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Inactivated hepatitis A vaccine in childhood: implications for disease control
Inactivated hepatitis A vaccine in childhood: implications for disease control D. Nalin *t, L. Brown t, B. Kuter t, C, Patterson +, B. McGuire +, A. Werzberger~, M. Santosham', S. Block ~', K. Reisinger °, B. Watson,~, S. Starr,~, L. Pickering +, J. Lewis +, W. Miller*, G. Calandra* and M. Blatter ° The experience to date with the Merck inactivated hepatitis A vaccine in healthy children 2-16 years old is reviewed. Comparison of responses to increasing doses indicates that an intramuscular dose of 25 units results in seroconversion of 99% of children by week 4 following a single dose. Antibody persistence rate is nearly 100% six months later, whether or not a second priming dose is given at week 8. This vaccine has proven highly immunogenic in children and has a favourable safety/tolerability profile. It should be useful for preexposure prophylaxis and control of hepatitis A, and should eventually replace immune globulin (Ig)./or this indication. Keywords: Hepatitis A; children; inactivated vaccine
INTRODUCTION Hepatitis A is caused by a picornavirus which spreads by the faecal/oral route, chiefly after contamination of food or water by faecally excreted virus from infected individuals. Hepatitis A virus (HAV) causes significant morbidity mainly in developed countries, where food and water quality, sanitation and hygiene prevent transmission to most young children, resulting in many older individuals susceptible to disease. Non-immune older populations, infected by ingestion of raw or undercooked contaminated foods or beverages, by contact with virus from inapparent cases, or via sex practices, develop clinical disease causing significant loss of school or work time. The annual cost of hepatitis A in the USA has been estimated to be US $200 million I. In underdeveloped nations the virus spreads easily due to widespread environmental faecal contamination. Asymptomatic early childhood infection usually provides long-lasting immunity. Developing countries in transition, with rapid improvements in water and food hygiene in some population sectors, have experienced massive outbreaks. Coexistence of subpopulations of high and low endemicity permits viral cross-contamination from the endemic to the non-immune sectors via food or water and has created explosive outbreaks in ~Merck Research Laboratories, West Point, PA, USA. *Kiryas Joel Institute of Medicine, Monroe, NY, USA. "lJohns Hopkins University, Baltimore, MD, USA. ~Physicians to Children and Adolescents, P.S.C., Bardstown, KY, USA. °Pittsburgh Pediatric Research, Inc., Pittsburgh, PA, USA. §Children's Hospital of Philadelphia, Philadelphia, PA, USA. +University of Texas Medical School, Houston, TX, USA. *To whom correspondence should be addressed 0264-410X/93/110S 15-03 1993 Butterworth-Heinemann Ltd
Chile, Korea and China. In the 1988 Shanghai outbreak, sewage contaminating raw clams led to > 350 000 clinical c a s e s 2.
The relatively mild or subclinical infections of children which do occur in the developed world are epidemiologically significant as a source of infection for older nonimmune siblings, parents, caretakers or other contacts. The growth of the day-care centre industry has facilitated viral spread from subclinically infected children to older non-immune contacts who, in contrast to infants and toddlers, typically develop significant clinical illness 3. Native American children and children in boarding or day schools, orphanages, summer camps, and homes for the disabled, or those who are mentally deficient or chronically ill, are similarly at high risk. The high proportion ( > 40%) of adult cases with no identified source of infection is perhaps attributable to infected young asymptomatic children who spread disease unnoticed. Improved control in developed countries must utilize methods of interrupting transmission, especially in children, either by passive prophylaxis or by active immunization. Immune globulin (Ig) can confer passive protection for up to 6 months 4.5, but requires repeated administration. The associated health-care costs, discomfort and nuisance render Ig non-feasible for costeffective hepatitis A control. Ig administration is also associated with several real or perceived risks 6-s, and in postexposure situations must be given within the first 2 weeks after exposure, necessitating costly and impracticable disease surveillance for early case detection. Ig is rarely used effectively in this manner, and is used chiefly among older European and US travellers and the military. It is unacceptable to most communities to give Ig to
Vaccine, Vol. 11, Suppl. 1, 1993
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Inactivated hepatitis A vaccine in childhood." D. Nalin et al. Table 1
Immunogenicity data from different studies 4 weeks
Protocol
Dose (U)
Regimen (weeks)
Seroconversion rate, % (n)
Dose range (2-12 years)
6 13 25 13 25 25 25
0, 0, 0, 0, 0, 0, 0,
92 81 94 85 97 99 99
Safety-tolerability (4-12 years) Efficacy (2-16 years)
8, 24 8, 24 8, 24 24 24 24 24
