Vaccinating Children After Chemotherapy for Acute Lymphoblastic Leukemia: A Canadian Immunization Research Network Study
Phase: PHASE4
Conditions: Acute Lymphoblastic Leukemia
Sponsor: Canadian Immunization Research Network

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VACCINATING CHILDREN AFTER CHEMOTHERAPY FOR  
ACUTE LYMPHOBLASTIC LEUKEMIA:  
A Canadian Immunization Research Network Study  
 
Research Protocol 
Study number:  
SI02 
Protocol Date:  
14 June 2017 
 
Principal Investigator:  
Karina Top, MD, MS, Departments of Pediatrics and Community Health & Epidemiology, 
Dalhousie University and Canadian Center for Vaccinology, IWK Health Centre, Halifax, NS 
 
Co-Investigators:  
 
 
Upton Allen, MD, Hospital for Sick Children, University of Toronto, Toronto, ON 
Julie Bettinger, PhD, MPH, Vaccine Evaluation Centre, British Columbia Children’s Hospital 
and University of British Columbia, Vancouver, BC 
Gaston De Serres, MD, PhD, Institut national de santé publique du Québec and Laval University, 
Quebec, QC 
Simon Dobson, MD, Vaccine Evaluation Centre, British Columbia Children’s Hospital and 
 
University of British Columbia 
Scott Halperin, MD, Departments of Pediatrics and Microbiology & Immunology, Dalhousie 
University and the Canadian Center for Vaccinology, IWK Health Centre 
Todd Hatchette, MD, Departments of Medicine and Microbiology & Immunology, Dalhousie 
University and Canadian Center for Vaccinology 
Taj Jadavji, MD, Alberta Children’s Hospital, University of Calgary, Calgary AB 
Tamara MacDonald, PharmD, IWK Health Centre 
Athena McConnell, MD, Royal University Hospital, Saskatoon, SK 
Jeffrey Pernica, MD, McMaster Children’s Hospital, McMaster University, Hamilton, ON 
Anne Pham-Huy, MD, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, 
 
ON 
Victoria Price, MBCHB, MMed, Department of Pediatrics, Dalhousie University and IWK 
Health Centre 
Caroline Quach, MD, Montreal Children’s Hospital, McGill University, Montreal, QC 
Rod Rassekh, MD, British Columbia Children’s Hospital, University of British Columbia 
Bruce Smith, PhD, Department of Mathematics & Statistics, Dalhousie University 
Lillian Sung, MD, Hospital for Sick Children, University of Toronto 
Bruce Tapiero, MD, Centre Hospitalier Universitaire de Ste-Justine, Montreal, QC 
Dat Tran, MD, Hospital for Sick Children, University of Toronto 
Wendy Vaudry, MD, Stollery Children’s Hospital, University of Alberta, Edmonton, AB 
Tania Watts, PhD, Department of Immunology, University of Toronto 
Rupesh Chawla, MD, Alberta Children’s Hospital, University of Calgary, Calgary AB 
Shaun Morris, MD, MPH, Hospital for Sick Children, University of Toronto 
Soren Gantt, MD, PhD, MPH, Vaccine Evaluation Centre, BC Children’s Hospital and UBC 
Earl Rubin, MD, Montreal Children’s Hospital, McGill University, Montreal, QC  

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1. 
Background and rationale 
 
1.1 Acute Lymphoblastic Leukemia 
 
Acute leukemias are the most common malignancies in children, accounting for 32% of all 
cancers in children <15 years of age. Acute lymphoblastic leukemia (ALL) accounts for 80% of 
childhood leukemia. The annual incidence of ALL is approximately 5 per 100,000 population, 
peaking at 9 per 100,000 among children 1 to 4 years of age.[1] With current chemotherapy 
protocols the prognosis is excellent with 5-year survival of over 85%. 
 
1.1.1 Chemotherapy regimens and their immunosuppressive effects 
At diagnosis, children are stratified as standard, high or very high risk, depending on clinical and 
genetic features. The clinical features that predict high risk ALL are: male sex, age <1 year or 
≥10 years at diagnosis, presenting peripheral white blood cell (WBC) count ≥50 x109/l. 
Treatment consists of multiple phases of multi-drug systemic and intrathecal chemotherapy: 
induction, consolidation, interim maintenance, delayed intensification and maintenance therapy. 
Total treatment course is approximately 2 years for girls and 3 years for boys. Most pediatric 
oncology centres in Canada use the treatment protocols developed by the Children’s Oncology 
Group (COG). Three centres use the protocols developed by the Dana-Farber Cancer Institute 
(DFCI) ALL Consortium.[2] Examples of standard and high risk COG and DFCI ALL protocols 
are shown in Tables 1 and 2.  
 
Table 1. COG ALL chemotherapy protocol (AALL0932) 
  
Induction 
Consolidation 
Interim 
Maintenance 
I/II 
Delayed Intensification 
Maintenance 
SR-ALL 
5 weeks 
4 weeks 
8 weeks 
8 weeks 
to complete 2-3 years 
total therapy 
Vincristine, 
Dexamethasone, 
Pegaspargase;  IT 
Methotrexate & 
Cytarabine 
Vincristine, 
Mercaptopurine; IT 
Methotrexate 
Vincristine, 
Methotrexate; 
IT Methotrexate 
Dexamethasone, 
Vincristine, 
Doxorubicin, 
Pegaspargase, 
Cyclophosphamide 
Thioguanine, 
Cytarabine; IT 
Methotrexate 
Vincristine, 
Dexamethasone, 
Mercaptopurine, 
Methotrexate; IT 
methotrexate 
HR-ALL 
5 weeks 
8 weeks 
9 weeks 
8 weeks 
to complete 2-3 years 
total therapy 
As above + 
Daunorubicin 
As above + 
Cyclophosphamide, 
Cytarabine, 
Pegaspargase 
As above with 
high dose 
Methotrexate + 
Leucovorin 
As above 
As above with 
Prednisone instead of 
Dexamethasone 
SR, standard risk; HR, high risk; IT, intrathecal 
 
Multi-drug chemotherapy leads to profound bone marrow suppression as well as specific 
impairment of innate, cell-mediated and humoral immune responses. Consequently, infection is 
the most common cause of treatment-related mortality, with a cumulative risk of 3%.[3-5] 
 
 

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Table 2. DFCI ALL treatment protocol 95-01.[2] 
  
Induction 
CNS therapy 
Intensification 
Continuation 
SR-ALL 
4 weeks 
3 weeks 
30 weeks 
Until 24 months 
continuous remission 
Vincristine,  
Prednisone,  
Doxorubicin 
Asparaginase; 
IT Cytarabine,  
IT Methotrexate,  
IT Hydrocortisone   
IT Methotrexate & 
Cytarabine +/- 
cranial radiation 
Vincristine,  
Prednisome 
Methotrexate 
6-Mercaptopurine 
Asparaginase  
Vincristine,  
Prednisome 
Methotrexate 
6-Mercaptopurine 
 
