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Combined hepatitis A and B vaccine in elderly
Vaccine 22 (2004) 303–304
Letter to the Editor Combined hepatitis A and B vaccine in elderly A recent report by Wolters et al. [1] presents results of a retrospective survey on the level of antibody response to hepatitis B virus surface antigen (anti-HBs) and antibody to hepatitis A virus (anti-HAV) in 104 unselected, mostly “elderly” persons (mean age 54, 17–84 years) after combined hepatitis A and B vaccination under “every day” conditions. An unexpected limited response to the combined vaccine was found with detectable anti-HAV in 71.2% and protective anti-HBs in only 37.5% of the vaccinees. The authors conclude that combined hepatitis A and B vaccination is not very effective in elderly persons. As our Centre for the Evaluation of Vaccination wrote the expert’s report on the combined hepatitis A and B vaccine for the European Regulatory authorities, we felt very concerned with the potential impact of this scientific publication (accessed electronically on 23 July 2003) and would like to comment on these observations in a broader perspective. We agree with the authors that ‘studies’ performed under every day conditions should receive more attention as they mimic the “every day” situation more exactly than do vaccine trials. However, performing such retrospective assessment has its limitations such as the well known problem of data validation and data generation. In addition, the weaker point in such “every day” studies is the unavoidable difficult interpretation of some outcome variables. In the first instance, it should be mentioned that in this study the mean time interval between completion of the vaccination course and control of antibody titres was 16.8 months (up to 36 months). Since there is no documentation on the subjects’ responses immediately after the vaccination course, it is impossible to differentiate between subjects who never responded and those who did respond initially but lost antibodies over time. Hence, one cannot claim that all subjects without antibodies after primary vaccination in this study are non-responders who “remained” negative for anti-HAV and/or anti-HBs. The seroprotection rate seen by Wolters et al. after the first additional dose of hepatitis B vaccine suggests that at least some of the anti-HBs seronegative vaccinees had been primed by the combined hepatitis A and B vaccine and developed immune memory, which is necessary for long-term protection. Extending the time interval between the last vaccine dose and blood sampling results in a lower seroprotection rate. For this reason, many organisations recommend to check the post-vaccination anti-HBs 1–3 months after the administration of the last hepatitis B
0264-410X/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2003.08.011
vaccine dose [2]. This could be designed prospectively in a future “every day” assessment. The immune response to the combined hepatitis A and B vaccine in adults below 40 years reported by Wolters et al. (anti-HBs seroprotection rate of 67% and anti-HAV seroconversion rate of 92%) is surprisingly low and in sharp contrast with published data so far. It is inconsistent with the extensive data collected in this age range after vaccination with the combined vaccine or the monovalent vaccines, which show that at least 95% of subjects achieve seroprotection for hepatitis B and on average 99% of subjects develop anti-HAV titres [3–5]. This might indicate that other potentially unidentified factors may have occurred in Wolters et al.’s study or a combination of known factors (e.g. age, gender, BMI, . . . ) which should be looked at very carefully. The effect of age on the immune response to the hepatitis A and B antigens is a well-known phenomenon, particularly for the latter antigen, which has been previously described in the literature for vaccines of different manufacturers [6–9]. Nevertheless, the results presented by Wolters et al. are remarkably inferior to those previously published. A retrospective analysis on data from five clinical trials with the combined hepatitis A and B vaccine in 264 subjects over 40 years, has recently been published [10]. Although a decrease in the anti-HBs immune response was observed, 89.1% of subjects were still seroprotected against hepatitis B in the group of vaccinees aged 51–60 years and 86.7% in the group above 61 years of age. In terms of the response to the hepatitis A antigen, anti-HAV antibody titres were lower with increasing age, but virtually all subjects (99.6%) were seropositive with antibody levels largely exceeding the seroconversion level, regardless of their age [10]. As mentioned by Wolters et al., the combined hepatitis A and B vaccine is at least as immunogenic as the corresponding monovalent hepatitis vaccines with even higher antibody titres elicited by the combination. This has been demonstrated in clinical development studies [3,11] or independent studies [12,13]. Interestingly, in a trial comparing the combined hepatitis A and B vaccine to monovalent hepatitis B vaccines from different manufacturers in an unselected population aged up to 80 years, the immune response to the combined vaccine seemed to be less influenced by age as compared to the monovalent hepatitis B vaccines [12], with up to 87% of subjects protected against hepatitis B after a vaccination course with the combined hepatitis A and B vaccine in the population over 60 years of age.
