Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients
Phase: PHASE2
Conditions: Hematopoietic Cell Transplantation Recipient, Malignant Neoplasm, Influenza
Sponsor: Vanderbilt-Ingram Cancer Center

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
DMID Protocol Number 16-0117 
Protocol Version 8.0                                                                                                                                             
 Date: 9/12/2019 
 
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Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
 
Protocol  
DMID Protocol Number 16-0117 
Version Number: 
Version 8.0 
Sep. 12, 2019 
 
Principal Investigator: 
Natasha Halasa, MD MPH 
Associate Professor of Pediatrics 
Pediatric Infectious Diseases 
1161 21st Ave South 
D7232 MCN 
Nashville, TN 37232 
Phone: 615-322-3346 
Fax: 615-343-9723 
natasha.halasa@vumc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Sites 
Site 
Co-Investigators 
Transplant 
Physician 
Vanderbilt University 
Dan Dulek, MD, Spyros Kalams, MD, 
Christopher Fonnesbeck, PhD 
Andrew Spieker, PhD (biostatistician)  
Carrie Kitko, MD 
Baylor School of Medicine, 
Texas Children’s Hospital 
Flor Munoz-Rivas, MD, MSc  
Claire Bocchini, MD  
Elizabeth Moulton, MD, PhD 
Swati Naik, MD 
Children’s Hospital of 
Philadelphia (CHOP) 
Susan Coffin, MD, MPH, Michael Russo, 
MD (advisors: Kristen Feemster, MD, MS, 
MPH. Brian Fisher, DO, MSCE, Hamid 
Bassiri, MD, PhD) 
Jason Freedman, 
MD, MSCE 
Children’s Mercy Hospital 
Jennifer Schuster, MD, MSCI, Christopher 
Harrison, MD, Barbara Pahud, MD 
Rakesh Goyal, 
MD 
Cincinnati Children’s 
Hospital 
Lara Danziger-Isakov, MD, MPH 
Michael Grimley, 
MD 
Nationwide Children’s 
Hospital 
Monica Ardura, DO, MSCS, Octavio 
Ramilo, MD 
Jeffery Auletta, 
MD 
Seattle Children’s Hospital 
Janet Englund, MD – Lead Co-
Investigator 
Paul Carpenter, 
MBBS 
St. Jude Children’s 
Research Hospital 
Patricia Flynn, MD, MS, Gabriela Maron, 
MD, MS 
Ewelina Mamcarz, 
MD  
UCSF (University of 
California San Francisco) 
Benioff Children’s Hospital 
Rachel Wattier, MD, MHS 
Christopher 
Dvorak, MD 
 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
DMID Protocol Number 16-0117 
Protocol Version 8.0                                                                                                                                             
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Statement of Compliance 
 
 
This clinical trial will be conducted in accordance with the protocol and Good Clinical Practices (GCP) as 
required by the following: 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 46; 21 
CFR Parts 50 and 56; 21 CFR Part 312). 
 
• 
ICH E6; 62 Federal Register 25691 (1997) 
 
• 
NIH Clinical Terms of Award 
All key personnel (all individuals responsible for the design and conduct of this study) have completed Human 
Subjects Protection Training. 
 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
DMID Protocol Number 16-0117 
Protocol Version 8.0                                                                                                                                             
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SIGNATURE PAGE 1 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
 
 
The Lead Investigator (Protocol Chair) should sign Signature Page 1. A copy of this Signature Page 1 
should be filed with the holder of the Regulatory documents and a copy should be maintained at the site. 
 
 
Principal Investigator: Natasha B. Halasa, MD, MPH 
       Print/Type 
 
 
Signed:  
Date: 
 
 
Name/Title 
 
 
 
 
 
 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
DMID Protocol Number 16-0117 
Protocol Version 8.0                                                                                                                                             
 Date: 9/12/2019 
 
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Signature Page 2 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary 
assurance that this trial will be conducted according to all stipulations of the protocol, including statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
The Investigator(s) of record (signatures(s) on 1572) from each participating clinical site should sign the 
Signature Page 2 as appropriate. The Signature Page 2 should be maintained at each site.  
 
 
Investigator(s) of Record:  
 
 
 
 
Print/Type 
Signed:________________________________________________ Date__________ 
Name/Title 
 
 
Institution: ________________________________________________  
Name 
 
 
 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
DMID Protocol Number 16-0117 
Protocol Version 8.0                                                                                                                                             
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Table of Contents 
 
 
A. 
Specific Aims and Hypothesis………………………………....……………………………………………..6 
B. 
Background and Significance……………………………………………………………...……...…..……..6 
C. 
Research Design and Methods…………….………………………………………….......……..…………10 
1.   Study Design……………………………………………………...…………….…....………...………....10 
2. Primary and Secondary Objectives………………………………………………..……....……….....11 
3. Study Area…………………………………………………………………………...…………...……......11 
4. Study Population: Inclusion/Exclusion………………………………………...…………………......12 
5. Treatment Groups…………….……………………………………...…………...……………………....16 
6. Data Collection…………..…………………...…………………………………...……………………….16 
7. Reporting Adverse Events……………………………………………………...………...……..…...….17 
8. Study Withdrawal/Discontinuation.………………….………………………..........………….......….17 
9. Follow-up Record Retention ……………..….…………………..…………………………..........……18 
10. Investigational Product Risk Information …………............…………………………............….….18 
11. Side Effects with Influenza Vaccine……..……….………….…………………...……...........………19 
12. Risk Information………………………………………..............………………………...........…..…….20 
13. Study Visit Schedule…………………………………………………………………...…...……..……..20 
14. Study Procedures/Evaluation ………..……………………………………………...…..…….….……21 
15. Laboratory Procedures………………………………………………………………...…..…….…..…..24 
16. Specification of Safety Parameters……………………...…………………………...…..…....………25 
17. Statistical Considerations……………………………………………………………...…….…....…….32 
18. Ethics/Protection of Human Subjects……………………………………………...………………….33 
19. Data Handling and Record Keeping………………………………………………...………..………..35 
20. Publication Policy …………………………………………………………………...………..…….……36 
21. Certificate of Confidentiality…………………………………………………………………………….36 
D. 
References………………………….…………………………….………………………...…......….…….….38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
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A. Specific Aims and Hypothesis: 
 
1. Hypothesis 1: We hypothesize that the high-dose trivalent inactivated influenza vaccine (HD-TIV) 
group will have a greater frequency of ≥4-fold rise, HAI titer ≥1:40, and higher geometric mean titer 
(GMT) to influenza A antigens compared to the standard dose quadrivalent inactivated influenza 
vaccine (QIV) group in pediatric hematopoietic stem cell transplant (HSCT) recipients.  
 
Specific aim 1: To determine whether HD-TIV compared with standard dose QIV will increase the 
probability of achieving either a ≥4-fold rise in HAI titer, a HAI titer ≥1:40, or higher GMT HAI to 
influenza A antigens in pediatric HSCT recipients.  
 
2. Hypothesis 2: The administration of HD-TIV in pediatric HSCT recipients will be well tolerated and the 
safety profile will be similar to standard dose QIV. 
 
Specific aim 2: To determine the frequency and severity of solicited local injection site adverse events 
and solicited systemic adverse events related to HD-TIV compared with standard dose QIV in pediatric 
HSCT recipients. 
 
3. Hypothesis 3: HD TIV vaccination will induce higher protective HAI titers and higher frequencies of 
circulating activated T-follicular (Tfh) cells and circulating B cell plasmablasts, it will also induce higher 
levels of influenza-specific B and T cell responses compared to standard dose QIV. 
 
Specific aim 3: To define the relationship between HAI titers, ex-vivo T and B cell phenotype, and ex-
vivo influenza-specific T and B cell response in pediatric HSCT recipients receiving either HD-TIV or 
standard dose QIV. 
 
B. Background and Significance: 
 
1. Burden of Influenza: 
Over 13,000 hematopoietic stem cell transplants (HSCT) are performed each year in the United States, 
according to the Center for International Blood and Marrow Transplant Research.1 Mortality due to infections is 
seen in 8-17% of HSCT patients who died within 100 days post-transplant.1 Influenza A and B are important 
causes of morbidity and mortality in high-risk individuals, including HSCT recipients;2 however, the majority of 
disease is due to circulating influenza A/H3N2 or influenza A/H1N1,3 including in hospitalized children.4 In a 
prospective viral surveillance study involving 37 European transplant centers, 3.5% of the patients had a 
documented respiratory virus, 16 subjects with influenza virus A, and of those 23%, of confirmed influenza 
patients died.5 Reported mortality rates in HSCT associated to influenza range around 15-17%;5,6 however, the 
rates are even higher in patients with influenza-associated pneumonia, where the case fatality rate in HSCT 
recipients varied from 9.5 to 75%.2,5-8 In the general population, an influenza epidemic can be associated with 
attack rates of 10–20%; however, attack rates are higher in individuals with cancer and HSCT recipients.9-12 
 
Moreover, significant morbidity and mortality were noted in HSCT recipients during the recent influenza 
A/H1N1 pandemic, with several reports of pneumonia, lower respiratory tract infections, rhabdomyolysis, and 
even death.13-19 Since immunosuppressed individuals can shed influenza virus for prolonged periods after 
infection, they pose significant risk for promoting nosocomial influenza outbreaks,20-22 and the development of 
antiviral resistance.23 HSCT recipients infected with pandemic influenza A/H1N1 and treated with oseltamivir 
had high rates of development of antiviral resistance while on antiviral therapy.18,24-26 The risks for severe 
influenza or fatal outcome in HSCT recipients include lymphopenia, older age in adults and younger age in 
children (<5 years), neutropenia, influenza soon after transplantation or chemotherapy, steroid treatment, and 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
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lack of early antiviral therapy.8,11,27,28 Thus, influenza infection in HSCT recipients poses both a significant 
individual and community risk. 
 
Machado et al. retrospectively reviewed vaccination records of 177 HSCT recipients to evaluate risk factors for 
acquiring influenza and the efficacy of influenza vaccination 6 months post-HSCT.2 Nasal washes from adult 
subjects and nasal aspirates from children were assessed for influenza by a direct immunofluorescence assay 
(DFA) during a single influenza season. Of the 43 subjects were eligible to receive the influenza vaccine, only 
19 (44%) subjects were immunized. Of the 19 subjects who did receive influenza vaccine, only two (10.5%) of 
them had nasal samples positive for influenza. Among the remaining 24 unvaccinated individuals, 12 (50%) 
were diagnosed with influenza infection. These data suggest a potential influenza vaccine efficacy of 80%.2 A 
limitation of this study, however, is that the investigators did not use PCR for diagnosis, a more sensitive 
method than DFA for detecting influenza virus. However, it is unclear whether this limitation may have led to an 
overestimation or underestimation of influenza vaccination efficacy in this population.29 
 
2. Prior Influenza Vaccine Trials in HSCT Recipients:  
Influenza vaccination is the primary mode for prevention of influenza infection. Protection is primarily mediated 
by virus-specific antibodies that depend on an intact humoral response. Both B cell and T cells responses are 
impaired in HSCT recipients, functional recovery of B and T lymphocytes can take up to 2 years or even 
longer.30 Limited data are available regarding influenza vaccine responses in pediatric HSCT recipients 
because the majority of influenza vaccine trials have been conducted in adult HSCT recipients.31-45 Only 5 of 
these trials included children, and only one exclusively included children, with total enrollment of 5 subjects.33 
Therefore, dedicated influenza vaccine trials in pediatric HSCT patients are needed.  
 