HR-ALL 
4 weeks 
3 weeks 
30 weeks 
Until 24 months 
continuous remission 
As above +/- 
Dexrazoxane  
As above + cranial 
radiation for all 
As above + Doxorubicin 
+/- Dexrazoxane 
As above 
 
Furthermore, while neutrophil counts return to normal after each cycle of chemotherapy, 
recovery of lymphocytes is much slower. Recovery of B lymphocytes has been observed to  
occur during maintenance chemotherapy, but T lymphocyte counts, particularly CD4+ T cells, 
remain low for over 6 months after chemotherapy.[6-8] Lymphocyte proliferation responses to 
mitogens and specific antigens may remain abnormal for 12 months or longer post-
chemotherapy.[8, 9] Various risk factors for delayed immune reconstitution have been reported, 
including younger age, older age, and high-risk ALL.[6-8] Children with delayed recovery of 
adaptive immune function may remain at increased risk of invasive infections long after they 
have returned to school and other community activities where their risk of exposure is high. 
 
1.2 Vaccine-preventable infections and waning vaccine-induced immunity 
 
ALL disproportionately affects children under 5 years of age, most of whom have not completed 
their preschool immunizations at the time of diagnosis.[1] These children are at high risk of 
complications from vaccine-preventable infections such as measles, varicella-zoster, and 
Streptococcus pneumoniae.[10-13]  Measles can be particularly severe in children with cancer, 
with 80% of patients suffering complications such as pneumonitis, and mortality of up to 
70%.[12] Children with ALL who are non-immune to varicella are at high risk of disseminated 
disease leading to pneumonitis and hepatitis.[10] Among children and adults with leukemia, the 
risk of invasive pneumococcal disease (IPD) has been reported to be 10 to 12-fold higher than in 
the general population.[13, 14] Additionally, vaccine failures leading to invasive infections, such 
as Haemophilus influenzae type b (Hib), have been reported in fully immunized children with 
ALL who were later found to have decreased titres to multiple vaccines.[15, 16] Herd protection 
may mitigate the risk of vaccine-preventable infection associated with waning vaccine immunity.  
There has been a recent resurgence of vaccine-preventable infections, such as measles and 
pertussis related to decreased vaccine coverage and/or inadequate duration of vaccine-induced 
protection among healthy children.[17, 18] While overall vaccine coverage rates in Canada have 
been stable over the past decade, coverage for several vaccines is below the 90-95% level needed 
for reliable herd protection.[19, 20] Additionally, vaccine coverage is not uniform; areas with 

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large numbers of underimmunized children can be more susceptible to disease outbreaks.[21] 
Outbreaks have also occurred in communities with high vaccine coverage, for example in 
Quebec in 2011 where over 700 cases of measles occurred in a community with >90% measles 
vaccine coverage.[22] Children with ALL typically return to school and community activities 
while they are on maintenance therapy, which puts them at risk of exposure to infectious 
diseases.  The failure of herd protection in these cases underscores the importance of ensuring 
optimal immunization of children with ALL. 
 
There is increasing evidence that antibody titres to vaccine antigens decrease over time in 
children who were fully vaccinated prior to chemotherapy.[23-26] A systematic review found 
that 25-35% of patients who had completed chemotherapy had antibody levels to tetanus and 
diphtheria that were below protective levels and 70% were susceptible to pertussis.[26] Among 
80 children with ALL treated between 2001 and 2010, approximately 30% of those who were 
seropositive to measles and 17% who were seropositive for varicella at diagnosis subsequently 
lost immunity to those antigens.[25] In another study of 100 ALL patients who were a mean of 2 
years post-chemotherapy, only 42-86% had protective titres to routine childhood vaccines 
including Hib, hepatitis B, diphtheria and rubella, compared to 96-100% of healthy controls.[23] 
Seventy-three percent of subjects had non-protective titres to ≥2 antigens. Studies conducted 
prior to the introduction of universal infant pneumococcal conjugate vaccination (PCV) reported 
that pneumococcal antibody concentrations were significantly lower in children with ALL who 
were 3-6 months post-chemotherapy compared to age-matched healthy controls.[27, 28] No 
published studies have evaluated the impact of infant PCV immunization on pneumococcal titres 
post-chemotherapy. 
 
1.3 Vaccination post-chemotherapy 
 
Responses to booster immunizations given after chemotherapy are variable, with poorer 
responses observed in children with high-risk versus standard-risk ALL in some studies.[24, 26, 
29] In one study of 46 children with ALL ages 1 to 18 years who were ≥6 months post-
chemotherapy, immunization with one dose of combined diphtheria-tetanus-pertussis-polio-Hib 
vaccine (DTaP-IPV-Hib), followed one month later by measles-mumps-rubella (MMR) and 
meningococcal serogroup C conjugate vaccine (MenC-C) resulted in significant increases in 
antibody titres with over 90% of subjects achieving protective levels and/or achieving a ≥4-fold 
increase in titres.[29] At one year post-immunization there was evidence of long-term protection 
against tetanus and measles in all patients tested. Other studies similarly reported good short-
term responses to DT, Hib and MMR vaccination, but long-term responses were not 
measured.[24, 30] No published studies have assessed the impact of PCV13 booster 
immunization on pneumococcal titres, but one study of 10-valent pneumococcal conjugate 
vaccine (PCV10) administered to children with ALL on chemotherapy found that 60% achieved 
titres >0.35 µg/ml (WHO standard for protection [31]) to 7/10 PCV serotypes.[32] These studies 
must rely on assessment of serologic correlates of protection because vaccine efficacy cannot be 
evaluated due to the low incidence of most vaccine-preventable infections in this small patient 
population. 
 
Guidelines in the United Kingdom and Australia recommend booster doses of routine vaccines 
such as DTaP, IPV, Hib, MMR and MenC-C for all patients with leukemia starting 6 months 

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after chemotherapy, but compliance with guidelines appears to be suboptimal.[33-35] The 
Australian guidelines also recommend administering one dose of PCV13 at least 6 months after 
completion of chemotherapy in patients not previously immunized followed by 23-valent 
pneumococcal polysaccharide vaccine (PPV23). However, a recent guideline by the Infectious 
Disease Society of America (IDSA) made no recommendations regarding booster vaccinations, 
citing insufficient evidence of the benefit of such an approach.[4]  
 
In Canada, there is no standard of care for immunization of children after chemotherapy for 
ALL. The National Advisory Committee on Immunization (NACI) recommends one dose of 
PCV13 followed by PPV23 in patients at high risk of IPD, including those with 
malignancies.[36]  
 
1.3.1 Immunization Practices in Canada 
To better understand immunization practices for patients with ALL at Canadian pediatric 
oncology centres, we conducted a survey of the 16 centres in the C17 group of pediatric oncology 
and bone marrow transplant centres in Canada. The survey was launched in October 2014. The 
results revealed wide variability in practices among the 10 centres responded. Four centres 
routinely provide immunizations after chemotherapy and at a fifth centre antibody titres are 
routinely measured and booster doses are recommended for patients with low titres. At one 
centre, the respondent remarked that his/her personal practice was to routinely measure titres and 
offer booster vaccinations but his/her colleagues’ practices varied. Four centres administer 
PCV13 and one administers PPV23 to children who have completed chemotherapy. Centres 
initiate immunization with inactivated vaccines either 3 or 6 months post-chemotherapy (at 4 and 
6 centres, respectively), while live-attenuated vaccines are administered 3, 6 or 12 months post-
chemotherapy across the ten participating centres. Respondents at only two centres reported that 
AEFI are monitored in patients with ALL, while three respondents were unsure. 
 
