Pediatr Transplantation 2015: 19: 219–228
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12419
Randomized, double-blind comparison of standard-dose vs. high-dose trivalent inactivated influenza vaccine in pediatric solid organ transplant patients GiaQuinta S, Michaels MG, McCullers JA, Wang L, Fonnesbeck C, O’Shea A, Green M, Halasa NB. (2015) Randomized, double-blind comparison of standard-dose vs. high-dose trivalent inactivated influenza vaccine in pediatric solid organ transplant patients. Pediatr Transplant, 19: 219–228. DOI: 10.1111/petr.12419. Abstract: Children who have undergone SOT mount a lower immune response after vaccination with TIV compared to healthy controls. HD or SD TIV in pediatric SOT was given to subjects 3–17 yr and at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60 lg) or the SD (15 lg) TIV. Local and systemic reactions were solicited after each vaccination, and immune responses were measured before and after each vaccination. Thirty-eight subjects were enrolled. Mean age was 11.25 yr; 68% male, 45% renal, 26% heart, 21% liver, 5% lung, and 5% intestinal. Twenty-three subjects were given HD and 15 SD TIV. The median time since transplant receipt was 2.2 yr. No severe AEs or rejection was attributed to vaccination. The HD group reported more tenderness and local reactions, fatigue, and body ache when compared to the SD cohort, but these were considered mild and resolved within three days. Subjects in the HD group demonstrated a higher percentage of four-fold titer rise to H3N2 compared to the SD group. HD influenza vaccine was well tolerated and may have increased immunogenicity. A phase 2 trial is needed to confirm.
Influenza is an important cause of morbidity and mortality worldwide. Each year, the influenza A and/or B viruses cause epidemics in the United States accounting for an annual average of 36 000 deaths and 114 000 hospitalizations (1). Individuals with underlying medical conditions, especially those who are immunosuppressed, including those undergoing SOT, are at risk for severe influenza disease (2, 3). Secondary complications have also been reported in individuals with influenza illness, including viral pneumonia,
Abbreviations: AE, adverse event; DSMB, data safety monitoring board; GMT, geometric mean titer; HAI, hemagglutination inhibition; HD, high-dose; IQR, interquartile range; ISM, independent safety monitor; SAE, serious adverse event; SD, standard-dose; SOT, solid organ transplantation; TIV, trivalent inactivated influenza vaccine; UPMC, University of Pittsburgh Medical Center.
Sarah GiaQuinta1, Marian G. Michaels2, Jonathan A. McCullers3,4, Li Wang5, Christopher Fonnesbeck5, Alice O’Shea1, Michael Green2 and Natasha B. Halasa1 1
Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA, 2Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA, 3Pediatrics, St. Jude Children’s Research Hospital, Memphis, TN, USA, 4Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA, 5Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
Key words: influenza – solid organ transplant – vaccine Natasha Halasa, MD MPH, Associate Professor of Pediatrics, Pediatric Infectious Diseases, 1161 21st Ave South, D7232 MCN, Nashville, TN 37232, USA Tel.: +1 615 322 3346 Fax: +1 615 343 7659 E-mail: [email protected] Accepted for publication 24 November 2014
bacterial pneumonia, and extra-pulmonary complications including myositis and myocarditis (4–7). Additionally, influenza infections in SOT recipients are associated with prolonged periods of viral shedding and allograft rejection (6, 8–10). Influenza vaccination is the primary mode of prevention of influenza infection in pediatric SOT recipients. However, limited data exist in the pediatric solid organ transplant population, with the majority of studies in either kidney or liver transplant recipients (11). In addition, conflicting data exist on immune responses to influenza vaccine in this population. Some studies demonstrate lower antibody responses in SOT recipients when compared to age-matched healthy controls, while another study revealed similar antibody titers, but decreased interferon gamma production in SOT recipients when compared to controls (12–16). Recently, a HD trivalent inactive influenza vaccine 219
GiaQuinta et al.
