smallpox vaccine


Summary: A live VACCINIA VIRUS vaccine of calf lymph or chick embryo origin, used for immunization against smallpox. It is now recommended only for laboratory workers exposed to smallpox virus. Certain countries continue to vaccinate those in the military service. Complications that result from smallpox vaccination include vaccinia, secondary bacterial infections, and encephalomyelitis. (Dorland, 28th ed)

Top Publications

  1. Gordon S, Cecchinato V, Andresen V, Heraud J, Hryniewicz A, Parks R, et al. Smallpox vaccine safety is dependent on T cells and not B cells. J Infect Dis. 2011;203:1043-53 pubmed publisher
    The licensed smallpox vaccine, ACAM2000, is a cell culture derivative of Dryvax. Both ACAM2000 and Dryvax are administered by skin scarification and can cause progressive vaccinia, with skin lesions that disseminate to distal sites...
  2. Hammarlund E, Lewis M, Hanifin J, Mori M, Koudelka C, Slifka M. Antiviral immunity following smallpox virus infection: a case-control study. J Virol. 2010;84:12754-60 pubmed publisher
  3. Moise L, McMurry J, Buus S, Frey S, Martin W, De Groot A. In silico-accelerated identification of conserved and immunogenic variola/vaccinia T-cell epitopes. Vaccine. 2009;27:6471-9 pubmed publisher
    ..This experimental validation of computational predictions illustrates the potential for immunoinformatics methods to identify candidate immunogens for a new, safer smallpox vaccine.
  4. Oseroff C, Kos F, Bui H, Peters B, Pasquetto V, Glenn J, et al. HLA class I-restricted responses to vaccinia recognize a broad array of proteins mainly involved in virulence and viral gene regulation. Proc Natl Acad Sci U S A. 2005;102:13980-5 pubmed
    ..Finally, most epitopes were highly conserved among vaccinia virus Western Reserve, variola major and modified vaccinia Ankara, supporting their potential use in vaccine and diagnostic applications. ..
  5. Greenberg R, Overton E, Haas D, Frank I, Goldman M, von Krempelhuber A, et al. Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects. J Infect Dis. 2013;207:749-58 pubmed publisher
    ..MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable ..
  6. Zielinski R, Smedley J, Perera P, Silvera P, Waldmann T, Capala J, et al. Smallpox vaccine with integrated IL-15 demonstrates enhanced in vivo viral clearance in immunodeficient mice and confers long term protection against a lethal monkeypox challenge in cynomolgus monkeys. Vaccine. 2010;28:7081-91 pubmed publisher
    ..Therefore, a safer smallpox vaccine that can match the efficacy of first generation vaccines is urgently needed...
  7. Wilck M, Seaman M, Baden L, Walsh S, Grandpre L, Devoy C, et al. Safety and immunogenicity of modified vaccinia Ankara (ACAM3000): effect of dose and route of administration. J Infect Dis. 2010;201:1361-70 pubmed publisher
  8. Golden J, Josleyn M, Hooper J. Targeting the vaccinia virus L1 protein to the cell surface enhances production of neutralizing antibodies. Vaccine. 2008;26:3507-15 pubmed publisher
    ..Furthermore, our results demonstrate that a DNA-based vaccine is capable of establishing protection from lethal orthopoxvirus challenges when administered as a prime and single boost without requiring adjuvant. ..
  9. Melamed S, Sharon M, Paran N, Nir P, Katz L, Lior K, et al. Tail scarification with Vaccinia virus Lister as a model for evaluation of smallpox vaccine potency in mice. Vaccine. 2007;25:7743-53 pubmed
    ..High correlation between "clinical take" and protective immunity allows the use of visual inspection to evaluate vaccine potency. ..

More Information


  1. Mitra Kaushik S, Cruz J, Stern L, Ennis F, Terajima M. Human cytotoxic CD4+ T cells recognize HLA-DR1-restricted epitopes on vaccinia virus proteins A24R and D1R conserved among poxviruses. J Immunol. 2007;179:1303-12 pubmed
  2. McKinney B, Reif D, Rock M, Edwards K, Kingsmore S, Moore J, et al. Cytokine expression patterns associated with systemic adverse events following smallpox immunization. J Infect Dis. 2006;194:444-53 pubmed
    ..and chemokines in vaccine recipients before and 1 week after primary immunization with Aventis Pasteur smallpox vaccine. We studied 74 individuals after vaccination, of whom 22 experienced a systemic adverse event and 52 did not...
