MILITARY MEDICINE, 179, 7:702, 2014
Should U.S. Troops Routinely Get Rabies Pre-Exposure Prophylaxis? 1LTChristopher D. Moe, MSC USA*; COL Paul B. Keiser, MC USAf
In September 2012, the Centers for Disease Control reported that both companies that manufacture rabies vaccine in the United States were unable to directly supply vaccines for pre-exposure prophylaxis (PrEP), the regimen given to those at risk of exposure to rabid animals. Later that same month, the Centers for Disease Control reported that one of the man ufacturers of rabies immune globulin (RIG) was unable to supply this product.1 RIG, which is administered emergently after an unvaccinated person is bitten by a potentially rabid animal, must be given before symptoms of rabies develop, which can occur within 1 week of exposure.2 Although restrictions on the supply of vaccine were lifted within a few months, the supply of RIG remains restricted.1 At our Forward Operating Base in eastern Afghanistan (Fig. 1), we had enough vaccine to administer PrEP to soldiers tasked with animal control duties on post (3 intramuscular [IM] doses on days 0, 7 and 21 or 28), and enough for a few rounds of postexposure prophylaxis (PEP; 4 IM doses on days 0, 3, 7, and 14) for minor (WHO Category II) contacts if needed. But, we were unable to replace our expired RIG. When a soldier in our battalion was bitten by a dog during a combat operation in a remote district, his wounds were immediately and thoroughly cleaned, but the lack of locally available RIG necessitated medical evacuation. Initial attempts to send an Air Ambulance to his location were thwarted by hostile fire, so further attempts had to be delayed until after dark. He was eventually taken to the U.S. Army medical facility at Jalalabad Airfield where he received the first dose of vaccine for PEP about 22 hours postexposure, but RIG was not available there either. He was then flown to the NATO base at Bagram Airfield and finally received RIG 32 hours postexposure. Although this seems like appropriate and timely medical care, the costs involved were substantial, as were the risks to the air crews and the rest of his unit who had to disrupt their mission to secure a landing zone for his evacuation and then continue without him. In this case, the risk of rabies was recognized and the course of treatment was apparent. In other instances, the risks are not appreciated, as illustrated by the death of a soldier from rabies ^Brigade Medical Operations, 1st Brigade Combat Team, 101st Airborne Division, Building A3781, 53rd Street, Fort Campbell, KY 42223. tViral Diseases Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Room 3N-03, Silver Spring, MD 20910. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Department of the Army or Department of Defense, doi: 10.7205/MILMED-D-14-00053
702
in 2011. An investigation into that case and a subsequent outreach program determined that neither he nor dozens of others who had been bitten by feral dogs while deployed sought timely treatment. ' Between 2001 and 2010, more than 20,000 animal bites were documented among U.S. service members, of which 643 occurred while deployed.4 Fewer than 4% of these received RIG, though how often this was a medical decision versus a supply issue is hard to determine. If logistical problems like those encountered in our case are considered, along with their costs and operational conse quences, a compelling case could be made for vaccinating all personnel deploying to rabies-enzootic areas, particularly Asia and Africa where the majority of rabies deaths occur.2 PrEP obviates the need for treatment with RIG because anti body levels are either adequate or readily boosted to a pro tective level by a shortened course of PEP (2 IM doses on days 0 and 3). According to Advisory Committee on Immunization Practices (ACIP) recommendations, “some international travelers might be candidates for pre-exposure vaccination if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care, including rabies vaccine and immune globulin, might be limited”.5 This description could be applied to thousands of troops every year. But there are those vaccine shortages, and the one in 2012 was not the first/1The current demand for rabies vaccines for PEP in the United States is about 100,000 doses per year to treat an average of 23,000 bites7 with a 4-dose regimen. If we were to include service members deploying to enzootic areas in the population getting PrEP, the annual demand for rabies vaccines in the United States would increase dramatically (each of the 40,000 troops who deployed in 2013 would have required 3 doses) and be subject to significant fluctuations with the operational tempo. At $150 per dose, such an immu nization policy would be costly to implement. For decades, there have been attempts to reduce costs and increase the supply of rabies vaccines by decreasing the dose, changing the route of administration,8 or developing new vaccines or adjuvants.9'10 A novel formulation would require a lengthy process to determine safety and efficacy before getting regulatory approval and, like any new vaccine product whose administration is made compulsory, be at risk of spawning its own controversy.11 By switching from a 1 mL IM dose to giving 0.1 mL intradermally (ID), however, the existing supply of vaccine could be stretched, and the cost per dose theoreti cally reduced, 5- to 10-fold. The ID route was previously approved in the United States,12 though neither manufacturer
MILITARY MEDICINE, Vol. 179, July 2014
Commentary
REFERENCES
FIGURE 1. One of many feral dogs that came into contact with U.S. troops during our 2012—13 deployment to Nangarhar province. Photo courtesy of MAJ J. Michael Torok, Provincial Reconstruction Team (PRT) Nangarhar.
