Poor immune response to a standard single dose non-adjuvanted vaccination against 2009 pandemic H1N1 influenza virus A in the adult and elder hemodialysis patients
Highlights
► We studied the efficacy of non-adjuvanted pH1N1/09 vaccination in dialysis patients. ► A standard single dose vaccination elicits good response rates in healthy population. ► The standard dose non-adjuvanted vaccination is ineffective in hemodialysis patients. ► Nutrition status and anemia may affect the response rates in hemodialysis patients. ► Higher dose or repeated vaccinations should be considered in hemodialysis population.
Introduction
Although influenza caused by 2009 pandemic H1N1 (pH1N1/09) virus has moved into post-pandemic period, the World Health Organization (WHO) still warned the pH1N1/09 virus might circulate for the coming years [1], [2]. Vaccination against pH1N1/09 virus is the primary method to prevent this infection, and both adjuvanted and non-adjuvanted pH1N1/09 vaccines with various amounts of antigen are demonstrated to induce adequate antibody responses in the general population [3], [4], [5], [6].
Dialysis patients infected with pH1N1/09 virus had higher hospitalization rate and mortality than the general population [7]. In hemodialysis patients, a single 3.75 μg- or 7.5 μg-dose adjuvanted vaccine against pH1N1/09 virus was reported to elicit 30–90% response rates, depending on different assay methods and arbitrary definitions of positive responses [8], [9], [10], [11], [12], [13]. However, because of small case number and/or not complying with the European and U.S. standard criteria in these studies, the efficacy of adjuvanted pH1N1/09 vaccination in hemodialysis population is still debatable. Furthermore, since the use of adjuvanted vaccine may have raised concerns for additional safety risks [14], and more data are needed to conclude adjuvants can reduce the amount of antigen needed [14], adjuvanted vaccines are not currently approved by many countries, such as the USA, Japan and Taiwan. To our knowledge, the adjuvanted pH1N1/09 vaccines, such as Focetria (Novartis), Arepanrix (GlaxoSmithKline), etc., were approved by the European Commission throughout the European Union [15], and Health Canada [16]. Since, November 2009, Taiwan has begun administering a single 15 μg-dose of monovalent, non-adjuvanted, inactivated split-virion pH1N1/09 vaccine to the citizens, including dialysis patients. More than 15 million doses have been administered until August 2010, during this vaccine campaign. Nevertheless, the efficacy of the standard single 15 μg-dose non-adjuvanted vaccines against pH1N1/09 virus has not been comprehensively evaluated in hemodialysis patients before. It is a critical issue because the non-adjuvanted vaccines containing 15 μg-dose of antigen of pH1N1/09 virus in the form of monovalent or trivalent seasonal influenza vaccines have been or will be injected to hemodialysis patients without data to prove their effectiveness.
In this study, we aimed to investigate the immunogenicity and the potential factors affecting the immune response to the standard single 15 μg-dose of non-adjuvanted pH1N1/09 vaccine according to the European [17] and U.S. standard criteria [18] for influenza vaccines (defined the response rates by standard hemagglutination inhibition (HI) tests, and further confirmed by microneutralization-enzyme-linked immunosorbent assay [microNT-ELISA]) in vaccine-naive hemodialysis patients.
Section snippets
Study population
All hemodialysis patients (305 pH1N1/09 vaccine-naive patients) in Kuo General Hospital, Tainan, Taiwan were screening, and we excluded patients with fever (temperature >38 °C)/flu-like symptoms since index case having pH1N1/09 virus infection was identified in Taiwan, history of allergy to vaccines or eggs, dialysis therapy less than 3 months, age less than 18 years old, taking immunosuppressive agents within 3 months, receiving any blood products including immunoglobulin in the prior 3 months,
Results
There were 250 eligible hemodialysis patients after screening, and 135 patients refused to participate. There was no significant difference in the baseline clinical characteristics (age, gender, comorbidity, etc.) of the patients who accepted versus declined to participate (data not shown). We enrolled 115 hemodialysis patients, but the sera were unexpectedly lost in 5 patients. Therefore, 110 hemodialysis patients and 173 healthy individuals were included in the statistical analyses.
Discussions
The standard HI criteria for an effective influenza vaccination from European and the USA [17], [18] require seroprotection rate >70%, seroconversion rate >40%, and fold increase of GM titer >2.5 in adult subjects 3 weeks after vaccination; while seroprotection rate> 60%, seroconversion rate >30%, and fold increase of GM titer >2.0 in the elder subjects. Furthermore, the U.S. acceptance criteria also demand the lower limit of the 95% confidence interval (CI) for seroconversion to be ≥40% for
Author contributions
As a first process, Chang YT and Sung JM designed research together with Wang JR but the duo have written the complete draft. Sung JM was instrumental in endeavoring the data analysis with the team of Chang YT, Guo CY, Tsai MS, Lin MD, and Wang JR. More over, Sung JM together with Chang YT, Guo CY, Cheng YY, and Wang JR had analyzed the data. In between, Chen CC and Shen D performed the clinical trial in healthy participants and collected the sera as the controls in this study.
Acknowledgements
Support: This work was partially supported by grants of NCKUH-10002004 to Chang YT and NCKUH-9903017 to Sung JM from National Cheng-Kung University, Tainan, Taiwan, ROC.
Financial disclosure: Shen D and Chen CH are employees of Adimmune Corporation, Taipei, Taiwan. No financial disclosure for other authors (Chang YT, Guo CY, Tsai MS, Cheng YY, Lin MT, Wang JR, and Sung JM).
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These authors contributed equally to this work.