Dengvaxia

Dengue tetravalent vaccine (live, attenuated).

After reconstitution, one dose (0.5 mL) contains: CYD dengue virus serotype 1^* 4.8 - 6.0 log₁₀ CCID₅₀/dose^**; CYD dengue virus serotype 2^* 4.8 - 6.0 log₁₀ CCID₅₀/dose^**; CYD dengue virus serotype 3^* 4.8 - 6.0 log₁₀ CCID₅₀/dose^**; CYD dengue virus serotype 4^* 4.8 - 6.0 log₁₀ CCID₅₀/dose^**.
^* Produced in serum-free Vero cells by recombinant DNA technology.
^** CCID₅₀: 50% Cell Culture Infectious Dose.
Prior to reconstitution, the vaccine is a white, homogenous, freeze-dried powder with possible retraction at the base, and may form a ring-shaped cake.
The solvent is a clear, colorless liquid.
Excipients with known effect: (see Precautions) Phenylalanine 41 micrograms; Sorbitol 9.38 milligrams.
Excipients/Inactive Ingredients: Powder: Essential amino acids including L-Phenylalanine, Non-essential amino acids, L-Arginine hydrochloride, Sucrose, D-Trehalose dehydrate, D-Sorbitol, Trometamol, Urea, Hydrochloric acid and Sodium hydroxide for pH adjustment.
Solvent for reconstitution: Sodium chloride, Water for injections.
No adjuvants and no preservatives are added.

Pharmacotherapeutic group: Viral vaccines. ATC code: J07BX.
Pharmacology: Pharmacodynamics: Mechanism of action: The vaccine contains live attenuated viruses. Following administration, the viruses replicate locally and elicit neutralizing antibodies and cell-mediated immune responses against the four dengue virus serotypes.
Immunogenicity: Immunogenicity data were collected in a total of approximately 3104 subjects 9 through 45 years of age from endemic areas who received at least one injection of the final formulation of the vaccine according to the claimed vaccination schedule in 10 randomized, observer-blinded, placebo-controlled Phase II to Phase III clinical studies. Most of the subjects were 9 through 17 years of age (n= 2810).
The immunogenicity data presented correspond to the neutralizing antibody titers for each serotype as measured with the plaque reduction neutralization test (PRNT). The results are presented as geometric mean titers (GMTs), expressed in reciprocal dilutions (1/dil), measured at baseline and 28 days after the third injection of the vaccine.
GMT data on subjects 18 through 45 years of age included in Phase II safety and immunogenicity studies conducted in endemic areas (CYD22, CYD28 and CYD47) and on subjects 9 through 17 years of age included in the 3 efficacy studies (Phase IIb efficacy study, CYD23, and the two large-scale Phase III efficacy studies, CYD14 and CYD15) are presented by study and region in the Dengue Group and in the Placebo Group in Table 1 (serotypes 1 and 2) and Table 2 (serotypes 3 and 4). (See Tables 1 and 2.)


