Pediatr Blood Cancer 2014;61:1013–1016
Immunogenicity of a 2009 Pandemic Influenza Virus A H1N1 Vaccine, Administered Simultaneously With the Seasonal Influenza Vaccine, in Children Receiving Chemotherapy ffy, MD,1* Petra Horva´th, MD,1 Lajos Muth, MD,1 Alexander So lyom, MD,1 Miklo s Garami, MD, PhD,2 Ga´bor Otto 2 3 1 4 Ga´bor Kova´cs, MD, PhD, Tibor Nya´ri, PhD, De´nes Molna´r, MD, PhD, Ga´bor Pauler, PhD, and Istva´n Jankovics5 Background. No examination of simultaneous vaccination against pandemic H1N1 and the seasonal influenza virus strains, in children with cancer receiving chemotherapy, are yet published. We investigated the immunogenicity of a whole-virion, inactivated, adjuvanted pandemic H1N1, and seasonal influenza vaccines administered simultaneously to children with cancer undergoing chemotherapy. Procedure. We prospectively enrolled 27 pediatric patients receiving therapy for various types of cancer. All received influenza vaccination once in a seasonal risk period. We checked hemaglutination-inhibition (HAI) antibody titers in the sera of patients before, and 21–28 days after vaccination. Seroprotective titer was defined as an antibody titer 40, and seroresponse as 4fold increase in antibody titers after vaccination. Results. The preand post-vaccination seroprotective rates were H1N1: 33–48%, H3N2: 56–78%, B: 0–15% for seasonal influenza, and for pandemic
H1N1: 15–37%. The seroresponse rates for seasonal influenza H1N1, H3N2, and B were 22%, 37%, and 22%, respectively, and 30% for the pandemic H1N1 vaccine. Conclusions. Whole-virion, inactivated, adjuvanted vaccine for the pandemic H1N1 Influenza A virus and the seasonal influenza vaccines were found safe and partially immunogenic in children with cancer receiving chemotherapy. The only determinants of responsiveness were lymphocyte count and serum immunoglobulin-G. Only influenza B vaccine elicited significant differences in differences in pre- and postvaccination seroprotective rates. The response to vaccination for pandemic H1N1 is as effective as other vaccines, however administration of a single vaccine during chemotherapy is more comfortable for pediatric cancer patients. Pediatr Blood Cancer 2014;61:1013–1016. # 2014 Wiley Periodicals, Inc.
Key words: chemotherapy; influenza; pandemic H1N1; pediatric oncology; vaccine
INTRODUCTION Seasonal influenza viruses and the pandemic influenza virus A (2009 H1N1) have caused significant morbidity and mortality around the world. In most patients, infection results in influenzalike symptoms without complications. In patients with cancer, influenza infection can result in prolongation of chemotherapy, and can cause serious complications, even death [1–7]. A possible option to prevent influenza infection and its complications, is vaccination. There is conflicting data regarding the effectiveness of seasonal influenza immunization in children during chemotherapy [8–26]. Randomized controlled trials (RCTs), and controlled clinical trials (CCTs), in which the serologic response to influenza vaccination of children with cancer was compared to other control groups, were analyzed in 2009. A more sufficient immune response was generally found in studies in which the majority of children had completed chemotherapy more than 1 month before vaccination [25]. After 2009, few studies investigated the immune response and safety of vaccines for the pandemic influenza virus A (2009 H1N1) in children with malignancy [26–28]. This prospective study evaluates the immune response and safety of concomittant trivalentinactivated vaccine for seasonal influenza viruses (H1N1A, H3N2A, and B), and monovalent-inactivated vaccine for the 2009 pandemic influenza virus A in children undergoing chemotherapy.
METHODS Patients We enrolled 1–18-year-old children receiving chemotherapy for various types of cancer at the Pediatric Oncohematology Units of the University of Pe´cs and Semmelweis University of Budapest, from November to December, in the years 2009 and 2010. The C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.24893 Published online 3 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
children enrolled for the study were the consecutive patients treated in the respective centers. We excluded children with a recent history of 2009 pandemic A vaccination, confirmed diagnosis of the pandemic influenza A (2009 H1N1) virus infection prior to the vaccination, and past history of allergy to eggs, as well as those who were receiving other vaccines during the study period.
Study Design The vaccination schedule was established according to the recommendation of the Infectology Department of the Hungarian National Healthcare Advisory Board, based on data from the Hungarian National Center of Epidemiology. The protocol for this study was approved by the Institutional Review Boards of the University of Pe´cs and Semmelweis University, Budapest. Sample collections were performed along with the rutin blood sampling involved in cancer treatment. Written consent was obtained from the parents of each child.
1
Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, University of Pe´cs, Pe´cs, Hungary; 2 Division of Pediatric Hematology and Oncology, II Department of Pediatrics, Semmelweis University of Budapest, Budapest, Hungary; 3 Institute for Medical Informatics, University of Szeged, Szeged, Hungary; 4Department of Information Technology, Faculty of Sciences, University of Pe´cs, Pe´cs, Hungary; 5National Centre for Epidemiology, Budapest, Hungary Conflict of interest: Nothing to declare. Correspondence to: Ga´bor Ottoffy, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, University of Pe´cs, Jozsef A.u. 7, 7623 H Pe´cs, Hungary. E-mail: [email protected]
Received 19 July 2013; Accepted 12 November 2013
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Vaccine and Schedule In 2009, the pandemic vaccine (Fluval P-Omninvest, Pilisborosjeno, Hungary) was a monovalent vaccine (with 6 mg hemagglutinin per 0.5 ml and aluminum phosphate gel adjuvant), the seasonal influenza vaccine (Fluval AB7-Omnivest) was a trivalent inactivated whole-virion influenza vaccine [29,30]. In 2010, a polyvalent vaccine containing both the seasonal and the pandemic strains, was produced by a method which met the requirements of the European Agency for the Evaluation of Medicinal Products for interpandemic influenza vaccines [30]. The reassortant vaccine virus strain A/ California/07/2009 H1N1-like NYMC X-179A was developed from an A/California/7/2009 H1N1 virus [31]. The virus strains of the seasonal vaccine (A/Brisbane/59/2007 H1N1-like; A/Brisbane/ 10/2007 H3N2-like; and B/Brisbane/60/2008-like strains) were chosen according to the European Union recommendations for the seasonal influenza vaccine composition for the season 2009– 2010 [32]. It contained 15 mg hemagglutinin per strain per dose. In 2009, for children 10 years old and older, 0.5 ml of the pandemic vaccine (monovalent) was injected into the left deltoid muscle, and 0.5 ml of the seasonal vaccine (trivalent) into the right deltoid muscle. In 2010, for children for children 10 years old and older, 0.5 ml of the combined (pandemic and seasonal vaccine— polyvalent) was administered on the left side. In children younger than 10 years old, 0.25 ml was injected. Vaccination schedule was determined according to the recommendations of the Infectology Department of the Hungarian National Healthcare Advisory Board, based on data from the National Center of Epidemiology, Budapest, Hungary [33]. Vaccination was performed 3–4 weeks after the last chemotherapy administration, and at least 2 days before the next chemotherapy treatment.
