Haemophilus Influenzae Type b Disease
Prior to the introduction of Haemophilus b conjugate
vaccines, Haemophilus influenzae type b (Hib) was the most frequent
cause of bacterial meningitis and a leading cause of serious, systemic
bacterial disease in young children worldwide.1-4
Hib disease occurred primarily in children under 5 years
of age, and in the United States prior to the initiation of a vaccine program
was estimated to account for nearly 20,000 cases of invasive infections
annually, approximately 12,000 of which were meningitis. The mortality rate
from Hib meningitis is about 5%. In addition, up to 35% of survivors develop
neurologic sequelae including seizures, deafness, and mental retardation.5,6
Other invasive diseases caused by this bacterium include cellulitis, epiglottitis,
sepsis, pneumonia, septic arthritis, osteomyelitis, and pericarditis.
Prior to the introduction of the vaccine, it was
estimated that 17% of all cases of Hib disease occurred in infants less than 6
months of age. The peak incidence of Hib meningitis occurred between 6 to 11
months of age. Forty-seven percent of all cases occurred by one year of age
with the remaining 53% of cases occurring over the next four years.2,20
Among children under 5 years of age, the risk of invasive
Hib disease is increased in certain populations including the following:
- Daycare attendees7,8,9
- Lower socio-economic groups10
- Blacks11 (especially those who lack the Km(1)
- Caucasians who lack the G2m(23) immunoglobulin allotype13
- Native Americans14-16
- Household contacts of cases17
- Individuals with asplenia, sickle cell disease, or
antibody deficiency syndromes.18,19
Prevention of H1b Disease with Vaccine
An important virulence factor of the Hib bacterium is its
polysaccharide capsule (PRP). Antibody to PRP (anti-PRP) has been shown to
correlate with protection against Hib disease.3,21 While the
anti-PRP level associated with protection using conjugated vaccines has not yet
been determined, the level of anti-PRP associated with protection in studies
using bacterial polysaccharide immune globulin or nonconjugated PRP vaccines
ranged from ≥ 0.15 to ≥ 1.0 mcg/mL.22-28
Nonconjugated PRP vaccines are capable of stimulating
B-lymphocytes to produce antibody without the help of T-lymphocytes
(T-independent). The responses to many other antigens are augmented by helper
T-lymphocytes (T-dependent). PedvaxHIB is a PRP-conjugate vaccine in which the
PRP is covalently bound to the OMPC carrier29 producing an antigen
which is postulated to convert the T-independent antigen (PRP alone) into a
T-dependent antigen resulting in both an enhanced antibody response and
Clinical Trials with PedvaxHIB
The protective efficacy of the PRP-OMPC component of
COMVAX was demonstrated in a randomized, double-blind, placebo-controlled study
involving 3486 Native American (Navajo) infants (The Protective Efficacy Study)
who completed the primary two-dose regimen for lyophilized PedvaxHIB. This
population has a much higher incidence of Hib disease than the United States
population as a whole and also has a lower antibody response to Haemophilus b
conjugate vaccines, including PedvaxHIB.14-16,30,31
Each infant in this study received two doses of either
placebo or lyophilized PedvaxHIB (15 mcg Haemophilus b PRP) with the first dose
administered at a mean of 8 weeks of age and the second administered
approximately two months later; DTP (Diphtheria and Tetanus Toxoids and whole
cell Pertussis Vaccine, Adsorbed) and OPV (Poliovirus Vaccine Live Oral
Trivalent) were administered concomitantly. In a subset of 416 subjects,
lyophilized PedvaxHIB (15 mcg Haemophilus b PRP) induced anti-PRP levels
> 0.15 mcg/mL in 88% and > 1.0 mcg/mL in 52% with a geometric mean titer
(GMT) of 0.95 mcg/mL one to three months after the first dose; the
corresponding anti-PRP levels one to three months following the second dose
were 91% and 60%, respectively, with a GMT of 1.43 mcg/mL. These antibody
responses were associated with a high level of protection.
