Hepatitis A in the US Army: epidemiology and vaccine development C. H. Hoke, Jr**, L. N. Binn*, J. E. Egan*, R. F. DeFraites*, P. O. MacArthy ~, B. L. Innis*, K. H. Eckels ,~, D. Dubois ,~, E. D Hondt '~, M. H. Sjogren .1, R. Rice, J.C. Sadoff, and W. H. Bancroft "2 Control of hepatitis A has been an important concern Jor US military forces in war and peace. Immune serum globulin, although effective, is exceedingly cumbersome to use. The prevalence of antibody against hepatitis A is decreasing in young American soldiers, putting them at risk of hepatitis A during deployment. The US Army has been an active participant in development of hepatitis A vaccine. The first successful cell-culture-derived, formalin-inactivated hepatitis A vaccine was developed at the Walter Reed Army Institute of Research. This prototype vaccine was shown, in 1986, to be safe and immunogenic for humans. Since then we have evaluated the following issues related to the use of inactivated hepatitis A vaccines in military populations. Immunogenicity of vaccine derived from the CLF and HM175 strains; immunogenicity of hepatitis A vaccine given by jet injector," immunogenicity of hepatitis A vaccine when given with hepatitis B vaccine; immunogenicity when given in shortened schedules; safety and immunogenicity in Thai children," and efficacy under field conditions in the tropics. The hepatitis A vaccines which we tested are safe and highly immunogenic. Immunization by jet gun confers immunity equivalent to immunization by needle. Hepatitis A vaccine is equally potent when given with hepatitis B vaccine. Data on rapid immunization schedules and efficao' are under evaluation. We conclude that hepatitis A vaccine is a major improvement in our ability to prevent hepatitis A in soldiers. Keywords: Military; sanitation; infectious hepatitis; prevention; jaundice; inactivated vaccine
INTRODUCTION Epidemic hepatitis, almost certainly due mainly to hepatitis A virus, has been recognized under many names as a military problem for centuries ~. Because of repeated epidemics of hepatitis during wartime, the need to protect soldiers in battle from disease caused by hepatitis A virus is clear. Immune serum globulin (lg) has been shown in many studies to protect against hepatitis A 2, and so Ig has been used routinely to protect soliders and civilian travellers. Soldiers are inoculated at deployment and every 4-6 months thereafter. With large deployments, continuous distribution of lg has proved impractical.
~Department of Virus Diseases, and §Department of Biologics Research, ¶ Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington DC 20307-5700, USA. *Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. "SmithKline Beecham Biologicals, Rixensart, Belgium. 1Present Address: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA. 2Present address: US Army Medical Research and Development Command, Fort Detrict, MD, USA. *To whom correspondence should be addressed 0264-410X/92/100S75-05 ~) 1992Butterworth-HeinemannLtd
Moreover, because of the constant risk of overseas deployment, soldiers may receive lg many times during their careers, a universally unpopular necessity. Active immunization by means of a vaccine is a highly desirable objective. Achieving this objective has been an important mission of the US Army Medical Research and Development Command (USAMRDC) for the past five decades. During Operation Desert Shield/Storm, depleted supplies of Ig led to a rapid acceleration of the development effort. In this paper, we review the military history of hepatitis A and the recent contributions of military investigators to the development and use of hepatitis A vaccine.
MILITARY HISTORY Hepatitis A has probably been a serious problem for military operations in every war (Table 1). Etiological diagnosis of outbreaks of epidemic hepatitis during wars in which no diagnostic capability existed is based on epidemiological features. Based on these features, it is safe to assume that a large proportion of such cases were due to hepatitis A virus 3. In the Civil War, epidemics of jaundice occurred
Vaccine, Vol. 10, Suppl. 1, 1992
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Hepatitis A in the US Army. C. H. Hoke et al. Table 1
Summary of epidemiological importance of hepatitis A in US military populations (adapted from Ref. 1)
Military era
Epidemiological impact
Civil War
Frequent outbreaks Recurrent outbreaks in same bivouac areas Devastating in prisoners of war Epidemic jaundice and dysentery recognized camp-associated diseases US Forces minimally affected Severe problem for British, French and German troops Severe problem for US forces Virus transmission continuous and widespread Occasional common source outbreak New recruits and officers were at highest risk Severe problem for Allied Forces New Zealand Forces Battle of El Alamein noted for epidemic of hepatitis One in seven soldiers affected Outbreaks uncontrolled by sanitary measures Reduction in outbreak required evacuation Axis forces in North Africa heavily affected Sporadic outbreaks occurred in US Forces in Germany in late 1940s High rates in US Forces crowded in Pusan perimenter 4000 cases in winter of 1950. 4 deaths Naval outbreak in Naples 156 cases on 14 ships Uncooked fish implicated Hepatitis rates of 5.7/1000 men in 1965 Rose to 6.7/1000 when Ig stopped San Diego 47/1000 attack rate Infected food handler implicated Child care centres recognized as important foci
World War I World War II
Post-World II Korea 1959
Vietnam 1974
1980