adverse events were monitored. On day 21–28, standard medical history and medications used during the days since the last visit were summarized, and physical examination was done before blood samples were collected. Safety variables were collected at follow-up visits through patient history and physical examination.
Statistical Analysis Data were analyzed using paired and Student’s t tests, chi-square test (or Fisher exact test) in the univariate analysis. Then the mixed model was applied to investigate the relationship between the outcome of vaccination (seroprotection/seroconversion) and the measured factors (immunoglobulin level, lymphocyte count, age). For each test, P-value 10 year/0.5 ml Cancer type Hematological malignancies Solid tumors Treatment type at first vaccination Intensive Maintenance Lymphocyte counta Lymphopenic (1.0 G/L) Not lymphopenic (>1.0 G/L) IgG levelb Age related normal Age related normal a
Proportion (%) of patients 15/27 (55.5) 12/27 (44.5) 13/27 (48.1) 14/27 (51.9) 12/27 (44.5) 15/27 (55.5) 22/27 (18.5) 5/27 (81.5) 6/26 (23.0) 20/26 (77.0) 5/19 (26.3) 14/19 (73.7)
Lymphocyte count on day 0 failed in one case; bIgG level on day 0 unavailable in six cases.
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TABLE II. The Pre- and Post-Vaccination Seroprotective Rates, and Seroresponse Rates for Seasonal Influenza Virus Strains and for the Pandemic H1N1Swl
Pre-vaccination seroprotective rates Post-vaccination seroprotective rates Post-vaccination seroresponse rates
H1N1
H3N2
B
H1N1Swl
9 (33.33%) 13 (48%) 6 (22.22%)
15 (55.55%) 21 (77.78%) 10 (37%)
0 (0%) 4 (14.8%) 6 (22.22%)
4 (14.8%) 10 (37%) 8 (29.62%)
H1N1, H3N2, B are seasonal influenza virus strains, and H1N1Swl is the pandemic influenza virus.
than for seasonal B and pandemic H1N1Swl (Fisher exact P < 0.001). The differences between pre- and post-vaccination seroprotective rates in the case of Influenza B were significant (P ¼ 0.038). No significant differences were found between preand post-vaccination seroprotective rate changes with other viruses (H1N1Swl P ¼ 0.064, H1N1 P ¼ 0.277, H3N2 P ¼ 0.160). We compared the pre- and post-vaccination seroprotective rate changes and seroresponse rate of each seasonal Influenza virus with the pandemic H1N1Swl virus by a paired t-test. Neither HAG seroprotective rate changes, nor seroconversion for seasonal H1N1–H1N1Swl, H3N2–H1N1Swl, B–H1N1Swl were significant using this method. Comparing the effect on seroprotection change and seroconversion of each virus type combined with age category (over and below 10 years) using binary logistic regression, there was no significant difference either in seroprotection rate changes or in seroconversion, between the different influenza virus strains. Lymphocyte counts at the time of vaccination were between 0.44 and 7.77 G/L (median: 1.34 G/L). Lymphocyte count above 1.0 G/L was significantly correlated with immune response after influenza vaccination (P ¼ 0.018). On the other hand, lymphocyte count above 1.0 G/L did not have a significant influence on seroprotection change. These results were independent of virus strain. The immunoglobulin G (IgG) levels at the time of vaccination were between 4.27 and 12.8 g/L (median: 7.32 g/L). Most (14/19) of the patients, had age related normal level of IgG at the time of vaccination. This was significantly correlated with immune response after influenza vaccination, independently of virus strain (P ¼ 0.01). Age related normal IgG level did not have a significant influence on seroprotection change (P ¼ 0.063). Type of malignancy and status of cancer therapy (maintenance or intensive treatment) did not significantly influence seroprotection change or seroconversion. There were no breakthrough influenza infections, and neither of the nonvaccinated patients suffered from influenza during this period.
Adverse Reactions We recorded no local adverse reactions (e.g., injection site induration, erythema, swelling, or warmth). One case of malaise (3.7%) was detected on the day after vaccination. No medical intervention was necessary. No vaccine related serious adverse events were observed.
