Survey about tolerance of the AS03-adjuvanted H1N1 influenza vaccine in children with rheumatic diseases
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- Sengler, C., Niewerth, M., Kallinich, T. et al. Clin Rheumatol (2014) 33: 137. doi:10.1007/s10067-013-2435-8
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The objective of this study is to evaluate complications and changes in health status (disease activity and flare) in response to the AS03-adjuvanted H1N1 vaccine in children with rheumatic diseases. We conducted a nationwide survey addressing paediatric rheumatology sites who participated in the national paediatric rheumatology database. Ninety patients were documented—38 % under treatment with biologicals—of whom 18 % suffered from complications (10 % local and 8 % systemic) with no relevant changes in median disease activity or flare rate during 4 weeks following the vaccination. The adjuvanted H1N1 influenza vaccine seems to be adequately tolerated in children with rheumatic diseases.
KeywordsChildrenDisease activityFlareH1N1 influenza vaccinationRheumatic disease
In the context of a pandemic situation, 2009/2010 authorities recommended to vaccinate adults and children with chronic diseases against the new H1N1 influenza (“swine flu”) who are at risk to suffer from a severe course of the influenza infection . The only available pandemic influenza vaccine in Germany contained the adjuvant AS03, which had not been regularly used in children. Furthermore, since adjuvants are used in vaccines to fortify the immune response to the relevant antigen, it has been speculated that they might also trigger undesirable immune reactions like induction of autoantibodies or triggering flares of pre-existing autoimmune diseases. Therefore, it was controversially discussed if children with autoimmune disorders should receive this pandemic vaccine.
We conducted a concise nationwide survey about reactions towards the vaccine and whether changes in health status could be seen and coincided with the vaccination in a group of children with rheumatic diseases.
From November 2009 until February 2010, paediatric rheumatologists, who participated in the national paediatric rheumatology database, were contacted and asked to document the following items on a questionnaire during a regular visit of their patients: date(s) of influenza vaccination, complications of vaccination and disease activity before and after vaccination in addition to diagnosis and current drug treatment. A complication was defined as health impairment clearly in excess of the common extent of a vaccine-associated reaction (according to the definition by the Paul-Ehrlich-Institut, Langen, Germany). This includes a local reaction like redness, swelling or pain at the injection site for more than 3 days or a systemic reaction like fever >39.5 °C, severe headache, pain in the extremities or lymph node swelling. The disease activity was rated by the treating physician before and after the influenza vaccination by a numeric rating scale (NRS, 0, none; 10, most severe). A disease flare was defined as a clinically relevant increase of disease activity judged by the treating physician. The SPSS version 18.0.1 (SPSS for Windows, Rel. 18.0.1. 2009. Chicago: SPSS Inc.) was used for all analyses.
Patients' characteristics and diagnoses
Cases, n (%)
Female, n (%)
Age in years at post-vaccination visit, median (IQR)
Juvenile idiopathic arthritis, n (%)
Systemic lupus erythematosus
Mixed connective tissue disease
Local complications were seen in 10 % and systemic complications in 8 % of the vaccinated patients. During a median follow-up of 4 weeks, no difference in disease activity before (median 1 on NRS) and after (median 1 on NRS) H1N1 influenza vaccination was seen.
Four patients (4.4 %) sustained a flare in a period of 2 to 5 weeks (median 3 weeks) after the vaccination. Diagnoses of these patients were extended oligoarthritis, rheumatoid factor (RF)-negative polyarthritis, RF-positive polyarthritis, and persistent oligoarthritis. Three of them were treated with TNF-alpha antagonists and two of them additionally with low-dose glucocorticoids. The patient with persistent oligoarthritis was off therapy.
The national committee for vaccination in Germany recommends the yearly influenza vaccination for all chronically ill or immunologically compromised children and adults . It has been shown that children with chronic rheumatic diseases responded to influenza vaccination despite immunosuppressive therapy with serum antibody titers similar to those in controls [2–4] so that vaccination is supposed to be an effective measure to prevent a potentially severe wild-virus disease in these patients.
