What are the potential side effects of the Japanese encephalitis (JE) vaccine?

Japanese Encephalitis Vaccine Side Effects

Most Common Reactions Are Mild and Self-Limited

The Japanese encephalitis vaccine (JE-VC) is generally well-tolerated with predominantly mild local and systemic reactions, occurring in approximately half of vaccinees, while serious adverse events are rare at approximately 1% of recipients. 1, 2

Local Reactions

In adults:

• Pain at injection site occurs in 28% after first dose and 18% after second dose 2
• Tenderness affects 29% after first dose and 23% after second dose 2
• Redness, swelling, and severe injection-site reactions each occur in ≤1% of recipients 1

In children:

• Redness is most common in children aged 2 months to <3 years 1, 2
• Pain and tenderness predominate in children aged 3-17 years 1, 2
• Injection-site tenderness occurred in 50% of children receiving the 0.5-mL dose 1

Systemic Reactions

In adults:

• Headache is most frequent: 22% after first dose, 13% after second dose 1, 2
• Myalgia occurs in 13% after first dose, 6% after second dose 1, 2
• Influenza-like illness and fatigue each affect 13% 1, 2

In children:

• Fever (≥100.4°F) develops in 9% within 7 days after first dose and 6% after second dose 1
• Fever rates are higher in children aged <3 years compared to older children 1
• Muscle pain occurs in 31% of children receiving the 0.5-mL dose 1

Serious Adverse Events Are Uncommon

Serious adverse events occur in approximately 1% of JE-VC recipients, with no serious neurologic events identified in the pivotal safety study of nearly 2,000 adults. 1, 2

Documented Serious Events in Clinical Trials

• Among 1,411 children, 23 (2%) reported serious adverse events within 7 months, most commonly pneumonia (n=6) and febrile seizures (n=5) 1
• Only 3 serious adverse events occurred within 2 weeks of vaccination: one febrile convulsion, one cellulitis, and one gastroenteritis 1
• One death from disseminated intravascular coagulation after suspected bacterial meningitis occurred 4 months post-vaccination and was deemed unrelated by investigators 1

Postlicensure Surveillance Data

No patterns of serious hypersensitivity, neurologic, or other serious adverse events considered vaccine-related were identified in U.S. surveillance covering >1 million doses distributed during 2009-2016. 1, 2

• Overall adverse event rate was 14.8-15.2 per 100,000 doses distributed 1
• This extensive surveillance provides reassurance about the safety profile in real-world use 1, 2

Allergic Reactions: Modern vs. Older Vaccines

Current Vero Cell-Derived Vaccine (JE-VC)

No serious allergic reactions occurred in any study group during prelicensure trials comparing JE-VC to placebo or older mouse brain-derived vaccine. 1, 2

• Only 2 cases of urticaria occurred among 2,650 participants in the pivotal safety study 1
• One case was generalized urticaria occurring 8 days post-vaccination, treated with cetirizine and resolved in 3 days 1
• Angioedema was not observed in clinical trials 1

Older Mouse Brain-Derived Vaccine (JE-MB)

The older mouse brain-derived vaccine had significantly higher rates of serious hypersensitivity reactions, estimated at 10-260 cases per 100,000 vaccinees. 1

• Reactions included generalized urticaria, angioedema of extremities/face/oropharynx, with accompanying bronchospasm and respiratory distress in some cases 1
• Most reactions occurred within 24-48 hours after first dose, but delayed onset (median 3 days, range 1-14 days) occurred after subsequent doses 1
• Persons with history of anaphylaxis or allergies were 2-11 times more likely to develop hypersensitivity reactions 1
• Gelatin stabilizer was implicated in some allergic reactions 1

Neurologic Safety Profile

The current JE-VC vaccine has an excellent neurologic safety profile with no serious neurologic events identified in clinical trials. 1, 2

Current Vaccine Safety

• Among JE-VC recipients, <1% had neurologic adverse events including febrile seizures (n=3), drooling (n=1), and dizziness (n=1), with rates similar to comparison vaccines 1
• No serious neurologic events were identified in the pivotal safety study 1

Historical Concerns with Mouse Brain-Derived Vaccine

• The older JE-MB vaccine raised concerns due to mouse brain substrate potentially containing myelin basic protein 1
• Moderate to severe neurologic symptoms (encephalitis, seizures, gait disturbances, parkinsonism) were reported at 0.1-2 cases per 100,000 vaccinees 1
• Cases of acute disseminated encephalomyelitis (ADEM) temporally associated with JE-MB led Japan to suspend routine vaccination in 2005 1
• WHO determined no evidence existed of increased ADEM risk and no causal link was demonstrated 1

Booster Dose Tolerability

Booster doses are well-tolerated with similar or lower reaction rates than primary series, and no serious adverse events were reported within 28 days of booster administration. 1, 2

Adults

• Tenderness in 19% and pain in 13% were most frequent local reactions 1
• Headache (11%) and fatigue (10%) were most common systemic reactions 1
• No serious adverse events occurred within 28 days 1

Children

• 8% had local adverse events and 14% had systemic adverse events within 7 days 1
• Two serious adverse events occurred within 1 month: one lumbar abscess and one dengue fever (4 weeks post-vaccination) 1

Concomitant Vaccination Considerations

With Hepatitis A Vaccine

Co-administration with hepatitis A vaccine increases reports of pain, redness, and swelling at injection site compared to either vaccine alone. 1, 2

• No other differences in safety or reactogenicity were observed 1
• Immunogenicity remained adequate for both vaccines 1

With Rabies Vaccine

Co-administration with rabies vaccine results in higher rates of both local (75% vs 63%) and systemic (60% vs 54%) reactions compared to JE-VC alone. 1, 2

Critical Clinical Pitfalls to Avoid

Patients should not be withheld from receiving a second dose due to mild reactions after the first dose. 2

• Solicited adverse events are more frequent after dose 1 than dose 2 in both adults and children 1
• In children aged 2-11 months, 46% reported events after dose 1 versus 28% after dose 2 1
• In children aged 1-17 years, 32% reported events after dose 1 versus 18% after dose 2 1

Monitor for delayed hypersensitivity reactions, particularly after subsequent doses. 2

• While most reactions with older vaccines occurred within 24-48 hours after first dose, delayed onset (up to 14 days) occurred after subsequent doses 1
• This pattern is less relevant with modern JE-VC but awareness remains important 2

Persons with history of severe allergies require counseling but are not absolutely contraindicated from vaccination with modern JE-VC. 1

• The older JE-MB vaccine showed 2-11 times higher risk in allergic individuals 1
• Modern JE-VC has not demonstrated this pattern in clinical trials 1, 2