Despite limited clinical data for influenza vaccine efficacy in this population, yearly vaccination is 
recommended, beginning 3-6 months after HSCT.46 However, the optimal post-transplantation vaccine 
schedule has not been established. Existing data for influenza vaccination in HSCT recipients are primarily 
from subjects who received influenza vaccination between 6 months and 3 years after HSCT.46 Thus, little data 
exist to support vaccinating pediatric HSCT recipients earlier than 6 months or later than 3 years post-
transplant.46 The percentage of HSCT recipients that achieve seroprotective hemagglutinin inhibition (HAI) 
titers (defined as 1:40) one month after standard influenza vaccination is very low when compared to healthy 
controls. While this impaired vaccine-induced immune response is likely due to incomplete immune 
reconstitution or immunosuppressive therapies, the exact immune mechanisms of HSCT recipients’ poor 
response to influenza vaccination are not well described. Notably, graft versus host disease (GVHD), low 
number of CD19+ B cells, and earlier timing of vaccination post-transplant have been implicated as factors 
associated with lower titers after influenza vaccine.8 
 
The authors in the 2013 publication, European Guidelines for the Prevention and Management of Influenza in 
HSCT Patients, recommends yearly inactivated influenza vaccine (IIV) each influenza season to HSCT 
recipients; vaccine is preferably given prior to the influenza season, usually at least 3 months after HSCT and a 
second dose of vaccine after 3–4 weeks is advised, although the second dose may only have marginal 
benefit.8 Results from trials comparing two doses of influenza vaccine are conflicting: some suggest no benefit 
with 2 doses, while others demonstrate an increase in influenza titers after the second dose in HSCT 
recipients.18,31,41,44,47 The trials that used ASO3-adjuvanted H1N1 vaccine, which is not available in the United 
States, suggest higher titers are induced with a 2-dose schedule.18,44,47  
In contrast, the 2013 IDSA Clinical Practice Guidelines for Vaccination of the Immunocompromised Host 
recommends yearly vaccine with IIV and it can be administered 6 months after HSCT or as early as 4 months 
after HSCT during an influenza outbreak.48 Thus, both the optimal timing of influenza vaccination and the ideal 
number of doses needed remain unclear. A better understanding of immune responses to influenza 
vaccination (e.g. B and T cell responses to influenza antigens) is also necessary. A promising strategy and 

Comparison of High vs. Standard Dose Flu Vaccine in Pediatric Stem Cell Transplant Recipients 
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only immediate practical alternative to overcome the poor immunogenicity of influenza vaccine may be to 
increase the antigen dose in the vaccine.49 This strategy has been successful in individuals 65 years, a group 
with a historically poor response to influenza vaccines compared to healthy young adults.50-52  
3. Prior Experience with HD-TIV in the Elderly:  
a. Phase 1 Trial: Since the elderly population responds poorly to standard dose influenza vaccine compared to 
younger adults, a higher dose influenza vaccine was hypothesized to be more immunogenic in this 
population.50 The first trial enrolled 202 adults ≥65 years who were randomly assigned to 15, 30, or 60 µg of 
hemagglutinin per strain or placebo.52 Mean serum HAI antibody titers one month after immunization in groups 
given 0, 15, 30 and 60 µg dosages were 23, 37, 50, and 61 against influenza A/H1N1; 43, 86, 91, and 125 
against influenza A/H3N2; and 10, 14, 18, and 24 against influenza B, respectively.52 Mean serum HAI and 
neutralizing antibody levels against the three vaccine antigens in participants given the 60µg dosage were 44% 
to 71% and 54% to 79,%, respectively, higher than those in participants given the standard 15 µg dosage. 
Among recipients with low pre-immunization antibody titers, the rate of seroconversion was nearly double for 
those who received 60 µg, as compared to 15 µg, dosage level.52 Dose-related increases in the occurrence of 
injection site reactions were observed, but all dosages were well tolerated. 
 
b. Phase 2 Trial: A multicenter, phase II, randomized, double-blind, stratified study enrolled individuals ≥65 
years of age to receive either 15 µg versus 60 µg of TIV.51 Oral temperature, injection site, and systemic 
symptoms and signs were recorded in a diary daily for one week after immunization. Sera were obtained 
before immunization and one month after immunization. A total of 414 subjects were enrolled, 206 received 
HD-TIV and 208 received standard dose TIV. Subjects given the HD-TIV reported more local and systemic 
reactions but only local pain and myalgia were significantly increased. The HD-TIV vaccine induced a higher 
frequency of ≥4-fold serum antibody increases in both HAI (16.8-27.9%) and neutralization tests (11.9-24.5%) 
for all three vaccine viruses in the total group as well as in subjects vaccinated and not vaccinated the previous 
year.51 Mean titers of antibody attained, the magnitude of antibody increases, and the frequencies of persons 
with final HAI antibody titers ≥1:32, ≥1:64, and ≥1:128 were all greater for the HD-TIV group in both serologic 
tests (e.g., HAI and neutralization assays), for all titer groups ≥1:32, ≥1:64, and ≥1:128), and for all vaccine 
viral strains compared to the standard dose TIV.51  
 
c. Phase 3 and 3b Trials, HD-TIV has Increased Immunogenicity and Efficacy in the Elderly: A phase III, 
multicenter, 
randomized, 
double-blind 
study 
enrolled 
individuals 65 years of age to compare HD-TIV to standard 
dose TIV.53 HD-TIV was administered to 2575 subjects and 
standard dose TIV was administered to 1262 subjects. 
Individuals who received HD-TIV had higher mean post-
vaccination GMT (Table 1). The HD-TIV vaccine met 
superiority criteria for both influenza A strains (>1.5 GMT ratio), and the responses for influenza B met non-
inferiority criteria. For all strains, seroprotection rates were higher in those individuals who received HD-TIV than 
in those who received standard dose TIV. Local reactions were more frequent in individuals who received HD-
TIV, but the reactions were mild to moderate. The superiority of immune responses to influenza A antigens in 
the HD-TIV, compared to the standard-dose group, in this phase III trial led to the licensure of HD-TIV in 
individuals 65 years.50 In addition, not only does the HD-TIV induced significantly higher antibody responses in 
this population, it provided better protection (relative efficacy, 24.2%) against laboratory-confirmed influenza 
illness compared to standard dose TIV.54 
 
4. Prior Experience with HD-TIV in the Immunocompromised Subjects:  
a. Adult HSCT Recipients. This single-center, randomized, double-blind, phase I safety and immunogenicity 
trial, conducted at Vanderbilt University, compared HD to standard dose TIV in adult allogeneic HSCT 
Table 1. 
HD-TIV 
Standard 
Dose 
GMT 
ratio 
H1N1 
116 
67 
1.7 
H3N2 
609 
333 
1.8 
B 
69 
52 
1.3 

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recipients, not on immunosuppressive therapy for treatment of active GVHD, and at least 6 months post-
transplant. Subjects were randomized in a 2:1 fashion to receive 2010-11 or 2011-12 TIV HD-TIV or standard 
dose TIV. Forty-four subjects were enrolled (19 in year 1 and 25 in year 2) at a median of 7.9 months after 
allogeneic HSCT, median age of 50.1 years, 61% male, and 100% white, and 29 HD and 15 SD subjects. HD 
group had higher median IgG level (676 vs. 469, p=0.025). The HD group reported more local symptoms 
compared to standard dose. No serious adverse events (SAEs) were attributed to the vaccine, and no 
differences in systemic reactions were noted. The HD group had a higher percentage of individuals with a HAI 
titer >1:40 to H3N2 after HD-TIV, (81% versus 36%, p=0.004) and higher GMT [207.9 versus 30.3, 177.6 95% 
CI difference, (63.5 - 401.8)], with GMT ratio 6.9. These results are published in Biology of Blood and Marrow 
Transplant.55 .  
b. Pediatric Solid Organ Transplant (SOT) Recipients. This multi-center, randomized, double-blind, phase I 
safety and immunogenicity trial, conducted at Vanderbilt and the Children’s Hospital of Pittsburgh during the 
2011-12 influenza season, compared HD to standard dose TIV in pediatric SOT patients. Enrollees were 3-17 
years of age and at least 6 months post-transplant. The mean age was 11.25 years, 68% were male, 
transplanted organs were 45% renal, 26% heart, 21% liver, 5% lung, and 5% intestinal, with median of 2.2 
years since transplant. Twenty-three subjects were given HD and 15 were given standard dose TIV. No 
individuals had rejection associated with vaccination. Fatigue and body ache were greater in the HD group 
compared to the standard dose group, but no differences in local reactions were noted. Subjects in the HD 
group had a higher percentage of a 4-fold rise to H3N2 compared to the standard dose group (56% versus 
13%, p=0.08). These results were published in Pediatric Transplantation.49 
c. Pediatric Acute Lymphoblastic Leukemia (ALL) Subjects. This single-center, randomized, double-blind, 
phase I safety and immunogenicity trial was conducted at Vanderbilt University, comparing HD to standard 
dose TIV in children 3-17 years of age with ALL. Fifty subjects were enrolled (20 in year 1 and 30 in year 2), 
with a mean age of 8.25 years, 62% were male, and 78% were receiving maintenance therapy. Thirty-four 
subjects were given HD and 16 were given standard dose. Safety data revealed no differences between the 
groups for total solicited systemic and local reactions; however, the standard dose group reported more fatigue 
and headache. No SAEs were attributed to vaccination. The immune response, measured by a ≥4-fold rise in 
HAI titer, was similar for each vaccine antigen in both groups; however, descriptive data in ALL recipients 
comparing specific B-cell immune response to each antigen suggest better responses with HD-TIV 
(unpublished data, Dr. Jon McCuller’s laboratory, St. Jude, Memphis, TN). The main results are published in 
Pediatric Blood Cancer.56 
5. Inclusion of Quadrivalent Inactivated Influenza Vaccine (QIV). Although two influenza B lineages have 
been co-circulating since the 1980s, TIV contains only one B strain, which provides little-to-no protection 
against the alternate B-lineage strain; however, about 70% of recent B viruses have been antigenically related 
to the B virus component of the trivalent flu vaccines.3 A standard-dose QIV is currently available and provides 
additional protection against the second B strain while retaining non-inferior immunogenicity to the other 3 TIV 
strains.57,58 High dose QIV will not be available for the upcoming influenza season (personal communication 
with Sanofi Pasteur). This study will be the first to evaluate standard dose QIV and HD-TIV in this population. 
6. Rationale. Patients who have undergone HSCTs have a higher burden of disease from influenza infection 
compared with healthy controls, with significant morbidity and mortality due to influenza disease. They are also 
at high risk of influenza-associated complications, particularly pneumonia. Thus, strategies to reduce influenza 
disease in this highly susceptible population are critical, especially since these individuals respond poorly to 
standard dose IIV. HD-TIV has increased immunogenicity and efficacy in adults ≥65 years compared with 
standard dose.54 Therefore, the use of HD-TIV appears to be a promising and practical alternative intervention 
to improve vaccine-induced immune responses in pediatric HSCT recipients. We hypothesize that HD-TIV 
will be more immunogenic compared with standard dose QIV and will remain well-tolerated in this 
vulnerable population. Thus, for this protocol we propose to compare the immunogenicity and safety of HD-
TIV to standard-dose QIV. 

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Since the majority of influenza illness is due to influenza A and HD-TIV licensure was based on influenza A 
antigen responses, the results of these studies could be generalizable to HD-QIV, should it become 
commercially available in the future. In addition, influenza B antigens have lower HAI titers compared to 
influenza A antigens, especially in children, including those without co-morbidities.59 Therefore, if the results 
from this trial reveal superior HAI titers to influenza A antigens, a HD-QIV vs. standard-dose QIV trial will not 
be necessary. Moreover, this study has significant potential to impact clinical practice in pediatric HSCT 
patients. Demonstration of safety and greater immunogenicity of HD-TIV versus standard dose QIV in this 
population could alter current influenza vaccine recommendations. Additionally, successful use of HD-TIV to 
enhance influenza-specific immune responses in pediatric HSCT patients could reduce influenza disease 
burden, morbidity, and mortality in these high-risk patients.  
 
C. Research Design and Methods:  
 
1. Study Design: The proposed study is a multi-center, phase II immunogenicity and safety trial comparing 
HD-TIV to standard dose QIV in pediatric HSCT recipients. Subjects will be randomized in a 1:1 fashion to 
receive either 2 doses of 0.5 mL HD-TIV (60µg of each influenza antigen) or 2 doses of standard dose QIV 
(15µg of each influenza antigen) of the season-specific vaccine 28-42 days apart. HAI and microneutralization 
(MN) titers to influenza virus antigens, phenotypic B and T cell responses, B and T cell specific influenza 
responses, complete blood count with differential and platelets (CBC d/p), quantitative CD4+/CD8+/CD19+ 
levels, and quantitative serum IgM and IgG concentrations will be measured prior to the first and second 
vaccine dose, 28-42 days after the second vaccine dose, and 180 days (+42 days) after second vaccine. If 
children are receiving intravenous (IV)/subcutaneous (SC) immunoglobulin (IG)  during any visit, additional 
sera will be collected to measure HAI and MN titers following IVIG/SCIG dose administration. A subset of 
children will have cellular immune responses measured 5-10 days after each vaccination. Approximately 20-40 
mL* of venous blood will be obtained at each of these visits. Parents/subjects will record solicited events for 7 
days after each vaccination (Day 0-7). On days 1-3 and 8-10, an attempt of telephone and/or electronic 
communication will be made to assess for solicited AEs following each vaccination. Each female of 
childbearing age will be given a pregnancy test before each vaccination. If she is pregnant, she will not be 
eligible for the study.  
 
