Journal of Infection (1992) 24, 327-331
EPIDEMIOLOGY
The role o f h e r d i m m u n i t y in an e p i d e m i c cycle o f hepatitis A P. J. R o o n e y a n d P. V. Coyle
Regional Virus Laboratory, Royal Victoria Hospital, Belfast B TI2 6BA, Northern Ireland, U.K. Accepted for publication 24 October 1991 Summary An epidemic of hepatitis A took place in Northern Ireland between 1984 and 199o. All ages of persons and geographical areas were involved. Children aged 5-14 years with Belfast addresses were particularly affected. Serologically confirmed cases in this group rose from five cases in 1984 to 93 cases in 1987 and fell to 19 cases in I99O. Of IOO samples of serum of Belfast children aged 5-14 years in late 1985, 23 were hepatitis A IgG positive, 95 % confidence limits being I5-2-32. 5. Of IOO similar children in late 1989, 19 were hepatitis A IgG positive, 95 % confidence limits being 11-8-28"1. Thus a substantial rise in herd immunity may not be necessary for the ending of such an epidemic in a society with good housing and sanitation.
Introduction E p i d e m i c cycles of enteroviral infection have been described previously in N o r t h e r n Ireland. 1 A c o m m o n feature has been a rise in the isolation rate of a particular virus f r o m a low baseline to a peak w h e r e u p o n the rate has fallen and some time later a different virus has become endemic. It is unclear what brings these cycles to an end but it is t h o u g h t that a rise in h e r d i m m u n i t y d u r i n g a cycle m a y lessen the n u m b e r of susceptible persons so that viral transmission is reduced. 2 T h e latest enterovirus with such an epidemic cycle was enterovirus 72, the virus of hepatitis A. T h e course of this epidemic was followed by detecting hepatitis A I g M in order to identify acute cases. F u r t h e r m o r e , by examining stored samples of serum obtained both before a n d after the epidemic for hepatitis A I g G , it was possible to determine h e r d i m m u n i t y at the beginning and at the end of the epidemic. Early analysis revealed that a l t h o u g h detection o f hepatitis A I g M increased in all age groups t h r o u g h o u t N o r t h e r n Ireland, children aged 5-14 years with Belfast addresses were particularly affected. By measuring herd i m m u n i t y in this small group we h o p e d to m i n i m i s e c o n f o u n d i n g factors and so determine the role o f herd i m m u n i t y in bringing the epidemic to an end. o163-4453/92/o3o327 +05 $03.00/0
9 1992 The British Society for the Study of Infection
P. J. ROONEY AND P. V. COYLE
328 200
150
,/' im I 0 0 L.)
50
-
X ~ x / X
O i Is1
2nd
Isl
2nd
Is't
2rid
Ist
2nd
Ist
2nd
Ist
84
84
85
85
86
86
87
87
88
88
89
2nd 89
1st 90
2nd 90
Year
Fig. x. HepatitisA IgM positivepersons by 6-monthly intervals. (-- [] ), Total N. Ireland; ( A ), Belfastall ages;( x ), Belfast 5-I 4 year age group, First 84 = first 6 months of x984 etc. M a t e r i a l s and m e t h o d s Samples of serum s u b m i t t e d b y clinicians were examined for hepatitis A I g M if specifically requested or if a clinical history suggesting hepatitis e.g. ' j a u n d i c e ' was given. T h e O r g a n o n kit was used for this purpose. Each patient's name, age and sex were recorded along with any other relevant information such as a history o f foreign travel. O n e h u n d r e d stored samples of serum o f children aged 5 - I 4 years with Belfast h o m e addresses or from hospitals in the Greater Belfast area taken during the period from July to D e c e m b e r I985 (i.e. just before the epidemic began) were examined for hepatitis A I g G b y means of the Organon T e k n i k a Anti-hepatitis A E L I S A . T h e samples had been s u b m i t t e d to the laboratory for various diagnostic procedures. T h e same criteria were used to select and test IOO samples o f serum obtained late in I989, i.e. just as the epidemic among Belfast children came to an end. Results
