Lupus (2014) 23, 1412–1416 http://lup.sagepub.com
CONCISE REPORT
Pandemic influenza immunization in primary antiphospholipid syndrome (PAPS): a trigger to thrombosis and autoantibody production? D Martins de Medeiros1, CA Silva1,2,*, C Bueno1, AC Medeiros Ribeiro1, V dos Santos T Viana1, J Freire Carvalho3 and E Bonfa1,* 1
Division of Rheumatology and; 2Pediatric Rheumatology Unit, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo; and 3 Division of Rheumatology, Universidade Federal da Bahia, Bahia, Brazil
Objective: The objective of this report is to conduct short- and long-term evaluation of a large panel of antiphospholipid (aPL) autoantibodies following pandemic influenza A/H1N1 nonadjuvant vaccine in primary antiphospholipid syndrome (PAPS) patients and healthy controls. Methods: Forty-five PAPS and 33 healthy controls were immunized with H1N1 vaccine. They were prospectively assessed at pre-vaccination, and three weeks and six months after vaccination. aPL autoantibodies were determined by an enzyme-linked immunosorbent assay (ELISA) and included IgG/IgM: anticardiolipin (aCL), anti-beta2glycoprotein I (anti-b2GPI); anti-annexin V, anti-phosphatidyl serine and anti-prothrombin antibodies. Anti-Sm was determined by ELISA and anti-double-stranded DNA (anti-dsDNA) by indirect immunofluorescence. Arterial and venous thrombosis were also clinically assessed. Results: Pre-vaccination frequency of at least one aPL antibody was significantly higher in PAPS patients versus controls (58% vs. 24%, p ¼ 0.0052). The overall frequencies of aPL antibody at pre-vaccination, and three weeks and six months after immunization remained unchanged in patients (p ¼ 0.89) and controls (p ¼ 0.83). The frequency of each antibody specificity for patients and controls remained stable in the three evaluated periods (p > 0.05). At three weeks, two PAPS patients developed a new but transient aPL antibody (aCL IgG and IgM), whereas at six months new aPL antibodies were observed in six PAPS patients and none had high titer. Anti-Sm and anti-dsDNA autoantibodies were uniformly negative and no new arterial or venous thrombosis were observed throughout the study. Conclusions: This is the first study to demonstrate that pandemic influenza vaccine in PAPS patients does not trigger short- and long-term thrombosis or a significant production of aPL-related antibodies (ClinicalTrials.gov, #NCT01151644). Lupus (2014) 23, 1412–1416. Key words: Vaccine; antiphospholipid antiphospholipid syndrome
Introduction Vaccination is an essential protective measure for patients with rheumatic diseases,1,2 including antiphospholipid syndrome (APS). Foreign protein *C.A.S. and E.B. contributed equally to this work. Correspondence to: Eloisa Bonfa´, Faculdade de Medicina da Universidade de Sa˜o Paulo, Disciplina de Reumatologia Av. Dr Arnaldo, n 455, 3 andar, sala 3190 – Cerqueira Ce´sar Sa˜o Paulo – SP – 05403-010 Brazil. Email: [email protected] Received 15 January 2014; accepted 29 May 2014
antibodies;
pandemic
influenza
A;
H1N1;
injection may provoke autoantibodies production and thrombosis in this specific population.3 There are, however, scarce reports suggesting that seasonal and pandemic influenza vaccination may induce antiphospholipid (aPL) autoantibodies in inflammatory rheumatic diseases, particularly in systemic lupus erythematosus (SLE) patients,4–7 with no data regarding new-onset thrombosis and aPL autoantibodies induction in primary antiphospholipid syndrome (PAPS) patients. Therefore, the objectives of our study were shortand long-term evaluation of a large panel of aPL autoantibodies following pandemic influenza
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at MOUNT ALLISON UNIV on June 13, 2015
10.1177/0961203314540351
Pandemic influenza immunization in PAPS DM de Medeiros et al.
1413
A/H1N1 non-adjuvanted vaccine in PAPS patients and healthy controls.