DISCUSSION The purpose of this study was to investigate the efficacy and safety of concomittant trivalent-inactivated vaccines for seasonal influenza viruses (H1N1A, H3N2A, and B), monovalent-inactivated vaccine for the 2009 pandemic influenza virus A, and a Pediatr Blood Cancer DOI 10.1002/pbc
combined (pandemic and seasonal vaccine—polyvalent) vaccine in 2010, in children with cancer undergoing chemotherapy. Vaccinations (H1N1A, H3N2A, B, and pandemic H1N1Swl) produced no significant adverse events, but resulted in limited seroresponse rates (22%, 37%, 22%, and 30%, respectively). These results were similar to response rates reported earlier for influenza viruses [8–26], and recently for pandemic influenza virus A [26–28]. Pre-vaccination seroprotective rates were significantly higher for seasonal influenza viruses H1N1A and H3N2A, than for seasonal B and pandemic H1N1Sw viruses (Table II). A possible explanation is that a significant time elapsed since the last Influenza B epidemic (2004–2005) affecting our region, while the H1N1Swl pandemic started at the time of vaccination in our study. The four detected seroprotective titers for pandemic H1N1Sw virus were all from samples obtained in 2010, and all patients had received a vaccination one year earlier. On the other hand, Influenza virus H3N2A is highly immunogenic, and seasonal Influenza virus H1N1A has a high circulate tendency. Our patients were receiving chemotherapy at the time of vaccination, thus limited seroprotection changes and seroresponse rates were expected. The proportion of patients achieving protective antibody levels to individual viral strains following vaccination has been reported to be 29–75% in children on chemotherapy [8,12,23]. A metaanalysis (Cochrane Database Syst Rev. 2013) has reported on the efficacy of influenza vaccination in stimulating an immunological response in children with cancer during chemotherapy, compared with control groups. Immune responses in children receiving chemotherapy were consistently weaker (fourfold rise of 38–65%) than those in children who had completed chemotherapy (50–86%) and in healthy children (53–89%) [35–38]. A pre-pandemic influenza A (H5N1) vaccine, prepared with same method (Fluval-Omninvest) as the vaccine used in this trial, was assessed in healthy children, where the rate of seroconversion was 75% and the rate of seroprotection was also 75%, 21 days after vaccination [39]. In this study, 15–78% of children achieved protective antibody levels to individual viral strains following vaccination. However, post-vaccination seroprotection rates were significantly, or nearly significantly higher than pre-vaccination rates in the case of Influenza virus B (pre-: 0%; post-vaccination: 15%, P ¼ 0.038), and pandemic H1N1Swl (pre-: 14.8%; post-vaccination: 37%, P ¼ 0.064). The significant difference in seroprotection changes may due not to the type of vaccine, but to the low pre-vaccination titers, specific to the two viruses mentioned above. In the present study, all children were receiving chemotherapy, and an immune response was observed in 22–37% of children. There was no significant difference in either postvaccination seroprotection change or seroconversion of the different seasonal influenza viruses when compared with the pandemic H1N1Swl virus, results similar to those obtained in healthy people [29].
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According to the vaccination recommendations for children below the age of 10 years, half the adult dose was used. Neither the type of vaccine (a trivalent seasonal vaccine and a monovalent pandemic H1N1Swl vaccine in 2009, and a polyvalent seasonal and pandemic vaccine in 2010), nor the age of patients, influenced the immune response and immunologic protection in our study. There is controversial data regarding lymphocyte count, and serum IgG level [8,9,12,13,14,15,26], as factors responsible for immune response after administration of influenza vaccine in children with cancer undergoing chemotherapy. The present study demonstrates that, for both seasonal viruses and the pandemic H1N1 virus, lymphocyte count above 1.0 G/L, and normal IgG level has significant influence on the immune response after vaccination. The immunoglobulin G (IgG) levels at the time of vaccination were in the normal range in most of our patients. One of the possible explanations of the normal values among patients treated with chemotherapy is, that half of the patients with the leukemia were already on maintenance therapy. On the other hand most of our patients had solid tumors. These underlying diseases in general do not affect the immunsystem and their treatment is often less myelosuppressive. Several reports suggest that a two-dose influenza vaccination series produces a better immune response than a one-dose vaccine for oncology patients receiving chemotherapy [8,11,12,13,15,23]. However, a recent comparison of the rates of seroconversion and seroprotection between patients who received two doses of H1N1 vaccine, and those who received one dose, did not show any significant difference [26]. In our study, we could only compare our results to those of other similar studies, being that we used a onedose vaccine. This study has several limitations. The patient sample was quite heterogeneous regarding the specific underlying diseases and type of cytostatic treatment. Statistically the study sample size was small and no control group was established. Therefore our findings should be treated with caution. On the other hand, we tried to counterbalance it with selecting patients into sample mostly received parenteral cytostatic treatment. Moreover, we published only results with p value under 1% and omitted nearly all plausible but not strictly provable findings (1% < P < 5%). Finally, safety measure we compared our findings with literature, whether they confirm mainstream theories.
CONCLUSION This report investigated on vaccination against pandemic H1N1 and the seasonal influenza viruses simultaneously, in children with cancer receiving chemotherapy. We confirmed that present pandemic vaccine can be safely co-administered with the 2009– 2010 seasonal influenza vaccine even in this population. There was no significant difference in either post-vaccination seroprotection change or seroconversion of the different seasonal influenza viruses when compared with the pandemic H1N1Swl virus. This strategy may enhance seroresponse to influenza vaccination if the absolute lymphocyte count is above 1.0 G/L, and IgG levels are in the age related normal reference range. These results were achieved with single-dose vaccines, which were well tolerated. Randomized control trials with larger sample sizes are needed to determine the
Pediatr Blood Cancer DOI 10.1002/pbc
optimal influenza vaccination regimen, with regard to timing, dosage, number of doses, and adjuvantation of the vaccine.