currently produces a formulation labeled for intradermal use. The safety and efficacy of ID rabies vaccination have been demonstrated in numerous clinical trials.13 Some studies have even shown that a single administration of ID vaccine at one or two sites can induce a protective level of antibodies in the short-term and immunologic memory that reliably responds to a booster dose of vaccine for at least the duration of a typical 6- to 12-month deployment.14,15 Switching from 3 IM doses to a 1- or 2-dose ID regimen could theoretically decrease vaccine costs for pre-exposure immunization 15- to 30-fold. This would bring the cost of rabies PrEP below that of other vaccines currently mandated for most deployments and, if shown to safely render RIG unnecessary, improve the ability to provide optimal care in a deployed environment. Given the number of areas in which the populations of dogs and other vectors are uncontrolled, the global rabies problem is tremendous with over 50,000 deaths estimated per year.” What works for the U.S. military may not work for other populations in which the prevalence of exposure and the costs of implementing different strategies vary,16 so pursuing multiple strategies would be prudent. But further research on the safety and efficacy of intradermal PrEP in a military population is the next reasonable step.
MILITARY MEDICINE, Vol. 179, July 2014
1. Centers for Disease Control (CDC): Vaccine and Immune Globulin Avail ability. Available at http://www.cdc.gov/rabies/resources/availability.html; accessed January 7, 2014. 2. World Health Organization (WHO): Rabies Fact Sheet No 99. Avail able at http://www.who.int/mediacentre/factsheets/fs099/en/; accessed January 7, 2014. 3. Montgomery N: Confusion, anger surround report of soldier’s rabies death. Stars and Stripes, January 27, 2012. Available at http://www.stripes.com/ news/confusion-anger-surround-report-of-soldier-s-rabies-death-1.166967; accessed January 7, 2014. 4. Armed Forces Health Surveillance Center (AFHSC): Animal bites, active and reserve components, U.S. Armed Forces, 2001-2010. MS MR 2011; 18(9): 12-5. 5. Manning SE, Rupprecht CE, Fishbein D, et al: Human rabies prevention— United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008; 57(RR-3): 1-28. 6. Bourhy H, Goudal M, Mailles A, Sadkowska-Todys M, Dacheux L, Zeller H: Is there a need for anti-rabies vaccine and immunoglobulins rationing in Europe? Euro Surveill 2009; 14(13): pii: 19166. 7. Rupprecht CE, Plotkin SA: Rabies vaccines. In: Vaccines, Ed 6, p 660. Edited by Plotkin SA, Orenstein WA, Offit PA. Philadelphia, PA, Elsevier, 2013. 8. Warrell MJ: Intradermal rabies vaccination: the evolution and future of pre- and post-exposure prophylaxis. Cun' Top Microbiol Immunol 2012; 351: 139-57. 9. DiStefano D, Antonello JM, Bett AJ, Medi MB, Casimiro DR, ter Meulen J: Immunogenicity of a reduced-dose whole killed rabies vaccine is significantly enhanced by ISCOMATRIX™ adjuvant, Merck amorphous aluminum hydroxylphosphate sulfate (MAA) or a synthetic TLR9 agonist in rhesus macaques. Vaccine 2013; 31(42): 4888-93. 10. Hu X, Liu R, Zhu N: Enhancement of humoral and cellular immune responses by monophosphoryl lipid A (MPLA) as an adjuvant to the rabies vaccine in BALB/c mice. Immunobiology 2013; 218(12): 1524-8. 11. Offit PA: Past is prologue. In: Deadly Choices: How the Anti-Vaccine Movement Threatens Us All, pp 105-25. New York: Basic Books, 2011. 12. Centers for Disease Control (CDC): Rabies prevention-United States, 1984. MMWR Morb Mortal Wkly Rep 1984; 33: 393-402, 407-8. 13. Wieten RW, Leenstra T, van Thiel PP, et al: Rabies vaccinations: are abbreviated intradermal schedules the future? Clin Infect Dis 2013; 56(3): 414-9. 14. Turner GS, Nicholson KG, Tyrrell DA, Aoki FY: Evaluation of a human diploid cell strain rabies vaccine: final report of a three year study of pre exposure immunization. J Hyg (Lond) 1982; 89(1): 101-10. 15. Khawplod P, Jaijaroensup W, Sawangvaree A, Prakongsri S, Wilde H: One clinic visit for pre-exposure rabies vaccination (a preliminary one year study). Vaccine 2012; 30(19): 2918-20. 16. Liu Q, ErtI HC: Preventative childhood vaccination to rabies. Expert Opin Biol Ther 2012; 12(8): 1067-75.
