Response to the SHINGRIX Varicella Zoster Virus (VZV) Vaccine in Chronic Lymphocytic Leukemia (CLL) Patients That Are Treatment Naive or Receiving Bruton s-Tyrosine Kinase Inhibitor (BTK-I) Therapy
Phase: PHASE2
Conditions: Safety and Tolerability, Compare SHINGRIX Vaccine Response Rates, Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

1
Protocol #19-H-0001
CLINICAL RESEARCH PROJECT
 Protocol 19-H-0001
Date:
April 20, 2020
Title:
Response to the SHINGRIX Varicella Zoster Virus (VZV) Vaccine in Chronic 
Lymphocytic Leukemia (CLL) Patients that are Treatment Naïve or Receiving Bruton’s-tyrosine 
Kinase Inhibitor (BTK-I) Therapy
Other identifying words: SHINGRIX, VZV, CLL, BTK-inhibitor, Ibrutinib, Acalabrutinib
Principal Investigator: 
Christopher Pleyer, M.D., HB, NHLBI (E)        301-827-3506                     Bldg 10, 4-5132
Subjects of Study:Number
Sex
Age range
Subjects:  
 108 (+15 ceiling to account for early dropout)
Either
 
Ages 18 and older
Project involves ionizing radiation? 
No
Off-site project? 
 No
Multi-institutional project? 
No
DSMB involvement?
 Yes

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Protocol #19-H-0001
1. PRÉCIS
This study aims to determine the efficacy of the SHINGRIX varicella zoster virus (VZV) vaccine in chronic 
lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) patients that are treatment naïve or 
receiving Bruton’s-tyrosine kinase inhibitor (BTK-I). (Note: Since CLL and SLL are considered the same 
disease, CLL/SLL will be referred to as CLL hereafter, unless otherwise specified).
Key Eligibility Criteria:
a.
Diagnosis of CLL or SLL
b.
Cohort 1: Treatment naïve CLL or SLL patients
c.
Cohort 2: Subjects must be receiving ibrutinib for at least 6 months prior to administration of the first 
vaccine dose
d.
Cohort 3: Subjects must be receiving acalabrutinib for at least 6 months prior to administration of the 
first vaccine dose
e.
Age 18 years
f.
ECOG performance status of 0-1
Design:
Patients with CLL will enroll on the study for the purpose of determining the SHINGRIX vaccine efficacy 
in patients who are treatment naïve or receiving BTK-I therapy. A series of 2 doses of SHINGRIX will be 
given at 0- and 3- month schedule by intramuscular injection. Subjects will be followed for 6 months and 
receive assessment of serologic response 6 months after the first vaccine dose administration.
Study Objectives:
Primary Objective:
a)
Determine the serologic response against VZV after completing the SHINGRIX (RZV) 2-dose 
vaccine series in the following populations:
a.
CLL patients that are treatment naïve (n=54)
b.
CLL patients receiving treatment with ibrutinib (n=27)
c.
CLL patients receiving treatment with acalabrutinib (n=27)
Secondary Objective:
a)
Determine the safety and tolerability of the SHINGRIX vaccine among CLL patients who are 
treatment naïve or receiving BTK-Is (ibrutinib or acalabrutinib).

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Protocol #19-H-0001
TABLE OF CONTENTS
1.
PRÉCIS.............................................................................................................................................2
2.
OBJECTIVES...................................................................................................................................4
3.
BACKGROUND...............................................................................................................................4
4.
STUDY DESIGN..............................................................................................................................9
5.
ELIGIBILITY ASSESSMENT and ENROLLMENT ....................................................................9
6.
TREATMENT PLAN......................................................................................................................11
7.
CLINICAL MONITORING ............................................................................................................11
8.
CRITERIA FOR RESPONSE......................................................................................................15
9.
ANCILLARY LABORATORY RESEARCH STUDIES .............................................................15
10. BIOSTATISTICAL CONSIDERATIONS ....................................................................................17
11. DATA AND SAFETY MONITORING..........................................................................................19
12. BIOSPECIMEN AND DATA MANAGEMENT PLAN ...............................................................22
13. HUMAN SUBJECTS PROTECTION..........................................................................................24
14. PHARMACEUTICALS..................................................................................................................29
15. REFERENCES ..............................................................................................................................31
16. APPENDIX .....................................................................................................................................33

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Protocol #19-H-0001
2. OBJECTIVES
Primary Objective:
a) Determine the serologic response against VZV after completing the SHINGRIX (RZV) 2-
dose vaccine series in the following populations:
a.
Chronic lymphocytic leukemia (CLL) patients that are treatment naïve (n=54)
b.
CLL patients receiving treatment with ibrutinib (n=27)
c.
CLL patients receiving treatment with acalabrutinib (n=27)
Secondary Objective:
a) Determine the safety and tolerability of the SHINGRIX vaccine among CLL patients who 
are treatment naïve or receiving a Bruton’s-tyrosine kinase inhibitor (BTK-I) (ibrutinib or 
acalabrutinib).
Exploratory Objectives:
a) Compare SHINGRIX vaccine response rates in patients on BTK-I treatment (ibrutinib and 
acalabrutinib) to response rates in treatment naïve CLL patients.
b) Compare SHINGRIX vaccine response rates between patients on ibrutinib and patients on 
acalabrutinib.
c)
Assess changes in VZV specific T cell mediated immunity in CLL patients following 
SHINGRIX vaccination
d) Assess kinetics of humoral and cell mediated immunity in CLL patients following 
SHINGRIX vaccination
3. BACKGROUND
3.1.
Clinical Background
This study aims to determine the efficacy of the SHINGRIX VZV vaccine in CLL patients that 
are treatment naïve or receiving BTK-I therapy.
Immune dysregulation is a hallmark of CLL, making these patients particularly vulnerable to 
infectious complications. Infections remain a major cause of death in patients with CLL.1 The 
implementation of vaccination strategies provides the opportunity to deliver high-value, cost-
effective care interventions. 

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Protocol #19-H-0001
To date, there is little evidence available to guide vaccination in immunocompromised 
individuals with cancer. Until recently, VZV vaccine prophylaxis was contraindicated in CLL 
patients, as there was only a live-vaccine variant available. A new recombinant, adjuvanted 
VZV vaccine (SHINGRIX) has the potential to reduce VZV infection/reactivation in this 
vulnerable population. It is currently unknown how effective the SHINGRIX vaccine is in 
protecting immunocompromised patients with CLL against VZV infection/reactivation. One 
study demonstrated that up to 80% of patients with hematologic malignancies (subjects with 
CLL were excluded) are able to mount an immune response to the SHINGRIX vaccine.2 
Looking at other vaccines, previous studies of the influenza vaccine in CLL patients have 
reported response rates ranging from 15 to 63%.3,4 In addition, it is unclear to what extent CLL 
patients treated with BTK inhibitors respond to vaccines. To date, only two published studies 
with less than 20 patients each have assessed influenza vaccine responses in CLL patients 
treated with BTK-Is, citing response rates between 7% and 26%.5,6 
The advent of BTK-Is (ibrutinib and acalabrutinib) has revolutionized the treatment of CLL in 
recent years, providing a targeted treatment approach that improves long-term outcomes and 
limits toxicities for these patients.7 Unlike chemo-immunotherapy that is given for a limited 
amount of time, CLL patients typically remain on daily BTK-I therapy for many months or even 
years.7 Ibrutinib results in partial reconstitution of humoral immunity in patients with CLL, 
however it targets B cell receptor (BCR) signaling that is critical in normal B lymphopoiesis and 
serum immunoglobulin G levels remain decreased during treatment.8 Seroconversion and 
subsequent host immunity after vaccine administration is reliant on an effective B-cell response 
and it is currently unclear how BTK-Is influence immune responses to vaccines. Surprisingly, 
some aspects of humoral immunity appear to be positively affected by ibrutinib therapy. A 
consistent increase in IgA has been observed in clinical trials of ibrutinib.9 The change in IgA 
appears to be clinically relevant, as in a phase 2 study, patients with greater improvements in 
IgA developed fewer infections.10 In addition, preclinical studies have demonstrated that BTK-
Is may improve immune function and surveillance by polarizing T cells towards a Th1 
predominant phenotype. This Th1 polarization is accompanied by an increase in Th1-mediated 
cytokines (e.g. IFN-). Additionally, BTK-Is attenuate the expression of T cell activation and 
pseudoexhaustion markers (HLA-DR and CD39) on T cells, conceivably causing a shift toward 
healthier effector T cells.11 Taken together, these effects may not only decrease infection risk, 
but may also enhance the efficacy of vaccines and immunotherapies to treat CLL.12-14

