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Modernizing stockpiles of medical countermeasures against smallpox: Benefits, risks, and knowledge gaps

Martin B. Oleksiewicz, DVM, PhD, Nina R. Steenhard, DVM, PhD, John-Erik Stig Hansen, MD, DMSc

Abstract


Objective: New smallpox medical countermeasures are entering the marketplace, offering the opportunity to modernize existing stockpiles. However, new smallpox countermeasures are developed under the animal rule, meaning that human efficacy data are lacking, and human safety data may be limited. Also, stockpile modernization would require prioritization of increasingly limited public funds. Approaches to address these issues are needed.

Methods: Smallpox vaccine data were gathered by literature search. The financial value of vaccination in the face of an outbreak was evaluated using a threat-based cost/benefit analysis model, involving i) estimation of the efficacy of new smallpox vaccines based on available clinical data on virus-neutralizing seroconversion in vaccinees, ii) estimation of the likelihood for a smallpox outbreak in Denmark, and iii) estimation of the expected life-saving effects of postevent vaccination.

Results: The authors estimated that i) the likelihood of a smallpox outbreak in Denmark is very low (one event in 200,000 years), ii) the expected efficacy of currently available and new vaccines is 95 and 75 percent, respectively, iii) the expected frequency of serious side effects from vaccination is between 100 and 10,000 fold lower for new than for existing vaccines, depending on modes of action.

Conclusions: Despite the very low likelihood for a smallpox outbreak, the potentially large consequences combined with the protective effect of vaccination make maintenance of the smallpox vaccine stockpile justified and valuable. For vaccination in the face of a smallpox outbreak, a high efficacy rather than a lowered rate of adverse effects would maximize the number of lives saved.


Keywords


health security, medical countermeasures, smallpox, bioterrorism, risk/benefit assessment

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References


Bartlett JG, Inglesby TV Jr, Borio L: Management of anthrax. Clin Infect Dis. 2002; 35: 851-858.

European Medicines Agency: Public Assessment Report, Imvanex. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002596/WC500147898.pdf. Accessed March 2015.

Grosenbach DW, Jordan R, Hruby DE: Development of the small-molecule antiviral ST-246 as a smallpox therapeutic. Future Virol. 2011; 6: 653-657.

Fenner F, Henderson DA, Arita I, et al.: Smallpox vaccine and vaccination in the intensified smallpox eradication programme. In Smallpox and Its Eradication. Geneva: World Health Organization, 1988: chap 11. Available at http://whqlibdoc.who.int/smallpox/9241561106.pdf. Accessed April 2014.

Krag P, Bentzon MW: The international reference preparation of smallpox vaccine. An international collaborative assay. Bull World Health Org. 1963; 29: 299-309.

Slater PE, Anis E, Leventhal A: Preparation for an outbreak of smallpox in Israel. Isr Med Assoc J. 2002; 4: 507-512.

Henderson DA, Inglesby TV, Bartlett JG, et al.: Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. 1999; 281: 2127-2137.

Eichner M: Analysis of historical data suggests long-lasting protective effects of smallpox vaccination. Am J Epidemiol. 2003; 158: 717-723.

Taub DD, Ershler WB, Janowski M, et al.: Immunity from smallpox vaccine persists for decades: A longitudinal study. Am J Med. 2008; 121: 1058-1064.

Cohen J: Bioterrorism. Smallpox vaccinations: How much protection remains? Science. 2001; 294: 985.

Wyeth Laboratories, Inc.: Dryvax smallpox vaccine [package insert]. Wyeth Laboratories Inc, Marietta, PA, 1988. Available at http://www.hhs.gov/ohrp/archive/dpanel/dryvax.pdf. Accessed April 2014.

Keckler MS, Reynolds MG, Damon IK, et al.: The effects of postexposure smallpox vaccination on clinical disease presentation: Addressing the data gaps between historical epidemiology and modern surrogate model data. Vaccine. 2013; 31: 5192-5201.

Kretzschmar M, Wallinga J, Teunis P, et al.: Frequency of adverse events after vaccination with different vaccinia strains. PLoS Med. 2006; 3: e272.