(Fluzone HD) with four times the standard antigenic dose was approved for use in individuals ≥65 yr of age. Historically, this population has been noted to respond poorly to the standard trivalent inactive influenza vaccine (TIV) when compared to younger adults (17). A phase 3 study found a statistically significant higher antibody response to both influenza A antigens in elderly patients who received the HD vaccine as compared to those receiving the SD TIV, thus leading to its licensure. In addition to significantly higher antibody responses in the population, the HD TIV provided better protection (relative efficacy, 24.2%) against laboratory-confirmed influenza illness than did SD TIV (18). Consequently, as SOT recipients have been noted to have lower titers to antigens included in the influenza vaccine when compared to healthy controls in some trials, it was hypothesized that a higher antigen dose would be safe in this population and may produce a robust immune response compared to standard influenza dosing.
All patients received either the SD TIV (Fluzoneâ; Sanofi Pasteur, Swiftwater, PA, USA) or the HD TIV (Fluzoneâ High Dose; Sanofi Pasteur), which has not yet been approved for pediatric patients. The 2011–2012 influenza vaccination was used in this study. The SD TIV and HD TIV contained 0.5 mL of either 15 or 60 lg, respectively, of each of the following: A/California/7/09 (H1N1)-like virus, A/Perth/16/2009 (H3N2)-like virus, and B/Brisbane/60/ 2008-like virus. Each subject received the vaccination intramuscularly in the right or left deltoid and was observed closely for at least 20 min post-vaccination. If the patient required two doses of the TIV (cohort 2), the doses were separated from each other by 28 (+14) days.
Methods
Study procedures
Study design
Parents or guardians were asked to record solicited reactogenicity events, which included local reactions (pain, tenderness, redness, swelling, and induration at the injection site) and systemic reactions (fevers, fatigue/malaise, headache, nausea, body ache/myalgia, general activity level, and vomiting), for seven days following vaccination. If the subject was 70% of the SD subjects achieving seroprotection for H3N2. Therefore, a phase 2 trial is needed to determine whether the HD influenza vaccine in pediatric SOT recipients will result in higher immunogenicity results compared to SD. Yearly influenza immunization with the inactivated influenza vaccine is recommended for all solid organ transplant recipients (11). However, many unanswered questions remain in this population with regard to routine influenza
HD influenza vaccine vs. standard dose
Fig. 3. The percent of subjects who reported systemic reactions by day in the HD and SD group.
vaccination. For example, in a review of influenza vaccine recommendations, the authors stated that there is insufficient data to recommend high dose, intradermal, or booster doses of influenza vaccines within the same season (11). In addition, the exact timing of when it is safe and effective to deliver the influenza vaccine after transplantation (e.g., 3–6 months after transplant) is not known. Authors of the same manuscript recommend that the influenza vaccines should not be given earlier than three months after transplantation or after intensified immunosuppression for rejection (11). However, in the 2013 IDSA Clinical Practice Guidelines for Vaccination of The Immunocompromised Host, the authors assert that the inactivated influenza vaccine may be administered despite intensive immunosuppression, particularly in an outbreak situation, but the data to support this recommendation are categorized as weak and low (25). In our cohort, we adminis-
tered influenza vaccination a minimum of six months following SOT; however, the median time after transplantation was 2.2 yr. Therefore, further studies are needed to investigate whether earlier influenza vaccination with HD influenza vaccines is safe and effective and whether a repeated dose is needed later in the influenza season when the immunosuppression regimen is waning, and these recipients may respond better to influenza vaccines (15). Influenza disease has been associated with rejection in solid organ recipients (26, 27). Specifically, in lung transplant recipients, influenza may mediate acute and chronic allograft rejection and bronchiolitis obliterans syndrome (28, 29). A theoretical concern and small case reports suggest the possible association of influenza vaccination and rejection (30, 31); however, larger studies do not find an association of graft rejection following influenza vaccination (32–34). As 225
