Correspondence

Poxvirus Dilemmas

N Engl J Med 1998; 339:2027-2028December 31, 1998

Article

To the Editor:

In their Sounding Board article, Breman and Henderson (Aug. 20 issue)1 promote a traditional, decades-old “contain and vaccinate” strategy of controlling smallpox that requires refinement to remain viable. The human immunodeficiency virus (HIV) emerged after the eradication of smallpox and poses new ethical and operational challenges to the control of poxviruses. Although vaccination against smallpox will preserve public health during an outbreak, it may cause fatal side effects in the HIV-infected population. A high rate of severe vaccine-related complications (generalized and progressive vaccinia and eczema vaccinatum) will make emergency control of poxviruses in regions with a high frequency of HIV difficult and reflect poorly on organizations that coordinate the response to outbreaks.

The exact threat smallpox vaccine (vaccinia) poses to HIV-infected persons is unknown, but the available data suggest that those with severe immunodeficiency are at risk. In 1990, therapeutic administration of autologous lymphocytes infected with a recombinant HIV–vaccinia virus was halted after three of eight HIV-infected subjects among a group of severely immunocompromised patients (fewer than 150 CD4 T cells per cubic millimeter) had symptoms of progressive vaccinia and died.2 These complications were not recognized as such, and the only treatment for severe complications, vaccinia immune globulin, was not administered.2,3 Treatment with vaccinia immune globulin improves the prognosis. In 1987, Redfield et al. reported a case of generalized vaccinia in an HIV-positive Army recruit.4 The symptoms resolved after a 12-week treatment with vaccinia immune globulin.

Widespread use of vaccinia immune globulin during a poxvirus crisis is unrealistic. As is the case for the vaccinia vaccine, the capacity to produce vaccinia immune globulin has most likely decreased, and stores of this product have probably deteriorated. Even if sufficient vaccinia immune globulin were available, the complex treatment regimen (a 70-kg person requires a 42-ml injection of vaccinia immune globulin every two to three days until symptoms abate5) involved would make widespread use of the product unfeasible. It would also be impossible to exclude HIV-positive persons from being vaccinated. Outbreak control requires widespread vaccination, so even if a quick method of screening for HIV were available, control of the outbreak would have to take precedence.

Current guidelines of the Centers for Disease Control and Prevention for vaccination against smallpox recognize the potential problems. Vaccination of HIV-positive persons is not considered “prudent,” and vaccination of relatives of immunocompromised persons is advised against.5 Yet following these guidelines will fail to protect public health during a smallpox emergency in areas with a large number of HIV-infected persons.

Craig Hooper
122 The Riverway, Boston, MA 02215

5 References

1. 1

   Breman JG, Henderson DA. Poxvirus dilemmas -- monkeypox, smallpox, and biologic terrorism. N Engl J Med 1998;339:556-559
   Full Text | Web of Science | Medline

2. 2

   Picard O, Lebas J, Imbert JC, Bigel P, Zagury D. Complications of intramuscular/subcutaneous immune therapy in severely immune-compromised individuals. J Acquir Immune Defic Syndr 1991;4:641-643
   Web of Science | Medline

3. 3

   Guillaume JC, Saiag P, Wechsler J, Lescs MC, Roujeau JC. Vaccinia from recombinant virus expressing HIV genes. Lancet 1991;337:1034-1035
   CrossRef | Web of Science | Medline

4. 4

   Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987;316:673-676
   Full Text | Web of Science | Medline

5. 5

   Vaccinia (smallpox) vaccine: recommendations of the Immunization Practices Advisory Committee. MMWR Morb Mortal Wkly Rep 1991;40(RR-14). [Erratum, MMWR Morb Mortal Wkly Rep 1992;41:31.]
   

Author/Editor Response

The authors reply:

To the Editor: Reinstitution of the use of smallpox vaccine (vaccinia) in areas where monkeypox is endemic would be warranted if the incidence and transmissibility of monkeypox in humans were increasing substantially and if the benefits of vaccination outweighed the risks. As we stated in our article, the available evidence does not indicate that the genetic, clinical, and epidemiologic features of human monkeypox have changed from the 1970s and 1980s to the present. There is no current justification for the use of vaccinia, given that fewer than 1000 confirmed and suspected cases of monkeypox in humans have been reported since 1970 in western and central Africa. More cases will occur as levels of immunity fall, the population increases, and more contacts occur between humans and monkeypox-carrying animals. It is imperative that an accurate profile of monkeypox in humans be obtained over time by intensified surveillance, and the World Health Organization is supporting such efforts.

Mr. Hooper underscores properly the dangers of administering smallpox vaccine to persons who are HIV-positive or who have AIDS and the impracticality of administering vaccinia immune globulin to all HIV-positive persons who are vaccinated in areas where monkeypox is endemic.1 The danger is very real, since the rate of HIV-positivity in parts of the Democratic Republic of the Congo (where the vast majority of cases of monkeypox in humans have occurred) is between 6.9 and 11.1 percent and is as high as 35.3 percent among patients with tuberculosis.2,3 Should a substantial monkeypox (or smallpox) epidemic occur, it would be highly desirable to have a vaccine that did not cause progressive vaccinia in immunosuppressed patients. The development of such a vaccine requires increased resources.

Joel G. Breman, M.D., D.T.P.H.
National Institutes of Health, Bethesda, MD 20892-2220

D.A. Henderson, M.D., M.P.H.
Johns Hopkins University, Baltimore, MD 21205-2179

3 References

1. 1

   Redfield RR, Wright DC, James WD, Jones TS, Brown C, Burke DS. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987;316:673-676
   Full Text | Web of Science | Medline

2. 2

   Mulanga-Kabeya C, Nzilambi N, Edidi B, et al. Evidence of stable HIV seroprevalences in selected populations in the Democratic Republic of the Congo. AIDS 1998;12:905-910
   CrossRef | Web of Science | Medline

3. 3

   Fischer PR, Toko RM. HIV seroprevalence in healthy blood donors in northeastern Zaire. Int J STD AIDS 1995;6:284-286
   Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Donald F Smee, Min-Hui Wong, Kevin W Bailey, James R Beadle, Karl Y Hostetler, Robert W Sidwell. (2004) Effects of four antiviral substances on lethal vaccinia virus (IHD strain) respiratory infections in mice. International Journal of Antimicrobial Agents 23:5, 430-437
   CrossRef

2. 2

   Donald F Smee, Robert W Sidwell. (2003) A review of compounds exhibiting anti-orthopoxvirus activity in animal models. Antiviral Research 57:1-2, 41-52
   CrossRef

3. 3

   Donald F Smee, Kevin W Bailey, Robert W Sidwell. (2002) Treatment of lethal cowpox virus respiratory infections in mice with 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine and its orally active diacetate ester prodrug. Antiviral Research 54:2, 113-120
   CrossRef

4. 4

   Donald F. Smee, Kevin W. Bailey, Min-Hui Wong, Robert W. Sidwell. (2001) Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Research 52:1, 55-62
   CrossRef