Another issue in the context of (auto)immune-mediated disease is the concern about triggering a flare with the vaccination. Several studies showed that the risk of disease flare, increased disease activity or serious adverse events after immunisation with various vaccines including influenza in children with autoimmune disease is low [2–6]. Recently, a study in JIA patients was published demonstrating that the adjuvant-free influenza A H1N1/2009 vaccine was effective with adequate immunogenicity with no short-term harmful effect on the disease itself .
In Europe, a new formula of influenza vaccine was introduced containing the adjuvant AS03 to increase the immune response and to induce a better cross-protection against possibly upcoming drift variants of the H1N1 influenza virus. This adjuvant has not yet widely been used in vaccines, so concern was raised about a possibly increased rate of adverse effects of such vaccine formulation. Roman et al. conducted an observer-blind, randomised trial on the immunogenicity and safety of one dose of influenza A H1N1v2009 vaccine formulated with and without AS03A adjuvant in adults and concluded that both vaccines were well tolerated with similar adverse event profiles though solicited injection site, and general symptoms were reported more frequently for the AS03A-adjuvanted vaccine . In an open-label randomised, multicenter study comparing the safety and immunogenicity of AS03B-adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in healthy children, Waddington et al. demonstrated that the adjuvanted split virion vaccine was more reactogenic with more frequent severe local (13 %) and systemic (5 %) reactions . In about the same range, we saw local and systemic complications to the adjuvanted H1N1 influenza vaccine in children with rheumatic diseases in our survey.
Since adjuvants stimulate the immune response non-specifically, there was an even greater concern that this vaccine might initiate autoimmune processes or—in already diseased persons—disease flares could be triggered. Gabay et al. could show in his study with the AS03-adjuvanted pandemic influenza vaccine in adult patients with inflammatory rheumatic diseases that this vaccination did not enhance the underlying disease activity during the subsequent at least 4 weeks in any disease group and the rate of disease exacerbation did not differ from the expected . Dell'Era et al. analysed effects of MF59-adjuvanted seasonal influenza vaccine in children with juvenile idiopathic arthritis and found that safety and tolerability were good and that this vaccination was not associated with any deterioration of markers of disease activity .
The reports in our survey showed that disease activity did not increase after vaccination with the AS03-adjuvanted H1N1 influenza vaccine during the median follow-up of 4 weeks. The flare rate was 4.4 % which is within the same range as reported in the general JIA population (4.8 %/month ).
The herein presented observations were based on spontaneous reports. Presumably, severe reactions and flares after vaccination were reported more likely so that the rate of complications and disease flares is rather over- than underestimated. Due to the low numbers of documented patients, we cannot comment on a specific diagnosis or therapy as a risk factor for vaccine complications.
To our knowledge, this is the first report about data regarding an AS03-adjuvanted vaccine in children with rheumatic diseases. Our results are reassuring since neither disease activity nor flare rate increased in our study population in response to the AS03-adjuvanted H1N1 influenza vaccine.
We would like to thank all the physicians who have contributed to the survey: Dr. B Rogalski (Bensheim); PD; Dr. K Gerhold (Berlin); Dr. HE Kössel (Brandenburg); F Weller; Dr. N Onken (Bremen); Prof. Dr. M Kirschstein (Celle); Dr. C Böschow (Cottbus); Dr. R Häfner; Dr. S Frohnmayer (Garmisch-Partenkirchen); Dr. T Müller (Halle); Prof. Dr. M Borte (Leipzig); PD; Dr. W Mannhardt-Laakmann (Mainz); Dr. E Miller-Wiegard (München); Dr. C Mokroß (Oldenburg); Prof. Dr. G Horneff (St. Augustin); and Dr. T Schwarz (Würzburg).
K. Minden received an unconditional research grant from Pfizer and AbbVie and honoraria from Pfizer, Roche, AbbVie, Medac and Novartis. H.-I. Huppertz is a member of the Advisory Board for Abbott, Pfizer, Roche and Swedish Orphan and received honoraria from Pfizer, Roche, GlaxoSmithKline and Sanofi-Pasteur.