(I) Main features o f the epidemic It is clear from Fig. i that an epidemic o f hepatitis A began in I986 and involved all age groups and all parts o f N o r t h e r n Ireland. T h e figures for the whole o f the province peaked in late I987 and then reached a low point i n / a t e I989. T h e s u b s e q u e n t rise was the result of greatly increased n u m b e r s o f cases in Counties D o w n and L o n d o n d e r r y . T h e epidemic in the G r e a t e r Belfast area ended in late I989 when serodiagnoses r e t u r n e d to approximately their preepidemic rate. T h e age distribution of serologically diagnosed cases during the period o f the main epidemic, i.e. I 9 8 6 - I 9 8 9 is shown in Fig. 2. T h e 5 - I 4 - y e a r age group
Herd immunity to hepatitis A
329
200
150 t.) 100
50
0
m
m
m
o4
59
I014
m
1519
m
m
2024
2529
m
n
m
m
5 0 - 55- 4 0 - 4 5 54 59 44 49 Age cohor,i (years)
mm
m
n
m
m
5054
5559
6064
6569
70+
Fig. 2. The age distribution of hepatitis A IgM positive persons i n N . Ireland I986-i989.
is most affected with a secondary peak in those aged 25-29 years. T h e male to female ratio for I g M positive persons for the period I984-I99O was I.I to I. (2) Assessment o f herd immunity
Of IOO samples of serum taken from Belfast children aged 5 - I 4 years in late I985 (just before the epidemic), 23 were positive for I g G related to hepatitis A, 95 % confidence intervals being I5"2 to 32.5 . Of IOO similar samples taken from late I989 onwards (just at the end of the Belfast epidemic), I9 were positive, 95 % confidence intervals being I 1.8-28.z. Confidence intervals were calculated by methods described by Gardner and Altman. 3 T h e r e was a trend for increasing seropositivity for I g G to hepatitis A with age. A m o n g IOO samples of serum taken late in I985, 9/55 from children aged 5-9 years ( i 6 % ) and I4/45 from children aged IO-I4 years (3z%) were positive. T h e corresponding figures for late I989 were 6/37 (I6 %) and I3/63 (2I %).
Discussion
It has been possible to study the epidemiological features of hepatitis A in N o r t h e r n Ireland for two main reasons. Firstly, the availability of a specific test for hepatitis A I g M removed the confounding effect of cases of hepatitis B which may be included in clinical notifications of infectious hepatitis. Second, all hepatitis A serological tests for a well-defined geographical area, i.e. N o r t h e r n Ireland, were performed in one local institutions and were not dispersed among a n u m b e r of laboratories. Epidemic cycles with 5-Io-year intervals are typical of the epidemiology of hepatitis A in countries with temperate climates, 4-6 and usually last for I 3 Years4' 7 although in some countries improved living conditions result in the virus being less easily spread so that epidemic cycles no longer occurfl T h e
330
P. J. R O O N E Y
A N D P. V. C O Y L E
epidemic curve in Belfast is that related to continuous person-to-person transmission rather than to a point source. In all these respects the epidemic in Belfast was characteristic of a community-wide outbreak. T h e age distribution of those diagnosed as having hepatitis A in this epidemic is typical with children below I5 years of age being most affected. 8 T h e few children in the o-4 age group diagnosed may reflect the fact that they are more likely than those in older age groups to have inapparent infection. 9,10 T h e y may also be under-represented since it is more difficult to obtain serum samples from them. T h e secondary peak at 25-29 years of age may reflect the fact that persons in this age group are often the carers of young children, s When the geographical distribution of serologically confirmed cases is examined, it appears that the Belfast area has now entered an inter-epidemic phase while counties Down and Londonderry are in an intra-epidemic phase. Previous outbreaks of enteroviral infection in Northern Ireland have come to an end without any active medical intervention. 1 T h e usefulness of h u m a n normal immunoglobulin in preventing spread of the virus is limited since so many infections are asymptomatic and consequently remain unrecognised but can still result in spread of the virus. Even so, mass passive immunisation has been useful in small, relatively closed communities. 