excellent response rate to a double dose of the combined hepatitis a and b vaccine in previous...

Excellent Response Rate to a Double Doseof the Combined Hepatitis A and B Vaccinein Previous Nonresponders to Hepatitis B Vaccine

Kristina Cardell,1 Britt Åkerlind,2 Matti Sällberg,3 and Aril Frydén1

Departments of 1Infectious Diseases and 2Clinical Microbiology, University Hospital, Linköping, and 3Division of Clinical Virology, KarolinskaInstitute at Karolinska University Hospital, Huddinge, Sweden

(See the editorial commentary by Diepolder, on pages 297– 8.)Background. Hepatitis B vaccine has been shown to be highly efficient in preventing hepatitis B. However,

5%–10% of individuals fail to develop protective levels (�10 mIU/mL) of antibodies to hepatitis B surface antigen(anti-HBs) and are considered to be nonresponders.

Methods. A total of 48 nonresponders and 20 subjects naive to the HBV vaccine received a double dose ofcombined hepatitis A and B vaccine (Twinrix) at 0, 1, and 6 months. The levels of anti-HBs and antibodies to hepatitisA virus (anti-HAV) were determined before vaccination and 1 month after each dose.

Results. Among 44 nonresponders, protective anti-HBs levels were found in 26 (59%) after the first dose and in42 (95%) after the third dose. Among the control subjects, the corresponding figures were 10% and 100%, respec-tively. All subjects seroconverted to anti-HAV. The titers of both anti-HBs and anti-HAV were lower in the previouslynonresponsive subjects (P � .01).

Conclusion. Revaccination of nonresponders to the standard hepatitis B vaccine regimen with a double dose ofthe combined hepatitis A and B vaccine was highly effective. This is most likely explained by the increased dose, apositive bystander effect conferred by the hepatitis A vaccine, or both.

Hepatitis B virus (HBV) is widely spread, and �350 mil-

lion people are estimated to be chronic carriers [1]. HBV

can cause acute hepatitis, which in some cases leads to

acute liver failure. Approximately 5% become chronic

carriers and are at risk of developing liver cirrhosis and

hepatocellular cancer. Transmission of HBV can be pre-

vented by vaccination [2]. After immunization, a serum

titer of antibodies to hepatitis B surface antigen (anti-

HBs) of �10 mIU/mL has been shown to be effective in

preventing disease and is the generally accepted level for

determining that a vaccine response has occurred [3].

Health care personnel are at risk of acquiring HBV

infection, and many authorities recommend vaccina-

tion [4]. After a standard 3-dose vaccination regime at 0,

1, and 6 months, the rate of response on the basis of an

anti-HBs titer of �10 mIU/mL is 90%–95%. Intramus-

cular and intradermal administration has been reported

to be equal in inducing seroconversion, but titers seem

to be higher with intramuscular administration [5, 6]. A

small portion of vaccinated individuals do not develop

anti-HBs titers of �10 mIU/mL after 3 or more doses

and are considered to be nonresponders. Risk factors for

nonresponse have been identified, including immuno-

suppressive disease, smoking, increasing age, male sex,

and high body mass index (BMI) [6, 7]. Genetic factors

also seem to play a role in the response [8 –11]. Several

methods to improve the response in nonresponders

have been suggested, such as giving the vaccine intra-

muscularly to those previously vaccinated intradermally

and vice versa [12–14]. Higher vaccine doses, adding

adjuvant substances (such as granulocyte-macrophage

colony-stimulating factor) [15, 16], and adding addi-

tional envelope protein (preS1 and preS2) [17] have also

been studied. The results in inducing seroconversion in

nonresponders have varied from 50% to 90% among

different studies and different revaccination protocols

Received 26 November 2007; accepted 28 February 2008; electronically pub-lished 10 June 2008.