REFERENCES 1. Kempe A, Hall CB, MacDonald NE, et al. Influenza in children with cancer. J Pediatr 1989;115:33–39. 2. Feldman S, Webster RG, Sugg M. Influenza in children and young adults with cancer: 20 cases. Cancer 1977;39:350–353. 3. Tasian SK, Park JR, Martin ET, et al. Influenza-associated morbidity in children with cancer. Pediatr Blood Cancer 2008;50:983–987. 4. Potter MN, Foot AB, Oakhill A. Influenza A and the virus associated haemophagocytic syndrome: Cluster of three cases in children with acute leukaemia. J Clin Pathol 1991;44:297–299. 5. Caselli D, Carraro F, Castagnola E, et al. Morbidity of pandemic H1N1 influenza in children with cancer. Pediatr Blood Cancer 2010;55:226–228. 6. Hajjar LA, Mauad T. Galas FR severe novel influenza A (H1N1) infection in cancer patients. Ann Oncol 2010;21:2333–2341. 7. Launes C, Rives S, Catala` A, et al. Pandemic influenza A (2009 H1N1) in children with acute lymphoblastic leukaemia. Br J Haematol 2010;149:874–878. 8. Chisholm JC, Devine T, Charlett A, et al. Response to influenza immunisation during treatment for cancer. Arch Dis Child 2001;84:496–500. 9. Chisholm J, Howe K, Taj M, et al. Influenza immunization in children with solid tumours. Eur J Cancer 2005;41:2280–2287. 10. Gross PA, Lee H, Wolff JA, et al. Influenza immunization in immunosuppressed children. J Pediatr 1978;92:30–35. 11. Hsieh Y, Lu MY, Kao CL, et al. Response to influenza vaccine in children with leukemia undergoing chemotherapy [RCT]. J Formos Med Assoc 2002;101:700–704. 12. Lange B, Shapiro SA, Waldman MT, et al. Antibody responses to influenza immunization of children with acute lymphoblastic leukemia. J Infect Dis 1979;140:402–406. 13. Matsuzaki A, Suminoe A, Koga Y, et al. Immune response after influenza vaccination in children with cancer. Pediatr Blood Cancer 2005;45:831–837. 14. Porter CC, Edwards KM, Zhu Y, et al. Immune responses to influenza immunization in children receiving maintenance chemotherapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 2004;42:36–40. 15. Steinherz PG, Brown AE, Gross PA, et al. Influenza immunization of children with neoplastic diseases. Cancer 1980;45:750–756. 16. Smithson WA, Siem RA, Ritts RE, et al. Response to influenza virus vaccine in children receiving chemotherapy for malignancy. J Pediatr 1978;93:632–634. 17. Brown AE, Steinherz PG, Miller DR, et al. Immunization against influenza in children with cancer: Results of a three-dose trial. J Infect Dis 1982;145:126. 18. Brydak LB, Rokicka-Milewska R, Jackowska T, et al. Kinetics of humoral response in children with acute lymphoblastic leukemia immunized with influenza vaccine in 1993 in Poland. Leuk Lymphoma 1997;26:163–169. 19. Brydak LB, Rokicka-Milewska R, Machala M, et al. Immunogenicity of subunit trivalent influenza vaccine in children with acute lymphoblastic leukemia. Pediatr Infect Dis J 1998;17:125–129. 20. Feery BJ, Matthews RN, Evered MG, et al. Antibody responses to influenza virus vaccine in patients with acute lymphocytic leukaemia. Aust Paediatr J 1979;15:177–180. 21. Ganz PA, Shanley JD, Cherry JD. Responses of patients with neoplastic diseases to influenza virus vaccine. Cancer 1978;42:2244–2247. 22. Gross PA, Gould AL, Brown AE. Effect of chemotherapy on the immune response to influenza virus vaccine: Review of published studies. Rev Infect Dis 1985;7:613–618. 23. Sumaya CV, Williams TE, Brunell PA. Bivalent influenza vaccine in children with cancer. J Infect Dis 1977;136:S656–S660. 24. Sumaya CV, Williams TE. Persistence of antibody after the administration of influenza vaccine to children with cancer. Pediatrics 1982;69:226–229. 25. Goossen GM, Kremer LCM, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer (Review). Cochrane Libr 2009; 2. 26. Hakim H, Allison KJ, Van De Velde LA, et al. Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults. Vaccine 2012;30:879– 885. 27. Bate J, Yung CF, Hoschler K, et al. Immunogenicity of pandemic (H1N1) 2009 vaccine in children with cancer in the United Kingdom. Clin Infect Dis 2010;51:e95–e104. 28. Yen TY, Jou ST, Yang YL, et al. Immune response to 2009 pandemic H1N1 influenza virus A monovalent vaccine in children with cancer. Pediatr Blood Cancer 2011;57:1154–1158. doi: 10.1002/pbc.23113 29. Vajo Z, Tamas F, Sinka L, et al. Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: A multicentre, randomised controlled trial. Lancet 2010;375:49–55. 30. Vajo Z, Kosa L, Szilva´sy I, et al. Yearly licensing studies from 1997 to 2007 of the inactivated whole virus seasonal influenza vaccine fluval—A useful approach to pandemic vaccine development even in less well developed countries? Influenza Other Respir Viruses 2008;2:211–218. 31. WHO. Availability of a candidate reassortant vaccine virus for the novel influenza A (H1N1) vaccine development. June, 2009; http://www.who.int/csr/resources/publications/swineflu/ivr153_20090608_en. pdf (accessed October 9, 2009). 32. European Directoriate for the Quality Medicines. European Pharmacopia, 5.8 CD, 7/2007 Strasbourg: European Directoriate for the Quality Medicines, 2007: 3406–3407. 33. Weekly epidemiological information and recommendations of the National Center for Epidemiology, Budapest, Hungary. 2009; December 04: 601–605 (in Hungarian). 34. Klimov A, Cox N. Serologic diagnosis of influenza virus infections by hemagglutination inhibition. Influenza Laboratory Course. Atlanta: Centres for Disease Control; 2003. 35. Ruben FL. Inactivated influenza virus vaccines in children. Clin Infect Dis 2004;38:678–688. 36. Harper SA, Fukuda K, Uyeki TM, et al. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2004;53:1–40. 37. Neuzil KM, Dupont WD, Wright PF, et al. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: The pediatric experience. Pediatr Infect Dis J 2001;20:733–740. 38. Goossen GM, Kremer LC, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer. Cochrane Database Syst Rev 2013;8:CD006484. 39. Vajo Z, Kosa L, Szilvasy I, et al. Safety and immunogenicity of a prepandemic influenza A (H5N1) vaccine in children. Pediatr Infect Dis J 2008;27:1052–1056.
