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Study on efficacy of influenza vaccination in renal allograft recipients
POSTTRANSPLANT PHYSIOLOGY
Study on Efficacy of Influenza Vaccination in Renal Allograft Recipients J. Wyzgał, L.B. Brydak, D. Zygier, L. Paczek, W. Rowinខ sខ ki, and T. Grochowiecki
B
ACTERIAL, viral, parasitic, and fungal infections are common causes of complications in patients after renal transplantation, resulting in death among 5% to 20% of recipients. They are much more susceptible to viral and bacterial infections, and elimination of infectious agents is significantly impaired in this group. Viral infections are the most common cause of death.1,2 Influenza is one of the most common respiratory disease. Infection caused by this virus may be serious and lead to severe complications including: primary viral pneumonia and secondary bacterial pneumonia. Pneumonia occurs in 25% to 30% of renal transplant patients. The course of influenza infection is known to be more severe in these patients. Because of impaired humoral and cellular immunity, recipients of renal allografts display increased morbidity and mortality rates due to influenza and its complications. Among renal transplant patients with undiagnosed and untreated pneumonia death occurs in 40% to 50% of cases. So far, the most effective method of protection against influenza is annual vaccination. The Advisory Committee of Immunization Practices (ACIP) recommends influenza vaccination especially for persons with immune deficiencies such as chronic medical disorders of the pulmonary or cardiovascular systems, metabolic diseases, renal dysfunction, and immunosuppressed patients. There are many reports showing that influenza vaccination in those patients is as effective and safe as in healthy people because it prevents or at least decreases the severity of the disease. The present study evaluated the kinetics of the appearance and/or increases in antihaemaglutinins or antineur-
0041-1345/0⫺2000/$–see front matter PII S0041-1345(01)02849-4 572
amidase antibodies in the blood of renal allografts recipients after influenza vaccination. METHODS The study involved 23 patients of the Institute of Transplantology, Medical University of Warsaw at average age 43.58 years old and average 5.95 years after renal transplantation. Patients were treated after transplantation with different immunosuppressive therapy according to the following scheme: 12 patients treated with prednisone, azathioprine and cyclosporine; 5 patients treated with prednisone and cyclosporine; 1 patient treated with prednisone, mycophenolate mofetil, and cyclosporine; 2 patients treated with prednisone and azathioprine; 3 patients treated with prednisone and mycophenolate mofetil. They were vaccinated against influenza in the end of November and beginning of December 1999. Each patient received a single dose of split influenza vaccination (Influvac Solvay Pharma) intramuscularly. This vaccine contained 15 g haemagglutinin of each of the following influenza strains: A/Beijing/262/95/H1N1, A/Sydney/5/97/H3N2, B/Beijing/184/93. Immunization was assessed by evaluation of antibody response to haemagglutinin (HI) and neuraminidase (NI) glycoproteins of influenza virus. Antibody titres were measured at the National Influenza Center (WHO) using serum samples collected prior to and 1 month and 3 months after immunization. Antibody levels From the Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, the Department of General and Transplantation Surgery, Transplantation Institute, and the Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland. Address reprint requests to Janusz Wyzgał, Transplantation Institute, Medical University of Warsaw ul. Nowogrodzka 59, 02-006 Warsaw, Poland. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 572–575 (2002)
EFFICACY OF INFLUENZA VACCINATION
573
Fig 1. Geometric mean titers (GMT) of antihaemagglutinin antibodies (HI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
were determined by the haemagglutinin neuraminidase inhibition tests. The humoral response was evaluated by the following parameters: geometric mean haemagglutinin (HI) and neuraminidase (NI) antibody titres (GMT) vaccination; mean fold increase from pretransplantation 1 month or 3 months after vaccination; protection rate-number of patients with HI antibody titres ⱖ 1:40 before
and after vaccination; and response rate-number of patients with at least a fourfold increase of HI antibody level after vaccination. Statistical analysis was performed using the Student’s t test and the nonparametric tests of Mann-Whitney unpaired test and the Wilcoxon paired test. Statistical software was Statistica for Windows Version 1.1.