(73/79) (56/69) (32/34) (68/66) (35/36) (97/98) (304/305)
28 weeks GMT 30 24 35 31 31 45 42
Seroconversion rate % (n) 100 (68/68) 100 (41/41) 100 (26/26) 100 (44/44) 100 (30/30) 100 (95/95) 100 (41/41) b
GMT 10 742 a 17 498 12 253 . 8 857 a 8 798 a 16 500" 7 579
GMT, geometric mean titre of responders only. Seroconversion rate measured by modified HAVAB assay. The 6 U dose was not tested on the 0, 24 week regimen a Five samples omitted per group because end-points were not available 41 completed to date
children every 6 months. Thus a protective paediatric vaccine with a favourable safety tolerability profile is needed to improve hepatitis A control. In recent studies of children 2- 16 years old ~, a formalin-inactivated, alumadjuvanted vaccine developed by Merck Research Laboratories from the CR326F strain, F' passage of HAV was well tolerated, highly immunogenic and 100% protective after a single dose containing 25 units (U) of viral antigen. This preliminary report reviews the paediatric experience with this vaccine. METHODS After safety had been demonstrated in 200 adults given one or more doses of the vaccine [(~25 U (1 U ~ 1 ng) of viral antigen per dose as measured by a hepatitis A virus antigen radioimmunoassay], paediatric studies were initiated. The preparation of the vaccine used in these studies has been previously reported m, and small lot to lot variations in production details have not altered safety or immunogenicity significantly. Healthy children and young adolescents 2 16 years old ( ~ 5 6 % male, 44% female) whose parents gave informed consent were entered if they had no history of immune deficiency or liver disease, no sensitivity to any vaccine component such as alum or thimerosal, no receipt of lg within 6 months before the study, and no other vaccination a month before (or a month after) administration of each hepatitis A vaccine dose. All were prescreened to confirm serostatus before vaccination. The volume of each injection was 0.5 or 0.6 ml depending on vaccine antigen concentration, given intramuscularly. Each dose contained 250 gg of AI(OH)3. Venous blood for serological tests was obtained before and during the study course at varying intervals (see Results). Serology was determined by a modified radioimmunoassay (HAVAB, Abbott) by comparison with the W H O standard antiserum ~,12. Titres of 10 m l U / m l and above are considered positive in this assay. Subsequently a randomized, double-blind, placebo-controlled protective efficacy triaP was carried out, involving 1037 children and using an intramuscular dose of 25 U of viral antigen or of matching placebo. Results are included in the response at week 4 of 305 of these children, and the levels at week 28 of 41 of them. A total of 1514 children (2-16 years old) have been vaccinated with one or more doses of 6 to 25 U viral antigen and were included in surveillance for serious adverse experiences; 504 received two doses 6 months
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V a c c i n e , Vol. 11, S u p p l . 1, 1993
apart and 182 received three doses (0, 2 months, 6 months), including 16 (all but one from one study) who were seropositive prior to vaccination. RESULTS
Safety and tolerability profile in children No serious adverse clinical or laboratory reaction has been reported in any vaccinee. Mild local transient discomfort at the site of injection was the major injectionrelated adverse experience, and was equally frequent in placebo or vaccine recipients.
lmmunogenieity The vaccine has proven rapidly immunogenic, with a single dose of 25 U yielding the highest (99%) 4 week seroconversion rates (by modified HAVAB) (Table I). By week 4 after one 25 U dose, the geometric mean titre ( G M T of 31-45 mlU/ml) was similar to levels of 31 to 49 m l U / m l measured the first week after a standard 0.06 ml/ kg dose of lg in adults ~3. lg kinetics have not been studied in healthy young children due to the need for numerous bleedings. However, early disappearance of detectable antibody after Ig, as in adults, has been shown 14. Elevated antibody titres were achieved one month after a 25 U booster dose at month 6 (0, 24 week regimen). The range of individual titres was 1213 441 200 mlU/ml; the overall G M T at week 28 was 10 070 m I U / ml. DISCUSSION The excellent safety and immunogenicity profile of this vaccine in these studies indicates that it would be appropriate to expand the experience with this vaccine. Older children at high risk of clinically significant disease, especially those in institutions or in communities with recurrent outbreaks, and children in affected areas or those travelling to endemic areas with their parents would be appropriate high priority target groups for vaccination. Universal paediatric use of this vaccine could be considered after accrual of evidence confirming long-lasting protection after seroconversion. Antibody titres are being monitored after 1 or 2 primary doses and after booster doses. Persistence studies are in progress to evaluate seropositivity for up to 5 years after the first injection. The strategy for vaccine control must take several
Inactivated hepatitis A vaccine in childhood." D. Nalin et al.
