Sex: U
Vaccine: HEP
Symptoms: Hepatitis B surface antibody negative, Hepatitis B surface antigen negative, No therapeutic response
Clinical narrative: This case as obtained from a literature report refers to a retrospective cohort study. The objectives of this study were to quantify the incidence of hepatitis B virus (HBV) vaccine nonresponse and identify clinical characteristics associated with vaccine nonresponse. Approval from the institutional review board was obtained before initiating the study. All of the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. A waiver of informed consent was obtained from the institutional review board for all of the patients in this study. A retrospective cohort study was performed between January 2011 and April 2012. Study inclusion criteria were age 18 years and older at initial vaccination, receipt of Hemodialysis (HD) treatment for above or equal to 1 month, receipt of above or equal to 1 dose of HBV vaccine as a patient undergoing HD, availability of anti-HBs laboratory values above or equal to 2 weeks after last HBV vaccine, and pre-vaccine anti-HBs value <10 mIU/mL, Patients with a history of HBV infection or current HBV infection were not eligible for inclusion. Data were extracted from the patient's medical records by a trained reviewer using a standardized data collection instrument. Data elements included demographics, comorbidities, concomitant medications, vaccination history after beginning HD treatment and laboratory values. Demographic characteristics included age at first vaccine administration, race, sex, height and weight. Body mass was also computed. Data elements related to the patient's medical history were the year that chronic HD treatment was initiated, primary cause for renal failure and corresponding International Classification of Diseases, 9th Revision, Clinical Modification codes, history of cancer, cancer status at the time of HBV vaccination, history of organ transplant, and history of immunosuppressant drugs. Use of immunosuppressant agents was restricted to tacrolimus, sirolimus, cyclosporine, mycophenolate, and azathioprine. In addition, the use of >20 mg/day of prednisone for 14 days or an equivalent dose of other corticosteroids was collected. The list of comorbidities was recorded and the total number of comorbid conditions was tallied. Abstracted medication data included the medication name, dose, frequency, start date, and end date. Vaccination history after beginning HD treatment included vaccine type, dates of administration, dose, and route of administration. The number of vaccine doses was collected as a continuous variable. The distribution of this variable was evaluated and categorized as <3 doses, 3 doses, and >3 doses because of no significant intracategory heterogeneity. Laboratory values were collected, including anti-hepatitis B surface antibodies (HBs) and hepatitis B surface antigen (HBsAg). These laboratory values were collected, including anti-hepatitis B surface antibodies (HBs) and hepatitis B surface antigen (HBsAg). These laboratory values were collected starting with one value before the first receipt of the HBV vaccine until the end of the data collection period. Nonresponse was defined as an anti-HBs value <10 mIU/mL. To assess anti-HBs as a continuous variable, anti-HBs values documented as <10 mIU/mL were imputed as a value of 9. Similarly, anti-HBs values documented in the patient's medical record >150 mIU/mL were imputed as a value of 151 mIU/mL. The mean (standard deviation (SD)) age of the patients at the time of first HBV vaccination was 62.9 (15.5) years. There were 56 patients (47%) who were partially vaccinated and had received fewer than 3 doses of the HBV vaccine. The incidence of vaccine nonresponse was 58% during the study period. There were 69 vaccine non-responders. There were no patients with HBsAg positivity, indicating that no new HBV infections were observed. The mean (SD) age at first vaccination was higher among vaccine non-responders than responders (65.9 (14.1) years vs 58.8 (6.5) years, respectively; P=0.01). The classification and regression tree (CART) identified age breakpoint was 58 years and older; in other words, age 58 years and older was more frequent among vaccine non-responders than vaccine responders. Interestingly, mean age at initiation of HD was also higher for vaccine non-responders than responders. Although the mean (SD) weight of vaccine responders and non-responders appeared to be similar, higher weight was more frequent among vaccine non-responders than responders. The CART-derived breakpoint for weight was >115kg. Similarly, body mass index was above or equal to 36.5 kg/m2 was more frequently observed among vaccine non-responders than responders. Most characteristics related to vaccine administration were similar for vaccine responders and non-responders. No statistically significant differences were observed in percentages of responders and non-responders who received the full three-dose series. In addition, 17 patients received supplemental vaccinations. No differences were observed between vaccine responders and non-responders with respect to the frequency and number of supplemental vaccinations administered. Dialysis vintage was significantly longer for responders than non-responders. The median (interquartile range (IQR)) time between the date of the last vaccination and the date of obtaining anti-HBs values post vaccination was significantly longer for vaccine non-responders than responders, 287 (171-327) days versus 143 (56-304) days, respectively. Among the 50 patients who responded to the vaccine, the median (IQR) duration of vaccine response was 358 (248-443) days. There were 13 (26%) initial vaccine responders who did not retain HBV protection and subsequently had anti-HBs titers <10 mIU/mL. The majority of clinical characteristics did not significantly differ between patients whose titers declined and those who retained their immune response. Mean (SD) body weight, however, was higher among patients whose immune response declined compared with those with anti-HBs titers above 10 mIU/mL (84.4 [15.5] kg vs 73.3 [15.7] kg, P = 0.03, respectively). The CART-derived breakpoint for the relation between body weight and loss of immune response was above or equal to 92.5 kg; a body weight in excess of this breakpoint was more common among patients whose immune response became undetectable relative to those whose remained >10 mIU/mL (46.2% vs 10.8%, P = 0.01, respectively). Similarly, the mean (SD) BMI was higher among patients with lost vaccine response compared with those who maintained protective levels of anti-HBs titers (29.0 [4.6] kg/m2 vs 25.5 [5.5] kg/m2, P = 0.05 respectively). A CART-derived breakpoint of above or equal to 25 kg/m2 BMI was more frequently observed among patients whose immunity declined compared with those who maintained an immune response (76.9% vs 43.2%, P=0.05, respectively). The median (IQR) duration of vaccine response also varied as a function of BMI. In this study, the vaccine preparation was uniform and all of the patients were administered the dialysis formulation of RECOMBIVAX HB by intramuscular injection; therefore, the heterogeneity of vaccine preparations was not an issue. This case refers to a 69 patients who were a part of the above mentioned retrospective cohort study. Mean age 54 years, mean age at first vaccination was 65.9 years, gender male 34 (49.3%), mean weight was 82.7 kg (two patients were 115kg or above), mean BMI was 29.0 (14 patients were of BMI 36.4 or above). The patients were vaccinated with RECOMBIVAX HB, intramuscular, (unknown strength, dose). Nonresponse was defined as an anti-HBs value <10mIU/mL. Total of 69 patients (58%) were identified as non-responders during the study. The outcome of the event was unknown. The author considered the events to be related to suspect therapy. Conclusions Overall, the frequency of nonresponse to the HBV vaccine was high among patients undergoing HD. The two covariants most predictive of vaccine nonresponse were advanced age at the time of vaccination and high BMI, the latter of which also predicted which patients were likely to maintain immunity. Until newer vaccine formations are able to improve response and retention by exploiting alternative immunogenic sites, future research should carefully examine the relation between body size and vaccine response to inform vaccination strategies targeting younger patients receiving HD and those who may soon require HD with current vaccine formulations. Use of higher doses of vaccine, more doses, longer needles, and alternative schedules are some of the novel vaccine dosing/administration strategies that could be evaluated to determine whether the probability of achieving anti-HBs values above 10 IU/mL can be improved. Additional information has been requested.