11 Epidemics of hepatitis A may come to an end when so many susceptible persons have been exposed to the virus that herd immunity is high enough to interrupt transmission. 10 Later, the birth of new susceptibles in inter-epidemic periods causes herd immunity to fall to such a degree that epidemic spread is again possible. 4 T h e degree of herd immunity required in order to terminate an epidemic is unclear. It may vary considerably from place to place depending on standards of hygiene and housing. Among Sioux Indians of South Dakota, one reservation had a seroprevalence among o-4-year-olds of 54"2 % for IgG related to hepatitis A just after an epidemic while a neighbouring reservation had a seroprevalence of 36"I % for that age group immediately before an epidemic. 7 These people live in poor social circumstances where the virus can spread easily. We had hoped that if a clear rise in herd immunity to hepatitis A had been found among Belfast children after the epidemic, this would help in deciding the uptake of a new hepatitis A vaccine 12 needed to prevent the virus circulating in the local community. That the percentage of children who were hepatitis IgG positive had not risen by the end of the epidemic was surprising. T h e r e are various interpretations of this. It may be that the groups tested for IgG were unrepresentative of the population in which the epidemic took place. For example, it was not possible to determine the social circumstances of either the patients involved in the outbreak or the group tested for IgG. Samples of serum from healthy children chosen at random and obtained before the outbreak would have been preferable to samples from patients. This, however, would have required prior knowledge of the outbreak. Consequently, clinical samples were used for the post-epidemic group in order to compare like with like. Another interpretation is that since IOO samples were tested for IgG both before and at the end of the outbreak, 95 % confidence limits are large and include the possibility of a rise in seroprevalence. A small rise in herd
H e r d i m m u n i t y to hepatitis A
33I
i m m u n i t y m a y b e e n o u g h to t e r m i n a t e a n e p i d e m i c in a w e s t e r n E u r o p e a n community with good housing and sanitation. A n i n t e r e s t i n g p o s s i b i l i t y is t h a t h e r d i m m u n i t y m a y n o t b e t h e m o s t i m p o r t a n t f a c t o r in b r i n g i n g s u c h a n o u t b r e a k to a n e n d . F o r e x a m p l e , a n o t h e r e n t e r o v i r u s ( p o s s i b l y o f l o w p a t h o g e n i c i t y ) m a y h a v e b e g u n to c i r c u l a t e in t h e p o p u l a t i o n a n d to h a v e i n t e r f e r e d w i t h t h e u p t a k e o f h e p a t i t i s A v i r u s f r o m t h e g u t . F i n a l l y , t h e r e w e r e n o o b v i o u s c h a n g e s in r e l e v a n t social c i r c u m s t a n c e s o f t h e p o p u l a t i o n , e.g. h o u s i n g d e n s i t y o r w a t e r s u p p l y . The population of Belfast may now experience a period of low incidence of h e p a t i t i s A a n d m a y well b e p r o t e c t e d b y a c t i v e i m m u n i s a t i o n b e f o r e t h e n e x t e p i d e m i c is d u e . T h i s , t h e r e f o r e , m a y h a v e b e e n t h e last o p p o r t u n i t y to s t u d y an epidemic of hepatitis A here before the introduction of active immunisation p e r m a n e n t l y alters t h e n a t u r a l c o u r s e o f e v e n t s . References
