be conducted to monitor the occurrence over time of severe dengue illness in vaccinated persons, particularly among vaccinated seronegative persons. not allow for serotyping the infecting virus (except by PRNT), and is susceptible to cross-reactivity with other flaviviruses, variable sensitivity by timing of specimen collection, and the need for multiple samples (IgG acute and convalescent samples). RT-PCR and NS1 tests offer earlier and more specific diagnosis (80%–90% sensitivity if assessed 1–3 days after the onset of illness) and are considered virological proof of infection.
There is no specific anti-viral treatment for dengue illness. Clinical management is based on supportive therapy, primarily judicious monitoring of intravascular volume replacement. Improvements in case management have reduced the case fatality rate of hospitalized dengue illness to less than 1%, whereas historically it was as high as 20%. Until the recent vaccine licensure, the only approach to control or prevent the transmission of dengue virus was through interventions targeting the vector, for which WHO recommends integrated vector management.
VACCINES
One dengue vaccine has been registered in several countries (CYD-TDV); this is a live attenuated (recombinant) tetravalent vaccine. Several other dengue vaccine candidates are in clinical development. After CYD-TDV, the 2 most advanced candidates are also tetravalent live attenuated (recombinant) vaccines and are currently under evaluation in Phase 3 trials. WHO has developed recommendations to ensure the quality, safety, and efficacy of live attenuated tetravalent dengue vaccines. CYD-TDV has been evaluated in 2 parallel Phase 3 randomized clinical trials, known as CYD14 and CYD15. CYD14 was conducted at sites in 5 countries in Asia (Indonesia, Malaysia, Philippines, Thailand and Viet Nam), with 10 275 participants. CYD15 was conducted at sites in 5 countries in Latin America (Brazil, Colombia, Honduras, Mexico, and Puerto Rico (USA)), with 20869 participants. In each of these trials, parti-cipants were randomized to receive vaccine or placebo (0.9% solution of sodium chloride) in a 2:1 ratio.
VACCINE CHARAC-TERISTICS, CONTENT, DOSAGE, ADMINIS-TRATION, STORAGE
CYD-TDV is a pro-phylactic, tetravalent, live attenuated viral vaccine. The vaccination schedule consists of 3 injections of 0.5 mL administered at 6-month intervals. The indication from the first licenses is for the prevention of dengue illness caused by dengue virus serotypes 1, 2, 3, and 4 in individuals 9–45 years or 9–60 years of age (depending on the license), living in dengue endemic areas.
CYD-TDV is available in a single-dose vial or in a multidose (5-dose) vial.
It is a freeze-dried product to be reconstituted before injection with either a sterile solution of 0.4% sodium chloride for the single-dose presentation or a sterile solution of 0.9% sodium chloride for the 5-dose presentation. After recons-titution, the 0.5 mL dose is to be administered by the subcutaneous route.
The diluent is provided as a pre-filled syringe for single-dose presentation. The CYD-TDV dengue vaccine contains no adjuvant or preservatives. The shelf-life of CYD-TDV is 36 months when stored between 2 °C and 8 °C.
EFFICACY
Vaccine efficacy against virologically-confirmed dengue illness was assessed during the active phase of surveillance (25 months post-enrolment) in CYD14 and CYD15. Per protocol vaccine efficacy against virolo-gically confirmed sympto-matic dengue illness of any serotype was 56.5% (95% CI 43.8%–66.4%) in CYD14, and 60.8% (95% CI 52.0%–68.0%) in CYD15 (from one month post dose 3 for 12 months).
In both trials, vaccine efficacy was lower against serotypes 1 (50.2%, 95% CI 35.6%– 61.5%) and 2 (39.6%, 95% CI 18.7%–55.2%) than against serotypes 3 (74.9%, 95% CI 65.1%–82.0%) and 4 (76.6%, 95% CI 65.0%–84.4%). Vaccine efficacy estimates were similar in the 2 Phase 3 trials despite variable epidemiological settings and ages at vaccination (2–14 years in CYD14 and 9–16 years in CYD15).
Vaccine efficacy estimates against virologically confirmed dengue illness for all serotypes were similar in the per protocol analysis cited above and in the intent-to-treat (ITT) analyses starting from the first dose. The over-all pooled estimate for CYD14 and CYD15 combined for virologically-confirmed dengue illnessof any serotype in the 25 months post-dose 1 (ITT) was 60.3%.The summary vaccine efficacy estimates reported above have included children of all ages in the Phase 3 trials, including those <9 years of age who are not included in the currently indicated age ranges.