1.4 Vaccine safety 
 
Studies of vaccine safety in immunocompromised patients have primarily focused on live 
attenuated vaccines (e.g., MMR, varicella).[4, 37, 38] One study demonstrated a similar risk of 
herpes zoster after varicella immunization, compared to natural infection, in children with ALL 
on maintenance chemotherapy.[38] There is one report of death in a child with ALL after 
varicella immunization, although that child was receiving chemotherapy.[39] One study of 39 
children immunized with PCV10 while on chemotherapy for ALL reported local reactions in 
73% and systemic symptoms in 41%, most frequently diarrhea. Only one patient experienced 
fever.[32] The systemic symptoms were considered to be most likely chemotherapy-related. The 
risk of adverse events following immunization (AEFI) with inactivated vaccines is assumed to be 
similar in immunocompromised children compared to healthy children, but the data supporting 
this assumption are limited.[4] Further data on the frequency, severity and impact of AEFI in 
children with ALL are needed.  
 
1.5 Rationale 
 
NACI has identified vaccine safety and effectiveness in immunocompromised individuals as a 
research priority for vaccines recently introduced in Canada (e.g., PCV13).[36] Among 

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physicians caring for pediatric ALL patients, there is currently a lack of empirical scientific 
evidence to guide immunization practices, which has likely contributed to the variation in 
practices observed in our survey. Although universal PCV immunization programs have been in 
place for a decade or more in many developed countries, there is a paucity of literature 
evaluating these vaccines in children with ALL. Infants have been immunized routinely with 
PCV in Canada since at least 2006, and the 13-valent vaccine has been available since 2010. 
Most children completing chemotherapy for ALL would have been immunized in infancy with 
PCV7, but many would never have received a dose of PCV13 or PPV23, which is not routinely 
administered to healthy children. Due to waning humoral immune responses, children who 
received PCV13 prior to diagnosis with ALL may also benefit from an additional dose of 
PCV13, and from PPV23 immunization. It is unclear whether children with ALL are receiving 
all recommended immunizations and whether they would benefit from additional booster doses 
of other vaccines such as tetanus-diphtheria-pertussis-containing vaccines (i.e., DTaP) after they 
complete chemotherapy.  
 
This study will be the first multi-centre study of vaccination in ALL survivors in Canada and 
among the largest prospective vaccination studies to date in this population. It will provide 
critical information to identify children with ALL who may be at greater risk for vaccine-
preventable infections due to low antibody titres, and will assess immunogenicity and safety of 
PCV13 and DTaP-IPV-Hib in this population. The study results will support the development of 
immunization recommendations for children with ALL. This study will also test a methodology 
to assess vaccine immunogenicity and safety in a high-risk population that, if successful, will be 
expanded to other groups of immunocompromised children and adults, such as patients who 
received bone marrow transplants, have primary immunodeficiency or are on high dose steroids. 
 
This study will be led by the Special Immunization Clinic (SIC) network as part of the Public 
Health Agency of Canada/Canadian Institutes for Health Research (PHAC/CIHR)-funded 
Canadian Immunization Research Network (CIRN), in collaboration with pediatric oncologists at 
the study sites. The SIC network, originally part of the PHAC/CIHR Influenza Research 
Network (PCIRN), was established in 2013 at 13 tertiary care centres across Canada to provide 
expertise in the clinical care of patients with prior AEFI and potential contraindications to 
immunization. SIC investigators employ a standard approach to patient assessment, vaccination 
and follow-up. De-nominalized data are transferred to a central database with patient consent. 
The network was designed as both a clinical service and a platform for research studies. Thus, 
the SIC Network is uniquely positioned to lead this study. 
 
 
2. 
Objectives 
 
• To identify risk factors for low baseline antibody titres to pneumococcal serotypes, tetanus, 
pertussis toxin, and varicella in previously immunized children diagnosed with ALL at ≥1 
year of age who completed chemotherapy within 6-12 months, as compared to 
immunocompetent age-matched controls. 
• To assess short and long-term immune responses to PCV13 followed by PPV23 in children 
immunized 6-12 months after completing chemotherapy for ALL. 

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• To assess short and long-term immune responses to a DTaP-IPV-Hib booster in children 
immunized 6-12 months after completing chemotherapy for ALL. 
• To estimate the frequency of medically-attended AEFI in children immunized after 
completing treatment for ALL. 
 
 
3. 
Methods 
 
3.1 Study design 
 
This will be a prospective multi-centre open-label clinical trial at 10 pediatric centres that are 
members of the SIC network and the C17 council which is comprised of the heads of the 16 
pediatric oncology and blood and marrow transplantation programs in Canada. Each 
participating site is run by a Site Investigator in conjunction with a nurse coordinator (SIC 
nurse). The coordinating site will be the Canadian Center for Vaccinology at the IWK Health 
Centre, Halifax, NS.  
 
Children who were diagnosed with ALL at ≥1 year of age, are within 3-12 months of completing 
chemotherapy, and have not received immunizations other than influenza since completing 
chemotherapy will be eligible. As most centres initiate immunization at 6 months post-
chemotherapy, children will be enrolled and immunized at the 6-month visit, where possible. 
Children can be enrolled as late as 12 months post-chemotherapy if they meet all other eligibility 
criteria. All participants will undergo a clinical assessment, and immunologic and serologic 
testing for pneumococcus, tetanus, pertussis and varicella. They will then be immunized with 
PCV13, DTaP-IPV-Hib, regardless of immunization history [unless PPV23 was received within 
the prior 12 months (see section 3.2.1)]. Other routine vaccines required as per provincial and 
centre-specific immunization policies will also be administered. Pneumococcal polysaccharide 
vaccine (PPV23) will be administered approximately 2 months after PCV13. Repeat serologic 
testing will be conducted at 2-3 months and 12-15 months after DTaP-IPV-Hib and PCV13 
immunization to assess short and long-term immune responses. 
 