Bray M: Pathogenesis and potential antiviral therapy of complications of smallpox vaccination. Antiviral Res. 2003; 58: 101-114.

ACAM2000 smallpox vaccine. Vaccines and Related Biological Products Advisory Committee (VRBPAC) Briefing Document. 2007. Available at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4292b2-02.pdf. Accessed April 2014.

Nalca A, Zumbrun EE: ACAM2000: The new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther. 2010; 4: 71-79.

Scientific review of variola virus research, 1999-2010. Geneva: World Health Organization, 2010. Available at http://whqlibdoc.who.int/hq/2010/WHO_HSE_GAR_BDP_2010.3_eng.pdf. Accessed April 2014.

Kennedy JS, Greenberg RN: IMVAMUNE: Modified vaccinia Ankara strain as an attenuated smallpox vaccine. Expert Rev Vaccines. 2009; 8: 13-24.

Kenner J, Cameron F, Empig C, et al.: LC16m8: An attenuated smallpox vaccine. Vaccine. 2006; 24: 7009-7022.

Arita I: Smallpox vaccine and its stockpile in 2005. Lancet Infect Dis. 2005; 5: 647-652.

Artenstein AW, Grabenstein JD: Smallpox vaccines for biodefense: Need and feasibility. Expert Rev Vaccines. 2008; 7: 1225-1237.

Graeden E, Fielding R, Steinhousw KE, et al.: Modeling the effect of herd immunity and contagiousness in mitigating a smallpox outbreak. Med Decis Making. 2014 (in press).

Henderson DA: Smallpox virus destruction and the implications of a new vaccine. Biosecur Bioterror. 2011; 9: 163-168.

Meyer H: Summary report on first, second and third generation smallpox vaccines, prepared for the WHO SAGE consultation on smallpox vaccines. Available at http://www.who.int/immunization/sage/meetings/2013/november/2_Smallpox_vaccine_review_updated_11_10_13.pdf. Accessed April 2014.

World Health Organization: WHO biosafety team inspection report, Vector, Russian Federation, October 3-9, 2012. Available at http://www.who.int/csr/disease/smallpox/VECTORreport31Oct13.pdf. Accessed April 2014.

World Health Organization: WHO biosafety inspection team report, CDC, USA, May 7-11, 2012. Available at http://www.who.int/csr/disease/smallpox/CDCreport31Oct13.pdf. Accessed April 2014.

Reardon S: Forgotten NIH smallpox virus languishes on death row. Nature. 2014; 514: 544.

Biagini P, Thèves C, Balaresque P, et al.: Variola virus in a 300-year-old Siberian mummy. N Engl J Med. 2012; 367: 2057-2059.

McCollum AM, Wilkins K, Karem KL, et al.: Poxvirus viability and signatures in historical relics. Emerg Infect Dis. 2014; 20: 177-184.

Shchelkunov SN, Totmenin AV, Babkin IV, et al.: Human monkeypox and smallpox viruses: Genomic comparison. FEBS Lett. 2001; 509: 66-70.

Shchelkunov SN: How long ago did smallpox virus emerge? Arch Virol. 2009; 154: 1865-1871.

Shchelkunov SN, Totmenin AV, Safronov PF: Analysis of the monkeypox virus genome. Virology. 2002; 297: 172-194.

Breman JG, Kalisa-Ruti, Steniowski MV, et al.: Human monkeypox, 1970-79. Bull World Health Org. 1980; 58: 165-182.

Sale AT, Melski JW, Stratman EJ: Monkeypox: An epidemiologic and clinical comparison of African and US disease. J Am Acad Dermatol. 2006; 55: 478-481.

Jezek Z, Grab B, Szczeniowski MV, et al.: Human monkeypox: Secondary attack rates. Bull World Health Org. 1988; 66: 465-470.

Khodakevich L, Jezek Z, Messinger D: Monkeypox virus: Ecology and public health significance. Bull World Health Org. 1988; 66: 747-752.

Learned LA, Reynolds MG, Wassa DW, et al.: Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003. Am J Trop Med Hyg. 2005; 73: 428-434.