Methods This study selected 60 PAPS patients who were included in a large (n ¼ 1668), prospective rheumatic-disease cohort conducted at a single site in Sa˜o Paulo, Brazil (Rheumatology Division, Hospital das Clı´ nicas da Universidade de Sa˜o Paulo), between March 2010 and April 2010, described in detail elsewhere.8 The control group included 33 healthy subjects. The protocol was approved by the local institutional review board and the trial was registered at clinicaltrials.gov under #NCT01151644. Patients and healthy controls All PAPS outpatients (Sapporo criteria9) were initially recruited by letter to participate in the Public Health influenza A H1N1/2009 vaccine campaign at the immunization center of our hospital. A blood sample was obtained from each participant immediately before vaccination, and three weeks and six months after vaccine. The exclusion criteria were: previous known infection with pandemic 2009 influenza A H1N1, anaphylactic response to vaccine components or to eggs, acute infection resulting in a fever of over 38 C at the time of vaccination, history of GuillainBarre´ syndrome or demyelination syndromes, previous vaccination with any live vaccine four weeks before the study or any inactivated vaccine two weeks before the study or blood transfusion within six months, hospitalization, failure to complete the protocol or refusal to participate in this study. All participants signed the informed consent. Sixty PAPS patients attended, but 15 were excluded: 11 for failure to complete the protocol and four for refusal to participate in this study. Therefore, 45 PAPS patients completed the study protocol. Vaccine The H1N1 vaccine, a novel, monovalent, non-adjuvanted, inactivated, split-virus vaccine, was produced by Butantan Institute/Sanofi Pasteur (Sa˜o Paulo, Brazil). The active substance is a split, inactivated influenza virus, containing antigens equivalent to the A/California/7/2009 (H1N1) virus-like strain (NYMCx-179A), one of the candidate reassortant vaccine viruses recommended by the World
Health Organization. The vaccine was prepared in embryonated chicken eggs, with the same standard techniques that are used for the production of seasonal trivalent inactivated vaccines, and it was presented in 5-ml multidose vials, with thimerosal added as a preservative (45 mg per 0.5 ml dose). All subjects were vaccinated with the pandemic 2009 influenza vaccine (A/California/7/2009/ Butantan Institute/Sanofi Pasteur). A single intramuscular dose (0.5 ml) of 15 mg hemagglutinin antigen, specific for the H1N1 A/California/7/2009-like virus, was administered. PAPS evaluation The following clinical parameters were prospectively evaluated in PAPS patients: venous thrombosis (documented deep vein thrombosis and/or pulmonary embolism), arterial thrombosis (clinically documented stroke, transient ischemic attacks or acute myocardial infarction) and thrombocytopenia ( 0.05) (Table 1). Table 2 includes the median aPL titers evaluation in PAPS and in healthy controls positive for the different antibodies’ specificities before vaccination. No differences were evidenced in the median titer of the five distinct IgG and IgM aPL antibodies tested in the three evaluated periods (before, and at three weeks and six months) in PAPS (p > 0.05) and healthy controls (p > 0.05) (Table 2). Power analyses revealed that all sequential tests performed for frequencies and antibodies titers were underpowered (
CONCISE REPORT
Pandemic influenza immunization in primary antiphospholipid syndrome (PAPS): a trigger to thrombosis and autoantibody production? D Martins de Medeiros1, CA Silva1,2,*, C Bueno1, AC Medeiros Ribeiro1, V dos Santos T Viana1, J Freire Carvalho3 and E Bonfa1,* 1
Division of Rheumatology and; 2Pediatric Rheumatology Unit, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo; and 3 Division of Rheumatology, Universidade Federal da Bahia, Bahia, Brazil
Objective: The objective of this report is to conduct short- and long-term evaluation of a large panel of antiphospholipid (aPL) autoantibodies following pandemic influenza A/H1N1 nonadjuvant vaccine in primary antiphospholipid syndrome (PAPS) patients and healthy controls. Methods: Forty-five PAPS and 33 healthy controls were immunized with H1N1 vaccine. They were prospectively assessed at pre-vaccination, and three weeks and six months after vaccination. aPL autoantibodies were determined by an enzyme-linked immunosorbent assay (ELISA) and included IgG/IgM: anticardiolipin (aCL), anti-beta2glycoprotein I (anti-b2GPI); anti-annexin V, anti-phosphatidyl serine and anti-prothrombin antibodies. Anti-Sm was determined by ELISA and anti-double-stranded DNA (anti-dsDNA) by indirect immunofluorescence. Arterial and venous thrombosis were also clinically assessed. Results: Pre-vaccination frequency of at least one aPL antibody was significantly higher in PAPS patients versus controls (58% vs. 24%, p ¼ 0.0052). The overall frequencies of aPL antibody at pre-vaccination, and three weeks and six months after immunization remained unchanged in patients (p ¼ 0.89) and controls (p ¼ 0.83). The frequency of each antibody specificity for patients and controls remained stable in the three evaluated periods (p > 0.05). At three weeks, two PAPS patients developed a new but transient aPL antibody (aCL IgG and IgM), whereas at six months new aPL antibodies were observed in six PAPS patients and none had high titer. Anti-Sm and anti-dsDNA autoantibodies were uniformly negative and no new arterial or venous thrombosis were observed throughout the study. Conclusions: This is the first study to demonstrate that pandemic influenza vaccine in PAPS patients does not trigger short- and long-term thrombosis or a significant production of aPL-related antibodies (ClinicalTrials.gov, #NCT01151644). Lupus (2014) 23, 1412–1416. Key words: Vaccine; antiphospholipid antiphospholipid syndrome