304
Letter to the Editor / Vaccine 22 (2004) 303–304
Several studies have shown that the underlying health status of vaccinees plays a role in the immune response to hepatitis B vaccine. The impact of medical conditions reported by Wolters et al. seems to be very strong with a 23% seroprotection rate against hepatitis B in subjects with underlying chronic disease versus 55% in healthy subjects. In the retrospective analysis mentioned above [10] with the combined hepatitis A and B vaccine, subjects with severe or debilitating diseases were excluded, but patients with chronic diseases such as hypertension, arthritis, asthma and hypothyroidism were included, as was the case in the Wolters et al.’s study, and they represented approximately half of the subject population over 40 years of age. The data show that these subjects with chronic diseases had anti-HAV seroconversion rates of 99% and anti-HBs seroprotection rates of over 90% [10]. In conclusion, uncontrolled, retrospective surveys as the one reported by Wolters et al. can lead to interesting hypotheses. However, these should then be tested in prospective trials, under “real life”, but controlled, conditions. Based on the conclusion from the paper, senior travellers may have the impression that a combined hepatitis A and B vaccine is of no value to them and remain unvaccinated. This is not really the aim nor from a the point of view of individual prevention neither from public health perspective. Only an assessment, where all aspects of the results are fully explored and where parameters that influence the vaccine response are identified, can yield valid conclusions that might be used to guide future vaccination practices. References [1] Wolters B, Junge U, Dziuba S, Roggendorf M. Immunogenicity of combined hepatitis A and B vaccine in elderly persons. Vaccine, 2003, accessed on 23 July 2003 [in press]. [2] Grosheide P, Van Damme P. In: Hallauer J, Kane M, McCloy E, Meheus A, Roure C, editors. Prevention and control of hepatitis B in the community (blue book). Communicable diseases series no. 1; 1996. p. 64. [3] Joines RW, Blatter M, Abraham B, et al. A prospective, randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix® ) with corresponding monovalent vaccines (Havrix® and EngerixTM -B® ) in adults. Vaccine 2001;19:4710–9.
[4] Safary A, André F. Over a decade of experience with yeast recombinant hepatitis B vaccine. Vaccine 1999;18(1–2):57–62. [5] André F, Van Damme P, Safary A, Banatvala J. Inactivated hepatitis A vaccine: immunogenicity, efficacy, safety and review of official recommendations for use. Expert Rev Vaccines 2002;1:9–23. [6] Fisman DN, Agrawal D, Leder K. The effect of age on immunologic response to recombinant hepatitis B vaccine: a meta-analysis. Clin Infect Dis 2002;35:1368–75. [7] Young MD, Schneider DL, Zuckerman AJ, Du W, Dickson B, Maddrey WC. Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine. Hepatology 2001;34:372–6. [8] Briem H, Safary A. Immungenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J Med Virol 1994;44:443–5. [9] Reuman PD, Kubilis P, Hurni W, Brown L, Nalin D. The effect of age and weight on the response to formalin inactivated alum-adjuvanted hepatitis A vaccine in healthy adults. Vaccine 1997;15:1157–61. [10] Stoffel M, Lievens M, Dieussaert I, Martin I, André F. Immunogenicity of TwinrixTM in older adults: a critical analysis. Expert Rev Vaccines 2003;2:9–14. [11] Ambrosch F, Wiedermann G, André F, et al. Clinical and immunological investigation of a new combined hepatitis A and hepatitis B vaccine. J Med Virol 1994;44:452–6. [12] Rendi-Wagner P, Kundi M, Stemberger H, et al. Antibody response to three recombinant hepatitis B vaccines: comparative evaluation of multicenter travel-clinic based experience. Vaccine 2001;19:2055– 60. [13] Czeschinski PA, Binding N, Witting U. Hepatitis A and hepatitis B vaccinations: immunogenicity of combined vaccine and of simultaneously or separately applied single vaccines. Vaccine 2000;18:1074–80.
