Key points
- The virus that causes smallpox is part of the genus (group) Orthopoxvirus. Since 1980, smallpox has been considered eradicated.
- The vaccines available that provide protection against smallpox can also provide cross-protection against other orthopoxviruses.
- After smallpox eradication, routine vaccination against smallpox among the general public was stopped because it was no longer needed.
Overview
Smallpox is a serious infectious disease caused by the variola virus. The disease spreads easily from person to person, causing high fever, and a distinctive, progressive skin rash.
Reminder
Available vaccines & manufacturer package inserts
There are two types of vaccines licensed in the United States that can prevent smallpox disease. Both vaccines are made from a virus called vaccinia, which is a poxvirus similar to variola virus, but less harmful.
ACAM2000
- Approved for the prevention of smallpox only.
- Approved by the FDA in 2007. It is approved for use in people who have a high chance of getting smallpox.
- It is also the preferred vaccine to protect against smallpox except in persons who are severely immunodeficient or with relative contraindications.
- During the 2022 mpox outbreak, ACAM2000 is allowed to be used under the Expanded Access Investigation New Drug Application (EA-IND)
- It is also the preferred vaccine to protect against smallpox except in persons who are severely immunodeficient or with relative contraindications.
- This vaccine contains a poxvirus strain that can cause a clinical infection in humans that can be transmitted to others. However, this vaccine cannot cause smallpox.
JYNNEOS
- Also known as Imvamune or Imvanex in other countries.
- Approved for the prevention of smallpox and mpox.
- The FDA approved JYNNEOS in 2019 for use in people ages 18 years and older and determined to be at high risk for smallpox or mpox infection.
- It is the preferred vaccine to protect against mpox.
- During the 2022 mpox outbreak, the FDA also issued an EUA for JYNNEOS use in people under ages 18 years and for alternative routes of administration for those ages 18 years and older.
- It is the preferred vaccine to protect against mpox.
- This vaccine contains a poxvirus strain that does not cause clinical infections.
Who should & should not get the vaccine
General public
After smallpox eradication, routine vaccination against smallpox among the general public was stopped because it was no longer needed.
Guidance for healthcare providers
Healthcare providers should consult CDC guidance for the most current information on who should or should not get a vaccine.
Side effects
ACAM2000
Common side effects
- Itching.
- Swollen lymph nodes.
- Sore arm.
- Fever.
- Headache.
- Body ache.
- Mild rash.
- Fatigue (tiredness).
Serious side effects
- Heart problems (including myocarditis and pericarditis).
- Swelling of the brain or spinal cord.
- Problems with the vaccination site blister, including infection.
- Spreading the virus to other parts of the body or to another person.
- Severe allergic reaction after vaccination.
- Accidental infection of the eye (may cause swelling of the cornea, causing watery, painful eyes and blurred vision, scarring of the cornea, and blindness).
JYNNEOS
Common side effects
- Injection site reactions, including pain, redness, swelling, hardening of the skin, and itching. Injection site reactions, except for pain, may occur more frequently after intradermal administration than after subcutaneous administration).
- Headache.
- Muscle pain.
- Fatigue (tiredness).
- Nausea.
- Change in appetite.
- Chills.
- Fever.
When to call 911
Vaccines, like any medicine, can have side effects. The most common side effects are usually mild and go away on their own.
Report possible adverse events to VAERS
A closer look at the safety data
ACAM2000
There are several serious adverse events that have been reported following the first vaccination or revaccination at a later date with ACAM2000.1These are serious risks and certain individuals who receive live vaccinia virus vaccine are more prone to these adverse events.
- Myocarditis and pericarditis
- The heart muscle and lining become inflamed. The package insert states the suspected cases were observed at a rate of 5.7 per 1,000 primary vaccinees.
- The heart muscle and lining become inflamed. The package insert states the suspected cases were observed at a rate of 5.7 per 1,000 primary vaccinees.
- General, progressive, and severe vaccinia
- This condition can occur in immunocompromised people and is caused by the uncontrolled replication of the vaccinia virus. The virus causes open wounds, and depending on the severity, can lead to death.
- This condition can occur in immunocompromised people and is caused by the uncontrolled replication of the vaccinia virus. The virus causes open wounds, and depending on the severity, can lead to death.
- Eczema vaccinatum resulting in permanent sequelae or death
- This occurs when the vaccinia virus spreads and causes an overall rash and systemic reactions.
- This occurs when the vaccinia virus spreads and causes an overall rash and systemic reactions.