GiaQuinta et al. Table 2. Immune responses before and after vaccination in subjects receiving either HD or SD influenza vaccine by HAI
A/California/7/2009 H1N1 % with ≥1:40 % with ≥4-fold rise Prevaccine GMT (95% CI) Post-vaccine GMT (95% CI) GMT difference estimate (95% CI) A/Perth/16/ 2009 H3N2 % with ≥1:40 % with ≥4-fold rise Prevaccine GMT (95% CI) Post-vaccine GMT (95% CI) GMT difference estimate (95% CI) B/Brisbane/60/2008 % with ≥1:40 % with ≥4-fold rise Prevaccine GMT (95% CI) Post-vaccine GMT (95% CI) GMT difference estimate (95% CI)
HD
SD
95.5% (21/22) 68% (15/22) 77.5 (35.2–170.5) 773.2 (374.6–1363.3) 695.7 (305.3–1299.2)
80% (12/15) 47% (7/15) 62 (20.9–155.1) 310.3 (124–718.4) 248.3 (32.9–681.9)
86% (19/22) 54% (12/22) 34.7 (21–55.7) 131.7 (76.7–233.5) 97 (35.8–194)
80% (12/15) 13% (2/15) 93.3 (47.4–195.5) 136.1 (71.8–254) 42.8 ( 64.4–170.5)
46% (10/22) 18% (4/22) 19.6 (14.2–26.8) 36.8 (23.3–60.6) 17.2 (1.9–42.4)
47% (7/15) 33% (5/15) 21.1 (11.4–48.9) 36.2 (18.9–83.2) 15.1 ( 15.4–62.1)
GMT difference between HD and SD estimate (95% CI)
p-value
0.14 0.19 15.5 ( 94.5–113.8) 462.9 ( 85.9–1112.4)
0.61 0.011 58.6 ( 146.1 to 8.6) 4.4 ( 131–113)
0.94 0.29 1.5 ( 26.7–11.4) 0.6 ( 42.6–32.4)
Boldface indicates significance.
there was increased antigen dose and theoretical potential for induction of rejection after HD influenza vaccination, the study was halted for two wk after the 15th patient was enrolled to monitor for rejection. In our cohort, graft rejection was not associated with influenza vaccination, and only one patient reported graft rejection, which occurred over five months following SD influenza vaccine. Our study did have some limitations. This was a phase 1 study with a small number of patients enrolled, and although we documented few increased local and systemic reactions with the HD TIV, further studies with a larger population are necessary to confirm these findings. Despite recruitment at two sites, our goal of 60 subjects was not achieved due to mandatory two-wk halting rules. Because we included all individuals who have undergone SOT, our population is heterogeneous, which may complicate the immunogenicity results. In addition, the HD group had a higher mean age, even though this was not statistically significant (p = 0.19); this may have played a role in the differences in immune responses. We also did not analyze based on immunosuppressive drug regimens or cell-mediated immune responses to influenza antigens, which may have affected immune responses and may have noted differences between the two groups, respectively (15, 35, 36). In conclusion, our study revealed that the HD TIV is safe and well tolerated in pediatric solid organ recipients when compared to SD TIV. A phase 2 trial is required to adequately assess 226
the immunogenicity of the HD TIV in this population and answer whether HD in this population is a better strategy. More importantly, as influenza continues to cause high morbidity and mortality, and not all pediatric SOT recipients achieve protective titers to SD TIV (15, 37), finding a more effective influenza vaccine for this population could be of great benefit. Authors’ contributions Sarah GiaQuinta, Marian Michaels, Michael Green, and Natasha B. Halasa: Conceptualized and designed the study; participated in the acquisition, analysis, and interpretation of data; helped draft the initial manuscript; and approved the final manuscript as submitted. Jonathan McCullers: Participated in the acquisition, analysis, and interpretation of data; critically reviewed and edited the manuscript; and approved the final manuscript as submitted; Li Wang and Christopher Fonnesbeck: Provided statistical guidance, carried out analyses, helped draft the initial manuscript, and approved the final manuscript as submitted; Alice O’Shea: Conceptualized and designed the study; participated in the acquisition, analysis, and interpretation of data; and approved the final manuscript as submitted.