Pierre Van Damme∗ Koen Van Herck Marie Van der Wielen Unit of Epidemiology and Social Medicine Centre for the Evaluation of Vaccination WHO Collaborating Centre, University of Antwerp Universiteitsplein 1, B-2610 Wilrijk, Belgium ∗ Corresponding author Tel.: +32-3-820-25-38/820-25-23/820-25-24 fax: +32-3-820-26-40 E-mail address: [email protected] (P. Van Damme)
Letter to the Editor Combined hepatitis A and B vaccine in elderly A recent report by Wolters et al. [1] presents results of a retrospective survey on the level of antibody response to hepatitis B virus surface antigen (anti-HBs) and antibody to hepatitis A virus (anti-HAV) in 104 unselected, mostly “elderly” persons (mean age 54, 17–84 years) after combined hepatitis A and B vaccination under “every day” conditions. An unexpected limited response to the combined vaccine was found with detectable anti-HAV in 71.2% and protective anti-HBs in only 37.5% of the vaccinees. The authors conclude that combined hepatitis A and B vaccination is not very effective in elderly persons. As our Centre for the Evaluation of Vaccination wrote the expert’s report on the combined hepatitis A and B vaccine for the European Regulatory authorities, we felt very concerned with the potential impact of this scientific publication (accessed electronically on 23 July 2003) and would like to comment on these observations in a broader perspective. We agree with the authors that ‘studies’ performed under every day conditions should receive more attention as they mimic the “every day” situation more exactly than do vaccine trials. However, performing such retrospective assessment has its limitations such as the well known problem of data validation and data generation. In addition, the weaker point in such “every day” studies is the unavoidable difficult interpretation of some outcome variables. In the first instance, it should be mentioned that in this study the mean time interval between completion of the vaccination course and control of antibody titres was 16.8 months (up to 36 months). Since there is no documentation on the subjects’ responses immediately after the vaccination course, it is impossible to differentiate between subjects who never responded and those who did respond initially but lost antibodies over time. Hence, one cannot claim that all subjects without antibodies after primary vaccination in this study are non-responders who “remained” negative for anti-HAV and/or anti-HBs. The seroprotection rate seen by Wolters et al. after the first additional dose of hepatitis B vaccine suggests that at least some of the anti-HBs seronegative vaccinees had been primed by the combined hepatitis A and B vaccine and developed immune memory, which is necessary for long-term protection. Extending the time interval between the last vaccine dose and blood sampling results in a lower seroprotection rate. For this reason, many organisations recommend to check the post-vaccination anti-HBs 1–3 months after the administration of the last hepatitis B
0264-410X/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2003.08.011
vaccine dose [2]. This could be designed prospectively in a future “every day” assessment. The immune response to the combined hepatitis A and B vaccine in adults below 40 years reported by Wolters et al. (anti-HBs seroprotection rate of 67% and anti-HAV seroconversion rate of 92%) is surprisingly low and in sharp contrast with published data so far. It is inconsistent with the extensive data collected in this age range after vaccination with the combined vaccine or the monovalent vaccines, which show that at least 95% of subjects achieve seroprotection for hepatitis B and on average 99% of subjects develop anti-HAV titres [3–5]. This might indicate that other potentially unidentified factors may have occurred in Wolters et al.’s study or a combination of known factors (e.g. age, gender, BMI, . . . ) which should be looked at very carefully. The effect of age on the immune response to the hepatitis A and B antigens is a well-known phenomenon, particularly for the latter antigen, which has been previously described in the literature for vaccines of different manufacturers [6–9]. Nevertheless, the results presented by Wolters et al. are remarkably inferior to those previously published. A retrospective analysis on data from five clinical trials with the combined hepatitis A and B vaccine in 264 subjects over 40 years, has recently been published [10]. Although a decrease in the anti-HBs immune response was observed, 89.1% of subjects were still seroprotected against hepatitis B in the group of vaccinees aged 51–60 years and 86.7% in the group above 61 years of age. In terms of the response to the hepatitis A antigen, anti-HAV antibody titres were lower with increasing age, but virtually all subjects (99.6%) were seropositive with antibody levels largely exceeding the seroconversion level, regardless of their age [10]. As mentioned by Wolters et al., the combined hepatitis A and B vaccine is at least as immunogenic as the corresponding monovalent hepatitis vaccines with even higher antibody titres elicited by the combination. This has been demonstrated in clinical development studies [3,11] or independent studies [12,13]. Interestingly, in a trial comparing the combined hepatitis A and B vaccine to monovalent hepatitis B vaccines from different manufacturers in an unselected population aged up to 80 years, the immune response to the combined vaccine seemed to be less influenced by age as compared to the monovalent hepatitis B vaccines [12], with up to 87% of subjects protected against hepatitis B after a vaccination course with the combined hepatitis A and B vaccine in the population over 60 years of age.