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In all age groups in all studies, an increase in GMTs was observed for each of the 4 serotypes 28 days after the third injection as compared to baseline, regardless of the region, i.e., Asia Pacific or Latin America.
Differences in GMTs 28 days after the third injection were observed depending on dengue immune status before the first injection, the age and the region. Overall: The higher the GMTs before the first injection, the higher the GMTs 28 days after the third injection; GMTs 28 days after the third injection were higher in subjects with neutralizing antibodies against dengue virus before the first injection compared to subjects with no detectable neutralizing antibodies against dengue virus before the first injection; Dengue immune status before the first injection is a confounding factor of age: the older the subject, the higher the GMTs before the first injection and the higher the GMTs 28 days after the third injection, i.e., the immune response in terms of GMTs 28 days after the third injection increases with age.
Data on long-term persistence of antibodies: In subjects 9 years of age and older in endemic areas, a decrease in the GMTs against all 4 serotypes was observed one year after the third injection and then a trend toward stabilization was observed in the subsequent years. The decrease in GMTs was variable depending on age and the dengue immune status of subjects before the first injection. Long-term GMTs for each serotype remained higher than GMTs before the first injection.
Efficacy: The efficacy of the vaccine was assessed in 3 randomized, observer-blinded, placebo-controlled efficacy studies: one supportive Phase IIb efficacy study (CYD23), and 2 pivotal large-scale Phase III efficacy studies conducted in 5 countries each, CYD14 in Asia and CYD15 in Latin America.
In the 2 pivotal Phase III studies, efficacy was assessed in a total of 17,230 subjects 9 through 16 years of age who received at least one injection of the vaccine: 3316 subjects 9 through 14 years of age in CYD14 and the entire study population in CYD15, i.e., 13,914 subjects 9 through 16 years of age. A time window of +/- 20 days was applied for the second and third injections. More than 70% of subjects were dengue immune at baseline.
In subjects 9 through 16 years of age, the efficacy of the vaccine against symptomatic virologically confirmed dengue (VCD) cases due to any and each of the 4 serotypes was demonstrated in both studies, CYD14 and CYD15, and in the meta-analysis. The assessment period extended from the first injection to the end of the active phase, i.e. over the 25-month period after the first injection.
The efficacy of the vaccine against severe VCD cases and against hospitalized VCD cases (i.e., hospital admission due to dengue, whatever the severity) were also evaluated. For severe VCD cases, two types of endpoints were considered: clinically severe VCD cases and VCD cases that met WHO criteria for Dengue Hemorrhagic Fever (DHF). Vaccine efficacy was demonstrated for these three endpoints in both studies and in the meta-analysis.
The efficacy results were also analyzed according to covariates, i.e., age at the time of the first injection and dengue immune status before the first injection. In subjects 9 through 16 years of age, no significant effect of age on vaccine efficacy was observed, while a higher efficacy against VCD (any serotype and any severity) was observed in subjects with prior dengue infection (i.e subjects with neutralizing antibodies against any of the 4 dengue serotypes prior vaccination) (81.9%; 95% CI: 67.2; 90.0) compared to the overall population (65.6%; 95% CI: 60.7; 69.9) (see Table 3).
The efficacy results in subjects 9 through 16 years of age are presented in Table 3 for each of the two phase III efficacy studies and in the meta-analysis. The results are presented for the entire active phase of 25 months.
Dengue immune status at baseline (i.e before the first injection) measured by PRNT is defined as: Subject with qualified (≥ 10 [1/dil], the lower limit of quantitation) neutralizing antibodies against at least one dengue serotype in the baseline sample; Subject without qualified (< the lower limit of quantitation) neutralizing antibodies against any of the 4 dengue serotype in the baseline sample. (See Table 3.)


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Pharmacokinetics: No pharmacokinetic studies have been performed on the vaccine.
Toxicology: Preclinical safety data: Non-clinical safety data revealed no special risks for humans based on a repeated-dose toxicity and local tolerance study, a distribution and shedding study, a neurovirulence study and a developmental and reproductive toxicology program.

Dengvaxia is indicated for reducing the risk of the event and severity of dengue disease caused by dengue virus serotype 1, 2, 3 and 4 in individuals 9 through 16 years of age living in endemic areas who have previously been infected with dengue virus (seropositive).

Posology: Primary vaccination: The primary vaccination schedule consists of 3 injections of one reconstituted dose (0.5 mL) to be administered at 6 month intervals.
If flexibility in the vaccination schedule is necessary, a time window of +/- 20 days is acceptable (see Pharmacology: Pharmacodynamics under Actions).
Dengvaxia should not be administered in individuals less than 9 years of age.
Booster dose: The need for a booster dose after primary vaccination with Dengvaxia has not been established.
Method of administration: Once the freeze-dried vaccine has been completely reconstituted using the solvent provided, it is administered by subcutaneous (SC) injection. The recommended injection site is the deltoid region.
Precautions to be taken before handling or administering the medicinal product: Do not administer by intravascular injection.
Dengvaxia must not be mixed with any other injectable vaccine(s) or medicinal product(s).
For instructions on reconstitution of Dengvaxia before administration, see Special precautions for disposal and other handling under Cautions for Usage.

No cases of overdose have been reported.

Dengvaxia must not be administered to individuals with a history of severe allergic reaction to any component of Dengvaxia or after prior administration of Dengvaxia or a vaccine containing the same components.
Administration of Dengvaxia must be postponed in individuals suffering from moderate to severe febrile or acute disease.
Dengvaxia must not be administered to individuals with congenital or acquired immune deficiency that impairs cell-mediated immunity, including immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids generally given for 2 weeks or more.
Dengvaxia must not be administered to individuals with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function.
Dengvaxia must not be administered to pregnant women.
Dengvaxia must not be administered to breastfeeding women.