Fig 2. Geometric mean titers (GMT) of antineuraminidase antibodies (NI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
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WYZGAŁ, BRYDAK, ZYGIER ET AL
Fig 3. Protection rate of antihaemagglutinin antibodies (HI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
RESULTS
There was significant increase (P ⬍ .0001) in the HI antibody levels at 1 and 3 months after vaccination compared with the levels prior to treatment. The relatively
highest antibody level was observed as a response to B/Beijing/184/93 antigen both at 1 and 3 months after vaccination. Geometric mean titres (GMT) of HI antibody after vaccination significantly increased at the 1 month and
Fig 4. Response rate of antihaemagglutinin antibodies (HI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
EFFICACY OF INFLUENZA VACCINATION
3-month time-points (Fig 1). The most prominent increase was in the response to B/Beijing/184/93 antigen. Also the geometric mean titres of antineuraminidase antibody were higher than before vaccination (Fig 2), albeit that these changes were less than the mean increases in antihaemagglutinin antibody titres during the same period. Protective level was reached by 86.7% to 100% of patients at 1 month after vaccination and 40 to 73.4% at 3 months after vaccination (Fig 3). The interesting point was that protective level evoked by A/Beijing/262/95 (H1N1) antigen was very low. Furthermore the response ratio to vaccination significantly high (P ⬍ .0001) namely, 86.7% to 100% at 1 month and 40% to 73.4% at 3 months (Fig 4). None of 25 patients developed influenza, experienced adverse reactions, or displayed deterioration of transplanted kidney function based on serum creatinine measurement. DISCUSSION
The main protective effect of influenza vaccination is due to the induced immune response toward haemagglutinin component. Antihaemagglutinin antibodies (HI) inhibit the attachment of influenza virus to target cell membrane receptors and neutralize virus infectivity. Depending on their concentration, they provide prevention against serious illness. Protection studies showed that HI antibody titres of ⱖ1:40 can be considered to be a protective threshold, beyond which it is unlikely that serious illness will occur. Unlike antihaemagglutinin antibodies, antineuraminidase antibodies are not involved in neutralization of virus infectivity. Their role in resistance to influenza virus infection lies in the inhibition of the release of mature viral particles from infected cells, thereby resulting in limitation of viral spread. There are no estimated values of antineuraminidase antibody titres that are considered to inhibit replication of the influenza virus. The question is whether HI antibody titers, which prevent infection in healthy people, provide similar protection in renal allograft recipients after active immunization with influenza vaccine. Another unresolved question is whether HI antibody levels
575
represent a good marker for the assessment of the efficacy of influenza vaccines in patients after renal transplantation, since not only humoral responses but also cellular immunity play an important role in protection against infections and disease severity of influenza. Moreover, the composition of the vaccines and the immunogenicity of their vaccine strains are also important. Reports on the immunogenicity of influenza vaccination in transplant recipients are contradictory. Blumberg4 reported a significant but lower antibody production in adult solid organ transplant recipients. Pediatric renal transplant recipients achieved titres similar to those of healthy controls.5 It is known that prednisone therapy in daily doses of 2 mg/kg are evident immunosuppressive resulting in a poorer immune response.6 Versluis showed that patients on cyclosporine A had a significantly lower immune response after influenza vaccination than those treated with azathioprine.7 We found no association between vaccine-elicited antibody responses and types of immunosuppressive therapy. No serious adverse reactions were observed among the vaccinated patients. From our study, we conclude that influenza vaccination is safe and effective in renal transplant recipients and induces a significant antibody response. Antibody titres are high enough to lessen the severity of the disease and reduce secondary complications or even prevent illness. REFERENCES 1. Briggs JD, Junor BJR: Oxford Textbook of Clinical Nefrology. Oxford: Oxford Medical Publication; 1992, p 1570 2. Kreis H, Legendre C: Oxford Textbook of Clinical Nefrology. Oxford: Oxford Medical Publication; 1992, p 1520 3. Tolkoff-Rubin NE, Rubin RH: Transplant Proc 18:168, 1986 4. Blumberg EA, Albano C, Pruett T, et al: Clin Inf Dis 22:295, 1996 5. Edvardsson VO, Flynn J, Deforest A, et al: Clin Transplant 10:556, 1996 6. Brydak LB, Roszkowska-Blaim M, Machala M, et al: Vaccine 18:3280, 2000 7. Versluis DJ, Beyer WEP, Masurel N, et al: Transplantation 42:376, 1986 8. Brydak LB, Rajowski T, Machala M, et al: Antiinf Drugs Chemother 16:151, 1998