whenever soldiers camped for long periods, especially when they camped in sites where outbreaks had occurred previously. Prisoners in prisoner of war camps were severely affected ~. During World War I, hepatitis was a major problem for British, French and German troops, but much less of a problem for Americans. The occurrence of jaundice 3 to 4 weeks following epidemics of dysentery was noted by British physiciansL In World War II, sporadic disease was widespread. Many well known outbreaks of hepatitis A occurred. Among the most noted was the epidemic that affected the Second New Zealand Division at the Battle of El Alamein. At 35 to 40 days following occupation of newly won territory by two brigades of front-line troops, an epidemic of hepatitis began. The territory had previously been held by German units which had experienced outbreaks of hepatitis. Eventually, 1059 out of 7500 (141/ 1000) soldiers developed hepatitis. The epidemic abated another 35-40 days after affected units withdrew from the occupied territory. Units occupying areas which had not been previously held had only 78 cases in 3900 men (20/1000), no more than the usual number of casesfi As described by Zuckerman, 'The epidemics of jaundice during the Second World War reached vast proportions: 200 000 cases occurred among US troops from 1942 to 1945 and over 5000 000 cases occurred among the German armies and civilians alone, according to Gutzeit, while huge epidemics swept through the allied forces, especially in the Mediterranean region. Indeed, the number of cases was so large as to influence the strategy of the war ~. Despite advances in the knowledge of the epidemiology of hepatitis, this infection remained a serious problem in military conflicts which have taken place in more recent years. Altogether, US Forces experienced > 180 000 cases of infectious hepatitis in World War II,
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with 106695 admissions, and a case fatality ratio of 0.3%. The annual admission rate per 1000 average strength was 4.37 over all. In the South West Pacific, the rate was 26 per 1000 average strength per year, in the Mediterranean 13/1000, in China Burma India 8/1000 and in Europe 7/10005 . American soldiers with acute hepatitis missed 6 to 8 weeks of dutyL These experiences indicated that outbreaks occurred when R~rces occupied areas previously occupied by ill enemy soldiers, that outbreaks could not be controlled by sanitary measures, that withdrawal from the territory was required to terminate an epidemic and that the rate of hepatitis may vary from zone to zone-'. Clearly, infectious hepatitis presented a severe health problem tk~r operating forces. Prevention of hepatitis was a major concern for military forces. However, the routes of transmission were not understood. The need for information was so great that human experiments were done in which volunteers ingested faecal preparations from soldiers with infectious hepatitis. The volunteers developed hepatitis, demonstrating that infectious hepatitis was transmitted by the t:aecal oral route and that the incubation period was about 21 days >. Following World War II, hepatitis A has become an intermittent public health problem for military populations. In the Korean conflict, an outbreak of hepatitis occurred when both American and Korean soldiers were crowded into the Pusan perimeter. In the autumn and winter of 1950, 4000 patients with hepatitis were hospitalizedL Many cases of hepatitis, some undoubtedly due to hepatitis A, occurred during the Vietnam conflict, despite the use oflg. In the Middle East, a large outbreak occurred in 1978 in French soldiers in Lebanon who had not received Ig (154 cases/1000 men per year). In recent years, child care centres have been recognized as a focus for transmission of hepatitis A on military posts~L In peace time. hepatitis A continues to affect the military.
100
60
\\%~
50
INTRODUCTION Epidemic hepatitis, almost certainly due mainly to hepatitis A virus, has been recognized under many names as a military problem for centuries ~. Because of repeated epidemics of hepatitis during wartime, the need to protect soldiers in battle from disease caused by hepatitis A virus is clear. Immune serum globulin (lg) has been shown in many studies to protect against hepatitis A 2, and so Ig has been used routinely to protect soliders and civilian travellers. Soldiers are inoculated at deployment and every 4-6 months thereafter. With large deployments, continuous distribution of lg has proved impractical.
~Department of Virus Diseases, and §Department of Biologics Research, ¶ Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington DC 20307-5700, USA. *Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. "SmithKline Beecham Biologicals, Rixensart, Belgium. 1Present Address: US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA. 2Present address: US Army Medical Research and Development Command, Fort Detrict, MD, USA. *To whom correspondence should be addressed 0264-410X/92/100S75-05 ~) 1992Butterworth-HeinemannLtd
Moreover, because of the constant risk of overseas deployment, soldiers may receive lg many times during their careers, a universally unpopular necessity. Active immunization by means of a vaccine is a highly desirable objective. Achieving this objective has been an important mission of the US Army Medical Research and Development Command (USAMRDC) for the past five decades. During Operation Desert Shield/Storm, depleted supplies of Ig led to a rapid acceleration of the development effort. In this paper, we review the military history of hepatitis A and the recent contributions of military investigators to the development and use of hepatitis A vaccine.