i. Connolly JH, Russell JD, Robinson FLJ, Canavan DA. Echovirus type 7 outbreak in Northern Ireland during 1984. Ulster M e d J 1985; 54: I9I-I95. 2. Melnick JL. Enteroviruses. In: Evans AS, Ed. Viral infections of humans, epidemiology and control 3rd ed. New York: Plenum Publishing, 1989: 191-264. 3. Gardner MJ, Altman DG. Confidence intervals rather than P values: estimation rather than hypothesis testing. Br Med J 1986; 292 : 746-75 o. 4. Shaw FE, Sudman JH, Smith SM et al. A community wide epidemic of hepatitis in Ohio. Am J Epidemiol 1986; x23: IO57-IO65. 5- Polakoff S. Reports of clinical hepatitis A from Public Health and hospital microbiological laboratories to the PHLS Communicable Disease Surveillance Centre during the period 198o-88. J Infect 199o; 2x : I I I - I I 7 . 6. Gust, ID, Feinstone SM. Epidemiology. In: Hepatitis A. Boca Raton, Florida: CRC Press, I988 : I63-I9I. 7. Shaw FE, Shapiro CN, Welty T K , Dill W, Reddington J, Hadler SC. Hepatitis transmission among the Sioux Indians of South Dakota. Am J Public Health I99O; 8o: IO9I-IO94. 8. Crusberg, TC, Burke WM, Reynolds JT, Morse LE, Reilly J, Hoffman AH. The reappearance of a classical epidemic of infectious hepatitis in Worcester, Massachusetts. Am J Epidemiol I978; xo7:545-551. 9. Lemon SM. Type A viral hepatitis. New developments in an old disease. N Engl J Med I985 ; 313 : IO59--IO67. IO. Gingrich GA, Hadler SC, Elder HA, Owen Ash K. Serological investigation of an outbreak of hepatitis A in a rural day care centre. Am J Public Health 1983 ; 73: II9O-1193. I I. Pavia AJ, Nielsen L, Armington L, Thurman DJ, Tierney E, Nichols CR. A communitywide outbreak of Hepatitis A in a religious community: impact of mass administration of immune globulin. Am J Epidemiol 199o; I ] I : lO85-1o93. 12. Gust, ID. Design of hepatitis A vaccines. Br Med Bull 199o; 46 (2): 319-328.
EPIDEMIOLOGY
The role o f h e r d i m m u n i t y in an e p i d e m i c cycle o f hepatitis A P. J. R o o n e y a n d P. V. Coyle
Regional Virus Laboratory, Royal Victoria Hospital, Belfast B TI2 6BA, Northern Ireland, U.K. Accepted for publication 24 October 1991 Summary An epidemic of hepatitis A took place in Northern Ireland between 1984 and 199o. All ages of persons and geographical areas were involved. Children aged 5-14 years with Belfast addresses were particularly affected. Serologically confirmed cases in this group rose from five cases in 1984 to 93 cases in 1987 and fell to 19 cases in I99O. Of IOO samples of serum of Belfast children aged 5-14 years in late 1985, 23 were hepatitis A IgG positive, 95 % confidence limits being I5-2-32. 5. Of IOO similar children in late 1989, 19 were hepatitis A IgG positive, 95 % confidence limits being 11-8-28"1. Thus a substantial rise in herd immunity may not be necessary for the ending of such an epidemic in a society with good housing and sanitation.
Introduction E p i d e m i c cycles of enteroviral infection have been described previously in N o r t h e r n Ireland. 1 A c o m m o n feature has been a rise in the isolation rate of a particular virus f r o m a low baseline to a peak w h e r e u p o n the rate has fallen and some time later a different virus has become endemic. It is unclear what brings these cycles to an end but it is t h o u g h t that a rise in h e r d i m m u n i t y d u r i n g a cycle m a y lessen the n u m b e r of susceptible persons so that viral transmission is reduced. 2 T h e latest enterovirus with such an epidemic cycle was enterovirus 72, the virus of hepatitis A. T h e course of this epidemic was followed by detecting hepatitis A I g M in order to identify acute cases. F u r t h e r m o r e , by examining stored samples of serum obtained both before a n d after the epidemic for hepatitis A I g G , it was possible to determine h e r d i m m u n i t y at the beginning and at the end of the epidemic. Early analysis revealed that a l t h o u g h detection o f hepatitis A I g M increased in all age groups t h r o u g h o u t N o r t h e r n Ireland, children aged 5-14 years with Belfast addresses were particularly affected. By measuring herd i m m u n i t y in this small group we h o p e d to m i n i m i s e c o n f o u n d i n g factors and so determine the role o f herd i m m u n i t y in bringing the epidemic to an end. o163-4453/92/o3o327 +05 $03.00/0
9 1992 The British Society for the Study of Infection
P. J. ROONEY AND P. V. COYLE
328 200
150
,/' im I 0 0 L.)
