Our prospective observational cohort study investigated the seroconversion rate to monovalent adjuvanted H1N1 inactivated influenza vaccine in clinically stable HD patients. The rate of seroconversion was 30.9% for all HD patients. It is even lower than the previously reported seroconversion rate for Korean diabetic patients by our group and much lower than the one reported for normal controls (68.1 ~ 84.4%) using the same vaccine [2, 5]. The reported seroconversion rate after influenza A/H1N1 vaccination is quite variable, from 33.3% to 64.2%, with contrasting results [6, 7]. Compared with the healthy controls, HD patients have a lower seroconversion rate and an inability to maintain adequate antibody titers over time [8–10]. The mechanism of uremia-associated hyporesponsiveness to vaccination is still incompletely understood.
Over the past decade, a large number of studies have shown that a variety of vaccines are less efficient in elderly persons . A clear association between older age and poor immune response to HBV vaccine was shown in recent meta-analysis in ESRD patients . Similarly, other studies showed that age significantly affected immune response to influenza A (H1N1) vaccine in general population [13, 14]. Goodwin et al. reported that after adjusting for vaccine and host factors, vaccine response in the elderly was approximately 1/4 as rigorous for H1 and B antigens and about 1/2 as rigorous for H3 antigens, compared to the antibody response in younger adults . The seroconversion rate of the elderly patients in the present study was no more than 20.5%. In the multivariate logistic regression analysis, age over 65 years was a significant risk factor for hyporesponsiveness to influenza vaccine. The mechanisms for age related change in the antibody response are not fully understood, however, memory CD4+ T cell impairment and imbalance in the production of Th1 and Th2 cytokines are considered to be related with the lower antibody response [16, 17].
In contrast, there are some studies that did not observe “age factors” influencing antibody response to influenza vaccines [18, 19]. The discrepancies in the different studies’ results may be explained by differences in types of vaccines used, use of adjuvants, host immune factors, and previous vaccinations .
A recent large cohort trial (n = 355) employing one dose schedule of pandemic H1N1 vaccine demonstrated encouraging immunogenic profile in both adults and elderly age-group . While it is still controversial, two doses of a pandemic vaccine to elicit an improved protective immune response has been recommended in high risk immunocompromised patients [21–23]. Our vaccination protocol consisted of one dose of intramuscular injection of monovalent adjuvanted (MF59C1) H1N1 inactivated influenza vaccine. The vaccine used in our trial fulfilled all international licensing criteria in both the adult and elderly age-groups [24, 25]. However, it elicited lower immune response in elderly age-group (over 65 years of age) compared to those of younger adults (37.4 ~ 53.5% vs. 68.1 ~ 84.4%, respectively). This immune response was significantly improved after a second dose of vaccine administration (76 ~ 91%) . Therefore, it may be prudent to measure baseline and post-vaccination protective antibody titers against the pandemic H1N1strain in high risk patients. Our results provide alarming information on low immune response to pandemic influenza vaccination in elderly HD patients and further clinical trials administering second or booster doses to improve seroconversion rates in high risk patients may be warranted.
In contrast to other studies [7, 10, 26], hemoglobin level less than 10 g/dL was a significant risk factor for impaired seroconversion in the present study. The relationship between anemia and poor antibody responsiveness after vaccination is an open question. However, anemia is commonly associated with inflammation and nutritional status of HD patients . There are several studies that reported inflammation and nutritional status as important risk factors of the hypo-responsiveness after vaccination. Fulop et al. observed that non-response group after influenza vaccination in the elderly patients had lower nutritional parameters such as hemoglobin, total protein, iron, vitamin E, and DHEA . Recent research by Chang et al. also suggested that hemoglobin level is a significant predictor for seroresponse and seroconversion in HD patients . Our study did not have enough power to assess the influence of inflammatory or nutritional parameters on seroconversion. However, considering these relationship, we suggest that anemia may be a risk factor for hypo-responsiveness after vaccination. Furthermore, when the patients were divided into 4 groups by hemoglobin level and age, Group 4 (Hb < 10 g/dL and Age ≥ 65 years) had a significant lower seroconversion rate and odds ratio for seroconversion compared with Group 1 (Hb ≥ 10 g/dL and Age < 65 years). Group 2 and 3 did not differ from the reference Group 1. These results show that combined age and anemia, defined as hemoglobin level less than 10 g/dL, are significant additional risk factors for seroconversion after influenza vaccination.
Other factors influencing seroconversion have been investigated in several trials but no definite common factor has been identified. Some investigators reported that very high ferritin levels may suppress antibody production following influenza vaccination in HD patients , but our results and other investigators have not found any definite association between iron status and seroconversion rate.
Recently, a weaker immune response to non-adjuvanted 2009 influenza A (H1N1) vaccine (Panenza®; Sanofi Pasteur, France) was reported in HD patients dialyzed twice a week whereas other HD patients undergoing dialysis 3 times a week showed comparable immune response to healthy controls .However, their results should be interpreted with caution as half of the study participants were underdialyzed and non-adjuvanted vaccine was used for vaccination. All of our patients underwent hemodialysis treatment 3 times a week and the achieved dialysis dose and time on dialysis were comparable between responders and non-responders. Moreover, most of other studies evaluating the efficacy of influenza A H1N1/2009 vaccine using adjuvanted vaccine have shown that dialysis dose or degree of uremia does not influence seroconversion [6, 7].
Compared to non-diabetic patients, diabetic patients had an impaired immune response to influenza vaccination . In our previous study on diabetic patients, only 48.6% of patients achieved seroconversion after a single-dose adjuvanted, inactivated, pandemic H1N1 influenza vaccination . The hemodialysis patients in the present study, however, did not show significant effect of DM on the seroconversion rate. Furthermore, subgroup analysis according to age and gender showed no significant effect of DM on seroconversion (data not shown). This observed discrepancy may be explained by several causes. First, age of our seroresponders in diabetic patients was younger compared to that of nonresponders (57.5 ± 11.1 vs. 65.1 ± 11.5 years, p = 0.021). Advanced age negatively affects the seroconvesion rate regardless of the patient’s status [12, 31]. Second, uremic milieu per se is commonly believed to be the cause of poor seroconversion in ESRD patients. Our results are in accord with recent study from Taiwan, which reported no significant differences between DM and non-DM HD patients . Another possible explanation might be the seroconversion rate of our patients was very low (30.8%) and could have undermined the effect of DM. Non-diabetic HD patients had a similarly poor seroconversion rate as their diabetic counterparts, suggesting that state of uremia per se is associated with substantial immunodeficiency.
There are several limitations in this study. First, healthy controls were not included in the study. Therefore, we could not compare the seroconversion rate between HD patients and healthy controls. However, the seroconversion rate for healthy Korean individuals using the same adjuvanted vaccine is 68.1%, clearly greater than our HD patients. Second, the number of patients is small and previous vaccination history was not surveyed. Nevertheless, the efficacy of influenza vaccination in the present study is relatively consistent with other studies . Third, long-term immunogenicity of influenza vaccination was not investigated in our study. Short term immune responses to influenza vaccination have been well studied but long-term immune response in HD patients are lacking. Long-term immunogenicity results would be more helpful in directing immunization schedule for these high risk patients.
In conclusion, we found that administration of a single dose adjuvanted monovalent H1N1 inactivated influenza vaccine induced relatively a poor immune response in HD patients. In particular the elderly HD patients with lower hemoglobin levels are at much increased risk. Further trials with larger number of patients and different vaccination schedules employing different vaccine doses or boosters are warranted.