Immunologic Efficacy of Heplisav B Vaccine in Patients Undergoing Treatment With Immunosuppressive Medications
Phase: PHASE1
Conditions: Hepatitis B
Sponsor: Baylor Research Institute

1 
 
CLINICAL PROTOCOL  
IND  No. 
18850 
Title: 
Immunologic Efficacy of Heplisav B Vaccine in Patients Undergoing 
Treatment with Immunosuppressive Medications   
 
 
Version 3: 
July 17, 2019 
 
 
 
 
Sponsor:        
Baylor Scott and White Research Institute 
 
Clinical Development Approval: 
 
 
 
Robert Perrillo, MD FAASLD 
Senior investigator 
Hepatology Division 
Baylor University Medical Center 
Adjunct Professor, UTSW 
Dallas, TX 
 
 
 
 
 
 
 
 
 
 
July 17, 2019 
Name 
Title, Department 
 
Date 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of Baylor Scott and White and Dynavax 
Technologies.   Acceptance of this document constitutes agreement by the recipient that no previously unpublished 
information contained herein will be published or disclosed without the prior written approval of Baylor University 
in conjunction with Dynavax Technologies with the exception that this document may be disclosed to study 
personnel under your supervision who need to know the contents for conducting the study and appropriate 
Institutional Review Boards (IRBs)/Ethics Committees (EC) under the condition that the personnel have agreed to 
keep this information confidential. The foregoing shall not apply to disclosure required by governmental 
regulations or laws, however, Baylor Scott and White Medical Center shall be promptly notified of any such 
disclosure. 
 

2 
 
INVESTIGATOR AGREEMENT PAGE 
Company Name 
Protocol Version No. 3 
July 17, 2019 
I will provide copies of the protocol, any subsequent protocol amendments and access to all 
information provided by the Sponsor to the study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational drug 
and the study protocol. 
I agree to conduct this clinical trial according to the attached protocol, except when mutually 
agreed to in writing. I also agree to conduct this study in compliance with all federal, state and 
local regulations, as well as with the requirements of the appropriate Institutional Review 
Board and any other institutional requirements. 
 
 
 
 
 
 
 
July 17, 2019 
Principal Investigator 
 
Date 
Printed Name: 
Robert Perrillo 
Institution: 
Baylor University Medical Center 
Address 
Sammons Cancer Center Building, Suite 950 
3410 Worth Street, Dallas, TX 75246 

3 
 
1.0 
TABLE OF CONTENTS 
 
 
IMMUNOLOGIC EFFICACY OF HEPLISAV-B DURING ISDT  
PAGES  
 
 
 
 
5-6 
 
STUDY SYNOPSIS (2.0) 
7 
 
LIST OF ABBREVIATIONS (3.0) 
8-12 
 
BACKGROUND (4.0) 
 
 
Potential Clinical Utility of a More Immunogenic HBV Vaccine 
1. Hepatitis B reactivation  
2. De novo hepatitis B after liver transplantation  
3. Prevention of recurrent hepatitis B after liver transplantation 
-Rationale/significance of proposed study in selected patient groups  
 receiving immunosuppressive drug therapy 
12 
 
Investigational agent (4.1) 
13 
 
Preclinical data (4.2) 
13-14  
Risks/Benefits of Study (4.3) 
14 
 
Dose Rationale (4.4) 
14 
 
Trial Conduct (4.5) 
14 
 
Population (4.6) 
15 
 
Schedule of Events (4.7) 
15 
 
TRIAL OBJECTIVES (5.0) 
16-17  
TRIAL DESIGN (6.0)   
 
 
Primary Study Endpoints/Secondary Endpoints (6.1) 
 
 
Study Design/Type (6.2) 
Randomization (6.3) 
Maintenance (6.4) 
Trial Treatment (6.5) 
 
 
Duration (6.6) 
 
 
Premature Drug Discontinuation (6.7) 
 
 
Product Accountability (6.8) 
 
 
Data Identification (6.9) 
17-19  
SELECTION AND WITHDRAWAL OF SUBJECTS (7.0) 
 
 
Inclusion Criteria (7.1) 
 
 
Exclusion Criteria (7.2) 
 
 
Vaccine Withdrawal (7.3) 
                          Clinical Hold on Further Group Enrollment (7.4) 
                          Subject Withdrawal (7.5) 
20 
 