Most subjects were initially followed until 15 to 18
months of age. During this time, 22 cases of invasive Hib disease occurred in
the placebo group (8 cases after the first dose and 14 cases after the second
dose) and only 1 case in the vaccine group (none after the first dose and 1
after the second dose). Following the primary two-dose regimen, the protective
efficacy of lyophilized PedvaxHIB was calculated to be 93% with a 95%
confidence interval (C.I.) of 57-98%. In the two months between the first and
second doses, the difference in number of cases of disease between placebo and
vaccine recipients (8 vs 0 cases, respectively) was statistically significant
(p=0.008). At termination of the study, placebo recipients were offered
vaccine. All original participants were then followed two years and nine months
from termination of the study. During this extended follow-up, invasive Hib
disease occurred in an additional 7 of the original placebo recipients prior to
receiving vaccine and in 1 of the original vaccine recipients (who had received
only 1 dose of vaccine). No cases of invasive Hib disease were observed in
placebo recipients after they received at least one dose of vaccine. Efficacy
for this follow-up period, estimated from person-days at risk, was 96.6% (95
C.I., 72.2-99.9%) in children under 18 months of age and 100% (95 C.I.,
23.5-100%) in children over 18 months of age.31 Thus, in this study,
a protective efficacy of 93% was achieved with an anti-PRP level of > 1.0
mcg/mL in 60% of vaccinees and a GMT of 1.43 mcg/mL one to three months after
the second dose.
Hepatitis B Disease
Hepatitis B virus is an important cause of viral
hepatitis. According to the Centers for Disease Control (CDC), there are an
estimated 200,000-300,000 new cases of Hepatitis B infection annually in the
United States.32 There is no specific treatment for this disease.
The incubation period for hepatitis B is relatively long; six weeks to six
months may elapse between exposure and the onset of clinical symptoms. The
prognosis following infection with hepatitis B virus is variable and dependent
on at least three factors: (1) Age — infants and younger children usually
experience milder initial disease than older persons but are much more likely
to remain persistently infected and become at risk of developing serious
chronic liver disease; (2) Dose of virus — the higher the dose, the more likely
acute icteric hepatitis B will result; and, (3) Severity of associated
underlying disease — underlying malignancy or pre-existing hepatic disease
predisposes to increased mortality and morbidity.34
Hepatitis B infection fails to resolve and progresses to
a chronic carrier state in 5 to 10% of older children and adults and in up to
90% of infants; chronic infection also occurs more frequently after initial
anicteric hepatitis B than after initial icteric disease.34
Consequently, carriers of HBsAg frequently give no history of having had
recognized acute hepatitis. It has been estimated that more than 285 million
people in the world today are persistently infected with hepatitis B virus.35
The CDC estimates that there are approximately 1 million-1.25 million chronic
carriers of hepatitis B virus in the USA.32 Chronic carriers
represent the largest human reservoir of hepatitis B virus.
A serious complication of acute hepatitis B virus
infection is massive hepatic necrosis while sequelae of chronic hepatitis B
include cirrhosis of the liver, chronic active hepatitis, and hepatocellular
carcinoma. Chronic carriers of HBsAg appear to be at increased risk of
developing hepatocellular carcinoma. Although a number of etiologic factors are
associated with development of hepatocellular carcinoma, the single most
important etiologic factor appears to be chronic infection with hepatitis B
virus.36 According to the CDC, hepatitis B vaccine is recognized as
the first anti-cancer vaccine because it can prevent primary liver cancer.67
The vehicles for transmission of the virus are most often
blood and blood products but the viral antigen has also been found in tears,
saliva, breast milk, urine, semen, and vaginal secretions. Hepatitis B virus is
capable of surviving for days on environmental surfaces exposed to body fluids
containing hepatitis B virus. Infection may occur when hepatitis B virus,
transmitted by infected body fluids, is implanted via mucous surfaces or
percutaneously introduced through accidental or deliberate breaks in the skin.