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Protocol #19-H-0001
This study will determine the SHINGRIX vaccine response rate in two large and clinically 
relevant CLL patient populations, including subjects who are (1) treatment naïve and (2) treated 
with a BTK-I. The resulting clinical findings have the potential to inform patients and clinicians 
about the yield and ideal timing of vaccine administration (prior to, or during BTK-I therapy) and 
may therefore guide clinical practice of the SHINGRIX vaccine administration to CLL patients.
3.2.
Indications for SHINGRIX Vaccination
The most recent guidelines from the Centers for Disease Control (CDC) Advisory Committee 
on Immunization Practices (ACIP)15 recommend the use of the SHINGRIX recombinant, 
adjuvanted vaccine over the ZOSTAVAX live-attenuated herpes zoster vaccine. Specifically, 
the recommendations include vaccinating all immunocompetent adults 50 years of age, 
including patients who previously received the live-attenuated herpes zoster vaccine, as well 
as patients with a history of herpes zoster. 
SHINGRIX is licensed for all persons aged 50 years of age, however the efficacy of the 
vaccine remains to be determined in immunocompromised individuals. The ACIP recommends 
the use of SHINGRIX in persons taking low-dose immunosuppressive therapy (e.g. <20 mg/day 
of prednisone or equivalent) and in persons anticipating immunosuppression or who have 
recovered from an immunocompromising illness.15 Immunocompromised individuals were 
excluded from the original SHINGRIX efficacy studies, however one follow-up study 
demonstrated that up to 80% of patients with hematologic malignancies (subjects with CLL 
were excluded) are able to mount an immune response to the SHINGRIX vaccine.2,16,17
3.3.
Summary of Clinical Safety
A brief summary of safety data from the SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) 
is provided in the table below. A large Phase III, multicenter, trial has already established safety 
of SHINGRIX in healthy and elderly adults.16 Most solicited local adverse reactions and 
systemic adverse events seen with SHINGRIX were considered by the subjects as mild and 
self-limiting and did not last more than 7 days with a median duration of 2-3 days. The incidence 
of solicited local and general symptoms was lower in subjects aged 70 years and older 
compared with those aged 50-59 years. There were no differences in the proportions of subjects 
reporting any grade 3 solicited local reactions between dose 1 and dose 2. Grade 3 solicited 
general adverse events (headache, shivering, myalgia, and fatigue) were reported more 
frequently by subjects after dose 2 (2.3%, 3.1%, 3.6%, and 3.5%, respectively) compared with 
dose 1 (1.4%, 1.4%, 2.3%, and 2.4%, respectively). 

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Protocol #19-H-0001
The following table lists the most frequently reported vaccine related adverse events (VRAEs) 
in subjects receiving SHINGRIX18:
Serious Adverse Events (SAEs)
In the 2 studies, SAEs were reported at similar rates in subjects who received SHINGRIX (2.3%) 
and placebo (2.2%) from the first administered dose up to 30 days post last vaccination16,17. 
SAEs were reported for 10.1% of subjects who received SHINGRIX and for 10.4% of subjects 
who received placebo from the first administered dose up to 1 year post last vaccination. 
Vaccine related serious adverse events (VRSAEs) were very rare, occurring overall in 0.2% of 
all patients receiving SHINGRIX (see table below for details)16:

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Protocol #19-H-0001
Optic ischemic neuropathy was reported in 3 subjects (0.02%) who received SHINGRIX (all 
within 50 days after vaccination) and 0 subjects who received placebo; available information is 
insufficient to determine a causal relationship with SHINGRIX.
3.4.
    Clinical and Scientific Justification
This study aims to provide critical information to clinicians and patients about the utility and 
feasibility of the SHINGRIX vaccine series administration in CLL patients who are treatment 
naïve or receiving BTK-I therapy.

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Protocol #19-H-0001
SHINGRIX is licensed for all persons aged 50 years of age. In addition, the CDC Advisory 
Committee on Immunization Practices (ACIP) recommends the use of SHINGRIX in persons 
anticipating immunosuppression or who have recovered from an immunocompromising 
illness.15 The SHINGRIX vaccine is highly effective and provides >90% protection rates even 
in the elderly (70 years of age) population.16 The SHINGRIX vaccine efficacy in CLL patients 
is currently unknown. Previous studies investigating the response to the influenza vaccine in 
CLL patients have demonstrated that these patients are able to mount an immune response to 
vaccines, albeit at a lower rate compared to healthy individuals.4,5 Herpes zoster is of particular 
concern in CLL, as these patients have an increased risk of VZV reactivation and ensuing 
complications.19,20 In summary, vaccination of CLL patients against SHINGRIX can be 
considered as part of supportive care to reduce their risk of herpes zoster and post-herpetic 
neuralgia. 
4. STUDY DESIGN
Patients with CLL will enroll on the study for the purpose of determining the SHINGRIX vaccine 
efficacy in patients who are treatment naïve or receiving BTK-I therapy. A series of 2 doses of 
SHINGRIX will be given at 0- and 3- months (+/- 15-day window) schedule by intramuscular 
injection. Subjects will be followed for 6 months and receive assessment of serologic response 
6 months (- 15-day, +180-day window) following the first vaccine administration.  After subjects 
complete response assessment, they may receive optional laboratory testing to document long-
term immunologic responses to the vaccine.
5. ELIGIBILITY ASSESSMENT and ENROLLMENT
5.1.
Inclusion Criteria
a.
Diagnosis of CLL/SLL which is made according to the updated criteria of the NCI Working 
Group21

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Protocol #19-H-0001
b.
Cohort 1: Treatment naïve CLL/SLL patients
c.
Cohort 2: Subjects must be receiving ibrutinib for at least 6 months prior to administration 
of the first vaccine dose
d.
Cohort 3: Subjects must be receiving acalabrutinib for at least 6 months prior to 
administration of the first vaccine dose
e.
No active, symptomatic VZV or herpes zoster infection within 12 months prior to vaccination
f.
No exposure to the live VZV vaccine (ZOSTAVAX) within 12 months prior to vaccination
g.
No prior exposure to the SHINGRIX vaccine 
h.
Age 18 years
i.
ECOG performance status of 0-1
j.
Able to comprehend the investigational nature of the protocol and provide informed consent
5.2.
Exclusion Criteria
a.
Female patients who are currently in pregnancy
b.
Any uncontrolled active systemic infection
c.
Any life-threatening illness, medical condition, or organ system dysfunction that, in the 
investigator’s opinion, could compromise the subject’s safety or put the study outcomes at 
undue risk
d.
Severe allergic reaction to any component of SHINGRIX
e.
Receive intravenous or subcutaneous immunoglobulin (IVIG) within 3 months prior to 
vaccination 
f.
Concomitant use of immunosuppressive agents (e.g. steroids, radiotherapy, chemotherapy)
g.
Hereditary or acquired immunodeficiency syndrome unrelated to chronic lymphocytic 
leukemia
h.
Non-English speaking individuals will be excluded from the study
5.3.
Patient Registration
On-Study Procedure: The appropriate informed consent will be obtained by an authorized 
associate investigator. The original copy of the informed consent will be filed electronically in 

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Protocol #19-H-0001
the subject’s Clinical Center medical record. A copy of the signed consent will be given to the 
subject.
6. TREATMENT PLAN
6.1.
Dosing Regimen
SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) - A series of 2 doses (0.5 ml each) will 
be given on a 0- and 3- months (+/- 15-day window) schedule via intramuscular injection. 
6.2.
Holding of Vaccine Administration
If medically necessary reasons to hold SHINGRIX occur during treatment (i.e. active systemic 
infection, impending workups for diagnostic and/or therapeutic purposes), SHINGRIX can be 
held based on the study team’s discretion and given when it is deemed safe. Longer than 
recommended intervals between doses do not reduce final antibody concentrations, although 
protection might not be attained until the recommended number of doses has been 
administered. Thus, an interruption in the vaccination schedule does not require restarting the 
entire series of vaccination or adding extra doses. If the vaccination series is interrupted after 
the first dose, the second dose should be administered as soon as possible. Subjects who 
receive the second SHINGRIX vaccine outside the +/- 15-day window period can receive the 
second vaccine dose but will be excluded from the final efficacy analysis.
6.3.
Permanent Discontinuation of Vaccine Administration
The study will be monitored to ensure that the occurrence of a specified set of vaccine related 
serious adverse events (VRSAEs) that occur during the treatment period does not substantially 
exceed an anticipated rate. VRSAEs may not exceed the reported rates in the Shingrix vaccine 
package insert. 
Subjects who are unable to receive the second SHINGRIX vaccine will be followed for safety. 
All adverse reactions that started within 7 days after study vaccine administration will be 
followed until resolution.
7. CLINICAL MONITORING
Samples will be ordered and tracked through the CRIS screens. Should a CRIS screen not be 
available, the NIH form 2803-1 will be completed and will accompany the specimen and be filed 
in the medical record. 
Results from other NIH protocols may be used as a part of the study evaluation. 