TREATMENT OF SUBJECTS (8.0) 
      
 
Medication (8.1) 

4 
 
Timing of Vaccine Initiation in Relation to Time of Initiation of Immune    
Suppressive Medication (8.2) 
 
        
Monitoring for Subject Compliance (8.3) 
20-21  
ASSESSMENT OF EFFICACY (9.0) 
 
 
Efficacy parameters (9.1) 
 
 
Method and Timing (9.2) 
21-23  
ASSESSMENT OF SAFETY (10.0) 
 
 
Safety Endpoints (10.1) 
 
 
Further Safety Considerations (10.2)   
Pregnancy Assessments (10.3) 
 
 
Method and Timing (10.4) 
 
 
Adverse Event Reporting (10.5) 
 
 
Definitions (10.6) 
 
 
Adverse Event Follow-up (10.7) 
24-25  
STATISTICAL PLAN (11.0) 
 
 
Statistical Methods (11.1) 
 
 
Subject Population for Analysis (11.2) 
 
 
Significance (11.3) 
 
 
Termination Criteria (11.4) 
 
 
Accountability Procedure (11.5) 
 
 
Deviation Reporting (11.6) 
25 
 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION (12.0) 
25 
 
QUALITY CONTROL AND QUALITY ASSURANCE (13.0) 
25 
 
ETHICAL CONSIDERATIONS (14.0) 
25 
 
DATA HANDLING AND RECORD KEEPING (15.0) 
25 
 
PUBLICATION PLAN (16.0) 
26-27  
LITERATURE (17.0) 
28 
 
Figure 1: Study Flow Chart 
29 
 
Table 1: Study Participation Table 
30-31  
Appendix 1   Adverse Event Data Capture Form 
32-34  
Appendix 2   Patient Related Outcome Assessments 
35                      Appendix 3  Quick View Table for Subject Withdrawal, Vaccine Withdrawal and  
                          Study Termination 
36-38  
Appendix 4  List of Potentially Immune-Mediated Medical Conditions 
 
                            
 
 

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2.0      STUDY SYNOPSIS 
 
 
 
 
 
 
  
Title of Study: 
Immunologic Efficacy of Heplisav B Vaccine in Patients Undergoing 
Treatment with Immunosuppressive Medications   
Sponsor: 
Baylor Scott and White Research Institute 
Phase of Development: 
Phase 1 (Medically immunosuppressed subjects) 
Objectives: 
Preliminary trial of Heplisav-B vaccine in medically 
immunosuppressed patients with co-primary objectives of 
vaccine immunogenicity and patient safety  
Study Design: 
This is an open label exploratory study of the immunologic efficacy 
and safety of an FDA licensed HBV vaccine that contains HsAg-
1018 adjuvant which has TLR 9 agonist properties (Heplisav-B).   
It will be used in patients treated with long term 
immunosuppressive drug therapy.  The patients will be given two 
doses of Heplisav-B, the first delivered at the baseline visit and 
the second at week 4.  Anti-HBs titers will be determined at 
baseline and at weeks 4, 8, 12, 24 and 60.  The proportion of 
those with seroprotective anti-HBs levels and the geometric 
mean titers of anti-HBs at each time interval will be compared 
with those observed in phase III trials of immunocompetent 
individuals receiving the same dosing schedule.   Individuals who 
fail to demonstrate protective levels of anti-HBs at week 8 will be 
given a third booster dose at week 12.  
Study Population: 
A total of 18 patients will be entered into the study including 3 
evenly sized groups of 6 as follows: Group A patients are taking 
tumor necrosis factor alpha or interleukin inhibitor therapy for 
underlying chronic inflammatory disorders; Group B patients are 
taking chemotherapy for solid organ malignancy; and Group C 
patients are either recipients of livers from anti-HBc positive 
donors or individuals transplanted for chronic HBV infection 
without recurrent hepatitis B at the time of enrollment.    
Serologic Characteristics Per Group: All patients in Groups A and 
B must be HBsAg negative but anti-HBc positive to qualify 
indicating that they have serologic evidence for resolved hepatitis 
B.    Those with low titer (<20 mIU) antibody will not be specifically 
excluded permitting observation of a possible anamnestic anti-
HBs response.  Patients in Group C will have either a remote 
history of liver transplant for HBV or receipt of an anti-HBc 
positive donor liver.  Eligibility requires HBsAg to be negative 
w/wo anti-HBc reactivity. 