Transmission of hepatitis B virus infection is often associated with close
interpersonal contact with an infected individual and with crowded living
Prevention of Hepatitis B Disease with Vaccine
Hepatitis B infection and disease can be prevented
through immunization with vaccines that contain viral surface antigen (HBsAg)
and induce formation of protective antibody (anti-HBs).38-39
Multiple clinical studies have defined a protective level
of anti-HBs as 1) 10 or more sample ratio units (SRU or S/N) as determined by
radioimmunoassay or 2) a positive result as determined by enzyme immunoassay.40-46
Note: 10 SRU is comparable to 10 mIU/mL of antibody.36 The ACIP and
an international group of hepatitis B experts consider an anti-HBs titer ≥ 10
mIU/mL an adequate response to a complete course of hepatitis B vaccine and
protective against clinically significant infection (antigenemia with or
without clinical disease).36,46
Clinical Trials with RECOMBIVAX HB
In clinical studies, 100% of 92 infants under 1 year of age
born of non-carrier mothers developed a protective level of antibody (anti-HBs ≥ 10
mIU/mL) after receiving three 5-mcg doses of RECOMBIVAX HB at intervals of 0,
1, and 6 months.31
In one clinical study of RECOMBIVAX HB (2.5 mcg), which examined a different regimen of RECOMBIVAX
HB, protective levels of antibody were achieved in 98% of 52 healthy infants
vaccinated at 2, 4, and 12 months of age. Protective anti-HBs levels were
achieved in 100% of 50 infants vaccinated at 2, 4, and 15 months of age.47
The protective efficacy of three 5-mcg doses of
RECOMBIVAX HB, given at birth (with Hepatitis B Immune Globulin), 1, and 6
months of age, has been demonstrated in neonates born of mothers positive for
both HBsAg and HBeAg (a core-associated antigenic complex which correlates with
high infectivity). In this trial, after nine months of follow-up, chronic
infection had not occurred in 96% of 130 infants.48 The estimated
efficacy in prevention of chronic hepatitis B infection was 95% as compared to
the infection rate in untreated historical controls.49
Immunogenicity of COMVAX
The immunogenicity of COMVAX (7.5 mcg Haemophilus b PRP,
5 mcg HBsAg) was assessed in 1602 infants and children 6 weeks to 15 months of
age in 5 clinical studies. In 2 controlled clinical trials (n=684), the immune
response of COMVAX was compared with that obtained using the monovalent
vaccines, PedvaxHIB (7.5 mcg Haemophilus b PRP) and RECOMBIVAX HB (5 mcg HBsAg)
given at separate sites, either concurrently or one month apart. The
immunogenicity of COMVAX was further assessed in 2 uncontrolled studies
(n=852). In the first, a complete three-dose series of COMVAX was administered
concurrently with other routine pediatric vaccines. In the second, COMVAX was
administered as the third dose of Haemophilus b PRP and HBsAg concurrently with
routine pediatric vaccines. COMVAX was also administered as the control arm in
the evaluation of an investigational vaccine (n=66).
These studies demonstrate COMVAX to be highly
immunogenic. The antibody responses are summarized below.
Antibody Responses to COMVAX in Infants Not Previously
Vaccinated with Hib or Hepatitis B Vaccine
In the pivotal, controlled, multicenter, randomized,
open-label study, 882 infants approximately 2 months of age, who had not
previously received any Hib or hepatitis B vaccine, were assigned to receive a
three-dose regimen of either COMVAX or PedvaxHIB plus RECOMBIVAX HB at
approximately 2, 4, and 12-15 months of age. The proportions of evaluable
vaccinees developing clinically important levels of anti-PRP (percent with
> 1.0 mcg/mL after the second dose, n=762) and anti-HBs (percent with ≥ 10
mIU/mL after the third dose, n=750) were similar in children given COMVAX or
concurrent PedvaxHIB and RECOMBIVAX HB (Table 1).
