Hepatitis B is a serious infectious disease causing

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1 Commentaries Hepatitis B Immunization in Health Care Workers Dealing with Vaccine Nonresponse Gregory A. Poland, MD Hepatitis B is a serious infectious disease causing substantial morbidity and mortality. 1 For health care workers (HCWs) in particular, occupational exposure is a real and continuing concern. 2 This risk appears to be greatest during the beginning years of a HCW s career, particularly during training, when exposure is maximal, and experience/ awareness of infection risk minimal. 3,4 For these reasons, the Advisory Committee on Immunization Practices (ACIP), as well as multiple professional societies, have recommended hepatitis B immunization for all HCWs, with a particular emphasis on immunizing students training in HCW professions. 4 6 In addition, starting in 1991, Occupational Health and Safety Administration (OHSA) mandated that all health care facilities offer hepatitis B vaccine to their employees. Despite these efforts, some people do not seroconvert with protective levels of antibody after receiving the currently available vaccines. Soon after licensure, studies began to document poorer immunogenicity in those who received vaccine injected into the buttocks Other studies have demonstrated significantly reduced immunogenicity in males, smokers, obese persons, increasing age, certain HLA haplotypes, 11 and in those who are immunocompromised. 12,13 To this list must be added studies describing slightly lower immunogenicity in certain subgroups of recipients of Recombivax HB (Merck Research Laboratories [MRL] West Point, PA), compared to Engerix-B (SmithKline Beecham Laboratories [SKB] Rixensauf, Belgium). 12,14,15 In this issue, Averhoff and colleagues present the results of a prospective, double-blind, randomized, clinical trial and concomitant decision analysis comparing the two licensed hepatitis B vaccines in HCWs. The results of this study confirm earlier findings regarding risk factors for nonresponse, mainly increasing age, chronic medical conditions, obesity, smoking, and male gender. In addition, the study found that one of the two available vaccines (Engerix-B) was more immunogenic among older ( 40 years of age) adults, and in a Mayo Vaccine Research Group, Clinical Pharmacology Unit, Mayo Clinic and Foundation, Rochester, Minnesota Address correspondence to Gregory A. Poland, MD, Chief, Mayo Vaccine Research Group, Clinical Pharmacology Unit, Mayo Clinic and Foundation, 611 C Guggenheim Building, 200 First Street, SW, Rochester, MN decision analysis model, found that 44 excess (0.34 per 100,000 person-years) chronic hepatitis B infections would result from the routine use of the less immunogenic MRL vaccine. Importantly, the overall seroconversion rate was 90% (SKB) versus 86% (MRL, P.03). This difference was confined only to recipients aged 40 years, with response rates of 87% (SKB) versus 81% (MRL, P.01), with GMCs of 1,000 miu/ml (SKB) versus 288 miu/ml (MRL, P.01). Hence, in persons aged 40 years, for every one nonresponder to SKB vaccine, there were 1.5 nonresponders to MRL vaccine. For nonresponders, 74% (56/74) of persons who received an additional 3 doses of SKB vaccine eventually responded, versus 62% (63/ 102) of nonresponders who received 3 additional doses of MRL vaccine (P NS). How should this data inform our clinical practice? First, we must ask whether the study was well designed was the study design appropriate, are the sample size and power appropriate, were the study subjects representative of all HCWs, and are there any obvious sources of error or bias? The study was carried out during December 1992 at three different sites in Louisiana. The determination of each subject s health and medical history was self-reported, raising issues of reliability and accuracy, although if anything, underreporting might be more likely. Subjects were randomized to one of two vaccines by a blocked, age-stratified ( 40 years of age and 40 years), randomization scheme. Both subjects and persons administering vaccine were blinded. Subjects received vaccine appropriately (in the deltoid muscle and on a 0, 1, 6 month schedule). Vaccine lot numbers were not reported, although single lots were used. The needle length used to administer vaccine was not reported and likely was not standardized within and between study sites. 16 This could influence antibody response, 17 and would have the effect of overestimating the true nonresponse rate, partly explaining the high rate (47%) of revaccination response among nonresponders after just one additional dose of vaccine. Postvaccination antibody testing was appropriately performed 1 month after the third dose of vaccine. Revaccination was offered to nonresponders, and antibody testing performed after one or three doses. Persons were classified as obese only if their body Am J Prev Med 1998;15(1) /98/$ American Journal of Preventive Medicine PII S (98)