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Protocol #19-H-0001
Please refer to Appendix A – Schedule of Events for a timeline of events. 
7.1.
Screening Assessment
a.
Patients currently enrolled in other protocols within the lymphoid malignancies section 
at NIH will not require an in-person screening visit. A chart review will be performed in 
order to determine whether patients are eligible based on inclusion and exclusion 
criteria (see section 5). Only women of childbearing potential require a negative 
pregnancy test that must be drawn no more than 15 days prior to signing consent.
b.
Self-referral of patients is permitted. Patients not currently enrolled in a protocol at the 
NIH will require an in-person screening visit performed under the Hematology Branch 
Screening protocol 97-H-0041 or any other available NIH screening protocol and must 
have an already established diagnosis of CLL. Patients can receive screening and 
baseline assessment at the same visit if they decide to enroll in this clinical trial.
7.2.
Baseline Assessment
a.
History and physical examination 
b.
Review of medications
c.
The following laboratory tests will be sent prior to administration of the first vaccine. 
Tests must be drawn no more than 30 days prior to the first vaccine dose. Tests 
performed at the NIH on a different protocol will be accepted.

CBC with differential

Acute Care Panel (includes Na, K, Cl, CO2, Creatinine, Glucose, Urea Nitrogen)

Hepatic Panel (includes Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin)

Total B-cell, NK-cell and T-cell counts

Immunoglobulin levels

HLA-typing (A,B,C,DR,DQ) [if not yet already performed at NIH on other protocols]

C-reactive protein

HIV screening test (only if there is no result available within 365 days prior to the 
first vaccine dose)

Research blood (up to 80ml) (Refer to Appendix C for a list of possible research 
tests)

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Protocol #19-H-0001
The following laboratory tests are optional and can be completed at any time between the 3- 
and 6-month assessment after the second vaccine dose is administered. Tests performed at 
the NIH on a different protocol will be accepted:

CBC with differential 

Acute Care Panel (includes Na, K, Cl, CO2, Creatinine, Glucose, Urea Nitrogen)

Hepatic Panel (includes Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin)

Total B-cell, NK-cell and T-cell counts 

Immunoglobulin levels

C-reactive protein

Research blood (up to 80ml) (Refer to Appendix C for a list of possible research 
tests)
7.3.
On study Evaluations
Subjects will be evaluated at 3 months (+/- 15-day window and 6 months (- 15-day,+180-day 
window) for while on the study. All adverse reactions that started within 7 days after study 
vaccine administration will be followed until resolution.
The following laboratory tests will be completed. Tests performed at the NIH on a different 
protocol will be accepted 

CBC with differential 

Acute Care Panel (includes Na, K, Cl, CO2, Creatinine, Glucose, Urea Nitrogen)

Hepatic Panel (includes Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin)

Total B-cell, NK-cell and T-cell counts 

Immunoglobulin levels

C-reactive protein

Pregnancy test (for women of childbearing potential and during the 3 month 
assessment only)

Research blood (up to 80ml) (Refer to Appendix C for a list of possible research 
tests)
7.4.
Response Assessment

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Protocol #19-H-0001
Response assessment will be performed 6 months (- 15-day, +180-day window) after receiving 
the first SHINGRIX vaccine dose. Laboratory tests drawn during on-study evaluations (Section 
7.3) will be used for the efficacy analysis. No additional tests are required.
7.5.
After Response Assessment (Optional)
After subjects complete response assessment, they may receive optional laboratory testing to 
document long-term immunologic responses to the vaccine. Additional laboratory testing is 
optional and will only be performed if the patient agrees.  
The following laboratory tests may be performed between 6 and 36 months after response 
assessment. Tests performed at the NIH on a different protocol will be accepted. 

CBC with differential 

Acute Care Panel (includes Na, K, Cl, CO2, Creatinine, Glucose, Urea Nitrogen)

Hepatic Panel (includes Alkaline Phosphatase, ALT, AST, Total Bilirubin, Direct 
Bilirubin)

Total B-cell, NK-cell and T-cell counts 

Immunoglobulin levels

Research blood (up to 80ml) (Refer to Appendix C for a list of possible research 
tests)
7.6.
Vaccine specific manifestations
Signs and/or symptoms that are possibly vaccine related may be evaluated by additional tests, 
procedures and specialist consultations in accordance with standard of care. 
7.7.
Exclusion of subjects who need to start or change treatment for CLL
The following subjects may receive the second vaccine dose (if not already received and 
considered medically safe and appropriate) but will not be included in the efficacy analysis of 
this trial:

Subjects receiving BTK-Is: Any situation necessitating discontinuation of BTK-I 
therapy for >4 weeks during the study period

Subjects that are treatment naïve: Any situation necessitating starting treatment for 
CLL during the study period 

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Protocol #19-H-0001
7.8.
Exclusion of subjects who start Intravenous Immunoglobulin (IVIG) Therapy
The following subjects may receive the second vaccine dose (if not already received and 
considered medically safe and appropriate) but will not be included in the efficacy analysis of 
this trial:

Any subject that starts IVIG during the study period (after the first vaccine 
administration until the response assessment at 6 months). 
7.9.
Exclusion of subjects with HIV seropositivity at baseline assessment from 
efficacy analysis
It is possible that a very small subset of patients may have seropositive titers for HIV at baseline 
assessment. This could indicate that patients may have may have had HIV exposure without 
knowing. These patients will be followed for safety monitoring, and if clinically indicated, be 
seen by an infectious disease specialist. Patients with seropositive titers at baseline will be 
offered to receive the second vaccine dose (patient choice) and will not be included in the 
efficacy analysis of this trial. 
An additional subject will be recruited to the study for each subject that is found to be HIV 
seropositive. 
8. CRITERIA FOR RESPONSE 
The response criteria for achieving serologic response against VZV  following the SHINGRIX 
vaccine are based on a validated luciferase immunoprecipitation assay detecting VZV anti-
glycoprotein E antibody.22 Serologic titers to assess response to the SHINGRIX vaccine will be 
drawn 6 months (- 15-day, +180-day window) after the first SHINGRIX vaccine administration. 
The primary endpoint is serologic response defined as ≥ four-fold rises in VZV anti-gE blood 
IgG titer achievement after completing the SHINGRIX (RZV) 2-dose vaccine series.
9. ANCILLARY LABORATORY RESEARCH STUDIES
9.1.
Collection of Samples
Research Blood Samples: A volume not to exceed 80 mL at each visit will be drawn for 
research blood samples.
9.2.
Intended Use

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Protocol #19-H-0001
The primary use of the samples is described in section 2 and section 8 of this protocol. 
Research blood specimens will be stored for potential future assessment of future descriptive 
or exploratory ancillary research studies. 
9.3.
Procedures for stored specimens
All samples will be stored under the direction of the PI of the study. Research samples will be 
stored using BSI in accordance with NHLBI DIR Biospecimen policy. All laboratory personnel 
with access to subject information will complete the NIH online course in Protection of Human 
Subjects. Laboratory personnel are assessed for competency prior to being permitted to work 
with research subject samples. Efforts to ensure protection of subject information include:
The laboratory is located in a controlled access building and laboratory doors are kept locked 
at all times. Visitors to the laboratory are required to be accompanied by laboratory staff at all 
times. 
Hard copy records or electronic copies of documents containing research subject information 
are kept in the locked laboratory or other controlled access locations. 
An electronic database is used to store information related to research subject samples 
processed by the laboratory. 
Upon specimen receipt each sample is assigned a unique number. 
Vials holding research subject samples are labeled with the sequential laboratory accession ID 
number that does not contain any personal identifier information. 
9.4.
Tracking
Samples will be ordered and tracked through the CRIS Research Screens. Should a CRIS 
screen not be available, the NIH form 2803-1 will be completed and will accompany the 
specimen and be filed in the medical record. Samples will not be sent outside NIH without IRB 
notification and an executed MTA or CTA. 
9.5.
End of study procedures
Samples from consenting subjects will be stored until they are no longer of scientific value or if 
a subject withdraws consent for their continued use, at which time they will be destroyed. 
At the closure of this study, remaining samples from research subjects will be transferred to an 
NHLBI approved biorepository.
9.6.
Loss or destruction of samples