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Copyright of Military Medicine is the property of AMSUS and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Should U.S. Troops Routinely Get Rabies Pre-Exposure Prophylaxis? 1LTChristopher D. Moe, MSC USA*; COL Paul B. Keiser, MC USAf
In September 2012, the Centers for Disease Control reported that both companies that manufacture rabies vaccine in the United States were unable to directly supply vaccines for pre-exposure prophylaxis (PrEP), the regimen given to those at risk of exposure to rabid animals. Later that same month, the Centers for Disease Control reported that one of the man ufacturers of rabies immune globulin (RIG) was unable to supply this product.1 RIG, which is administered emergently after an unvaccinated person is bitten by a potentially rabid animal, must be given before symptoms of rabies develop, which can occur within 1 week of exposure.2 Although restrictions on the supply of vaccine were lifted within a few months, the supply of RIG remains restricted.1 At our Forward Operating Base in eastern Afghanistan (Fig. 1), we had enough vaccine to administer PrEP to soldiers tasked with animal control duties on post (3 intramuscular [IM] doses on days 0, 7 and 21 or 28), and enough for a few rounds of postexposure prophylaxis (PEP; 4 IM doses on days 0, 3, 7, and 14) for minor (WHO Category II) contacts if needed. But, we were unable to replace our expired RIG. When a soldier in our battalion was bitten by a dog during a combat operation in a remote district, his wounds were immediately and thoroughly cleaned, but the lack of locally available RIG necessitated medical evacuation. Initial attempts to send an Air Ambulance to his location were thwarted by hostile fire, so further attempts had to be delayed until after dark. He was eventually taken to the U.S. Army medical facility at Jalalabad Airfield where he received the first dose of vaccine for PEP about 22 hours postexposure, but RIG was not available there either. He was then flown to the NATO base at Bagram Airfield and finally received RIG 32 hours postexposure. Although this seems like appropriate and timely medical care, the costs involved were substantial, as were the risks to the air crews and the rest of his unit who had to disrupt their mission to secure a landing zone for his evacuation and then continue without him. In this case, the risk of rabies was recognized and the course of treatment was apparent. In other instances, the risks are not appreciated, as illustrated by the death of a soldier from rabies ^Brigade Medical Operations, 1st Brigade Combat Team, 101st Airborne Division, Building A3781, 53rd Street, Fort Campbell, KY 42223. tViral Diseases Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Room 3N-03, Silver Spring, MD 20910. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Department of the Army or Department of Defense, doi: 10.7205/MILMED-D-14-00053
702
in 2011. An investigation into that case and a subsequent outreach program determined that neither he nor dozens of others who had been bitten by feral dogs while deployed sought timely treatment. ' Between 2001 and 2010, more than 20,000 animal bites were documented among U.S. service members, of which 643 occurred while deployed.4 Fewer than 4% of these received RIG, though how often this was a medical decision versus a supply issue is hard to determine. If logistical problems like those encountered in our case are considered, along with their costs and operational conse quences, a compelling case could be made for vaccinating all personnel deploying to rabies-enzootic areas, particularly Asia and Africa where the majority of rabies deaths occur.2 PrEP obviates the need for treatment with RIG because anti body levels are either adequate or readily boosted to a pro tective level by a shortened course of PEP (2 IM doses on days 0 and 3). According to Advisory Committee on Immunization Practices (ACIP) recommendations, “some international travelers might be candidates for pre-exposure vaccination if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care, including rabies vaccine and immune globulin, might be limited”.5 This description could be applied to thousands of troops every year. But there are those vaccine shortages, and the one in 2012 was not the first/1The current demand for rabies vaccines for PEP in the United States is about 100,000 doses per year to treat an average of 23,000 bites7 with a 4-dose regimen. If we were to include service members deploying to enzootic areas in the population getting PrEP, the annual demand for rabies vaccines in the United States would increase dramatically (each of the 40,000 troops who deployed in 2013 would have required 3 doses) and be subject to significant fluctuations with the operational tempo. At $150 per dose, such an immu nization policy would be costly to implement. For decades, there have been attempts to reduce costs and increase the supply of rabies vaccines by decreasing the dose, changing the route of administration,8 or developing new vaccines or adjuvants.9'10 A novel formulation would require a lengthy process to determine safety and efficacy before getting regulatory approval and, like any new vaccine product whose administration is made compulsory, be at risk of spawning its own controversy.11 By switching from a 1 mL IM dose to giving 0.1 mL intradermally (ID), however, the existing supply of vaccine could be stretched, and the cost per dose theoreti cally reduced, 5- to 10-fold. The ID route was previously approved in the United States,12 though neither manufacturer
MILITARY MEDICINE, Vol. 179, July 2014
Commentary
REFERENCES
FIGURE 1. One of many feral dogs that came into contact with U.S. troops during our 2012—13 deployment to Nangarhar province. Photo courtesy of MAJ J. Michael Torok, Provincial Reconstruction Team (PRT) Nangarhar.