Potential conflicts of interest: none reported.Financial support: County of Östergötland, Sweden; Swedish Cancer Foundation

(grant 3825B0712XCC to M.S.).Reprints or correspondence: Dr. Kristina Cardell, Dept. of Infectious Diseases,

University Hospital, S–581 85 Linköping, Sweden ([email protected]).

The Journal of Infectious Diseases 2008; 198:299 –304© 2008 by the Infectious Diseases Society of America. All rights reserved.0022-1899/2008/19803-0002$15.00DOI: 10.1086/589722

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[12–18]. In some smaller studies, a high response rate has been

noted. In one study, nonresponders to intramuscular vaccine

were vaccinated with repetitive intradermal doses every second

week (with a maximum of 4 doses), and 17 (94%) of 18 re-

sponded to this regime [14]. In another study, 62 (89%) of 70

public safety workers who had been previously vaccinated intra-

dermally responded after 3 additional doses of standard-dose

intramuscular vaccine [12]. A higher vaccine dose is recom-

mended in immunocompromised subjects, such as patients un-

dergoing hemodialysis [19]. To protect individuals at high risk

for hepatitis B exposure against becoming infected with HBV,

there is a need for effective regimes that can make nonrespond-

ers respond to hepatitis B vaccine. The combined hepatitis A and

B vaccine has been shown to be very effective in inducing sero-

conversion to both hepatitis A virus (HAV) and HBV in healthy

vaccinees. [20]. Some studies have shown even higher anti-HAV

levels with the combined vaccine than with the monovalent vac-

cine in healthy adults [21], whereas other studies have not been

able to show this [22, 23]. The aim of the present study was (1) to

see whether a high dose of hepatitis B antigen, normally used for

immunocompromised patients, in combination with hepatitis A

vaccine could induce protective anti-HBs titers (�10 mIU/mL)

in healthy nonresponders to hepatitis B vaccine and (2) to inves-

tigate the humoral immune response to hepatitis B vaccine in

nonresponders, compared with that in vaccine-naive individu-

als.

METHODS

Subjects. Health care workers known to be nonresponders to

hepatitis B vaccine were asked to participate in a prospective

study. Participants were chosen from a group of vaccinees who

had participated in a previous study of intradermal hepatitis B

vaccine given at 0, 1, and 6 months in the Department of Infec-

tious Diseases, University Hospital, Linköping, Sweden. All vac-

cinees in the previous study had been vaccinated by 2 nurses who

had vast experience with intradermal immunization. Nonre-

sponders were defined as those who had received at least 4 doses

of recombinant hepatitis B vaccine (Engerix-B; 0.1 mL intrader-

mally; GlaxoSmithKline) without developing anti-HBs titers of

�10 mIU/mL; after measurement of anti-HBs, all had received a

forth dose followed by new anti-HBs testing, which still showed

anti-HBs titers of �10 mIU/mL. All participants received oral

and written study information, and all gave oral informed con-

sent for participation in the study. Healthy adults who were �18

years of age and seronegative for HAV and HBV were chosen

from people who contacted the department for vaccination to

serve as the reference group. The reference group consisted

mainly of health care workers and students in health care sci-

ence. Exclusion criteria for the study were the presence of serious

diseases affecting the immune system and pregnancy. All were

negative for hepatitis B surface antigen (HBsAg), antibody to

hepatitis B core antigen, anti-HBs, and anti-HAV before inclu-

sion. All subjects in the study were vaccinated intramuscularly at

0, 1, and 6 months with 2.0 mL of combined hepatitis A and B

vaccine (Twinrix; GlaxoSmithKline) at the Department of Infec-

tious Diseases, University Hospital, Linköping. Blood samples

were drawn 5 times during the study period: before the first dose,

immediately before the second dose, 1 month after the second

dose, immediately before the third dose, and 1 month after the

third dose. Adverse events were registered in a questionnaire

administered after each dose; additionally, nurses inquired

about adverse events each time a sample was drawn and before

each new dose. The study was approved by the Ethics Committee

of the Health University, Linköping, Sweden.