Acknowledgments We wish to acknowledge the subjects, their families, and the transplant physicians and coordinators that helped in recruitment into this trial. We would also like to acknowledge our ISMs: Judy Martin, S. Elizabeth Williams, and Toni Darville; the research nurses at Pittsburgh Nurses: Noreen Jeffrey and Diane Gwin; and Lee Ann Van De Velde and Shane Gansebom for their excellent technical assistance. The trial was supported by investigator-initiated grant by Sanofi Pasteur. The project publication described was also partially supported by CTSA award No.
HD influenza vaccine vs. standard dose UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Disclosures
Dr. Halasa received grant support from Sanofi Pasteur, Gilead, and Pfizer. References 1. THOMPSON WW, SHAY DK, WEINTRAUB E. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003: 289: 179–186. 2. APALSCH AM, GREEN M, LEDESMA-MEDINA J, NOUR B, WALD ER. Parainfluenza and influenza virus infections in pediatric organ transplant recipients. Clin Infect Dis 1995: 20: 394–399. 3. ISON MG, MICHAELS MG. RNA respiratory viral infections in solid organ transplant recipients. Am J Transplant 2009: 9: S166–S172. 4. CHON WJ, KADAMBI PV, HARLAND RC, et al. Changing attitudes toward influenza vaccination in U.S. kidney transplant programs over the past decade. Clin J Am Soc Nephrol 2010: 5: 1637–1641. 5. ISON MG. Antiviral therapies for respiratory viral infections in lung transplant patients. Antivir Ther 2012: 17(1 Pt B): 193– 200. 6. ISON MG, HIRSCH HH. Influenza: A recurrent challenge to transplantation. Transpl Infect Dis 2010: 12: 95–97. 7. LOPEZ-MEDRANO F, AGUADO JM, LIZASOAIN M, et al. Clinical implications of respiratory virus infections in solid organ transplant recipients: A prospective study. Transplantation 2007: 84: 851–856. 8. WEINSTOCK DM, GUBAREVA LV, ZUCCOTTI G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N Engl J Med 2003: 348: 867–868. 9. ISON MG, HAYDEN FG. Viral infections in immunocompromised patients: What’s new with respiratory viruses? Curr Opin Infect Dis 2002: 15: 355–367. 10. BRIGGS JD, TIMBURY MC, PATON AM, BELL PR. Viral infection and renal transplant rejection. Br Med J 1972: 4: 520–522. 11. KUMAR D, BLUMBERG EA, DANZIGER-ISAKOV L, et al. Influenza vaccination in the organ transplant recipient: Review and summary recommendations. Am J Transplant 2011: 11: 2020–2030. 12. NAILESCU C, XU X, ZHOU H, et al. Influenza vaccine after pediatric kidney transplant: A Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol 2011: 26: 459–467. 13. MADAN RP, TAN M, FERNANDEZ-SESMA A, et al. A prospective, comparative study of the immune response to inactivated influenza vaccine in pediatric liver transplant recipients and their healthy siblings. Clin Infect Dis 2008: 46: 712–718. 14. LONG CB, RAMOS I, RASTOGI D, et al. Humoral and cell-mediated immune responses to monovalent 2009 influenza A/H1N1 and seasonal trivalent influenza vaccines in high-risk children. J Pediatr 2012: 160: 74–81. 15. CORDERO E, MANUEL O. Influenza vaccination in solid-organ transplant recipients. Curr Opin Organ Transplant 2012: 17: 601–608. 16. GOTOH K, ITO Y, SUZUKI E, et al. Effectiveness and safety of inactivated influenza vaccination in pediatric liver transplant recipients over three influenza seasons. Pediatr Transplant 2011: 15: 112–116.
17. CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC). Licensure of a high-dose inactivated influenza vaccine for persons aged >or=65 years (Fluzone High-Dose) and guidance for use – United States. MMWR Morb Mortal Wkly Rep 2010: 59: 485–486. 18. DIAZGRANADOS CA, DUNNING AJ, KIMMEL M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med 2014: 371: 635–645. 19. AMERICAN ACADEMY OF PEDIATRICS COMMITTEE ON INFECTIOUS DISEASES. Recommendations for prevention and control of influenza in children, 2011-2012. Pediatrics 2011: 128: 813–825. 20. MCMANUS M, FRANGOUL H, MCCULLERS JA, WANG L, O’SHEA A, HALASA N. Safety of high dose trivalent inactivated influenza vaccine in pediatric patients with acute lymphoblastic leukemia. Pediatr Blood Cancer 2014: 61: 815–820. 21. KEITEL WA, CATE TR, ATMAR RL, et al. Increasing doses of purified influenza virus hemagglutinin and subvirion vaccines enhance antibody responses in the elderly. Clin Diagn Lab Immunol 1996: 3: 507–510. 22. COUCH RB, WINOKUR P, BRADY R, et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 2007: 25: 7656–7663. 23. FALSEY AR, TREANOR JJ, TORNIEPORTH N, CAPELLAN J, GORSE GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 2009: 200: 172–180. 24. WHO Expert Committee on biological standardization. World Health Organ Tech Rep Ser 2011: 963: 1–244. 25. RUBIN LG, LEVIN MJ, LJUNGMAN P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014: 58: e44–e100. 26. VILCHEZ RA, MCCURRY K, DAUBER J, et al. Influenza virus infection in adult solid organ transplant recipients. Am J Transplant 2002: 2: 287–291. 27. KUMAR D, MICHAELS MG, MORRIS MI, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solidorgan transplants: A multicentre cohort study. Lancet Infect Dis 2010: 10: 521–526. 28. BILLINGS JL, HERTZ MI, SAVIK K, WENDT CH. Respiratory viruses and chronic rejection in lung transplant recipients. J Heart Lung Transplant 2002: 21: 559–566. 29. BILLINGS JL, HERTZ MI, WENDT CH. Community respiratory virus infections following lung transplantation. Transpl Infect Dis 2001: 3: 138–148. 30. BLUMBERG EA, FITZPATRICK J, STUTMAN PC, HAYDEN FG, BROZENA SC. Safety of influenza vaccine in heart transplant recipients. J Heart Lung Transplant 1998: 17: 1075–1080. 31. DANZIGER-ISAKOV L, CHERKASSKY L, SIEGEL H, et al. Effects of influenza immunization on humoral and cellular alloreactivity in humans. Transplantation 2010: 89: 838–844. 32. VERMEIREN P, AUBERT V, SUGAMELE R, et al. Influenza vaccination and humoral alloimmunity in solid organ transplant recipients. Transpl Int 2014: 903–908. 33. BALUCH A, HUMAR A, EURICH D, et al. Randomized controlled trial of high-dose intradermal versus standard-dose intramuscular influenza vaccine in organ transplant recipients. Am J Transplant 2013: 13: 1026–1033. 34. CANDON S, THERVET E, LEBON P, et al. Humoral and cellular immune responses after influenza vaccination in kidney transplant recipients. Am J Transplant 2009: 9: 2346–2354. 35. ZEMAN AM, HOLMES TH, STAMATIS S, et al. Humoral and cellular immune responses in children given annual immunization with trivalent inactivated influenza vaccine. Pediatr Infect Dis J 2007: 26: 107–115.
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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1 (a) Toxicity grading scale for local reactions. (b) Toxicity grading scale for systemic reactions.