6 
 
Safety Evaluation: 
Yes 
Efficacy Evaluation: 
Yes 
Schedule of Events: 
In the absence of appropriate documentation, all patients will 
initially be screened for HBsAg, anti-HBc, and anti-HBs status by 
qualitative testing at a screening visit.  Patients in Group A and B 
found to be anti-HBs positive will be tested for anti-HBs quant 
within one week to confirm final eligibility.   Two doses of 
Heplisav-B will be administered at a baseline visit and 4 weeks 
later.  Anti-HBs levels will be assessed at the baseline visit and 
again at weeks 4, 8, 12, 24 and 60.  All patients who fail to respond 
with seroprotective anti-HBs levels (≥ 10 mIU/mL) at week 8 will 
be given a third dose of vaccine at week 12 and followed until 
week 60.  Liver transplant patients (Group C) will be vaccinated 
and followed in  the same manner as Groups A and B. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

7 
 
3.0     LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase (Serum Glutamic Pyruvic Transaminase) 
AST (SGOT) 
Aspartate aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
IRB 
Institutional Review Board 
µg 
Microgram 
MAAE 
Medically attended adverse event 
mL 
Milliliter 
PE 
Physical examination 
piMMCs 
Potentially immune-mediated medical conditions 
SAE 
Serious Adverse Event 
SGOT (AST) 
Serum Glutamic Oxaloacetic Transaminase 
SGPT (ALT) 
Serum Glutamic Pyruvic Transaminase 
NsCap 
HBsAg negative, anti-HBc positive 
ISDT 
Immunosuppressive drug therapy 
HBV  
Hepatitis B virus 
HBVr 
Hepatitis B virus reactivation 
HBIg  
Hepatitis B immune globulin 
HBsAg-1018 
Vaccine adjuvant for Heplisav-B 
 

8 
 
4.0. BACKGROUND 
Hepatitis B vaccination is recommended for all immunocompromised persons at risk for hepatitis 
B infection.1 However, traditional recombinant HBV vaccines have limited efficacy in this situation 
even when given in higher dosage.2,3  In addition, the relatively cumbersome 3 dose regimen with 
traditional HBV vaccines has been associated with disappointingly low rates of vaccine 
completion.4 
Recently, the Food and Drug Administration has licensed a new HBV vaccine (Heplisav-B®) which 
incorporates HBsAg particles bound to 1018 immunostimulatory sequence which serves as a TLR 
9 agonist.  The incorporation of the HBsAg-1018 adjuvant makes the vaccine considerably more 
immunogenic than traditional HBV vaccines that contain a solid phase alum adjuvant.  In addition, 
Heplisav-B offers the advantage of only requiring two doses given at 0 time and 4 weeks later.    
This vaccine stimulates a directed immune response to hepatitis B surface antigen (HBsAg) 
instead of the multi-pathway, broad immunostimulatory response induced by alum adjuvant.  
Two randomized controlled clinical trials in immunocompetent adults and a third randomized, 
controlled study in patients with chronic kidney failure have shown Heplisav-B to be considerably 
more immunogenic when compared to a traditional recombinant vaccine (Engerix®).5-8 Heplisav-
B given in two doses 4 weeks apart induced significantly higher seroprotection (anti-HBs ≥ than 
10 miU/ml) rates when compared to Engerix given in a 3 dose regimen at 0, 4 weeks and 24 
weeks.   Increased immunogenicity was evident by 8 weeks after the second dose of Heplisav-B.   
Also, geometric mean titers of anti-HBs were significantly greater with Heplisav-B doses starting 
at week 12.   In a randomized, controlled trial in patients with chronic kidney failure, a group that 
demonstrates attenuated responses to traditional vaccine, patients were randomized to 3 
injections of Heplisav-B or to Engerix given in a double dosage at four intervals.   While 
seroprotection rates were only slightly higher in the Heplisav-B group (89% vs 81.9%), geometric 
mean titers of anti-HBs were significantly higher in the Heplisav-B group (587 miU/ml versus 156 
miU/mL) by week 28.  
It is important to note that adverse event profiles did not differ between the vaccines used in 
these studies.5-8  One case of granulomatosis with polyangitis was reported 170 days after the 
second dose in the Heplisav B group but the collective data from these trials demonstrated that 
the vaccine did not induce autoimmune disorders at a higher than expected frequency (Dynavax 
Technologies, data on file)   Moreover, the frequencies and titers of ANA and anti-dsDNA were 
comparable in the two vaccine treatment groups in these studies.   
Potential Clinical Utility of a More Immunogenic HBV Vaccine 
The development of a more immunogenic vaccine that induces rapid protection against HBV has 
particular relevance in situations where timely induction of neutralizing anti-HBs is desirable and 