Study visits and bloodwork will be coordinated with routine blood draws wherever possible. 
Baseline antibody titres will be compared to age-matched immunocompetent controls. Vaccine 
responses will be compared to healthy vaccine recipients in published clinical trials. 
Multivariable analysis will be conducted to identify predictors of low baseline antibody titres 
after chemotherapy and poor immune responses to vaccination.  
 
Adverse events following immunization will be captured through standardized telephone 
interviews conducted by the SIC nurse coordinator on days 8-10 and 30-33 post-immunization. 
Severity of AEFI will be classified as outlined in section 5.3 and a formal causality assessment 
based on a published algorithm (e.g., [40]) will be conducted for all events of moderate impact or 
greater (see section 5.3.1 for definitions). 
 
 
 
 

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3.2 Subjects, recruitment and consent 
 
3.2.1 Cases 
Inclusion criteria 
• Diagnosed with standard risk, high risk or very high risk ALL  
• Age at diagnosis: ≥1 year of age (age at enrollment: ≥3 years) 
• Completed chemotherapy 3 to 12 months prior to enrollment 
• No evidence of ALL relapse or secondary malignancy 
• No known primary immunodeficiency 
• No receipt of pneumococcal or tetanus-containing vaccines since completing 
chemotherapy 
• No history of allergy to any component of PCV13 
• Caregiver and/or participant is English or French-speaking and able to provide written 
informed consent 
 
Exclusion criteria 
• Infantile ALL 
• Evidence of disease relapse or secondary malignancy 
• History of underlying primary immunodeficiency 
• Transplant recipient  
• Received intravenous immunoglobulin (IVIG) within past 9 months or other blood 
products within the prior 3 months. 
• Children who received PPV23 within 12 months of enrollment will not be eligible to 
receive PCV13 or PPV23. These children can still participate in the baseline evaluation, 
receive DTaP-Hib-IPV vaccine, and have tetanus and pertussis serology measured at 2 
and 12-15 months post-immunization. 
 
3.2.2 Controls:  
 
Inclusion criteria 
• Children 3-18 years of age, age-matched to cases  
• Caregiver and/or participant is English or French-speaking and able to provide written 
informed consent 
 
Exclusion criteria 
• History of primary or secondary immunodeficiency including aplastic anemia, 
malignancy, nephrotic syndrome, malabsorption or severe malnutrition  
• Immunosuppressive therapy within 3 months of enrollment (excluding inhaled 
corticosteroids) 
• Received intravenous immunoglobulin (IVIG) within past 9 months or other blood 
products within the prior 3 months. 
 
3.2.3 Recruitment and Consent 
The oncologists and/or clinic nurses will identify potentially eligible subjects with ALL. 

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Caregivers of eligible patients will then be approached to participate in the study during routine 
outpatient visits to the pediatric oncology clinic. The consent form will be reviewed with 
caregivers by a research nurse, oncologist or oncology clinic nurse. Participants’ and caregivers’ 
questions will be answered and written informed consent will be obtained. 
 
Children 3-18 years of age who are not immunocompromised will be recruited as controls from 
among children requiring venous blood draws in the outpatient laboratory, siblings of 
participants with ALL, prior study participants who have consented to future contact, and other 
methods depending on the study site. Caregivers of potentially eligible children will be 
approached by study staff in the outpatient laboratory or clinic, or contacted by the study team 
via telephone, email or mail and invited to participate. As above, written informed consent will 
be obtained after the consent form is reviewed and the participants’ and caregivers’ questions 
have been answered. Controls will be frequency age-matched to cases to ensure that the age 
distribution of cases and controls is similar. Three participating sites will be responsible for 
recruiting approximately 75 control subjects. The coordinating site will conduct the age-
matching of controls to cases. 
 
 
4. 
Study Plan 
 
4.1 Timeline 
 
July–December 2014: Protocol development (pending final results of an institutional survey of 
immunization practices at pediatric oncology and HSCT centres) 
January 2015–April 2015: External scientific review, finalize protocol  
May – June 2015: Finalize REB documents, REB submission 
November 2015–August 2017: Patient recruitment/enrollment (22 months) 
April 2017–January 2018: Recruitment of control subjects 
August 2018: Patient follow-up completed 
December 2017–January 2019: Laboratory analysis; data analysis, presentation of preliminary 
results, manuscript preparation 
January–March 2019: Final data analysis 
March–May 2019: Complete final manuscripts, presentations  
 
4.2 Visit procedures 
 
The study will involve three clinic visits (with the option for a separate screening visit before 
visit 1) and four follow up telephone calls. Visits and blood draws will be coordinated with 
regular follow up visits in the oncology clinic wherever possible. Procedures are summarized in 
Table 3. 
 
Table 3. Schedule of Study Activities 
Procedures  
for patients 
 
Visit 
1 
Follow up 
Phone call 
8-10 days  
post V1 
Follow 
up Phone 
call 
30-33 
days post 
Visit 2 
2 months 
Post V1† 
Follow up 
Phone call 
8-10 days  
post V2 
Follow up 
Phone call 
30-33 days 
post V2 
Visit 3 
12-15 
months 
post V1 

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V1 
Informed 
Consent 
X* 
 
 
 
 
 
 
Past Medical 
History 
X* 
 
 
 
 
 
 
Current Health 
Status  
X* 
 
 
 
 
 
 
Medications 
X* 
 
 
 
 
 
 
Review of 
Immunization 
Records 
X* 
 
 
 
 
 
 
Vital signs 
X 
 
 
 
 
 
 
Immune 
Markers  
(CBC, qIgs, T 
and B subsets) 
X 
 
 
 
 
 
 
Vaccine 
serologies 
X 
 
 
X 
 
 
X 
PCV13 and 
DTaP 
Immunization 
X 
 
 
 
 
 
 
PPV23 
immunization 
 
 
 
X 
 
 
 
Phone Call 
(adverse events) 
 
X 
X 
 
X 
X 
 
qIgs: quantitative immunoglobulins; *Maybe be conducted as part of a screening visit at 3-5 
months post-treatment. †Visit can occur up to 3 months post-immunization. 
 
Visit 1 (Baseline assessment): 
After providing informed consent, participants with ALL will undergo a standardized health 
evaluation, including review of past medical history, current health status, and medications, and 
vital signs as part of routine clinical care. Immunization records will be obtained from the 
participant’s vaccination card, medical chart, family physician or public health. Varicella 
serology results at time of ALL diagnosis (measured as part of routine care) will be obtained 
from the medical record. The above activities can be completed as part of a separate screening 
visit at 3-5 months post-treatment, with visit 1 then scheduled at 6 months post-treatment to 
collect bloodwork and administer immunizations. 
 
