Smallpox Medication

Updated: Jul 28, 2020
  • Author: Aneela Naureen Hussain, MD, MBBS, FAAFM; Chief Editor: John L Brusch, MD, FACP  more...
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Medication Summary

The first antiviral for treatment of smallpox disease, tecovirimat (TPOXX), was approved by the US Food and Drug Administration (FDA) in July 2018. The FDA approved a second antiviral according to the animal rule, brincidofovir, for treatment of smallpox in June 2021

The only prevention is vaccination. Certain medications, including topical idoxuridine and cidofovir, can be used under investigational new drug (IND) protocol for the management of smallpox. [30]

Secondary bacterial infections of the skin can be treated with semisynthetic penicillins (nafcillin, oxacillin, dicloxacillin) or first-generation cephalosporins (eg, cefazolin, cephalexin) or clindamycin. Ampicillin/sulbactam or amoxicillin/clavulanate can also be used. A history of prior adverse reactions or hypersensitivity is the primary contraindication.

The vaccinia virus vaccine is delivered by the scarification method, which involves dipping a bifurcated needle into the vaccine and poking the tip of the needle into the skin 3 times (15 times if revaccination). Successful vaccination is marked by the typical vaccinia (jennerian or major) reaction, which consists of a visible papule by day 3 that becomes vesicular by day 5-6 and pustular by day 7-10. The pustule resolves with scab separation by day 21. Maximal erythema and induration associated with vaccination usually occurs at days 8-12. (See the images below.)

Smallpox vaccination with bifurcated needle. Recon Smallpox vaccination with bifurcated needle. Reconstituted vaccine is held between the prongs of the needle and injected subcutaneously by multiple punctures; 15 rapid strokes, at right angles to the skin over the deltoid muscle, are made within a 5-mm area. Courtesy of the World Health Organization.
Smallpox vaccination. Evolving primary vaccination Smallpox vaccination. Evolving primary vaccination appearance. Courtesy of the US Centers for Disease Control and Prevention.

Antivirals, Other

Class Summary

In the event an individual exposed to smallpox is unable to promptly receive the vaccine, tecovirimat or brincidofovir may be obtained from the US government’s Strategic National Stockpile for treatment. 

Tecovirimat (TPOXX)

Antiviral agent; targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus. It is approved by the FDA and indicated for treatment of human smallpox disease caused by variola virus in adults and children who weigh at least 13 kg.

Brincidofovir (Tembexa)

Brincidofovir effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which then acts to inhibit viral replication. Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis by incorporation of cidofovir into the growing viral DNA chain. This results in reductions in the rate of viral DNA synthesis. It is indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates.


Vaccines, Live, Viral

Class Summary

Vaccinia vaccine promotes active immunity against the smallpox virus by inducing specific antibodies. Currently available stocks of vaccinia vaccine were derived from the vaccinia strain maintained at the New York Board of Health. Wyeth Laboratories manufactured the last batches of the vaccine (Dryvax) in the early 1980s. These batches were made by using the calf lymph method, and they were lyophilized but are no longer available.

The vaccine contains live vaccinia virus but does not contain variola virus, the virus that causes smallpox. Vaccinia is a member of the Orthopoxvirus genus, which includes smallpox (variola), cowpox, monkeypox, gerbilpox, camelpox, and others. Following inoculation, the vaccine induces an immune reaction that serves to protect against smallpox. [32]

Several attenuated vaccinia vaccine candidates are undergoing investigation, with ACAM2000 receiving FDA approval as a replacement for Dryvax. [33, 34]  Another vaccine (smallpox [vaccinia] and monkeypox vaccine, live, nonreplicating [Jynneos]) has also been approved by the FDA for immunization of adults at high risk for smallpox or monkeypox infection. [26, 27]

New, cell-derived lots of vaccinia appear to have adverse effect profiles similar to the older, calf lymph–derived lots.