epidemiological facts into account. In underdeveloped nations where asymptomatic infection in infancy is almost universal and provides life-long immunity, there is no role for this vaccine except for use in non-immune travellers to such areas. In nations in transition, nonimmune population sectors less likely to acquire infection in infancy should receive the vaccine, preferably after age 2 or 3 years. Children younger than 2 or 3 years in such areas are best permitted the risk of acquiring the asymptomatic or mild infections of young infancy. In the developed countries, where disease outbreaks in children occur more frequently in recognized risk groups such as children in day-care, the institutionalized, campers, swimmers and children in areas affected by outbreaks, vaccination early in life (from 2 months to 2 years) is likely to be most beneficial, assuming life-long protection is afforded or is maintainable by a few booster doses, and that immune memory remains intact. Early immunity will help reduce risk of disease in day-care centres and other high risk foci. Equally important, this strategy will reduce spread from mild or asymptomatic paediatric cases to non-immune older siblings, playmates, parents, guardians and casual contacts who often develop significant clinical illness. A previous study noted that seronegative adult case contacts in an endemic area, whose antibody titres after exposure to wild virus had apparently fallen to undetectable levels, responded with an anamnestic IgG antibody rise (with no IgM) and were protected from clinical hepatitis A ~5. This suggests that should vaccinees" titres after seroconversion wane to undetectability, they will probably continue to be protected from clinical hepatitis A disease as long as their immune memory is intact. In such cases, the 3~4 week incubation period following exposure to an infective dose of virus is probably sufficient to permit a protective anamnestic antibody response. In any case, the sharp rise in antibody levels achieved after the booster dose at 6 months suggests that immune memory has been stimulated and that long-lasting persistence of detectable antibody or of potential anamnestic responses should occur. Universal use of this vaccine will be facilitated by the development of multivalent vaccine formulations of several combined paediatric vaccines already recommended for universal use, such as recombinant hepatitis B vaccine, conjugated Haemophilus influenzae vaccines and diphtheria-pertussis-tetanus. Long-lasting immunity, affordability and a favourable cost/benefit ratio will be essential for the development of universal paediatric use. Combination vaccines, by reducing the required
number of clinic visits, will help to make universal immunization against hepatitis A feasible. REFERENCES 1 Hadler, S.C. Global impact of hepatitis A virus infection: changing patterns. In: Viral Hepatitis and Liver Disease. (Eds F.B. Hollinger, S.M. Lemon and H. Margolis) Williams & Wilkins, Baltimore, 1991, pp. 14-20 2 Hu, M., Kang, L. and Yao, G. An outbreak of viral hepatitis A in Shanghai. In: (Eds L. Bianchi, W. Gerok, K.-P. Maier and F. Deinhardt) Infectious Diseases of the Liver. Falk Symposium No. 54, Kluwer Academic Publishers, Dordrecht, Boston, London, 1990, pp. 361~372 3 Hadler, S.C. and McFarland, L. Hepatitis in day-care centers: epidemiology and prevention. Rev. Infect. Dis. 1986, 8, 548-557 4 Kark, J. Pre-exposure prophylaxis with immune serum globulin for prevention of viral hepatitis in army recruits. J. EpidemioL Commun. Health 1982, 36, 176-182 5 Conrad, M.E. and Lemon, S.M. Prevention of endemic ictedc viral hepatitis by administration of immune serum gamma globulin. J. Infect. Dis. 1987, 156, 56-63 6 Lever, A.M., Webster, A.D.B., Brown, D. and Thomas, H.C. Non-A non-B hepatitis occurring in agammaglobulinemic patients after intravenous immunoglobulin. Lancet 1984, ii, 1062-1064 7 Albersheim, S.G., Smyth, J.A., Solimano, A. and Cook, D. Passively acquired human immunodeficiency virus seropositivity in a neonate after hepatitis B immunoglobulin. J. Pediat. 