Elsevier

Vaccine

Volume 30, Issue 33, 13 July 2012, Pages 5009-5018
Vaccine

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

https://doi.org/10.1016/j.vaccine.2012.05.016Get rights and content

Abstract

Background

Hemodialysis patients have higher risk of mortality and morbidity when infected with 2009 pandemic H1N1 (pH1N1/09) virus. Depending on different methodologies and criteria, previous studies reported variable response rates to adjuvanted vaccines against pH1N1/09 virus in hemodialysis patients, however, the efficacy of non-adjuvanted vaccines, which are currently used in many countries such as the USA and Asian areas, has not been comprehensively evaluated in hemodialysis population before.

Methods

We evaluated the efficacy of a standard single15 μg-dose of non-adjuvanted monovalent pH1N1/09 vaccine (AdimFlu-S) in vaccine-naïve 110 hemodialysis and 173 healthy participants. When enrolling, all participants had not any clinical symptom or sign suggesting pH1N1/09 infection since the index case was identified in Taiwan. Sera from all participants were tested by hemagglutination inhibition (HI) and micro-neutralization-ELISA (microNT-ELISA) tests before and 21 days after vaccination. The outcome parameters were seroconversion rate (≥4-fold in HI titer with titer ≥1:40), seroprotection rate (HI titers ≥1:40), seroresponse rate (≥4-fold increase in HI or microNT-ELISA titer), fold of increase in geometric mean (GM) titers, and adverse effects.

Results

In method A analyses, we included all participants’ data in final analyses, and the seroconversion rates and the fold increase of GM titer after vaccination were 25.4% and 1.8 in adult (18–60-year olds) hemodialysis subgroup, and 23.4% and 1.8 in elder (>60-year olds) hemodialysis subgroup based on HI titers, which were all significantly lower than those of the corresponding healthy control subgroups. Similar trends were observed based on microNT-ELISA titers, further validating the results. Multivariable analysis revealed hemoglobin and cholesterol levels were significant predictors for seroresponse in hemodialysis patients, suggesting the possible impacts of nutrition status and anemia. In method B analyses, we excluded participants with pre-vaccination seroprotection (based on HI or microNT-ELISA criteria) in final analyses. The response rates in various subgroups from method B analyses were also similar as those from method A analyses. No severe adverse effect was noted.

Conclusions

According to the European and U.S. criteria, a single 15 μg-dose of non-adjuvanted pH1N1/09 vaccination is safe but ineffective in both adult and elder hemodialysis patients. Further studies using multiple doses or higher antigen amount are warrant to define the most appropriate regimen.

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).

References (43)

  • F.S. Dawood et al.

    Emergence of a novel swine-origin influenza A (H1N1) virus in humans

    N Engl J Med

    (2009)
  • M.E. Greenberg et al.

    Response to a monovalent 2009 influenza A (H1N1) vaccine

    N Engl J Med

    (2009)
  • T.W. Clark et al.

    Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine

    N Engl J Med

    (2009)
  • D. Marcelli et al.

    Influenza A(H1N1)v pandemic in the dialysis population: first wave results from an international survey

    Nephrol Dial Transplant

    (2009)
  • G. Temiz et al.

    Immune response after a single vaccination against 2009 influenza A H1N1 in hemodialysis patients

    Ren Fail

    (2010)
  • L. Labriola et al.

    Immunogenicity of an adjuvanted 2009 pandemic influenza A (H1N1) vaccine in haemodialysed patients

    Nephrol Dial Transplant

    (2011)
  • N.E. Broeders et al.

    Influenza A/H1N1 vaccine in patients treated by kidney transplant or dialysis: a cohort study

    Clin J Am Soc Nephrol

    (2011)
  • M. Crespo et al.

    Efficacy of influenza A H1N1/2009 vaccine in hemodialysis and kidney transplant patients

    Clin J Am Soc Nephrol

    (2011)
  • S. Beaudreuil et al.

    Efficacy and safety of the H1N1 monovalent vaccine in renal-transplant recipients and dialysis patients

    Hum Vaccin

    (2011)
  • N. Dunne et al.

    Anatomical failure following laparoscopic antireflux surgery (LARS): does it really matter?

    Ann R Coll Surg Engl

    (2010)
  • Summary of the European Public Assessment Report (EPAR) for Focetria....
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    These authors contributed equally to this work.

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