  3. Hooper J, Golden J, Ferro A, King A. Smallpox DNA vaccine delivered by novel skin electroporation device protects mice against intranasal poxvirus challenge. Vaccine. 2007;25:1814-23 pubmed
    ..To our knowledge, this is the first demonstration of a protective immune response being elicited by microneedle-mediated skin electroporation. ..
  4. Strikas R, Neff L, Rotz L, Cono J, Knutson D, Henderson J, et al. US Civilian Smallpox Preparedness and Response Program, 2003. Clin Infect Dis. 2008;46 Suppl 3:S157-67 pubmed publisher
    ..delivered training and educational materials for smallpox preparedness in many formats, developed detailed smallpox vaccine information statements about vaccine contraindications and vaccination site care, and established mechanisms ..
  5. Amanna I, Slifka M, Crotty S. Immunity and immunological memory following smallpox vaccination. Immunol Rev. 2006;211:320-37 pubmed
    The smallpox vaccine consists of live vaccinia virus and is generally considered the gold standard of vaccines, since it is the only one that has led to the complete eradication of an infectious disease from the human population...
  6. Berhanu A, King D, Mosier S, Jordan R, Jones K, Hruby D, et al. ST-246 inhibits in vivo poxvirus dissemination, virus shedding, and systemic disease manifestation. Antimicrob Agents Chemother. 2009;53:4999-5009 pubmed publisher
    ..Second, by reducing virus shedding from those prophylactically immunized with a smallpox vaccine or harboring variola virus infection, ST-246 could reduce the risk of virus transmission to susceptible ..
  7. Lantto J, Haahr Hansen M, Rasmussen S, Steinaa L, Poulsen T, Duggan J, et al. Capturing the natural diversity of the human antibody response against vaccinia virus. J Virol. 2011;85:1820-33 pubmed publisher
    ..We have characterized the human antibody response to smallpox vaccine (VACV Lister) in immunized volunteers and isolated a large number of VACV-specific antibodies that recognize ..
  8. Wiser I, Balicer R, Cohen D. An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies. Vaccine. 2007;25:976-84 pubmed
    ..Manufacturers try to combine smallpox vaccine past experience with technological advances in vaccine development to achieve protection similar to that of ..
  9. Nishiura H, Eichner M. Estimation of the duration of vaccine-induced residual protection against severe and fatal smallpox based on secondary vaccination failure. Infection. 2006;34:241-6 pubmed
  10. Olmsted S, Grabenstein J, Jain A, Comerford W, Giambo P, Johnson P, et al. Use of an electronic monitoring system for self-reporting smallpox vaccine reactions. Biosecur Bioterror. 2005;3:198-206 pubmed
  11. Ami Y, Izumi Y, Matsuo K, Someya K, Kanekiyo M, Horibata S, et al. Priming-boosting vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin and a nonreplicating vaccinia virus recombinant leads to long-lasting and effective immunity. J Virol. 2005;79:12871-9 pubmed
    ..These results suggest that a recombinant M. bovis BCG-based vector may have potential as an HIV/AIDS vaccine when administered in combination with a replication-deficient vaccinia virus DIs vector in a priming-boosting strategy. ..
  12. Taub D, Ershler W, Janowski M, Artz A, Key M, McKelvey J, et al. Immunity from smallpox vaccine persists for decades: a longitudinal study. Am J Med. 2008;121:1058-64 pubmed publisher
    ..The threat of smallpox resulting from bioterrorist action has prompted a reassessment of the level of immunity in current populations...
  13. Johnson M, Damon I, Karem K. A rapid, high-throughput vaccinia virus neutralization assay for testing smallpox vaccine efficacy based on detection of green fluorescent protein. J Virol Methods. 2008;150:14-20 pubmed publisher
    ..The assay is quick, accurate, provides a large dynamic range and is well suited for large-scale vaccination studies using standard adherent cell lines. ..
  14. Haralambieva I, Ovsyannikova I, Dhiman N, Kennedy R, O Byrne M, Pankratz V, et al. Common SNPs/haplotypes in IL18R1 and IL18 genes are associated with variations in humoral immunity to smallpox vaccination in Caucasians and African Americans. J Infect Dis. 2011;204:433-41 pubmed publisher
    ..and cytokine receptor genes) in a racially diverse cohort of 1056 healthy adults after a single dose of smallpox vaccine. Associations between single-nucleotide polymorphisms (SNPs)/haplotypes and vaccinia virus-specific ..
  15. Calvo Calle J, Strug I, Nastke M, Baker S, Stern L. Human CD4+ T cell epitopes from vaccinia virus induced by vaccination or infection. PLoS Pathog. 2007;3:1511-29 pubmed
    ..Moreover, the epitope identification approach developed here should find application to other large-genome pathogens. ..