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Pediatric Transplantation DOI: 10.1111/petr.12419
Randomized, double-blind comparison of standard-dose vs. high-dose trivalent inactivated influenza vaccine in pediatric solid organ transplant patients GiaQuinta S, Michaels MG, McCullers JA, Wang L, Fonnesbeck C, O’Shea A, Green M, Halasa NB. (2015) Randomized, double-blind comparison of standard-dose vs. high-dose trivalent inactivated influenza vaccine in pediatric solid organ transplant patients. Pediatr Transplant, 19: 219–228. DOI: 10.1111/petr.12419. Abstract: Children who have undergone SOT mount a lower immune response after vaccination with TIV compared to healthy controls. HD or SD TIV in pediatric SOT was given to subjects 3–17 yr and at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60 lg) or the SD (15 lg) TIV. Local and systemic reactions were solicited after each vaccination, and immune responses were measured before and after each vaccination. Thirty-eight subjects were enrolled. Mean age was 11.25 yr; 68% male, 45% renal, 26% heart, 21% liver, 5% lung, and 5% intestinal. Twenty-three subjects were given HD and 15 SD TIV. The median time since transplant receipt was 2.2 yr. No severe AEs or rejection was attributed to vaccination. The HD group reported more tenderness and local reactions, fatigue, and body ache when compared to the SD cohort, but these were considered mild and resolved within three days. Subjects in the HD group demonstrated a higher percentage of four-fold titer rise to H3N2 compared to the SD group. HD influenza vaccine was well tolerated and may have increased immunogenicity. A phase 2 trial is needed to confirm.
Influenza is an important cause of morbidity and mortality worldwide. Each year, the influenza A and/or B viruses cause epidemics in the United States accounting for an annual average of 36 000 deaths and 114 000 hospitalizations (1). Individuals with underlying medical conditions, especially those who are immunosuppressed, including those undergoing SOT, are at risk for severe influenza disease (2, 3). Secondary complications have also been reported in individuals with influenza illness, including viral pneumonia,
Abbreviations: AE, adverse event; DSMB, data safety monitoring board; GMT, geometric mean titer; HAI, hemagglutination inhibition; HD, high-dose; IQR, interquartile range; ISM, independent safety monitor; SAE, serious adverse event; SD, standard-dose; SOT, solid organ transplantation; TIV, trivalent inactivated influenza vaccine; UPMC, University of Pittsburgh Medical Center.
Sarah GiaQuinta1, Marian G. Michaels2, Jonathan A. McCullers3,4, Li Wang5, Christopher Fonnesbeck5, Alice O’Shea1, Michael Green2 and Natasha B. Halasa1 1
Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA, 2Pediatrics, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA, 3Pediatrics, St. Jude Children’s Research Hospital, Memphis, TN, USA, 4Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN, USA, 5Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
Key words: influenza – solid organ transplant – vaccine Natasha Halasa, MD MPH, Associate Professor of Pediatrics, Pediatric Infectious Diseases, 1161 21st Ave South, D7232 MCN, Nashville, TN 37232, USA Tel.: +1 615 322 3346 Fax: +1 615 343 7659 E-mail: [email protected] Accepted for publication 24 November 2014
bacterial pneumonia, and extra-pulmonary complications including myositis and myocarditis (4–7). Additionally, influenza infections in SOT recipients are associated with prolonged periods of viral shedding and allograft rejection (6, 8–10). Influenza vaccination is the primary mode of prevention of influenza infection in pediatric SOT recipients. However, limited data exist in the pediatric solid organ transplant population, with the majority of studies in either kidney or liver transplant recipients (11). In addition, conflicting data exist on immune responses to influenza vaccine in this population. Some studies demonstrate lower antibody responses in SOT recipients when compared to age-matched healthy controls, while another study revealed similar antibody titers, but decreased interferon gamma production in SOT recipients when compared to controls (12–16). Recently, a HD trivalent inactive influenza vaccine 219
GiaQuinta et al.
(Fluzone HD) with four times the standard antigenic dose was approved for use in individuals ≥65 yr of age. Historically, this population has been noted to respond poorly to the standard trivalent inactive influenza vaccine (TIV) when compared to younger adults (17). A phase 3 study found a statistically significant higher antibody response to both influenza A antigens in elderly patients who received the HD vaccine as compared to those receiving the SD TIV, thus leading to its licensure. In addition to significantly higher antibody responses in the population, the HD TIV provided better protection (relative efficacy, 24.2%) against laboratory-confirmed influenza illness than did SD TIV (18). Consequently, as SOT recipients have been noted to have lower titers to antigens included in the influenza vaccine when compared to healthy controls in some trials, it was hypothesized that a higher antigen dose would be safe in this population and may produce a robust immune response compared to standard influenza dosing.