- Fetal death
- Pregnant people who have received a live vaccinia virus vaccine are more susceptible to spontaneous abortion (miscarriage).
- Pregnant people who have received a live vaccinia virus vaccine are more susceptible to spontaneous abortion (miscarriage).
- Encephalitis, Encephalomyelitis and Encephalopathy
- These are conditions of inflammation of brain, spinal cord, or both.
- These are conditions of inflammation of brain, spinal cord, or both.
- Erythema multiforme major (EMM), including Stevens-Johnson Syndrome (SJS)
- EMM is a skin reaction from an infection or medication. SJS is a rare and serious disorder that affects skin, moist surfaces of the body (such as inside of mouth and throat), genitals, and eyes.
- EMM is a skin reaction from an infection or medication. SJS is a rare and serious disorder that affects skin, moist surfaces of the body (such as inside of mouth and throat), genitals, and eyes.
- Ocular complications and blindness
- When the vaccinia virus enters the eye region, it can cause eyelid infections, swelling, sensitivity to light, irritation and damage to the cornea, and possible blindness.
- When the vaccinia virus enters the eye region, it can cause eyelid infections, swelling, sensitivity to light, irritation and damage to the cornea, and possible blindness.
Acute ischemic cardiac events (ICE)2
In March 2008, ACAM2000 replaced the previous stockpiled smallpox vaccine, Dryvax®, as the only licensed smallpox vaccine at the time. While not routinely administered, ACAM2000 was administered to people entering military service and those working in labs handling variola (smallpox) virus. As part of the post-licensure marketing commitments for ACAM2000, FDA, CDC, Department of Defense, and the vaccine manufacturer, gathered additional safety data on adverse events following vaccination. In March 2011, a routine safety data review within Vaccine Adverse Event Reporting System (VAERS), co-managed by CDC and FDA, identified a safety concern of acute ischemic cardiac events (ICE) following ACAM2000 vaccination.
Researchers reviewed all reports to VAERS submitted from March 1, 2008 through June 30, 2013, following ACAM2000 vaccination. Possible ICE cases were identified by searching for specific medical terms, including myocardial ischemia (lack of blood flow back to the heart), acute myocardial infarction (heart attack), and ischemia (restriction of blood supply to any part of the body). A clinical review of the cardiovascular reports identified 16 cases of myocarditis/pericarditis (inflammation of the heart muscle or lining of the heart) and 15 ICE cases. This review did not confirm the concerns of ICE following ACAM2000. The study also suggested that with pre-vaccination screening of ACAM2000, cardiac events in a generally healthy population remain uncommon.
JYNNEOS
The overall JYNNEOS clinical trial program included 22 studies and a total of 7,859 people ages 18 through 80 years of age who received at least 1 dose of JYNNEOS. Findings included:
- People with skin conditions (either active or history of skin conditions such as eczema or atopic dermatitis) who received JYNNEOS experienced mild to moderate skin reactions from the vaccine. No safety concerns were found during this study in people with skin conditions.3
- During a study of the vaccine and placebo groups, there were three cases of heart palpitations, two cases of tachycardia, and no cases of myocarditis or pericarditis detected. Overall, data did not suggest an increased risk of myocarditis or pericarditis after vaccination with JYNNEOS compared with placebo controls.456
- Across all 22 clinical trials, the safety profile of JYNNEOS was favorable in all populations, including people with HIV or other immunocompromising conditions. 7There were no clinically relevant differences in the safety or the reactogenicity of JYNNEOS in populations who were or were not previously exposed to a vaccinia virus vaccine.
- The reported complications from live vaccinia virus vaccines, such as rashes caused by the virus (including generalized and progressive vaccinia), erythema multiforme (skin reaction from an infection or medication), or encephalitis, were not observed during the clinical trials for JYNNEOS.
How CDC monitors vaccine safety
CDC and the Food and Drug Administration (FDA) are committed to ensuring that vaccines provided to the public are safe and effective. Once vaccines are licensed or authorized for emergency use in the United States, CDC and FDA continuously monitor them through several safety systems.