2 mass index (BMI) exceeded the 95th percentile compared to the NHANES II reference population. This is problematic and may represent an overly lenient definition, given the general prevalence of obesity in the United States, particularly in the Southern U.S. states such as Louisiana. This would have the possible effect of biasing against finding a stronger relationship between obesity and nonresponse, and again may have resulted in the high nonresponse rates observed in the study. Thirty percent of these HCWs were smokers, a rate higher than most U.S. HCWs, 18 almost 15% reported having a chronic disease, and the mean age of subjects was 41 years. Hence, the available data suggest that the study group may have been biased toward factors that would lead to higher nonresponse rates than might be expected from a truly representative cross-section of all U.S. HCWs. Laboratory testing and thresholds as described were appropriate. Finally, the statistical analysis was appropriate, although the study s power to determine a difference in response rates among nonresponders exclusively receiving an additional 3-dose series of one or another of the vaccines was limited (type II error). Lastly, the results of the decision analysis suggested that exclusive use of the MRL vaccine among HCWs aged 40 years, would lead to an estimated excess lifetime risk of 44 chronic HBV infections and 8 cases of chronic liver disease. Despite the minor concerns above, the data from this paper are clear and helpful; there are persons with definable risk factors who are at risk for hepatitis B vaccine nonresponse, and this has particular relevance to HCWs. Readers should be aware of several clinically important issues related to hepatitis B vaccine immunogenicity. First, age appears to have a significant effect on vaccine-induced antibody levels, although the exact mechanism remains unclear. Among 20-year-old recipients, 95% seroconvert, compared to 86% for 40-yearolds, and 47% for persons 60 years. 13 Secondly, obesity, even with deltoid injection, also appears to significantly influence vaccine-induced antibody levels. 12,14,19 We have hypothesized that obesity per se may not be the cause of lower response rates, rather that inadequate needle length may be an important issue. 17 This derives from reports of suboptimal immunogenicity rates due to vaccine being administered into the gluteal fat pad by an inadequate, short needle We have reported deltoid fat pad thickness determined by high-resolution ultrasound scanning in HCWs at our institution, and correlated this with routinely obtained and easily available weight measurement. 17 This revealed that a 1-inch (25 mm) needle allowed sufficient penetration of deltoid muscle for the weight range of men studied (47 through 117 kg). A 5/8-inch (16 mm) needle was adequate for women weighing less than 60 kg, a 1-inch (25 mm) needle is recommended for women between 60 and 90 kg, and for those over 90 kg, a 1.5-inch (38 mm) needle should be considered. Thus, the standard 5/8-inch needle is inadequate for all but the thinnest female subjects. Thirdly, both males and smokers also have diminished antibody responses to hepatitis B vaccine. Again, the mechanism(s) behind these findings are unknown. 13 As a result of these nonresponse rates, the American College of Physician s (ACP) Task Force on Adult Immunization recommends that postvaccination serologic testing be performed in vaccine recipients who are 30 years of age and older, persons with risk factors for nonresponse, and those at high risk for hepatitis B exposure (sharps injury, blood and body fluid). The ACIP and the Hospital Infection Control Practices Advisory Committee also recommend postvaccination antibody testing in HCWs who have contact with patients or blood and are at risk for sharp injuries. Such postvaccine antibody testing should take place anywhere from 1 6 months after the last dose of vaccine [ACP] 5 or 1 2 months later [ACIP]. To aid those who must make decisions about HCWs who are at risk of nonresponse, or who appear to be nonresponders, Figures 1 and 2 are presented. This is the author s personal approach and in several instances involves judgments for which there are