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Protocol #19-H-0001
Should we become aware that a major breech in our plan for tracking of samples has occurred, 
the IRB and the NHLBI Clinical Director will be notified. The PI will report destroyed samples if 
samples become unsalvageable because of environmental factors (ex. broken freezer or lack 
of dry ice in a shipping container). Samples will also be reported as lost if they are lost in transit 
between facilities or misplaced by a researcher. 
10.BIOSTATISTICAL CONSIDERATIONS
10.1.
Primary Endpoint
The primary efficacy endpoint will be the serologic response against VZV following completion 
of the SHINGRIX 2-dose vaccine series. Refer to section 8 for definitions of response.
10.2.
Secondary Endpoint
The safety endpoint will be safety and tolerability of the SHINGRIX vaccine among subjects 
who are treatment naïve or taking BTK-Is (ibrutinib or acalabrutinib).
10.3.
 Sample size 
This study consists of three separate groups of patients with CLL receiving (1) treatment naïve, 
(2) BTK-I treatment with ibrutinib and (3) BTK-I treatment with acalabrutinib. The primary 
analysis will examine the three groups of patients separately. Statistical tests will not be 
adjusted for multiplicity.
In the first group (treatment naïve CLL), we hypothesize that the study subjects who are 
treatment naïve will have SHINGRIX vaccine response rates more than 30%. Let p be the 
response rate, we will test the null hypothesis H0: p=30% versus the alternative H1: p ≠30% with 
a two-sided type I error of 0.05. A sample size of 54 evaluable subjects will have 83% power to 
detect a 20% difference based on a two-sided one-sample Z-test for proportion. We estimate 
the response proportion to be approximately 50% for this group, thus this group of 54 subjects 
will yield a two-sided 95% confidence interval of the response rate with the confidence limits 
within +/- 14%.
In each of the second (CLL treated with ibrutinib) and third (CLL treated with acalabrutinib) 
groups, the sample size is determined by testing the null hypothesis that the study subjects 
treated with BTK-Is will not be able to mount a response to the SHINGRIX vaccine series. Let 
p be the response rate, we will test the null hypothesis H0: p≤10% versus the alternative H1: p 
>10% with a type I error of 0.05. When the true response rate is 30%, a sample size of 27 
evaluable subjects will have 86% power to detect a 20% difference based on a one-sided 

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Protocol #19-H-0001
binominal test. The null hypothesis is rejected if 6 or more vaccine responses are observed in 
27 subjects. We estimate the response proportion to be approximately 30% for each group, 
thus a sample size of 27 subjects will yield a two-sided 95% confidence interval of the response 
rate with the confidence limits within +/- 18%.
Therefore, we plan to enroll 27 evaluable subjects in each of the BTK-I treatment cohorts and 
54 evaluable subjects in the treatment naïve cohort. As an important exploratory objective, we 
will compare the vaccine response rates between subjects in cohort 1 and subjects in the 
combined cohort 2 and cohort 3. The study will have over 88% power to detect a 30% difference 
if the response rate in the treatment naïve cohort is greater than 40% based on a two-sided 
two-sample Z-test for comparing two proportions.
Up to 15 additional subjects may be enrolled to account for early discontinuation before 
completing response assessment due to non-treatment related reasons. Subjects who 
discontinue study treatment early due to non-treatment related reasons are not included in the 
evaluation of the primary endpoint.
10.4.
Statistical Methods
The planned analyses will include descriptive statistics on the proportions of response 
probability to the SHINGRIX vaccine. The response probabilities will be estimated using the 
sample proportions and their inferences including confidence intervals and hypotheses testing 
will be evaluated. Regression analysis will be used to assess the factors that may influence the 
response to the SHINGRIX vaccine.
10.5.
Off Study Criteria
a.
Per research subject choice: Research subjects may withdraw from study at any time. 
b.
Death
c.
Per principal investigator decision: Should any of the following events occur, the subject 
will be followed until resolution of the event and then taken off study: 

Subject becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements, which might increase risk or substantially 
compromise the interpretation of study results. 

Subject develops a medical condition preventing the safe administration of the 
second vaccine dose (e.g. severe hypersensitivity reaction to the first vaccine dose).

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Protocol #19-H-0001

The principal investigator may take any research subject off study if it is determined 
that this would be in the best interest of the subject.
d.
Lost to follow-up
e.
CLL Disease Progression or Transformation (refer to section 7.6)
f.
Need to Start IVIG (refer to section 7.7)
g.
Need to omit or delay administration of 2nd Vaccine Dose (Refer to section 6.3 and 6.4)
h.
Detection of HIV on baseline evaluation (refer to section 7.8)
10.6.
Off-Study Procedure
A subject who goes off study will have an off-study note placed in the medical record.
11.DATA AND SAFETY MONITORING
11.1.
Safety Monitoring 
Principal Investigator: Accrual, efficacy and safety data will be monitored by the principal 
investigator (PI). The PI will also provide appropriate delegation of responsibilities to other 
members of the research staff. All data will be collected in a timely manner and reviewed by the 
PI and/or their designee for toxicity. 
NIH Intramural IRB: Accrual and safety data will be monitored and reviewed annually by the 
Institutional Review Board (IRB). Prior to implementation of this study, the protocol and the 
proposed subject consent will be reviewed and approved by the properly constituted 
Institutional Review Board (IRB) operating according to the 45 Code of Federal Regulations 
Part 46. This committee will also approve all amendments to the protocol or informed consent, 
and conduct continuing annual review so long as the protocol is open to accrual of subjects.
NHLBI Hematology DSMB:  The NHLBI Hematology Data Safety and Monitoring Board will 
review the protocol at 6 to 12 month intervals and the interval will be determined by DSMB. A 
progress report will be forwarded to the DSMB at these times and their recommendations will 
be expeditiously implemented. The DSMB may recommend early termination of the study for 
considerations of safety and efficacy.
11.2.
Assessment of Safety
Definitions
Definitions are per Policy 801 “Reporting Research Events”.

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Protocol #19-H-0001
Severity
Definitions found in the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 
v5.0) will be used for grading the severity (intensity) of AEs:
1
Mild
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2
Moderate
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL* 
3
Severe
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
4
Life-
threatening
Life-threatening consequences; urgent intervention indicated. 
5
Death
Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Attribution of Adverse Events
Relationship
Attribution
Description
Unrelated
The AE is clearly NOT related to the 
intervention
Unrelated to 
intervention
Unlikely
The AE is doubtfully related to the 
intervention
Possibly
The AE may be related to the intervention
Probably
The AE is likely related to the intervention
Related to 
intervention
Definitely
The AE is clearly related to the intervention
Pregnancy

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Protocol #19-H-0001
Before study enrollment, females of childbearing potential must agree to use contraception 
while vaccines are being administered. However, should a pregnancy occur in a female study 
subject, consent to provide follow-up information regarding the outcome of the pregnancy and 
the health of the infant until 30 days old will be requested.
A female subject must immediately inform the Investigator if she becomes pregnant from the 
time of consent to 90 days after the last dose of vaccine. The Investigator should counsel the 
subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 90 days after the last dose of vaccine must be reported. All pregnancies will be followed for 
outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery of 
the fetus. Any congenital anomaly/birth defect noted in the infant must be reported as a serious 
adverse event. 
11.3.
Documenting and Reporting of Adverse Events and Serious Adverse Events
Investigators will assess the occurrence of AEs and SAEs that start within 7 days after the first 
and second vaccine dose at all subject evaluation time points during the study. All AEs and 
SAEs whether volunteered by the subject, discovered by study personnel during questioning, 
or detected through physical examination, clinically significant laboratory test, or other means 
will be recorded in the subject’s medical record.
Additionally, research subjects will receive an adverse event diary. Subjects will be asked to 
document any local (injection site) or systemic adverse effects that start within 7 days after 
receiving the first and second vaccine dose. Subjects will also be given contact information of 
at least one study team member, in order to address any potential questions or concerns about 
the vaccine and/or adverse effects. (See appendix B for adverse event diary). 
All adverse reactions that started within 7 days after study vaccine administration will be 
followed until resolution, or until the Investigator assesses the subject as stable, a new 
anticancer therapy is initiated, or the subject is lost to follow-up or withdraws consent. 
Resolution/stable means the subject has returned to baseline state of health or the Investigator 
does not expect any further improvement or worsening of the event. 
In view of the underlying illness of CLL, many patients will enter the study with abnormal 
blood counts that would meet criteria as grade 3 toxicity, and thus AEs regarding hematologic 

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lab values including thrombocytopenia, anemia or leukocytosis will not be evaluable. 
However, we will collect hematologic laboratory values in the subject’s source documents.
11.4.
NIH IRB and CD reporting 
Expedited Reporting
Events requiring expedited reporting will be submitted to the IRB per Policy 801 “Reporting 
Research Events”.
Reports to the IRB at the time of Continuing Review:
The PI or designee will refer to HRPP Policy 801 “Reporting Research Events” to determine 
IRB reporting requirements.
Reports to the CD:
The PI or designee will refer to NHLBI DIR Policy to determine CD reporting requirements and 
timelines. 
12.BIOSPECIMEN AND DATA MANAGEMENT PLAN
12.1.
Data Management
The principal investigator will be responsible for overseeing entry of data into an in-house 
password protected electronic system and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts to ensure that data is verifiable and 
evaluable. Data will be abstracted from Clinical Center progress notes as well as from progress 
notes forwarded from the subjects’ home physician. Laboratory data from NIH will be imported 
electronically from CRIS into an in-house clinical trial database. Laboratory values from 
referring home physicians will be entered into the system. 
We will maintain the confidentiality of identifiable private information collected in this Clinical 
Trial and protect the privacy of the individual human subjects. Primary data containing 
individually identifiable information obtained during the conduct of the protocol will be kept in 
secure network drives or in approved alternative sites that comply with NIH information security 
standards. Neither individual personal identifiers nor the key linking coded data to individuals 
will be released to third parties without prior IRB approval and an executed CDA or MTA. 
Identifiable data will not be sent outside NIH without prior IRB approval or appropriate conditions 
for disclosure outlined in the executed CDA or MTA. 