Baseline laboratory evaluation will include complete blood count, quantitative serum 
immunoglobulins (IgA, IgG, IgM), peripheral blood T and B cell subsets and antibody titres to 
the following vaccine antigens: tetanus toxoid, pertussis toxin (PT), varicella, and pneumococcal 
serotype-specific IgG. If serum immunoglobulins, T and B cell subsets or antibody titres were 
measured within one month prior to enrollment, those results can be obtained as baseline results, 
in lieu of repeating the testing.   
 
Participants will be immunized with PCV13, DTaP-IPV-Hib (If DTaP-IPV-Hib is not available, 
DTaP-IPV and Hib may be administered separately) in addition to the “catch-up” vaccines 

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required according to the schedule currently followed at their centre. Vaccines will be 
administered in the SIC or oncology clinic, where possible, but may be administered by the 
primary care physician or public health. Vaccines must administered within two months of the 
baseline assessment and within 12 months of completing chemotherapy. The SIC nurse will 
obtain vaccination details from the vaccine provider within 7 days of the vaccination visit. 
 
Telephone follow-up for AEFI: 
A study nurse will contact caregivers (or participants where appropriate) by telephone on days 8-
10 and 30-33 after each immunization to elicit local and systemic symptoms and their severity 
using a standard questionnaire.  
 
Visit 2 (2 months post-immunization) 
Serologic responses will be measured to tetanus, PT and pneumococcus. PPV23 will be 
administered. If necessary, this visit can be delayed to 3 months post-immunization. 
 
Visit 3 (12-15 months after visit 1): 
Serologic responses will be measured to tetanus, PT and pneumococcus.  
 
Blood sampling will be coordinated with routine blood draws, which are conducted at most 
follow up visits. 
 
Controls:  
Past medical history will be reviewed for any excluding conditions and once informed consent 
has been obtained, immunization records will be obtained as described above. Serum will be 
collected to measure “baseline” antibody titres to tetanus, PT, varicella, and pneumococcal 
serotypes, based on the vaccinations received. There will be no further follow-up of controls. 
 
4.3 Obtaining, Handling, Storage, Shipment of Specimens 
 
Whole blood (up to 15 ml for visit 1 and 5ml for visits 2 and 3) will be collected by 
venipuncture. Specimens will be labelled with the participant’s study number and the date the 
sample was drawn. Samples will be processed on-site for complete blood cell count and 
differential, quantitative IgG, IgA and IgM levels and T and B lymphocyte subsets. 
 
4.3.1 Immunologic assessment 
Quantitative immunoglobulins 
Up to 5 ml of whole blood will be collected for baseline quantitative measurement of total IgA, 
IgG and IgM levels.  Samples will be processed at the local clinical laboratory according to 
standard procedures and denominalized results will be transferred to the coordinating centre. At 
some centres this testing is conducted as part of routine clinical care.  
 
Lymphocyte subsets 
Up to 5 ml of whole blood will be collected for baseline quantitative measurement of T, B and 
NK lymphocyte subsets. Samples will be processed for flow cytometry at the local laboratory 
according to standard procedures and denominalized results will be transferred to the 
coordinating centre.  

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4.3.2 Serologic testing 
Up to 5 mL of whole blood will be collected in a serum separator tube by venipuncture. After 
collection, blood will be kept at room temperature for 30 minutes to clot.  Blood will then be 
centrifuged for 10 minutes at approximately 2500 RPM. Serum will be separated, aliquoted and 
frozen at -20°C in the local clinical or research laboratory.  
 
Samples will be batch shipped on dry ice to the Canadian Center for Vaccinology’s research 
laboratory at the IWK Health Centre in Halifax, NS approximately every 3-6 months where they 
will be stored at -80°C until they are processed locally and/or shipped to other laboratories as 
below.  
 
Tetanus, pertussis toxoid and varicella IgG measurement will be conducted at the Canadian 
Center for Vaccinology laboratory using validated enzyme immunoassays.  
 
Pneumococcal serotype-specific IgG levels to vaccine serotypes will be measured at McGill 
University Health Centre. 
  
4.4 Modifying/Discontinuing Planned Vaccination/Treatment 
 
4.4.1 Temporary Contraindications 
Prior to immunization, possible contraindications to vaccination will be reviewed. If temporary 
contraindications are present, vaccination will be postponed and re-attempted within the 
allowable time frame for enrolment (up to 12 months post-chemotherapy). 
 
Temporary contraindications to vaccination are as follows: 
• An acute illness with or without fever (temperature > 38.0ºC). 
 
4.4.2 Definite Contraindications 
Subject has a known hypersensitivity to any component of the vaccine. 
 
4.5 Clinical Supplies 
 
As per policies at each study site. Where additional supplies are needed above what is considered 
routine clinical care, the costs will be covered in the study budget. 
 
4.6 Products 
 
Only licensed vaccines will be administered to participants including: PCV13 (Prevnar®13, 
Pfizer Canada, Inc.), PPV23 (Pneumovax® 23, Merck Canada Inc., or Pneumo 23®, sanofi 
pasteur Ltd.) and DTaP-IPV-Hib (Pediacel®, sanofi pasteur Ltd, or Infanrix®-IPV/Hib, 
GlaxoSmithKline Inc).  
 
4.6.1 PCV13 
This vaccine will be administered according to NACI guidelines for children at high risk of IPD, 
with the exception that all participants will receive a dose of PCV13, regardless of whether they 

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have previously received a dose of PCV13 after 12 months of age and prior to inititation of 
chemotherapy. This practice is already conducted routinely at four Canadian pediatric oncology 
sites, based on our recent survey. However, as per NACI guidelines, if a participant received 
PPV23 within 12 months of enrolment, they will not be eligible to receive PCV13. 
 
4.6.2 PPV23 
This vaccine will be administered according to NACI guidelines for children at high risk of IPD. 
Children who have previously received PPV23 will not be reimmunized. 
 
4.6.3 DTaP-IPV-Hib 
This formulation of diphtheria-tetanus-pertussis vaccine is licensed for children up to 7 years of 
age due to the increased risk of local reactions in older children and adolescents from the higher 
doses of diphtheria toxoid and acellular pertussis antigens. Administration of this vaccine to all 
participants regardless of age would be in keeping with current guidelines in the UK and 
Australia for patients who have completed chemotherapy for ALL. Additionally, based on our 
survey, the majority of pediatric centres administer DTaP-IPV-Hib to all bone marrow transplant 
recipients regardless of age due to evidence of improved vaccine responses in this population,  in 
keeping with current IDSA guidelines.[4] The administration of the Hib component is consistent 
with NACI guidelines for patients with hematologic malignancies.   
 
If DTaP-IPV-Hib is not available, DTaP-IPV plus Hib vaccine may be given.  
 
5. 
Surveillance, Monitoring and Assessment  
 
5.1 Immunologic Status 
 
Immunologic status will be assessed by quantitative measurement of total IgA, IgG and IgM and 
by assessment of T, B and NK lymphocyte subsets, as available at the local laboratory.  At a 
minimum the following will be assessed on all patients:  
• total white blood cell count, total lymphocyte count, total and percentages of:  total T 
cells (CD3+), , CD4+ T cells, CD8+ T cells, CD4/CD8 ratio, B cells (CD19+), and 
NK cells (CD56+/CD16+).  
 