A post-hoc pooled analysis limited to those >9 years of age in CYD14 and CYD15 was carried out. Pooled efficacy estimates in the 25 months following dose 1 limited to partici-pants aged =9 years are similar to those for the full trial population. Vaccine efficacy was 65.6% (95% CI 60.7%–69.9%) against virologically-confirmed dengue illness of any serotype in the >9 years population, and in the subset for which base-line serostatus was assessed the efficacy was 81.9% (95% CI 67.2%–90.0%) in those seropositive at base-line and 52.5% (95% CI 5.9%–76.1%) in those seronegative at baseline.
Vaccine efficacy varied by country, with efficacy ranging from 31.3% (95% CI 1.3%–51.9%) in Mexico to 79.0% (95% CI 52.3%–91.5%) in Malaysia. This variability in efficacy likely reflects at least in part the baseline seropositivity and circulating serotypes, both of which affect the per-formance of the vaccine.
Vaccine efficacies against virologically-confirmed dengue illness resulting in hospitalization or non-hospitalized severe dengue illness were higher in the 25 months following dose 1 than for virologically confirmed dengue illness of any severity. Pooled vaccine efficacies against hospitalized dengue illness were 72.7% and 80.8% among participants of all ages and those = 9 years, respectively. The corresponding pooled efficacy estimates against virologically-confirmed severe dengue illness were 79.1% and 93.2% (95% CI 77.3%–98.0%) among participants of all ages and those = 9 years, respectively.
DURATION OF PROTECTION
Vaccine efficacy against virologically-confirmed dengue illness of any severity has been measured in the first and second years post dose 1. Active surveillance is currently being re-initiated, so that vaccine efficacy 5–6 years post dose 1 can be evaluated. Data on hospitalized dengue illness have been collected throughout the trials, though with different surveillance systems in different phases of the trial. These data were reviewed for assessment of protection during the duration of the Phase 3 trials. For hospitalized dengue illness in ages included in the indication (9–16 years), the estimated yearly RR of hospitalized dengue illness typically remained below 1, suggesting a sustained protective effect. In all age groups, the RR of severe dengue illness among vaccinated compared to controls was lower during the first 2 years of the trials than during the later years. These data may reflect potential waning of protection among all age groups.
VACCINE SAFETY
Local and systemic adverse reactions following CYD-TDV are comparable to those recorded for other live attenuated vaccines. Safety data across multiple clinical trials that used the final formulation and final vaccination schedule have been pooled for the age range of 9–60 years, both in endemic and non-endemic areas. Solicited systemic reactions occurred in 66.5% of CYD-TDV recipients compared to 59% of placebo recipients. The most common solicited systemic reactions were headache (>50%), malaise (>40%), and myalgia (>40%). Fever occurred in 5% and 16% of participants in the CYD-TDV recipients aged 18–60 years and 9–17 years, respectively. Approximately 10% of solicited systemic reactions were Grade 3, mostly related to headache and fever. Solicited injection-site reactions occurred in 49.6% of CYD-TDV recipients compared to 38.5% of placebo recipients. Among solicited injection site reactions, the most common was pain, reported by 45.2% of CYD-TDV recipients aged 18–60 years and 49.2% in those aged 9–17 years. Of all solicited injection site reactions, <1% were Grade 3. In the Phase 3 trials, the number of serious adverse events was similar in the CYD and placebo groups (respectively 5% and 6% in CYD14, and 4.1% and 4.4% in CYD15). There is a hypothetical risk of acute viscerotropic or neurotropic disease due to the YF 17D backbone, but no cases have been detected to date.
CO-ADMINISTRATION
Co-administration studies previously conducted in children outside the indicated age range, in which CYD-TDV was co-administered with YF vaccine, DTaP-IPV/ Hib, and MMR, did not identify any safety concerns (data were comparable when vaccines were co-administered or given alone), and that the immunogenicity profiles were satisfactory both for CYD-TDV and for co-administered vaccines.
