ClinicalTrials.gov identifier: NCT01006681.
Vaccination Against HINI Among Patients with Rheumatic Diseases
Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus among patients with rheumatic diseases†
Version of Record online: 29 JUN 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis Care & Research
Volume 63, Issue 7, pages 1062–1067, July 2011
How to Cite
Elkayam, O., Amir, S., Mendelson, E., Schwaber, M., Grotto, I., Wollman, J., Arad, U., Brill, A., Paran, D., Levartovsky, D., Wigler, I., Caspi, D. and Mandelboim, M. (2011), Efficacy and safety of vaccination against pandemic 2009 influenza A (H1N1) virus among patients with rheumatic diseases. Arthritis Care Res, 63: 1062–1067. doi: 10.1002/acr.20465
- Issue online: 29 JUN 2011
- Version of Record online: 29 JUN 2011
- Accepted manuscript online: 18 MAR 2011 12:15PM EST
- Manuscript Accepted: 28 FEB 2011
- Manuscript Received: 27 OCT 2010
To assess the efficacy and safety of vaccination against pandemic H1N1 virus in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) compared with healthy controls.
The study population comprised 41 RA patients, 21 SLE patients, 17 PsA patients, 15 AS patients, and 25 healthy controls. All were vaccinated using the Novartis MF59-adjuvanted H1N1v monovalent influenza vaccine. The immunogenicity of the vaccine was assessed on day 1 and again 4 weeks later by hemagglutination inhibition assay. Geometric mean titers and seroconversion rates were calculated for each group. The safety of the vaccine was evaluated using the 28-joint Disease Activity Score (DAS28) for RA and PsA, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).
The proportion of baseline protective levels of antibodies against H1N1 was similar in all but the AS group, in which it was lower. The geometric mean titers increased significantly in all 5 groups. A substantial proportion of patients and controls responded to the vaccine. The healthy controls demonstrated a better response than each of the other groups: 84% versus 56% for RA, 67% for SLE, 59% for PsA, and 53% for AS. Multivariate logistic regression analysis identified RA and PsA as parameters of significantly lower response. The DAS28, BASDAI, and SLEDAI remained unchanged after vaccination.
Vaccination against pandemic H1N1 using an adjuvanted H1N1v monovalent influenza is safe and induced an appropriate response in patients with RA, SLE, PsA, and AS.
In the spring of 2009, a new swine-origin influenza virus A (H1N1) emerged in Mexico and quickly spread worldwide through human-to-human transmission, prompting the World Health Organization (WHO) to raise the pandemic alert to level 6 (1, 2). The virus spread rapidly throughout the world, affecting mainly children and young populations (1). Since March 2009, hundreds of thousands of cases of A/H1N1 influenza have been confirmed worldwide. The presence of the virus was confirmed in most countries of the world. As of February 2010, throughout the world 1,538,439 people had the disease and 16,836 died from disease complications. The first cases of H1N1 were reported in Israel in April 2009. Since then, 10,267 subjects were confirmed as patients, although, as decided by the WHO to minimize diagnostic testing, the estimate is much higher. Ninety died from disease complications; serious illness cases that required hospitalization in intensive care increased, mostly among high-risk groups (http://www.health.gov.il/h1n1/world.asp).
The spectrum of clinical presentation varied from asymptomatic cases to primary viral pneumonia that resulted in respiratory failure, acute respiratory distress, multiorgan failure, and death (3). The majority of severe pandemic 2009 H1N1 cases were associated with underlying medical conditions, including obesity, pregnancy, and cardiovascular diseases (4). In South Africa, respiratory failure secondary to swine-origin influenza A (H1N1) was associated with human immunodeficiency virus (HIV), immunosuppressive drugs, and tuberculosis (5). The severity of the condition in some patients and the high rate of infectivity of the virus led to the development of pandemic H1N1 influenza vaccines, which were launched by the end of 2009 (6).
Infection is one of the leading causes of morbidity and mortality in patients with rheumatic diseases (7, 8). This propensity to infections is due to the impaired immune system inherent to the disease itself or secondary to the use of immunosuppressive drugs, including biologic agents (9). Seasonal influenza vaccination is recommended in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) (10), and has been found to be safe and to induce a satisfactory humoral response, although lower than that measured in healthy controls (11, 12). The purpose of this study was to assess the efficacy and safety of vaccination against pandemic H1N1 in a large population of patients with 4 rheumatic diseases.
Significance & Innovations
The rapid spread of pandemic H1N1 influenza prompted the development of adjuvanted vaccines.
The efficacy and safety of these vaccines have been evaluated in immunocompetent populations but not in immunosuppressed patients with rheumatic diseases.
We herewith evaluate the safety of the vaccine in terms of its effect on the autoimmune disease as well as the immunogenicity of a single shot of vaccine.