Where available, in addition to the above, an expanded panel of cell surface markers will be 
measured to determine total and percentages of the following subpopulations: 
• memory T cells (CD3+/CD4+/CD45RO+) 
• naïve T cells (CD3+/CD4+/CD45RA+) 
• regulatory T cells (CD3+/CD4+/CD25+) 
• activated T cells (CD3+/CD4+/HLA-DR+) 
• memory B cells (CD19+/CD27+) 
• unswitched B cells (CD19+/sIgD+)  
 
5.2 Immune Responses to Vaccines 
 
Vaccine antigens to be tested include tetanus, pertussis toxoid, varicella and 14 pneumococcal 
vaccine serotypes (1, 3, 4, 5, 6B, 7F, 8, 9V, 9N, 12F, 14, 18C, 19F, 23F). Of the pneumococcal 

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serotypes tested, 10 are included in both PCV13 and PPV23 (1, 3, 4, 6B, 7F, 9V, 18C, 19F, 23F) 
and 3 are only included in PPV23 (8, 9N, 12F). Vaccine responses will be determined by 
measurement of GMT to vaccine antigens pre-vaccination, 2 months and 12-15 months post-
vaccination, and calculating GMT ratios. An adequate vaccine response will be defined as GMT 
ratio ≥4 (post-vaccination/pre-vaccination). For pneumococcal serotypes, GMT ≥0.35 µg/ml is 
the World Health Organization accepted correlate of protection in clinical trials,[31] while GMT 
≥0.50 µg/ml has been used in other studies of immunocompromised children.[27, 41] The 
proportion of participants with GMT at or above these thresholds at baseline, at 2 months post-
PCV13, and at 12-15 months post-PCV13+PPV23 immunization will be reported for each 
serotype. Vaccine titres will also be reported as “seropositive” or “seronegative” for tetanus and 
varicella.  
 
5.3 Adverse Events 
 
5.3.1 Definitions 
 
Adverse event following immunization (AEFI): Any untoward medical occurrence in a patient 
that is temporally associated with vaccination and not clearly attributable to another known cause 
[42].  
 
Serious adverse event (SAE): The Public Health Agency of Canada defines a serious adverse 
event following immunization as any untoward medical occurrence that: 
o Requires in-patient hospitalization or prolongation of existing hospitalization for >24 
hours 
o Results in permanent disability 
o Is a congenital anomaly or birth defect 
o Is fatal 
 
High impact AEFI: event that results in hospitalization for 24hrs or less or medical supervision 
out of hospital or requires ≥3 physician assessments for AEFI and/or leads to disability >3 days 
(unable to perform daily activities, unable to go to work, unable to attend school).  
 
Moderate impact AEFI: event that requires an unscheduled physician visit, including emergency 
department visit or new or change in medication or leads to 1-3 days of disability. 
 
Low impact AEFI: event managed by immunization clinic staff, with telephone advice or during 
previously scheduled appointment, and/or resulting in <24 hours of disability. 
 
5.3.2 Adverse Event Monitoring 
A study nurse will contact caregivers by telephone on days 8-10 and 30-33 post-immunization to 
elicit local and systemic symptoms and their severity using a standard questionnaire. Patients 
with AEFI requiring medical attention will be reviewed by the site investigator according to SIC 
network protocols, including a causality assessment using a published algorithm.[40]  
 

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Decisions regarding reimmunization of patients who experience AEFI will be made by the SIC 
investigator in consultation with the oncologist, patient and their family. 
 
5.3.3 Reporting of Serious Adverse Events 
AEFI will be reported to public health authorities according to provincial and national 
guidelines. All SAEs will be reviewed by the principal investigator and discussed with co-
investigators in a timely manner, as appropriate. AEFI will be reported to public health as per 
local guidelines. There will be no external safety monitoring board as all vaccines are currently 
approved for use in this population and will be provided per standard of care. 
 
 
6. 
Data Management and analysis 
 
6.1 Responsibility for the analysis 
 
The Principal Investigator will take primary responsibility for the analysis. The analysis will be 
conducted by data analysts at the Canadian Center for Vaccinology (CCfV), IWK Health Centre.  
 
6.2 Sample size and Power 
 
Approximately 278 new cases of ALL are diagnosed annually in Canadian children <15 years of 
age.[1] We estimate that approximately 50-60% of children diagnosed with ALL will complete 
chemotherapy, and consent to participate in the study. We expect to recruit 75–80 children over 
the enrollment period. To ensure adequate power (>75%) to assess differences in vaccine 
responses according to treatment protocol, at least 30 subjects will be recruited from centres 
using DCFI protocols, with the remainder recruited from COG centres. Seventy-five age-
matched control subjects will be recruited. If at least 60% of controls have protective antibody 
titres, a sample of at least 75 cases will give 77% power to detect a ≥20% absolute difference in 
the proportion of cases achieving seroprotection. This sample size will also give 90% power to 
detect a standardized difference in mean log titre of ≥0.53 between cases and controls. 
 
Safety assessment: With a total sample size of 75 vaccinees, the probability of detecting at least 
one occurrence of an AEFI that occurs at a frequency of ≥2% in the population is 0.78 and the 
probability of detecting an AEFI that occurs at a frequency of ≥1% in the population is 0.53. 
 
6.3 Variables 
 
6.3.1 Outcomes 
The primary outcomes are the proportion of participants with protective titres (≥0.35 µg/ml) to 
the PCV13 serotypes tested, at baseline (compared to age-matched controls), 2 months and 12-15 
months post PCV13+PPV23. 
 
Secondary outcomes include baseline GMTs and frequency of protective titres to varicella, 
pertussis toxin and tetanus among ALL patients versus controls, short-term (baseline to 2 months 
after vaccination) and long-term (baseline to 12-15 months) vaccine responses to DTaP, based on 
GMT ratios, the proportion of subjects with protective titres (e.g., tetanus, varicella) and/or the 

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proportion with an adequate immune response (defined as GMT ratio ≥4 at 2 and 12-15 months 
post-vaccination). 
 
Safety assessment: The primary outcome is frequency of AEFI of moderate impact or greater 
(see definitions in section 5.3). The secondary outcomes are frequency of any AEFI and 
frequency of AEFI deemed to be causally associated with vaccination.  
 
6.3.2 Independent variables 
 
Demographics: Patient’s month/year of birth, sex, province of residence 
 
Medical history: Age at diagnosis of ALL, disease risk category (standard risk, high risk or very 
high risk), treatment protocol used, time to disease remission, total length of treatment, current 
disease status, vaccine-preventable infections (before and after re-immunization).  
 
