Side Effects of Dengvaxia (dengue tetravalent vaccine, live)

Dengvaxia (dengue tetravalent vaccine, live) is a vaccine indicated for the prevention of dengue disease caused by dengue virus serotypes 1, 2, 3 and 4. Dengvaxia is approved for use in individuals 9 through 16 years of age with laboratory-confirmed previous dengue infection and living in endemic areas.

Common side effects of Dengvaxia include

• injection site reactions (pain, bruising, itching, and numbness),
• feeling unwell (malaise),
• abdominal pain,
• vomiting,
• indigestion/heartburn,
• generalized redness,
• spinning sensation (vertigo),
• asthma crisis, and
• hives.

Serious side effects of Dengvaxia include

• increased risk of severe dengue disease when the vaccinated individual is subsequently infected with any dengue virus serotype. 

Drug interactions of Dengvaxia include other vaccines. Immunosuppressive therapies may reduce the immune response to Dengvaxia, including

• irradiation,
• antimetabolites,
• alkylating agents,
• cytotoxic drugs and
• corticosteroids (used in greater than physiologic doses).

No specific studies of Dengvaxia have been performed among pregnant women.

Human data are not available to assess the impact of Dengvaxia on milk production, its presence in breast milk, or its effects on the breastfed child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Dengvaxia and any potential adverse effects on the breastfed child from Dengvaxia or from the underlying maternal condition.

Warnings and precautions

Increased Risk of Severe Dengue Disease Following Dengvaxia in Persons not Previously Infected with Dengue Virus

In unvaccinated individuals, first dengue infections rarely cause severe dengue, while second dengue infections with a different serotype are associated with an increased risk of severe dengue.

Dengvaxia administration to individuals not previously infected by dengue virus is associated with an increased risk of severe dengue disease when the vaccinated individual is subsequently infected with any dengue virus serotype. Therefore, healthcare professionals must evaluate individuals for prior dengue infection to avoid vaccinating individuals who have not been previously infected by dengue virus.

Previous infection by dengue virus can be evaluated through a medical record of previous laboratory-confirmed dengue infection or through serotesting prior to vaccination. There is no FDA cleared test available to determine a previous dengue infection. Available non-FDA cleared tests may yield false positive results (e.g., due to cross-reactivity with other flaviviruses).

Other Side Effects

Nonserious adverse reactions were

• injection site pain,
• hematoma,
• pruritus and
• anesthesia.

Nonserious systemic adverse reactions were

• malaise,
• abdominal pain,
• vomiting,
• dyspnea,
• generalized erythema,
• vertigo,
• asthma crisis and
• urticaria.

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.
• The safety of Dengvaxia in subjects 9 through 16 years of age was evaluated in 9 randomized, placebo-controlled, multicenter clinical trials.
• In these studies, a total of 19,102 subjects 9 through 16 years of age received at least one dose of Dengvaxia and 9,484 received placebo (0.9% sodium chloride).
• Overall, 50.9% of trial participants who received Dengvaxia or placebo were female.
• Racial groups were reported as
  • 18.9% Asian,
  • 13% American Indian or Alaska native,
  • 6.4% caucasian,
  • 2.6% black, and
  • 59.1% as other.
• In the largest study (Study 1, NCT01374516; N = 20,869) conducted in four Latin American countries and Puerto Rico, most subjects (99.9%) reported Hispanic ethnicity.
• All studies enrolled subjects irrespective of evidence of previous dengue infection.

Solicited Adverse Reactions

In a multi-center, observer-blind, randomized (2:1), placebo-controlled trial conducted in four Latin American countries and Puerto Rico (Study 1, NCT01374516), 2,000 subjects (out of a total of 20,869 subjects) were recruited during the first 2 months of enrollment for inclusion in the reactogenicity subset. Solicited adverse reactions were recorded daily for 14 days following each vaccination.

Table 1 presents the frequency and severity of solicited injection site reactions reported within 7 days and systemic adverse reactions reported within 14 days following receipt of Dengvaxia or placebo.

Table 1: Percentages of Subjects with Solicited Injection Site Reactions within 7 Days and Systemic Adverse Reactions within 14 Days Following Receipt of Each Dose of Dengvaxia or Placebo in Children and Adolescents 9 through 16 Years of Age in Study 1

