To the Editor:
Autologous stem cell transplant (SCT) is an upfront therapeutic modality for children with malignancies such as high-risk neuroblastoma and atypical teratoid rhabdoid tumour and a salvage option for children with lymphoma and a variety of solid tumours. The administration of high-dose myeloablative chemotherapy during conditioning increases vulnerability to infection. Influenza infection can result in significant complications, in particular progression to pneumonia, in patients who have undergone autologous SCT [1, 2]. Influenza vaccination is recommended to prevent infection in children following autologous SCT , however, there is limited evidence regarding its benefit in this population . Due to the paucity of data, we performed a prospective multicentre study to evaluate the immunogenicity of the seasonal inactivated influenza vaccine in children who have undergone autologous SCT compared with healthy matched controls.
Recruitment was undertaken during the Southern Hemisphere influenza seasons of 2013–2016 (March to September) from three tertiary paediatric haematology, oncology and bone marrow transplant units in Australia (Princess Margaret Hospital for Children, Perth; Queensland Children’s Hospital, Brisbane; Women’s and Children’s Hospital, Adelaide). Children between the ages of 6 months and 18 years who were ≥6 months and ≤2 years post autologous SCT were eligible. Healthy siblings were recruited as age-matched controls. Exclusion criteria included anaphylaxis to previous doses of any influenza vaccine, a history of egg anaphylaxis, receipt of intravenous immunoglobulin within the last 3 months, a history of Guillain–Barre syndrome or current medical condition that would be compromised by inclusion in the study. Informed consent was obtained from the parents of each child prior to recruitment.
The study was conducted as previously described . In brief, participants were vaccinated with inactivated influenza vaccine according to national Australian guidelines . Blood was taken prior to each vaccination and 4 weeks following the final vaccination to assess influenza-specific immune responses. Following collection, blood samples were centrifuged and sera stored at −20 °C. At the end of each influenza season, the samples were sent to the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory (VIDRL) where standardised hemagglutinin inhibition (HI) assays were performed to determine specific influenza antibody titres towards each virus in the vaccine . Viruses used for HI analysis were egg propagated. All patients enrolled in the study that developed influenza-like illness were instructed to be present for clinical review. Influenza detection was performed on a nasopharyngeal aspirate using polymerase chain reaction.
There were 44 children enrolled in the study; 22 children who had undergone autologous SCT and 22 healthy controls. The groups were frequency matched according to age (mean age: 6.7 vs. 6.9 years, p = 0.90) and sex (females: 59.1% vs. 54.5%, p = 0.76). Primary underlying diagnoses comprised high-risk neuroblastoma (n = 16), atypical teratoid rhabdoid tumour (n = 2), Ewing sarcoma (n = 2), primary mediastinal B-cell lymphoma (n = 1) and medulloblastoma (n = 1). Conditioning regimens comprised busulfan/melphalan (n = 13), carboplatin/etoposide/melphalan (n = 5), carboplatin/thiotepa (n = 3) and carmustine/etoposide/cytarabine/melphalan (n = 1). The cell dose infused ranged between 2.6 and 10 × 106 CD34/kg. The majority of children were vaccinated within 12 months from receipt of autologous SCT (6– <12 months = 15 vs. ≥12 months = 7), had a normal lymphocyte count for age at the time of vaccination (n = 15/22) and received two doses of the vaccine (n = 16/22).
The percentage of children in the autologous SCT group that were susceptible to each strain of the vaccine prior to the first dose was 91% to H3N2, 95% to H1N1 and 91% to the B strain. Susceptibility of the healthy age-matched controls was 41% to H3N2, 68% to H1N1 and 95% to the B strain. Seroprotection occurred in 68.2% to H3N2, 22.7% to H1N1 and 27.3% to B strain in children who received autologous HSCT compared with 95.5%, 81.8% and 68.2% for healthy age-matched controls (Table 1). Seroconversion occurred in 54.5% for H3N2, 22.7% for H1N1 and 27.3% for B strain in children who received autologous SCT, while 68.2% of healthy age-matched controls seroconverted to each of the respective strains (Table 1). For children in the autologous HSCT group who received two doses of the vaccine and seroconverted to H3N2, the second dose of the vaccine was required in 89% for seroconversion to occur.
According to criteria established by the Committee for Proprietary Medicinal Products (CPMP) , children who had undergone autologous SCT demonstrated a significant response to the H3N2 strain (geometric mean fold increase (GMFI) 5.95, 95% CI 3.12–11.34, p = 0.004) (Table 1). Healthy age-matched controls demonstrated significant response to all vaccine strains according to CPMP criteria: H3N2 strain (GMFI 9.67, 95% CI 4.92–19.00, p < 0.001; seroprotection 95.5%, 95% CI 86.8–99.9, p = 0.005), H1N1 strain (GMFI 8.79, 95% CI 4.79–16.15, p < 0.001) and B strain (GMFI 10.29, 95% CI 5.45–19.43, p < 0.001), with seroconversion occurring in 68.2% (95% CI 48.7–87.6, p = 0.003) to all three vaccine strains (Table 1). There were no adverse effects following vaccination in either the autologous SCT or healthy age-matched control group, and laboratory-proven influenza infection was not identified in any of the study participants. There was no significant difference in GMFI response between children who received an autologous SCT compared with the previously reported allogeneic HSCT group , to any vaccine strain (H3N2 p = 0.949; H1N1 p = 0.126; B p = 0.277; B(2016) p = 0.266; two-sample t test), consistent with findings reported in an adult population .