Methods of virological serology. All testing of HBV mark-

ers were performed at the clinical microbiology laboratory of

University Hospital, Linköping. Measurement of anti-HBs levels

was done using the AxSYM AUSAB assay (Abbott Laboratories).

Samples with anti-HBs concentrations reported as �1000

mIU/mL were diluted using the automated dilution protocol.

Samples with anti-HBs concentrations reported as �25,000

mIU/mL by the automated dilution protocol were diluted using

a manual dilution of 1:25. The amount of anti-HBs in samples

was determined using a calibration curve. Measurement of anti-

HAV levels was done using the AxSYM HAVAB 2.0 quantitative

assay (Abbott Laboratories). The dynamic range of this assay is

0 –100 mIU/mL. For anti-HAV levels of �100 mIU/mL, a stan-

dard dilution protocol described by the manufacturer was used.

For anti-HAV levels of �20,000 mIU/mL, no further dilution

protocol existed. Therefore, no further dilution was done. These

titers are referred to as 20,000 mIU/mL in the statistical analyses.

Statistical analyses. The study was designed as an open

trial. We estimated that, with a study group of �50 nonrespond-

ers and a reference group of 20 previously unvaccinated healthy

individuals, we would be able to answer our questions—that is,

we would be able to show differences between the groups (but

not similarities), and the reference group would show whether

the vaccination schedule would work in a normal population.

Differences in demographic data between the groups were ana-

lyzed by t test. For comparing titers after each dose, the Mann-

Whitney rank-sum test was used; for response rates after each

dose, Fisher’s exact test was used. We also analyzed the influence

of such cofactors as smoking, age, BMI, and sex on the results.

For this analysis, we used a general linear model. The model was

selected by beginning with a full model that included all interac-

tions allowed by the data; then reducing interactions, starting

from highest order stepwise; and then reducing the main effects

if they were not part of the interactions. For anti-HBs titers, we

choose to do the calculations with logarithmic data, because of

the wide variation in levels and because the effect for anti-HBs

seemed to be multiplicative rather than additional; we used nu-

meric values for anti-HAV titers. Correlation between log anti-

HBs and anti-HAV titers after 3 doses was measured. The

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Minitab software package (version 13) was used for the statistical

analyses.

RESULTS

Patient demographics. A total of 48 nonresponders were en-

rolled, of whom 44 completed the study. Of the 4 who did not

complete it, 1 moved abroad during the study period, 1 did not

show up for further vaccination for unknown reasons, 1 was

impossible to evaluate because the subject’s blood samples were

accidentally misplaced in the laboratory, and 1 experienced se-

vere tiredness after the first dose and did not receive any further

doses (this occurrence was reported to the Swedish Medical

Products Agency, which concluded that it could have been a

vaccine-related adverse event). Twenty healthy HAV- and HBV-

nonimmune adults were enrolled in the reference group, all of

whom completed the study. Apart from the tiredness described

above, no serious adverse events were seen in either the nonre-

sponder group or the reference group.

Demographic data are shown in table 1. Because all of the

subjects in the nonresponder group and the majority of those in

the reference group were either health care workers or students

in health care science, there was an overrepresentation of women

in this study (reflecting that more women than men work in

health care). In the nonresponder group, 13 subjects were smok-

ers, 1 had stopped smoking immediately before inclusion, and

an additional 4 had stopped 4 –5 years before entering the study.

The corresponding figures for the reference group were 1

smoker and 2 previous smokers. For 2 persons in the nonre-

sponder group and 1 in the reference group, smoking data were

not available. Mean BMI was higher in the nonresponder group

(mean, 25.5; range, 20.0 –35.6) than in the reference group

(mean, 24.4; range, 19.3–30.9), as was the mean age (50 [range,

21– 69] years in the nonresponder group vs. 34 [range, 20 –59]

years in the reference group) (P � .001 for both comparsions).