1988, 112, 915-916. 8 Burks, A.W., Sampson, H.A. and Bukley, R.H. Anaphylactic reactions after gamma globulin administration in patients with hypogamma globulinemia: detection of IgE antibodies to IgA. N. Engt. J. Med. 1986, 314, 560-564 9 Werzberger, A., Mensch, B., Kuter, B., Brown, L., Lewis, J., Sitrin, R., Miller, W., Shouval, D., Wiens, B., Calandra, G., Ryan, J., Provost, P. and Nalin, D. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N. EngL J. Med. 1992, 327, 453-457 10 Lewis, J.A., Armstrong, M.E., Larson, V.M., Emini, E.A., Mithun, K., Ellerbeck, E., Nalin, D., Provost, P. and Calandra, G. Use of a live, attenuated hepatitis A vaccine to prepare a highly purified, formalininactivated hepatitis A vaccine. In: Viral Hepatitis and Liver Disease. (Eds F. B. Hollinger, S. M. Lemon and H. Margolis), Williams & Wilkins, Baltimore, 1991, pp. 94-97 11 Provost, P.J., Bishop, R.P., Gerety, R.J., Hilleman, M.R., McAleer, W.J., Scolnick, E.M and Stevens, C.E. New findings in live attenuated hepatitis A vaccine development. J. Med. ViroL 1986, 20, 165-175 12 Gerety, R.J., Smallwood, L.A., Finlayson, J.S. and Tabor, E. Standardization of the antibody to hepatitis A virus (anti-HAV) content of immunoglobulin. Dev. BioL Stand. 1983, 54, 411-416 13 Shouval, D., Ashur, Y., Adler, R., Nalin, D., Calandra, G., Lewis, J., Miller, W. and Ryan, J. Comparison of immune serum globulin (ISG) with a formalin inactivated, alum adjuvanted hepatitis A. Presented at the 5th European Congress of Clinical Microbiology and Infectious Diseases, Oslo, Norway, Sept. 9-11, 1991, Program Abstract No. 2. 14 Gustafson, T.L., Sehulster, L.M. Immune globulin and serology tests for hepatitis A. J. Infect. Dis, 1983, 148, 360-361 15 Villarejos, V.M., Serra, C.J., Anderson-Visona, K. and Mosley, J.W. Hepatitis A virus infection in households. Am. J. Epidemiol. 1982, 115, 577-586
Vaccine, Vol. 11, Suppl. 1, 1993
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INTRODUCTION Hepatitis A is caused by a picornavirus which spreads by the faecal/oral route, chiefly after contamination of food or water by faecally excreted virus from infected individuals. Hepatitis A virus (HAV) causes significant morbidity mainly in developed countries, where food and water quality, sanitation and hygiene prevent transmission to most young children, resulting in many older individuals susceptible to disease. Non-immune older populations, infected by ingestion of raw or undercooked contaminated foods or beverages, by contact with virus from inapparent cases, or via sex practices, develop clinical disease causing significant loss of school or work time. The annual cost of hepatitis A in the USA has been estimated to be US $200 million I. In underdeveloped nations the virus spreads easily due to widespread environmental faecal contamination. Asymptomatic early childhood infection usually provides long-lasting immunity. Developing countries in transition, with rapid improvements in water and food hygiene in some population sectors, have experienced massive outbreaks. Coexistence of subpopulations of high and low endemicity permits viral cross-contamination from the endemic to the non-immune sectors via food or water and has created explosive outbreaks in ~Merck Research Laboratories, West Point, PA, USA. *Kiryas Joel Institute of Medicine, Monroe, NY, USA. "lJohns Hopkins University, Baltimore, MD, USA. ~Physicians to Children and Adolescents, P.S.C., Bardstown, KY, USA. °Pittsburgh Pediatric Research, Inc., Pittsburgh, PA, USA. §Children's Hospital of Philadelphia, Philadelphia, PA, USA. +University of Texas Medical School, Houston, TX, USA. *To whom correspondence should be addressed 0264-410X/93/110S 15-03 1993 Butterworth-Heinemann Ltd
Chile, Korea and China. In the 1988 Shanghai outbreak, sewage contaminating raw clams led to > 350 000 clinical c a s e s 2.