*Note, for all blood draws, if blood is being drawn and discarded for clinical reasons, blood volumes can 
exceed 40 mls.   
 
Individuals enrolled in the study during one season will be asked if they would like to participate in the study 
during a second year, i.e. the following season. Subjects who participate a second year will not be asked to 
participate a third time. For the 2019-2020 season, subjects who were enrolled and participated in the study for 
the first time during the 2018-2019 season will be approached and asked to participate a second year.   
 
Influenza Surveillance: Active surveillance for influenza-like symptoms will begin when influenza season 
starts in each site’s community. Influenza season begins in the specific community, defined as in previous trials 
by identification of at least 2 positive respiratory tests for influenza, with at least 10% of diagnostic tests 
positive during 2 consecutive weeks in the local clinical or research laboratory.60,61  Enrollment will continue 
during influenza season with nasal swabs obtained at all main visits during the influenza season to document 
the occurrence of influenza virus detection both prior to and after vaccination.   
 
During the influenza season, the study staff will attempt to do a weekly telephone and/or electronic 
communication with the participants to detect and document any influenza like illness (ILI). 
 
If subjects meet ILI criteria (see below), a nasal swab will be collected. 
 

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ILI criteria:  One of following criteria met: 
• 
Fever: ≥38.3°C (101°F); or 
• 
Two or more of any of the following: respiratory symptoms (rhinorrhea, sinus congestion, post-
nasal drip, shortness of breath, cough, wheezing, sputum production, sore throat, sneezing, watery 
eyes, ear pain, hoarseness); or systemic symptoms (myalgias and headache) 
2. Primary and Secondary Study Objectives: 
 
a. Primary Objectives:  
i. To determine whether HD-TIV compared with standard dose IV will increase the probability of 
achieving a ≥4-fold rise in HAI titers, ≥1:40 HAI titer, or higher GMT titers to influenza A 
antigens in pediatric HSCT recipients. 
 
b. Secondary Objectives: 
i. To determine whether HD-TIV compared with standard dose QIV will increase the probability 
of achieving a ≥4-fold rise in HAI titers, ≥1:40 HAI titer, or higher GMT titers to influenza B 
antigens in pediatric HSCT recipients. 
ii. To determine the frequency and severity of solicited local injection site adverse events (e.g. 
pain/ tenderness, redness, and swelling/Induration at injection site) with HD-TIV compared to 
standard QIV in pediatric HSCT recipients. 
iii. To determine the frequency and severity of solicited systemic adverse events (e.g. fevers, 
headache, fatigue/malaise, nausea, body ache/myalgia, general activity level, and vomiting) 
with HD-TIV compared to standard dose QIV in pediatric HSCT recipients. 
iv. To define the relationship between HAI titers, ex-vivo T and B cell phenotype, and ex-vivo 
influenza-specific T and B cell response in pediatric HSCT recipients receiving either HD-TIV 
or standard dose QIV.  
v. To correlate HAI responses to MN responses. 
vi. To compare the persistence of HAI and MN titers for all four antigen seven months after the 
last vaccine dose.  
vii. To compare influenza detection by PCR during influenza season in pediatric HSCT recipients 
receiving either HD-TIV or standard dose QIV. 
viii. To assess HAI and MN response in children undergoing two consecutive years of vaccination 
using the same antigen dose. 
ix. To evaluate neuraminidase inhibition titers (NAI) responses in children undergoing two 
consecutive years of vaccination and correlate them to HAI responses. 
 
 
 
3. Study Area: The study will be conducted in the Outpatient Pediatric Oncology/HSCT Clinics or Clinical Trial 
Centers at the following sites: Table 2 includes yearly average number of HSCT transplants per site (Table 2).  
Table 2. Sites and Average Number of Yearly Allogeneic Transplants 
Site 
Average Number 
of Yearly 
transplants 
Potential During Study 
Period 
Children’s Mercy Hospital 
25 
56 
Columbus Nationwide Children’s Hospital  
25 
56 
Vanderbilt University  
30 
68 
Children’s Hospital of Philadelphia (CHOP) 
35 
79 
Seattle Children’s Hospital  
50 
113 
St. Jude Children’s Research Hospital  
50 
113 

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4. Study Population:  
 
A. A target of at least 200 pediatric patients who received an allogeneic HSCT over three 
enrollment years (2016-2017, 2017-2018, 2018-2019) and met the inclusion/exclusion criteria 
outlined below: 
1. Inclusion criteria 
a. Allogeneic HSCT recipients who are 3-35 months post-transplant; 
b. 3-17 years of age, inclusive;  
c. Available for duration of study; 
d. Patients with stable GVHD for at least 4 weeks will be eligible (stable is defined as having no 
major increases in systemic immunosuppressive therapy for GVHD; adjustments of established 
medications to obtain a stable target level are acceptable and do not impact eligibility). 
Parent/legal guardian willing and capable of signing written informed consent; 
e. Parent/legal guardian expected to be available for entire study; 
f. Parent/legal guardian can be reached by telephone and/or electronic communication.  
g. Subjects must have a platelet count of ≥30,000 to receive the immunizations. Patients requiring 
platelet transfusions are eligible to enroll and must have a platelet count ≥30,000 within 72 
hours prior to their immunization, or platelet count ≥75,000 without transfusion documented 
within 30 days for subjects <12 months post-transplant and within 90 days for subjects 12-35 
months post-transplant. 
 
2. Exclusion criteria 
a. History of hypersensitivity to previous influenza vaccination or severe hypersensitivity to 
eggs/egg protein;  
b. History of Guillain-Barre syndrome; 
c. Evidence of hematologic malignancy or disease relapse post-transplant (stable mixed 
chimerism is permitted); 
d. History of receiving current year seasonal influenza vaccine post-transplant; 
e. Pregnant female; 
f. History of proven influenza disease after September 1, 2018 prior to enrollment  
g. Non-allogeneic (e.g. autologous) or syngeneic hematopoietic SCT recipients;  
h. History of known active infection with HIV, Hepatitis B or Hepatitis C; 
i. 
History of known severe latex hypersensitivity;  
j. 
Subjects who have received stem cell boost or delayed donor lymphocyte infusion within 90 
days prior to enrollment, including day of enrollment; 
k. Receipt of IVIG/SCIG <27 days prior to calendar day of vaccination;  
l. 
Subjects who have participated in year 1 and/or 2 of the study, and received study vaccine 
 
Criteria for temporarily delaying vaccine administration: The following conditions are temporary or self-
limiting, and a subject may be included in the study once the condition has resolved, provided that the subject 
is otherwise eligible: 1). Fever ≥100.4ºF/38.0ºC (oral measurement), or an acute illness within 48 hours of 
UCSF (University of California San Francisco) 
Benioff Children’s Hospital 
50 
113 
Cincinnati Children’s Hospital  
90 
203 
Texas Children’s Hospital 
100 
225 
TOTAL 
455 
1026 

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enrollment 2). Receipt of any live vaccines within four weeks or any inactivated vaccines within two weeks 
prior to potential study vaccination.  
 
Note: if patients were eligible for vaccine 1, they will be eligible to receive vaccine 2 regardless of any changes 
on their GVHD status, unless it is deemed not medically safe to receive influenza vaccine.  
 
For subjects who were enrolled and vaccinated in 2016-17, 2017-18, or 2018-19, the goal is to enroll 
individuals who participated in the previous influenza season year and administer the same vaccination as the 
previous year. These subjects are referred to as repeaters. For example, subjects enrolled in 2016-17 could re-
enroll in 2017-18, subjects enrolled in 2017-18 could re-enroll in 2018-19, and subjects in 2018-19 are deemed 
eligible to re-enroll in 2019-20 as repeaters. Subjects may only enroll as a repeater one time and must enroll 
the year after their original enrollment. Subjects must receive at least one vaccine to be eligible as a repeater 
in the subsequent year. 
 
B. Enrollment Criteria for Subjects who Participated in the previous influenza season  
• 
Repeaters will retain their original study ID and their randomization number 
• 
Previous screen failures will not be enrolled. 
• 
If visit 4 from the previous influenza season and visit 1 from the current influenza season 
year occur on the same day, lab results from visit 4 (prior to consent) can be part of visit 
1. 
1. Inclusion criteria 
 
a. Available for duration of study; 
b. Patients with stable GVHD for at least 4 weeks will be eligible (stable is defined as no major 
change in systemic immunosuppressive therapy for worsening GVHD; adjustment of actual 
dose to obtain a stable target level is acceptable).  
c. Subjects must have a platelet count of ≥30,000 to receive the immunizations. Patients requiring 
platelet transfusions are eligible to enroll and must have a platelet count ≥30,000 within 72 
hours prior to their immunization, or platelet count ≥75,000 without transfusion documented 
within 30 days for subjects <12 months post-transplant and within 90 days for subjects 12-35 
months post-transplant. 
d. Parent/legal guardian willing and capable of signing written informed consent; 
e. Parent/legal guardian expected to be available for entire study; 
f. Parent/legal guardian can be reached by telephone and/or electronic communication.  
2. Exclusion criteria 
a. History of hypersensitivity to previous influenza vaccination or severe hypersensitivity to 
eggs/egg protein;  
b. History of Guillain-Barre syndrome; 
c. Evidence of hematologic malignancy or disease relapse post-transplant (stable mixed 
chimerism is permitted); 
d. History of receiving current year seasonal influenza vaccine post-transplant; 
e. Pregnant female; 
f. History of proven influenza disease after September 1, 2019 but prior to enrollment  
g. History of known active infection with HIV, Hepatitis B or Hepatitis C; 
h. Subjects who have received stem cell boost or delayed donor lymphocyte infusion within 90 
days of enrollment, including day of enrollment 
i. 
Receipt of IVIG/SCIG <27 days prior to calendar day of vaccination 
j. 
Non-allogeneic (e.g. autologous) or syngeneic hematopoietic SCT recipients;  
k. Subjects who have participated in year 1 and/or 2 of the study and received study vaccine. 
 

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Criteria for temporarily delaying vaccine administration: The following conditions are temporary or self-
limiting, and a subject may be included in the study once the condition has resolved, provided that the subject 
is otherwise eligible: 1). Fever ≥100.4ºF/38.0ºC (oral measurement), or an acute illness within 48 hours of 
enrollment 2). Receipt of any live vaccines within four weeks or any inactivated vaccines within two weeks prior 
to potential study vaccination. 
 
Note: if patients were eligible for vaccine 1, they will be eligible to receive vaccine 2 regardless of any changes 
on their GVHD status, unless it is deemed not medically safe to receive influenza vaccine. 
 
Note: Previous Screen failures who were not vaccinated can be enrolled and will be assigned the same study 
ID number.  

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An overview of the study schedule and procedures are described in Table 3.  
Table 3. 
Screeni
ng  
period 
Visit  
1 
Phone
/ 
email  
Optio
nal  
Visit 
Visit  
2 
Pho
ne/ 
Emai
l 
Option
al  
Visit 
Visit  
3 
Influenza 
Season 
Visit 
4 
^^ 
 
June 
30th 
Days 
 
0 
1-3 and 
8-10* 
days 
 
5-10 
days 
after 
visit 1 
28-42 
days 
 
1-3 
and 8-
10* 
days 
after 
visit 2 
5-10 days 
after visit 
2 
28-42 
days 
after 
visit 2 
 
180 
±42 
days 
after 
visit 2 
Day 0 
until 
June 
30th 
Consent 
X 
X 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
 
X 
 
 
X 
 
 
 
 
 
 
Physical 
examination#, 
oral temperature 
 
X 
 
 
X 
 
 
 
 
 
 
Peripheral 
venipuncture or 
via central line 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
HAI, NAI, and 
microneutralizati
on assay 
 
X** 
 
 
X** 
 
 
X** 
 
X 
 
B/T cell 
responses 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
CBC d/p# 
 
X 
 
 
X 
 
 
X 
 
X 
 
Quantitative 
CD4, and CD8, 
CD19# 
 
X 
 
 
X 
 
 
X 
 
X 
 
Quantitative 
serum IgG, IgM# 
 
X 
 
 
X 
 
 
X 
 
X 
 
Study vaccine 
administration 
(HD-TIV or 
standard dose) 
 
X 
 
 
X 
 
 
 
 
 
 
Memory aid 
review 
 
 
X 
 
 
X 
 
 
 
 
 
Adverse event 
assessment 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant 
medication 
collection 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immunizations 
reviewed 
 
X 
 
 
X 
 
 
X 
 
X 
 
Telephone 
and/or  
Electronic 
communication 
 
 
X 
 
 
X 
 
 
Weekly 
 
 
Pregnancy Test 
(if applicable) 
 
X 
 
 
X 
 
 
 
 
 
 
Collection of 
Nasal Swab for 
PCR testing for 
Influenza*** 
 
X^ 
 
 
X^ 
 
 
X^ 
If 
symptom
atic 
X^ 
 
X 
Proven clinical 
influenza illness 
##review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
*8-10 day telephone and/or electronic communication are not required if the subject is seen at the optional visit 
within this window period; 

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# If these tests/procedures are performed as standard of care prior to enrollment, but on same calendar day of 
vaccination, they will not need to be repeated and these data can be collected as part of study information.   
**a second blood draw will be obtained post-IVIG/SCIG if IVIG/SCIG is administered at this visit.  
^a swab will be collected during influenza season. 
*** Nasal swabs will be collected from symptomatic patients throughout the study period.  
## Proven clinical influenza illness is any breakthrough influenza illness confirmed by laboratory testing (i.e. 
Rapid antigen assay, PCR, virus culture, ,etc. 
^^ Optional for repeaters in the 2019-20 season 
 
5. Treatment Groups: There will be two groups – HD-TIV versus standard dose QIV. The children will be 
randomized in a 1:1 HD-TIV (100 subjects) versus standard dose QIV (100 subjects) for current enrollment 
season.  
 