In this study, we identify that children who have undergone autologous SCT are highly susceptible to each influenza strain and that the inactivated influenza vaccine is safe and provides immunogenicity to the H3N2 strain in children who have received autologous SCT. While this positive finding provides strength to support the recommendation for influenza vaccination following autologous SCT in children, response to the H1N1 and B strains was poor. Poor responses have also been reported in adults receiving trivalent inactivated influenza vaccine and in a mixed adult-predominant study population receiving the AS03-adjuvanted 2009 H1N1 vaccine post autologous SCT [9,10,11].
Poor response may be reflected by the timing of immunisation, with the majority of children in our study vaccinated within 1 year of autologous SCT. Transplant to vaccination interval is known to be a predictor of response, with longer duration increasing the likelihood of response . This is supported by higher GMFI values in children vaccinated ≥12 months following autologous SCT in our study (H3N2: GMFI ≥ 12 months 8.48 (95% CI 1.98–36.39) vs. <12 months 5.04 (2.54–9.99); H1N1: 2.97 (1.07–8.25) vs. 1.91 (1.30–2.81); B: 5.38 (1.10–26.47) vs. 1.52 (0.93–2.48)). Despite these findings, given the protection afforded against H3N2 and that timing of vaccination is influenced by the seasonality of influenza, we do not advocate delaying vaccination for children post autologous SCT on this premise.
In conclusion, our study shows that the inactivated influenza vaccine is safe and provides immunogenicity to the H3N2 strain in children who have received an autologous SCT. Despite the limitation of small numbers, this remains the only paediatric-specific study to assess immunogenicity of the inactivated influenza vaccine following autologous SCT and provides support for the recommendation of annual influenza vaccine administration in this population. However, additional research is required to identify host factors that may influence response and to further develop vaccines in an effort to improve immunogenicity to the H1N1 and B strains.
Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39:1300–6.
Whimbey E, Elting LS, Couch RB, Lo W, Williams L, Champlin RE, et al. Influenza A virus infections among hospitalized adult bone marrow transplant recipients. Bone Marrow Transplant. 1994;13:437–40.
Cordonnier C, Einarsdottir S, Cesaro S, Di Blasi R, Mikulska M, Rieger C, et al. Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19:e200–12.
Dulek DE, de St Maurice A, Halasa NB. Vaccines in pediatric transplant recipients-Past, present, and future. Pediatr Transplant. 2018;22:e13282.
Ryan AL, Wadia UD, Jacoby P, Cheung LC, Kerr F, Fraser C, et al. Immunogenicity of the inactivated influenza vaccine in children who have undergone allogeneic haematopoietic stem cell transplant. Bone Marrow Transplant. 2019. https://doi.org/10.1038/s41409-019-0728-5. [Epub ahead of print]
Australian Technical Advisory Group on Immunisation. The Australian Immunisation Handbook, 10th Ed. Canberra: Australian Government Department of Health, 2013.
WHO Global Influenza Surveillance Network. Manual for the laboratory diagnosis and virological surveillance of influenza, 2011. Available from URL: https://www.who.int/influenza/gisrs_laboratory/manual_diagnosis_surveillance_influenza/en/. Accessed 15 Oct 2019.
Committee for Proprietary Medicinal Products (CPMP). Note for guidance on harmonisation of requirements for influenza vaccines. CPMP/BWP/214/96. European Agency for the Evaluation of Medicinal Products (EMEA). March 1997.
Gandhi MK, Egner W, Sizer L, Inman I, Zambon M, Craig JI, et al. Antibody responses to vaccinations given within the first two years after transplant are similar between autologous peripheral blood stem cell and bone marrow transplant recipients. Bone Marrow Transplant. 2001;28:775–81.
Pauksen K, Linde A, Hammarstrom V, Sjolin J, Carneskog J, Jonsson G, et al. Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients. Clin Infect Dis. 2000;30:342–8.
Engelhard D, Zakay-Rones Z, Shapira MY, Resnick I, Averbuch D, Grisariu S, et al. The humoral immune response of hematopoietic stem cell transplantation recipients to AS03-adjuvanted A/California/7/2009 (H1N1)v-like virus vaccine during the 2009 pandemic. Vaccine. 2011;29:1777–82.
Engelhard D, Nagler A, Hardan I, Morag A, Aker M, Baciu H, et al. Antibody response to a two-dose regimen of influenza vaccine in allogeneic T cell-depleted and autologous BMT recipients. Bone Marrow Transplant. 1993;11:1–5.
RSK (NHMRC APP1142627) and CCB (NHMRC APP1111596) are supported by Fellowships from the National Health and Medical Research Council of Australia. This study was funded by a Perth Children’s Hospital Foundation Project Grant and a Pfizer Cancer Competitive Research Grant. The WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, is supported by the Australian Government Department of Health. This study was approved by the Child and Adolescent Health Service Ethics Committee (Ethics Approval Number 1988/EP), with ethical approval granted at all sites under the National Mutual Acceptance agreement. The study was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12614000240640).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Ryan, A.L., Wadia, U.D., Jacoby, P. et al. Immunogenicity of the inactivated influenza vaccine in children who have undergone autologous stem cell transplant. Bone Marrow Transplant 55, 1829–1831 (2020). https://doi.org/10.1038/s41409-019-0770-3