As with any vaccine, vaccination with Dengvaxia may not protect 100% of vaccinated individuals. It is recommended to continue personal protection measures against mosquito bites after vaccination.
As a precaution, healthcare professionals should follow-up and appropriately manage any vaccines with signs and symptoms of dengue fever, with particular attention to dengue warning signs (e.g., high fever, severe abdominal pain or tenderness, persistent vomiting, mucosal bleeding, somnolence and hyperactivity according to WHO guidelines 2009).
In individuals who have not been previously infected by the dengue virus, an increased risk of hospitalization for dengue and clinically severe dengue (predominantly grade 1 or 2 Dengue Hemorrhagic Fever [WHO 1997]) has been observed in the long-term follow up of clinical trials (see Adverse Reactions).
Vaccination should only be recommended when the potential benefits outweigh the potential risks (for those living in areas with a high dengue seroprevalence or where epidemiological data indicate a high burden of dengue disease). Healthcare professionals would need to assess the likelihood of prior dengue infection in these individuals before vaccinating. For individuals who have not been previously infected by dengue virus, vaccination should not be recommended. Previous infection by dengue virus can be substantiated through serotesting where available.
For patients receiving treatment with high doses of systemic corticosteroids given for 2 weeks or more (daily receipt of prednisone or equivalent 20 mg or 2 mg/kg body weight is considered as a substantially immunosuppressive dose), it is advisable to wait until immune function has recovered, i.e., for at least 4 weeks after stopping treatment, before administering Dengvaxia.
Vaccination is not recommended for individuals without prior dengue infection, living in non-endemic areas, who travel to endemic areas.
Dengvaxia must not be administered by intravascular injection under any circumstances.
In individuals who have a history of serious or severe reactions within 48 hours after a prior administration of Dengvaxia or of a vaccine containing similar components, the risks and benefits of administering Dengvaxia must be carefully considered.
Before administering any biological, the person responsible for administration must take all precautions to prevent allergic or other reactions. As with all injectable vaccines, appropriate medical treatment and supervision must always be readily available in the event of an anaphylactic reaction following administration of the vaccine. Epinephrine (1:1000) and other appropriate agents used to control immediate allergic reactions must be available to treat unexpected events such as anaphylaxis.
Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to injection with a needle. Procedures should be in place to prevent injury from falling and to manage syncopal reactions.
No studies have been performed on the interference of Dengvaxia with laboratory and/or diagnostic tests.
The tip caps of the pre-filled syringes contain a natural rubber latex derivative, which may cause allergic reactions in latex sensitive individuals.
Dengvaxia contains phenylalanine, sodium and sorbitol: Dengvaxia contains 41 micrograms of phenylalanine in each 0.5 ml dose of single dose presentation. Phenylalanine may be harmful for people with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up becuase the body cannot remove it properly.
Dengvaxia contains less than 1mmol of sodium (23 mg) per 0.5 ml dose, that is to say essentially "sodium-free".
Dengvaxia contains 9.38 milligrams of sorbitol in each 0.5 ml dose of single dose presentation.
Effects on ability to drive and use machines: No studies have been performed on the effects of the vaccine on the ability to drive or to use machines.

Pregnancy: Pregnancy constitutes a contraindication (see Contraindications).
Women of childbearing age should avoid becoming pregnant for 4 weeks after receiving any injection of Dengvaxia.
Animal studies did not indicate any direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Breastfeeding: Dengvaxia is contraindicated during breastfeeding (see Contraindications).
It is not known whether this vaccine is excreted into human milk. The effect on breastfed infants of administration of Dengvaxia to their mothers has not been studied.
Animal studies did not indicate any direct or indirect harmful effects with respect to lactation (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Fertility: No specific studies have been performed on fertility.
Animal studies did not indicate any harmful effects with respect to female fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Data in subjects 9 years of age or older: Summary of the safety profile: A total of approximately 20,667 subjects 9 through 60 years of age received at least one injection of the final formulation of Dengvaxia according to the claimed vaccination schedule in 13 randomized, observer-blinded, placebo-controlled Phase II to Phase III clinical studies.
The safety profile was assessed in a total of 1547 subjects 18 through 60 years of age and 19,120 subjects 9 through 17 years of age. To support the indication, the safety profile presented as follows is focused on the pooled analysis of safety data in children and adolescents from 9 years of age, i.e. subjects 9 through 17 years of age. Reactogenicity was assessed in a subset of 3068 out of those 19,120 subjects.
Safety was monitored during the first 28 days following each injection in the reactogenicity subset, and serious adverse event (SAEs), including dengue cases, were collected throughout the studies in all subjects, up to at least 6 months after the last injection of the vaccine.
In subjects 9 through 17 years of age, the most frequently reported ARs following any injection of the vaccine were headache, injection site pain, malaise and myalgia.
The ARs were usually mild to moderate in severity and of short duration (0 to 3 days). Onset was typically observed 0 to 3 days after the injection, except for fever which appeared within 14 days after the injection.
Systemic ARs tended to be less frequent after the second and third injections as compared to the first injection.
Tabulated list of adverse reactions: Adverse reactions are listed according to the following frequency categories: Very common: ≥ 1/10 (≥ 10%), Common: ≥ 1/100 to < 1/10 (≥ 1% and < 10%), Uncommon: ≥ 1/1000 to < 1/100 (≥ 0.1% and < 1%), Rare: ≥ 1/10,000 to < 1/1000 (≥ 0.01% and < 0.1%), Very Rare: <1/10,000 (≥ 0.01%).
ARs within 28 days after any injection in subjects 9 through 17 years of age are presented in Table 4, based on safety data collected during clinical studies. (See Table 4.)