50
-
X ~ x / X
O i Is1
2nd
Isl
2nd
Is't
2rid
Ist
2nd
Ist
2nd
Ist
84
84
85
85
86
86
87
87
88
88
89
2nd 89
1st 90
2nd 90
Year
Fig. x. HepatitisA IgM positivepersons by 6-monthly intervals. (-- [] ), Total N. Ireland; ( A ), Belfastall ages;( x ), Belfast 5-I 4 year age group, First 84 = first 6 months of x984 etc. M a t e r i a l s and m e t h o d s Samples of serum s u b m i t t e d b y clinicians were examined for hepatitis A I g M if specifically requested or if a clinical history suggesting hepatitis e.g. ' j a u n d i c e ' was given. T h e O r g a n o n kit was used for this purpose. Each patient's name, age and sex were recorded along with any other relevant information such as a history o f foreign travel. O n e h u n d r e d stored samples of serum o f children aged 5 - I 4 years with Belfast h o m e addresses or from hospitals in the Greater Belfast area taken during the period from July to D e c e m b e r I985 (i.e. just before the epidemic began) were examined for hepatitis A I g G b y means of the Organon T e k n i k a Anti-hepatitis A E L I S A . T h e samples had been s u b m i t t e d to the laboratory for various diagnostic procedures. T h e same criteria were used to select and test IOO samples o f serum obtained late in I989, i.e. just as the epidemic among Belfast children came to an end. Results
(I) Main features o f the epidemic It is clear from Fig. i that an epidemic o f hepatitis A began in I986 and involved all age groups and all parts o f N o r t h e r n Ireland. T h e figures for the whole o f the province peaked in late I987 and then reached a low point i n / a t e I989. T h e s u b s e q u e n t rise was the result of greatly increased n u m b e r s o f cases in Counties D o w n and L o n d o n d e r r y . T h e epidemic in the G r e a t e r Belfast area ended in late I989 when serodiagnoses r e t u r n e d to approximately their preepidemic rate. T h e age distribution of serologically diagnosed cases during the period o f the main epidemic, i.e. I 9 8 6 - I 9 8 9 is shown in Fig. 2. T h e 5 - I 4 - y e a r age group
Herd immunity to hepatitis A
329
200
150 t.) 100
50
0
m
m
m
o4
59
I014
m
1519
m
m
2024
2529
m
n
m
m
5 0 - 55- 4 0 - 4 5 54 59 44 49 Age cohor,i (years)
mm
m
n
m
m
5054
5559
6064
6569
70+
Fig. 2. The age distribution of hepatitis A IgM positive persons i n N . Ireland I986-i989.
is most affected with a secondary peak in those aged 25-29 years. T h e male to female ratio for I g M positive persons for the period I984-I99O was I.I to I. (2) Assessment o f herd immunity
Of IOO samples of serum taken from Belfast children aged 5 - I 4 years in late I985 (just before the epidemic), 23 were positive for I g G related to hepatitis A, 95 % confidence intervals being I5"2 to 32.5 . Of IOO similar samples taken from late I989 onwards (just at the end of the Belfast epidemic), I9 were positive, 95 % confidence intervals being I 1.8-28.z. Confidence intervals were calculated by methods described by Gardner and Altman. 3 T h e r e was a trend for increasing seropositivity for I g G to hepatitis A with age. A m o n g IOO samples of serum taken late in I985, 9/55 from children aged 5-9 years ( i 6 % ) and I4/45 from children aged IO-I4 years (3z%) were positive. T h e corresponding figures for late I989 were 6/37 (I6 %) and I3/63 (2I %).
