What evidence supports current recommendations for monkeypox vaccination?

Introduction
Monkeypox virus (MPV) is an orthopoxvirus in the family Poxviridae.¹ The MPV genome is 96.3% identical to smallpox, which is a variola virus that is now eradicated.² Human monkeypox was first identified in 1970 in a 9-month-old baby.³ Outbreaks continued but were predominantly contained within Africa.⁴ In May 2022, multiple cases of MPV were seen in nonendemic countries. As of September 22, 2022, there had been more than 24,500 confirmed MPV cases in the U.S.⁵ This is the largest outbreak seen outside of Africa.⁶ On August 4, 2022, President Biden declared the MPV outbreak a public health emergency.⁷

The current 2022 MPV variant (Clade IIb) appears to have 40 mutations from the closest MPV variant.⁴ The current variant spreads most commonly in men who have sex with men. Transmission is through contact with skin lesions, body fluids, or respiratory droplets from an infected individual. The incubation period is 3 to 17 days and illness can last 2 to 4 weeks, which affords ample time for individuals to unknowingly spread the virus to others and further the outbreak.⁸

Vaccine Recommendations
The Center for Disease Control and Prevention (CDC) has released interim guidance for both nonpharmacologic (ie, avoiding contact with bodily fluids of potentially infected persons, including respiratory secretions) and pharmacologic monkeypox prevention strategies.⁹ Currently the CDC recommends monkeypox vaccination in specific populations rather than a mass vaccination strategy. The current recommendations include pre-exposure prophylaxis (PrEP) in people whose jobs may expose them to monkeypox, such as those who perform diagnostic testing, research laboratory workers, or healthcare workers designated by public health authorities.¹⁰ Post-exposure prophylaxis (PEP) is recommended for individuals who have had known contact with infected individuals or presumed contact.¹¹ Presumed contact includes individuals with a known sexual partner in the past 14 days with MPV or who have had multiple sexual partners in the past 14 days in a geographic area with known MPV. The monkeypox vaccine is recommended to be administered within 4 days of exposure and may have diminished effect if given between 4 and 14 days after exposure. Vaccination after the onset of signs or symptoms of monkeypox is likely not beneficial.

Vaccines
There are currently 2 MPV vaccines available in the United States. Jynneos (known as Imvamune or Imvamax outside of the United States) is a Food and Drug Administration (FDA)-approved vaccine for both smallpox and monkeypox.¹² It is a live, non-replicating, modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine. Jynneos is approved as a 2-dose series (each 0.5 mL subcutaneously) with doses separated by 4 weeks.¹¹ Due to a limited supply of the vaccine, a modified vaccination strategy of 2 x 10⁷ TCID₅₀ MVA-BN 0.1 mL intradermally (2 doses given 4 weeks apart) can be used under an Emergency Use Authorization.¹³ Jynneos must be stored in a freezer between -25 and -15 degrees Celsius or refrigerated between 2 and 8 degrees Celsius.¹⁴ Once Jynneos is thawed and stored in the refrigerator, it must be used within 8 weeks. One of the challenges with using the intradermal route to increase vaccine supply is the stability of the vial once it is punctured (store in refrigerator and discard after 8 hours). This presents the issue of scheduling an adequate number of individuals within the appropriate time frame to prevent vaccine waste. Scarring after intradermal vaccine administration is possible; therefore, individuals with a history of keloid scars are recommended to receive the vaccine subcutaneously.

ACAM2000 is a live smallpox (vaccinia) vaccine that is available off-label for MPV vaccination under an Expanded Access Investigational New Drug (EA-IND) protocol.¹⁵ Vaccinia viruses have more adverse reactions and contraindications than MVA-BN vaccines since they are live and replicating. ACAM2000 is administered via percutaneous vaccination with a bifurcation needle depositing 1 droplet of vaccine on the skin followed by 15 jabs with the needle through the droplet within a diameter of about 5 mm (scarification).¹⁶ The vaccine is stored frozen until ready for use. After reconstitution, it must be used within 6 to 8 hours if kept at room temperature. Unused, reconstituted vaccine may be stored in a refrigerator for up to 20 days.