The relatively mild or subclinical infections of children which do occur in the developed world are epidemiologically significant as a source of infection for older nonimmune siblings, parents, caretakers or other contacts. The growth of the day-care centre industry has facilitated viral spread from subclinically infected children to older non-immune contacts who, in contrast to infants and toddlers, typically develop significant clinical illness 3. Native American children and children in boarding or day schools, orphanages, summer camps, and homes for the disabled, or those who are mentally deficient or chronically ill, are similarly at high risk. The high proportion ( > 40%) of adult cases with no identified source of infection is perhaps attributable to infected young asymptomatic children who spread disease unnoticed. Improved control in developed countries must utilize methods of interrupting transmission, especially in children, either by passive prophylaxis or by active immunization. Immune globulin (Ig) can confer passive protection for up to 6 months 4.5, but requires repeated administration. The associated health-care costs, discomfort and nuisance render Ig non-feasible for costeffective hepatitis A control. Ig administration is also associated with several real or perceived risks 6-s, and in postexposure situations must be given within the first 2 weeks after exposure, necessitating costly and impracticable disease surveillance for early case detection. Ig is rarely used effectively in this manner, and is used chiefly among older European and US travellers and the military. It is unacceptable to most communities to give Ig to
Vaccine, Vol. 11, Suppl. 1, 1993
$15
Inactivated hepatitis A vaccine in childhood." D. Nalin et al. Table 1
Immunogenicity data from different studies 4 weeks
Protocol
Dose (U)
Regimen (weeks)
Seroconversion rate, % (n)
Dose range (2-12 years)
6 13 25 13 25 25 25
0, 0, 0, 0, 0, 0, 0,
92 81 94 85 97 99 99
Safety-tolerability (4-12 years) Efficacy (2-16 years)
8, 24 8, 24 8, 24 24 24 24 24
(73/79) (56/69) (32/34) (68/66) (35/36) (97/98) (304/305)
28 weeks GMT 30 24 35 31 31 45 42
Seroconversion rate % (n) 100 (68/68) 100 (41/41) 100 (26/26) 100 (44/44) 100 (30/30) 100 (95/95) 100 (41/41) b
GMT 10 742 a 17 498 12 253 . 8 857 a 8 798 a 16 500" 7 579
GMT, geometric mean titre of responders only. Seroconversion rate measured by modified HAVAB assay. The 6 U dose was not tested on the 0, 24 week regimen a Five samples omitted per group because end-points were not available 41 completed to date
children every 6 months. Thus a protective paediatric vaccine with a favourable safety tolerability profile is needed to improve hepatitis A control. In recent studies of children 2- 16 years old ~, a formalin-inactivated, alumadjuvanted vaccine developed by Merck Research Laboratories from the CR326F strain, F' passage of HAV was well tolerated, highly immunogenic and 100% protective after a single dose containing 25 units (U) of viral antigen. This preliminary report reviews the paediatric experience with this vaccine. METHODS After safety had been demonstrated in 200 adults given one or more doses of the vaccine [(~25 U (1 U ~ 1 ng) of viral antigen per dose as measured by a hepatitis A virus antigen radioimmunoassay], paediatric studies were initiated. The preparation of the vaccine used in these studies has been previously reported m, and small lot to lot variations in production details have not altered safety or immunogenicity significantly. Healthy children and young adolescents 2 16 years old ( ~ 5 6 % male, 44% female) whose parents gave informed consent were entered if they had no history of immune deficiency or liver disease, no sensitivity to any vaccine component such as alum or thimerosal, no receipt of lg within 6 months before the study, and no other vaccination a month before (or a month after) administration of each hepatitis A vaccine dose. All were prescreened to confirm serostatus before vaccination. The volume of each injection was 0.5 or 0.6 ml depending on vaccine antigen concentration, given intramuscularly. Each dose contained 250 gg of AI(OH)3. Venous blood for serological tests was obtained before and during the study course at varying intervals (see Results). Serology was determined by a modified radioimmunoassay (HAVAB, Abbott) by comparison with the W H O standard antiserum ~,12. Titres of 10 m l U / m l and above are considered positive in this assay. Subsequently a randomized, double-blind, placebo-controlled protective efficacy triaP was carried out, involving 1037 children and using an intramuscular dose of 25 U of viral antigen or of matching placebo. Results are included in the response at week 4 of 305 of these children, and the levels at week 28 of 41 of them. A total of 1514 children (2-16 years old) have been vaccinated with one or more doses of 6 to 25 U viral antigen and were included in surveillance for serious adverse experiences; 504 received two doses 6 months
S16
V a c c i n e , Vol. 11, S u p p l . 1, 1993
apart and 182 received three doses (0, 2 months, 6 months), including 16 (all but one from one study) who were seropositive prior to vaccination. RESULTS
Safety and tolerability profile in children No serious adverse clinical or laboratory reaction has been reported in any vaccinee. Mild local transient discomfort at the site of injection was the major injectionrelated adverse experience, and was equally frequent in placebo or vaccine recipients.
