Immunogenicity of combined hepatitis A and B vaccine in elderly persons

Immunogenicity of combined hepatitis A and B vaccine in elderly persons

Vaccine 21 (2003) 3623–3628 Immunogenicity of combined hepatitis A and B vaccine in elderly persons Bernd Wolters a , Ulrich Junge b , Stefan Dziuba ...

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Vaccine 21 (2003) 3623–3628

Immunogenicity of combined hepatitis A and B vaccine in elderly persons Bernd Wolters a , Ulrich Junge b , Stefan Dziuba c , Michael Roggendorf a,∗ b

a Institute of Virology, University of Essen, 45122 Essen, Germany Department of Medicine, Städtische Kliniken Rosenhöhe, 33647 Bielefeld, Germany c Internistische Praxis, Ostpark 10, 33604 Bielefeld, Germany

Accepted 16 May 2003

Abstract More and more elderly people travel to areas where hepatitis A and B are endemic. Their immune system is less effective than in young persons. Therefore, it has to be insured that these travelers have protective immunity after vaccination. In a retrospective study we measured anti hepatitis virus (anti-HAV) and anti-HBs in elderly persons (N = 104, mean age 54 years) after combined hepatitis A/B vaccination under every-day conditions. After complete vaccination only 36 (34.6%) had antibodies against both viruses. Only 23 (29%) of 80 vaccinees older than 40 years were protected against hepatitis B and 52 (65%) against hepatitis A. The response to the vaccination decreased with increasing age. Vaccination against hepatitis B—but not against hepatitis A—was also influenced by the presence of chronic disease. After one booster 87% of the anti-HAV negative vaccinees developed protective anti-HAV antibodies. Anti-HBs can be expected in about 50% of the HBV negative vaccinees with every single booster. These results indicate that combined hepatitis A/B vaccination is not very effective in elderly persons. After complete vaccination their anti-HAV and anti-HBs antibodies have to be controlled to insure protection. In case of vaccination-failure boosters are very effective. © 2003 Elsevier Science Ltd. All rights reserved. Keywords: Vaccine; Elderly people; Hepatitis A; Hepatitis B

1. Introduction Active vaccination against hepatitis A and hepatitis B is successfully used worldwide. Hepatitis A virus (HAV) infection is acquired by fecal–oral route, especially under poor sanitary conditions. In 2001, about 40% of the reported cases of hepatitis A in Germany were acquired in foreign countries [1]. Hepatitis B virus (HBV) is less often transmitted to travelers but this infection can become chronic leading to liver cirrhosis [2]. Besides monovalent vaccines against hepatitis A and B, a combined vaccine containing HBsAg and HAV-Ag is available [3]. This vaccine reduces the number of injections, thus improving compliance and lowering costs. All combined hepatitis vaccines are well tolerated and proved to be effective in clinical studies with young adults [4–6]. Using the ∗ Corresponding author. Tel.: +49-201-723-3550; fax: +49-201-723-5929. E-mail address: [email protected] (M. Roggendorf).

common immunization scheme (i.m. injections into the deltoid muscle at months 0, 1, 6), most study groups found an anti-HAV response in more than 98% of persons aged between 20 and 39 years. Recorded anti-HBs seroconversion rates are 92–100% [3,7–9]. We recently described a breakthrough of hepatitis A infection after complete hepatitis A/B vaccination in a 55-year-old patient [10]. Thirty-two days after shellfish consumption he, his wife and three children developed acute icteric hepatitis A. The patient had completed combined hepatitis A/B vaccination 3 months before exposure, his wife (59 years) had incomplete (one shot 16 days before infection), the children no vaccination. Except for mild hypertension the patient was healthy and showed good response to other vaccines. The only obvious explanation for this vaccination failure is the patients age. Because of this breakthrough we determined the immunity against hepatitis A and B of all—mainly elderly patients— who were vaccinated in the same physicians office under the same every-day conditions.

