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Immune Status in a Primary Smallpox Vaccinee Who Failed to Develop an Immunization Site Reaction
To the Editor: The last case of smallpox occurred in 1977, and the world was declared free of the disease in 1980.1 In the United States, recommendations for smallpox vaccination were withdrawn in 1971 for the general public, 1976 for health care workers, 1982 for international travelers, and 1990 for military personnel.2 Due to an increased threat of biowarfare and bioterrorism, immunization against smallpox has now resumed for certain health care workers and military personnel. First-time vaccinees are considered protected after a "major reaction" (papule, pustule, scab, scar) at the immunization site.2 In a nonimmune person who is not immunosuppressed, the expected response to primary vaccination is the development of a papule at the site of vaccination 2 to 5 days after percutaneous administration of vaccinia vaccine. The papule becomes vesicular, then pustular, and reaches its maximum size in 8 to 10 days. The pustule dries and forms a scab, which separates within 14 to 21 days after vaccination, leaving a scar.2 Fewer than 5% of primary vaccinees fail to develop such reactions.3-4 In a recent report on the US military experience, among 623 244 primary inoculations, minimal reactions were seen in approximately 4%.5 Revaccinees often have less pronounced responses.
Report of a Case
After screening revealed no prior smallpox vaccination and no contraindications, a 25-year-old man received a primary smallpox vaccination. The patient returned 8 days later (when the reaction would be expected to be maximal) to have the vaccination site examined and no reaction was seen. He reported having had only a transient small red spot at the vaccination site and denied that any bump, blister, or scab had appeared. All other persons administered vaccine from the same vial developed major reactions. Another attempt was made 13 days after first one, but he again reported only transient local erythema. A third vaccination was given 29 days after the first one, from a different vial. The site was examined daily for 10 days but revealed no reaction.
The following laboratory results were normal: complete blood cell count, IgG, IgM, IgA, IgE, total hemolytic complement; numbers, percentages and ratios of B cells, T cells, T-cell subsets and natural killer cells; functional antibody to tetanus, diphtheria, and pneumococcus; and lymphocyte responses to antigens (candida and tetanus) and mitogens. Human immunodeficiency virus antibody assay was negative.
Vaccinia-specific immune responses were analyzed.6-7 The patient demonstrated a positive antibody status with a reciprocal titer of 172 (>20 is seropositive). However, a vaccinia-stimulated lymphocyte proliferation index was low at 3.5 (<3 is negative). There was a lack of measurable interferon- production when the patient’s T cells were stimulated with vaccinia and a complete lack of cytolytic activity by his T cells against vaccinia-infected target cells.
Comment
One possible explanation for this patient’s failure to demonstrate a reaction at the site of smallpox immunization is previous vaccination because revaccinees often have less pronounced reactions. However, his age and lack of vaccine scar argue strongly against this. Rather, it appears that immunization attempts in this first-time smallpox vaccinee led to a humoral immune response despite not having a major vaccination site reaction. His cutaneous responses to the second and third vaccination attempts may have been dampened by his having made antibody to the first attempt. This would not, however, explain his lack of cutaneous response to the initial attempt.
He developed little or no T-cell response detectable by any of 3 vaccinia-specific assays. This lack of cellular immune response may be related to his failure to have a vaccination site reaction, although persons with cellular immunodeficiency would actually be expected to have an exaggerated reaction (vaccinia necrosum).2 Vaccinia immunization itself may cause a transient decrease in T-cell responsiveness; however, this has been reported only in revaccinees, and has not blunted vaccination site reactions.8 It is not clear whether this patient is protected against smallpox. Vaccinia-specific antibody suggests a memory response, but the lack of cell-mediated responses warrants concern.
We suggest the following when a first-time smallpox vaccinee fails to demonstrate a major reaction. Consider inadequate vaccine or technique: evaluate storage conditions and reconstitution of the vaccine, and whether other recipients developed major reactions. Consider the potential for unreported prior vaccination based on birth year 1971 or earlier, health care worker status in 1976 or earlier, international travel in 1982 or earlier, military member in 1990 or earlier, or presence of a smallpox scar. Make a second vaccination attempt using a different lot of vaccine at a different site and inspect daily for reaction. If the second attempt fails, make a third. If the third attempt fails to elicit a major reaction, consider consultation with a research laboratory that can perform assessment of both humoral and cellular immunity to vaccinia.
Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US government.
Access to Data: Dr Kelso had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.
Financial Disclosure: None.
John M. Kelso, MD
jmkelso{at}nmcsd.med.navy.mil
Division of Allergy
Naval Medical Center
San Diego, Calif
Kevin M. Kuhn, MD
Explosive Ordnance Disposal Mobile Unit 3
Naval Amphibious Base
Coronado, Calif
Frances K. Newman, MS
Division of Infectious Diseases and Immunology
Saint Louis University School of Medicine
St Louis, Mo
Jeffrey S. Kennedy, MD
Center for Infectious Disease and Vaccine Research
University of Massachusetts Medical School
Worcester
Sharon E. Frey, MD
Division of Infectious Diseases and Immunology
Saint Louis University School of Medicine
St Louis, Mo
1. Fenner F, Henderson DA, Arita I, et al. Smallpox and Its Eradication. Geneva, Switzerland: World Health Organization; 1988.
2. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Morb Mortal Wkly Rep. 2001;50(RR-10):1-25.
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3. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346:1265-1274.
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4. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA. 2003;289:3278-3282.
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5. Wollenberg A, Engler R. Smallpox, vaccination and adverse reactions to smallpox vaccine. Curr Opin Allergy Clin Immunol. 2004;4:271-275.
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6. Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox vaccine. N Engl J Med. 2002;346:1275-1280.
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7. Newman FK, Frey SE, Blevins TP, et al. Improved assay to detect neutralizing antibody following vaccination with diluted or undiluted vaccinia (Dryvax) vaccine. J Clin Microbiol. 2003;41:3154-3157.
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8. Mathew A, Ennis FA, Rothman AL. Transient decreases in human T-cell proliferative responses following vaccinia immunization. Clin Immunol. 2000;96:100-107.
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Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2005;293:677-678.
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