The anti-PRP response after the second dose among infants
given COMVAX in this study was 72.4% (C.I. 68.7, 76.0) > 1.0 mcg/mL with a
GMT=2.5 mcg/mL (C.I. 2.2, 2.8) and was comparable to that of infants given the
PedvaxHIB and RECOMBIVAX HB controls which was 76.3% (C.I. 70.2, 82.5) with a
GMT=2.8 mcg/mL (C.I. 2.2, 3.5). These responses exceed the response of Native
American (Navajo) infants in a previous study of lyophilized PedvaxHIB (60%
> 1.0 mcg/mL; GMT=1.43 mcg/mL) that was associated with a 93% reduction in
the incidence of invasive Hib disease. The efficacy of COMVAX in the prevention
of invasive Hib disease is expected to be similar to that obtained with
monovalent lyophilized PedvaxHIB in the Protective Efficacy Trial (see CLINICAL
PHARMACOLOGY, Clinical Trials with PedvaxHIB).
The anti-HBs response after the third dose among infants
given COMVAX in this study was 98.4% ≥ 10 mIU/mL (C.I. 97.0, 99.3) with a
GMT of 4467.5 (C.I. 3786.3, 5271.3) compared to 100.0% (C.I. 97.9, 100.0) with
a GMT of 6943.9 (C.I. 5555.9, 8678.7) among infants given COMVAX or concurrent
PedvaxHIB and RECOMBIVAX HB.
Although the difference in anti-HBs GMT is statistically
significant (p=0.011), both values are much greater than the level of 10 mIU/mL
previously established as marking a protective response to hepatitis B.42,44-46,51,52
These GMTs are higher than those observed in young infants who received the
currently licensed regimen of RECOMBIVAX HB consisting of 5-mcg doses
administered on the standard 0, 1, and 6-month schedule (GMT ~ 1359.9 mIU/mL).53-55
In addition, two studies have shown that infants given 2.5-mcg doses of
RECOMBIVAX HB according to the schedule used for COMVAX (2, 4, and 12-15 months
of age) developed GMTs of 1245-3424 mIU/mL.47,64 While a difference
in GMT may result in differential retention of ≥ 10 mIU/mL of anti-HBs
after a number of years, this is of no apparent clinical significance because
of immunologic memory.56,57
Because the HBsAg component of COMVAX induces a
comparable anti-HBs response to that obtained with RECOMBIVAX HB, the efficacy
of COMVAX is expected to be similar (Table 1).
Table 1: Antibody Responses to COMVAX, PedvaxHIB, and
RECOMBIVAX HB in Infants Not Previously Vaccinated with Hib or Hepatitis B
||Anti-PRP % Subjects with > 0.15 mcg/mL > 1.0 mcg/mL
|Anti-PRP GMT (mcg/mL)
||Anti-HBs % Subjects ≥ 10 mIU/mL
||Anti-HBs GMT (mIU/mL)
|(7.5 mcg PRP,
|5 mcg HBsAg)
|(7.5 mcg PRP)
|*Postvaccination responses were determined approximately
two months after doses 1 and 2.
** Postvaccination responses were determined approximately one month after
administration of dose 3. More than three-quarters of the infants in the study
received DTP and OPV concomitantly with the first two doses of COMVAX or
PedvaxHIB plus RECOMBIVAX HB, and approximately one-third received M-M-R® II
(Measles, Mumps, and Rubella Virus Vaccine Live) with the third dose of these
vaccines at 12 or 15 months of age.