0264-410X/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0264-410X(03)00399-2

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2. Methods 2.1. Vaccinees and immunization One hundred and four persons (53 male, 51 female, mean age 54 years, range 17–84 years) were vaccinated from July 1997 until May 2000. All vaccinees had normal liver enzymes, did not suffer from any malignancies or consuming diseases nor were they under immunosuppressive therapy. All known diseases were documented. All patients had to pay themselves for the vaccination and the antibody controls. The vaccination schedule followed strictly the recommendations of the manufacturer (1 ml Twinrix® containing 720 ELISA units of inactivated hepatitis A antigen and 20 ␮g recombinant hepatitis B surface antigen absorbed on aluminum phosphate injected into the right or left deltoid muscle at months 0, 1 and 6). All batches used were documented. The vaccines were stored at 4 ◦ C prior to use. All vaccinations were done by the physician himself who has long-standing experience. Persons showing no seroprotection were recommended a booster vaccination with monovalent vaccine.

Table 1 Anti-HAV and anti-HBs-antibodies after combined vaccination against hepatitis A/B Complete vaccination

N = 104

Percentage

Age (mean age: 54 years)

Anti-HAV positive, anti-HBs positive Anti-HAV negative, anti-HBs positive Anti-HAV positive, anti-HBs negative Anti-HAV negative, anti-HBs negative

36

34.6

48.8

3

2.9

44

38

36.2

54

27

26.3

60.9

antibodies (mean age 60.9 years versus 48.8 years; P < 0.001). There was a significant age difference between vaccinees with and without anti-HBs (48.5 years versus 57.2 years; P < 0.05), as well as with and without anti-HAV (51.8 years versus 59.2 years; P < 0.05). Among 80 vaccinees older than 40 years, 23 (29%) were protected against hepatitis B and 52 (65%) against hepatitis A (Fig. 1). It has been shown that anti-HBs decreases rapidly after vaccination. Therefore we correlated the protection rate to

2.2. Laboratory methods and statistics Antibodies against HAV and HBsAg were determined with commercially available microparticle enzyme immunoassays (Axsym HAVAB 2.0® , Axsym AUSAB II® , Abbott, Wiesbaden). The thresholds for seroprotection were defined as an anti-HAV antibody concentration of ≥20 IU/l and an anti-HBs antibody concentration of at least 10 IU/l. Statistics were performed using t-test or chi-square test. Differences were considered to be significant at the 5% level (SPSS statistical software, version 9.0, Chicago).

3. Results A total of 104 persons received combination vaccine against hepatitis A and B (Twinrix® ). For the 312 vaccinations, 27 different batches were used. Antibodies against HAV were found in 74 (71.2%) and against HBsAg in 39 (37.5%) of the 104 vaccinees. Protective antibodies against both viruses were found in 36 persons (34.6%), no anti-HAV nor anti-HBs antibodies in 27 vaccinees (26%) (Table 1). Seroconversion rates were determined in the group of healthy persons and those with chronic disease. Detailed information about their health status are listed in Table 2. Antibodies against hepatitis A virus were found at the same percentage in both groups whereas anti-HBs was found significantly less often in persons with underlying chronic disease (Table 3). The frequency of seroconversion decreased with increasing age of the vaccinees. Those without antibodies were significantly older than those with anti-HBs and anti-HAV

Table 2 Antibody response in all vaccinees with regard to their health status N

Percentage

Anti-HAV positive, anti-HBs positive (N = 36, male = 15, female = 21) Healthy 23 64 Chronic disease 13 36 Thyroid struma 9 25 Parkinson’s disease 2 5.5 History of akromegaly 1 2.7 Hypertension 1 2.7 Anti-HAV negative, anti-HBs positive (N = 3, male = 1, female = 2) Healthy 3 100 Chronic disease 0 0 Anti-HAV positive, anti-HBs negative (N = 38, male = 21, female = 17) Healthy 10 26 Chronic disease 28 74 Thyroid struma 10 26 Hypertension 8 21 Coronary heart disease 4 11 Diabetes type II 2 5.3 Asthma 1 2.6 Psoriasis 1 2.6 Endometriosis 1 2.6 Renal insufficiency (compensated) 1 2.6 Anti-HAV negative, anti-HBs negative (N = 27, male = 14, female = 13) Healthy 11 41 Chronic disease 16 59 Hypertension 7 26 Coronary heart disease 6 22 Thyroid struma 2 7.4 Arthritis 1 3.7