Discussion
It has been possible to study the epidemiological features of hepatitis A in N o r t h e r n Ireland for two main reasons. Firstly, the availability of a specific test for hepatitis A I g M removed the confounding effect of cases of hepatitis B which may be included in clinical notifications of infectious hepatitis. Second, all hepatitis A serological tests for a well-defined geographical area, i.e. N o r t h e r n Ireland, were performed in one local institutions and were not dispersed among a n u m b e r of laboratories. Epidemic cycles with 5-Io-year intervals are typical of the epidemiology of hepatitis A in countries with temperate climates, 4-6 and usually last for I 3 Years4' 7 although in some countries improved living conditions result in the virus being less easily spread so that epidemic cycles no longer occurfl T h e
330
P. J. R O O N E Y
A N D P. V. C O Y L E
epidemic curve in Belfast is that related to continuous person-to-person transmission rather than to a point source. In all these respects the epidemic in Belfast was characteristic of a community-wide outbreak. T h e age distribution of those diagnosed as having hepatitis A in this epidemic is typical with children below I5 years of age being most affected. 8 T h e few children in the o-4 age group diagnosed may reflect the fact that they are more likely than those in older age groups to have inapparent infection. 9,10 T h e y may also be under-represented since it is more difficult to obtain serum samples from them. T h e secondary peak at 25-29 years of age may reflect the fact that persons in this age group are often the carers of young children, s When the geographical distribution of serologically confirmed cases is examined, it appears that the Belfast area has now entered an inter-epidemic phase while counties Down and Londonderry are in an intra-epidemic phase. Previous outbreaks of enteroviral infection in Northern Ireland have come to an end without any active medical intervention. 1 T h e usefulness of h u m a n normal immunoglobulin in preventing spread of the virus is limited since so many infections are asymptomatic and consequently remain unrecognised but can still result in spread of the virus. Even so, mass passive immunisation has been useful in small, relatively closed communities. 11 Epidemics of hepatitis A may come to an end when so many susceptible persons have been exposed to the virus that herd immunity is high enough to interrupt transmission. 10 Later, the birth of new susceptibles in inter-epidemic periods causes herd immunity to fall to such a degree that epidemic spread is again possible. 4 T h e degree of herd immunity required in order to terminate an epidemic is unclear. It may vary considerably from place to place depending on standards of hygiene and housing. Among Sioux Indians of South Dakota, one reservation had a seroprevalence among o-4-year-olds of 54"2 % for IgG related to hepatitis A just after an epidemic while a neighbouring reservation had a seroprevalence of 36"I % for that age group immediately before an epidemic. 7 These people live in poor social circumstances where the virus can spread easily. We had hoped that if a clear rise in herd immunity to hepatitis A had been found among Belfast children after the epidemic, this would help in deciding the uptake of a new hepatitis A vaccine 12 needed to prevent the virus circulating in the local community. That the percentage of children who were hepatitis IgG positive had not risen by the end of the epidemic was surprising. T h e r e are various interpretations of this. It may be that the groups tested for IgG were unrepresentative of the population in which the epidemic took place. For example, it was not possible to determine the social circumstances of either the patients involved in the outbreak or the group tested for IgG. Samples of serum from healthy children chosen at random and obtained before the outbreak would have been preferable to samples from patients. This, however, would have required prior knowledge of the outbreak. Consequently, clinical samples were used for the post-epidemic group in order to compare like with like. Another interpretation is that since IOO samples were tested for IgG both before and at the end of the outbreak, 95 % confidence limits are large and include the possibility of a rise in seroprevalence. A small rise in herd