 
 
 
 
 
 
 
 
a. Randomization: Subjects will be randomized 1:1 to either HD-TIV or standard dose QIV. Randomization 
will be frequency-matched within each site to ensure balance between the groups and will be implemented 
using the Randomization Module within Vanderbilt’s REDCap database. The investigational pharmacy at each 
of the 9 institutions will distribute the assigned study vaccine. Because we are evaluating the immunogenicity 
of early timing of influenza vaccine post-transplant, we will limit enrollment to 60 (30%) subjects to ≥12 months 
post-transplant.  
 
For block randomization: 
1. For subjects 12-35 months since transplant, we will do block randomization on the following 
question: “Is the subject currently being treated for GVHD with systemic steroids?” (yes/no); if yes, they 
will be evenly distributed for randomization.  
2. For subjects 3-11 months since transplant, block randomization will be on the following question: “Is the 
subject currently being treated for GVHD with systemic steroids or does the subject fall into one or 
more the following criteria: history of campath (alemtuzumab); history of anti-thymocyte globulin (ATG); 
cord transplant; haploidentical transplant; or post-transplant cytoxan (cyclophosphamide)?” 
3. Repeaters will retain their randomization number given from their initial enrollment and will not be re-
randomized 
 
b. Enrollment: Subjects will be enrolled from the Outpatient Pediatric Oncology/HSCT units, clinics, or clinical 
research centers at each institution. The healthcare team will help identify individuals who are eligible and will 
ask permission to be approached about the study. The research team will inform the subjects and their 
parents/guardians of the study and its procedures. Consent will be given to them to review. Ample time will be 
given to explain the study and answer any questions prior to signing the consent.  
 
6. Data Collection:  
The following information will be collected from each subject but not limited to:  
Treatment Group 
Target # (all study 
years) 
Group 1 
0.5 mL HD-TIV 
100 
Group 2 
0.5 mL standard 
dose QIV 
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a. Type of transplant: (Bone marrow, peripheral blood, both bone marrow and peripheral blood, cord 
blood or cord blood and peripheral blood; type of HSCT (HLA-identical sibling, HLA-mismatched 
relative, unrelated) 
b. Underlying disease name and underlying disease risk  
c. Transplant cell dose  
d. Transplant conditioning regimen and post-transplant immunosuppressive medications 
e. History of acute or chronic GVHD  
f. GVHD status  
g. HLA match 
h. History of IVIG/SCIG administration  
i. 
Chimerism status  
j. 
Gender (patient/donor gender) 
k. Race/ethnicity  
l. 
Age  
m. Social History (school, daycare, etc.) 
n. Household members (# of children) 
o. History of influenza vaccination (pre and post-transplant) 
p. Past medical history 
q. CMV status (donor/recipient) and CMV viral load information 
r. Medications 
 
7. Reporting Adverse Events:  
The investigator is responsible for reporting: 
 
• 
Any Grade 3 Adverse event that is not attributable to underlying disease for which the transplant was 
undertaken, or not attributable to GVHD, or not attributable to complications of immunosuppressive 
medications that are observed or reported through 7 days following vaccination (Day 0 through Day 7), 
regardless of their relationship to study product. 
 
• 
Any other AE will not be reported unless it meets the SAE criteria (see Section 16.f). 
 
Initial vaccine reactions will be assessed for at least 15 minutes after vaccination. Subjects will be asked to 
record both solicited vaccine reactions and any unsolicited AEs on a memory aid for 7+ days after each 
vaccination (Day 0 through Day 7). Study personnel will attempt contacting the subjects by telephone and/or 
electronic communication at 1-3 days and 8-10 days after vaccination to review any AEs and SAEs. Adverse 
events and serious adverse events will be collected through 7 days following vaccination.  
 
Solicited systemic AEs will be collected for 7+ days post each vaccination and will include the following: 
fevers, headache, fatigue/malaise, nausea, body ache/myalgia, general activity level, and vomiting. Solicited 
injection site AEs will include the following: pain, tenderness, redness/erythema, and swelling/induration at 
injection site. 
Reporting of Deviations: All deviations will be reported to the IRB at the time of annual continuing review. 
Note: if the deviation affects patient safety and/or risk, the event will be reported immediately.  
8. Study Withdrawal / Discontinuation: 
a. Reasons for Withdrawal or Discontinuation of Study Product 
1. Subjects will be able to withdraw from the study at any time point.  
2. A study subject will be discontinued from participation in the study if the following occur: 

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a. Any clinical adverse event (AE), laboratory abnormality, intercurrent illness, or other medical 
condition or situation occurs such that continued participation in the study would not be in the 
best interest of the subject. However, the subject may continue to be followed for safety 
purposes.  
b. Development of any exclusion criteria may be cause for discontinuation from the study, except 
for individuals who were 17 at enrollment and turned 18 year old during the study. 
c. Subjects may be removed from the study for failure to make follow-up visits.  
d. Subjects may be removed from the study if new information becomes available that makes 
further participation unsafe.  
b. Handling of Withdrawals 
Every attempt should be made to collect all data specified by the protocol relative to study vaccine 
received, including post-immunization blood samples. All AEs will be followed to adequate resolution or 
until considered stable. 
 
9. Follow-up Record Retention:  
No follow-up visits are needed once the study is completed. A copy of the paper records will be retained for at 
least 7 years after completion of the study. The information stored in the ONCORE and/or REDCap database 
will be kept indefinitely. The samples (blood) collected will be labeled with the same numeral ID and stored in 
the respective laboratories: HAI and MN to Sanofi laboratory and nasal specimens and PBMCs to Vanderbilt. 
With the permission of the subjects any leftover samples will be kept and used for future research and will be 
stored at Vanderbilt. A separate IRB approval will be sought prior to the use of these samples. 
 
10. Investigational Product and Risk Information:  
Fluzone Quadrivalent® a Federal Drug Administration (FDA)-approved vaccine and is recommended for all 
pediatric patients ≥6 months.62  
 
Fluzone® HD-TIV has not yet been approved for individuals <65 years of age. The current seasonal influenza 
vaccine will be used for each study year (e.g. 2016-2017 or 2017-2018 or 2018-2019 or 2019-2020). 
a. Acquisition: Fluzone Quadrivalent® and Fluzone® HD-TIV, preservative free, licensed product 
formulated for the 2016-2017 and/or 2017-2018 and/or 2018-2019 and/or 2019/2020 influenza season 
will be donated by Sanofi Pasteur and distributed to each site of the 9 institutions.  
b. Formulation, Packaging, and Labeling: Fluzone Quadrivalent® and Fluzone® HD-TIV, 
preservative free, licensed product, Sanofi Pasteur, Swiftwater, PA. The 2016-2017 recommendations 
are the following: an A/California/7/2009 (H1N1)-like virus; an A/Hong Kong/4801/2014 (H3N2)-like 
virus; and a B/Brisbane/60/2008-like virus (this is a B/ Victoria lineage virus) in both products except in 
Fluzone Quadrivalent®, there is an additional B/Phuket/3073/2013-like virus (this is a B/ Yamagata 
lineage virus). The Fluzone package inserts for the 2016-2017 influenza season for both vaccines will 
be available in the Protocol Library.  
Fluzone Quadrivalent® and Fluzone® HD, preservative free, licensed product formulated for the 2017-
2018 influenza season, Sanofi Pasteur, Swiftwater, PA will by obtained. Formulation, Packaging, and 
Labeling: Fluzone Quadrivalent® and Fluzone® HD, preservative free, licensed product, Sanofi 
Pasteur, Swiftwater, PA. The 2017-2018 recommendations are the following: A/Michigan/45/2015 
(H1N1)pdm09-like virus; an A/Hong Kong/4801/2014 (H3N2)-like virus; and a B/Brisbane/60/2008-like 
virus (this is a B/ Victoria lineage virus); and in Fluzone Quadrivalent®, additional B virus, 
B/Phuket/3073/2013-like virus, (this is a B/ Yamagata lineage virus). The Fluzone package inserts for 
the 2017-2018 influenza season for both vaccines will be available in the Protocol Library.  
Fluzone Quadrivalent® and Fluzone® HD, preservative free, licensed product formulated for the 2018-
2019 influenza season, Sanofi Pasteur, Swiftwater, PA will by obtained. Formulation, Packaging, and 
Labeling: Fluzone Quadrivalent® and Fluzone® HD, preservative free, licensed product, Sanofi 

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Pasteur, Swiftwater, PA. The 2018-2019 recommendations are the following: A/Michigan/45/2015 
(H1N1)pdm09-like virus; an A/Singapore/INFIMH-16-0019/2016 (H3N2)-like virus; and a 
B/Colorado/06/2017-like virus (this is a B/ Victoria lineage virus); and in Fluzone Quadrivalent®, 
additional B virus, B/Phuket/3073/2013-like virus, (this is a B/ Yamagata lineage virus). The Fluzone 
package inserts for the 2018-2019 influenza season for both vaccines will be available in the Protocol 
Library.  
The 2019-2020 influenza strain recommendations are the following: A/Brisbane/02/2018 (H1N1)pdm09-
like virus; A/Kansas/14/2017 (H3N2)-like virus; and B/Colorado/06/2017-like virus (B/Victoria/2/87 
lineage)  for both HD-TIV and SD-QIV; and in Fluzone Quadrivalent®, additional B virus, 
B/Phuket/3073/2013-like virus (B/Yamagata lineage). The Fluzone package inserts for the 2019-2020 
influenza season for both vaccines will be available in the Protocol Library. 
c. Product Storage and Stability: The vaccine will be stored in the original package to protect from 
light. The vaccine will be stored in secure, limited-access, temperature-monitored refrigerator 
environments at 2°C to 8°C (35.6°F to 46.4°F) until needed. The temperature of the storage unit will be 
monitored for the duration of the trial, and documentation of proper dedicated storage will be 
maintained. It will not be frozen. In the event of accidental deep-freezing or disruption of the cold chain, 
vaccines will not be administered.  
d. Dosage, Preparation and Administration of Study Intervention/ Investigational Product 
Either dose (0.5 ml) of TIV or QIV (Fluzone® HD-TIV, Sanofi Pasteur) or (Fluzone Quadrivalent®, 
Sanofi Pasteur  will be administered intramuscularly in either the right or left arm. In preparing either 
vaccine, the pre-filled syringe will be gently shaken and visually inspected for particulate matter and/or 
discoloration prior to administration (the TIV/QIV may normally be clear to slightly opalescent). If either 
condition exists, the pre-filled syringe will not be used. 
 
Subjects will be randomized in a 1:1 fashion to receive either 2 doses of 0.5 mL HD-TIV (60µg of each 
influenza antigen) or 2 doses of standard dose QIV (15µg of each influenza antigen) of the current seasonal 
influenza vaccine (e.g. 2016-2017 or 2017-2018 or 2018/2019 or 2019/2020) 28-42 days apart. The repeaters 
retain their randomization code. 
 
Each of these study products will be labeled according to manufacturer specifications and include the 
statement “Caution: New Drug – Limited by Federal Law to Investigational Use.” 
 
e. Modification of Study Intervention/Investigational Product for a Participant 
No dose modifications will be allowed.  
 