Immunization history: number of doses of each vaccine received prior to ALL diagnosis and 
while receiving chemotherapy, vaccine products received, age at immunization, type of vaccine 
provider, interval from last chemotherapy to immunization, and varicella serology results at ALL 
diagnosis. 
 
Immunologic status: absolute lymphocyte count, total IgG level; total T cells, CD4+ T cells, 
CD8+ T cells, CD4/CD8 T cell ratio, memory and naïve T cells; total, memory and naïve B cells, 
NK cell counts.  
 
6.4 Statistical Methods 
 
Immune responses: Immune markers (see 5.2) will be compared to age-specific reference values. 
Baseline GMTs with 95% confidence intervals and proportion with protective titres at baseline 
will be reported for cases and controls, stratified by interval since last vaccination. Varicella 
titers will be compared pre-chemotherapy (i.e., at diagnosis) and post-chemotherapy and the 
proportion with loss of immunity will be reported. The proportion of subjects with GMT ratios 
≥4 or protective titres at 2 and 12-15 months post-vaccination will be reported for pneumococcal 
vaccines (PCV13+PPV23) and DTaP-IPV-Hib, stratified by age, ALL treatment protocol (COG 
versus DFCI), interval from last chemotherapy to immunization, and ALL risk category. Vaccine 
responses will be compared to the expected responses in healthy children based on published 
clinical trials. Differences among categorical variables will be assessed by Pearson’s χ2 test or 
with Fisher exact test when expected cell sizes are <5. Independent predictors of low baseline 
GMTs to tetanus toxoid and pneumococcal serotypes and of an adequate immune response to 
PCV13+PPV23 vaccination and DTaP-IPV-Hib booster will be assessed using multivariable 
regression models.  
 
Safety assessment: The frequency of low impact, moderate impact and high impact or serious 
AEFI will be reported by vaccine type, age and ALL risk category, and compared to the 
published frequencies in healthy children. The frequency of events deemed to be related to 
vaccination based on the causality algorithm will also be reported. 
 

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All statistical analyses will be conducted using SAS® version 9.4 (Cary, NC). 
 
 
6.5 Data Management 
 
Data management will be the responsibility of the data manager at the CCfV. Data will be stored 
on a secure server at the CCfV and all files will be password-protected. All source documents, 
including consent forms and copies of data collection forms, will be stored in a locked cabinet in 
a secure area at each study site. Source documents will be retained by site investigators for 10 
years after study completion.  
 
7. 
Ethical Considerations 
 
This research protocol will be submitted to the Research Ethics Board (REB) at each 
participating site for ethical approval, along will all other necessary documents. At each site, the 
study will be initiated once approval from the local REB has been received.  
 
This study will be conducted in accordance with the latest version of the Declaration of Helsinki, 
ICH Good Clinical Practice regulatory guidelines, and requirements regarding ethical committee 
review, and other statutes and regulations regarding the protection of the rights and welfare of 
subjects participating in the study.  
 
7.1 Potential Harms and Benefits 
 
Clinical assessments will be performed as per routine clinical care. Blood samples for this study 
will be collected in conjunction with routine blood draws for clinical care when possible and the 
minimum additional volume required to conduct the required tests will be collected (5 to 15 ml). 
There is the risk of discomfort related to venipuncture in some patients with ALL who would 
only require blood by fingerstick for their routine tests (e.g., CBC).  
 
Participants with ALL may experience adverse events following PCV13, PPV23 or DTaP-IPV-
Hib immunization. For most participants, administration of these vaccines will be consistent with 
NACI guidelines. Expected adverse events include local reactions, fever, headache, and malaise. 
In patients who have previously received a full infant series of PCV13 (2, 4 and 12 months) prior 
to chemotherapy, they may be at higher risk of developing a large local reaction at the injection 
site (pain, swelling, erythema ≥10 cm diameter). Such reactions can be managed with 
acetaminophen or non-steroidal anti-inflammatory agents. There is also a risk of large local 
reactions after DTaP-IPV-Hib in children ≥7 years of age. As discussed in section 4.6, the 
vaccine schedule proposed in this study is in keeping with current practice at some Canadian 
centres and in other jurisdictions. There is a small risk of unexpected adverse events. Participants 
will be monitored for adverse events as outlined above. 
 
There will be direct benefits to participants with ALL. They may receive a more detailed clinical 
and immunological assessment than would be routinely conducted, and will receive close follow 
up after vaccination. In some cases they will receive additional vaccines that may not be 
routinely administered at all sites and which are expected to confer additional protection against 

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invasive pneumococcal disease, tetanus, diphtheria and pertussis. Their immunological and 
serological test results will be shared with site investigators who will discuss them with the 
primary oncologist, participant and family, as appropriate for clinical care. However, due to the 
need batch samples and to test pre and post-vaccination samples concurrently for some assays, 
results may not be available in a timely manner. The information learned from this study will 
support the development of immunization guidelines for patients with ALL that will lead to 
improvements in care. In this study, the benefits outweigh the potential harms. 
 
For control participants, participation in this study involves minimal to low risk. Participants 
who already require venipuncture for another indication will only be asked to agree to have a 
small additional sample (3-10 ml) drawn for study purposes. The only risk is related to a breach 
of their confidential information which will be minimized by the measures outlined below. For 
participants undergoing venipuncture only for the purposes of this study, the potential harms 
include pain, bleeding, or bruising, fainting, and very rarely, infection. These discomforts are 
brief and transient. There will be no direct benefits to controls.  
 
Individual results will not be routinely available to healthcare providers of controls as the clinical 
relevance of such results in immunocompetent children following the routine immunization 
schedule is uncertain. However, if the principal and/or site investigator determines that antibody 
titers are sufficiently low to raise concerns regarding an unidentified health problem in a 
participant, the results will be sent to the primary care provider with recommendation for follow 
up and/or referral for further evaluation.   
 
7.2 Alternative treatments/management 
 
As discussed above, there is no accepted standard of care for immunization of patients after 
chemotherapy for ALL and practices vary between centres. The alternative to PCV13 and PPV23 
boosters would be no additional vaccination against pneumococcus and clinical assessment of 
febrile episodes and empiric antibiotics if serious bacterial infection is suspected. Alternatives to 
DTaP-IPV-Hib immunization would be to postpone immunization in children who are up to date 
for age or to administer Tdap or Tdap-IPV (with reduced diphtheria and pertussis antigens) for 
children ≥7 years of age. DTaP-IPV is an alternative in children <7 years of age who require a 
booster dose. 
 
7.3 Informed Consent Process 
 
The consent form will be reviewed with caregivers by the SIC nurse, research coordinator, the 
oncologist or oncology clinic nurse. All participants/controls or their primary caregiver will be 
asked to consent to the following: permit study staff to access the patient’s chart and contact 
other healthcare providers as necessary to retrieve immunization records and other clinical 
information, collection of additional blood for serology, transfer specimens and clinical data to 
the coordinating centre in Halifax (CCfV) and to send serum specimens to McGill University for 
pneumococcal serotype-specific IgG testing (if necessary). Some participants (ALL and controls) 
will also be asked to consent to venipuncture for study bloodwork, if venipuncture is not required 
for routine blood work. Consent will also be sought to allow future contact for participation in 
other studies.  