no definitive data. Figure 1 presents an approach to hepatitis B immunization of the HCW. For HCWs who are aged 40 years, the data of Averhoff et al. suggest a slight advantage to using the SKB vaccine formulation. This might also be a logical choice in other persons at high risk for nonresponse, such as those who are immunocompromised, smokers, and obese. In such persons, I attempt to measure anti-hbs antibody 4 12 weeks after the last dose of the series. Persons with antibody levels 10 miu/ml can be regarded as nonresponders, those 10 miu/ml but 100 miu/ml as hyporesponders, and those 100 miu/ml as responders. The latter two groups are protected against chronic disease due to hepatitis B infection. However, the hypo-responder group is at risk of being falsely labeled as a nonresponder if antibody testing occurs when waning may have occurred such that the anti-hbs is 10 miu/ml. Of interest is that a small percentage of subjects with anti-hbs antibody levels 10 miu/ml due to waning antibody, can develop asymptomatic hepatitis B infection and seroconversion after exposure, although no cases of chronic infection/disease have been reported. 20,21 Figure 2 presents an algorithm for dealing with apparent nonresponders. Since the majority of nonresponders are likely to be hypo-responders whose antibody level has waned with time to a level 10 miu/ml, the first step is to determine the time interval between anti-hbs sampling and the last dose of hepatitis B vaccine. If this exceeds 6 months, a single dose, with a recheck of anti-hbs level 4 12 weeks later is 74 American Journal of Preventive Medicine, Volume 15, Number 1

3 Figure 1. Algorithm for initial hepatitis B immunization in health care workers. appropriate. If the antibody level remains negative, and there are no risk factors for nonresponse, this dose may be considered the first dose of a second complete series (at the usual dosage to minimize costs), and the series is finished with a second dose 1 month and a third dose 6 months later, and the anti-hbs level again determined. For persons who remain nonresponders, or who otherwise have risk factors for nonresponse, use of a higher dose level (the so-called dialysis preparation ) seems appropriate, again with anti-hbs levels determined 4 12 weeks after the last dose of vaccine. In this latter scenario, the MRL vaccine offers the advantage of a single 40-mcg injection, rather than the two 20-mcg injections required by the SKB preparation. Persons who remain true nonresponders should be counseled regarding their lack of immunity to hepatitis B and the need to receive postexposure prophylaxis. Finally, the paper by Averhoff and colleagues incrementally adds to the database of information needed to guide rational immunization policy. The relatively high rates of nonresponse noted in this and other studies (711, 1,257, 1,336) are sufficient to warrant more anti-hbs testing than is currently being done among HCWs. HCWs who are obese, immunocompromised, at high risk of hepatitis B exposure, are over age 30, and who are smokers, should undergo anti-hbs testing after completion of the hepatitis B series. 5,6 Additionally, the data suggest the need for more immunogenic vaccines, particularly for older persons and those with conditions that diminish antibody response to the currently available vaccines. Despite the excellent vaccines now available, we should not be satisfied, but instead continue to advance the science by developing even more immunogenic vaccines that ideally require only 1 or 2 injections, Am J Prev Med 1998;15(1) 75

4 Figure 2. Algorithm for hepatitis B revaccination in known or suspected nonresponders. or perhaps a nonparenteral route of administration. 22 Such vaccines are being devised and tested. 23,24 The remaining question raised by this paper is whether there are significant differences in immunogenicity between the SKB and MRL vaccines. This paper and others suggest that there are indeed small differences in immunogenicity that are statistically significant, at least among persons aged 40 years. In part this may relate to the lower antigen content of the MRL vaccine (10 mcg versus 20 mcg in the SKB vaccine). For the vast majority of recipients, however, there is no evidence that these differences are clinically significant or meaningful. Averhoff and colleagues provide data suggesting that for the subset of persons at higher risk of nonresponse, or known nonresponders, one may want to consider the SKB vaccine. To date, I am unaware of any other data gathered in a prospective, blinded, randomized clinical trial that provide defini- 76 American Journal of Preventive Medicine, Volume 15, Number 1