Unsolicited Non-Serious Adverse Reactions

• In Study 1, 1.2% of subjects in the Dengvaxia group (16/1,333) and 0.8% of subjects in the placebo group (5/664) reported at least 1 unsolicited non-serious adverse reaction within 28 days following any dose.
• In this study, 0.7% of the subjects in the Dengvaxia group and 0.5% in the placebo group reported at least one unsolicited non-serious injection site adverse reaction.
• The unsolicited non-serious adverse reactions were
  • injection site pain,
  • hematoma,
  • pruritus and anesthesia in the vaccine group and
  • pain and induration in the control group.
• In this study, 0.5% of the subjects in the Dengvaxia group and 0.3% in the placebo group reported at least one unsolicited non-serious systemic adverse reaction.
• The unsolicited non-serious systemic adverse reactions were
  • malaise,
  • abdominal pain,
  • vomiting,
  • dyspnea,
  • generalized erythema,
  • vertigo,
  • asthma crisis and urticaria in the vaccine group and
  • pruritus and lymphadenitis in the control group.
• Most unsolicited non-serious adverse reactions started within 3 days of any injection and resolved within 3 days or less.
• A total of 2 subjects (one subject with asthma crisis and urticaria occurring the day of the first dose, and one subject with malaise occurring 20 days after the first dose) in the Dengvaxia group (0.2%) and none in the placebo group reported unsolicited non-serious Grade 3 (significant; prevents daily activity) adverse reactions.

Severe Dengue Following Vaccination With Dengvaxia And Subsequent Dengue Infection

• Subjects were monitored for severe dengue from Day 0 (day of first study vaccination) to Month 60-72 (after first study vaccination) in three multi-center, observer-blind, randomized (2:1), placebo-controlled trials conducted in Latin America and Puerto Rico (Study 1, NCT01374516) and the Asia-Pacific region (Study 2, NCT01373281; Study 3, NCT00842530).
• A subset of 3,203 subjects (80.1%) enrolled in Study 3 were reconsented to participate in an extension study to evaluate safety of Dengvaxia for 72 months (Study 4, NCT01983553).
• A total of 18,265 children and adolescents 9 through 16 years of age enrolled in these trials received at least one dose of Dengvaxia.
• Table 2 presents the incidences and hazard ratios of severe dengue from Month 13 to Month 60-72 post-vaccination with Dengvaxia or placebo in children and adolescents 9 through 16 years of age, by dengue baseline serostatus.
• An increased rate of severe dengue was observed following vaccination with Dengvaxia and subsequent infection with any dengue virus serotype in persons not previously infected by dengue virus.

Table 2: Number of Events and Incidence of Severe Dengue* From Month 13 to Month 60-72^† in Children 9 through 16 Years of Age, by Previous Dengue Infection Status, in Studies 1, 2, 3 and 4

Non-Fatal Serious Adverse Events

• In the 9 studies conducted among subjects 9 through 16 years of age (NCT 01374516, NCT01373281, NCT00842530, NCT00993447, NCT00875524, NCT00788151, NCT00880893, NCT01187433, NCT01254422), subjects were monitored for serious adverse events (SAEs) for at least 6 months after the last dose of Dengvaxia.
• The proportions of subjects who reported at least 1 non-fatal SAE within 28 days following any dose were 0.6% (123/19,102) in the Dengvaxia group and 0.8% (73/9,484) in the placebo group.
• The following events were considered related to Dengvaxia:
  • asthma attack (day of Dose 1),
  • urticaria (day of Dose 2) and
  • convulsion (day of Dose 1).
• The proportions of subjects who reported at least 1 non-fatal SAE after 28 days and up to 6 months after any dose were similar in the 2 groups: 2.8% in the Dengvaxia group (534/19,102) and 3.2% in the placebo group (307/9,484). None of these SAEs were considered related to the vaccination.

Deaths

• From the first administered dose up to Month 72, 51 deaths (0.3%) for subjects who received Dengvaxia and 26 deaths (0.3 %) for subjects who received placebo were reported in the 9 studies conducted among subjects 9 though 16 years of age.
• None of the deaths were considered related to vaccination.
• Causes of death among subjects were consistent with those generally reported in children and adolescent populations.

Data From Post-Marketing Experience

• In addition to events reported in clinical trials for Dengvaxia, the following adverse events have been spontaneously reported during post-approval use.
• Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine.
• The following adverse events were included based on one or more of the following factors: severity, frequency of reporting, or strength of evidence for a causal relationship to Dengvaxia.

Immune System Disorders

• Allergic including anaphylactic reactions.

Infections And Infestations

• Severe dengue infection, including hospitalization and death, in individuals for whom dengue infection status prior to vaccination was unknown and who were subsequently infected with dengue following vaccination.

Concomitant Administration With Other Vaccines

• Data are not available to establish the safety and immunogenicity of concomitant administration of Dengvaxia with recommended adolescent vaccines.

Immunosuppressive Treatments

• Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to Dengvaxia.

Drug/Laboratory Test Interactions

• Dengvaxia may cause temporary depression of tuberculin purified protein derivative (PPD) test sensitivity, leading to false negative results.
• Tuberculin testing should be performed before Dengvaxia is administered or at least 1 month following vaccination with Dengvaxia.