9 
 
whenever attenuated responses to traditional HBV vaccine may otherwise be anticipated.  Both 
of these issues are relevant in patients who are immunosuppressed due to medication.  This is 
especially relevant in patients with resolved hepatitis B due to long term persistence of the 
genomic template for viral transcription in liver tissue and an inherent risk that hepatitis B viral 
reactivation may occur when immunosuppressed (see 1, below). 
Thus, this protocol is an exploratory trial to assess the safety and effectiveness of Heplisav-B in 
three common clinical situations where patients are medically immunosuppressed: (1) in patients 
given tumor necrosis factor (TNF) or interleukin inhibitor therapy for chronic inflammatory 
disorders; (2) in patients placed on cancer chemotherapy for solid organ malignancy; and (3) in 
patients who are immunosuppressed after liver transplantation either done for a) chronic 
hepatitis B or for b) the same or other indications during which they receive a liver from an anti-
HBc positive donor. 
1. Hepatitis B reactivation.  Hepatitis B reactivation (HBVr) is defined by a sudden increase in HBV 
DNA and ALT/AST level, and is most frequently caused by immunosuppressive drug therapy 
(ISDT) where it is thought to occur because of a loss of immunologic control over HBV replication.  
Many cases of HBVr are subclinical or mild, but it also can be severe enough to cause liver failure.  
Hepatitis B reactivation during ISDT not only occurs in HBsAg-positive patients but also in those 
who are HBsAg negative yet anti-HBc positive.9   This is a serologic profile that is typically 
observed in cases of resolved hepatitis B.  As many as 60 to 80% of anti-HBc positive persons 
have detectable anti-HBs and this has been associated with a reduced rate of HBVr in several 
observational studies of HBsAg negative, anti-HBc patients treated with ISDT.9   
Current management recommendations to reduce the risk of HBVr in HBsAg negative/anti-HBc 
positive patients during ISDT vary depending on the immunologic potency of the drug(s) used 
and the serologic profile of the patient.   It is currently recommended that persons with resolved 
hepatitis B  who are taking tumor necrosis factor or interleukin inhibitor either receive 
prophylactic antiviral therapy or close monitoring of aminotransferase and HBV DNA levels.  This 
dichotomous recommendation Is based on data collected from large observational studies 
showing a relatively low rate (0 to 5%) of HBVr when anti-HBc positive patients take these biologic 
agents without anti-HBV prophylaxis.12   In contrast, anti-HBc positive patients undergoing cancer 
chemotherapy are considerably more likely to reactivate (10 to 20%), and standard 
recommendations call for antiviral prophylaxis during chemotherapy and for as long as 12 
months after discontinuation if rituximab or other B cell depleting agents are used.10,11   
The protective role of neutralizing anti-HBs has not been well defined in patients receiving ISDT.  
However, there are indications that high titers of anti-HBs may be helpful in preventing 
reactivation during cancer chemotherapy.  In one observational study it was found that patients 
with non Hodgkin’s lymphoma who had anti-HBs titers >100 mIU failed to demonstrate HBV 