PATIENTS AND METHODS
Five groups of subjects participated in this study. All of the patients were consecutive outpatients routinely treated at the Department of Rheumatology of the Tel Aviv Medical Center. Group 1 included 41 patients diagnosed as having RA according to the American College of Rheumatology (ACR) criteria for RA (13), group 2 included 21 patients diagnosed as having SLE according to the ACR criteria for SLE (14), group 3 included 17 patients diagnosed as having psoriatic arthritis (PsA) according to the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria (15), group 4 included 15 patients diagnosed as having ankylosing spondylitis (AS) according to the modified New York criteria (16), and group 5 included 25 healthy hospital personnel matched for age and sex to groups 2, 3, and 4.
The H1N1v vaccine was the Novartis MF59-adjuvanted H1N1v monovalent influenza vaccine, Focetria. Each 0.5-ml dose contains 7.5 μg of H1N1 hemagglutination antigen and the full dose of the oil-in-water emulsion adjuvant, MF59 (Novartis Vaccines).
The study was approved by the ethics committee of the medical center. Appropriate informed consent was obtained from all patients, and the clinical research was conducted in accordance with guidelines for human experimentation specified by the Tel Aviv Sourasky Medical Center. All subjects received 1 dose of Focetria by intramuscular injection in the deltoid and were vaccinated in the period between November 2009 and January 2010. Exclusion criteria were pregnancy, a history of vaccination allergy, a known allergy to egg products, hyposplenism, active disease necessitating a recent change in drug regimen, and treatment with rituximab. Patients were evaluated clinically, and blood was drawn for serologic testing on the day of vaccination and 4–6 weeks later.
Each subject gave a complete history, including the use of medications, and underwent a physical examination before receiving the vaccination. Baseline and a 4–6-week clinical assessment of disease activity included erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels for all participants, the 28-joint Disease Activity Score (DAS28) (17) for the RA and PsA patients, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) for the SLE patients (18), and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (19) for the AS patients.
Immunogenicity of the vaccine.
The immunogenicity of the vaccine was tested by the hemagglutination inhibition (HI) test. The pre- and postimmunization HI antibodies were tested at the Central Virology Laboratory of the Israeli Ministry of Health using the HI test according to a standard WHO procedure (20). Sera were separated, code labeled, and stored at −20°C until tested. They were treated with receptor-destroying enzyme cholera filtrate to remove nonspecific inhibitors, and with turkey red blood cells to remove nonspecific agglutinins. The treated sera were tested by an HI test against the A/California/7/2009 (H1N1v) antigen. The working dilution (test dose) of each antigen contained 4 hemagglutination units in 25 μl of antigen. Test doses were diluted in phosphate buffered saline and added to the serial dilution of the antiserum. The HI titer was determined as the highest dilution of serum that completely inhibited hemagglutination of red blood cells. The titer of an antiserum that did not show any inhibition was recorded as <1/10. Humoral response was defined as a 4-fold or greater rise in titer, or as a rise from a nonprotective baseline level of <1/40 to ≥1/40 in HI antibodies 4 weeks after vaccination (21, 22). Geometric mean titers of antibodies were calculated to assess the immunity of the entire group.
Nonparametric tests were used for the analysis, since most parameters were not normally distributed (based on the Shapiro-Wilk test). In addition, parametric tests were performed for the log-transformation of the parameters. Associations between the response to vaccination and patient group and medication use were examined using the chi-square and Fisher's exact tests. The Mann-Whitney U test and t-tests for independent samples were used to compare patients who had a humoral response to vaccination to nonresponders with respect to clinical parameters, including the use of medications at baseline, change in disease indices (i.e., number of tender and swollen joints, morning stiffness, pain intensity), and ESR and CRP levels. Change in medication use was evaluated by McNemar's test, change in the number of medications by the nonparametric Wilcoxon test, and change in medication dose by paired t-tests. A binomial logistic regression model was constructed to assess the importance of the different variables relative to the immunogenicity response. Statistical analyses were carried out using the SPSS system for Windows, release 14.0.
Characteristics of patients and control subjects.
Tables 1 and 2 summarize the clinical and demographic characteristics of the patients and controls. All 5 groups were similar in age, while the proportion of men was significantly higher among the AS patients compared to the RA (P = 0.009) and SLE (P = 0.006) groups (Table 1). Two-thirds of the RA patients were treated with methotrexate, while one-third received tumor necrosis factor α (TNFα) blockers. More than 70% of the SLE patients were treated with hydroxychloroquine, and more than 80% of the PsA and AS patients were receiving anti-TNFα blockers (Table 2).