Thomassen HA, Fuller T, Asefi-Najafabady S, et al.: Pathogenhost associations and predicted range shifts of human monkeypox in response to climate change in central Africa. PLoS One. 2013; 8: e66071.

Meltzer MI, Damon I, Leduc JW, et al.: Modeling potential responses to smallpox as a bioterrorist weapon. Emerg Infect Dis. 2001; 7: 959-969.

Porco TC, Holbrook KA, Fernyak SE, et al.: Logistics of community smallpox control through contact tracing and ring vaccination: A stochastic network model. BMC Public Health. 2004; 4: 34.

Glasser JW, Foster SO, Millar JD, et al.: Evaluating public health responses to reintroduced smallpox via dynamic, socially structured, and spatially distributed metapopulation models. Clin Infect Dis. 2008; 46(suppl 3): S182-S194.

Kaplan EH, Craft DL, Wein LM: Analyzing bioterror response logistics: The case of smallpox. Math Biosci. 2003; 185: 33-72.

Halloran ME, Longini IM Jr, Nizam A, et al.: Containing bioterrorist smallpox. Science. 2002; 298: 1428-1432.

Brouwers L, Boman M, Camitz M, et al.: Micro-simulation of a smallpox outbreak using official register data. Euro Surveill. 2010; 15: pii: 19651.

Gronvall GK, Trent D, Borio L, et al.: The FDA animal efficacy rule and biodefense. Nat Biotechnol. 2007; 25: 1084-1087.

Rosenthal SR, Merchlinsky M, Kleppinger C, et al.: Developing new smallpox vaccines. Emerg Infect Dis. 2001; 7: 920-926.

Kempe CH, Bowles C, Meiklejohn G, et al.: The use of vaccinia hyperimmune gamma-globulin in the prophylaxis of smallpox. Bull World Health Org. 1961; 25: 41-48.

Marennikova SS: The use of hyperimmune antivaccinia gammaglobulin for the prevention and treatment of smallpox. Bull World Health Org. 1962; 27: 325-330.

Frey SE, Winokur PL, Hill H, et al.: Phase II randomized, double-blinded comparison of a single high dose (5 × 10 TCID) of modified vaccinia Ankara compared to a standard dose (1 × 10 TCID) in healthy vaccinia-naive individuals. Vaccine. 2014; 32: 2732-2739.

Frey SE, Winokur PL, Salata RA, et al.: Safety and immunogenicity of IMVAMUNE(R) smallpox vaccine using different strategies for a post event scenario. Vaccine. 2013; 31: 3025-3033.

Engler RJ, Nelson MR, Collins LC, et al.: A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. PLoS One. 2015; 10(3): e0118283.

Danish Ministry of Health: Operational plan in the event of a smallpox threat or outbreak in or outside of Denmark (document in Danish). 2004. Available at http://sundhedsstyrelsen.dk/publ/Publ2004/Koppeplan_juni_2004_SST.pdf. Accessed April 2014.

Lane JM, Goldstein J: Evaluation of 21st-century risks of smallpox vaccination and policy options. Ann Intern Med. 2003; 138: 488-493.

Mack T: A different view of smallpox and vaccination. N Engl J Med. 2003; 348: 460-463.

Frey SE, Newman FK, Kennedy JS, et al.: Clinical and immunologic responses to multiple doses of IMVAMUNE (Modified Vaccinia Ankara) followed by Dryvax challenge. Vaccine. 2007; 25: 8562-8573.

Petersen BW, Damon IK, Pertowski CA, et al.: Clinical guidance for smallpox vaccine use in a postevent vaccination program. MMWR Recomm Rep. 2015; 64(RR-02): 1-26.

Rotz LD, Khan AS, Lillibridge SR, et al.: Public health assessment of potential biological terrorism agents. Emerg Infect Dis. 2002; 8(2): 225.

Meltzer MI: Risks and benefits of pre-exposure and postexposure smallpox vaccination. Emerg Infect Dis. 2003; 9: 1363-1370.




DOI: https://doi.org/10.5055/ajdm.2015.0195

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