Primary immunization as soon as possible after exposure or at the first sign of infection is indicated for the prevention and management of smallpox. Currently, US military personnel, US Department of Defense civilian employees, and health care professionals are recommended candidates to receive the vaccination because they will likely be at highest risk in case of a biologic attack (eg, bioterrorism).

Next-generation vaccines are available from the SNS and may prove useful in patients with severe immunosuppression. [35] Aventis Pasteur smallpox vaccine (APSV) and Imvamune (Bavarian Nordic) are the next-generation vaccines for this subgroup of patients and are not FDA approved. However, Imvamune is part of the national strategic stockpile and would be released in case of national emergency under EUA. [36, 37, 38]

Vaccinia virus vaccine (ACAM2000)

This agent is made from vaccinia, which is related to, but different from, the virus that causes smallpox. It contains live vaccinia virus and works by causing a mild infection that stimulates an immune response that effectively protects against smallpox without actually causing disease.

The vaccine contains live vaccinia virus but does not contain variola virus, the virus that causes smallpox. Vaccinia is a member of the Orthopoxvirus genus, which includes smallpox (variola), cowpox, monkeypox, gerbilpox, camelpox, and others. Following inoculation, the vaccine induces an immune reaction that serves to protect against smallpox.

ACAM2000 is derived from Dryvax, a smallpox vaccine that was approved in 1931 but that is no longer being manufactured. The US military resumed vaccination of at-risk personnel in 1999 after concluding that the disease posed a potential bioterrorism threat.

ACAM2000 was studied in 2 populations: (1) persons who had never been vaccinated for smallpox and (2) those who had received smallpox vaccination many years earlier. The percentage of unvaccinated persons who developed a successful immunization reaction was similar to that of Dryvax. ACAM2000 was also found to be acceptable as a booster in persons previously vaccinated for smallpox.

Because ACAM2000 contains live vaccinia virus, care must be taken to prevent the virus from spreading from the inoculation site to other parts of the body and to other individuals. To minimize known risks, vaccine licensing is subject to a Risk Minimization Action Plan (RiskMAP), which requires providers of the vaccine and patients to be educated about vaccination risks.

The medication guide explains proper care of the vaccination site and provides information about serious adverse effects associated with ACAM2000.

In studies, about 1 in 175 healthy adults who received smallpox vaccine for the first time developed myocarditis and/or pericarditis. Of the 10 affected adults, 4 had no symptoms at the end of the study, and symptoms resolved in all but 1 patient.

It is administered in a single percutaneous dose. Its use after exposure, but prior to rash, can eradicate clinical manifestations of smallpox. It is contraindicated in patients with severe immunosuppression.

Smallpox (vaccinia) and monkeypox vaccine, live, nonreplicating (Jynneos)

Vaccine is derived from a vaccinia virus, a virus that is closely related to, but less harmful than, variola or monkeypox viruses and can protect against both of these diseases. It is indicated for prevention of smallpox and monkeypox disease in adults who are at high risk for smallpox or monkeypox infection. It is administered as a 2-dose series administered 4 weeks apart.


Immune Globulins

Class Summary

Indicated for passive immunity. Vaccinia immunoglobulin (VIG) is used for amelioration of some vaccinia-related complications. VIG is produced from pooled human sera taken from vaccinia-immunized individuals and is available only from the CDC. VIG has been effective when administered early in cases of vaccinia necrosum and eczema vaccinatum. VIG has not been effective in cases of encephalopathy. The use of VIG for generalized vaccinia reactions is usually not necessary. Intravenous VIG (CNJ-016) has been approved by the FDA.

Vaccinia immune globulin intravenous (VIGIV, CNJ-016)

VIGIV is derived from human plasma and is manufactured from pooled plasma donors who received booster immunizations with smallpox vaccine. It contains increased antibody levels against vaccinia virus. It is indicated to treat rare adverse reactions and aberrant infections caused by vaccinia virus, including accidental implantation in the eyes, mouth, other potentially hazardous areas; eczema vaccinatum; progressive vaccinia; severe, generalized vaccinia; and vaccinia infections in immunocompromised individuals.