  16. Davies D, Wyatt L, Newman F, Earl P, Chun S, Hernandez J, et al. Antibody profiling by proteome microarray reveals the immunogenicity of the attenuated smallpox vaccine modified vaccinia virus ankara is comparable to that of Dryvax. J Virol. 2008;82:652-63 pubmed
    ..MVA) is a highly attenuated vaccinia virus that is under consideration as an alternative to the conventional smallpox vaccine Dryvax. MVA was attenuated by extensive passage of vaccinia virus Ankara in chicken embryo fibroblasts...
  17. Putz M, Alberini I, Midgley C, Manini I, Montomoli E, Smith G. Prevalence of antibodies to Vaccinia virus after smallpox vaccination in Italy. J Gen Virol. 2005;86:2955-60 pubmed
    ..By using these data and demographic considerations, it was predicted that, in 2003, 46 % of the Italian population were positive for both IMV and EEV, 42 % were negative for both and 12 % were positive for one antigen. ..
  18. Morikawa S, Sakiyama T, Hasegawa H, Saijo M, Maeda A, Kurane I, et al. An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection. J Virol. 2005;79:11873-91 pubmed
    ..These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV. ..
  19. Moyron Quiroz J, McCausland M, Kageyama R, Sette A, Crotty S. The smallpox vaccine induces an early neutralizing IgM response. Vaccine. 2009;28:140-7 pubmed publisher
  20. Nishiura H, Brockmann S, Eichner M. Extracting key information from historical data to quantify the transmission dynamics of smallpox. Theor Biol Med Model. 2008;5:20 pubmed publisher
    ..In this review, we summarize what has already been clarified and point out needs to analyze previous smallpox outbreaks systematically. ..
  21. Vora S, Damon I, Fulginiti V, Weber S, Kahana M, Stein S, et al. Severe eczema vaccinatum in a household contact of a smallpox vaccinee. Clin Infect Dis. 2008;46:1555-61 pubmed publisher
    ..eczema vaccinatum after exposure to his father, a member of the US military who had recently received smallpox vaccine. The father had a history of inactive eczema but reportedly reacted normally to the vaccine...
  22. Ovsyannikova I, Kennedy R, O Byrne M, Jacobson R, Pankratz V, Poland G. Genome-wide association study of antibody response to smallpox vaccine. Vaccine. 2012;30:4182-9 pubmed publisher
    We performed a genome-wide association study (GWAS) of antibody levels in a multi-ethnic group of 1071 healthy smallpox vaccine recipients...
  23. Ferrier Rembert A, Drillien R, Meignier B, Garin D, Crance J. Safety, immunogenicity and protective efficacy in mice of a new cell-cultured Lister smallpox vaccine candidate. Vaccine. 2007;25:8290-7 pubmed
    It is now difficult to manufacture the first-generation smallpox vaccine, as the process could not comply with current safety and manufacturing regulations...
  24. McMahon A, Zinderman C, Ball R, Gupta G, Braun M. Comparison of military and civilian reporting rates for smallpox vaccine adverse events. Pharmacoepidemiol Drug Saf. 2007;16:597-604 pubmed
    ..These results suggest that in the case of smallpox vaccine AEs, there may be systematic differences in reporting completeness between the civilian and military sectors, ..
  25. Frey S, Newman F, Kennedy J, Sobek V, Ennis F, Hill H, et al. Clinical and immunologic responses to multiple doses of IMVAMUNE (Modified Vaccinia Ankara) followed by Dryvax challenge. Vaccine. 2007;25:8562-73 pubmed
    ..IMVAMUNE vaccination prior to Dryvax reduced virus replication at the Dryvax site, decreased the size of the primary cutaneous lesion, and decreased the time to healing but did not completely ameliorate the immune response. ..
  26. Nishiura H, Dietz K, Eichner M. The earliest notes on the reproduction number in relation to herd immunity: Theophil Lotz and smallpox vaccination. J Theor Biol. 2006;241:964-7 pubmed
  27. Puissant B, Combadiere B. Keeping the memory of smallpox virus. Cell Mol Life Sci. 2006;63:2249-59 pubmed
    ..In addition, the potent immunostimulatory action of poxvirus vectors has led to development and evaluation of new-generation vaccine candidates, which will be discussed in this review. ..
  28. Kenner J, Cameron F, Empig C, Jobes D, Gurwith M. LC16m8: an attenuated smallpox vaccine. Vaccine. 2006;24:7009-22 pubmed
    ..LC16m8, an attenuated, replicating smallpox vaccine derived from the Lister strain of vaccinia, is currently licensed in Japan where it was safely used in over ..