10 
 
reactivation during CHOP combined with B cell depletion therapy whereas those with lower anti-
HBs titers frequently did.13   Furthermore, a more recent meta-analysis of 20 studies of resolved 
hepatitis B patients with hematologic malignancy documented that anti-HBs positivity was 
associated with reduced HBVr risk (pooled odds ratio of 0.21) when compared to resolved cases 
who lacked anti-HBs.  Unfortunately, qualitative rather than quantitative assessments of anti-
HBs have been used in the vast majority of studies which makes it difficult to assess the 
relationship between anti-HBs concentration and protection against HBV reactivation or the 
protective benefit of periodic booster dosing in the transplant setting .14  (See section 2, below). 
2. De novo hepatitis B after liver transplantation.  The use of cadaveric (or living)  donors  
harvested from individuals found to be negative for HBsAg but positive for anti-HBc has become 
a standard practice due to the urgent need for an expanded donor pool.    De novo HBV infection 
in HBV susceptible recipients of these organs occurs in more than of 50% of cases if not given 
antiviral prophylaxis.15   Such patients are generally treated with long-term antiviral prophylaxis 
which is sometimes combined with peri-operative hepatitis B immune globulin.15,16   The 
concentration of anti-HBs that would be partially protective against de novo hepatitis B in this 
setting has not been defined.  However, recent studies using multiple booster doses of HBV 
vaccine have reported successful termination of HBIg and long term antiviral prophylaxis in 
recipients of anti-HBc-positive livers provided they develop sustained anti-HBs titers greater than 
100 mIU/ml.17     
3. Prevention of recurrent hepatitis B after liver transplantation.  Patients transplanted for 
chronic HBV infection are treated with hepatitis B immune globulin (HBIg) for variable periods 
along with a third generation nucleoside analogue with anti-HBV potency to prevent recurrence 
of HBsAg, HBV DNA, and overt hepatitis B.  The nucleoside analogue therapy must be given 
indefinitely.  HBIg contains high titers of anti-HBs and serum anti-HBs concentrations of 100 
miU/ml or greater were shown to be partially effective in the prevention of recurrent hepatitis B 
before nucleoside analogue therapy was developed.  Attempts to vaccinate such patients in 
preparation for transplantation often fail due to the immune suppression effect of end stage liver 
disease, the requirement for a second or third dose in patients with short waiting times, and 
because transplant recipients are immunosuppressed after surgery with tacrolimus, 
mycophenolate, rapamycin or other anti-rejection therapies.   
Why is this Study Being Done?   Rationale/Significance of Proposed Study In Selected Patient 
Groups Receiving Immunosuppressive Drug Therapy 
Chronic ISDT results in an attenuated antibody response to new and repeat antigen exposure.   
B cell depletion therapy further results in rapid attrition of pre-existing anti-HBs.9   Weakened 
antibody responses to HBV vaccine during ISDT can be important factors when trying to protect 
a patient with resolved hepatitis B from HBVr or in preventing recurrent or de novo hepatitis B 

11 
 
after liver transplantation.  The proposed study is the first known to the investigator in which 
patients are administered HBsAg-1018 containing vaccine immediately before or during ISDT.  It 
is also the first to use this vaccine in persons with serologic evidence for resolved hepatitis B.  
However, vaccinating anti-HBc positive patients who are taking ISDT can be justified by 
previously published studies.   First, as many as 40% of patients with the serologic profile of 
resolved hepatitis have seroprotective levels of anti-HBs due to the fact that exposure to HBV 
may have occurred remotely in the past.  Second, an anamnestic boost in anti-HBs has been 
reported in a substantial minority of immunocompetent anti-HBc positive individuals after a 
single dose of traditional HBV vaccine.18  In consideration of these findings, the current study 
will not exclude anti-HBc positive patients who have weak anti-HBs levels (<20 mIU/ml).   Third, 
the medical literature supports a lower frequency of HBVr in anti-HBs positive individuals over a 
broad range of ISDTs.9,14  Fourth, some studies using quantitative anti-HBs assays have reported 
greater protection against HBVr in persons having a high anti-HBs titer compared to individuals 
with low titer or no detectable anti-HBs.13 
Heplisav-B vaccine has been shown to more quickly result in seroprotective levels of anti-HBs 
and higher geometric mean titers than traditional HBV vaccine in immunocompetent recipients 
including the elderly, persons with diabetes mellitus, and patients with chronic kidney failure. 
These are important groups to have studied because It can be anticipated that some recipients 
may have had age or disease-related subclinical immune deficiency.  
 