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Protocol #19-H-0001
12.2.
End of study procedures
Data will be stored in locked cabinets and/or in a password protected database until it is no 
longer of scientific value.
12.3.
Loss or destruction of data
Should the research team become aware that a major breach in the plan to protect patient 
confidentiality and trial data has occurred, the IRB will be notified.
12.4.
Publication Policy
Given the research mandate of the NIH, patient data including the results of testing and 
responses to treatment will be entered into an NIH-authorized and controlled research 
database. Any future research use will occur only after appropriate human subject protection 
institutional approval such as prospective NIH IRB review and approval or an exemption from 
the NIH Office of Human Subjects Research (OHSR). 
12.5.
Data Sharing and Future Use of Data
Research data may be shared with qualified non-collaborator recipients following publication of 
the primary research results after removal of PII and IRB approval.  Future research use of data 
not defined in the research protocol may occur only after IRB review and approval or an 
exemption from the NIH OHSRP.  Refusal of a research subject participant to permit future use 
of data--other than required in the protocol --will be honored.  Limitations in data sharing and 
future use of data due to contractual obligations (e.g., CRADAs) or intellectual property 
proceedings (such as patent filings) will be honored.
12.6.
Future Use of Biospecimens
Following analyses of biospecimens for primary research purposes, remaining samples suitable 
for future research will be stored in manner that conforms with DIR policy (such as BSI) or in a 
publicly accessible research biospecimen repository following IRB or OHSRP approval, as 
applicable. Biospecimens may be destroyed only when permitted by the clinical director and 
the IRB.
Any future research use of biospecimens not defined in the protocol in which NHLBI 
investigators are engaged in research (e.g., they are undertaking research activities and hold 
the key that identifies research subjects) requires IRB review and approval. Coded 
biospecimens (NHLBI investigators hold the key that identifies research subjects) to be shared 
outside of NIH for future research use requires IRB review and approval (for research 

24
Protocol #19-H-0001
collaborations) or submission of a determination to OHSRP (for non-collaborative research), 
and an executed transfer agreement.  Unlinked biospecimens (no key to identify research 
subjects exists) to be shared outside of NIH for future research use requires submission of a 
determination to OHSRP and an executed transfer agreement.  There are a few types of 
biospecimens that do not require IRB or OHSRP approval for future research use outside of 
NIH, such as specimens from deceased individuals (refer to OHSRP SOP5, Appendix A for 
complete list); an executed transfer agreement is required in these special cases.  Refusal of a 
research subject participant to allow for future use of identifiable biospecimens--other than 
required in the protocol or for appropriate regulatory purposes --will be honored.
13.HUMAN SUBJECTS PROTECTION
The investigator(s) accept their responsibilities for protecting the rights and welfare of human 
research subjects and will permit, with reasonable advance notice and at reasonable times, the 
designated research monitors to monitor the conduct of the research, as well as to audit source 
documents to the extent necessary to verify compliance with FDA Good Clinical Practice and 
the approved protocol.
13.1.
Rationale for Subject Selection
Subjects from any gender and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria. CLL are rare neoplasms that comprise a substantial proportion of all leukemia 
in middle-aged persons and most commonly occur among elderly persons in western 
populations.
In order to avoid issues with language barriers and the potential inaccuracies in the study team’s 
understanding completion of the AE diary, the investigators have decided not to enroll non-
English speaking subjects.
13.2.
 Special Patient Populations
Justification for exclusion of patients with hereditary or acquired immunodeficiency 
syndromes
Vaccine efficacy is known to be decreased in patients with immunodeficiency. The purpose of 
this study is to determine whether patients with CLL (itself known to cause immunodeficiency) 
can mount an immune response to vaccines. Including patients with additional 
immunodeficiency states would be a potential confounding factor.
Justification for exclusion of pregnant women

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Protocol #19-H-0001
There are no clinical studies that were done on pregnant women taking SHINGRIX. 
Additionally, it is highly unlikely that a woman of pre-menopausal age will present with CLL at 
the Clinical Center. CLL is a malignancy of B cells that predominantly affects the elderly 
population. Diagnosis is typically made in adults over the age of 50 and more than half of the 
people with CLL are over the age of 70.
Justification for exclusion of children
Patients under the age of 18 are excluded because inclusion of an occasional younger patient 
will not provide generalizable information that would justify their inclusion on this study. In 
addition, pediatric patients with CLL are extremely rare and it is indeed doubtful that these 
exceptional cases are part of the same disease spectrum.
Justification for exclusion of cognitively impaired subjects 
Cognitively impaired and institutionalized persons will not participate in this study. Cognitively 
impaired persons may have difficulties accurately self-reporting adverse events which could 
compromise the safety of the subject and the validity of study findings. Subjects must be able 
to provide informed consent and understand and comply with the treatment plan and follow-up.
Inclusion of NIH Staff

NIH staff (employees, NIH contractors, special volunteers, guest researchers, and 
trainees) may voluntarily participate in this protocol.

Recruitment, enrollment and compensation of NIH staff will be consistent with the 
Guidelines for the Inclusion of Staff in NIH Intramural Research Studies (April 2016) 
(SOP 14F) and NIH Policy Manual Chapter 2300-630-3,:”Leave Policy for NIH 
Employees Participating in NIH Medical Research Studies” (HRPP SOP 14F).
13.3.
Recruitment plan
The study will be listed on the following websites: clinicaltrials.gov, NIH Clinical Center (CC) 
Search the Studies, the CC Recruitment Website (with dedicated study webpage using IRB 
approved language, and Craigslist, the Leukemia and Lymphoma Foundation, Physician’s 
Desk Query, and the National Heart, Lung and Blood Institute patient recruitment webpages. A 
recruitment plan will be developed by the NHLBI Patient Recruitment Office (PRO) that will 
include IRB-approved recruitment materials and tools, developed in partnership with OPR, to 
include recruitment flyers, iStock photos for marketing the study, and Public Service 
Announcement (PSA) including recruitment language for use with social media (Facebook and 
Twitter), OPR and NIH Listservs, ResearchMatch.org, Craigslist postings, NIH Record and 

26
Protocol #19-H-0001
Clinical Center News internal publications and other potential official NIH external publications 
as available. An informational letter to physicians will be available for electronic (and hard copy 
as appropriate) distribution to local and national clinical contacts. All options mentioned in PSA 
(i.e. ResearchMatch, Craigslist, publications, etc.) may be used for recruitment: Social media 
language may be posted on any and all official NIH accounts and those of CLL advocacy 
groups, such as the CLL Society and Leukemia and Lymphoma Foundation.
13.4.
Payment and Reimbursement for participation
a.
General

Subjects will not be compensated for their participation in this study. There is no 
payment for the blood samples obtained for research.
b.
Travel, food, and lodging will be consistent with NIH guidelines. 
13.5.
Risks and Discomfort
Risks related to SHINGRIX
Most solicited local adverse reactions and systemic adverse events seen with SHINGRIX were 
considered by the subjects as mild and self-limiting, with the median duration of 2-3 days.
A summary of safety data from the SHINGRIX vaccine is described in section 3.3. 
Contraindications to Vaccine Administration
History of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine or after 
a previous dose of SHINGRIX. 
Risks related to blood draws
No major risks are involved with blood draws. Minor complications including bleeding, pain, and 
hematoma formation at the site of blood draws or rarely an infection may occur.
Risks related to pregnancy and nursing mothers
There are no available human data to establish whether there is vaccine-associated risk with 
SHINGRIX in pregnant women.
A reproductive and developmental toxicity study was performed in female rats administered 
SHINGRIX or the AS01B adjuvant alone prior to mating, during gestation, and during 
lactation. The total dose was 0.2 mL on each occasion (a single human dose of SHINGRIX is 