11. Side Effects with Influenza Vaccination. The side effects listed in the package insert include:  
a. Local Reactions: In placebo-controlled studies among adults, the most frequent side effect of vaccination 
is soreness at the vaccination site (affecting 10%–64% of subjects) that lasts ≤ 2 days. These local 
reactions typically are mild and rarely interfere with the person’s ability to conduct usual daily activities.  
 
b. Systemic Reactions: Fever, malaise, myalgia, and other systemic symptoms can occur following 
vaccination and most often affect persons who have had no exposure to the influenza virus antigens in the 
vaccine (e.g., young children). These reactions begin 6 to 12 hours after vaccination and can persist for 1–
2 days. Recent placebo-controlled trials demonstrate that among older persons and healthy young adults, 
administration of split-virus vaccine is not associated with higher rates of systemic symptoms (e.g., fever, 
malaise, myalgia, and headache) when compared with placebo injections. Immediate, presumably allergic 
reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza 
vaccination. These reactions probably result from hypersensitivity to certain vaccine components; the 
majority of reactions likely are caused by residual egg protein. Although current influenza vaccines contain 

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only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among 
persons who have severe egg allergy. Persons who have experienced hives, have had swelling of the lips 
or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a 
physician for appropriate evaluation to help determine if vaccine should be administered. Persons who 
have documented immunoglobulin E (IgE)–mediated hypersensitivity to eggs, including those who have 
had allergic responses to egg protein–also might be at increased risk for allergic reactions to influenza 
vaccine, persons with known allergies to eggs or who developed an allergic reaction to previous influenza 
vaccines will not be enrolled in this study. The tip caps of the prefilled syringes may contain natural rubber 
latex, which may cause allergic reactions in latex sensitive individuals. (Therefore, individuals with history 
of hypersensitivity to previous influenza vaccination or severe hypersensitivity to eggs/egg protein are 
excluded).  
 
The adverse event profile of TIV administration in pediatric immunocompromised recipients has been 
comparable to that reported in healthy individuals receiving TIV.63 With the exception of soreness at the 
injection site, adverse reactions to TIV are uncommon.64 Minor reported side effects include: low grade 
fever, chills, local redness, bruising, pain, swelling at injection site, headache, malaise, and/or joint or 
muscle pain. Very rare side effects include severe weakness or unusual feeling in the arms or legs, high 
fever, and/or unusual bleeding. In some years, Guillain-Barre syndrome has been reported but rarely in 
children.64-66 
 
12. Risk Information:  
a. Influenza vaccine: The adverse event profile of TIV administration in hematopoietic SCT recipients 
has been comparable to that reported in healthy individuals receiving TIV.34,35,46 With the exception of 
soreness at the injection site, adverse reactions to TIV or QIV are uncommon.64 Minor reported side effects 
include: low grade fever, chills, local redness, bruising, pain, swelling at injection site, headache, malaise, 
and/or joint or muscle pain. Very rare side effects include severe weakness or unusual feeling in the arms 
or legs, high fever, and/or unusual bleeding. In some years, Guillain-Barre syndrome has been reported, 
but rare in children.65,66 
 
b. Blood draw risk: Pain, redness, soreness, bruising, or very rarely infection may occur at the needle 
stick site. Rarely some people faint. If subjects have central venous catheters, blood will be obtained 
through their catheter.  
 
c. Nasal swab: minor discomfort from nasal swabs, and a rare event of bleeding from a nasal swab. If 
this occurs, pressure will be applied to the nares to stop the bleeding.  
 
 
 
13. Study Visit Schedule: (see Table 3 for details) 
 
a. Screening: Subjects will be screened by history and physical exam to make sure that all eligibility 
criteria are met. No baseline laboratory screening will be performed prior to enrollment. However, if 
CBC d/p, quantitative CD4, CD8, CD19, IgM and IgG are obtained as part of standard of care prior to 
enrollment and on the same calendar day as vaccination, these data will be collected and will not need 
to be repeated after consent is signed.  In addition, consent may be obtained prior to visit 1.  
b. Enrollment/Baseline: Prior to each vaccination, inclusion and exclusion criteria, as well as any reason 
to delay vaccination will be reviewed. 
c. Follow up: Follow-up telephone and/or electronic communication will be completed both 1-3 and 8-10 
days after each vaccination visit.  If the subject is seen as part of the optional visit and this visit is within 

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the 8-10 days communication window period, this would replace the 8-10 day telephone and/or 
electronic communication. 
d. Final Study Visit: The final visit will be 180 ± 42 days after visit 2. 
e. Unscheduled Visits:  
May occur for further evaluations of AEs/SAEs. 
• 
Review current health status since the last visit. 
• 
Memory aid will be reviewed if the unscheduled visit occurs within 7 days of vaccination. 
• 
All concomitant medications will be recorded if the early termination occurs within 28 days of 
vaccination. 
• 
A targeted physical examination and vital signs may be performed, as indicated. 
Early Termination Visit: Subject Withdrawal Criteria: Subjects have the right to withdraw from the 
study at any time. 
Events Which Warrant Withdrawal: The investigator may drop/withdraw a subject from the study if 
deemed appropriate. Criteria for termination of a subject include: lost to follow-up, non-compliance with 
the protocol, and/or clinically significant adverse events (e.g., immediate allergic reaction to vaccine, 
severe or anaphylactic in type), which constitute contraindications to further vaccine administration. 
Data Collection for Withdrawn Subjects: Every attempt should be made to collect all data specified by the 
protocol relative to study vaccine received, including post-immunization blood samples. 
 
14. Study Procedures/Evaluation: 
Screening Periods/Supplemental Visit, prior to Visit 1, Day 0.   
• 
Subject and/or Parents/legal guardians are able to sign written informed consent prior to Visit 1.  Also, if 
individuals sign a consent and are later deemed not eligible for vaccination, then this will also be listed 
as a supplemental visit with screen failure.  If the subject was temporarily unable to receive vaccine and 
later becomes eligible (as in the case of recent prior other vaccine receipt), they can proceed with the 
following study procedures.   
Days0 to 90 :  
Patients requiring platelet transfusions are eligible to enroll and must have a platelet count ≥30,000 within 72 
hours prior to their immunization. For subjects <12 months post-transplant, if a platelet count of ≥75,000 is 
documented without transfusion support within 30 days of the immunization or 12-35 months post-transplant 
within 90 days, then an additional platelet count does not need to be repeated prior to immunization.  
. 
Visit 1: Day 0:  
• 
Subject and/or Parents/legal guardians will sign written Informed Consent if not already signed prior to 
Visit 1. 
• 
Medical history  
o Inclusion/exclusion criteria will be checked 
o Prior/concomitant medications will be recorded 
o Written documentation of prior influenza immunizations will be collected 
• 
Targeted physical examination will be conducted including measurement of oral temperature (must be 
<100.4ºF/38ºC). Except for oral temperature, if a physical exam is completed as a part of standard of 
care, another physical exam does not need to be completed. For females of childbearing age a 
pregnancy test will be performed.  
• 
Approximately 20-40 mL of blood will be collected by venipuncture or from a central line prior to 
vaccination for HAI and MN assays to influenza virus antigens, phenotypic B, and T cell responses, B 
and T cell specific influenza responses,  CBC d/p, quantitative CD4+/CD8+/CD19+ levels, and 
quantitative serum IgM and IgG concentrations (if CBC d/p, quantitative CD4, CD8, CD19, IgM, and 
IgG are obtained as part of standard of care prior to enrollment and on the same calendar day as 
vaccination, these data will be collected and will not need to be repeated) 

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• 
Study vaccine will be administered. 
• 
Study staff or clinical research center staff will observe the subjects closely for at least 15 minutes post-
vaccination, with appropriate medical treatment readily available in case of rare anaphylactic reaction 
following the administration of vaccines. 
• 
If IVIG/SCIG is given the same day, it may be given before or after the vaccination, and a second blood 
draw will be obtained post-IVIG/SCIG if administered on same calendar day. 
• 
A memory aid form with reaction measurements, a measurement gauge, thermometer and instructions will 
be provided for the subject to record oral temperatures and any general or local reactions occurring during 
the vaccination day (day 0) and the next 7 days. Information on the memory aid form will be collected from 
the subject through telephone calls and/or electronic communication in the week following vaccination or 
received by mail. If memory aid data were not received by any of the methods mentioned, subjects may 
return it on the day of their next visit. 
• 
The subject will be given contact information for study personnel. The subject will be educated about any 
potential reactions following vaccination. They will be instructed to contact study personnel for reactions 
that are Grade 3, as well as any other medical event that is concerning to subject. 
• 
Only during influenza season, a nasal swab will be obtained regardless of symptoms.  
 
Days 0-7: 
After the vaccination:  
• 
The following data will be recorded on the memory aid form by the subjects each day: 
o Oral temperature 
o Local reactions 
o General reactions 
o Concomitant medications given 
 
Days 1-3 and Days 8-10: Telephone and/or electronic communication: 
• 
An attempt of telephone and/or electronic communication will be made/sent between Days 1-3 and again 
on Days 8-10 to:  
• 
Appropriate data will be collected and they will ensure the memory aid forms are being completed 
correctly  
• 
Any adverse events that have occurred will be collected 
• 
Questions the subject may have will be answered 
• 
Any concomitant medication will be recorded  
• 
If the subject is seen as part of the optional visit and this visit is within the 8-10 days communication 
window period, this would replace the 8-10 day telephone and/or electronic communication. 
 
Visit 2: Days 28-42 
• 
Medical history  
o Inclusion/exclusion criteria will be checked- patients will be eligible to receive vaccine 2 if they 
received vaccine 1, regardless of GVHD status changes- but changes must be documented. 
o Concomitant medications will be recorded 
• 
Targeted physical examination will be conducted including measurement of oral temperature (must be 
< 100.4ºF/38ºC). If a physical exam is completed as a part of standard of care, another physical exam 
does not need to be completed. For females of childbearing age a pregnancy test will be performed.  
• 
Approximately 20-40 mL of blood will be collected by venipuncture or from a central line prior to 
vaccination for HAI and MN assays to influenza virus antigens, phenotypic B, and T cell responses, B 
and T cell specific influenza responses,  CBC d/p, quantitative CD4+/CD8+/CD19+ levels, and 
quantitative serum IgM and IgG concentrations. 
• 
Study vaccine will be administered. 

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• 
The subjects will be observed closely for at least 15 minutes post-vaccination, with appropriate medical 
treatment readily available in case of rare anaphylactic reaction following the administration of 
vaccines. 
• 
If IVIG/SCIG is given the same day, it may be given before or after the vaccination, and a second blood 
draw will be obtained post-IVIG/SCIG if administered on same calendar day. 
• 
A memory aid form with reaction measurements, a measurement gauge, thermometer and instructions will 
be provided for the subject to record oral temperatures and any general or local reactions occurring during 
the vaccination day (day 0) and the next 7 days. Information on the memory aid form will be collected from 
the subject through telephone calls and/or electronic communication in the week following vaccination or 
received by mail. If memory aid data were not received by any of the methods mentioned, subjects may 
return it on the day of their next visit. 
• 
The subject will be given contact information for study personnel. The subject will be educated about any 
potential reactions following vaccination. They will be instructed to contact study personnel for reactions 
that are Grade 3, as well as any other medical event that is concerning to the subject. 
• 
Only during influenza season, a nasal swab will be obtained, regardless of symptoms. 
 
Days 0-7: After the second vaccination: 
 
• 
The following data will be recorded on the memory aid form by the subjects each evening: 
o Oral temperature 
o Local reactions 
o General reactions 
o Concomitant medications given 
 
Days 1-3 and Days 8-10 after second vaccination: Telephone and/or electronic communication 
• 
An attempt of telephone and/or electronic communication will be made/sent between Days 1-3 and again 
on Days 8-10:  
• 
Appropriate data will be collected, and they will ensure the memory aid forms are being completed 
correctly  
• 
Any adverse events that have occurred will be collected 
• 
Questions the subject may have will be answered 
• 
Any concomitant medication will be recorded 
 
Visit 3: 28-42 Days after Visit 2 
• 
Solicited AEs/unsolicited AEs will be reviewed and recorded in through 7 days following vaccination #2 
• 
Targeted physical examination will be conducted if indicated.  
• 
Any concomitant medication will be recorded. 
• 
Any new immunizations since last visit will be reviewed and recorded. 
• 
Approximately 20-40 mL of blood will be collected for HAI and MN assays to influenza virus antigens, 
phenotypic B, and T cell responses, B and T cell specific influenza responses, CBC d/p, quantitative 
CD4+/CD8+/CD19+ levels, and quantitative serum IgM and IgG concentrations. 
• 
A second blood draw will be obtained post-IVIG/SCIG if administered. 
• 
Only during influenza season, a nasal swab will be obtained, regardless of symptoms. 
• 
For the 2019/2020 enrollment season, subjects who are not able to return for visit 3 will have an 
arrangement for a blood draw to be done locally and shipped to the research team. Subjects will also be 
called and asked about their health and medication changes. Also, they will be asked to collect a nose 
swab and mail it to the research team. 
 
