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Smallpox Vaccination and the HIV-Infected Patient: A Roundtable

In April 2002, the CDC requested that the Advisory Committee on Immunization Practices (ACIP) update the recommendations regarding smallpox vaccination that it had published a year earlier. The new guidelines, developed in conjunction with the National Vaccine Advisory Committee (NVAC) and the Healthcare Infection Control Practices Advisory Committee (HICPAC), call for the formation of smallpox response teams in each state and for voluntary pre-event vaccination programs for healthcare workers, with the goal of having a number of vaccinated healthcare workers in each acute care facility. The guidelines make clear that HIV infection is a contraindication to pre-event smallpox vaccination. As this issue was being uploaded to the web, the CDC was announcing plans to provide smallpox vaccination -- with a very high threshold for what constitutes a contraindication -- to individuals potentially exposed to monkeypox, after 54 potential cases of monkeypox infection were identified in 4 states. To discuss the issue of smallpox vaccination and HIV infection, ACC Executive Editor Matthew O'Rourke spoke with Dr. John Bartlett (Chief, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore), Dr. Carlos del Rio (Chief of Medicine, Grady Memorial Hospital, Atlanta, and Associate Editor of ACC), Dr. Alfred DeMaria, Jr. (Assistant Commissioner of Public Health, Massachusetts Department of Public Health, Boston), and Dr. Kent A. Sepkowitz (Director, Hospital Infection Control, Sloan-Kettering Cancer Center, New York City).

HIV infection, regardless of CD4-cell count, is considered a contraindication to smallpox vaccination in the current pre-event voluntary vaccination plan. What are the dangers of smallpox vaccination in HIV-infected individuals, and how is HIV screening being handled among volunteers?

Dr. Bartlett: Most institutions that I know of that are offering vaccination are making an HIV test available but not demanding it. People who test positive are not vaccinated. However, should an HIV-infected person inadvertently be vaccinated, the risk of developing serious complications is very small.

Dr. Sepkowitz: It's very likely that an HIV-infected volunteer already has been vaccinated inadvertently. Working backward from seroprevalence estimates, researchers estimate that in the 1980s approximately 300 HIV-infected individuals received smallpox vaccination. We have the one famous case, a soldier with advanced but undiagnosed HIV who developed disseminated vaccinia. My guess is that, as with other live-virus vaccines, smallpox vaccination does not pose a very high risk to individuals with well-controlled HIV infection.

The fact that we're vaccinating healthcare workers makes the assessment and disclosure of HIV risk much more difficult. I can't imagine a worse place to be tested, if you are at risk, than your own hospital. The disincentive for a healthcare worker to disclose a risk for HIV infection is very strong.

Dr. DeMaria: In Massachusetts, we're trying to make this program as voluntary as possible and ensure that no questions are asked of anyone who does not elect to get vaccinated. We aren't having a problem with people declining participation.

Dr. Bartlett: I think that we now have enough reasons not to get vaccinated that no one is really going to be suspicious of someone who bows out.

How serious is the risk of secondary vaccinia transmission -- so called contact vaccinia -- from healthcare workers to HIV-infected patients or contacts? Are volunteers being screened for their degree of contact with immunocompromised individuals? Should they receive furloughs?

Dr. DeMaria: In Massachusetts, we encourage volunteers who are concerned about HIV infection to get tested, but we also ask them to consider whether they might have close contacts who might be at risk for contact vaccinia, and we tell them that this might be a reason not to get vaccinated.

Dr. del Rio: We have furloughed a reservist who was vaccinated. The risk is theoretical, but we felt uncomfortable having this person perform clinical duties. Our hospital has approved the furlough of anyone who is vaccinated; however, if we had several people receive the vaccine at the same time, it would certainly create some staffing problems.

Dr. Bartlett: Hopkins is insisting on a furlough from patient contact for everybody who receives vaccination, regardless of where they work or what populations they treat. I can't say that I necessarily agree with this policy.

Dr. DeMaria: I was involved in the HICPAC discussions about whether or not furlough would be recommended in the national guidelines, and the weight of the evidence suggests that there is a risk but that it is quite low and must be balanced against the known risk of short-staffing. We had evidence coming in from the vaccination of healthcare workers in Israel, at the NIH, and in the U.S. military, and published evidence on how the semipermeable membrane contains the virus; all of this information underscored how low the risk of contact vaccinia is for patients using recommended procedures. Having had personal experience with vaccination now, I think that the combination of the dressing, infection-control practices, and daily inspection of the injection site reduces the risk to close to nil. However, if I were responsible for operating a burn unit, a transplant unit, or an HIV unit, then I might consider reassignment as an extra precaution.