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In addition to the above, participants with ALL or their caregivers will be asked to consent to: 
administration of PCV13, PPV23 and DTaP-IPV-Hib vaccines, and telephone and/or email 
contact from study team to collect information on AEFI. Those who have contraindications to or 
refuse one or two specific vaccines may still be included in the study. Participants and 
caregivers’ questions will be answered and written informed consent will be obtained.  
 
7.4 Confidentiality of Data 
 
Confidentiality will be maintained within legal limits in the review of study records and consent 
forms, which may contain the identity of the subject. All appropriate measures will be taken to 
minimize the risk of a breach of confidentiality. Access to documents with personal identifiers 
including consent documents and patient contact information will be restricted to the site 
investigator and research nurse. Participants will be assigned a unique identifier that will be used 
on anonymized data collection forms and blood samples sent to the coordinating centre. Results 
of serological tests conducted and/or coordinated by the lead site will be transmitted to study 
sites using the patient’s unique identifier. All measures will be taken to ensure that participants’ 
confidentiality is maintained from samples send to, and results obtained from, external labs. Only 
denominalized data will be entered into the centralized database. The study site will be entered as 
a two-digit code and only the month and year of birth of the patient will be collected and entered 
to minimize the risk of patients being identified by their clinical information. Once the data have 
been verified and submitted to the central research database, the data will be locked preventing 
further changes. Access to the database will be restricted to the data manager and data analyst. 
The database will be stored on a password-protected secure server that will only be accessible to 
study staff.  
 
7.5 Monitoring, Auditing, and Archiving 
 
The study will not be monitored by an external agency. Audits or inspections may be made by 
the Research Ethics Board at the coordinating site or sub-sites to ensure that the study has been 
conducted in accordance with the protocol and ICH/GCP. The investigator will retain all source 
documents on-site, including consent forms and copies of case report forms for 2 years after 
completion of the study.  Study records will be stored in long-term off-site storage for a 
minimum of 10 years. 
 
7.6 Participant compensation 
 
Participants will receive a $10 gift card as a token of appreciation for their participation. 
 
7.7 Dissemination of results 
 
Traditional and non-traditional dissemination methods will be used, including publications (2-3 
manuscripts expected), presentations at national and international scientific meetings, 
presentations to expert committees advisory to public health, to the C17 Council, and Children’s 
Oncology Group. 
 

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8. 
Budget  
 
This study is funded by Canadian Institutes for Health Research and the Public Health Agency of 
Canada as part of the Canadian Immunization Research Network. In addition, Pfizer will be 
approached to provided in kind support to supply PCV13 to children who are not eligible for 
coverage under their provincial immunization programs (approximately 50 individuals).  
 
Table 4. Overall Budget Summary 
CI1302.CIRN Three Year (2014-2017) Project Budget Summary 
  
Fixed Costs for Lead Site* 
             9,676  
Fixed Costs for 9 Subsites* 
           54,720  
Variable Costs Vaccine Safety Evaluation†, N = 150 
           23,400  
Variable Costs Vaccine Immunogenicity†, N = 200 
           35,950  
Data Management and Analysis 
           25,208  
Travel to conference (2x $1500) 
             3,000  
Publication costs ($1000) 
             1,000  
Laboratory Testing Costs 
         147,402  
  
  
TOTAL BUDGET    $      300,356  
    
*Includes personnel costs (research coordinator) and expendables; †Includes personnel costs for 
patient enrollment, field supplies, compensation 
 
Table 5. Sample subsite Budget* 
CI1302.CIRN Three Year (2014-2017) Project Sub Site Budget  
  
  
  
Costs by Position and Type: 
  
SIC Nurse/Coordinator ($50/hr + 20% benefits): 
  
     REB submission and renewals 
 $                  2,880  
     Field Administration 
                     1,800  
     Study Site Closure  
                        360  
     Subject costs 
  
          Vaccine Immunogenicity 
  
          ALL Patients (3h/subject), N = 20 
                     3,540  
          Controls (1.8h/subject), N = 15 
                     1,620  
          Vaccine Safety Evaluation (2.6/subject), N = 20 
                     1,560  
          Participant compensation ($10/participant) N=35 
                        350  
Expendables: 
  
     Communications: Phone/Fax/Teleconference 
                        200  
     General Office Supplies 
                        200  
     Photocopying/Printing 
                        200  
     Archival of Study Documents 
                        200  

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     Laboratory Shipping Costs 
                        600  
     Vaccine Immunogenicity Field Supplies 
                         550  
  
  
TOTAL BUDGET    $                14,060  
  
  
*Based on estimated number of patients recruited at sites recruiting control subjects. *Site 
budgets do not include lab testing costs, which should be invoiced quarterly  
 
 
8.1 Budget Description 
 
8.1.1 Personnel costs  
 
Research coordinator/nurse 
Fixed costs: Site set-up & coordination (50 h per site in year 1 and 20h per site in years 2-3) 
Prepare documents for REB approval and renewal, develop contacts with personnel in oncology 
clinic and outpatient laboratory (e.g., booking clerks, clinic nurses, physicians) to ensure that 
study personnel are notified when eligible patients will be seen, and that data forms are 
completed and informed consent requested. Store consent forms, source documents and patient 
contact information. Additional 15h per year allocated to lead site to coordinate 
receiving/shipping/storage of samples and collection of case report forms. 
Variable costs:  
ALL patients: Explain the study and consent form, and invite the patient to sign the consent form.  
Complete clinical evaluation, review immunization records, complete case report forms. 
Coordinate bloodwork and administer immunizations. Conduct telephone interviews after 
vaccination to assess the occurrence of AEFI, report AEFI. Transmit case report forms and 
patient samples to the coordinating center in Halifax where data will be entered in the central 
database. Respond to the queries regarding the information on that patient.  
 
Control participants: Approach participants in outpatient laboratory, describe study, and invite 
them to participate. Review eligibility, obtain informed consent, coordinate blood collection, 
obtain immunization record, submit information to data centre. 
 
Data manager & Statistical Analyst 
Include database development, data entry at coordinating site, data cleaning, development of the 
statistical analysis and conduct of the analysis. 
 
Financial administrator 
Develops study budget, drafts contracts for subsites and coordinates payment. 
 
8.1.2 Laboratory costs 
 
Include cost, clinical lab set up fees, baseline and post-immunization vaccine serologies for cases 
and controls, and immunologic testing (e.g., T and B cell subsets) when not covered as part of 
routine clinical care, shipping costs and field supplies.   

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