 
 

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Influenza Surveillance:  
Active surveillance for influenza-like symptoms will begin when influenza season starts at each site’s 
community. Influenza season begins in the specific community, defined as in previous trials by identification of 
at least 2 positive respiratory tests for influenza, with at least 10% of diagnostic tests positive during 2 
consecutive weeks in the local clinical or research laboratory.60,61 Enrollment will continue during influenza 
season with nasal swabs  obtained at all main visits to document the occurrence of influenza virus detection 
both prior to and after vaccination.   
 
Study staff will attempt to collect nasal swabs from patients who meet the ILI criteria during the entire study 
period.  
 
When the flu season starts, the study staff will attempt to do a weekly telephone and/or electronic 
communication with the participants to detect and document any influenza like illness (ILI). Patients who meet 
the ILI criteria will be asked to collect a nasal swab and mail it back to the study site. 
 
ILI criteria:  One of following criteria met: 
• 
Fever: ≥38.3°C (101°F); or 
• 
Two or more of any of the following: respiratory symptoms (rhinorrhea, sinus congestion, post-
nasal drip, shortness of breath, cough, wheezing, sputum production, sore throat, sneezing, watery 
eyes, ear pain, hoarseness); or systemic symptoms (myalgias and headache). 
 
A nasal swab will be collected. If distance is an issue or if symptoms start on a weekend, subjects will be given 
PrimeStore MTM to take to their local pediatrician’s office, or with proper instructions, home collection can be 
done, and arrangements will be made for specimens to be sent either to the local academic center or directly 
to Vanderbilt in Nashville, TN. Specimens should be collected within 7 days of onset of symptoms, ideally 
within 48 hours.  
 
Note: For subjects who finish their visit 4 before the end of the flu season, influenza surveillance will continue 
until the end of the flu season at their site’s community.  
 
Visit 4: 180 Days ±42 after Visit 2 
• 
Approximately 20-40mL of blood will be collected for HAI and MN assays to influenza virus antigens, 
phenotypic B, and T cell responses, B and T cell specific influenza responses, CBC d/p, quantitative 
CD4+/CD8+/CD19+ levels, and quantitative serum IgM and IgG concentrations. 
• 
A second blood draw will be obtained post-IVIG/SCIG if administered. 
• 
Only during influenza season, a nasal swab will be obtained, regardless of symptoms. 
• 
For the 2019/2020 enrollment season, visit 4 will be optional and subjects who volunteer to participate will 
have the procedures outlined above. 
 
Optional visits: 5-10 days after each vaccination  
• 
Only those subjects who volunteer, will return for a blood draw only. 
• 
Approximately 20-40 mL of blood will be collected for B and T cells responses.  
• 
If within the 8-10 days phone call window, this would replace the 8-10 day telephone and/or electronic 
communication. 
 
Note: Data for proven clinical influenza infection will be collected during the study period and through June 
30th. 
 
15. Laboratory Procedures: 

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a. Specimen Preparation, Handling, and Shipping: Blood will be collected from a vein or from a 
central line from subjects. Study personnel or clinical research staff will collect the blood 
samples, label without personal identifiers, and deliver to the laboratory for preparation of serum 
and freezing of the sera until further testing and/or shipment to Sanofi laboratory for HAI and 
MN testing and B and T cell influenza-specific testing at Vanderbilt. Other clinical labs will be 
sent the local lab.  
b. Hemagglutination Inhibition Assays (HAI): Sera will be shipped to Sanofi laboratory for HAI 
testing. Sera will be initially diluted 1:10 per protocol. 67 Pre-vaccination and post-vaccination 
sera will be analyzed simultaneously to minimize variability in the HAI assay. HAI titers will be 
determined for each influenza antigen included in QIV 2016-2017 or 2017-2018 or 2018-2019. 
c. Neuraminidase Inhibition Assays (NAI): Sera will be shipped to Vanderbilt for NAI testing and 
results will be compared to HAI. NAI testing will be done at Dr. Florian Krammer’s lab in Mt. 
Sinai.  
d. Microneutralization assays: Sera will be shipped to Sanofi laboratory for MN testing and 
results will be compared to HAI.68 
e. Influenza-specific B and T cell Responses and Immunophenotyping of B and T cells: 
Samples will be collected at baseline, 5-10 days (optional) and 28-42 days after each 
vaccination and 180 days (+42 days) after second vaccination. After ficolle separation, 
peripheral blood mononuclear cells (PBMC) will be cryopreserved for future analysis. Each site 
will do this locally and the off-sites will ship to Dr. Sypros Kalams laboratory at Vanderbilt in 
Nashville, TN. This will ensure all time points from each individual can be evaluated 
simultaneously. We propose to study B and T cell responses to vaccination with mass cytometry 
technology (CyTOF), and functional assays such as in-vitro IL-21 production in response to 
vaccine antigen.  
f. Nasal swabs: a nasal swab will be collected by either using viral transport media or using 
PrimeStore MTM, which can be stored at room temperature until ready for shipment to 
Vanderbilt in Nashville, TN for PCR testing for influenza. 
 
16. Specification of Safety Parameters: 
Safety will be assessed by frequency, incidence and severity of AEs and SAEs solicited in-clinic and via 
memory aids, telephone and/or electronic communication conversations, concomitant medications, and 
periodic physical evaluations.  
 
Safety monitoring plan post 15 minute vaccination: Either a nurse, NP, or LPN will administer the vaccine. 
The subject will wait at least 15 minutes to be observed by the research staff or clinical research staff. These 
individuals will be in a location that will have access to individuals with advanced cardiac life support skills.  
 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
a. Adverse Events, Reactogenicity, Serious Adverse Events 
The investigator is responsible for reporting: 
• 
Any Grade 3 Adverse event that is not attributable to underlying disease for which the transplant was 
undertaken, or not attributable to GVHD, or not attributable to complications of immunosuppressive 
medications and are observed or reported through 7 days following vaccination, regardless of their 
relationship to study product. 
• 
Any other AE will not be reported unless it meets the SAE criteria (see Section 16.f). 
A physician, nurse, nurse practitioner, and/or physician’s assistant will assess initial vaccine reactions for at 
least 15 minutes after vaccination. Subjects will be asked to record both solicited vaccine reactions 

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(reactogenicity) and any unsolicited AEs on a memory aid for 7+ days after each vaccination (Day 0 through 
Day 7). Study personnel will attempt to contact the subjects by telephone and/or electronic communication at 1 
to 3 days and again 8-10 days after each vaccination to review any AEs and SAEs.  
AEs and SAEs will be collected through 7 days following each vaccination. Adverse events will be followed 
until resolution or until considered stable. Solicited injection site AEs will include the following: pain, 
tenderness, erythema/redness, and swelling/induration (Table 4). Solicited systemic AEs will be collected for 
7+ days post each vaccination and will include the following: fevers, fatigue/malaise, headache, nausea, body 
ache/myalgia, generally activity, and vomiting (Table 5).  
 
b. Definition of Adverse Event:  
Adverse Event: The International Conference on Harmonization (ICH) guideline E6 defines an AE as any 
untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product regardless of its causal relationship to the study treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally related to the 
use of medicinal (investigational) product. The occurrence of an AE may come to the attention of study 
personnel during study visits and interviews or by a vaccine recipient presenting for medical care.  
AEs must be graded for severity and relationship to study product (see below). Severity can be assessed by a 
licensed clinician (i.e., physician, nurse, nurse practitioner, physician’s assistant). Relationship to study product 
can only be assessed by a clinician licensed to make medical diagnoses (i.e. physician, nurse practitioner, 
physician’s assistant) listed on the Form FDA 1572.  
Adverse events characterized as intermittent require documentation of onset and duration of each episode. 
The start and stop date of each reported AE will be recorded on the data collection forms and eCRF. 
c. Severity of Event: AEs will be assessed by the clinician using a protocol defined grading system. For 
events not included in the protocol defined grading system, the following guidelines will be used to quantify 
severity:  
• 
Grade 1 -Mild: events require minimal or no treatment and do not interfere with the patient’s daily activities. 
• 
Grade 2 -Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Grade 3 -Severe: events interrupt a patient’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating or Life-threatening, i.e. any adverse drug 
experience that places the patient or subject, in the view of the investigator, at immediate risk of death from 
the reaction as it occurred. It does not include a reaction that had it occurred in a more severe form, might 
have caused death. 
 
d. Relationship to study products/vaccines:  
The investigator’s assessment of the relationship of an AE to the study drug/vaccine is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. AEs must have their possible 
relationship to study vaccine assessed using the following terms: related or not related. In a clinical trial, the 
study product must always be suspect. To help assess, the following guidelines are used. 
• 
Related – The event is temporally related to the administration of the study product and no other etiology 
explains the event. 
• 
Not Related – The event is temporally independent of study product and/or the event appears to be 
explained by another etiology. 

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e. Reactogenicity:  
Reactogenicity events are AEs that are known to occur with this type of vaccine. The following Toxicity Grading 
Scales will be used to grade local and systemic (both quantitative and subjective) reactions:  
 
 
 
 
Table 4. Local Solicited Adverse Events 
Local Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain 
Subject is aware of 
pain but it does not 
interfere with daily 
activity and no pain 
medication is taken 
Subject is aware of 
pain; there is 
interference with daily 
activity or it requires 
therapeutic measures  
Subject is aware of pain 
and it prevents daily 
activity or requires a 
healthcare visit 
Tenderness 
The area 
immediately 
surrounding the 
injection site hurts 
only when touched 
and it does not 
interfere with daily 
activity  
The area immediately 
surrounding the 
injection site hurts 
only when touched 
and it interfere with 
daily activity  
The area immediately 
surrounding the 
injection site hurts when 
touched and it prevents 
daily activity 
Swelling/Induration 
Does not interfere 
with daily activity  
Interferes with daily 
activity  
Prevents daily activity 
Erythema/Redness 
0.5 to 2.5 cm 
>2.5 cm to <5 cm 
 
≥5 cm 
 
Induration/Swelling 
0.5 to 2.5 cm 
>2.5 cm to <5 cm 
 
≥5 cm 
 
 
Table 5. Systemic Solicited Adverse Events 
Systemic 
(Subjective) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fatigue/Malaise 
No interference with 
activity 
Some interference with 
activity 
Incapacitating, prevent s daily 
activity, may necessitate medical 
care or absenteeism 
Headache 
No interference with 
activity 
Some interference with 
activity 
Incapacitating, prevents daily 
activity, may necessitate medical 
care or absenteeism 
Nausea 
No interference with 
activity 
Some interference with 
activity 
Incapacitating, prevents daily 
activity, may necessitate medical 
care or absenteeism 
Body ache/myalgia 
(not at injection site) 
Less active than 
normal without 
interference with 
Less active than 
normal with 
interference with 
Incapacitating, prevents daily 
activity, may necessitate medical 
care or absenteeism 

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essential daily tasks 
(e.g. eating, sleeping) 
essential daily tasks 
(e.g. eating, sleeping) 
General activity 
level 
Less active than 
normal without 
interference with 
essential daily tasks 
(e.g. eating, sleeping) 
Less active than 
normal with 
interference with 
essential daily tasks 
(e.g. eating, sleeping) 
Incapacitating, prevents daily 
activity, may necessitate medical 
care or absenteeism 
Vomiting 
1-2 times a day 
3-4 times a day 
>4 times a day 
Systemic 
(Quantitative) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever (°C) – ORAL 
≥38.0 - <38.3 
≥100.4 < 101° F 
≥38.3 - <39 
≥ 101 - < 102° F 
≥39 
≥ 102° F 
f. Serious Adverse Event:  
An SAE is defined as an AE meeting one of the following conditions: 
• 
Results in death during the period of protocol defined surveillance except deaths that are the result of 
trauma or accident. 
• 
Is life-threatening (defined as a subject at immediate risk of death at the time of the event). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization during the period of protocol-
defined surveillance. 
• 
Results in a persistent or significant disability/incapacity. 
• 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical judgment, the event 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Note* 
The SAEs should not be attributable to underlying disease for which the transplant was undertaken, or not 
attributable to GVHD, or not attributable to complications of immunosuppressive medications. 
 
g. Reporting Procedures: 
Adverse events including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected for unsolicited adverse events includes event 
description, date of onset, investigator assessment of severity, investigator assessment of relationship to study 
product, date of resolution of the event, seriousness, and outcome. The severity of non-serious AEs will be 
assessed by a licensed clinician (i.e., medical doctor, nurse, nurse practitioner, physician’s assistant). The 
relationship of non-serious AEs will be assessed by a licensed clinician (i.e., medical doctor, nurse practitioner, 
physician assistant) listed on the Form FDA 1572. All AEs occurring during the AE reporting period of the study 
will be documented appropriately regardless of relationship. AEs will be followed to adequate resolution or until 
considered stable.  
 