MILITARY HISTORY Hepatitis A has probably been a serious problem for military operations in every war (Table 1). Etiological diagnosis of outbreaks of epidemic hepatitis during wars in which no diagnostic capability existed is based on epidemiological features. Based on these features, it is safe to assume that a large proportion of such cases were due to hepatitis A virus 3. In the Civil War, epidemics of jaundice occurred
Vaccine, Vol. 10, Suppl. 1, 1992
$75
Hepatitis A in the US Army. C. H. Hoke et al. Table 1
Summary of epidemiological importance of hepatitis A in US military populations (adapted from Ref. 1)
Military era
Epidemiological impact
Civil War
Frequent outbreaks Recurrent outbreaks in same bivouac areas Devastating in prisoners of war Epidemic jaundice and dysentery recognized camp-associated diseases US Forces minimally affected Severe problem for British, French and German troops Severe problem for US forces Virus transmission continuous and widespread Occasional common source outbreak New recruits and officers were at highest risk Severe problem for Allied Forces New Zealand Forces Battle of El Alamein noted for epidemic of hepatitis One in seven soldiers affected Outbreaks uncontrolled by sanitary measures Reduction in outbreak required evacuation Axis forces in North Africa heavily affected Sporadic outbreaks occurred in US Forces in Germany in late 1940s High rates in US Forces crowded in Pusan perimenter 4000 cases in winter of 1950. 4 deaths Naval outbreak in Naples 156 cases on 14 ships Uncooked fish implicated Hepatitis rates of 5.7/1000 men in 1965 Rose to 6.7/1000 when Ig stopped San Diego 47/1000 attack rate Infected food handler implicated Child care centres recognized as important foci
World War I World War II
Post-World II Korea 1959
Vietnam 1974
1980
whenever soldiers camped for long periods, especially when they camped in sites where outbreaks had occurred previously. Prisoners in prisoner of war camps were severely affected ~. During World War I, hepatitis was a major problem for British, French and German troops, but much less of a problem for Americans. The occurrence of jaundice 3 to 4 weeks following epidemics of dysentery was noted by British physiciansL In World War II, sporadic disease was widespread. Many well known outbreaks of hepatitis A occurred. Among the most noted was the epidemic that affected the Second New Zealand Division at the Battle of El Alamein. At 35 to 40 days following occupation of newly won territory by two brigades of front-line troops, an epidemic of hepatitis began. The territory had previously been held by German units which had experienced outbreaks of hepatitis. Eventually, 1059 out of 7500 (141/ 1000) soldiers developed hepatitis. The epidemic abated another 35-40 days after affected units withdrew from the occupied territory. Units occupying areas which had not been previously held had only 78 cases in 3900 men (20/1000), no more than the usual number of casesfi As described by Zuckerman, 'The epidemics of jaundice during the Second World War reached vast proportions: 200 000 cases occurred among US troops from 1942 to 1945 and over 5000 000 cases occurred among the German armies and civilians alone, according to Gutzeit, while huge epidemics swept through the allied forces, especially in the Mediterranean region. Indeed, the number of cases was so large as to influence the strategy of the war ~. Despite advances in the knowledge of the epidemiology of hepatitis, this infection remained a serious problem in military conflicts which have taken place in more recent years. Altogether, US Forces experienced > 180 000 cases of infectious hepatitis in World War II,
S76
V a c c i n e , Vol. 10, Suppl. 1, 1992
with 106695 admissions, and a case fatality ratio of 0.3%. The annual admission rate per 1000 average strength was 4.37 over all. In the South West Pacific, the rate was 26 per 1000 average strength per year, in the Mediterranean 13/1000, in China Burma India 8/1000 and in Europe 7/10005 . American soldiers with acute hepatitis missed 6 to 8 weeks of dutyL These experiences indicated that outbreaks occurred when R~rces occupied areas previously occupied by ill enemy soldiers, that outbreaks could not be controlled by sanitary measures, that withdrawal from the territory was required to terminate an epidemic and that the rate of hepatitis may vary from zone to zone-'. Clearly, infectious hepatitis presented a severe health problem tk~r operating forces. Prevention of hepatitis was a major concern for military forces. However, the routes of transmission were not understood. The need for information was so great that human experiments were done in which volunteers ingested faecal preparations from soldiers with infectious hepatitis. The volunteers developed hepatitis, demonstrating that infectious hepatitis was transmitted by the t:aecal oral route and that the incubation period was about 21 days >. Following World War II, hepatitis A has become an intermittent public health problem for military populations. In the Korean conflict, an outbreak of hepatitis occurred when both American and Korean soldiers were crowded into the Pusan perimeter. In the autumn and winter of 1950, 4000 patients with hepatitis were hospitalizedL Many cases of hepatitis, some undoubtedly due to hepatitis A, occurred during the Vietnam conflict, despite the use oflg. In the Middle East, a large outbreak occurred in 1978 in French soldiers in Lebanon who had not received Ig (154 cases/1000 men per year). In recent years, child care centres have been recognized as a focus for transmission of hepatitis A on military posts~L In peace time. hepatitis A continues to affect the military.
100
60
\\%~
50