Use of Heplisav-B in patients with prior hepatitis B (Groups A and B). 
Prevention of HBVr. 
It is the opinion of the investigator that the immunologic efficacy of Heplisav-B in patients with 
resolved hepatitis B is an extremely important clinical area to study because it offers the potential 
to change current management recommendations for the prevention of HBVr during ISDT.19  This 
is very relevant in (a) persons undergoing immunosuppressive treatment for chronic 
inflammatory disorders which are considered to be autoimmune in nature and b) individuals who 
are undergoing treatment with cancer chemotherapy where the risk of HBVr is particularly high 
due to the higher level of immune suppression.  Further insight into the clinical relevance of a 
more immunogenic vaccine to prevent HBVr during ISDT in these two groups is provided below. 
1. Group A (chronic inflammatory disorders). A rapid and highly effective response to 
vaccination might supplant any concern about the need for antiviral therapy in patients treated 
with tumor necrosis factor or interleukin inhibitor therapy for chronic rheumatic, intestinal or 
dermatologic disorders.   Taken together this is a large patient population with current 
estimates of use for TNF inhibitor therapy being 3 million people in the United States.   Major 
quality of life improvement may occur using TNF inhibitor therapy but this often requires the 

12 
 
use of long-term ISDT.  This indefinite exposure to ISDT can put the patient at prolonged risk of 
HBVr.  At the current time routine antiviral prophylaxis is not recommended in this setting 
because HBVr rates are quite variable in the literature and anti-HBV prophylaxis would have to 
be given indefinitely. 19 
2. Group B (cancer chemotherapy).  The rapid induction of high titer anti-HBs following 
vaccination with Heplisav-B either delivered prior to or soon after starting chemotherapy could 
prove helpful in preventing HBVr in resolved hepatitis B patients treated for solid organ 
malignancy.13,14  Such patients have the highest risk for HBVr when compared with the other 
groups (A and C) proposed in this study.  Reactivation frequency varies from 10 to 20% for 
anthracycline based chemotherapy and 20 to 50% for lymphoma therapy that includes rituximab.   
The demonstration of high titers of anti-HBs with Heplisav-B during cancer chemotherapy would 
be a significant breakthrough because anti-HBs levels ≥ 100 mIU/ml have been shown to be 
associated with significantly lower rates of HBVr during rituximab treatment.9,13 
3. Group C: susceptible recipients of anti-HBc-positive livers.  Until recently, HBV susceptible 
recipients of cadaveric liver donations were routinely vaccinated for hepatitis B at Baylor Scott 
and White and other programs throughout the United States.   In part, this was done because of 
the possibility that a high MELD score recipient might acquire an organ from an anti-HBc positive 
donor.   Vaccination completion was often not completed, however, prior to transplant and the 
use of HBIg and long term antiviral prophylaxis ultimately made de novo hepatitis B a treatable 
condition.  To prevent de novo infection, however, requires indefinite antiviral prophylaxis, 
possibly life long.  Should Heplisav-B induce high anti-HBs titers in these immune suppressed 
patients, it could limit antiviral drug exposure by deploying a periodic booster dose strategy.17 
Group C: patients transplanted for chronic hepatitis B.    These patients currently are treated 
with short duration HBIg and life-long antiviral prophylaxis.   All continue to take anti-rejection 
therapy indefinitely.   Hepatitis B vaccine is not used in these patients prior to transplant.  
Frequent double dose inoculations of HBV vaccine post transplant have been given in clinical 
trials in an attempt to eliminate antiviral therapy in highly selected patient groups.  However,  
most  studies have failed to reliably induce protective anti-HBs titers with a few notable 
exceptions.20   Patients with successful prophylaxis remain HBsAg negative, anti-HBc positive, and 
HBV DNA negative (similar to resolved cases of hepatitis B), but anti-HBs is almost always non 
detectable after liver transplantation for hepatitis B.  This suggests that patients without 
recurrent hepatitis B might be at continued risk for recurrence if antiviral therapy were to be 
withdrawn.  It would be instructive to see if high levels (>100 mIU/ml) of protective anti-HBs 
could reliably be induced in these patients using a routine booster dose strategy and if this could 
lessen the requirement for life long antiviral treatment.    
4.1. Investigational Agent  
Heplisav B 