Resources
- https://www.fda.gov/media/75792/download
- McNeil, M. M., Cano, M., R Miller, E., Petersen, B. W., Engler, R. J., & Bryant-Genevier, M. G. (2014). Ischemic cardiac events and other adverse events following ACAM2000(®) smallpox vaccine in the Vaccine Adverse Event Reporting System. Vaccine, 32(37), 4758–4765. https://doi.org/10.1016/j.vaccine.2014.06.034
- Greenberg, R. N., Hurley, M. Y., Dinh, D. V., Mraz, S., Vera, J. G., von Bredow, D., von Krempelhuber, A., Roesch, S., Virgin, G., Arndtz-Wiedemann, N., Meyer, T. P., Schmidt, D., Nichols, R., Young, P., & Chaplin, P. (2015). 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, 10(10), e0138348. https://doi.org/10.1371/journal.pone.0138348
- Overton, E. T., Lawrence, S. J., Wagner, E., Nopora, K., Rösch, S., Young, P., Schmidt, D., Kreusel, C., De Carli, S., Meyer, T. P., Weidenthaler, H., Samy, N., & Chaplin, P. (2018). 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, 13(4), e0195897. https://doi.org/10.1371/journal.pone.0195897
- Greenberg, R. N., Hay, C. M., Stapleton, J. T., Marbury, T. C., Wagner, E., Kreitmeir, E., Röesch, S., von Krempelhuber, A., Young, P., Nichols, R., Meyer, T. P., Schmidt, D., Weigl, J., Virgin, G., Arndtz-Wiedemann, N., & Chaplin, P. (2016). 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, 11(6), e0157335. https://doi.org/10.1371/journal.pone.0157335
- Zitzmann-Roth, E. M., von Sonnenburg, F., de la Motte, S., Arndtz-Wiedemann, N., von Krempelhuber, A., Uebler, N., Vollmar, J., Virgin, G., & Chaplin, P. (2015). Cardiac safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population. PloS one, 10(4), e0122653. https://doi.org/10.1371/journal.pone.0122653
- Overton, E. T., Stapleton, J., Frank, I., Hassler, S., Goepfert, P. A., Barker, D., Wagner, E., von Krempelhuber, A., Virgin, G., Meyer, T. P., Müller, J., Bädeker, N., Grünert, R., Young, P., Rösch, S., Maclennan, J., Arndtz-Wiedemann, N., & Chaplin, P. (2015). 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 infectious diseases, 2(2), ofv040. https://doi.org/10.1093/ofid/ofv040
- Duffy J, Marquez P, Moro P, Weintraub E, Yu Yon, Boersa P, Donahue JG, Glanz JM, Goddard K, Hambidge SJ, Lewin B, Lewis N, Rouse D, Shimabukuro T. Safety Monitoring of JYNNEOS Vaccine During the 2022 Mpox Outbreak – United States, May 22-October 21, 2022.MMWR Morb Mortal Wkly Rep. 2022 Dec 9;71:51:1555-1559.
- Rao AK, Petersen BW, Whitehill F, Razeq JH, Isaacs SN, Merchlinsky MJ, Campos-Outcalt D, Morgan RL, Damon I, Sanchez PJ, Bell BP. Use of JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) for Preexposure Vaccination of Persons at Risk for Occupational Exposure to Orthopoxviruses: Recommendations of the Advisory Committee on Immunization Practices — United States, 2022.MMWR. 2022 Jun 3;71(22):734-742.
- Decker MD, Garman PM, Hughes H, Yacovone MA, Collins LC, Fegley CD, Lin G, DiPietro G, Gordon DM. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. 2021 Sep 15;39(39):5541-5547. Epub 2021 Aug 26.
- Faix DJ, Gordon DM, Perry LN, Raymond-Loher I, Tati N, Lin G, DiPietro G, Selmani A, Decker MD. Prospective Safety Surveillance study of ACAM2000 smallpox vaccine in deploying military personnel.Vaccine. 2020 Oct 27;38(46):7323-7330. Epub 2020 Sep 20.
- Pittman PR, Hahn M, Lee HS, Koca C, Samy N, Schmidt D, Hornung J, Weidenthaler H, Heery CR, Meyer TPH, Silbernagl G, Maclennan J, Chaplin P. Phase 3 Efficacy Trial of Modified Vaccinia Ankara as a Vaccine against Smallpox.N Engl J Med. 2019 Nov 14;381(20):1897-1908.
- Turner Overton E, Lawrence SJ, Wagner E, Nopora K, Rösch S, Young P, Schmidt D, Kreusel C, De Carli S, Meyer TP, Weidenthaler H, Samy N, Chaplin P. 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 Apr 13;13(4): e0195897.