304
Letter to the Editor / Vaccine 22 (2004) 303–304
Several studies have shown that the underlying health status of vaccinees plays a role in the immune response to hepatitis B vaccine. The impact of medical conditions reported by Wolters et al. seems to be very strong with a 23% seroprotection rate against hepatitis B in subjects with underlying chronic disease versus 55% in healthy subjects. In the retrospective analysis mentioned above [10] with the combined hepatitis A and B vaccine, subjects with severe or debilitating diseases were excluded, but patients with chronic diseases such as hypertension, arthritis, asthma and hypothyroidism were included, as was the case in the Wolters et al.’s study, and they represented approximately half of the subject population over 40 years of age. The data show that these subjects with chronic diseases had anti-HAV seroconversion rates of 99% and anti-HBs seroprotection rates of over 90% [10]. In conclusion, uncontrolled, retrospective surveys as the one reported by Wolters et al. can lead to interesting hypotheses. However, these should then be tested in prospective trials, under “real life”, but controlled, conditions. Based on the conclusion from the paper, senior travellers may have the impression that a combined hepatitis A and B vaccine is of no value to them and remain unvaccinated. This is not really the aim nor from a the point of view of individual prevention neither from public health perspective. Only an assessment, where all aspects of the results are fully explored and where parameters that influence the vaccine response are identified, can yield valid conclusions that might be used to guide future vaccination practices. References [1] Wolters B, Junge U, Dziuba S, Roggendorf M. Immunogenicity of combined hepatitis A and B vaccine in elderly persons. Vaccine, 2003, accessed on 23 July 2003 [in press]. [2] Grosheide P, Van Damme P. In: Hallauer J, Kane M, McCloy E, Meheus A, Roure C, editors. Prevention and control of hepatitis B in the community (blue book). Communicable diseases series no. 1; 1996. p. 64. [3] Joines RW, Blatter M, Abraham B, et al. A prospective, randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix® ) with corresponding monovalent vaccines (Havrix® and EngerixTM -B® ) in adults. Vaccine 2001;19:4710–9.
[4] Safary A, André F. Over a decade of experience with yeast recombinant hepatitis B vaccine. Vaccine 1999;18(1–2):57–62. [5] André F, Van Damme P, Safary A, Banatvala J. Inactivated hepatitis A vaccine: immunogenicity, efficacy, safety and review of official recommendations for use. Expert Rev Vaccines 2002;1:9–23. [6] Fisman DN, Agrawal D, Leder K. The effect of age on immunologic response to recombinant hepatitis B vaccine: a meta-analysis. Clin Infect Dis 2002;35:1368–75. [7] Young MD, Schneider DL, Zuckerman AJ, Du W, Dickson B, Maddrey WC. Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine. Hepatology 2001;34:372–6. [8] Briem H, Safary A. Immungenicity and safety in adults of hepatitis A virus vaccine administered as a single dose with a booster 6 months later. J Med Virol 1994;44:443–5. [9] Reuman PD, Kubilis P, Hurni W, Brown L, Nalin D. The effect of age and weight on the response to formalin inactivated alum-adjuvanted hepatitis A vaccine in healthy adults. Vaccine 1997;15:1157–61. [10] Stoffel M, Lievens M, Dieussaert I, Martin I, André F. Immunogenicity of TwinrixTM in older adults: a critical analysis. Expert Rev Vaccines 2003;2:9–14. [11] Ambrosch F, Wiedermann G, André F, et al. Clinical and immunological investigation of a new combined hepatitis A and hepatitis B vaccine. J Med Virol 1994;44:452–6. [12] Rendi-Wagner P, Kundi M, Stemberger H, et al. Antibody response to three recombinant hepatitis B vaccines: comparative evaluation of multicenter travel-clinic based experience. Vaccine 2001;19:2055– 60. [13] Czeschinski PA, Binding N, Witting U. Hepatitis A and hepatitis B vaccinations: immunogenicity of combined vaccine and of simultaneously or separately applied single vaccines. Vaccine 2000;18:1074–80.
Pierre Van Damme∗ Koen Van Herck Marie Van der Wielen Unit of Epidemiology and Social Medicine Centre for the Evaluation of Vaccination WHO Collaborating Centre, University of Antwerp Universiteitsplein 1, B-2610 Wilrijk, Belgium ∗ Corresponding author Tel.: +32-3-820-25-38/820-25-23/820-25-24 fax: +32-3-820-26-40 E-mail address: [email protected] (P. Van Damme)