13 
 
4.2. Preclinical Data 
Included in Investigator’s Brochure [Feb, 2019, revision 16]. 
 
4.3. Risk/Benefits of Study 
The risk benefit ratio for this study is considered to be low to moderate only.  There are several 
reasons for this presumed level of risk.  Acute myocardial infarction was reported in 19 patients, 
as compared with 3 patients taking the traditional vaccine.  Additional evidence, however,  
considering the presence of risk factors does not support a clear cause and effect relationship.  
The risk of immune mediated events with Heplisav B appears to be very low.  The results of 
multiple phase III studies which included more than 5,000 non-infected immune competent 
patients have shown that it is not associated with a disproportionate amount of immune events, 
including the origination of what are commonly considered to be autoimmune disorders or 
potentially immune-mediate medical conditions (piMMCs).  In those few situations where 
immune mediated disorders appeared to arise after vaccination, an outside panel of experts did 
not attribute them to vaccination.  Also, Heplisav-B vaccination was not associated with an 
unusual frequency of ANA or anti-ds-DNA antibodies.   Certain relatively common immunologic 
disorders such as juvenile diabetes, hypo or hyperthyroidism, and rheumatoid arthritis were not 
more common when compared with those given traditional vaccine.   One reason for this may be 
that the 1018-HBsAg adjuvant is not anticipated to promote innate immunity to host tissue 
proteins because TLR activation is primarily a defense mechanism against infecting microbes 
rather than host tissue antigens.   Also, it has been proposed that the 1018 adjuvant stimulates 
a directed immune response to HBsAg instead of the multi-pathway, broad immunostimulatory 
response induced by alum adjuvant [Investigator’s Brochure, February 2019, revision 16].   
Patients receiving chemotherapy are not anticipated to have an unusual frequency of adverse 
effects to the vaccine.  In this study it is anticipated that all HBsAg negative, anti-HBc positive 
cancer patients will be placed on the standard of care antiviral prophylaxis which greatly 
minimizes the chances for HBV reactivation (HBVr).  Thus, HBVr is very unlikely to interrupt the 
study.   Should the vaccine prove to be highly immunogenic in cancer patients, rapid induction of 
seroprotective anti-HBs could further reduce the risk of HBVr.  
The risk for acute cellular rejection of the liver should be minimal because this requires an 
orchestrated T lymphocyte response to alloantigens expressed on the surface of liver cells.  
Moreover, transplanted patients will have had remote transplantation (> 3 years) and are much 
less likely to undergo acute cellular rejection.  Should the vaccine be highly immunogenic in these 
patients, it might eliminate the need for the very costly hepatitis B immune globulin (HBIg) 
immunoprophylaxis and ultimately might decrease the need for life-long antiviral prophylaxis 
after transplantation for hepatitis B.  As with anti-HBc-positive cancer patients, all patients 
transplanted for hepatitis B and those given an anti-HBc positive liver organ will receive the 
standard of care antiviral prophylaxis to recurrent hepatitis B and de novo infection, respectively. 

14 
 
A third dose of the vaccine is unlikely to result in adverse events.   This has been given to several 
hundred hemodialysis patients in phase III studies and there were no disproportionate adverse 
event outcomes when compared to historical cohorts who were administered four doses of 
Engerix  [Investigator’s Brochure, Feb 2019, version 16].  
Potential benefit. If seroprotective levels of anti-HBs are demonstrated in medically 
immunosuppressed individuals, the potential benefit to society could be very large.   For example, 
there are more than 3 million people in the US who are taking long term biologic 
immunosuppressive therapy for chronic inflammatory disorders and with a population 
prevalence for anti-HBc alone of 5 percent, this could reduce the need to depend on potentially 
life-long antiviral prophylaxis in 100,000 to 150,000 cases.   This same figure of 5% prevalence of 
anti-HBc in the general population can be applied to individuals undergoing chemotherapy for 
malignancy (estimated incidence of 68,760 anti-HBc positive cases undergo chemotherapy in the 
United States each year). 21  Long term antiviral prophylaxis may be associated with unanticipated 
adverse events and is economically costly.  Taken together, approximately 5 to 8% of all adults 
transplanted require antiviral therapy either to prevent recurrent hepatitis B or to prevent de 
novo infection. 
4.4. Dose Rationale 
The standard 0.5 ml dose of Heplisav-B will be delivered at baseline (0 time) and 4 weeks later.   
Immunologic efficacy will be compared to historical cohorts in phase III trials of the vaccine.   In 
the event that a seroprotective level of anti-HBs (< 10 mIU/ml) does not develop by week 8, a 
booster dose of Heplisav-B vaccine will be given at week 12.    
4.5. Trial Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board, and according to Good Clinical Practice standards.  No deviation from the protocol 
will be implemented without the prior review and approval of the IRB except where it may be 
necessary to eliminate an immediate hazard to a research subject.  In such case, the deviation 
will be reported to the IRB as soon as possible. 
4.6. Population 
This is an exploratory observational study of 18 individuals divided into 3 equal sized groups of 
six patients (Groups A, B, and C).  Groups A (chronic inflammatory disorders) and B (patients on 
cancer chemotherapy for solid organ malignancy) will be limited to patients with resolved 
hepatitis B as defined by the absence of HBsAg and the presence of anti-HBc in serum.   Patients 
who have low titer anti-HBs at baseline (< 20 mIU) will not be excluded.  Group C (liver transplant) 
patients will be HBsAg negative and anti-HBc positive after transplantation for hepatitis B or 
seronegative for all HBV markers if a recipient of an anti-HBc positive donor organ. 
 