All patients received either the SD TIV (Fluzoneâ; Sanofi Pasteur, Swiftwater, PA, USA) or the HD TIV (Fluzoneâ High Dose; Sanofi Pasteur), which has not yet been approved for pediatric patients. The 2011–2012 influenza vaccination was used in this study. The SD TIV and HD TIV contained 0.5 mL of either 15 or 60 lg, respectively, of each of the following: A/California/7/09 (H1N1)-like virus, A/Perth/16/2009 (H3N2)-like virus, and B/Brisbane/60/ 2008-like virus. Each subject received the vaccination intramuscularly in the right or left deltoid and was observed closely for at least 20 min post-vaccination. If the patient required two doses of the TIV (cohort 2), the doses were separated from each other by 28 (+14) days.
Methods
Study procedures
Study design
Parents or guardians were asked to record solicited reactogenicity events, which included local reactions (pain, tenderness, redness, swelling, and induration at the injection site) and systemic reactions (fevers, fatigue/malaise, headache, nausea, body ache/myalgia, general activity level, and vomiting), for seven days following vaccination. If the subject was 70% of the SD subjects achieving seroprotection for H3N2. Therefore, a phase 2 trial is needed to determine whether the HD influenza vaccine in pediatric SOT recipients will result in higher immunogenicity results compared to SD. Yearly influenza immunization with the inactivated influenza vaccine is recommended for all solid organ transplant recipients (11). However, many unanswered questions remain in this population with regard to routine influenza
HD influenza vaccine vs. standard dose
Fig. 3. The percent of subjects who reported systemic reactions by day in the HD and SD group.
vaccination. For example, in a review of influenza vaccine recommendations, the authors stated that there is insufficient data to recommend high dose, intradermal, or booster doses of influenza vaccines within the same season (11). In addition, the exact timing of when it is safe and effective to deliver the influenza vaccine after transplantation (e.g., 3–6 months after transplant) is not known. Authors of the same manuscript recommend that the influenza vaccines should not be given earlier than three months after transplantation or after intensified immunosuppression for rejection (11). However, in the 2013 IDSA Clinical Practice Guidelines for Vaccination of The Immunocompromised Host, the authors assert that the inactivated influenza vaccine may be administered despite intensive immunosuppression, particularly in an outbreak situation, but the data to support this recommendation are categorized as weak and low (25). In our cohort, we adminis-
tered influenza vaccination a minimum of six months following SOT; however, the median time after transplantation was 2.2 yr. Therefore, further studies are needed to investigate whether earlier influenza vaccination with HD influenza vaccines is safe and effective and whether a repeated dose is needed later in the influenza season when the immunosuppression regimen is waning, and these recipients may respond better to influenza vaccines (15). Influenza disease has been associated with rejection in solid organ recipients (26, 27). Specifically, in lung transplant recipients, influenza may mediate acute and chronic allograft rejection and bronchiolitis obliterans syndrome (28, 29). A theoretical concern and small case reports suggest the possible association of influenza vaccination and rejection (30, 31); however, larger studies do not find an association of graft rejection following influenza vaccination (32–34). As 225
GiaQuinta et al. Table 2. Immune responses before and after vaccination in subjects receiving either HD or SD influenza vaccine by HAI
A/California/7/2009 H1N1 % with ≥1:40 % with ≥4-fold rise Prevaccine GMT (95% CI) Post-vaccine GMT (95% CI) GMT difference estimate (95% CI) A/Perth/16/ 2009 H3N2 % with ≥1:40 % with ≥4-fold rise Prevaccine GMT (95% CI) Post-vaccine GMT (95% CI) GMT difference estimate (95% CI) B/Brisbane/60/2008 % with ≥1:40 % with ≥4-fold rise Prevaccine GMT (95% CI) Post-vaccine GMT (95% CI) GMT difference estimate (95% CI)
HD
SD
95.5% (21/22) 68% (15/22) 77.5 (35.2–170.5) 773.2 (374.6–1363.3) 695.7 (305.3–1299.2)
80% (12/15) 47% (7/15) 62 (20.9–155.1) 310.3 (124–718.4) 248.3 (32.9–681.9)
86% (19/22) 54% (12/22) 34.7 (21–55.7) 131.7 (76.7–233.5) 97 (35.8–194)
80% (12/15) 13% (2/15) 93.3 (47.4–195.5) 136.1 (71.8–254) 42.8 ( 64.4–170.5)
46% (10/22) 18% (4/22) 19.6 (14.2–26.8) 36.8 (23.3–60.6) 17.2 (1.9–42.4)
47% (7/15) 33% (5/15) 21.1 (11.4–48.9) 36.2 (18.9–83.2) 15.1 ( 15.4–62.1)
GMT difference between HD and SD estimate (95% CI)
p-value
0.14 0.19 15.5 ( 94.5–113.8) 462.9 ( 85.9–1112.4)
0.61 0.011 58.6 ( 146.1 to 8.6) 4.4 ( 131–113)
0.94 0.29 1.5 ( 26.7–11.4) 0.6 ( 42.6–32.4)
Boldface indicates significance.