Any medical condition that is present at screening will be considered a baseline condition and will not be 
reported as an AE. If the severity of any pre-existing medical condition increases during the study period, then 
it will be recorded as an AE. 

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h. Serious Adverse Event Detection and Reporting 
SAEs as defined in Section 16.f will be: 
• 
Notified to the IND Sponsor/Lead PI (Dr. Natasha Halasa), local site PI and/or Sub-Is and DMID 
Pharmacovigilance Group (PVG) within 24 hours of knowledge of the SAE. 
• 
Assessed for severity and relationship by a licensed clinician listed on the FDA Form 1572 as the PI or 
a Sub-Investigator. 
• 
Recorded on the appropriate SAE report form. 
• 
Followed through resolution by a study physician. 
• 
Reviewed by an Independent Safety Monitor (ISM), Data and Safety Monitoring Board (DSMB) 
(periodic review unless related), DMID, and IRB. 
• 
SAEs related to the study vaccine that are unexpected and fatal or life-threatening will be reported to 
the FDA no later than 7 calendar days after SAE awareness.  
• 
SAEs related to the study vaccine that are unexpected and serious (not fatal or life-threatening) are to 
be reported to the FDA no later than 15 calendar days after SAE awareness.  
• 
All other SAEs will be submitted with the FDA Annual Report in summary form. 
• 
All SAEs unexpected and deemed related to the study vaccine will be reported to Sanofi within 7-15 
calendar days after SAE awareness. 
SAEs occurring through 7 days following vaccination will also be reported to the local IRB within 1-2 calendar 
days as the team becomes aware of the SAE or per local IRB protocol/procedures.  
Any AE that meets a protocol-defined serious criterion as defined in Section 16.f will be submitted immediately 
(within 24 hours of site awareness) on a SAE form to the DMID Pharmacovigilance Group, to the following 
address: 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) 
SAE FAX Phone Number: 1-800-275-7619 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, selected SAE data fields must also be entered into the database. Refer to the 
protocol-specific MOP for details regarding this procedure. 
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance Group and 
should be provided as soon as possible. 
The site will send a copy of the SAE report(s) to the ISM when they are provided to the DMID 
Pharmacovigilance Group. The DMID Medical Monitor and DMID Clinical Project Manager will be notified of 
the SAE by the DMID Pharmacovigilance Group. The DMID Medical Monitor will review and assess the SAE 
for regulatory reporting and potential impact on study subject safety and protocol conduct. 
At any time after completion of this study, if the site Principal Investigator or appropriate sub-investigator 
becomes aware of an SAE that is suspected to be related to study product, the site Principal Investigator or 
appropriate sub-investigator will report the event to the DMID Pharmacovigilance Group. 
MedWatch reports will also be submitted to the DMID Pharmacovigilance Group. 

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i. Independent Safety Monitor (ISM) and the Data Safety Monitoring Board (DSMB): 
An Independent Safety Monitor (ISM) is a physician at the enrollment site with relevant expertise whose 
primary responsibility is to provide independent medical assessment in a timely fashion at each site. Each site 
will have an ISM and back-up ISM. Participation is for the duration of the study.  
The ISM should be able to readily access participant records in real time, have the privileges to examine the 
subject, and provide an independent medical assessment and recommendation to the IND sponsor and DMID. 
The primary focus of the ISM is to independently review all SAEs with follow-up through resolution and 
thoroughly investigate those events considered unexpected. Clinical and laboratory data, clinical records, and 
other study-related records should be made available for ISM review. The ISM may be a faculty member at the 
clinical site but will not be under the direct supervision of the PI. It is the responsibility of the PI to ensure that 
the ISM is appraised of all new safety information relevant to the study product and the study.  
Safety oversight will be conducted by a Data Safety and Monitoring Board (DSMB) that is an independent 
group with expertise to interpret data from this study and will monitor subject safety and advise DMID and the 
IND sponsor. The DSMB members will be separate and independent of study personnel participating in this 
study and should not have scientific, financial, or other conflict of interest related to this study. The committee 
will consist of a minimum of 3 members. A simple majority will be considered a quorum for meeting purposes. 
The DSMB will operate under the rules of a DMID-approved charter that will be written at the organizational 
meeting of the DSMB and defines the data elements to be assessed and the procedures for data reviews. At 
this time, each data element that the DSMB needs to assess will be clearly defined. Procedures for DSMB 
reviews/meetings will be defined in the charter. The DSMB will review applicable data to include, but not limited 
to, overall study progress and participant, clinical, safety, reactogenicity, and immunogenicity data. Reports 
may include enrollment and demographic information, medical history, concomitant medications, physical 
assessments, clinical laboratory values, dosing compliance, and solicited and unsolicited AE/SAEs. Additional 
data may be requested by the DSMB, and interim statistical reports may be generated as deemed necessary 
and appropriate by the IND sponsor and DMID. The DSMB may receive data in aggregate and presented by 
treatment arm. The DSMB may also be provided with expected and observed rates of the expected AEs in an 
unblinded fashion, and may request the treatment assignment be unblinded for an individual subject if required 
for safety assessment. The DSMB will review grouped and unblinded data in the closed session only. The 
DSMB will meet and review this data at scheduled time points or ad hoc as needed during this study as 
defined in the DSMB charter. As an outcome of each review/meeting, the DSMB will make a recommendation 
to the IND sponsor and DMID as to the advisability of proceeding with study vaccinations (as applicable), and 
to continue, modify, or terminate this trial. 
DMID or the DSMB chair may convene the DSMB on an ad hoc basis according to protocol criteria or if there 
are immediate concerns regarding observations during the course of this trial. The DMID Medical Monitor is 
empowered to stop enrollment and study vaccinations if adverse events that meet the halting criteria are 
reported. The DMID Medical Monitor and the ISM will be responsible for reviewing SAEs in real time. The 
DSMB will review SAEs on a regular basis and ad hoc during this study. 
The DSMB will review study progress and participant, clinical, safety, reactogenicity, and immunogenicity data 
at the following times: 
o Data review for safety and reactogenicity at specified times during the course of this trial – every 6 
months, starting after the first patient is enrolled until the end of the study. 
o Final review – 6 to 8 months after clinical database lock to review the cumulative unblinded safety, 
reactogenicity, and immunogenicity data for this study.  The data will be provided in a standard 

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summary format.  The DSMB may be asked to provide recommendations in response to questions 
posed by the IND sponsor and DMID. 
o Ad hoc when a halting rule is met, for immediate concerns regarding observations during this study, or 
as needed – for a specific safety concern, such as SAE deemed related to the study vaccine. 
 
j. Halting Rules: 
The ISM of each site, DMID, and DSMB will be provided safety data in order to advise on matters of safety, 
including halting the trial. The safety data will consist of immediate reactogenicity events (in the 15 minutes 
after vaccination), reactogenicity events recorded on the memory aid (each day for the week after vaccination), 
AEs, and SAEs. The data will be entered into ONCORE and/or REDCap and provided to the ISM, DMID, and 
DSMB for review. The presentation of the data will include whether any events contributing towards a halting 
rule have been met. The frequency of DSMB review will be defined in the charter.  
The study will be halted (for further DSMB review/recommendation) if any of the following occur and it was not 
the result of trauma or accident, scheduled hospitalization or surgery, and is not attributable to disease relapse, 
GVHD, or and infection due to the immunosuppressed state of the patient. No new subjects will be enrolled if: 
1. If one subject has an SAE and the adverse event is deemed severe within 7 days of vaccine 
that is determined to be related to the study vaccine by the site PI in consultation with the site 
ISM and the study PI, no new subjects will be enrolled. The SAEs will be reviewed by the DSMB 
for the relationship with the study vaccine and further discussed with DMID to determine 
continuation of the study. 
2. If four or more subjects have the same Grade 3 event in any reactogenicity category (excluding 
grade 3 redness/ induration size or grade 3 fever) that is determined to be study vaccine-
related, no new subjects will be enrolled. The AEs will be reviewed by the DSMB for the 
relationship with the study vaccine. For 2019-20, based on safety data from the previous years, 
the number of subjects will be increased to eight prior to halting. 
3. 3 or more subjects have urticaria considered to be study vaccine-related. 
4. 1 or more subjects have intramuscular injection-site ulceration, abscess, or necrosis. 
5. 1 or more subjects have laryngospasm, bronchospasm or systemic anaphylaxis within 24 hours 
of administration of study vaccine. 
6. 1 or more subjects have acute weakness of limbs or cranial nerve innervated muscles. 
7. Any death occurring within the first 7 days following administration of study vaccine.  
 
 
If any of the halting rules are met, the study will not proceed with the remaining enrollment or vaccinations 
without a review by and recommendation from the DSMB to proceed. CBER will be notified if a stopping rule 
has been met at any time during the study. DMID retains the authority to suspend additional enrollment and 
study interventions/administration of study product during the entire trial, as applicable. 
 
k. Safety Oversight: 
The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data monitoring for its investigator-
initiated and NIH-NCI funded clinical trials through its Data and Safety Monitoring Committee (DSMC). The 
Committee maintains authority to intervene in the conduct of studies as necessary to ensure clinical research 
performed at VICC achieves the highest quality standards. 
  
l. Data and Safety Monitoring Committee/Quality Assurance:  
The Vanderbilt-Ingram Cancer Center (VICC) oversees patient safety and data monitoring for clinical trials 
through the Data and Safety Monitoring Committee (DSMC). The committee will convene on a quarterly basis 
and ad-hoc as necessary. The DSMC provides oversight of the internal audit function. During audits the 

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Quality Assurance (QA) auditor will review selected case histories. In addition they will conduct a regulatory 
and pharmacy audit as needed. The data presented to the DSMC will be blinded unless the committee 
requests un-blinded data. The DSMC will determine if the findings in the audit report require a response from 
the Principal Investigator. After reviewing submitted corrective action plans, the committee has the authority to 
approve the continuation of the study, increase the frequency of auditing, suspend accrual, or terminate a 
protocol; however, this will be in discussion with the DSMB.  
 
This trial will be monitored continuously by the study’s principal investigator and on a weekly and monthly basis 
by the Research Team. Quarterly safety and monitoring reports are available to the DSMC. The DSMC 
reviews all serious adverse events reported during the previous quarter for all clinical trials active at the VICC 
and makes recommendations to address concerns of patient safety. Since data from REDCap will be 
transferred to Oncore, the DSMC will be able review all safety data from all nine sites.  
 
A Quality Assurance auditor under the direction of the DSMC will audit this clinical trial quarterly for compliance 
with adverse event reporting, regulatory and studies requirements, and data accuracy and completion. Audit 
reports detailing the findings are provided to the DSMC. 
 
Any DSMC communications regarding safety evaluations will be shared with the Chair of DSMB and the 
DSMB. This information will also be shared with FDA-CBER and NIH.  
 
m. Blinding: 
All study staff, subjects, and their parent/guardians will be blinded to which vaccine the subject will receive, 
except for an un-blinded vaccinator.  This individual will not inform the study team, subjects, and/or their 
parent/guardians which vaccine they administered to the subject.  The un-blinded vaccinator will not participate 
in any other study activities.  If the study vaccine is provided in a blinded manner, then research staff will be 
able to administer the vaccine, and an un-blinded vaccinator will not be necessary. The pharmacy will be un-
blinded and will have a record of which vaccine was given to each subject.  
 
n. Vaccine Labeling Plan: 
The following statement will be used: “Caution: New Drug – Limited by Federal (or United States) law to 
investigational use” and subjects and parents/guardians will be informed of this during the consent process.   
 
17. Statistical Considerations: 
a. Sample Size Calculations: A total of 200 children will be targeted, with 100 in each group. This 
is based on the assumption, with 80% power, that 20% of the children in the standard dose 
group will achieve a protective titer compared to 40% of the HD-TIV group for at least one 
influenza antigen. Accounting for a 20% drop out rate, 100 children in each group will be 
needed.  
 