Dr. Sepkowitz: I agree that we have a ton more information than we had 6 months or a year ago, and the risk seems ever smaller. However, I think that if we had to engage in a mass vaccination effort, the risk of secondary vaccinia transmission would be quite different because it would be much harder to guard against.

Dr. DeMaria: Of course, if we needed to engage in mass vaccination, then secondary transmission might be advantageous.

Dr. Sepkowitz: Regardless, the risk for contact vaccinia is hypothetical. People with T-cell defects are at risk from vaccination itself, but it hasn't been shown that they are at risk for contact vaccinia. The people clearly at risk for developing complications from secondary transmission are those with abnormal skin. The risk of contact vaccinia on an HIV unit is probably quite modest compared with the risk on a burn unit.

In terms of post-event vaccination, what are the recommendations for HIV-infected individuals? At what level of potential smallpox exposure do you start vaccinating people regardless of HIV status or CD4-cell count?

Dr. DeMaria: The post-event plan calls for mass vaccination with very few contraindications, all depending on where the smallpox attack occurs.

Dr. Bartlett: Let me ask this: If someone has an exposure to smallpox, is there a contraindication to vaccination? I assume that the answer is no. After all, if somebody is immunosuppressed to the point where they are at risk for a bad reaction to vaccinia, they'd almost certainly die with smallpox.

Dr. Sepkowitz: But it's a question of the intensity of the exposure and how much VIG is available. VIG -- an isotonic sterile solution of the immunoglobulin fraction of plasma from vaccinia-vaccinated individuals -- is the only treatment and preventive modality available for complications of vaccinia.

Dr. Bartlett: True. The group that would likely receive vaccine in the event of a smallpox attack would be any face-to-face contacts with a case after the rash is apparent, healthcare workers, first responders, and any contacts with unexplained fever or other symptoms. With such exposure, the vaccine would be strongly recommended. With others, however, I would expect it to be on a somewhat more voluntary basis, and so I'd expect that vulnerable individuals such as those with HIV infection, could be furloughed or receive VIG simultaneously.

Dr. Sepkowitz: I think that a standard definition of exposure will be difficult to come by; an enormous number of people will probably fall into a gray zone.

Dr. DeMaria: Indeed, if there's a release of smallpox in Boston, what would you do in Baltimore or in Atlanta? Would you vaccinate the general population regardless of HIV status or other contraindications?

Dr. del Rio: I would probably encourage HIV-infected individuals with a low CD4-cell count not to get vaccinated if the exposure was far away, but if they wanted to get vaccinated, I would oblige. I'd advise against vaccination more strongly for someone who isn't a healthcare worker than for someone who is.

Dr. Bartlett: How does this sound for a policy? If there has been an exposure in the U.S., you provide vaccine to HIV-infected individuals who have a CD4 count that is more than 200 cells/mm³ or 50 cells/mm³, some arbitrary threshold for severe immunosuppression, whereas you provide vaccine plus VIG to HIV-infected individuals whose CD4-cell count is below that threshold.

Dr. Sepkowitz: That is what was done in the old days in children with congenital immunodeficiencies, and it seemed to work. However, it would leave a big hole in the VIG supply.

Dr. Bartlett: On the basis of the U.S. military's experience in the 1980s, the CD4-cell count threshold could be quite low. Out of the approximately 300 HIV-infected individuals who were vaccinated, the only individual who had a complication didn't have any CD4 cells. There's probably a gray zone, but the threshold could be as low as 20 cells/mm³. However, based on the unknown nature of the risk of a smallpox release, we have decided not to vaccinate HIV-infected individuals regardless of CD4-cell count, despite the fact that in those with high CD4-cell counts, the risk is very small.

Dr. del Rio: I know of a patient who decided to get vaccinated despite the fact that he is HIV-infected. He's on therapy and is doing well with a CD4 count of more than 400 cells/mm³. He developed a fairly significant local reaction: His arm became quite swollen, but other than that, he did fine. I would have advised him not to get vaccinated, but he elected to do so. If he had had a CD4 count of less than 200 cells/mm³, I think it would have been a very different story, but I'm not sure. I'm certain that other HIV-infected individuals have been vaccinated, and it would be interesting to see that data; however, because HIV status is a contraindication to vaccination, such evidence would be difficult to gather.

Dr. DeMaria: We have the responsibility not to vaccinate people who reveal a contraindication such as HIV, regardless of their wish to be vaccinated as part of the pre-event program, and, if such information becomes available to us after vaccination, we are responsible for entering it into a database. This has happened to us, not with HIV, but with other contraindications.

Dr. Bartlett: More than 100 women have received vaccine while pregnant.

What role, if any, does previous vaccination play in the risk of vaccination to HIV-infected individuals?