Throughout the history of smallpox vaccination, preference has shifted from the live vaccinia vaccine to MVA vaccine, largely due to safety concerns. Special populations such as those who are pregnant or breastfeeding, have 3 or more major cardiac risk factors (hypertension, diabetes, hyperlipidemia, smoking, or a first-degree family member with heart disease before age 50 years), have atopic dermatitis, eczema, or other exfoliative skin condition, human immunodeficiency virus (HIV) or any other congenital or acquired immunodeficiency (including from medications), or have a prior history of MPV should not receive ACAM2000.¹⁷

Literature review
There is no data available on clinical efficacy of Jynneos and ACAM2000 in preventing MPV infection or disease, either in the past or in the current outbreak. Jynneos was originally approved for smallpox based on immunogenicity compared to the prior smallpox vaccine ACAM2000.^16,18 The Table summarizes the available immunogenicity studies for MVA-BN vaccines, which are all limited to evidence of smallpox antibody production. This table only includes MVA-BN vaccines since most vaccines given in the U.S. during the current MVP outbreak will likely be the MVA-BN formulation.

Summary
MVA-BN vaccines have shown effective smallpox seroconversion and relative safety in healthy individuals and special populations, including those with HIV, undergoing hematopoietic stem cell transplant, and with atopic dermatitis.^18-28 Limited data with intradermal MVA-BN administration shows similar immunogenicity and safety compared to subcutaneous and intramuscular administration.^24,29 Cutaneous reactions are more common with intradermal administration than with subcutaneous or intramuscular, but overall, there is no increase in serious reactions.

Conclusion
The current MPV outbreak in the U.S. is facing limited vaccine supply and vaccination challenges, including storage and stability requirements, patient-reported vaccine eligibility, and ensuring compliance with a multiple vaccine series. No clinical studies have demonstrated that vaccination decreases MPV infection, but immunogenicity studies suggest that MVA-BN vaccines are relatively safe and lead to smallpox seroconversion that may prevent MPV infection in humans; further data showing that vaccines decrease MPV infection are needed. Individuals who received the MVA-BN vaccine in immunogenicity studies are similar to the higher risk individuals who should receive Jynneos rather than ACAM2000. Populations not studied include pregnant and lactating individuals, and those with cardiac risk factors, eczema, or congenital or other acquired immunodeficiencies. First-generation vaccines such as ACAM2000 have more safety concerns than the MVA-BN vaccines, particularly adverse cardiac events.¹⁶ Although intradermal administration of Jynneos is allowed, this may result in more local adverse events than subcutaneous or intramuscular administration. Further study of the efficacy and safety of intradermal Jynneos administration is underway.³⁰