27
Protocol #19-H-0001
0.5 mL). This study revealed no adverse effects on fetal or pre-weaning development due to 
SHINGRIX.
If research subjects should become pregnant while enrolled in the study, they will no longer 
receive further vaccine doses.
13.6.
Risks in Relation to Benefits
Risk to Adult Subjects
The benefits to the subject could be a reduction in the risk of acquiring herpes zoster and post-
herpetic neuralgia.
Overall there is greater than minimal risk with prospect of benefit for achieving immunity against 
herpes zoster VZV infection.
Risk to NIH Staff
The study involves greater than minimal risk with the prospect of direct benefit to individual 
subjects.
13.7.
Informed Consent Processes and Procedures
Informed consent shall be documented using the current IRB‐approved consent form, which 
should be downloaded from the NIH Clinical Center active consent website. Each participant 
will receive an oral and written explanation of the goals, procedures, and risks of this study.  
When consent is obtained, the consent document(s) must be signed and dated by the subject, 
and the person obtaining consent. Effective January 21, 2019 a witness to the long form 
consent is no longer required.. The original, signed informed consent document will be placed 
in the medical record, and the subject will receive a signed copy of the informed consent 
document. Documentation of informed consent and the signed consent form will be maintained 
in CRIS. 
The investigational nature and research objectives of this trial, the procedure and its attendant 
risks and discomforts will be carefully explained to the subject and a signed informed consent 
document will be obtained prior to entry onto this study. 
At any time during participation in the protocol, should new information become available 
relating to risks, adverse events, or toxicities, this information will be provided orally or in writing 
to all enrolled or prospective patient participants. Documentation will be provided to the IRB 
and if necessary the informed consent amended to reflect relevant information. 

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Protocol #19-H-0001
If there is an unexpected enrollment of a research participant for which there is no translated 
extant IRB approved consent document, the principal investigator and or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, 45 CFR 46.117 (b) (2), and 21 CFR50.27 (b) (a)0. The summary that will be used 
is the English version of the extant IRB approved consent document. 
We request prospective IRB approval of the use of the short form for up to a maximum of 5 
research subjects in a given language and will notify the IRB at the time of continuing review of 
the frequency of the use of the Short Form. Should we reach the threshold of 5, we will notify 
the IRB of the need for an additional use of the Short Form and that we will have that consent 
document translated into the given inherent language. 
Consent process for NIH Staff
Per Standard Operating Procedure 14F, Research Involving NIH Staff as Subjects, the 
following guidelines apply to NIH staff who participate in intramural research studies:

Neither participation nor refusal to participate as a subject in this protocol will have an 
effect, either beneficial or adverse, on the participant’s employment or position at NIH.

Employee subjects’ privacy and confidentiality will be respected by protocol and 
consenting staff the same as for all subjects participating in research protocols. 
However, all subjects will be made aware that there are limits to these protections.

The PI, through the consenting staff member, will make the “NIH Information Sheet on 
Staff Research Participation” available to staff members who are considering enrolling 
in research. (SOP 14F, Appendix D of this protocol).

If the individual requesting to participate in the protocol is a co-worker, the consent 
from the NIH staff member (co-worker) will not be obtained by the staff member’s 
direct supervisor but by another research staff member who is approved for obtaining 
informed consent and who is not a co-worker.
13.8.
CONFLICT OF INTEREST
The Principal Investigator assures that each associate investigator listed on the protocol title 
page received a copy of the NIH’s Guide to preventing conflict of interest. No members of the 
research team reported a potential conflict of interest. 
13.9.
TECHNICAL TRANSFER AGREEMENTS

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Protocol #19-H-0001
A CRADA is being executed between NHLBI and Dr. David Koelle, University of Washington, 
Seattle, WA to assess changes in VZV specific T cell mediated immunity in CLL patients 
following SHINGRIX vaccination. NHLBI will provide de-identified peripheral blood samples 
for analysis.
14.PHARMACEUTICALS
14.1.
SHINGRIX
Product description
SHINGRIX is commercially available and FDA approved. Note for more detailed and 
comprehensive background information please refer to the SHINGRIX package insert.18 
The study team with refer to the most recent package insert for prescribing information. Storage, 
preparation, dosage and administration will be performed per the CCND policy for Medication 
Preparation and the SOP for Medication Administration.
Co-Administration of Other Vaccines
Subjects may receive a different vaccine on the same day as SHINGRIX. If subjects receive 
two vaccines on the same day each vaccine must be administered in a separate extremity. 
Local adverse reactions will be attributed to the vaccine that was given at the involved local 
site. Systemic reactions that are expected as per the package insert(s) will be attributed to both 
vaccines.
14.2.
FDA regulatory considerations
An IND application with the FDA is not required for this project.  The proposed research with 
the SHINGRIX vaccine meets the exemption requirements noted in 21 CRF 312.2, specifically: 
1.
The drug product is lawfully marketed in the United States.
2.
The investigation is not intended to be reported to FDA as a well-controlled study in support 
of a new indication and there is no intent to use it to support any other significant change in the 
labeling of the drug. 
3.
In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug. 
4.
The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).

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Protocol #19-H-0001
5.
The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
6.
The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).

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Protocol #19-H-0001
15.REFERENCES
1.
Strati P, Parikh SA, Chaffee KG, et al. Relationship between co-morbidities at diagnosis, survival and ultimate 
cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol 2017; 
178(3): 394-402.
2.
Oostvogels L. Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Candidate Vaccine in 
Adults with Hematologic Malignancies: A Phase III, Randomized Clinical Trial.  IDSA Week; 2017.
3.
van der Velden AM, Mulder AH, Hartkamp A, Diepersloot RJ, van Velzen-Blad H, Biesma DH. Influenza 
virus vaccination and booster in B-cell chronic lymphocytic leukaemia patients. Eur J Intern Med 2001; 12(5): 420-4.
4.
Gribabis DA, Panayiotidis P, Boussiotis VA, Hannoun C, Pangalis GA. Influenza virus vaccine in B-cell 
chronic lymphocytic leukaemia patients. Acta Haematol 1994; 91(3): 115-8.
5.
Sun C, Gao J, Couzens L, et al. Seasonal Influenza Vaccination in Patients With Chronic Lymphocytic 
Leukemia Treated With Ibrutinib. JAMA Oncol 2016; 2(12): 1656-7.
6.
Douglas AP, Trubiano JA, Barr I, Leung VK, Slavin MA, Tam CS. Ibrutinib may impair serological responses 
to influenza vaccination. Haematologica 2017.
7.
Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic 
Leukemia. The New England journal of medicine 2015; 373(25): 2425-37.
8.
Sun C, Tian X, Lee YS, et al. Partial reconstitution of humoral immunity and fewer infections in patients with 
chronic lymphocytic leukemia treated with ibrutinib. Blood 2015; 126(19): 2213-9.
9.
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic 
leukemia. The New England journal of medicine 2013; 369(1): 32-42.
10.
Sun C, Wiestner A. Prognosis and therapy of chronic lymphocytic leukemia and small lymphocytic lymphoma. 
Cancer Treat Res 2015; 165: 147-75.
11.
Pleyer C, Wiestner A, Sun C. Immunological changes with kinase inhibitor therapy for chronic lymphocytic 
leukemia. Leukemia & lymphoma 2018: 1-9.
12.
Robinson HR QJ, Baskar S, Cook E, Ahn IE, Herman SE, Rader C, Wiester A. Activity of CD19/CD3 
Bispecific Antibodies in Chronic Lymphocytic Leukemia. 59th ASH Annual Meeting, Atlanta, GA; 2017.
13.
Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving 
a Th1-selective pressure in T lymphocytes. Blood 2013; 122(15): 2539-49.
14.
Kondo K, Shaim H, Thompson PA, et al. Ibrutinib modulates the immunosuppressive CLL microenvironment 
through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. 
Leukemia 2017.
15.
Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices 
for Use of Herpes Zoster Vaccines. MMWR Morbidity and mortality weekly report 2018; 67(3): 103-8.
16.
Cunningham AL, Lal H, Kovac M, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of 
Age or Older. The New England journal of medicine 2016; 375(11): 1019-32.
17.
Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older 
adults. The New England journal of medicine 2015; 372(22): 2087-96.
18.
(FDA) 
FDA. 
SHINGRIX 
Package 
Insert. 
2018. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM581605.pdf 
(accessed 
1/29/18 2018).
19.
Melchardt T, Weiss L, Greil R, Egle A. Viral infections and their management in patients with chronic 
lymphocytic leukemia. Leukemia & lymphoma 2013; 54(8): 1602-13.
20.
Yawn BP, Saddier P, Wollan PC, St Sauver JL, Kurland MJ, Sy LS. A population-based study of the incidence 
and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clinic proceedings 2007; 82(11): 
1341-9.
21.
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute-Working Group 1996 guidelines. Blood 2008; 111(12): 5446-56.
22.
Cohen JI, Ali MA, Bayat A, et al. Detection of antibodies to varicella-zoster virus in recipients of the varicella 
vaccine by using a luciferase immunoprecipitation system assay. Clinical and vaccine immunology : CVI 2014; 21(9): 
1288-91.
23.
Gilbert PB, Gabriel EE, Miao X, et al. Fold rise in antibody titers by measured by glycoprotein-based enzyme-
linked immunosorbent assay is an excellent correlate of protection for a herpes zoster vaccine, demonstrated via the 
vaccine efficacy curve. The Journal of infectious diseases 2014; 210(10): 1573-81.