*** C.I.'s of comparisons: Dose 2 Anti-PRP: 95% C.I. on difference in % > 1.0
mcg/mL (-11.2, 3.1); 95% C.I. on ratio of GMT (0.69, 1.17) Dose 3 Anti-HBs: 95%
C.I. on difference in % ≥ 10 mIU/mL (-2.9, -0.6); 95% C.I. on ratio of GMT
Antibody Responses to COMVAX in Infants Previously
Vaccinated with Hepatitis B Vaccine at Birth
Two clinical studies assessed antibody responses to a
three-dose series of COMVAX in 128 evaluable infants who were previously given
a birth dose of hepatitis B vaccine. Table 2 summarizes the anti-PRP and
anti-HBs responses of these infants. The antibody responses were clinically
comparable to those observed in the pivotal trial of COMVAX (Table 1).
Table 2: Antibody Responses to COMVAX in Infants
Previously Vaccinated with Hepatitis B Vaccine at Birth
||Age (months) at Vaccination
||Anti-PRP % Subjects with > 0.15 mcg/mL > 1.0 mcg/mL
||Anti-PRP GMT (mcg/mL)
||Anti-HBs % Subjects > 10 mIU/mL
||Anti-HBs GMT (mIU/mL)
|Study 1 [N=126]
|Study 2 [N=19]
|Postvaccination responses were determined approximately 2
months after dose 2 and 1 month after dose 3.
** Postvaccination responses were determined approximately 2 months after doses
1, 2, and 3. Infants in these studies received DTP and OPV or eIPV (enhanced
inactivated poliovirus vaccine) concomitantly with the first two doses of
COMVAX, while the third dose of COMVAX was given concomitantly with DTaP
(diphtheria and tetanus and acellular pertussis), OPV, and M-M-R® II at 14-15
months of age (Study 1) or with just M-M-R® II at 15 months of age (Study 2).
Interchangeability of COMVAX and Licensed Haemophilus b
Conjugate Vaccines or Recombinant Hepatitis B Vaccines
Among 58 children previously given a primary course of
PedvaxHIB, 90% (95% C.I. 78.8%, 96.1%) developed an anti-PRP response > 1
mcg/mL with a GMT of 9.6 mcg/mL (95% C.I. 6.6, 14.1) in response to a dose of
COMVAX at 12-15 months of age. Among 683 children previously given a primary
course of another HIB or HIB-containing vaccine, 99% (95% C.I. 97.9%, 99.6%)
developed an anti-PRP response > 1 mcg/mL with a GMT of 14.9 mcg/mL (95% C.I.
13.7, 16.3) in response to a dose of COMVAX at 12-15 months of age.
In another study, COMVAX was administered either
concomitantly or six weeks after vaccination with M-M-R® II and VARIVAX®
(Varicella Virus Vaccine Live, Oka/Merck). Among 149 children who previously
received 2 doses of monovalent Hepatitis B vaccine, 100% (95% C.I. 97.6%,
100.0%) developed an anti-HBs response ≥ 10 mIU/mL with a GMT of 2194.6
mIU/mL (95% C.I. 1667.8, 2887.8) in response to a dose of COMVAX at 12-15
months of age.
Antibody Responses to COMVAX and Concurrently
Immunogenicity results from open-labeled studies indicate
that COMVAX can be administered concomitantly with DTP, DTaP, OPV, IPV
(inactivated poliomyelitis vaccine), M-M-R II, and VARIVAX using separate sites
and syringes for injectable vaccines.
DTP and DTaP
After a primary series of DTP (2, 4, 6 months of age)
given concomitantly with COMVAX (2 and 4 months of age), 98.2% of 57 infants
developed a 4-fold rise in antibody to diphtheria, 100% of 57 infants developed
a 4-fold rise in antibody to tetanus, and 89.5% to 96.5% of 57 infants
developed a 4-fold rise in antibody to pertussis antigens, depending on the
assay used and adjusted for maternal antibody. In this trial, after 2 doses of
COMVAX, 79.0% of 62 infants developed anti-PRP > 1.0 mcg/mL and after 3 doses
(2, 4, and 15 months of age), 100% of 59 infants developed ≥ 10 mIU/mL of
After a primary series of DTaP and COMVAX given
concomitantly at 2, 4, and 6 months of age, 100% of 18 infants had ≥ 0.01
antitoxin units/mL to diphtheria and tetanus and 94.4% to 100% of 18 infants
developed a ≥ 4-fold rise in antibody to pertussis antigens, depending on
the assay used and adjusted for maternal antibody. In this trial, after 2 doses
of COMVAX, 85.7% of 63 infants developed anti-PRP > 1.0 mcg/mL and after 3
doses administered on the compressed schedule of 2, 4, and 6 months of age,
92.9% of 56 infants developed > 10 mIU/mL of anti-HBs.
