Your browser is unsupported

We recommend using the latest version of IE11, Edge, Chrome, Firefox or Safari.

What evidence supports current recommendations for monkeypox vaccination?

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.

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.

Table. Human studies evaluating immunogenicity and safety of MVA-BN vaccines18-27
Population and Intervention
Seroconversion results
Serious safety events
Overton, 202019
HIV-positive adults
MVA-BNa (Imvamune)
Standard dose (SD): SC at weeks 0 and 4
Double dose (DD): 2 SDs SC at weeks 0 and 4
Booster Dose (BD): SD SC at weeks 0 and 4 followed by a booster dose at week 12
Seroconversion rate at week 6: 100%, except for 1 participant in the BD group
Seroconversion rate after 12 months: DD 72.7% and SD 66.7%
14.9% of all participants had severe AE
n=1 severe pancreatitis
n=1 mildly increased troponin I
(both in the BD group)
Pittman, 201918
Healthy soldiers deployed to South Korea, aged 18-42 years
Vaccine-naïve (n=440)
2 SC doses of MVA at weeks 0 and 4 followed by 1 dose of ACAM2000 injected by scarification at week 8
SD injected by scarification at week 0
Seroconversion rate:
MVA group at week 6: 100%
ACAM2000 group at week 4: 97.3%
Major cutaneous reactions MVA vs ACAM2000: 23% vs 92.5%
Most common AE in ACAM2000 group: lymphadenopathy (51%), headache (38%), myalgia (36%), and contact dermatitis (23%)
Overton, 201820
Vaccine-naïve (n=3003)
MVA-BNa (Imvamune)
2 SC doses at weeks 0 and 4
Seroconversion rate 2 weeks after second dose: 99.5%
n=3 troponin elevations (vaccine group)
Jackson, 201721
Healthy, aged 18-40 years
Vaccine-naïve (n=435)
MVA-BNa (Imvamune)  
Arm A: SC at weeks 0 and 4 via S&N
Arm B: SC at weeks 0 and 2 via S&N
Arm C: SC at weeks 0 and 3 via S&N
Arm D: SC at weeks 0 and 4 via JI
PRNT seroconversion at 8 days after the second dose:
Arm A: 99%
Arm B: not numerically reported, visually lower than the other 3 arms
Arm C: not numerically reported, visually lower than arms A and D
Arm D: 92%
n=1 NSTEMI 117 days after first dose by S&N
n=1 hives and erythema of both ears and swelling of one ear within 2 hours after the second dose
Darsow, 201622
Atopic dermatitis (atopic eczema and allergic rhinitis)
Vaccine-naïve (n=60)
MVA-BNa (Imvamune)
2 SC doses on weeks 0 and 4
Seroconversion at day 14: 80%-93%
Seroconversion at day 28: 100%
n=1 hepatic enzyme elevation (mild allergic rhinitis group)
Greenberg, 201623
Healthy, aged 56-80 years
Vaccine experienced
MVA-BNa (Imvamune)
2 SC MVA-BN injections at weeks 0 and 4 (MM group)
SC injection week 0 and MVA-BN week 4 (PM group)
PRNT seroconversion rates:
MM group:
2 weeks after the first dose of MVA-BN: 73.8%
2 weeks after the second dose: 90%
PM group:
2 weeks after MVA-BN (week 6): 77.6%
n=5 cardiac symptoms or ECG changes (MM group)
Frey, 201524
Vaccine-naïve (n=440)
MVA-BNa (Imvamune)
Lyophilized SC 1 × 108 TCID50
Liquid SC 1 × 108 TCID50
Liquid ID 2 × 107 TCID50, 2 doses at weeks 0 and 4
Seroconversion after the second dose:
Lyophilized SC: 99.3%
Liquid SC: 98.0%
Liquid ID: 100%
Statistically significantly more maximum local reactogenicity in the liquid ID group after the first and second doses compared to SC groups
Greenberg, 201525
Atopic dermatitis vs healthy
Vaccine-naïve (n=632)
MVA-BNa (Imvamune)
2 SC doses at weeks 0 and 4
Seroconversion rate 2 weeks after the second dose:
Atopic dermatitis: 97.2%
Healthy: 98.1%
Higher injection site erythema and swelling in atopic dermatitis
n=1 extraocular muscle paralysis (healthy subject)
Overton, 201526
HIV-infected vs healthy controls, CD4+ count 200-750 cells/µL, aged 18-55 years
2 SC doses at weeks 0 and 4
Seroconversion rate at week 6:
HIV-infected, smallpox-naïve: 97.5%
HIV-uninfected, smallpox-naïve: 100%
HIV-infected, smallpox-experienced: 99%
HIV-uninfected, smallpox-experienced: 100%
n=1 injection-site dermatitis
n=1 decrease in neutrophils
n=1 partial incomplete left branch bundle block (all HIV-infected subjects)
Vollmar, 200627
Healthy Caucasian males, aged 20-55 years
Groups 1-4: Vaccine-naïve (n=68)
Group 5: Previously smallpox vaccinated (n=18)
MVA-BNa (Imvamune) 1 dose days 0 and 28
Group 1: 106 TCID50 SC
Group 2: 107 TCID50 SC
Group 3: 108 TCID50 SC
Group 4: 108 TCID50 IM
MVA-BNa (Imvamune)
Group 5: 1 dose of 108 TCID50 SC
Seroconversion rate:
On day 28:
Group 1: 28%
Group 2: 44%
Group 3: 81%
Group 4: 88%
On day 42:
Group 1: 39%
Group 2: 81%
Group 3 & 4: 100%
Group 5: 100% after a single dose
a MVA-BN manufactured by IDT Biologika GmbH (Dessau-Roßlau, Germany) and supplied by Bavarian Nordic (Kvistgård, Denmark).
Abbreviations: AE: adverse event(s), ECG: electrocardiogram, HIV: human immunodeficiency virus, ID: intradermal(ly), IM: intramuscular(ly), JI: jet injector, MVA: Modified vaccinia Ankara, MVA-BN: modified vaccinia Ankara-Bavarian Nordic, PRNT: plaque reduction neutralizing tests, S&N: syringe and needle, SC: subcutaneously, TCID: tissue culture infective doses.