B. Wolters et al. / Vaccine 21 (2003) 3623–3628 Table 3 Anti-HAV and anti-HBs seroprotection rates following vaccination with Twinrix® Na

%SP-HAVb

%SP-HBV38c

All subjects 104

71

38

Sex Female Male

53 51

72 71

P = 0.9

43 31

P = 0.2

Age (years) <40 40–60 >60

24 37 43

92 68 63

P < 0.05

67 24 33

P < 0.005

47 57

70 72

P = 0.85

55 23

P < 0.001

Disease Healthy Chronic disease a

N, number of subjects. %SP-HAV, percentage seroprotection against hepatitis A. c %SP-HBV, percentage seroprotection against hepatitis B. b

time point of testing after completed vaccination (Fig. 2). Sixty-one percent of the vaccinees were tested within the first 18 months and showed a seroprotection rate against HBV of 46%. The mean time interval between completion of the vaccination and control of antibody titer was 16.8 months (range 1–36 months). Persons without anti-HBs antibodies had a longer time interval between vaccination and examination of their serostatus than those with protective titers (P < 0.05). This difference was not statistically significant for antibodies against hepatitis A virus (P = 0.07).

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The low seroconversion rate may be due to prior exposure to HBV or low level carriage of HBV. We tested 18 vaccinees (28%) without seroprotection against HBV for HBsAg and anti-HBc antibodies. All vaccinees were negative excluding previous infection or HBsAg carrier status. A booster vaccination was proposed to all persons, who remained negative for anti-HAV and/or anti-HBs. Not all patients agreed, because they had to pay themselves also for the booster injection. One monovalent booster was given to 23 (77%) of those negative for anti-HAV (Fig. 3a) and to 53 (82%) of those negative for anti-HBs (Fig. 3b). After one booster seroprotective antibodies against HBsAg were found in 24 of 53 persons (45%). Eight of the remaining anti-HBs negative vaccinees were boostered a second time and four of them developed protective anti-HBs thereafter. Twenty-three persons were given a first booster with hepatitis A vaccine and 20 of them developed anti-HAV (87%). Two of the still anti-HAV negative persons received a second booster and both turned seropositive thereafter.

4. Discussion Protection of elderly people against hepatitis A and B is a growing problem because nowadays an increasing number of them travel abroad. About 11% of 32.3 million Germans going abroad in 2000 were 65 years or older [11]. Many of them visit countries where hepatitis A and B are endemic and vaccination is recommended. According to our study a great number of elderly travelers are not protected, despite complete vaccination.

Fig. 1. Antibody response to combined hepatitis A/B vaccination in different age groups.

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Fig. 2. Protection rate and time point of testing after completed vaccination.

Prospective, randomized trials found seroconversion rates up to 95% (HBV) and 99.6% (HAV) in young (the majority was under 40 years of age) and healthy persons [3–8]. In this retrospective study we found an unexpected poor response to the combined vaccine with antibodies against hepatitis A

in 71.2% and against hepatitis B in only 37.5% of the vaccinees. Several reasons may be responsible for these results. Inadequate storage conditions—especially freezing—can damage the vaccine [12,13]. The vaccines were therefore stored as short as possible in a refrigerator at 2–8 ◦ C.

Fig. 3. (a) Antibody response following booster injections in those vaccinees being negative for anti-HAV (a), anti-HBs (b) after complete vaccination with combined hepatitis A/B vaccine.