Immunogenicity of a 2009 Pandemic Influenza Virus A H1N1 Vaccine, Administered Simultaneously With the Seasonal Influenza Vaccine, in Children Receiving Chemotherapy ffy, MD,1* Petra Horva´th, MD,1 Lajos Muth, MD,1 Alexander So lyom, MD,1 Miklo s Garami, MD, PhD,2 Ga´bor Otto 2 3 1 4 Ga´bor Kova´cs, MD, PhD, Tibor Nya´ri, PhD, De´nes Molna´r, MD, PhD, Ga´bor Pauler, PhD, and Istva´n Jankovics5 Background. No examination of simultaneous vaccination against pandemic H1N1 and the seasonal influenza virus strains, in children with cancer receiving chemotherapy, are yet published. We investigated the immunogenicity of a whole-virion, inactivated, adjuvanted pandemic H1N1, and seasonal influenza vaccines administered simultaneously to children with cancer undergoing chemotherapy. Procedure. We prospectively enrolled 27 pediatric patients receiving therapy for various types of cancer. All received influenza vaccination once in a seasonal risk period. We checked hemaglutination-inhibition (HAI) antibody titers in the sera of patients before, and 21–28 days after vaccination. Seroprotective titer was defined as an antibody titer 40, and seroresponse as 4fold increase in antibody titers after vaccination. Results. The preand post-vaccination seroprotective rates were H1N1: 33–48%, H3N2: 56–78%, B: 0–15% for seasonal influenza, and for pandemic
H1N1: 15–37%. The seroresponse rates for seasonal influenza H1N1, H3N2, and B were 22%, 37%, and 22%, respectively, and 30% for the pandemic H1N1 vaccine. Conclusions. Whole-virion, inactivated, adjuvanted vaccine for the pandemic H1N1 Influenza A virus and the seasonal influenza vaccines were found safe and partially immunogenic in children with cancer receiving chemotherapy. The only determinants of responsiveness were lymphocyte count and serum immunoglobulin-G. Only influenza B vaccine elicited significant differences in differences in pre- and postvaccination seroprotective rates. The response to vaccination for pandemic H1N1 is as effective as other vaccines, however administration of a single vaccine during chemotherapy is more comfortable for pediatric cancer patients. Pediatr Blood Cancer 2014;61:1013–1016. # 2014 Wiley Periodicals, Inc.
Key words: chemotherapy; influenza; pandemic H1N1; pediatric oncology; vaccine
INTRODUCTION Seasonal influenza viruses and the pandemic influenza virus A (2009 H1N1) have caused significant morbidity and mortality around the world. In most patients, infection results in influenzalike symptoms without complications. In patients with cancer, influenza infection can result in prolongation of chemotherapy, and can cause serious complications, even death [1–7]. A possible option to prevent influenza infection and its complications, is vaccination. There is conflicting data regarding the effectiveness of seasonal influenza immunization in children during chemotherapy [8–26]. Randomized controlled trials (RCTs), and controlled clinical trials (CCTs), in which the serologic response to influenza vaccination of children with cancer was compared to other control groups, were analyzed in 2009. A more sufficient immune response was generally found in studies in which the majority of children had completed chemotherapy more than 1 month before vaccination [25]. After 2009, few studies investigated the immune response and safety of vaccines for the pandemic influenza virus A (2009 H1N1) in children with malignancy [26–28]. This prospective study evaluates the immune response and safety of concomittant trivalentinactivated vaccine for seasonal influenza viruses (H1N1A, H3N2A, and B), and monovalent-inactivated vaccine for the 2009 pandemic influenza virus A in children undergoing chemotherapy.
METHODS Patients We enrolled 1–18-year-old children receiving chemotherapy for various types of cancer at the Pediatric Oncohematology Units of the University of Pe´cs and Semmelweis University of Budapest, from November to December, in the years 2009 and 2010. The C
2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.24893 Published online 3 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
children enrolled for the study were the consecutive patients treated in the respective centers. We excluded children with a recent history of 2009 pandemic A vaccination, confirmed diagnosis of the pandemic influenza A (2009 H1N1) virus infection prior to the vaccination, and past history of allergy to eggs, as well as those who were receiving other vaccines during the study period.
Study Design The vaccination schedule was established according to the recommendation of the Infectology Department of the Hungarian National Healthcare Advisory Board, based on data from the Hungarian National Center of Epidemiology. The protocol for this study was approved by the Institutional Review Boards of the University of Pe´cs and Semmelweis University, Budapest. Sample collections were performed along with the rutin blood sampling involved in cancer treatment. Written consent was obtained from the parents of each child.
1
Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, University of Pe´cs, Pe´cs, Hungary; 2 Division of Pediatric Hematology and Oncology, II Department of Pediatrics, Semmelweis University of Budapest, Budapest, Hungary; 3 Institute for Medical Informatics, University of Szeged, Szeged, Hungary; 4Department of Information Technology, Faculty of Sciences, University of Pe´cs, Pe´cs, Hungary; 5National Centre for Epidemiology, Budapest, Hungary Conflict of interest: Nothing to declare. Correspondence to: Ga´bor Ottoffy, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, University of Pe´cs, Jozsef A.u. 7, 7623 H Pe´cs, Hungary. E-mail: [email protected]
Received 19 July 2013; Accepted 12 November 2013
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Vaccine and Schedule In 2009, the pandemic vaccine (Fluval P-Omninvest, Pilisborosjeno, Hungary) was a monovalent vaccine (with 6 mg hemagglutinin per 0.5 ml and aluminum phosphate gel adjuvant), the seasonal influenza vaccine (Fluval AB7-Omnivest) was a trivalent inactivated whole-virion influenza vaccine [29,30]. In 2010, a polyvalent vaccine containing both the seasonal and the pandemic strains, was produced by a method which met the requirements of the European Agency for the Evaluation of Medicinal Products for interpandemic influenza vaccines [30]. The reassortant vaccine virus strain A/ California/07/2009 H1N1-like NYMC X-179A was developed from an A/California/7/2009 H1N1 virus [31]. The virus strains of the seasonal vaccine (A/Brisbane/59/2007 H1N1-like; A/Brisbane/ 10/2007 H3N2-like; and B/Brisbane/60/2008-like strains) were chosen according to the European Union recommendations for the seasonal influenza vaccine composition for the season 2009– 2010 [32]. It contained 15 mg hemagglutinin per strain per dose. In 2009, for children 10 years old and older, 0.5 ml of the pandemic vaccine (monovalent) was injected into the left deltoid muscle, and 0.5 ml of the seasonal vaccine (trivalent) into the right deltoid muscle. In 2010, for children for children 10 years old and older, 0.5 ml of the combined (pandemic and seasonal vaccine— polyvalent) was administered on the left side. In children younger than 10 years old, 0.25 ml was injected. Vaccination schedule was determined according to the recommendations of the Infectology Department of the Hungarian National Healthcare Advisory Board, based on data from the National Center of Epidemiology, Budapest, Hungary [33]. Vaccination was performed 3–4 weeks after the last chemotherapy administration, and at least 2 days before the next chemotherapy treatment.