OPV and IPV
After a primary series of OPV (2, 4, 6 months of age)
given concomitantly with COMVAX (2 and 4 months of age), 98.3% of 60 infants
had neutralizing antibody ≥ 1:4 to poliovirus type 1, 100% of 57 infants
had neutralizing antibody ≥ 1:4 to poliovirus type 2 and 98.1% of 53
infants had neutralizing antibody ≥ 1:4 to poliovirus type 3. In this
trial, after 2 doses of COMVAX, 79.0% of 62 infants developed anti-PRP > 1.0
mcg/mL and after 3 doses, 100% of 59 infants developed ≥ 10 mIU/mL of anti-HBs.
After a primary series of IPV and COMVAX given
concomitantly at 2, 4, and 6 months of age, 100% of 38 infants had neutralizing
antibody ≥ 1:4 to poliovirus types 1, 2, and 3. In this trial, after 2
doses of COMVAX, 85.7% of 63 infants developed anti-PRP > 1.0 mcg/mL and
after 3 doses administered on the compressed schedule of 2, 4, and 6 months of
age, 92.9% of 56 infants developed ≥ 10 mIU/mL of anti-HBs.
M-M-R II and VARIVAX
After concomitant vaccination of M-M-R II and VARIVAX
with COMVAX (12 to 15 months of age), 99.4% of 313 children developed antibody
to measles, 99.2% of 354 children developed antibody to mumps, 100% of 358
children developed antibody to rubella and 100% of 276 children developed
antibody to varicella. In this trial, infants received the primary series of
Hib vaccine and the first two doses of Hepatitis B vaccine in the first year of
life. After the dose of COMVAX, 97.8% of 368 infants developed > 1.0 mcg/mL
of anti-PRP and 99.2% developed ≥ 10 mIU/mL of anti-HBs.
1. Cochi, S.L., et al. JAMA 253: 521-529, 1985.
2. Schlech, W.F., III, et al. JAMA 253: 1749-1754, 1985.
3. Peltola, H., et al. N Engl J Med 310: 1561-1566, 1984.
4. Cardoz, M., et al. Bull WHO 59: 575-584, 1981.
5. Sell, S.H., et al. Pediatr 49: 206-217, 1972.
6. Taylor, H.G., et al. Pediatr 74: 198-205, 1984.
7. Hay, J.W., et al. Pediatr 80(3): 319-329, 1987.
8. Redmond, S.R., et al. JAMA 252: 2581-2584, 1984.
9. Istre, G.R., et al. J Pediatr 106: 190-195, 1985.
10. Fraser, D.W., et al. J Infect Dis 127: 271-277, 1973.
11. Tarr, P.I., et al. J Pediatr 92: 884-888, 1978.
12. Granoff, D.M., et al. J Clin Invest 74: 1708-1714,
13. Ambrosino, D.M., et al. J Clin Invest 75: 1935-1942,
14. Coulehan, J.L., et al. Pub Health Rep 99: 404-409,
15. Â Losonsky, G.A., et al. Pediatr Infect Dis J 3:
16. Ward, J.I., et al. Lancet 1: 1281-1285, 1981.
17. Ward, J.I., et al. N Engl J Med 301: 122-126, 1979.
18. Ward, J.I., et al. J Pediatr 88: 261-263, 1976.
19. Bartlett, A.V., et al. J Pediatr 102: 55-58, 1983.
20. Centers for Disease Control. MMWR 34(15): 201-205,
21. Santosham, M., et al. N Engl J Med 317: 923-929,
22. Siber, G.R., et al. Infect Immun 45: 248-254, 1984.
23. Smith, D.H., et al. Pediatr 52: 637-644, 1973.
24. Robbins, J.B., et al. Pediatr Res 7: 103-110, 1973.
25. Kaythy, H., et al. J Infect Dis 147: 1100, 1983.
26. Peltola, H., et al. Pediatr 60: 730-737, 1977.
27. Ward, J.I., et al. Pediatr 81: 886-893, 1988.
28. Daum, R.S., et al. Pediatr 81: 893-897, 1988.
29. Marburg, S., et al. J Am Chem Soc 108: 5282-5287,
30. Letson, G.W., et al. Pediatr Infect Dis J 7(111):
31. Data on file at Merck Research Laboratories.
32. Centers for Disease Control. MMWR 40(RR-1):1-25,
34. Robinson, W.S. “Principles and Practice of Infectious
Diseases,” G.L. Mandell; R.G. Douglas; J.E. Bennett (eds), vol. 2, New York,
John Wiley & Sons, 1985,
35. Maynard, J. E., et al. “Viral Hepatitis and Liver
Disease”, A.J. Zuckerman (ed.), Alan R. Liss, Inc., 1988, pp. 967-969.
36. Centers for Disease Control. MMWR 39(RR-2): 5-26,
37. Wands, J.R., et al. “Principles of Internal
Medicine,” G.W. Thorn, R.D. Adams, E. Braunwald, K.J. Isselbacher, R.G.
Petersdorf (eds), vol. 2, McGraw-Hill,
1977, pp. 1590-1598.
38. Sitrin, R.D., Wampler, D.E., Ellis, R.W. Survey of
licensed hepatitis B vaccines and their production processes. In: Ellis RW, ed.
Hepatitis B vaccines in clinical
practice. New York: Marcel Dekker, Inc., 1993,
39. West, D.J. Scope and design of hepatitis B vaccine
clinical trials. In Ellis RW, ed. Hepatitis B vaccines in clinical practice.
New York: Marcel Dekker, Inc.,
1993, pp. 159-177.
40. Hadler, S.C., et al. NEJM 315(4): 209-214, 1986.
41. Szmuness, W., et al. NEJM 303: 833-841, 1980.
42. Francis, D.P., et al. Ann Int Med 97: 362-366, 1982.
43. Szmuness, W., et al. NEJM 307: 1481-1486, 1982.
44. Szmuness, W., et al. Hepatology 1: 377-385, 1981.
45. Coutinho, R.A., et al. BMJ 286: 1305-1308, 1983.
46. International Group: Immunisation against hepatitis
B, Lancet 1(8590): 875-876, 1988.
47. Keyserling, H.L., et al. J Pediatr 125(1): 67-69,
48. Stevens, C.E.; Taylor, P.E.; Tong, M.J., et al.
“Viral Hepatitis and Liver Diseases.” A.J. Zuckerman (ed.), Alan R. Liss, Inc.,
1988, pp. 982-983.
49. Stevens, C.E., et al. Pediatr 90(1, Part 2): 170-173,
51. Centers for Disease Control. MMWR 34: 313-24, 329-35,
52. Centers for Disease Control. MMWR 36: 353-60, 366,
53. West, D.J., et al. Pediatr Clin North Am 37: 585-601,
54. Seto, D., et al. Pediatr Res 31(4 Pt 2): 179A, 1992.
55. Froehlich, H. Pediatr Res 31(4 Pt 2): 92A, 1992.
56. Jilg, W., et al. Infection 17: 70-6, 1989.
57. West, D.J., et al. Vaccine 14: 1019-27, 1996.
64. Reisenger, K.S., et al. Pediatr Res (4 pt. 2): 179A,
67. Centers for Disease Control. Federal Register,
64(35):9044-9045, February 23, 1999.