References

1. Monkeypox. World Health Organization website. May 19, 2022. https://www.who.int/news-room/fact-sheets/detail/monkeypox. Accessed September 23, 2022.
2. Shchelkunov SN, Totmenin AV, Babkin IV, et al. Human monkeypox and smallpox viruses: genomic comparison. FEBS Lett. 2001;509(1):66-70. doi:10.1016/s0014-5793(01)03144-1
3. McCollum AM. Smallpox & Other Orthopoxvirus-Associated Infections. CDC website. August 10, 2022. https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/smallpox-and-other-orthopoxvirus-associated-infections. Accessed September 23, 2022.
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7. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. August 4, 2022. https://www.hhs.gov/about/news/2022/08/04/biden-harris-administration-bolsters-monkeypox-response-hhs-secretary-becerra-declares-public-health-emergency.html. Accessed September 23, 2022.
8. Key Characteristics for Identifying Monkeypox. CDC website. August 23, 2022. https://www.cdc.gov/poxvirus/monkeypox/clinicians/clinical-recognition.html. Accessed September 23, 2022.
9. How to Protect Yourself. CDC website. July 29, 2022. https://www.cdc.gov/poxvirus/monkeypox/prevention/protect-yourself.html. Accessed September 23, 2022.
10. Monkeypox and Smallpox Vaccine Guidance. CDC website. June 2, 2022. https://www.cdc.gov/poxvirus/monkeypox/clinicians/smallpox-vaccine.html#pre-exposure. Accessed September 23, 2022.
11. Interim Clinical Considerations for Use of Jynneos and ACAM2000 Vaccines During the 2022 U.S. Monkeypox Outbreak. August 22, 2022. https://www.cdc.gov/poxvirus/monkeypox/considerations-for-monkeypox-vaccination.html. Accessed September 23, 2022.
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13. Review Memorandum. FDA website. August 9, 2022. https://www.fda.gov/media/160785/download. Accessed September 23, 2022.
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16. ACAM2000. Package Insert. Emergent Product Development Gaithersburg Inc; 2018. Accessed September 12, 2022.
17. Vaccination Administration Considerations for Specific Populations. CDC website. August 9, 2022. https://www.cdc.gov/poxvirus/monkeypox/interim-considerations/special-populations.html. Accessed September 23, 2022.
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19. Overton ET, Lawrence SJ, Stapleton JT, et al. A randomized phase II trial to compare safety and immunogenicity of the MVA-BN smallpox vaccine at various doses in adults with a history of AIDS. Vaccine. 2020;38(11):2600-2607. doi:10.1016/j.vaccine.2020.01.058
20. Overton ET, Lawrence SJ, Wagner E, et al. Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: a randomised, double blind, placebo controlled phase III trial. PLoS One. 2018;13(4):e0195897. doi:10.1371/journal.pone.0195897
21. Jackson LA, Frey SE, El Sahly HM, et al. Safety and immunogenicity of a modified vaccinia Ankara vaccine using three immunization schedules and two modes of delivery: A randomized clinical non-inferiority trial. Vaccine. 2017;35(13):1675-1682. doi:10.1016/j.vaccine.2017.02.032
22. Darsow U, Sbornik M, Rombold S, et al. Long-term safety of replication-defective smallpox vaccine (MVA-BN) in atopic eczema and allergic rhinitis. J Eur Acad Dermatol Venereol. 2016;30(11):1971-1977. doi:10.1111/jdv.13797
23. Greenberg RN, Hay CM, Stapleton JT, et al. A randomized, double-blind, placebo-controlled phase II trial investigating the safety and immunogenicity of modified vaccinia Ankara smallpox vaccine (MVA-BN®) in 56-80-year-old subjects. PLoS One. 2016;11(6):e0157335. doi:10.1371/journal.pone.0157335
24. Frey SE, Wald A, Edupuganti S, et al. Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects. Vaccine. 2015;33(39):5225-5234. doi:10.1016/j.vaccine.2015.06.075
25. Greenberg RN, Hurley MY, Dinh DV, et al. A multicenter, open-label, controlled phase II study to evaluate safety and immunogenicity of MVA smallpox vaccine (IMVAMUNE) in 18-40 year old subjects with diagnosed atopic dermatitis. PLoS One. 2015;10(10):e0138348. doi:10.1371/journal.pone.0138348
26. Overton ET, Stapleton J, Frank I, et al. Safety and immunogenicity of modified vaccinia Ankara-Bavarian Nordic smallpox vaccine in vaccinia-naive and experienced human immunodeficiency virus-infected individuals: an open-label, controlled clinical phase II trial. Open Forum Infect Dis. 2015;2(2):ofv040. doi:10.1093/ofid/ofv040
27. Vollmar J, Arndtz N, Eckl KM, et al. Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine. 2006;24(12):2065-2070. doi:10.1016/j.vaccine.2005.11.022
28. Walsh SR, Wilck MB, Dominguez DJ, et al. Safety and immunogenicity of modified vaccinia Ankara in hematopoietic stem cell transplant recipients: a randomized, controlled trial. J Infect Dis. 2013;207(12):1888-1897. doi:10.1093/infdis/jit105
29. Wilck MB, Seaman MS, Baden LR, et al. Safety and immunogenicity of modified vaccinia Ankara (ACAM3000): effect of dose and route of administration. J Infect Dis. 2010;201(9):1361-1370. doi:10.1086/651561
30. Trial to Evaluate the Immunogenicity of Dose Reduction Strategies of the MVA-BN Monkeypox Vaccine. Clinicaltrials.gov website. Updated September 19, 2022. https://clinicaltrials.gov/ct2/show/NCT05512949?term=jynneos&draw=2&rank=3. Accessed September 23, 2022.

Prepared by:
Justyna Fydrych, PharmD
PGY2 Drug Information Resident

October 2022

The information presented is current as of August 26, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.