Strain 
Expected 
Seroprotection 
HD-TIV 
Expected 
Seroprotection 
standard dose  
N (HD) 
N (SD) 
Power 
Total N 
with 20% 
drop out 
Expected HD-TIV seroprotection is twice as of standard dose  
A 
40% 
20% 
80 
80 
80% 
200 
A 
50% 
25% 
55 
55 
80% 
138 
A 
60% 
30% 
40 
40 
80% 
100 
A 
70% 
35% 
28 
28 
80% 
70 
 
b. Immunogenicity analysis: The probability of achieving a 4-fold (or greater) rise in post-
vaccination HAI titers relative to baseline, as well as the probability of a HAI titer greater than 

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1:40, will be estimated using a binomial model. We will calculate the Bayesian posterior 
distribution of the probabilities under all 4 combinations of standard and HD-TIV crossed with a 
single dose and two doses. From these probabilities, odds ratios will be calculated along with 
95% credible intervals. These quantities will be modeled as a logit-linear function of several 
covariates, including CD4+/CD8+/CD19+ and IgG levels, absolute neutrophil and lymphocyte 
count (or their ratio), time from post-transplant to enrollment, type of preparative regimen, donor 
status, and stem cell source. In addition, the distributions of geometric mean HAI titers for high 
and standard dose recipients will be estimated via log-normal models and expressed as ratios in 
order to evaluate the evidence for higher GMT in the HD-TIV sample, after one and two 
vaccines. In addition, we will compare each group to document if they meet serological criteria 
by WHO biological standards for influenza vaccines (>40% for seroconversion, GMT >2.5-fold 
increase, and >70% with≥1:40).69 
 
c. Safety analysis: For the primary analysis of the safety data, the proportion of subjects in each 
group experiencing at least one solicited AE will be calculated along with 95% posterior credible 
intervals. The difference between the rates of solicited AEs between the groups will be 
estimated by calculating the posterior 95% credible interval of the difference in proportions. For 
each group and each event, solicited and unsolicited AEs will be descriptively summarized. 
Severities of solicited and unsolicited AEs will also be descriptively summarized for each group 
and each type of event. Descriptive statistics will include number experiencing event, mean and 
95% posterior credible interval. Maximum size of redness and swelling may be descriptively 
summarized for each group and event; proportion of events lasting longer beyond Day 3 may 
also be descriptively summarized. 
 
d. Specific B and T cells responses: We will estimate the association between HAI titers and 
expression of ICOS and CD40L on CD4+CXCR5+ T cells. We anticipate that the frequency of 
circulating TFH cells with expression of ICOS and CD40L will directly correlate with higher 
influenza titers. We will also estimate the association between HAI titers and the distribution of 
circulating plasmablasts (CD19+CD27+CD38+), using either parametric linear models or 
Gaussian processes if the relationship cannot adequately be modeled linearly. In addition to the 
phenotypic analysis, we will perform in vitro stimulation of PBMC with influenza antigen. We will 
measure the degree of ICOS and CD40L expression of CD4+CXCR5+ T cells in the presence 
or absence of antigen, and model the relationship between response and HAI titer, where we 
predict responders to have higher HAI titers. Comparisons between marker expression on 
CD4+CXCR5+ T cells in the presence or absence of antigen and correlations between HAI titer 
and Marker expression on CD4+CXCR5+ T cells will be evaluated by building models that 
regresses T cell counts on HAI titers. We will compare both linear and non-linear fits to the data, 
and choose the optimal model as determined by a model selection criterion, such as AIC. 
Should the parametric models not adequately fit the data, we will use a semi-parametric 
regression via Gaussian processes as a robust alternative. 
 
e. Influenza-Like-Illness assessment. The percentage of individuals in each group that test 
positive for influenza by PCR and the number of ILIs in each group during the influenza season 
will be compared. 
 
18. Ethics/Protection of Human Subjects: 
 
a. Ethical Standard:  
The investigator(s) will ensure that this study is conducted in full conformity with the principles of the Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of the National 

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Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and 
codified in 45 CFR 46, 21 CFR 312, 21 CFR 50, 56, and, if applicable, ICH E6; 62 Federal Regulations 25691 
(1997). 
 
b. Institutional Review Board: 
1. The protocol, informed consent documents, and all types of volunteer educational information 
must be submitted to the IRB for review and must be approved before the study is initiated. 
2. The responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial. 
3. Should amendments to the protocol be required, the amendments will be written by the study 
team and submitted to the FDA and IRB.  
4. The investigator is responsible for keeping the IRB apprised of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but at least once a year. The 
investigator must also keep the IRB informed of any significant adverse events.  
5. The study may be discontinued for administrative reasons or if new data about the 
investigational product/regimen resulting from this or any other studies become available, and/or 
on advice of the DSMB, DSMC, Investigator, and/or IRB. If a study is prematurely terminated or 
suspended, the Investigator shall promptly inform the IRB of the reason for termination or 
suspension. 
6. If for any reason the study is prematurely terminated, the Investigator will promptly inform the 
subject’s parent or legal guardian and ensure appropriate therapy and follow-up for volunteers. 
7. All key study staff regularly undergo training in human subjects issues conducted by the 
participating site or their IRBs. 
 
c. Informed Consent Process: 
1. In obtaining and documenting informed consent, investigators and the research team will comply with the 
applicable regulatory requirements, Good Clinical Practice, and ethical principles. The written Informed 
Consent (IC) Form will be approved by the Institutional Review Board/Ethics Committee (IRB/EC) prior to 
starting the study. 
2. Potential subjects will be informed about the scope of the study, expected benefits, and possible risks. 
They will also be informed that participation is voluntary and can be terminated at any time without reason. 
3. The extent of confidentiality of subject records is defined in the IC and applicable data protection legislation 
will be provided to the parent/legal guardian. Subjects will be informed that the sponsor or sponsor’s 
designee, monitor, auditor, IRB/EC, and the regulatory authority (ies) will be granted direct access to the 
subject’s original medical records for verification of clinical trial procedures and/or data, without violating 
laws and regulations. By signing a written IC form, the subject’s legally acceptable representative is 
authorizing such access. 
4. The IC will be explained thoroughly to the subject. Ample time will be given to answer all questions. A 
signature will be obtained prior to any study procedures. A signed and dated copy of the IC will be given to 
the subject’s parents/guardians and subject.  
5. Subjects may also receive IRB approved information about the vaccines to be used in the study. 
6.  Assents will be used for children in this study (verbal assents for children 3-6 years, if applicable, and 
signed assents for children 7-17 years of age).  
 
d. Exclusion of Women, Minorities, and Children (Special Populations): 

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This study will be inclusive of children 3-17 years of age HSCT recipients who meet the inclusion/exclusion 
criteria, regardless of religion, sex, or ethnic background.  
 
e. Subject Confidentiality: 
1. All information will be in the research record that will be handled by the research personnel. The 
results of the research study may be published, but volunteers’ names or identities will not be 
revealed. Records will remain confidential.  
2. In order to maintain subject confidentiality, records will be kept locked and results of tests will be 
coded to prevent association with volunteers’ names. This confidentiality is extended to cover 
testing of biological samples in addition to the clinical information relating to participating 
subjects. Volunteers’ records will be available to the FDA, NIH, external monitors, and the IRB. 
3. The study protocol, documentation, data and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any 
unauthorized third party, without prior written approval of the sponsor. 
4. The following confidential information will be collected into folders and stored in a safe, locked 
location, identified only by code number: age, gender, race, family history, social history, full 
address, phone number (home, cell, and work), and date of birth, fax number, secondary name, 
birth history, and contact number, and email address of the subject’s parent/legal guardian. 
5. The records will be sent to storage after study completion and data analysis. 
6. Serum samples will be collected during this study and stored with their subject ID as the only 
identifiers. Laboratory assays containing data from the study will be labeled only with volunteer 
code numbers. 
7. The information in the REDCap or ON-Core database will only include non-identifiable 
information. 
f. Study Discontinuation: 
If the study is discontinued, enrolled subjects will continue to be followed for safety assessments. No further 
doses of vaccine will be administered. Samples will be stored at Vanderbilt. 
 
g. Future Use of Stored Specimens: 
Subjects will be asked for permission to keep any remaining specimen for possible use in future research 
studies, such as testing for antibodies against other viruses or bacteria. By the end of the study, all samples 
will be stored at Vanderbilt. The samples may be shared with other investigators. The samples will not be sold 
or used directly for production of any commercial product. No human genetic tests will be performed on 
samples prior to obtaining new, written permission (consent) from the subject. Each sample will be labeled with 
a unique number to protect the subject’s confidentiality. There is a small risk of loss of confidentiality. The 
samples will be stored indefinitely. 
 
There are no benefits to subjects in the collection, storage, and subsequent research use of specimens. 
Reports about future research done with subject’s samples will NOT be kept in their health records, but 
subject’s samples may be kept with the study records or in other secure areas. Subjects can decide if they 
want their samples to be used for future research or have their samples destroyed at the end of the study. A 
subject’s decision can be changed at any time prior to the end of the study by notifying the study doctors or 
nurses in writing. However, if a subject consents to future use and some of their blood has already been used 
for research purposes, the information from that research may still be used.  
 
19. Data Handling and Record Keeping: 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness of the data 
reported. All data collection forms should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black or blue ink is required to ensure clarity of reproduced copies. When making a 

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change or correction, cross out the original entry with a single line and initial and date the change. Do not 
erase, overwrite, or use correction fluid or tape on the original.  
 
a. Data Capture Methods: 
For all the sites, the data will be entered into a standardized, secured database: REDCap (Research Electronic 
Data Capture) system. REDCap is a secure, web-based application designed to support data capture for 
research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data downloads to 
common statistical packages; and 4) procedures for importing data from external sources.70 The research team 
at each site will be given a user name and pass codes to be able to enter data from their sites locally.  
 
At Vanderbilt, safety data from REDCap maybe transferred to On-line Clinical Oncology Research 
Environment = ONCORE (OnCore) is a highly secure, web based, cancer specific, and customizable system 
that provides fully integrative clinical data management and study administration capabilities developed in an 
ongoing collaborative effort with National Cancer Institute (NCI) designated Comprehensive Cancer Centers. It 
fully integrates study administration functionality including protocol tracking, patient registration, NCI reporting, 
review committee tracking, and SAE tracking, with clinical data management functionality including electronic 
case report forms (eCRF) design, clinical data capture, protocol and regulatory compliance monitoring. Also 
the system is capable in storing basic protocol information (e.g., IRB approval dates, dates for annual 
renewals, etc.) and clinical trials research data. Oncore allows the investigator to define specific protocol 
requirements and generate data collection forms. Creation of the data collection form is done with a single 
button click after the parameters of an individual protocol have been specified. Oncore permits specification of 
study protocols, management of patient enrollment, clinical data entry and viewing, and the generation of 
patient or study-specific reports based on time stamping. OnCore is embedded with a comprehensive domain 
repository of standard reference codes and forms to promote standardization. The sources for the repository 
include CDUS, CTC, CDEs from NCI, ICD, MedDRA and various best practices from contributing NCI-
designated Comprehensive Cancer Centers. OnCore provides several reporting features specifically 
addressing NCI Summary 3 and Summary 4 and other reporting requirements. Data may also be exported in a 
format suitable for import into other database, spreadsheets or analysis systems (such as SPSS). This system 
will be used to manage all Vanderbilt Ingram Cancer Center (VICC) clinical trials data. OnCore is maintained 
and supported in the VICC Clinical and Research Informatics Resource. A copy of the paper records will be 
retained for at least 7 years after completion of the study. The information stored in the ONCORE and REDCap 
database will be kept indefinitely.  
 
 20. Publication Policy: 
The intention of this study is to publish the data from this trial. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. 
 
21. Certificate of Confidentiality: 
To protect privacy, we have received a Certificate of Confidentiality.  With this Certificate, the researchers 
cannot be forced to release information that may identify the research subject, even by a court subpoena, in 
any federal, state, or local civil, criminal, administrative, legislative, or other proceedings.  The researchers will 
use the Certificate to resist any demands for information that would identify the subject, except as explained 
below. 
 

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The Certificate cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects, like this study, or for information 
that must be released in order to meet the requirements of the Federal Food and Drug Administration (FDA). 
 
A Certificate of Confidentiality does not prevent the subject from voluntarily releasing information about 
themselves or their involvement in this research.  If any person or agency obtains a written consent to receive 
research information, then the researchers may not use the Certificate to withhold that information.  
  
The Certificate of Confidentiality does not prevent the researchers from reporting without the subject’s consent, 
information that would identify the subject as a participant in the research project regarding matters that must 
be legally reported including: child and elder abuse, sexual abuse, or wanting to harm themselves or others.   
 
The Certificate of Confidentiality applies only under US law. 
 
 
 
 
 
 
 

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resistance in a critically Ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin 
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Engelhard D, Nagler A, Hardan I, 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. 
32. 
Gandhi MK, Egner W, Sizer L, 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 
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