Antibody responses. Of the 44 nonresponders who com-

pleted the study, 26 (59%), 35 (80%), and 42 (95%) developed anti-

HBs levels of �10 mIU/mL after the first dose, the second dose, and

the complete 3-dose schedule, respectively. In the reference group,

the corresponding figures were 2 (10%) of 20, 19 (95%) of 20, and

20 (100%) of 20, respectively (figure 1). Of the 2 nonresponders, 1

did not have a detectable anti-HBs level, and 1 had an anti-HBs level

of 8.5 mIU/mL. Both of these individuals were smokers. After 3

doses, a total of 35 nonresponders (80%) developed anti-HBs titers

of �100 IU/mL. All subjects in the reference group had an anti-HBs

titer of �100 IU/mL after 3 doses. All subjects in both groups re-

sponded to hepatitis A vaccine and developed anti-HAV. Taken

together, these data indicate that previous nonresponders show an

anamnestic response to revaccination, given that significantly more

subjects developed protective anti-HBs levels after the first injection

(26/44 [59%] vs. 2/20 [10%]; P � .001, Fisher’s exact test). Thus,

despite the absence of protective levels of anti-HBs from the

previous vaccination, the immune systems of these subjects were

primed to HBsAg, suggesting that they may, in fact, have been

protected against infection. The present revaccination schedule

was highly effective in inducing seroconversion, given that there

was no statistical difference in frequency after 3 doses (42/44 vs.

20/20; difference not significant). However, anti-HBs as well as

anti-HAV levels were significantly lower in the nonresponder

group than in the reference group (P � .001 and P � .001, re-

spectively). This suggests that nonresponder status with respect

to HBsAg may not be an isolated immunological event but

rather reflect a more general phenomenon. Anti-HAV and anti-

HBs levels after each dose for all individuals are shown in figures

2 and 3, respectively, with the median marked for all doses and

groups.

Table 1. Summary of demographic data.

GroupSex, no.

male/femaleAge, mean

(range), years BMI, mean (range)Smoking,

no.

Nonresponders 5/39 50 (21–69) 25.5 (20.1–35.6) 13Reference group 2/18 34 (20–59) 24.4 (19.3–30.9) 1

P 1.0 �.001 .310 .003

NOTE. BMI, body mass index.

Figure 1. No. of vaccinees who achieved a protective level (�10mIU/mL) of antibodies to hepatitis B surface antigen (anti-HBs) after eachdose in the nonresponder group and in the reference group. P values fordifferences in the response rate between the 2 groups are given (Fisher’sexact test).


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When analyzing the influence of other factors known to cor-

relate with the rate of response to a complete hepatitis B vacci-

nation schedule by use of a general linear model, we found that

both a high BMI (P � .001) and smoking (P � .004) were as-

sociated with lower anti-HBs levels and that a high BMI was

associated with lower anti-HAV levels (P � .016). The effect of

these factors seemed to be more pronounced in the nonre-

sponder group than in the reference group for both anti-HBs

and anti-HAV. A correlation between anti-HBs and anti-HAV

titers after 3 doses was found, with a correlation coefficient of

0.648 for log anti-HBs and anti-HAV titers (P � .001).

DISCUSSION

The absence of protective levels of antibodies (i.e., nonresponder

status) after hepatitis B vaccination is a clinical problem, and

several methods to correct it have been tested [12–18]. In the

present study, we used a high dose of the combined hepatitis A

and B vaccine and obtained an excellent seroconversion rate

(95%) among nonresponders. Other studies have shown simi-

larly high response rates. In one study, intradermally vaccinated

nonresponders were inoculated with 3 doses of intramuscular

vaccine, and a response rate of 89% was achieved; however, non-

responders in this study had received only 3 doses of intradermal

vaccine, and only 49% were primary responders [12]. In another

study, repetitive intradermal doses were given as described

above to nonresponders to at least 5 doses of hepatitis B vaccine,

and 94% responded [14]. One could conclude from these studies

and from our present data that the response seems to be dose

dependent. We also found that 59% of the nonresponders devel-

oped a protective anti-HBs level after the first dose, compared

with only 10% in the reference group. This strongly suggests that

the immune system of nonresponders was primed by the previ-

ous round of vaccination. Subsequently, some or most nonre-

Figure 3. Levels of antibodies to hepatitis B surface antigen (anti-HBs) after each dose in the nonresponder group and in the referencegroup. Lines indicate medians. P values for differences in anti-HBs levelafter each dose between the 2 groups are given (Mann-Whitney rank-sum test).