  29. Moss B. Smallpox vaccines: targets of protective immunity. Immunol Rev. 2011;239:8-26 pubmed publisher
  30. Xiao Y, Aldaz Carroll L, Ortiz A, Whitbeck J, Alexander E, Lou H, et al. A protein-based smallpox vaccine protects mice from vaccinia and ectromelia virus challenges when given as a prime and single boost. Vaccine. 2007;25:1214-24 pubmed
    ..Long-term partial protection was also seen in mice challenged with vaccinia virus 6 months after initial vaccinations. Thus, this work represents a step toward the development of a practical subunit smallpox vaccine.
  31. Rudraraju R, Ramsay A. Single-shot immunization with recombinant adenovirus encoding vaccinia virus glycoprotein A27L is protective against a virulent respiratory poxvirus infection. Vaccine. 2010;28:4997-5004 pubmed publisher
    ..This study is the first demonstration that a single-shot subunit vaccine encoding a poxvirus protein confers protection against the mortality and morbidity associated with poxvirus infection. ..
  32. Sejvar J, Labutta R, Chapman L, Grabenstein J, Iskander J, Lane J. Neurologic adverse events associated with smallpox vaccination in the United States, 2002-2004. JAMA. 2005;294:2744-50 pubmed
    ..Serious neurologic adverse events, such as postvaccinal encephalitis, Bell palsy, and Guillain-Barré syndrome, occurred in accordance with expected ranges. ..
  33. Kaufman D, Goudsmit J, Holterman L, Ewald B, Denholtz M, Devoy C, et al. Differential antigen requirements for protection against systemic and intranasal vaccinia virus challenges in mice. J Virol. 2008;82:6829-37 pubmed publisher
    ..Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the ..
  34. Vollmar J, Arndtz N, Eckl K, Thomsen T, Petzold B, Mateo L, et al. Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine. 2006;24:2065-70 pubmed
    A Phase I trial was performed to investigate the safety and immunogenicity of the third generation smallpox vaccine MVA-BN (IMVAMUNE), a highly attenuated clone derived from the Modified Vaccinia Virus Ankara strain 571, in naive and pre-..
  35. Nishiura H, Schwehm M, Eichner M. Still protected against smallpox? Estimation of the duration of vaccine-induced immunity against smallpox. Epidemiology. 2006;17:576-81 pubmed
    ..These findings suggest that successful primary vaccination offered full protection for a few decades, with partial protection from severe smallpox possibly lasting a lifetime, for a substantial fraction of the population. ..
  36. Graham P, LaRussa P, Kohl K. Robust take following exposure to vaccinia virus: case definition and guidelines of data collection, analysis, and presentation of immunization safety data. Vaccine. 2007;25:5763-70 pubmed
  37. Cohen J, Hohman P, Preuss J, Li L, Fischer S, Fedorko D. Detection of vaccinia virus DNA, but not infectious virus, in the blood of smallpox vaccine recipients. Vaccine. 2007;25:4571-4 pubmed
    ..Throat swabs were negative by PCR and culture. Thus, while some blood specimens contained vaccinia virus DNA, infectious virus was not detected. Current guidelines for deferral of blood donation in vaccinees seem appropriate. ..
  38. Nishiura H, Eichner M. Interpreting the epidemiology of postexposure vaccination against smallpox. Int J Hyg Environ Health. 2008;211:219-26 pubmed
  39. Davies D, Molina D, Wrammert J, Miller J, Hirst S, Mu Y, et al. Proteome-wide analysis of the serological response to vaccinia and smallpox. Proteomics. 2007;7:1678-86 pubmed
    ..Reserve, WR) proteome to profile antibody reactivities after primary infection or boosting with the licensed smallpox vaccine, Dryvax, and with archival convalescent smallpox sera...
  40. Garza N, Hatkin J, Livingston V, Nichols D, Chaplin P, Volkmann A, et al. Evaluation of the efficacy of modified vaccinia Ankara (MVA)/IMVAMUNE against aerosolized rabbitpox virus in a rabbit model. Vaccine. 2009;27:5496-504 pubmed publisher
    ..This study shows that IMVAMUNE can be a very effective vaccine against aerosolized RPXV...
  41. Yu W, Fang Q, Zhu W, Wang H, Tien P, Zhang L, et al. One time intranasal vaccination with a modified vaccinia Tiantan strain MVTT(ZCI) protects animals against pathogenic viral challenge. Vaccine. 2010;28:2088-96 pubmed publisher
    ..This study established proof-of-concept that the attenuated replicating MVTT(ZCI) may serve as a safe noninvasive smallpox vaccine candidate.