|Controls (n = 25)||RA (n = 41)||SLE (n = 21)||PsA (n = 17)||AS (n = 15)|
|Age, mean ± SD years||46.5 ± 12.1||52.6 ± 14.5||41.7 ± 11.5||48.5 ± 11.8||47.2 ± 13.3|
|Seasonal influenza vaccination, no. (%)||10 (40)||34 (82.9)||12 (57.1)||12 (70.6)||2 (13.3)|
|Disease duration, median (range) years||9 (0.5–54)||11 (3–57)||12 (1–30)||14 (2–25)|
|DAS28, mean ± SD|
|Baseline||4.4 ± 1.3||3.2 ± 1.2|
|After 4–6 weeks||4.4 ± 1.3||3.1 ± 1.3|
|BASDAI, mean ± SD|
|Baseline||2.2 ± 1.7|
|After 4–6 weeks||3.4 ± 2.4|
|SLEDAI, mean ± SD|
|Baseline||0.9 ± 1|
|After 4–6 weeks||0.3 ± 0.7|
|RA (n = 41)||SLE (n = 21)||PsA (n = 17)||AS (n = 15)|
|No. (%) patients||25 (61)||3 (14.3)||7 (41.2)||1 (6.7)|
|Dosage, mean ± SD mg/week||15 ± 4.6||13.3 ± 3.8||12.5 ± 5.2|
|No. (%) patients||19 (46.3)||15 (71.4)||3 (17.6)||None|
|Dosage, mean ± SD mg/week||11.5 ± 7.5||8.7 ± 5.6||8 ± 3.5|
|TNFα blockers, no. (%) patients||13 (31.7)||None||14 (82.4)||12 (80)|
|Infliximab||5 (12.2)||6 (35.3)||8 (53.3)|
|Etanercept||5 (12.2)||4 (23.5)||2 (13.3)|
|Adalimumab||3 (7.3)||4 (23.5)||2 (13.3)|
|Hydroxychloroquine, no. (%) patients||6 (14.6)||15 (71.4)||None||None|
Immunogenicity of the vaccine.
Four weeks after being vaccinated, all RA, SLE, AS, and PsA patients and healthy participants displayed significant increases in their geometric mean titers of the HI antibody against A/California/7/2009 (H1N1v): from 5.72 to 64.29 (P < 0.0001) for the RA patients, from 6.91 to 70.93 (P ≤ 0.0001) for the SLE patients, from 5.6 to 55.5 (P ≤ 0.001) for the PsA patients, from 2.33 to 57.04 (P ≤ 0.0001) for the AS patients, and from 4.3 to 127 in the healthy control group (P ≤ 0.0001) (Figure 1).
Individual responses to vaccination.
The proportion of baseline protective levels of antibodies (above 1/40) against H1N1v was similar in all but the AS patients: specifically, it was 24% for the RA patients, 24% for the SLE patients, 29% for the PsA patients, 7% for the AS patients, and 28% for the healthy controls (Figure 2). This indicated that most of the patients and controls did not demonstrate protective levels before vaccination, suggesting that despite the rapid spread of the virus, fewer than one-quarter of the subjects had been exposed to the virus prior to vaccination. Some participants were immunized against seasonal influenza (Table 1); the interval time between receiving the 2 vaccines was on average 1.5 months (median 1.5 months, range 0.1–3.5 months). Previous seasonal influenza vaccination did not affect the proportion of baseline seroprotection (25.7% among the 70 patients vaccinated against influenza versus 25.8% in the 31 nonvaccinated patients).
A substantial proportion of patients and controls responded to the H1N1v vaccine. However, while the proportion of responders was similar for the patients with RA (56%), SLE (67%), PsA (59%), and AS (53%), it was significantly higher for the healthy controls (84%; P = 0.04 compared to the RA group) (Figure 2). The percentage of patients who achieved a seroprotective level after vaccination (including patients who already had a baseline protective level before vaccination) was high: 92% for the controls, 71% for the RA patients, 76% each for the SLE and PsA patients, and 60% for the AS patients.
Predictors of response.
The multivariate logistic regression analysis identified RA and PsA as parameters predictive of having a significantly lower response (P = 0.03 and P = 0.05, respectively). Likewise, an association was found between the use of infliximab and leflunomide and a significantly lower response (P = 0.04 and P = 0.02, respectively). Among the 19 patients treated with infliximab, 52.6% responded to vaccination in comparison with 77.2% of patients not treated with infliximab. None of the 4 RA patients treated with leflunomide responded to the vaccine. No association was found between the humoral response and the parameters of age, sex, disease duration, DAS28, SLEDAI, BASDAI, ESR and CRP levels, the use or dose of prednisone or methotrexate, or having received a previous seasonal influenza vaccination.
Safety of the vaccine.
The most common adverse event was a local transient reaction at the site of the injection, which was present in 26 (27.6%) of the 94 patients compared to 1 (5.9%) of the 17 healthy subjects. The parameters of disease activity remained stable among the RA, SLE, PsA, and AS patients (Table 1).