H e r d i m m u n i t y to hepatitis A
33I
i m m u n i t y m a y b e e n o u g h to t e r m i n a t e a n e p i d e m i c in a w e s t e r n E u r o p e a n community with good housing and sanitation. A n i n t e r e s t i n g p o s s i b i l i t y is t h a t h e r d i m m u n i t y m a y n o t b e t h e m o s t i m p o r t a n t f a c t o r in b r i n g i n g s u c h a n o u t b r e a k to a n e n d . F o r e x a m p l e , a n o t h e r e n t e r o v i r u s ( p o s s i b l y o f l o w p a t h o g e n i c i t y ) m a y h a v e b e g u n to c i r c u l a t e in t h e p o p u l a t i o n a n d to h a v e i n t e r f e r e d w i t h t h e u p t a k e o f h e p a t i t i s A v i r u s f r o m t h e g u t . F i n a l l y , t h e r e w e r e n o o b v i o u s c h a n g e s in r e l e v a n t social c i r c u m s t a n c e s o f t h e p o p u l a t i o n , e.g. h o u s i n g d e n s i t y o r w a t e r s u p p l y . The population of Belfast may now experience a period of low incidence of h e p a t i t i s A a n d m a y well b e p r o t e c t e d b y a c t i v e i m m u n i s a t i o n b e f o r e t h e n e x t e p i d e m i c is d u e . T h i s , t h e r e f o r e , m a y h a v e b e e n t h e last o p p o r t u n i t y to s t u d y an epidemic of hepatitis A here before the introduction of active immunisation p e r m a n e n t l y alters t h e n a t u r a l c o u r s e o f e v e n t s . References
i. Connolly JH, Russell JD, Robinson FLJ, Canavan DA. Echovirus type 7 outbreak in Northern Ireland during 1984. Ulster M e d J 1985; 54: I9I-I95. 2. Melnick JL. Enteroviruses. In: Evans AS, Ed. Viral infections of humans, epidemiology and control 3rd ed. New York: Plenum Publishing, 1989: 191-264. 3. Gardner MJ, Altman DG. Confidence intervals rather than P values: estimation rather than hypothesis testing. Br Med J 1986; 292 : 746-75 o. 4. Shaw FE, Sudman JH, Smith SM et al. A community wide epidemic of hepatitis in Ohio. Am J Epidemiol 1986; x23: IO57-IO65. 5- Polakoff S. Reports of clinical hepatitis A from Public Health and hospital microbiological laboratories to the PHLS Communicable Disease Surveillance Centre during the period 198o-88. J Infect 199o; 2x : I I I - I I 7 . 6. Gust, ID, Feinstone SM. Epidemiology. In: Hepatitis A. Boca Raton, Florida: CRC Press, I988 : I63-I9I. 7. Shaw FE, Shapiro CN, Welty T K , Dill W, Reddington J, Hadler SC. Hepatitis transmission among the Sioux Indians of South Dakota. Am J Public Health I99O; 8o: IO9I-IO94. 8. Crusberg, TC, Burke WM, Reynolds JT, Morse LE, Reilly J, Hoffman AH. The reappearance of a classical epidemic of infectious hepatitis in Worcester, Massachusetts. Am J Epidemiol I978; xo7:545-551. 9. Lemon SM. Type A viral hepatitis. New developments in an old disease. N Engl J Med I985 ; 313 : IO59--IO67. IO. Gingrich GA, Hadler SC, Elder HA, Owen Ash K. Serological investigation of an outbreak of hepatitis A in a rural day care centre. Am J Public Health 1983 ; 73: II9O-1193. I I. Pavia AJ, Nielsen L, Armington L, Thurman DJ, Tierney E, Nichols CR. A communitywide outbreak of Hepatitis A in a religious community: impact of mass administration of immune globulin. Am J Epidemiol 199o; I ] I : lO85-1o93. 12. Gust, ID. Design of hepatitis A vaccines. Br Med Bull 199o; 46 (2): 319-328.