5 tive direction in this regard. Regardless, all health care workers at risk of hepatitis B should have the benefit of hepatitis B vaccine, and for those at high risk of nonresponse, postvaccination determination of immunity and appropriate follow-up care are warranted. The author would like to acknowledge the critical review and helpful comments of Alan J. Wright, MD, and James J. Lipsky, MD. In addition, Dr. Poland receives research grant funding from Merck Research Laboratories and SmithKline Beecham Laboratories. References 1. Shapiro CN. Epidemiology of hepatitis B. Pediatr Infect Dis J 1993;12: Gibas A, Blewett DR, Schoenfield DA, Dienstag JL. Prevalence and incidence of viral hepatitis in health workers in the prehepatitis B vaccination era. Am J Epidemiol 1992;136: Centers for Disease Control. Update on adult immunization: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40: Mast EE, Alter MJ. Prevention of hepatitis B virus infection among health-care workers. In: Ellis RW, ed. Hepatitis B vaccines in clinical practice. New York: Marcel Dekker, Inc.; 1993: ACP Task Force on Adult Immunization, Infectious Diseases Society of America. Guide for Adult Immunization. 3rd ed. Philadelphia, PA: American College of Physicians; Center for Disease Control. Immunizations of health-care workers. MMWR 1997;46: Centers for Disease Control and Prevention. Suboptimal response to hepatitis B vaccine given by injection into the buttock. MMWR 1985;34: Lemon SM, Weber DJ. Immunogenicity of plasma-derived hepatitis B vaccine: relationship to site of injection and obesity. J Gen Intern Med 1986;11: Lindsay KL, Herbert DA, Gitnick GL. Hepatitis B vaccine: low postvaccination immunity in hospital personnel given gluteal injections. Hepatology 1985;5: Shaw FE, Jr., Guess HA, Roets JM, Mohr FE, Coleman PJ, Mandel EJ, et al. Effect of anatomic injection site, age and smoking on the immune response to hepatitis B vaccination. Vaccine 1989;7: Alper CA, Kruskall MS, Marcus-Bagley D, Craven DE, Katz AJ, Brink SJ, et al. Genetic prediction of nonresponse to hepatitis B vaccine. N Engl J Med 1989;321: Wood RC, MacDonald KL, White KE, Hedburg CW, Hanson M, Osterholm MT. Risk factors for lack of detectable antibody following hepatitis B vaccination of Minnesota health care workers. JAMA 1993;270: Hadler SC, Margolis HS. Hepatitis B immunization: vaccine types, efficacy, and indications for immunization. Curr Clin Top Infect Dis 1992;12: Anonymous. Risk factors for lacking detectable antibody following hepatitis B vaccination with recombinant vaccines in Minnesota health-care workers. Minn Dept Health Dis Cont Newsltr 1992;20: Roome AJ, Walsh SJ, Cartter ML, Hadler JL. Hepatitis B vaccine responsiveness in Connecticut public safety personnel. JAMA 1993;270: Poirier MK, Poland GA, Jacobson RM. Parameters potentially affecting interpretation of immunogenicity and efficacy data in vaccine trials: are they adequately reported? Vaccine 1996;14: Poland GA, Borrud A, Jacobson RM, McDermott K, Wollan PC, Brakke D, et al. Determination of deltoid fat pad thickness: implications for needle length in adult immunization. JAMA 1997;277: Nelson DE, Emont SL, Brackbill RM, Cameron LL, Peddicord J, Fiore MC. Cigarette smoking prevalence by occupation in the United States. J Occup Med 1994;36: Weber DJ, Rutala WA, Samsa GP, Santimaw JE, Lemon SM. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. JAMA 1985;254: Wainwright RB, McMahon BJ, Bulkow LR, Parkinson AJ, Harpster AP, Hadler SC. Duration of immunogenicity and efficacy of hepatitis B vaccine in a Yupik Eskimo population: preliminary results of an 8-year study. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral Hepatitis and Liver Disease. Baltimore, MD: Williams & Wilkins; 1991: Hadler SC, Coleman PJ, O Malley P, Judson FN, Altman N. Evaluation of long-term protection by hepatitis B vaccine for seven to nine years in homosexual men. In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease. Baltimore, MD: Williams & Wilkins; 1991: Hibberd PL, Rubin RH, Dienstag JL. Needs unfulfilled by current hepatitis B vaccines. In: Ellis RW, ed. Hepatitis B vaccines in clinical practice. New York: Marcel Dekker, Inc.; 1993: Ellis R, ed. Hepatitis B vaccines in clinical practice. New York: Marcel Dekker, Inc.; Poland GA, Heineman T, Clements ML, Van Nest G, Morand M, Izu A, Eiden J, Hsu HH. Enhanced immunogenicity of a hepatitis B vaccine using MF-59, a novel oil-in-water adjuvant. Gastroenterology 1997;112(suppl 4):A1361. Am J Prev Med 1998;15(1) 77