lmmunogenieity The vaccine has proven rapidly immunogenic, with a single dose of 25 U yielding the highest (99%) 4 week seroconversion rates (by modified HAVAB) (Table I). By week 4 after one 25 U dose, the geometric mean titre ( G M T of 31-45 mlU/ml) was similar to levels of 31 to 49 m l U / m l measured the first week after a standard 0.06 ml/ kg dose of lg in adults ~3. lg kinetics have not been studied in healthy young children due to the need for numerous bleedings. However, early disappearance of detectable antibody after Ig, as in adults, has been shown 14. Elevated antibody titres were achieved one month after a 25 U booster dose at month 6 (0, 24 week regimen). The range of individual titres was 1213 441 200 mlU/ml; the overall G M T at week 28 was 10 070 m I U / ml. DISCUSSION The excellent safety and immunogenicity profile of this vaccine in these studies indicates that it would be appropriate to expand the experience with this vaccine. Older children at high risk of clinically significant disease, especially those in institutions or in communities with recurrent outbreaks, and children in affected areas or those travelling to endemic areas with their parents would be appropriate high priority target groups for vaccination. Universal paediatric use of this vaccine could be considered after accrual of evidence confirming long-lasting protection after seroconversion. Antibody titres are being monitored after 1 or 2 primary doses and after booster doses. Persistence studies are in progress to evaluate seropositivity for up to 5 years after the first injection. The strategy for vaccine control must take several
Inactivated hepatitis A vaccine in childhood." D. Nalin et al.
epidemiological facts into account. In underdeveloped nations where asymptomatic infection in infancy is almost universal and provides life-long immunity, there is no role for this vaccine except for use in non-immune travellers to such areas. In nations in transition, nonimmune population sectors less likely to acquire infection in infancy should receive the vaccine, preferably after age 2 or 3 years. Children younger than 2 or 3 years in such areas are best permitted the risk of acquiring the asymptomatic or mild infections of young infancy. In the developed countries, where disease outbreaks in children occur more frequently in recognized risk groups such as children in day-care, the institutionalized, campers, swimmers and children in areas affected by outbreaks, vaccination early in life (from 2 months to 2 years) is likely to be most beneficial, assuming life-long protection is afforded or is maintainable by a few booster doses, and that immune memory remains intact. Early immunity will help reduce risk of disease in day-care centres and other high risk foci. Equally important, this strategy will reduce spread from mild or asymptomatic paediatric cases to non-immune older siblings, playmates, parents, guardians and casual contacts who often develop significant clinical illness. A previous study noted that seronegative adult case contacts in an endemic area, whose antibody titres after exposure to wild virus had apparently fallen to undetectable levels, responded with an anamnestic IgG antibody rise (with no IgM) and were protected from clinical hepatitis A ~5. This suggests that should vaccinees" titres after seroconversion wane to undetectability, they will probably continue to be protected from clinical hepatitis A disease as long as their immune memory is intact. In such cases, the 3~4 week incubation period following exposure to an infective dose of virus is probably sufficient to permit a protective anamnestic antibody response. In any case, the sharp rise in antibody levels achieved after the booster dose at 6 months suggests that immune memory has been stimulated and that long-lasting persistence of detectable antibody or of potential anamnestic responses should occur. Universal use of this vaccine will be facilitated by the development of multivalent vaccine formulations of several combined paediatric vaccines already recommended for universal use, such as recombinant hepatitis B vaccine, conjugated Haemophilus influenzae vaccines and diphtheria-pertussis-tetanus. Long-lasting immunity, affordability and a favourable cost/benefit ratio will be essential for the development of universal paediatric use. Combination vaccines, by reducing the required