Study on Efficacy of Influenza Vaccination in Renal Allograft Recipients J. Wyzgał, L.B. Brydak, D. Zygier, L. Paczek, W. Rowinខ sខ ki, and T. Grochowiecki
B
ACTERIAL, viral, parasitic, and fungal infections are common causes of complications in patients after renal transplantation, resulting in death among 5% to 20% of recipients. They are much more susceptible to viral and bacterial infections, and elimination of infectious agents is significantly impaired in this group. Viral infections are the most common cause of death.1,2 Influenza is one of the most common respiratory disease. Infection caused by this virus may be serious and lead to severe complications including: primary viral pneumonia and secondary bacterial pneumonia. Pneumonia occurs in 25% to 30% of renal transplant patients. The course of influenza infection is known to be more severe in these patients. Because of impaired humoral and cellular immunity, recipients of renal allografts display increased morbidity and mortality rates due to influenza and its complications. Among renal transplant patients with undiagnosed and untreated pneumonia death occurs in 40% to 50% of cases. So far, the most effective method of protection against influenza is annual vaccination. The Advisory Committee of Immunization Practices (ACIP) recommends influenza vaccination especially for persons with immune deficiencies such as chronic medical disorders of the pulmonary or cardiovascular systems, metabolic diseases, renal dysfunction, and immunosuppressed patients. There are many reports showing that influenza vaccination in those patients is as effective and safe as in healthy people because it prevents or at least decreases the severity of the disease. The present study evaluated the kinetics of the appearance and/or increases in antihaemaglutinins or antineur-
0041-1345/0⫺2000/$–see front matter PII S0041-1345(01)02849-4 572
amidase antibodies in the blood of renal allografts recipients after influenza vaccination. METHODS The study involved 23 patients of the Institute of Transplantology, Medical University of Warsaw at average age 43.58 years old and average 5.95 years after renal transplantation. Patients were treated after transplantation with different immunosuppressive therapy according to the following scheme: 12 patients treated with prednisone, azathioprine and cyclosporine; 5 patients treated with prednisone and cyclosporine; 1 patient treated with prednisone, mycophenolate mofetil, and cyclosporine; 2 patients treated with prednisone and azathioprine; 3 patients treated with prednisone and mycophenolate mofetil. They were vaccinated against influenza in the end of November and beginning of December 1999. Each patient received a single dose of split influenza vaccination (Influvac Solvay Pharma) intramuscularly. This vaccine contained 15 g haemagglutinin of each of the following influenza strains: A/Beijing/262/95/H1N1, A/Sydney/5/97/H3N2, B/Beijing/184/93. Immunization was assessed by evaluation of antibody response to haemagglutinin (HI) and neuraminidase (NI) glycoproteins of influenza virus. Antibody titres were measured at the National Influenza Center (WHO) using serum samples collected prior to and 1 month and 3 months after immunization. Antibody levels From the Department of Immunology, Transplantology and Internal Medicine, Transplantation Institute, the Department of General and Transplantation Surgery, Transplantation Institute, and the Department of General, Vascular and Transplant Surgery, Medical University of Warsaw, Warsaw, Poland. Address reprint requests to Janusz Wyzgał, Transplantation Institute, Medical University of Warsaw ul. Nowogrodzka 59, 02-006 Warsaw, Poland. © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 572–575 (2002)
EFFICACY OF INFLUENZA VACCINATION
573
Fig 1. Geometric mean titers (GMT) of antihaemagglutinin antibodies (HI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
were determined by the haemagglutinin neuraminidase inhibition tests. The humoral response was evaluated by the following parameters: geometric mean haemagglutinin (HI) and neuraminidase (NI) antibody titres (GMT) vaccination; mean fold increase from pretransplantation 1 month or 3 months after vaccination; protection rate-number of patients with HI antibody titres ⱖ 1:40 before
and after vaccination; and response rate-number of patients with at least a fourfold increase of HI antibody level after vaccination. Statistical analysis was performed using the Student’s t test and the nonparametric tests of Mann-Whitney unpaired test and the Wilcoxon paired test. Statistical software was Statistica for Windows Version 1.1.