adverse events were monitored. On day 21–28, standard medical history and medications used during the days since the last visit were summarized, and physical examination was done before blood samples were collected. Safety variables were collected at follow-up visits through patient history and physical examination.
Statistical Analysis Data were analyzed using paired and Student’s t tests, chi-square test (or Fisher exact test) in the univariate analysis. Then the mixed model was applied to investigate the relationship between the outcome of vaccination (seroprotection/seroconversion) and the measured factors (immunoglobulin level, lymphocyte count, age). For each test, P-value 10 year/0.5 ml Cancer type Hematological malignancies Solid tumors Treatment type at first vaccination Intensive Maintenance Lymphocyte counta Lymphopenic (1.0 G/L) Not lymphopenic (>1.0 G/L) IgG levelb Age related normal Age related normal a
Proportion (%) of patients 15/27 (55.5) 12/27 (44.5) 13/27 (48.1) 14/27 (51.9) 12/27 (44.5) 15/27 (55.5) 22/27 (18.5) 5/27 (81.5) 6/26 (23.0) 20/26 (77.0) 5/19 (26.3) 14/19 (73.7)
Lymphocyte count on day 0 failed in one case; bIgG level on day 0 unavailable in six cases.
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TABLE II. The Pre- and Post-Vaccination Seroprotective Rates, and Seroresponse Rates for Seasonal Influenza Virus Strains and for the Pandemic H1N1Swl
Pre-vaccination seroprotective rates Post-vaccination seroprotective rates Post-vaccination seroresponse rates
H1N1
H3N2
B
H1N1Swl
9 (33.33%) 13 (48%) 6 (22.22%)
15 (55.55%) 21 (77.78%) 10 (37%)
0 (0%) 4 (14.8%) 6 (22.22%)
4 (14.8%) 10 (37%) 8 (29.62%)
H1N1, H3N2, B are seasonal influenza virus strains, and H1N1Swl is the pandemic influenza virus.
than for seasonal B and pandemic H1N1Swl (Fisher exact P < 0.001). The differences between pre- and post-vaccination seroprotective rates in the case of Influenza B were significant (P ¼ 0.038). No significant differences were found between preand post-vaccination seroprotective rate changes with other viruses (H1N1Swl P ¼ 0.064, H1N1 P ¼ 0.277, H3N2 P ¼ 0.160). We compared the pre- and post-vaccination seroprotective rate changes and seroresponse rate of each seasonal Influenza virus with the pandemic H1N1Swl virus by a paired t-test. Neither HAG seroprotective rate changes, nor seroconversion for seasonal H1N1–H1N1Swl, H3N2–H1N1Swl, B–H1N1Swl were significant using this method. Comparing the effect on seroprotection change and seroconversion of each virus type combined with age category (over and below 10 years) using binary logistic regression, there was no significant difference either in seroprotection rate changes or in seroconversion, between the different influenza virus strains. Lymphocyte counts at the time of vaccination were between 0.44 and 7.77 G/L (median: 1.34 G/L). Lymphocyte count above 1.0 G/L was significantly correlated with immune response after influenza vaccination (P ¼ 0.018). On the other hand, lymphocyte count above 1.0 G/L did not have a significant influence on seroprotection change. These results were independent of virus strain. The immunoglobulin G (IgG) levels at the time of vaccination were between 4.27 and 12.8 g/L (median: 7.32 g/L). Most (14/19) of the patients, had age related normal level of IgG at the time of vaccination. This was significantly correlated with immune response after influenza vaccination, independently of virus strain (P ¼ 0.01). Age related normal IgG level did not have a significant influence on seroprotection change (P ¼ 0.063). Type of malignancy and status of cancer therapy (maintenance or intensive treatment) did not significantly influence seroprotection change or seroconversion. There were no breakthrough influenza infections, and neither of the nonvaccinated patients suffered from influenza during this period.
Adverse Reactions We recorded no local adverse reactions (e.g., injection site induration, erythema, swelling, or warmth). One case of malaise (3.7%) was detected on the day after vaccination. No medical intervention was necessary. No vaccine related serious adverse events were observed.