Dr. Bartlett: If they have a high CD4-cell count, I assume that they will respond in a manner similar to that of HIV-negative individuals who were previously vaccinated. However, if they have a low CD4-cell count, they may behave like a primary vaccinee simply because they have a wrecked immune system and probably don't have antigenic recall: Cellular immunity probably is more important than humoral immunity for the response to the vaccine.

Dr. DeMaria: As for any risks of secondary transmission, a previously vaccinated HIV-negative individual who is revaccinated will shed less vaccinia than a primary vaccine recipient, making contact vaccinia that much less likely.

Any final thoughts?

Dr. Sepkowitz: I would stress the need to increase the VIG supply because if we ever need to engage in mass vaccination, we're going to need lots of VIG for immunosuppressed patients. If you go back and look at the famous New England Journal of Medicine article about the HIV-infected soldier who developed complications from smallpox vaccination, you'll find that he received 12 doses of VIG. So I think that the premise that 1 dose will suffice applies only to children.

Dr. Bartlett: Is the current supply of VIG for intravenous or intramuscular delivery? The old supply was given at 40 mL intramuscularly, and it was punishing. The only reason that it was delivered that way was because it was concentrated and contained a lot of protein. I assume that the new stuff will be given intravenously. I was under the impression that the supply was being augmented fairly substantially as people have been vaccinated.

Dr. DeMaria: Currently, enough intravenous VIG is on hand to cover any anticipated adverse events of the pre-event program. Plasma is being collected from vaccinated individuals to dramatically augment the intravenous VIG supply in case the mass vaccination plan needs to be implemented.

Dr. Bartlett: It is worth noting that VIG is the only therapeutic modality with any merit as an adjuvant to vaccination or as a treatment for atopic-dermatitis-complicated vaccinia. Even the value of VIG is not established because it was never subjected to controlled trials. However, the researchers who used it are completely convinced that it worked, at least in the childhood form of atopic dermatitis vaccinia. I don't know how good the data are regarding the use of VIG for complications of progressive vaccinia. In the review of progressive vaccinia in Clinical Infectious Diseases, there doesn't appear to be a survival benefit from VIG.

Dr. Sepkowitz: Among the people who had experience in smallpox vaccination back in the 1960s, there is little enthusiasm for VIG as a treatment modality for progressive vaccinia, which is the most likely complication of vaccination in a person with AIDS.

Dr. Bartlett: Potent combination antiretroviral therapy is probably the best protection against complications in an HIV-infected patient who needs to receive vaccine, and it may be the best treatment for such complications. It wasn't vaccinia that finally killed that soldier. He died a couple of years later of cryptococcal infection. Thus, vaccine recipients who develop complications will likely live long enough so that there's time to elicit an immune response to antiretroviral therapy.

— John Bartlett, MD, Carlos del Rio, MD, Alfred DeMaria, MD, and Kent A. Sepkowitz, MD

Published in AIDS Clinical Care July 1, 2003

FURTHER READING

Bartlett J et al. Smallpox vaccination in 2003: Key information for clinicians. Clin Infect Dis 2003 Apr 1 ; 36:883-902.

• Medline abstract (Free)

Bartlett JG. Smallpox vaccination and patients with human immunodeficiency virus infection or acquired immunodeficiency syndrome. Clin Infect Dis 2003 Feb 15 ; 36:468-71.

• Medline abstract (Free)

Bray M and Wright ME. Progressive vaccinia. Clin Infect Dis 2003 Mar 15 ; 36:766-74.

• Medline abstract (Free)

Massachusetts Department of Public Health Smallpox Pre-Event Vaccination Plan. 2002 Dec 12 (www.state.ma.us/dph/bioterrorism/advisorygrps/word_files/smallpox_preevent_vaccination_plan_draft_12_02.doc).

Mack T. A different view of smallpox and vaccination. N Engl J Med 2003 Jan 30 ; 348:460-3.

• Original article (Subscription may be required)
• Medline abstract (Free)

Redfield RR et al. Disseminated vaccinia in a military recruit with human immunodeficiency virus (HIV) disease. N Engl J Med 1987 Mar 12 ; 316:673-6.

• Medline abstract (Free)

Sepkowitz KA. How contagious is vaccinia? N Engl J Med 2003 Jan 30 ; 348:439-46.

• Original article (Subscription may be required)
• Medline abstract (Free)

Supplemental recommendations on adverse events following smallpox vaccine in the pre-event vaccination program: Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2003 Apr 4 ; 52:282-4.

• Medline abstract (Free)

Wharton M et al. Advisory Committee on Immunization Practices; Healthcare Infection Control Practices Advisory Committee. Recommendations for using smallpox vaccine in a pre-event vaccination program. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 2003 Apr 4 ; 52 (RR-7):1-16.

• Medline abstract (Free)