currently produces a formulation labeled for intradermal use. The safety and efficacy of ID rabies vaccination have been demonstrated in numerous clinical trials.13 Some studies have even shown that a single administration of ID vaccine at one or two sites can induce a protective level of antibodies in the short-term and immunologic memory that reliably responds to a booster dose of vaccine for at least the duration of a typical 6- to 12-month deployment.14,15 Switching from 3 IM doses to a 1- or 2-dose ID regimen could theoretically decrease vaccine costs for pre-exposure immunization 15- to 30-fold. This would bring the cost of rabies PrEP below that of other vaccines currently mandated for most deployments and, if shown to safely render RIG unnecessary, improve the ability to provide optimal care in a deployed environment. Given the number of areas in which the populations of dogs and other vectors are uncontrolled, the global rabies problem is tremendous with over 50,000 deaths estimated per year.” What works for the U.S. military may not work for other populations in which the prevalence of exposure and the costs of implementing different strategies vary,16 so pursuing multiple strategies would be prudent. But further research on the safety and efficacy of intradermal PrEP in a military population is the next reasonable step.
MILITARY MEDICINE, Vol. 179, July 2014
1. Centers for Disease Control (CDC): Vaccine and Immune Globulin Avail ability. Available at http://www.cdc.gov/rabies/resources/availability.html; accessed January 7, 2014. 2. World Health Organization (WHO): Rabies Fact Sheet No 99. Avail able at http://www.who.int/mediacentre/factsheets/fs099/en/; accessed January 7, 2014. 3. Montgomery N: Confusion, anger surround report of soldier’s rabies death. Stars and Stripes, January 27, 2012. Available at http://www.stripes.com/ news/confusion-anger-surround-report-of-soldier-s-rabies-death-1.166967; accessed January 7, 2014. 4. Armed Forces Health Surveillance Center (AFHSC): Animal bites, active and reserve components, U.S. Armed Forces, 2001-2010. MS MR 2011; 18(9): 12-5. 5. Manning SE, Rupprecht CE, Fishbein D, et al: Human rabies prevention— United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2008; 57(RR-3): 1-28. 6. Bourhy H, Goudal M, Mailles A, Sadkowska-Todys M, Dacheux L, Zeller H: Is there a need for anti-rabies vaccine and immunoglobulins rationing in Europe? Euro Surveill 2009; 14(13): pii: 19166. 7. Rupprecht CE, Plotkin SA: Rabies vaccines. In: Vaccines, Ed 6, p 660. Edited by Plotkin SA, Orenstein WA, Offit PA. Philadelphia, PA, Elsevier, 2013. 8. Warrell MJ: Intradermal rabies vaccination: the evolution and future of pre- and post-exposure prophylaxis. Cun' Top Microbiol Immunol 2012; 351: 139-57. 9. DiStefano D, Antonello JM, Bett AJ, Medi MB, Casimiro DR, ter Meulen J: Immunogenicity of a reduced-dose whole killed rabies vaccine is significantly enhanced by ISCOMATRIX™ adjuvant, Merck amorphous aluminum hydroxylphosphate sulfate (MAA) or a synthetic TLR9 agonist in rhesus macaques. Vaccine 2013; 31(42): 4888-93. 10. Hu X, Liu R, Zhu N: Enhancement of humoral and cellular immune responses by monophosphoryl lipid A (MPLA) as an adjuvant to the rabies vaccine in BALB/c mice. Immunobiology 2013; 218(12): 1524-8. 11. Offit PA: Past is prologue. In: Deadly Choices: How the Anti-Vaccine Movement Threatens Us All, pp 105-25. New York: Basic Books, 2011. 12. Centers for Disease Control (CDC): Rabies prevention-United States, 1984. MMWR Morb Mortal Wkly Rep 1984; 33: 393-402, 407-8. 13. Wieten RW, Leenstra T, van Thiel PP, et al: Rabies vaccinations: are abbreviated intradermal schedules the future? Clin Infect Dis 2013; 56(3): 414-9. 14. Turner GS, Nicholson KG, Tyrrell DA, Aoki FY: Evaluation of a human diploid cell strain rabies vaccine: final report of a three year study of pre exposure immunization. J Hyg (Lond) 1982; 89(1): 101-10. 15. Khawplod P, Jaijaroensup W, Sawangvaree A, Prakongsri S, Wilde H: One clinic visit for pre-exposure rabies vaccination (a preliminary one year study). Vaccine 2012; 30(19): 2918-20. 16. Liu Q, ErtI HC: Preventative childhood vaccination to rabies. Expert Opin Biol Ther 2012; 12(8): 1067-75.
703
Copyright of Military Medicine is the property of AMSUS and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
