Smallpox Medication

Updated: Nov 17, 2015
  • Author: Aneela Naureen Hussain, MD, MBBS, FAAFM; Chief Editor: Mark R Wallace, MD, FACP, FIDSA  more...
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Medication

Medication Summary

No treatment has been approved by the US Food and Drug Administration (FDA) for smallpox, and 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.

Cidofovir analogs CMX001 and the extracellular virus inhibitor ST-246 are in human safety trials for orthopoxvirus treatment. [27]

Secondary bacterial infections of the skin can be treated with semisynthetic penicillins (nafcillin, oxacillin, dicloxacillin, cloxacillin) 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 Dryvax 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.
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Antivirals, Other

Class Summary

Cidofovir is currently approved for the treatment of cytomegalovirus (CMV) infections, but not for smallpox. However, animal models support the potential usefulness of this agent in smallpox. Given immediately after exposure, cidofovir has shown some benefit in the prevention of vaccinia, monkeypox, and cowpox. Pulmonary viral levels and pneumonitis were also reduced in animal models of cowpox.

Cidofovir (Vistide)

Cidofovir is a viral DNA polymerase inhibitor licensed for use in humans for the treatment of CMV retinitis in patients infected with the human immunodeficiency virus (HIV). Based on animal models, this agent may have some benefit in prevention of Orthopoxvirus infection and may decrease the risk of pneumonitis. It has not been studied in humans for smallpox infections.

Cidofovir analogs CMX001 and the extracellular virus inhibitor ST-246 are in human safety trials for orthopoxvirus treatment.

Two newer agents (Tecovirimat and Liposomal Cidofovir) are in late developmental stages. In case of bioterrorism or outbreak, these compounds would be available through emergency use authorization (EUA). [31]

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Antivirals, Ophthalmic

Class Summary

Idoxuridine is approved for the treatment of CMV retinitis. In the event of ocular involvement with smallpox, it may be given, but its efficacy is undocumented.

Idoxuridine (Herplex)

Idoxuridine is an analog of thymidine. It blocks the reproduction of herpes simplex virus by producing incorrect DNA copies that prevent the virus from infecting or destroying tissue. A 15-40% resistance rate has been reported. Idoxuridine has not been studied for smallpox infections and for the treatment of orthopoxviruses in humans. Its benefit is theoretical.

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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. [28]

Several attenuated vaccinia vaccine candidates are undergoing investigation, with ACAM2000 receiving FDA approval as a replacement for Dryvax. [29, 30]

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).

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, which is the only other smallpox vaccine licensed by the FDA. Dryvax, which was approved in 1931, is now in limited supply because it 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; next-generation vaccinations are indicated for these patients. [32] LC16 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. [33, 34, 38]

Vaccinia virus vaccine (Dryvax)

Dryvax 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 variola virus, cowpox virus, monkeypox virus, gerbilpox virus, camelpox virus, and others. Following inoculation, the vaccine induces an immune reaction that serves to protect against smallpox. (Monkey kidney cells and human fibroblast cell lines are currently under investigation to produce vaccinia vaccine.)

Dryvax 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.

Regional lymphadenopathy, mild fever, and malaise often accompany redness and swelling.

An accelerated reaction can be seen in a partially immune recipient, and it is identifiable with a reaction similar to the primary jennerian reaction in character and staging (although its pace is accelerated). Pustule formation occurs at days 4-7, and scab separation occurs at approximately day 14. The balance between vaccine potency and individual residual immunity to vaccinia determines the pace of the reaction.

Successful vaccination provides 95% immunity for approximately 10 years; successful revaccination likely provides protection for several decades. Individuals with known exposure to smallpox should be vaccinated within 4 days to protect against illness.

More research is currently ongoing to further explore the live variola virus, [37] particularly in the context of bioterrorism.

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Immune Globulins

Class Summary

These agents are indicated for passive immunity. Vaccinia immunoglobulin (VIG) is the only drug available 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.

Intravenous vaccinia immunoglobulin, human (CNJ-016)

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

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