number of clinic visits, will help to make universal immunization against hepatitis A feasible. REFERENCES 1 Hadler, S.C. Global impact of hepatitis A virus infection: changing patterns. In: Viral Hepatitis and Liver Disease. (Eds F.B. Hollinger, S.M. Lemon and H. Margolis) Williams & Wilkins, Baltimore, 1991, pp. 14-20 2 Hu, M., Kang, L. and Yao, G. An outbreak of viral hepatitis A in Shanghai. In: (Eds L. Bianchi, W. Gerok, K.-P. Maier and F. Deinhardt) Infectious Diseases of the Liver. Falk Symposium No. 54, Kluwer Academic Publishers, Dordrecht, Boston, London, 1990, pp. 361~372 3 Hadler, S.C. and McFarland, L. Hepatitis in day-care centers: epidemiology and prevention. Rev. Infect. Dis. 1986, 8, 548-557 4 Kark, J. Pre-exposure prophylaxis with immune serum globulin for prevention of viral hepatitis in army recruits. J. EpidemioL Commun. Health 1982, 36, 176-182 5 Conrad, M.E. and Lemon, S.M. Prevention of endemic ictedc viral hepatitis by administration of immune serum gamma globulin. J. Infect. Dis. 1987, 156, 56-63 6 Lever, A.M., Webster, A.D.B., Brown, D. and Thomas, H.C. Non-A non-B hepatitis occurring in agammaglobulinemic patients after intravenous immunoglobulin. Lancet 1984, ii, 1062-1064 7 Albersheim, S.G., Smyth, J.A., Solimano, A. and Cook, D. Passively acquired human immunodeficiency virus seropositivity in a neonate after hepatitis B immunoglobulin. J. Pediat. 1988, 112, 915-916. 8 Burks, A.W., Sampson, H.A. and Bukley, R.H. Anaphylactic reactions after gamma globulin administration in patients with hypogamma globulinemia: detection of IgE antibodies to IgA. N. Engt. J. Med. 1986, 314, 560-564 9 Werzberger, A., Mensch, B., Kuter, B., Brown, L., Lewis, J., Sitrin, R., Miller, W., Shouval, D., Wiens, B., Calandra, G., Ryan, J., Provost, P. and Nalin, D. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N. EngL J. Med. 1992, 327, 453-457 10 Lewis, J.A., Armstrong, M.E., Larson, V.M., Emini, E.A., Mithun, K., Ellerbeck, E., Nalin, D., Provost, P. and Calandra, G. Use of a live, attenuated hepatitis A vaccine to prepare a highly purified, formalininactivated hepatitis A vaccine. In: Viral Hepatitis and Liver Disease. (Eds F. B. Hollinger, S. M. Lemon and H. Margolis), Williams & Wilkins, Baltimore, 1991, pp. 94-97 11 Provost, P.J., Bishop, R.P., Gerety, R.J., Hilleman, M.R., McAleer, W.J., Scolnick, E.M and Stevens, C.E. New findings in live attenuated hepatitis A vaccine development. J. Med. ViroL 1986, 20, 165-175 12 Gerety, R.J., Smallwood, L.A., Finlayson, J.S. and Tabor, E. Standardization of the antibody to hepatitis A virus (anti-HAV) content of immunoglobulin. Dev. BioL Stand. 1983, 54, 411-416 13 Shouval, D., Ashur, Y., Adler, R., Nalin, D., Calandra, G., Lewis, J., Miller, W. and Ryan, J. Comparison of immune serum globulin (ISG) with a formalin inactivated, alum adjuvanted hepatitis A. Presented at the 5th European Congress of Clinical Microbiology and Infectious Diseases, Oslo, Norway, Sept. 9-11, 1991, Program Abstract No. 2. 14 Gustafson, T.L., Sehulster, L.M. Immune globulin and serology tests for hepatitis A. J. Infect. Dis, 1983, 148, 360-361 15 Villarejos, V.M., Serra, C.J., Anderson-Visona, K. and Mosley, J.W. Hepatitis A virus infection in households. Am. J. Epidemiol. 1982, 115, 577-586
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