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Hospitalized and/or clinically severe dengue fever in long-term safety follow-up data: In an exploratory analysis of up to 6 years of follow up from the first injection in three efficacy studies, an increased risk of hospitalization for dengue including clinically severe dengue (predominantly Dengue Hemorrhagic Fever grade 1 or 2 [WHO 1997]) has been observed in vaccinees with no previous dengue infection. In subjects 9 years of age or older, it was estimated that during a 5 year follow-up about 5 additional hospitalized dengue cases or 2 additional severe dengue cases per 1000 vaccinees with no previous dengue infection could occur following vaccination. Estimates from the long-term analysis suggest the onset of increased risk was mainly during the 3^rd year following the first injection.
This increased risk was not observed in individuals who have been previously infected by dengue virus, where it was estimated that 15 hospitalized dengue cases or 4 severe dengue cases could be prevented per 1000 vaccinees with previous dengue infection during 5 years of follow up from the first injection.

Dengvaxia must not be mixed with any other injectable vaccine(s) or medicinal product(s).
Separate syringes and needles, separate injection sites and preferably separate limbs must be used if any other vaccine(s) or medicinal product(s) is/are concomitantly administered.
Dengvaxia has been evaluated in one clinical study on concomitant administration with Tdap (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed) (688 subjects, 9 to 60 years of age), and in two clinical studies with two HPV vaccines (Human Papillomavirus Vaccine, Recombinant) (528 subjects, 9 to 13 years of age and 480 subjects, 9 to 14 years of age).
There was no evidence of an increased rate of reactogenicity or change in the safety profile of the vaccines when Tdap and HPV vaccines were administered concomitantly with Dengvaxia in any of these studies. Antibody responses to Dengvaxia and Tdap vaccine or HPV vaccine components were not negatively affected by concomitant administration.
For patients receiving treatment with immunoglobulins or blood products containing immunoglobulins, such as blood or plasma, it is advisable to wait for at least 6 weeks, and preferably for 3 months, following the end of treatment before administering Dengvaxia, in order to avoid neutralization of the attenuated viruses contained in the vaccine.
For immunosuppressive therapy or corticosteroid therapy, see Contraindications and Precautions.

Incompatibilities: In the absence of compatibility studies, Dengvaxia must not be mixed with any other injectable vaccine(s) or medicinal product(s).
Special precautions for disposal and other handling: Contact with disinfectants is to be avoided since they may inactivate the vaccine viruses.
Separate syringes and needles, separate injection sites and preferably separate limbs must be used if any other vaccine(s) or medicinal product(s) is/are concomitantly administered.
Dengvaxia is reconstituted by transferring all of the solvent (0.4% sodium chloride solution) provided in the blue-labeled pre-filled syringe into the vial of freeze dried powder with a yellowish green flip off cap. The pre-filled syringe is fitted with a sterile needle for this transfer. The vial is then gently swirled. After complete dissolution, a 0.5 mL dose of the reconstituted suspension is withdrawn into the same syringe. For injection, the syringe should be fitted with a new sterile needle.
The suspension should be visually inspected prior to administration. After reconstitution, Dengvaxia is a clear, colorless liquid with the possible presence of white to translucent particles (of endogenous nature).
After reconstitution with the solvent provided, Dengvaxia must be used immediately.
Any unused product or waste material should be disposed of, preferably by heat inactivation or incineration, in accordance with local regulations.

Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the outer carton in order to protect from light.
For storage conditions after reconstitution of Dengvaxia, see Shelf-life as follows.
Shelf-life: 3 years (36 months).
After reconstitution with the solvent provided, Dengvaxia should be used immediately. However, in-use stability studies have shown that the reconstituted vaccine can be kept for up to 6 hours between 2°C and 8°C (i.e., in a refrigerator) and protected from light.

Vaccines, Antisera & Immunologicals

J07BX - Other viral vaccines ; Used for active immunizations.

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