Regulatory Decision Summary for Imvamune

Benefits:

• Imvamune being a non-replicating construct, it offers a safer option for immunization against smallpox, monkeypox and related orthopoxvirus infection and disease, for both currently at-risk personnel and for mass vaccination during a potential orthopoxvirus outbreak.
• Available data indicate safety and efficacy, including in immunocompromised populations that have contraindications for receiving conventional smallpox vaccines, e.g. individuals with human immunodeficiency virus (HIV) or atopic dermatitis.

Risks:

• Available data revealed no special risks or safety concerns following Imvamune administration. No cases of Adverse event of special interests (AESIs) observed with replicating smallpox vaccines were observed with Imvamune, in 7,871 subjects in completed clinical trials. These AESIs are also highly unlikely to occur with Imvamune, which is replication incompetent in human cells, and therefore cannot be transmitted or cause dispersed vaccinia-infection. In addition, the recommended administration of Imvamune via the subcutaneous (SC) or intramuscular (IM) route also excludes the risk of autoinoculation and viral spread since it does not lead to a take reaction. Therefore, this risk has neither been observed so far with Imvamune nor is it expected with future use.
• No confirmed case of myocarditis, pericarditis, endocarditis or any other type of cardiac inflammatory disease (or related syndromes) was recorded, but cardiac AESIs were reported to occur in 1.3% (95/7,093) of Imvamune recipients and 0.2% (3/1,206) of placebo recipients who were smallpox vaccine-naïve. Cardiac AESIs were reported to occur in 2.1% (16/766) of Imvamune recipients who were smallpox vaccine-experienced. The higher proportion of Imvamune recipients who experienced cardiac AESIs was driven by 28 cases of asymptomatic post-vaccination elevation of troponin-I in two studies, that used a different troponin assay than was used in the other previous studies, and had no placebo controls. The clinical significance of these asymptomatic post-vaccination elevations of troponin-I is unknown. Among the cardiac AESIs reported, 6 cases (0.08%) were considered to be causally related to Imvamune vaccination and included tachycardia, electrocardiogram (ECG) T wave inversion, abnormal ECG, ECG ST segment elevation, abnormal ECG T wave, and palpitations. None of the cardiac AESIs considered causally related to study vaccination were considered serious.
• The most likely vaccination error is intradermal (ID) vaccine application, especially given experience with replicating smallpox vaccines. The consequences of an ID vaccination were assessed in a study. The ID route was found to be non-inferior to the SC route, although more local reactogenicity was observed. Imvamune can also safely be applied via intramuscular (IM) injection.

Thus: The benefit/risk assessment is positive, in favor of the extension of Imvamune indications to include monkeypox and related orthopoxviruses.

Based on the evaluation of the data submitted, and as labelled, Biologic and Radiopharmaceutical Drugs Directorate (BRDD) considers that this EUSNDS, control number 233914, for Imvamune, indicated for active immunization against smallpox, monkeypox, and related orthopoxvirus infection and disease in adults 18 years of age and older determined to be at high risk for smallpox, monkeypox or related orthopoxvirus infection complies with the Food and Drug Regulations. A Notice of Compliance (NOC) is recommended.