- Greenberg RN, Hay CM, Stapleton JT, Marbury TC, Wagner E, Kreitmeir E, Rösch S, von Krempelhuber A, Young P, Nichols R, Meye TP, Schmidt D, Weigl J, Virgin G, Arndtz-Wiedemann N, Chaplin P. 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 Jun 21;11(6):e0157335. eCollection 2016.
- Petersen BW, Harms TJ, Reynolds MG, Harrison LH. Use of Vaccinia Virus Smallpox Vaccine in Laboratory and Health Care Personnel at Risk for Occupational Exposure to Orthopoxviruses — Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2015.MMWR. 2016 Mar 18;65(10):257-262.
- Greenberg RN, Hurley MY, Dinh DV, Mraz S, Gomez Vera J, von Bredow D, von Krempelguber A, Roesch S, Virgin G, Arndtz-Wiedemann N, Meyer TP, Schmidt D, Nichols R, Young P, Chaplin P. 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 Diagnoses Atopic Dermatitis.PLoS One. 2015 Oct 6;10(10):e0138348. Epub 2015 Oct.
- Frey SE, Wald A, Edupuganti S, Jackson LA, Stapleton JT, El Sahly H, El-Kamary SS, Edwards K, Keyserling H, Winokur P, Keitel W, Hill H, Goll JB, Anderson EL, Grahan IL, Johnston C, Mulligan M, Rouphael N, Atmar R, Patel S, Chen W, Kotloff K, Creech CB, Chaplin P, Belshe RB. Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects.Vaccine.2015 Sep 22;33(39):5225-34. Epub 2015 Jul 2.
- Turner Overton E, Stapleton J, Frank I, Hassler S, Goepfert PA, Barker D, Wagner E, von Krempelhuber A, Virgin G, Meyer TP, Müller J, Bädeker N, Grünert R, Young P, Rösch S, Maclennan J, Arndtz-Wiedemann N, Chaplin P. Safety and Immunogenicity of Modified Vaccinia Anakara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naïve and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial.Open Forum Infect Dis. 2015 May 5;2(2):ofv040. eCollection 2015.
- Zitzmann-Roth EM, von Sonnenburg F, de la Motte S, Arndtz-Wiedemann N, von Krempelhuber A, Uebler N, Vollmar J, Virgin G, Chaplin P. Cardiac Safety of Modified Vaccinia Ankara for vaccination against smallpox in a young, healthy study population.PLoS One. 2015 Apr 16;10(4):e0122653. eCollection 2015.
- Petersen BW, Damon IK, Pertowski CA, Meaney-Delman D, Guarnizo JT, et al. Clinical Guidance for Smallpox Vaccine Use in a Postevent Vaccination Program. MMWR. 2015;64(RR02):1-26.
- McNeil MM, Cano M, Miller E, Petersen BW, Engler RJ, Bryant-Genevier MG. Ischemic cardiac events and other adverse events following ACAM2000(®) smallpox vaccine in the Vaccine Adverse Event Reporting System. Vaccine. 2014 Aug 20;32(37):4758-65.
- Tack DM, Karem KL, Montgomery JR, Collins L, Bryant-Genevier MG, et al. Unintentional transfer of vaccinia virus associated with smallpox vaccines: ACAM2000(®) compared with Dryvax(®)Hum Vaccin Immunother. 2013 Jul;9(7):1489-96.
- Verardi PH, Titong A, Hagen CJ. A vaccinia virus renaissance: new vaccine and immunotherapeutic uses after smallpox eradicationHum Vaccin Immunother. 2012 Jul;8(7):961-70.
- CDC. Newly Licensed Smallpox Vaccine to Replace Old Smallpox Vaccine. MMWR 2008; 57(08):207–8.
- Greenberg RN, Kennedy JS. ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008 Apr;17(4):555-64
- Poland GA, Grabenstein JD, Neff JM. The US smallpox vaccination program: a review of a large modern era smallpox vaccination implementation programVaccine. 2005 Mar 18;23(17-18):2078-81.
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- Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis. 1970 Oct;122(4):303-9.
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- https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6402a1.htm
- Pittman, P. R., Hahn, M., Lee, H. S., Koca, C., Samy, N., Schmidt, D., Hornung, J., Weidenthaler, H., Heery, C. R., Meyer, T. P. H., Silbernagl, G., Maclennan, J., & Chaplin, P. (2019). Phase 3 Efficacy Trial of Modified Vaccinia Ankara as a Vaccine against Smallpox. The New England journal of medicine, 381(20), 1897–1908. https://doi.org/10.1056/NEJMoa1817307