In the European Union, according to the European Centre for Disease Prevention and Control (ECDC) data, between May and July 2022, around 2,682 cases of monkeypox were reported in 23 EU member states (Austria, Belgium, Bulgaria, Germany, Greece, Denmark, Ireland, Spain, Italy, Latvia, Luxembourg, Malta, the Netherlands, Poland, Portugal, Romania, Slovenia, Hungary, Finland, France, Croatia, Czech Republic, and Sweden), as well as Norway and Iceland. In most of the affected individuals, skin lesions were identified around the genital area, indicating that transmission likely occurs through close physical contact during sexual activity.

1. Imvanex (modified vaccinia Ankara – Bavarian Nordic (MVA-BN) virus) – a vaccine initially approved through the centralized procedure of the EU, initially against smallpox, but subsequently, in July 2022, also against monkeypox (EMA 2022a).
2. JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Non-Replicating) – a vaccine against smallpox and monkeypox, authorized for use by the Food and Drug Administration (FDA) (FDA 2019).

The manufacturer of both mentioned vaccines, Jynneos and Imvanex, is the company Bavarian Nordic. According to the European Centre for Disease Prevention and Control (ECDC) assessment, affected countries are recommended to consider the possibility of early vaccination post-exposure using Bavarian Nordic’s third-generation vaccine to prevent the disease or reduce its severity.

1. Tecovirimat SIGA 200 mg hard capsules (INN Tecovirimat) – authorized for use through a centralized procedure in early 2022 (EMA 2022b). According to the approved summary of product characteristics, this medication is indicated for the treatment of various viral infections in adults and children weighing at least 13 kg, including smallpox, monkeypox, or cowpox. Treatment with Tecovirimat should commence as soon as possible after diagnosis. The recommended dosage for adult patients weighing over 40 kg is 600 mg (three capsules of 200 mg each) every 12 hours for 14 days, with the final package containing a total of 84 hard capsules.
2. The second authorized medication is TPOXX 200 mg (INN Tecovirimat), indicated for the treatment of smallpox caused by the variola virus in adults and pediatric patients weighing at least 13 kg. Based on an FDA recommendation, it is also indicated for patients with MPOX (FDA 2023).

By the end of August 2022, according to the World Health Organization (WHO), the reported cases of MPOX worldwide in week 34 (August 22^nd to 28^th, 2022) indicated a 13.7% increase compared to the previous week, with 6,746 newly reported cases in week 34 compared to 5,931 in week 33 (WHO 2022a, 2022b) (Fig. 1). The majority of cases in the last four weeks were reported from the Pan American (66.9%) and European regions of the WHO (32.3%). The reported information for the top ten most affected countries includes the US (17,333 cases), Spain (6,543 cases), Brazil (4,493 cases), Germany (3,455 cases), France (3,421 cases), the UK (3,340 cases), Peru (1,434 cases), Canada (1,228 cases), the Netherlands (1,160 cases), and Portugal (846 cases), representing 88.5% of all registered cases worldwide. Six of these countries are in Europe. As of August 31^st, Bulgaria has confirmed four cases with laboratory results.

Figure 1. 

Distribution of cases by month (January 2022-August 2022) for the six WHO regions.

The European Commission, based on information received from member states and in accordance with the approved 2022 work plan of the Health Emergency Preparedness and Response Authority (HERA), conducted negotiations with Bavarian Nordic and purchased over 330,000 doses of the JYNNEOS vaccine in several stages (HERA 2022). The decision to procure doses of the vaccine approved in the United States, rather than the Imvanex vaccine, was due to Bavarian Nordic’s ability to deliver JYNNEOS doses quickly, while Imvanex production would have taken longer, delaying deliveries to member states. Subsequently, the purchased doses were donated to requesting member states based on the pro-rata principle, aiming for an even distribution of doses according to each country’s population. Priority was given to delivering vaccines to EU member states that had the highest number of confirmed cases at the time of the donation agreement between the respective member state and the European Commission, represented by the HERA Directorate-General. This direct procurement of the JYNNEOS vaccine sets a precedent as it marks the first instance of the EU budget being used through the EU4Health program to directly purchase vaccine doses that are later donated to member states.

The first delivery of 5,300 doses of the JYNNEOS vaccine was made on June 28, 2022, with Spain being the first country to benefit from the donation after the United States, as it was one of the most affected countries at that time (Olivier 2022). It’s important to note that for a member state to receive the JYNNEOS vaccine as a donation, the respective member state must enter into a donation agreement with the European Commission and confirm that the FDA-approved vaccine can be applied within the territory of the receiving member state.

The logistics for delivery were carried out through the EU Civil Protection Mechanism, with deliveries made to the following member states: Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, and Sweden. Even quantities of the vaccine were delivered to Ukraine, Norway, and Iceland. The three countries that received the largest donations of vaccine doses were Germany, Italy, and France, which were among the most affected by the spread of MPOX.

To prevent and avoid the establishment of endemic outbreaks of MPOX in the European Union, on November 17, 2022, the signing of a Framework Agreement between Bavarian Nordic and HERA, representing the European Commission, was announced for the delivery of the vaccine. Fourteen member states participate in the Framework Agreement, allowing them to deliver up to 2 million doses of the vaccine within their territory between 2023 and 2024 (European Commission 2022a).