Fig 2. Geometric mean titers (GMT) of antineuraminidase antibodies (NI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
574
WYZGAŁ, BRYDAK, ZYGIER ET AL
Fig 3. Protection rate of antihaemagglutinin antibodies (HI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
RESULTS
There was significant increase (P ⬍ .0001) in the HI antibody levels at 1 and 3 months after vaccination compared with the levels prior to treatment. The relatively
highest antibody level was observed as a response to B/Beijing/184/93 antigen both at 1 and 3 months after vaccination. Geometric mean titres (GMT) of HI antibody after vaccination significantly increased at the 1 month and
Fig 4. Response rate of antihaemagglutinin antibodies (HI) after influenza vaccination in renal allograft recipients (epidemic season 1999/2000).
EFFICACY OF INFLUENZA VACCINATION
3-month time-points (Fig 1). The most prominent increase was in the response to B/Beijing/184/93 antigen. Also the geometric mean titres of antineuraminidase antibody were higher than before vaccination (Fig 2), albeit that these changes were less than the mean increases in antihaemagglutinin antibody titres during the same period. Protective level was reached by 86.7% to 100% of patients at 1 month after vaccination and 40 to 73.4% at 3 months after vaccination (Fig 3). The interesting point was that protective level evoked by A/Beijing/262/95 (H1N1) antigen was very low. Furthermore the response ratio to vaccination significantly high (P ⬍ .0001) namely, 86.7% to 100% at 1 month and 40% to 73.4% at 3 months (Fig 4). None of 25 patients developed influenza, experienced adverse reactions, or displayed deterioration of transplanted kidney function based on serum creatinine measurement. DISCUSSION
The main protective effect of influenza vaccination is due to the induced immune response toward haemagglutinin component. Antihaemagglutinin antibodies (HI) inhibit the attachment of influenza virus to target cell membrane receptors and neutralize virus infectivity. Depending on their concentration, they provide prevention against serious illness. Protection studies showed that HI antibody titres of ⱖ1:40 can be considered to be a protective threshold, beyond which it is unlikely that serious illness will occur. Unlike antihaemagglutinin antibodies, antineuraminidase antibodies are not involved in neutralization of virus infectivity. Their role in resistance to influenza virus infection lies in the inhibition of the release of mature viral particles from infected cells, thereby resulting in limitation of viral spread. There are no estimated values of antineuraminidase antibody titres that are considered to inhibit replication of the influenza virus. The question is whether HI antibody titers, which prevent infection in healthy people, provide similar protection in renal allograft recipients after active immunization with influenza vaccine. Another unresolved question is whether HI antibody levels
575
represent a good marker for the assessment of the efficacy of influenza vaccines in patients after renal transplantation, since not only humoral responses but also cellular immunity play an important role in protection against infections and disease severity of influenza. Moreover, the composition of the vaccines and the immunogenicity of their vaccine strains are also important. Reports on the immunogenicity of influenza vaccination in transplant recipients are contradictory. Blumberg4 reported a significant but lower antibody production in adult solid organ transplant recipients. Pediatric renal transplant recipients achieved titres similar to those of healthy controls.5 It is known that prednisone therapy in daily doses of 2 mg/kg are evident immunosuppressive resulting in a poorer immune response.6 Versluis showed that patients on cyclosporine A had a significantly lower immune response after influenza vaccination than those treated with azathioprine.7 We found no association between vaccine-elicited antibody responses and types of immunosuppressive therapy. No serious adverse reactions were observed among the vaccinated patients. From our study, we conclude that influenza vaccination is safe and effective in renal transplant recipients and induces a significant antibody response. Antibody titres are high enough to lessen the severity of the disease and reduce secondary complications or even prevent illness. REFERENCES 1. Briggs JD, Junor BJR: Oxford Textbook of Clinical Nefrology. Oxford: Oxford Medical Publication; 1992, p 1570 2. Kreis H, Legendre C: Oxford Textbook of Clinical Nefrology. Oxford: Oxford Medical Publication; 1992, p 1520 3. Tolkoff-Rubin NE, Rubin RH: Transplant Proc 18:168, 1986 4. Blumberg EA, Albano C, Pruett T, et al: Clin Inf Dis 22:295, 1996 5. Edvardsson VO, Flynn J, Deforest A, et al: Clin Transplant 10:556, 1996 6. Brydak LB, Roszkowska-Blaim M, Machala M, et al: Vaccine 18:3280, 2000 7. Versluis DJ, Beyer WEP, Masurel N, et al: Transplantation 42:376, 1986 8. Brydak LB, Rajowski T, Machala M, et al: Antiinf Drugs Chemother 16:151, 1998