DISCUSSION The purpose of this study was to investigate the efficacy and safety of concomittant trivalent-inactivated vaccines for seasonal influenza viruses (H1N1A, H3N2A, and B), monovalent-inactivated vaccine for the 2009 pandemic influenza virus A, and a Pediatr Blood Cancer DOI 10.1002/pbc
combined (pandemic and seasonal vaccine—polyvalent) vaccine in 2010, in children with cancer undergoing chemotherapy. Vaccinations (H1N1A, H3N2A, B, and pandemic H1N1Swl) produced no significant adverse events, but resulted in limited seroresponse rates (22%, 37%, 22%, and 30%, respectively). These results were similar to response rates reported earlier for influenza viruses [8–26], and recently for pandemic influenza virus A [26–28]. Pre-vaccination seroprotective rates were significantly higher for seasonal influenza viruses H1N1A and H3N2A, than for seasonal B and pandemic H1N1Sw viruses (Table II). A possible explanation is that a significant time elapsed since the last Influenza B epidemic (2004–2005) affecting our region, while the H1N1Swl pandemic started at the time of vaccination in our study. The four detected seroprotective titers for pandemic H1N1Sw virus were all from samples obtained in 2010, and all patients had received a vaccination one year earlier. On the other hand, Influenza virus H3N2A is highly immunogenic, and seasonal Influenza virus H1N1A has a high circulate tendency. Our patients were receiving chemotherapy at the time of vaccination, thus limited seroprotection changes and seroresponse rates were expected. The proportion of patients achieving protective antibody levels to individual viral strains following vaccination has been reported to be 29–75% in children on chemotherapy [8,12,23]. A metaanalysis (Cochrane Database Syst Rev. 2013) has reported on the efficacy of influenza vaccination in stimulating an immunological response in children with cancer during chemotherapy, compared with control groups. Immune responses in children receiving chemotherapy were consistently weaker (fourfold rise of 38–65%) than those in children who had completed chemotherapy (50–86%) and in healthy children (53–89%) [35–38]. A pre-pandemic influenza A (H5N1) vaccine, prepared with same method (Fluval-Omninvest) as the vaccine used in this trial, was assessed in healthy children, where the rate of seroconversion was 75% and the rate of seroprotection was also 75%, 21 days after vaccination [39]. In this study, 15–78% of children achieved protective antibody levels to individual viral strains following vaccination. However, post-vaccination seroprotection rates were significantly, or nearly significantly higher than pre-vaccination rates in the case of Influenza virus B (pre-: 0%; post-vaccination: 15%, P ¼ 0.038), and pandemic H1N1Swl (pre-: 14.8%; post-vaccination: 37%, P ¼ 0.064). The significant difference in seroprotection changes may due not to the type of vaccine, but to the low pre-vaccination titers, specific to the two viruses mentioned above. In the present study, all children were receiving chemotherapy, and an immune response was observed in 22–37% of children. There was no significant difference in either postvaccination seroprotection change or seroconversion of the different seasonal influenza viruses when compared with the pandemic H1N1Swl virus, results similar to those obtained in healthy people [29].
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According to the vaccination recommendations for children below the age of 10 years, half the adult dose was used. Neither the type of vaccine (a trivalent seasonal vaccine and a monovalent pandemic H1N1Swl vaccine in 2009, and a polyvalent seasonal and pandemic vaccine in 2010), nor the age of patients, influenced the immune response and immunologic protection in our study. There is controversial data regarding lymphocyte count, and serum IgG level [8,9,12,13,14,15,26], as factors responsible for immune response after administration of influenza vaccine in children with cancer undergoing chemotherapy. The present study demonstrates that, for both seasonal viruses and the pandemic H1N1 virus, lymphocyte count above 1.0 G/L, and normal IgG level has significant influence on the immune response after vaccination. The immunoglobulin G (IgG) levels at the time of vaccination were in the normal range in most of our patients. One of the possible explanations of the normal values among patients treated with chemotherapy is, that half of the patients with the leukemia were already on maintenance therapy. On the other hand most of our patients had solid tumors. These underlying diseases in general do not affect the immunsystem and their treatment is often less myelosuppressive. Several reports suggest that a two-dose influenza vaccination series produces a better immune response than a one-dose vaccine for oncology patients receiving chemotherapy [8,11,12,13,15,23]. However, a recent comparison of the rates of seroconversion and seroprotection between patients who received two doses of H1N1 vaccine, and those who received one dose, did not show any significant difference [26]. In our study, we could only compare our results to those of other similar studies, being that we used a onedose vaccine. This study has several limitations. The patient sample was quite heterogeneous regarding the specific underlying diseases and type of cytostatic treatment. Statistically the study sample size was small and no control group was established. Therefore our findings should be treated with caution. On the other hand, we tried to counterbalance it with selecting patients into sample mostly received parenteral cytostatic treatment. Moreover, we published only results with p value under 1% and omitted nearly all plausible but not strictly provable findings (1% < P < 5%). Finally, safety measure we compared our findings with literature, whether they confirm mainstream theories.
CONCLUSION This report investigated on vaccination against pandemic H1N1 and the seasonal influenza viruses simultaneously, in children with cancer receiving chemotherapy. We confirmed that present pandemic vaccine can be safely co-administered with the 2009– 2010 seasonal influenza vaccine even in this population. There was no significant difference in either post-vaccination seroprotection change or seroconversion of the different seasonal influenza viruses when compared with the pandemic H1N1Swl virus. This strategy may enhance seroresponse to influenza vaccination if the absolute lymphocyte count is above 1.0 G/L, and IgG levels are in the age related normal reference range. These results were achieved with single-dose vaccines, which were well tolerated. Randomized control trials with larger sample sizes are needed to determine the
Pediatr Blood Cancer DOI 10.1002/pbc
optimal influenza vaccination regimen, with regard to timing, dosage, number of doses, and adjuvantation of the vaccine.