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.

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



  1. Monkeypox. World Health Organization website. May 19, 2022. 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. Accessed September 23, 2022.
  4. Kumar N, Acharya A, Gendelman HE, Byrareddy SN. The 2022 outbreak and the pathobiology of the monkeypox virus. J Autoimmun. 2022;131:102855. doi:10.1016/j.jaut.2022.102855
  5. 2022 U.S. Map & Case Count. CDC website. September 22, 2022. Accessed September 23, 2022.
  6. Titanji BK, Tegomoh B, Nematollahi S, et al. Monkeypox: a contemporary review for healthcare professionals. Open Forum Infect Dis. 2022;9(7):ofac310. doi:10.1093/ofid/ofac310
  7. Biden-Harris Administration Bolsters Monkeypox Response; HHS Secretary Becerra Declares Public Health Emergency. August 4, 2022. Accessed September 23, 2022.
  8. Key Characteristics for Identifying Monkeypox. CDC website. August 23, 2022. Accessed September 23, 2022.
  9. How to Protect Yourself. CDC website. July 29, 2022. Accessed September 23, 2022.
  10. Monkeypox and Smallpox Vaccine Guidance. CDC website. June 2, 2022. 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. Accessed September 23, 2022.
  12. Monkeypox Vaccination Basics. CDC website. August 30, 2022. Accessed September 23, 2022.
  13. Review Memorandum. FDA website. August 9, 2022. Accessed September 23, 2022.
  14. Monkeypox Vaccine Storage and Handling Summary. CDC website. Accessed September 23, 2022.
  15. ACAM2000 Vaccine. CDC website. August 9, 2022. Accessed September 23, 2022.
  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. Accessed September 23, 2022.
  18. Pittman PR, Hahn M, Lee HS, et al. Phase 3 efficacy trial of modified vaccinia Ankara as a vaccine against smallpox. N Engl J Med. 2019;381(20):1897-1908. doi:10.1056/NEJMoa1817307
  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. website. Updated September 19, 2022. 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.