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16.APPENDIX
16.1.
Appendix A – Schedule of Events
Footnotes for Schedule of Events:
[R] Optional, drawn at discretion of clinical team 
X Mandated
Y Mandated, unless HLA-Typing has already been performed as part of a prior protocol at NIH
X* Mandated for women of childbearing potential only
X** Mandated only if no HIV test available within 365 days prior to first vaccine administration
C Chart Review

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Protocol #19-H-0001
16.2.
Appendix B – Adverse Event Diary for Patients

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Protocol #19-H-0001
16.3.
Appendix C – IRB-Approved Hematology Branch Laboratory Research Studies
DESCRIPTION OF LABORATORY STUDY BY BRANCH SECTION
A
Stem Cell Allotransplantation Section (Dr. A. John Barrett)
A.1
Measurement of lymphocyte function and immune responses directed toward 
allogeneic tissues, malignant cells, and infectious agents.  Assay of a variety of 
antigens, including standard proliferation, cytotoxicity, and intracellular cytokine 
detection including GVHD predictive markers. Measurement of antigen-specific 
responses including employment of tetramers, ELISPOT technique, gene 
amplification-based assays, and flow cytometry.  Selection of cells using 
immunomagnetic beads or flow cytometry.  Culture, expansion, and selection of cells. 
Surface marker analysis of PB MC using flow cytometry. Cytokine/chemokine 
analysis of plasma/serum samples using ELISA and/or Luminex techniques.
A.2
Generation of cell lines for the study of immune cell interactions with other cells. 
Transformation of B-lymphocytes using Epstein-Barr virus.  Derivation of malignant 
cell lines from patient leukemic or solid tumor samples.
A.3
Infection of cells and cell lines with recombinant genes to ascertain the effects of 
expressed molecules on immune responses and on growth and development. 
Transfection of cell lines with specific molecules to study antigen-specific responses.
A.4
Assays of peripheral blood and bone marrow progenitor cells including primitive and 
late erythroid progenitor-derived colonies, myelomonocytic colonies, and primitive 
multi- potential progenitor-derived colonies.
A.5
Injection of human cells into experimental animals to study the immune system and 
the growth of normal and malignant cells under varying conditions.
A.6
Testing of selection methods, cell isolation, and cell expansion leading to the 
development of new cell-based therapies requiring scale-up for clinical application.
A.7
Identification of individual T cell clones by their T cell receptor sequence.
A.8
Measurement of tumor and tissue specific antigens in cells of subjects and donors by 
mRNA,protein, or peptide expression in cells or fluids.

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Protocol #19-H-0001
A.9
Laser capture micro dissection of cells from biopsies for GVHD to determine 
clonotypes.
A.10
DNA and RNA typing of genes that control immune responses in lymphocytes.
A.11
Microassay studies utilizing cellular DNA, cDNA, and RNA for neoplasia and host-
tumor interactions.
A.12
Serum, blood and tissue markers of post-transplant tissue injury, particularly 
endothelial cell damage. Investigation of transplant survivors for metabolic 
derangements related to cardiac and vascular risk such as lipoprotein profiles, insulin 
resistance, diabetes markers, growth hormone signaling, hypertension, renal 
dysfunction.
B
Molecular Hematopoiesis  Section  (Dr. Cynthia Dunbar) 
B.1
Flow cytometric analysis of cell surface and cytoplasmic proteins, including cell 
adhesion molecules, putative retroviral receptors, and markers of differentiation, using 
bone marrow and mobilized peripheral blood cells.
B.2
Hematopoietic progenitor-derived colony ascertainment in vitro (as described above), 
and engraftment of immunodeficient mice for detection of human stem cell number 
and function.
B.3
Testing ability of hematopoietic progenitor cells to be transduced with retroviral, 
lentiviral, and novel gene transfer vectors in vitro.
B.4
Reprogramming of adult mature cells, including skin fibroblasts and blood cells, into 
induced pluripotent stem cells in vitro.
C
Cell Biology Section (Dr. Neal Young) 
C.1
Studies of blood and bone marrow hematopoietic progenitor numbers, including early 
and late erythroid progenitors, myelomonocytic progenitors, and multi-potential 
progenitor cells.  In addition, bone marrow may be placed in long-term bone marrow 
culture to assess the function of stroma and stem cells and to assay more primitive 
progenitors, as well as organelle culture.  Whole or selected bone marrow populations 
are cultured short-term for CD34 cell expansion.

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Protocol #19-H-0001
C.2
Assays of apoptosis in hematopoietic cells and their progeny, using flow cytometric 
methods such as annexin and caspase-3 staining, propidium iodide uptake, and 
mitochondrial permeability tests.
C.3
Separation and functional study of cell populations characteristic of paroxysmal 
nocturnal hemoglobinuria, identified by absence of glycosylphosphatidylinositol 
anchored proteins.
C.4
Studies of mutation rates in hematopoietic cells and in buccal mucosa cells, using 
conventional hypoxanthine phosphoribosyltransferase activity functional assays, 
sequencing of mitochondrial DNA after specific gene amplification, and measurement 
of GPI-anchored deficient cells in blood and bone marrow.
C.5
Assays of immune function of T-cells, including intracellular cytokine staining, 
ELISPOT, semiquantitative gene amplification for gamma-interferon, tumor necrosis 
factor, interleukin-2, and other cytokines, and functional assessment in co-culture 
using specific neutralizing monoclonal antibodies.  In addition, peripheral blood 
lymphocytes are subjected to spectratyping for CDR3 size distribution as well as 
nucleotide sequence of CDR3 peaks obtained.
C.6
Studies of engraftment of human normal and diseased bone marrow and peripheral 
blood in immunodeficient mice in order to determine the presence of hematopoietic 
repopulating stem cells as well as functional differences among selected populations.
C.7
Flow cytometric analysis of blood and bone marrow for lymphocyte phenotype, 
especially for evidence of activation of lymphocytes, for markers of apoptosis, and for 
antigens associated with primitive and mature hematopoietic cell populations.
C.8
Flow cytometric analysis of blood and bone marrow for hematopoietic stem cell 
progenitors and CD34 positive cells.
C.9
Studies of chromosomal instability in myelopdysplastic syndromes including BM cell 
and CD34 cell response to PAS crosslinking and examination of the cytotoxic effect 
of lymphocytes to the abnormal clone of cells.
C.10
Surface Enhanced Laser/Desorption Ionization (SELDI)  time-of-flight mass 
spectrometry (Ciphergen)  (proteomics methodology).
C.11
Mitochondrial DNA (mtDNA) sequence heterogeneity.
C.12
Measurement of EBV viral load.

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Protocol #19-H-0001
C.13
Measurement of EBV LMP-1 via RT-PCR for LMP-1 RNA or flow cytometry for 
LMP-1.
C.14
Outgrowth assay of EBV transformed B cells.
C.15
Quantification of serumchemokines and cytokines (e.g. SDF-1, IL-10, IL-6, CXCR4, 
CXCL12).
C.16
Quantification of EBV cytotoxic T cells (tetramerstaining).
C.17
Telomere length measurement by Southern blot, Q-PCR, flow-fish, in situ 
hybridization and STELA
C.18
Telomere repair complex gene mutations by nucleotide sequencing of some or all of 
the following:  DKC1 ,TERC, TERT, SBDS, NOp10 , NHP2.
C.19
Analysis of  inflammatory markers and/or bacterial, viral, fungal or protozoal elements 
in plasma or serum using molecular, colorimetric, enzymatic, flow cytometric or other 
assays in subjects receiving immunosuppressive therapy, chemotherapy and/or bone 
marrow transplantation.
C.20
Confocal microscopic imaging of bone marrow.
C.21
Characterization of intracellular signaling proteins by cell permeabilization and flow 
cytometry, and quantitative immunoblots.
C.22
Assays for chromosomal aneuploidy by florescence in situ hybridization (FISH) and 
other molecular techniques.
C.23
Conversion of human dermal fibroblasts into hematopoietic progenitors using Oct4 
transfection.
C.24
Quantification of gene expression with RNA-seq
C.25
Characterization of chromatin and promoter/enhancer landscapes with ATAC-seq
C.26
Measurement of protein markers with SomaLogic's SOMAscan assay
D.1
Assays of serum, blood cells, and bone marrow cells for B19 parvovirus and possible 
B19  variants using gene amplification, cell culture, and hematopoietic colony 
inhibition assays.