Introduction Vaccination is an essential protective measure for patients with rheumatic diseases,1,2 including antiphospholipid syndrome (APS). Foreign protein *C.A.S. and E.B. contributed equally to this work. Correspondence to: Eloisa Bonfa´, Faculdade de Medicina da Universidade de Sa˜o Paulo, Disciplina de Reumatologia Av. Dr Arnaldo, n 455, 3 andar, sala 3190 – Cerqueira Ce´sar Sa˜o Paulo – SP – 05403-010 Brazil. Email: [email protected] Received 15 January 2014; accepted 29 May 2014
antibodies;
pandemic
influenza
A;
H1N1;
injection may provoke autoantibodies production and thrombosis in this specific population.3 There are, however, scarce reports suggesting that seasonal and pandemic influenza vaccination may induce antiphospholipid (aPL) autoantibodies in inflammatory rheumatic diseases, particularly in systemic lupus erythematosus (SLE) patients,4–7 with no data regarding new-onset thrombosis and aPL autoantibodies induction in primary antiphospholipid syndrome (PAPS) patients. Therefore, the objectives of our study were shortand long-term evaluation of a large panel of aPL autoantibodies following pandemic influenza
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at MOUNT ALLISON UNIV on June 13, 2015
10.1177/0961203314540351
Pandemic influenza immunization in PAPS DM de Medeiros et al.
1413
A/H1N1 non-adjuvanted vaccine in PAPS patients and healthy controls.
Methods This study selected 60 PAPS patients who were included in a large (n ¼ 1668), prospective rheumatic-disease cohort conducted at a single site in Sa˜o Paulo, Brazil (Rheumatology Division, Hospital das Clı´ nicas da Universidade de Sa˜o Paulo), between March 2010 and April 2010, described in detail elsewhere.8 The control group included 33 healthy subjects. The protocol was approved by the local institutional review board and the trial was registered at clinicaltrials.gov under #NCT01151644. Patients and healthy controls All PAPS outpatients (Sapporo criteria9) were initially recruited by letter to participate in the Public Health influenza A H1N1/2009 vaccine campaign at the immunization center of our hospital. A blood sample was obtained from each participant immediately before vaccination, and three weeks and six months after vaccine. The exclusion criteria were: previous known infection with pandemic 2009 influenza A H1N1, anaphylactic response to vaccine components or to eggs, acute infection resulting in a fever of over 38 C at the time of vaccination, history of GuillainBarre´ syndrome or demyelination syndromes, previous vaccination with any live vaccine four weeks before the study or any inactivated vaccine two weeks before the study or blood transfusion within six months, hospitalization, failure to complete the protocol or refusal to participate in this study. All participants signed the informed consent. Sixty PAPS patients attended, but 15 were excluded: 11 for failure to complete the protocol and four for refusal to participate in this study. Therefore, 45 PAPS patients completed the study protocol. Vaccine The H1N1 vaccine, a novel, monovalent, non-adjuvanted, inactivated, split-virus vaccine, was produced by Butantan Institute/Sanofi Pasteur (Sa˜o Paulo, Brazil). The active substance is a split, inactivated influenza virus, containing antigens equivalent to the A/California/7/2009 (H1N1) virus-like strain (NYMCx-179A), one of the candidate reassortant vaccine viruses recommended by the World
Health Organization. The vaccine was prepared in embryonated chicken eggs, with the same standard techniques that are used for the production of seasonal trivalent inactivated vaccines, and it was presented in 5-ml multidose vials, with thimerosal added as a preservative (45 mg per 0.5 ml dose). All subjects were vaccinated with the pandemic 2009 influenza vaccine (A/California/7/2009/ Butantan Institute/Sanofi Pasteur). A single intramuscular dose (0.5 ml) of 15 mg hemagglutinin antigen, specific for the H1N1 A/California/7/2009-like virus, was administered. PAPS evaluation The following clinical parameters were prospectively evaluated in PAPS patients: venous thrombosis (documented deep vein thrombosis and/or pulmonary embolism), arterial thrombosis (clinically documented stroke, transient ischemic attacks or acute myocardial infarction) and thrombocytopenia ( 0.05) (Table 1). Table 2 includes the median aPL titers evaluation in PAPS and in healthy controls positive for the different antibodies’ specificities before vaccination. No differences were evidenced in the median titer of the five distinct IgG and IgM aPL antibodies tested in the three evaluated periods (before, and at three weeks and six months) in PAPS (p > 0.05) and healthy controls (p > 0.05) (Table 2). Power analyses revealed that all sequential tests performed for frequencies and antibodies titers were underpowered (