Figure 2. Levels of antibodies to hepatitis A virus (HAV) after eachdose in the nonresponder group and in the reference group. Lines indicatemedians. The difference in anti-HAV level between the reference groupand the nonresponder group after 3 doses was statistically significant(P � .001, Mann-Whitney rank-sum test).


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sponders might actually be protected against hepatitis B despite

the absence of protective anti-HBs levels, consistent with previ-

ous observations [24]. Only 2 of the nonresponders failed to

produce protective levels of anti-HBs, and of these only 1 was

completely negative for anti-HBs, suggesting a true nonre-

sponder status. Thus, true nonresponder status seems to be quite

rare, whereas most subjects who fail to respond to the first round

of hepatitis B vaccination are merely poor responders.

In the present study, we also confirmed the effects of previ-

ously noted factors predisposing to nonresponder status. For

example, both of the nonresponders who failed to respond to

revaccination were smokers. However, many others had this risk

factor, suggesting that smoking alone cannot explain their poor

anti-HBs responses. Other known risk factors for nonresponder

status seemed to affect the anti-HBs titers to a greater degree in

the nonresponder group than in the reference group, indicating

that other factors, such as genotype, could influence the results.

Our results suggest that a high dose of HBsAg in combination

with the hepatitis A antigen could offer a clinically relevant ap-

proach to correcting nonresponder status in persons who are not

already immune to hepatitis A and for whom protection against

hepatitis B is essential. It has been shown that, in healthy indi-

viduals, anti-HBs levels are higher when the combined vaccine is

used than when a vaccine containing HBsAg alone is used [25]. It

is therefore likely that, with the combined hepatitis A and B

vaccine (Twinrix), the hepatitis A component might act as an

adjuvant for the hepatitis B response. Our present data certainly

favor this hypothesis. Titers are of less importance according to

present consensus recommendations, which state that once the

titer reaches �10 mIU/mL there is no need for further testing or

booster doses in immunologically competent persons [26].

A potentially important observation was that both anti-HBs

and anti-HAV titers were significantly lower in the nonre-

sponder group than in the reference group. This would imply

that nonresponder status after the first round of hepatitis B vac-

cination reflects a more general inability to rapidly generate high

levels of antibodies in response to vaccination. Our findings sug-

gest that, in these individuals, the reduced ability to respond to

hepatitis B vaccine could be associated with a generally reduced

capacity to produce vaccine-induced antibodies. To test this hy-

pothesis, it would be of interest to investigate whether nonre-

sponders or low responders to hepatitis B vaccine also have poor

response to other vaccine antigens after immunization. Another

explanation for the reduced levels of both anti-HBs and anti-

HAV in the nonresponder group could be that, whereas the hep-

atitis A component acts as an adjuvant to the hepatitis B re-

sponse, the hepatitis B antigen (or immune response) had a

negative effect on the hepatitis A response. Additional studies are

needed to elucidate this issue.

In conclusion, in light of the present results, we propose that a

double dose of the combined hepatitis A and B vaccine can be

safely and effectively used to induce protective levels of anti-HBs

in nonresponders to the traditional hepatitis B vaccine among

those nonimmune to hepatitis A.

Acknowledgments

Vaccine was supplied by GlaxoSmithKline. Liselott Lindvall and KerstinSamuelsson, nurses in the Department of Infectious Diseases, performedvaccination and collected blood samples. Inga-Lill Lundin, technician in theDepartment of Clinical Microbiology, analyzed all samples for serologicaldata.

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