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Protocol #19-H-0001
D.2
Assays of blood, bone marrow, liver, and other tissues for potentially novel viruses, 
using a variety of techniques including RNA and DNA assays, differential display, 
gene amplification with conserved and random primers, cell culture assays, 
immunohistochemical methods, and inocculation of mice, rabbits, and monkeys, as 
well as antibody measurements.
D.3
Assays of blood, bone marrow, and liver for known viruses, including herpesviruses 
such as cytomegalovirus, human herpesviruses 6, 7, and 8, enteric viruses such as A-
6, circiviruses, and parvoviruses, using assays as in (2).
D.4
Spectra-typing of blood cells to determine response to known or putative viral 
infections.
D.5
HLA typing or subtyping to determine risk factors/determinants for hepatitis-AA 
studies.
D.6
Cytotoxic lymphocyte assays with intracellular cytokine measurement for determining 
anti-viral response and lymphocyte cloning to obtain clones with specific antiviral 
activity.
E
Solid Tumor Section (Dr. Richard Childs)
E.1
Cr51 cytotoxicity assay to evaluating killing of patient tumor cells by patient NK cell 
clones and T-cells.
E.2
ELISA for IL-12  maturity of DC's made from subjects monocytes.
E.3
ELISA for IFN ã to evaluate specificity of CTL clones.
E.4
H thymidine uptake to evaluate proliferation potential of antigen specific T-cells.
E.5
PCR of STR to assess chimerism status of cellular subsets grown in-vitro or retrieved 
from subjects post-transplant.
E.6
Flow sorting of PBL and/or tissue samples to evaluate chimerism of different subsets.
E.7
Surface marker analysis of peripheral blood mononuclear cells using flow cytometry.
E.8
cDNA expression arrays to evaluate T-cells expression/gene patterns in subjects with 
GVHD and a GVT effect.
E.9
Geno typing of tumor or tissue samples by high density cDNA arrays.
E.10
VHL mutation analysis on kidney cancer tissue.

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Protocol #19-H-0001
E.11
Transduction of dendritic and tissue cells with tumor antigens using plasmids, viral 
vectors and hybrid fusions.
E.12
Lasar capture microdisection of cells from tumor biopsies and tissue samples  to 
determine origin (donor vs patient).
E.13
Quantification of polyoma virus BK exposure by serology and PCR in stem cell 
transplant donors and recipients from blood and urine samples.
E.14
Quantification of polyoma virus BK specific T cells in stem cell transplant donors and 
recipients from peripheral blood samples.
E.15
Determination of origin of neovasculature endothelial cells in tumor and tissue 
samples obtained from subjects post transplant.
E.16
Quantification of lymphocyte subsets CD34 progenitors and endovasculator 
progenitors in G-CSF mobilized peripheral cell allografts.
E.17
Testing for polyoma virus BK latency in CD34 progenitors, B cells and T cells in the 
G-CSF mobilized peripheral cell allografts.
E.18
Determination of etiology of membraneous nephropathy using serum from subjects.
E.19
Serum Proteomic patterns analysis to diagnose complications related to allogeneic 
transplantation.
E.20
Determine cell origin (donor vs patient) of tissue samples using IHC, IF, sorting, and 
FISH.
F
Lymphoid Malignancies Section (Dr. Adrian Wiestner)
F.1
Culture of cells from research subjects to investigate molecular disease mechanisms, 
model host tumor interactions, and to test effect of drugs on cell survival and cellular 
functions.
F.2
Generation of stable cell lines for the study of hematologic malignancies.
F.3
Modifications of cells using standard expression systems or biologic molecules, e.g. 
interfering RNA, to investigate the effects of candidate genes on cellular functions.
F.4
Identification and monitoring of B or T cell populations as identified by flow 
cytometry and by their B cell or T cell receptor expression.

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Protocol #19-H-0001
F.5
Measurement of gene expression in cells or tissues. Techniques frequently used 
include gene expression profiling on microarrays, quantitative RT-PCR, Western 
blotting, flow cytometry and ELISA assays.
F.6
Analysis of chromosomal abnormalities or mutations in malignant cells and non-
malignant cells including FISH technology and DNA sequencing.
F.7
Assays of immune function of B-cells and T-cells, including intracellular cytokine 
staining, ELISPOT, quantitative RT-PCR for cytokines or other immune regulatory 
genes.
F.8
Analysis of antibody specificities in serum and antigen specificity of the B-cell 
receptor on cells. Techniques may include expression of antibodies in phage display 
systems, generation of antibodies in cell culture systems and use of such antibodies to 
screen for cognate antigens.
F.9
Transplantation of human cells into mice (xenograft model) to study disease biology 
and to investigate the effect of experimental therapy.
F.10
Measurements of drug concentrations, biologic molecules and disease markers in 
blood, serum, and plasma.

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Protocol #19-H-0001
16.4.
Appendix D
NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION (APRIL 2016) 
As an NIH employee, contractor, Special Volunteer, Guest Researcher, or trainee, you may 
participate in intramural research studies unless it is prohibited by your Institute or Center 
(IC), or if you are excluded by the criteria of the protocol in which you want to enroll. The 
inclusion of NIH staff in a particular protocol must also be approved by the IRB. You may be 
motivated by altruism, a commitment to research in your own or related fields, or want access 
to clinical trials of potential direct therapeutic benefit. When deciding, you should make an 
informed decision about participation. This information sheet offers some points to consider 
for NIH staff who are considering research participation at NIH. 
First, similar to any individual who is considering research participation, you should seek 
adequate information about the study purpose, what is required of you in terms of procedures, 
interventions and time, and the potential risks and benefits of participation. For more 
information, see the NIH Clinical Center’s public website “Are Clinical Studies for You?” at 
http://www.cc.nih.gov/participate/studies.shtml. 
When you are thinking about participation in a research study that is being conducted by your 
supervisor, or others with whom you work closely in your laboratory, branch, or unit, you 
should consider some additional factors: 
A. Possible bias: Are you confident that you can be unbiased about reporting answers, side 
effects, or other information that could influence the study outcome or risk to you? 
B. Confidentiality: Has the principal investigator (PI) spoken about what
information will be collected from you as part of the study? Has the PI discussed
what information will be available to those within, and outside, the study team? If
applicable, are you comfortable sharing your medical history (including, for
example, mental health history or STDs) and your social history (e.g. substance
use) with study investigators who may be your coworkers, or with the possibility
of them discovering something about your health during the study (e.g.
pregnancy status or a new diagnosis)? Although every effort will be made to
protect your information and keep it private and confidential, your information
may, depending on the nature of the protocol, become available in medical
records or to authorized users outside of the study team. Discuss any concerns
with the PI.

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Protocol #19-H-0001
C. Pressure: Do you perceive any pressure or expectations from your supervisor or 
colleagues regarding participation? Could that pressure influence your decision or make 
it difficult for you to choose whether or not to participate? Remember that it is your choice 
whether or not to participate and that your decision to participate or not should not have 
an effect, either beneficial or adverse, on your position at NIH. 
D. Time and Compensation: Can you take time off from work to complete the study 
requirements or participate solely during non-duty hours? Can you receive compensation 
for your participation in this study? Will your supervisor give you permission to participate 
during work hours? See the NIH Policy Manual 2300630-3 Leave Policy for NIH 
Employees Participating in NIH Medical Research Studies.
E. Consent Process: Is the person obtaining your consent for the study your supervisor, a 
subordinate, or co-worker? If so, is there an independent person monitoring the consent 
process? If the study PI is a supervisor and intends to obtain consent from you, an 
independent person (e.g., through Bioethics or the NIMH Human Subjects Protections Unit 
[HSPU], or others as approved by the IRB) must monitor the consent process. If the person 
obtaining consent from you is a co-worker then an independent person (e.g., through 
Bioethics or the NIMH HSPU, or others as approved by the IRB) may be required to monitor 
the consent process, as determined by the IRB for the specific study. 
If you are thinking of enrolling as a subject at the NIH Clinical Center and you have any 
questions or concerns, please contact the Office of Human Subjects Research Protections 
(OHSRP) at 301-402-3444 and/ or the Patient Representative if you are thinking of enrolling as 
a subject at the NIH Clinical Center on 301-496-2626. If you are at a NIH site outside the Clinical 
Center then please contact local site leadership.