In response to the epidemic situation, the European Health Emergency Preparedness and Response Authority (DG HERA) negotiated with the manufacturer Meridian/SIGA. As a result of the negotiations on September 26, 2022, 10,000 therapeutic courses of the medicinal product TPOX (INN Tecovirimat) were purchased. The purchase was made through rescEU funds to treat patients in member states with immediate needs. The purchased therapeutic courses of the medicinal product are available to all Union member states participating in the European Union Civil Protection Mechanism (European Commission 2022b).

On October 23, 2023, the signing of a Framework Agreement for the delivery of the medicinal product was announced. Thirteen EU member states are participating in the Framework Agreement, with a total contract value of 18 million euros. Therefore, member states will be able to deliver specific antiviral vaccines to their citizens when needed (SIGA Therapeutics 2023).

From the report published on August 14, 2023, regarding the spread of MPOX across all 6 regions of the World Health Organization, a clear trend of a sharp decrease in MPOX cases is evident in the European region (Fig. 2). Besides Europe, the only other region where a decrease in MPOX cases is observed is North and South America. According to data from the European Centre for Disease Prevention and Control (ECDC), administered doses of the vaccine produced by Bavarian Nordic between September 2022 and February 2023 exceeded 333,000 across 25 countries within the European Union and the European Economic Area (European Center for Disease prevention and control 2023).

Figure 2. 

Distribution of cases by month (January 2022-August 2023) for the six WHO regions.

Alongside actions at the European level concerning preventive measures and treatment of those affected by MPOX, Bulgaria has also implemented prevention measures based on the recommendation of European health authorities. A special ordinance, Minister of Health Order No. N-5 of November 29, 2022, has been issued for the conditions and procedures for conducting diagnostics, prevention, and control of monkeypox (Ministry of Health 2022). This ordinance defines the conditions and procedures for conducting diagnostics, prevention, and control of monkeypox, including:

1. Conditions and procedures for isolation, including mandatory isolation of individuals with monkeypox.
2. Conditions and procedures for quarantine, including mandatory quarantine for contacts of individuals with monkeypox.
3. Criteria for identifying contacts of individuals with monkeypox.

Regarding therapeutic options, there remains an open question about the possibility of using the vaccine Jynneos or the medicinal product TPOXX (INN: Tecovirimat) in Bulgaria. The Law on Medicinal Products for Human Use (LMPHU) allows treatment of a specific patient with a medicinal product not approved under LMPHU, through a special order from a hospital, under conditions specified by the Minister of Health (Article 9 of LMPHU).

Additionally, the Minister of Health, upon a motivated proposal from the Chief State Health Inspector and coordinated with the Executive Director of the Executive Agency of Medicines, can authorize treatment for a specific period with a medicinal product not approved under Chapter Three of LMPHU when the country faces an epidemic caused by pathogens or toxins, or when there’s presumed or confirmed distribution of chemical agents or nuclear radiation, and there’s no appropriate authorized medicinal product in Bulgaria or the EU is available (Article 10 of LMPHU).

The Jynneos vaccine does not fall within the scope of Articles 9 and 10 of the Law on Medicinal Products for Human Use. These provisions allow the use of unapproved medicinal products in the country for specific patients, but only for the purpose of treating specific diseases and in compliance with the regulations and requirements of the secondary normative act (Ordinance No. 10 of November 17, 2011, regarding the conditions and procedures for treating unapproved medicinal products in the Republic of Bulgaria, medicinal products applied outside the conditions of the authorization for use, and compassionate use medicinal products, as well as the conditions and procedures for inclusion, changes, exclusion, and supply of medicinal products from the list under Article 266a, para. 2 of the law on medicinal products for human use). The medicinal product represents a vaccine intended not for treatment but for prophylaxis and prevention of monkeypox.

Since explicit legal provisions for the application of unauthorized medicinal products for prophylaxis are not available, the possibility remains open for discussion concerning Article 9 of the Law on Medicinal Products in Human Medicine (LMPHU), and consequently, Regulation No. 10/2011 by analogy for medicinal products used for prophylaxis. This would require a prior assessment by medical specialists from the perspective of safeguarding human health, safety, risks, benefits, etc. For this purpose, medical specialists would need to compare the goals, risks, and benefits when applying unauthorized medicinal products for treatment versus their potential application for prophylaxis, assessing their similarities and differences.

Regarding the medicinal product TPOXX, which is authorized by the FDA but lacks authorization from the European Medicines Agency, there exists a regulatory issue with its application. Despite its therapeutic purpose, it couldn’t be applied based on Regulation No. 10/2011 because another approved medicinal product, specifically Tecovirimat SIGA 200 mg hard capsules, exists within the European Union territory. Additionally, the Regulation explicitly requires treatment to be conducted in hospital conditions, excluding the possibility of the medicinal product being used in outpatient settings. In a reported clinical case, Ivanov and colleagues describe two patients infected with monkeypox virus, where therapy was conservatively managed due to the lack of Tecovirimat in Bulgaria (Ivanov 2023).