  42. Casey C, Iskander J, Roper M, Mast E, Wen X, Torok T, et al. Adverse events associated with smallpox vaccination in the United States, January-October 2003. JAMA. 2005;294:2734-43 pubmed
    ..To describe results from the comprehensive DHHS smallpox vaccine safety monitoring and response system...
  43. Adamo J, Meseda C, Weir J, Merchlinsky M. Smallpox vaccines induce antibodies to the immunomodulatory, secreted vaccinia virus complement control protein. J Gen Virol. 2009;90:2604-8 pubmed publisher
    ..immune globulin was used to screen the secreted proteins from cells infected with Dryvax or the candidate smallpox vaccine LC16m8 to determine whether the protective humoral response included antibodies against secreted viral ..
  44. Meseda C, Weir J. Third-generation smallpox vaccines: challenges in the absence of clinical smallpox. Future Microbiol. 2010;5:1367-82 pubmed publisher
    ..However, there has been renewed interest in smallpox vaccine development due in part to zoonotic poxvirus infections and the possibility of a re-emergence of smallpox, as ..
  45. Kennedy R, Poland G. The identification of HLA class II-restricted T cell epitopes to vaccinia virus membrane proteins. Virology. 2010;408:232-40 pubmed publisher
    ..This information may prove useful in peptide and protein-based subunit vaccine development as well as in the study of CD4 responses to poxviruses. ..
  46. Precopio M, Betts M, Parrino J, Price D, Gostick E, Ambrozak D, et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses. J Exp Med. 2007;204:1405-16 pubmed
    ..This quality of the CD8(+) T cell response may be at least partially responsible for the profound efficacy of these vaccines in protection against smallpox and serves as a benchmark against which other vaccines can be evaluated. ..
  47. Garcia A, Meseda C, Mayer A, Kumar A, Merchlinsky M, Weir J. Characterization and use of mammalian-expressed vaccinia virus extracellular membrane proteins for quantification of the humoral immune response to smallpox vaccines. Clin Vaccine Immunol. 2007;14:1032-44 pubmed
    The licensed smallpox vaccine Dryvax is used as the standard in comparative immunogenicity and protection studies of new smallpox vaccine candidates...
  48. Greenberg R, Kennedy J. ACAM2000: a newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008;17:555-64 pubmed
    ..and animal welfare); and iii) use of variola as a weapon for bioterrorism, a new and safer vaccinia-based smallpox vaccine derived from new cell culture-based technology was proposed. Federally funded work by Acambis, Inc...
  49. Kennedy R, OVSYANNIKOVA I, Poland G. Smallpox vaccines for biodefense. Vaccine. 2009;27 Suppl 4:D73-9 pubmed publisher
    ..Given the ongoing concerns regarding the use of variola as a biological weapon, this review will focus on the licensed vaccines as well as current research into next-generation vaccines to protect against smallpox and other poxviruses. ..
  50. Parrino J, McCurdy L, Larkin B, Gordon I, Rucker S, Enama M, et al. Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax challenge in vaccinia-naïve and vaccinia-immune individuals. Vaccine. 2007;25:1513-25 pubmed
    ..MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. ..
  51. Neff J, Modlin J, Birkhead G, Poland G, Robertson R, Sepkowitz K, et al. Monitoring the safety of a smallpox vaccination program in the United States: report of the joint Smallpox Vaccine Safety Working Group of the advisory committee on immunization practices and the Armed Forces Epidemiological Board. Clin Infect Dis. 2008;46 Suppl 3:S258-70 pubmed publisher
    ..on Immunization Practices and the Department of Defense Armed Forces Epidemiological Board formed a joint Smallpox Vaccine Safety Working Group (SVS WG) to provide independent safety oversight for smallpox vaccination safety-..
  52. Phelps A, Gates A, Hillier M, Eastaugh L, Ulaeto D. Comparative efficacy of modified vaccinia Ankara (MVA) as a potential replacement smallpox vaccine. Vaccine. 2007;25:34-42 pubmed
    ..In this study we have examined the longevity and efficacy of immunity induced by a non-replicating smallpox vaccine candidate, modified vaccinia Ankara (MVA) in a murine model using intranasal and aerosol routes of infection...
  53. Kennedy J, Greenberg R. IMVAMUNE: modified vaccinia Ankara strain as an attenuated smallpox vaccine. Expert Rev Vaccines. 2009;8:13-24 pubmed publisher
    ..We review the Phase I clinical trial safety profile and immune responses and compare them with other smallpox vaccines, including ACAM2000 and Dryvax. ..