The results of this study showed that vaccination against H1N1 was safe and induced a satisfactory response in patients with RA, SLE, PsA, and AS, although the humoral response was lower in patients with RA and PsA than in the other groups. In view of the rapid spread of the H1N1 virus and the absence of data on the rate of infection in these populations, the need for vaccination had been uncertain when vaccines became available. We have now demonstrated that only a minority of patients and controls had been exposed to the virus prior to vaccination, thereby justifying the need for vaccination. Moreover, more than 70% of our subjects achieved protective levels of antibodies to H1N1v after having been vaccinated.
These results are consistent with the large amount of data on the safety and efficacy of vaccination against influenza in RA, SLE, and PsA. Influenza vaccination of RA patients generates a satisfactory humoral response (12) that is lower than (12) or similar to (23, 24) that of healthy controls. The use of prednisone, disease-modifying antirheumatic drugs, and TNFα blockers does not significantly affect the response to influenza vaccination (12, 11, 23, 24), while rituximab severely impairs it (25, 26). The immune response to influenza vaccine in SLE patients is lower than that seen in adults in the general population, particularly among older patients and those being treated with immunosuppressive medications (27, 28).
Infection by the H1N1 virus may be severe and even fatal in immunocompromised patients. Kling et al reported the case of a woman with obesity and psoriasis who died from the complications of infection by H1N1 1 week after her first infusion with infliximab (29). The clinical course of 10 immunocompromised patients, 5 of whom were being treated with corticosteroids, was characterized by a clinical picture similar to that of nonimmunocompromised patients, but with a prolonged course and higher mortality (30). Likewise, influenza A H1N1 caused substantial morbidity in recipients of 230 solid-organ transplants, provoking pneumonia in 73 (32%) of those patients, necessitating hospitalization in an intensive care unit in 37 (16%), and resulting in the death of 10 (4%) (31).
The data on the response to vaccination against pandemic H1N1 in other populations of immunocompromised patients are scarce, this subject having been studied only in patients with HIV. Vaccination of 120 adults infected with HIV with an unadjuvanted, inactivated, split-virus H1N1 vaccine resulted in a response rate of only 60% (32). Immunization of HIV patients with an adjuvanted vaccine induced a response in up to 69% of patients (33).
The use of adjuvanted vaccine has raised concerns about the possible induction of autoimmunity or flares of underlying autoimmune disease (34). Squalene has been speculated as a possible cause of the Gulf War syndrome, since antibodies to squalene were detected in the blood of most of the affected individuals (35), and macrophagic myofasciitis has been associated with multiple injections of aluminum-based vaccines (34). Despite the fact that the vaccine used in our study was adjuvanted, it did not produce any short-term exacerbation of the underlying autoimmune diseases.
To our knowledge, this is the first report on the efficacy and safety of vaccination against H1N1 in patients with rheumatic diseases, and our results confirmed previous observations on the safety and efficacy of influenza vaccination in this patient population. Vaccination against H1N1v of patients with a variety of rheumatic diseases was found to be justified by the findings of a low number of patients who had been exposed prior to vaccination taken together with the induction of a satisfactory and an apparently safe response. We are aware of the limitations of this study, which included a small number of patients, a heterogeneous population, and a short period of time of assessment, the latter for purposes of safety. Likewise, the actual capacity of the vaccine to prevent clinical H1N1 disease was not evaluated. We recommend long-term studies in high-volume institutions to confirm our results.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Elkayam had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Elkayam, Schwaber, Grotto, Caspi, Mandelboim.
Acquisition of data. Elkayam, Wollman, Arad, Brill, Paran, Levartovsky, Wigler, Caspi.
Analysis and interpretation of data. Elkayam, Amir, Mendelson, Mandelboim.
- 1Centers for Disease Control and Prevention (CDC). Update: novel influenza A (H1N1) virus infections–worldwide, May 6, 2009. MMWR Morb Mortal Wkly Rep 2009; 58: 453–8.
- 4Centers for Disease Control and Prevention (CDC). Deaths and hospitalizations related to 2009 pandemic influenza A (H1N1): Greece, May 2009–February 2010. MMWR Morb Mortal Wkly Rep 2010; 59: 682–6.
- 14Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus [letter]. Arthritis Rheum 1997; 40: 1725., for the
- 20Committee for Proprietary Medicinal Products (CPMP). Note for guidance on harmonization of requirements for influenza vaccines. 1997. URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003945.pdf.
- 21Committee for Proprietary Medicinal Products (CPMC). Concept paper on the revision of the CPMP/BWP note for guidance on harmonization of requirements for influenza vaccines. 2001. CPMP/EPW/1045/01.
- 22Advanced laboratory techniques for influenza diagnosis. Washington, DC: US Department of Health, Education and Welfare; 1975., , , .