WHO POSITION
Countries should consider introduction of the dengue vaccine CYD-TDV only in geographic settings (national or subnational) where epidemiological data indicate a high burden of disease. In defining populations to be targeted for vaccination, prior infection with dengue virus of any serotype, as measured by sero-prevalence, should be approximately 70% or greater in the age group targeted for vaccination in order to maximize public health impact and cost effectiveness. Vaccination of populations with seroprevalence between 50% and 70% is acceptable but the impact of the vaccination programme may be lower. Dengue vaccine intro-duction should be a part of a comprehensive dengue control strategy, including wellexecuted and sustained vector control, evidence-based best practices for clinical care for all patients with dengue illness, and strong dengue surveillance. Vaccine introduction must be accompanied by a targeted communication strategy. Decisions about introduction require careful assessment at the country level, including consi-deration of local priorities, national and subnational dengue epidemiology, predicted impact and cost-effectiveness with country-specific inputs, affordability and budget impact. At the time of introduction, countries are encouraged to have a functional pharmacovigilance system with at least minimal capacity to monitor and manage adverse events following immunization. Countries considering vaccination should also have a dengue surveillance system able to detect and report hospitalized and severe dengue cases consistently over time.
If CYD-TDV is introduced, it should be administered as a 3-dose series given on a 0/6/12 month schedule. However, additional evidence is needed to determine whether simplified schedules may elicit equivalent or better protection. Should a vaccine dose be delayed for any reason, the vaccine course should be resumed (not restarted), maintaining the 6-month interval between subsequent doses. Because of the 12-month duration of the immunization schedule and to enable better vaccine monitoring, countries should have systems in place for tracking vaccination. Because of the association of CYD-TDV with increased risk of hospitalized and severe dengue illness in the 2–5 year age group, CYD-TDV is not recommended for use in children under 9 years of age, consistent with current labelling. The target age for routine vaccination should be defined by each country, based on maximizing vaccination impact and programmatic feasibility of targeting specific age groups. Some countries may experience the highest incidence of dengue illness among adults and may consider vaccinating populations up to 45 years of age in routine prog-rammes. Introduction of a routine CYD-TDV vacci-nation programme at 9 years of age in settings meeting the criteria outlined above is expected to result in a 10%–30% reduction in symptomatic and hospitalized dengue illness over 30 years. Catch-up campaigns targeting older age groups may be considered if additional impact is desired and the additional costs can be met, although most models predicted that a one-off catch-up campaign for children aged 9–17 years prevented a similar number of symptomatic and hospi-talized dengue cases per dose of vaccine delivered as in a routine vaccination programme at 9 years of age. Because the risk of immunological inter-ference due to co-administration of live with non-live vaccines is considered small, co-administration is permissible with these and other non-live attenuated vaccines. Co-administration may be desirable to reduce programmatic costs associated with school-based vaccination programmes.
CYD-TDV has not been studied as an intervention for dengue outbreak control. Although the 3-dose vaccine may be introduced during an outbreak as part of an overall dengue control strategy, vaccination is not expected to have a significant impact on the course of the ongoing outbreak. Any deployment of the vaccine in the context of an outbreak should only be done in areas that meet the recommended seroprevalence criteria for introduction of dengue vaccine in routine programmes.
There is presently no recommendation concerning CYD-TDV in pregnant and lactating women due to lack of sufficient data in this population. However, the limited data collected during the clinical trials on inadvertent immunization of pregnant women have yielded no evidence of harm to the fetus or pregnant woman. Women of child-bearing age who are targeted for vaccination do not need to be tested for pregnancy. Until data become available from forthcoming studies in HIV-infected individuals or other persons with immune deficiency, there is no recommendation concerning the use of CYD-TDV in HIV-infected or immuno-compromised individuals. There is no recommendation for vaccination of travellers or health-care workers at this time.
Dengue surveillancea should be strengthened, particularly in the context of emerging infections with clinical similarities to dengue and in areas of the world for which data are scarce or absent. Use of standardized case definitions is encouraged to enhance data sharing and comparability across regions. With the increase in false-positive results from serological testing of CYD-TDV vaccinated individuals, diagnostic testing should move to virological confirmation whenever possible.
Important research and implementation questions remain for CYD-TDV. Research on reduced or shorter interval dosing schedules and safety in pregnant women are high priorities. An approach to evaluate epidemiologic data based on high-quality age-stratified surveillance is needed to infer likely seroprevalence by age in order to target vaccination efforts where seroprevalence data are not available. As the vaccine is introduced in endemic countries, determination of vaccine effectiveness by dose and duration of protection and long-term impact of vaccine programmes will be research priorities. However, it should be noted that using surveillance data to monitor population impact of a vaccination programme may be challenging as the year-to-year variability in dengue virus transmission may be greater than the expected vaccine impact on dengue illness. Special studies should be conducted to monitor the occurrence over time of severe dengue illness in vaccinated persons, particularly among vaccinated seronegative persons.