REFERENCES 1. Kempe A, Hall CB, MacDonald NE, et al. Influenza in children with cancer. J Pediatr 1989;115:33–39. 2. Feldman S, Webster RG, Sugg M. Influenza in children and young adults with cancer: 20 cases. Cancer 1977;39:350–353. 3. Tasian SK, Park JR, Martin ET, et al. Influenza-associated morbidity in children with cancer. Pediatr Blood Cancer 2008;50:983–987. 4. Potter MN, Foot AB, Oakhill A. Influenza A and the virus associated haemophagocytic syndrome: Cluster of three cases in children with acute leukaemia. J Clin Pathol 1991;44:297–299. 5. Caselli D, Carraro F, Castagnola E, et al. Morbidity of pandemic H1N1 influenza in children with cancer. Pediatr Blood Cancer 2010;55:226–228. 6. Hajjar LA, Mauad T. Galas FR severe novel influenza A (H1N1) infection in cancer patients. Ann Oncol 2010;21:2333–2341. 7. Launes C, Rives S, Catala` A, et al. Pandemic influenza A (2009 H1N1) in children with acute lymphoblastic leukaemia. Br J Haematol 2010;149:874–878. 8. Chisholm JC, Devine T, Charlett A, et al. Response to influenza immunisation during treatment for cancer. Arch Dis Child 2001;84:496–500. 9. Chisholm J, Howe K, Taj M, et al. Influenza immunization in children with solid tumours. Eur J Cancer 2005;41:2280–2287. 10. Gross PA, Lee H, Wolff JA, et al. Influenza immunization in immunosuppressed children. J Pediatr 1978;92:30–35. 11. Hsieh Y, Lu MY, Kao CL, et al. Response to influenza vaccine in children with leukemia undergoing chemotherapy [RCT]. J Formos Med Assoc 2002;101:700–704. 12. Lange B, Shapiro SA, Waldman MT, et al. Antibody responses to influenza immunization of children with acute lymphoblastic leukemia. J Infect Dis 1979;140:402–406. 13. Matsuzaki A, Suminoe A, Koga Y, et al. Immune response after influenza vaccination in children with cancer. Pediatr Blood Cancer 2005;45:831–837. 14. Porter CC, Edwards KM, Zhu Y, et al. Immune responses to influenza immunization in children receiving maintenance chemotherapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 2004;42:36–40. 15. Steinherz PG, Brown AE, Gross PA, et al. Influenza immunization of children with neoplastic diseases. Cancer 1980;45:750–756. 16. Smithson WA, Siem RA, Ritts RE, et al. Response to influenza virus vaccine in children receiving chemotherapy for malignancy. J Pediatr 1978;93:632–634. 17. Brown AE, Steinherz PG, Miller DR, et al. Immunization against influenza in children with cancer: Results of a three-dose trial. J Infect Dis 1982;145:126. 18. Brydak LB, Rokicka-Milewska R, Jackowska T, et al. Kinetics of humoral response in children with acute lymphoblastic leukemia immunized with influenza vaccine in 1993 in Poland. Leuk Lymphoma 1997;26:163–169. 19. Brydak LB, Rokicka-Milewska R, Machala M, et al. Immunogenicity of subunit trivalent influenza vaccine in children with acute lymphoblastic leukemia. Pediatr Infect Dis J 1998;17:125–129. 20. Feery BJ, Matthews RN, Evered MG, et al. Antibody responses to influenza virus vaccine in patients with acute lymphocytic leukaemia. Aust Paediatr J 1979;15:177–180. 21. Ganz PA, Shanley JD, Cherry JD. Responses of patients with neoplastic diseases to influenza virus vaccine. Cancer 1978;42:2244–2247. 22. Gross PA, Gould AL, Brown AE. Effect of chemotherapy on the immune response to influenza virus vaccine: Review of published studies. Rev Infect Dis 1985;7:613–618. 23. Sumaya CV, Williams TE, Brunell PA. Bivalent influenza vaccine in children with cancer. J Infect Dis 1977;136:S656–S660. 24. Sumaya CV, Williams TE. Persistence of antibody after the administration of influenza vaccine to children with cancer. Pediatrics 1982;69:226–229. 25. Goossen GM, Kremer LCM, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer (Review). Cochrane Libr 2009; 2. 26. Hakim H, Allison KJ, Van De Velde LA, et al. Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults. Vaccine 2012;30:879– 885. 27. Bate J, Yung CF, Hoschler K, et al. Immunogenicity of pandemic (H1N1) 2009 vaccine in children with cancer in the United Kingdom. Clin Infect Dis 2010;51:e95–e104. 28. Yen TY, Jou ST, Yang YL, et al. Immune response to 2009 pandemic H1N1 influenza virus A monovalent vaccine in children with cancer. Pediatr Blood Cancer 2011;57:1154–1158. doi: 10.1002/pbc.23113 29. Vajo Z, Tamas F, Sinka L, et al. Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: A multicentre, randomised controlled trial. Lancet 2010;375:49–55. 30. Vajo Z, Kosa L, Szilva´sy I, et al. Yearly licensing studies from 1997 to 2007 of the inactivated whole virus seasonal influenza vaccine fluval—A useful approach to pandemic vaccine development even in less well developed countries? Influenza Other Respir Viruses 2008;2:211–218. 31. WHO. Availability of a candidate reassortant vaccine virus for the novel influenza A (H1N1) vaccine development. June, 2009; http://www.who.int/csr/resources/publications/swineflu/ivr153_20090608_en. pdf (accessed October 9, 2009). 32. European Directoriate for the Quality Medicines. European Pharmacopia, 5.8 CD, 7/2007 Strasbourg: European Directoriate for the Quality Medicines, 2007: 3406–3407. 33. Weekly epidemiological information and recommendations of the National Center for Epidemiology, Budapest, Hungary. 2009; December 04: 601–605 (in Hungarian). 34. Klimov A, Cox N. Serologic diagnosis of influenza virus infections by hemagglutination inhibition. Influenza Laboratory Course. Atlanta: Centres for Disease Control; 2003. 35. Ruben FL. Inactivated influenza virus vaccines in children. Clin Infect Dis 2004;38:678–688. 36. Harper SA, Fukuda K, Uyeki TM, et al. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2004;53:1–40. 37. Neuzil KM, Dupont WD, Wright PF, et al. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: The pediatric experience. Pediatr Infect Dis J 2001;20:733–740. 38. Goossen GM, Kremer LC, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer. Cochrane Database Syst Rev 2013;8:CD006484. 39. Vajo Z, Kosa L, Szilvasy I, et al. Safety and immunogenicity of a prepandemic influenza A (H5N1) vaccine in children. Pediatr Infect Dis J 2008;27:1052–1056.