there was increased antigen dose and theoretical potential for induction of rejection after HD influenza vaccination, the study was halted for two wk after the 15th patient was enrolled to monitor for rejection. In our cohort, graft rejection was not associated with influenza vaccination, and only one patient reported graft rejection, which occurred over five months following SD influenza vaccine. Our study did have some limitations. This was a phase 1 study with a small number of patients enrolled, and although we documented few increased local and systemic reactions with the HD TIV, further studies with a larger population are necessary to confirm these findings. Despite recruitment at two sites, our goal of 60 subjects was not achieved due to mandatory two-wk halting rules. Because we included all individuals who have undergone SOT, our population is heterogeneous, which may complicate the immunogenicity results. In addition, the HD group had a higher mean age, even though this was not statistically significant (p = 0.19); this may have played a role in the differences in immune responses. We also did not analyze based on immunosuppressive drug regimens or cell-mediated immune responses to influenza antigens, which may have affected immune responses and may have noted differences between the two groups, respectively (15, 35, 36). In conclusion, our study revealed that the HD TIV is safe and well tolerated in pediatric solid organ recipients when compared to SD TIV. A phase 2 trial is required to adequately assess 226
the immunogenicity of the HD TIV in this population and answer whether HD in this population is a better strategy. More importantly, as influenza continues to cause high morbidity and mortality, and not all pediatric SOT recipients achieve protective titers to SD TIV (15, 37), finding a more effective influenza vaccine for this population could be of great benefit. Authors’ contributions Sarah GiaQuinta, Marian Michaels, Michael Green, and Natasha B. Halasa: Conceptualized and designed the study; participated in the acquisition, analysis, and interpretation of data; helped draft the initial manuscript; and approved the final manuscript as submitted. Jonathan McCullers: Participated in the acquisition, analysis, and interpretation of data; critically reviewed and edited the manuscript; and approved the final manuscript as submitted; Li Wang and Christopher Fonnesbeck: Provided statistical guidance, carried out analyses, helped draft the initial manuscript, and approved the final manuscript as submitted; Alice O’Shea: Conceptualized and designed the study; participated in the acquisition, analysis, and interpretation of data; and approved the final manuscript as submitted.
Acknowledgments We wish to acknowledge the subjects, their families, and the transplant physicians and coordinators that helped in recruitment into this trial. We would also like to acknowledge our ISMs: Judy Martin, S. Elizabeth Williams, and Toni Darville; the research nurses at Pittsburgh Nurses: Noreen Jeffrey and Diane Gwin; and Lee Ann Van De Velde and Shane Gansebom for their excellent technical assistance. The trial was supported by investigator-initiated grant by Sanofi Pasteur. The project publication described was also partially supported by CTSA award No.
HD influenza vaccine vs. standard dose UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.
Disclosures
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Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1 (a) Toxicity grading scale for local reactions. (b) Toxicity grading scale for systemic reactions.
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