B. Wolters et al. / Vaccine 21 (2003) 3623–3628

Avoiding storage led to a high number of applied batches (N = 27). We found no relation between certain batches and lack of immune response. No batch was outdated. There was no reason to assume failures in the production of the vaccine used. Suboptimal response was found to be associated with the application of the vaccine in the gluteal muscle area [12,14]. The site of injection in all of our 104 vaccinees was the right or left deltoid muscle. The experienced physician used adequate long needles to ascertain optimal effect of the vaccines. Combined vaccine is at least as immunogenic as the corresponding monovalent hepatitis vaccines. With combined vaccine the reported antibody titers were even higher [8,9]. Therefore we do not expect other results when using monovalent vaccines. The failure to respond to vaccination may be explained by previous exposure to hepatitis B virus or low level carriage of HBV. Twenty-eight percent of non-responders in our study could be tested for HBsAg and anti-HBc antibodies and all were found to be negative. These findings indicate that the low seroconversion rate is not explained by low level carriage of HBV. In addition a representative population based study in Germany show that the mean prevalence of HBsAg carriage was 0.6% and “anti-HBc alone” is found in 0.8% [15]. Those “anti-HBc alone” positive individuals were often vaccinated in clinical studies to distinguish whether isolated anti-HBc is related to false positive results or related to prior exposure to HBV. In various reports, the seroprotection rates reported after three doses of hepatitis B vaccine were between 70 and 90% [16,17]. Combined [18] and monovalent vaccines [5,19,20] induce antibodies which persists for many years especially in those vaccinees who developed initial high titers of anti-HBs. Using monovalent hepatitis B vaccine Jilg et al. [21] showed that those persons with initially moderate antibody response (less than 100 U/l anti-HBs) the antibody level dropped within 18 months. Intervals between completion of the vaccination and antibody control varied in our study between 1 and 36 months. We confirm that the time point of testing after completion of vaccination influence the protection rate of the 104 vaccinees (Fig. 2). However those tested within 18 months had only a HBV seroprotection rate of 46%. The only reason for our poor vaccination success is the age of our unselected population. Only 29% of 80 vaccinees older than 40 years had protection against hepatitis B and 65% against hepatitis A. It has been shown that vaccination against hepatitis B is less immunogenic in healthy elderly people [22–29]. In contrast to our results other studies showed good immune response to hepatitis A vaccination in all age groups up to 65 years [25,30,31]. We did not select vaccinees and included persons with many different chronic diseases. Excluding patients with chronic disease would have prevented most persons older

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than 60 years from joining our study. The most common diagnosis was hypertension and uncomplicated struma nodosa. Healthy persons had a significant better immune response against HBV than those with underlying disease. The fact, that diseases modulating the immune system influence the hepatitis B vaccination is well documented [32,33]. Our data indicate that this holds also true for patients with rather mild disease. De Rave et al. [29] studied 112 volunteers (without life-threatening disease) aged 59 years and over. Besides the age the only significant factor influencing the response to vaccination was the use of medication reflecting general health or mild disease. They found 58% HBV seroprotection rate in these elderly people. In contrast, the immune response against HAV was not influenced by disease. The relationship between chronic disease and vaccination against hepatitis A has not been investigated before. We recommended booster vaccination to all participants without seroprotection. About half of our anti-HBs negative vaccinees became anti-HBs positive with every additional booster, similar to previous studies [34,35]. One additional shot of a monovalent HAV vaccine was successful in 87%. With the second booster dose all persons developed protective antibodies. Booster applications in anti-HAV negative vaccinees was never described before. Our study shows that hepatitis A/B vaccination is not very effective in elderly persons. After complete vaccination they have to be tested for anti-HAV and anti-HBs. Antibody testing is best done 4–8 weeks or at least 18 months after vaccination to identify those persons with only short lasting protection. Many of the elderly vaccinees need booster injections to insure save protection. Additional clinical studies are needed to find an optimal vaccine dose and better vaccination schedule for all elderly people with or without chronic disease.

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