15 
 
4.7. Schedule of Events 
The schedule of events can be seen in Table 1.   Patients will be seen and consented at a screening 
visit to determine eligibility.   It is anticipated that most if not all of the serologic data needed to 
qualify the patient will be available by review of electronic records at the screening visit.   If not, 
one or more of the serologic HBV markers will be tested at screening.  The serologic studies for 
HBV must have been done within the past year.   Turnaround times are less than 5 days and so 
there should be no lagging data needed at the time the patients receive their first dose of vaccine 
28-30 days later.   There will also be a 28-30 day window between the first vaccine inoculation 
visit and the second vaccine inoculation visit.  The 12, 24, and week 60 visits will have a one week 
± window. 
In the event of an intercurrent acute illness that either places the patient at added risk or makes 
vaccine adverse event relatedness difficult to interpret, every effort will be made to bring the 
patient back when the illness is resolved and preferably no longer than one week of the initially 
specified time. 
  
Heplisav-B vaccine will be delivered at the baseline/enrollment visit (visit # 2 considered to be 
day 0) and again 4 weeks later.   In the unlikely event that anti-HBs titer is ≥ 300 mIU/ml after a 
single dose of vaccine, patients will not be given a second dose.    All individuals who do not have 
protective levels of anti-HBs (> 10 mIU/ml) after two doses at week 8 will be given a third identical 
dose of vaccine at the week 12 visit.    
 
Adverse events (e.g, localized skin reactions, fever) that occur soon after vaccination will be 
assessed by weekly telephone assessments and patients will be asked to record changes in 
underlying disease activity on a Patient Related Outcome Measurement form.  These will be 
distributed at the enrollment visit and subsequent visits.   They will initially be completed by the 
patient and completed as needed by the investigator and coordinators at all study visits.    Data 
on all AEs will be recorded on an Adverse Event Data Capture form (Appendix 1).   These will be 
filled out by the study coordinator in conjunction with the investigator at each visit.  
 
 
5.0. TRIAL OBJECTIVES 
There are two co- primary objectives: (1.) To assess immunogenicity of Heplisav-B and (2.) to 
assess safety in medically immunosuppressed patients.   The former will require assessing the 
proportion of patients who respond with seroprotective levels (>10 mIU/ml) of anti-HBs and who 
maintain this response until study completion at week 60.  The second objective will require 
follow up of all patients for one year after the last dose of vaccine during which time all adverse 
events will be collected.  

16 
 
6.0. TRIAL DESIGN 
The study is non blinded and exploratory only.    
The clinical algorithm describing the study is depicted in Figure 1.   Actions taken at clinic visits 
is depicted in Table 1. 
6.1. Primary Study Endpoints/Secondary Endpoints 
Primary endpoints: determination of (1) adequate safety and (2) immunologic efficacy of 
Heplisav-B in patients taking ISDT. Immunologic efficacy will be determined by the seroprotection 
rate (SPR) or percentage of patients who have anti-HBs titers greater than 10 mIU/ml at weeks 
24 and 60.   Secondary endpoints include (1) determination of the percentage of patients with 
anti-HBs titers ≥ 100 mIU/ml at weeks 24 and 60.  Both (1) and (2) as well as geometric mean titer 
of anti-HBs at all study visit intervals will be will be compared to those observed with historical 
immune competent cohorts who received identical dosing with Heplisav-B.  An additional 
secondary endpoint will to determine the proportion of patients on ISDT who require a third dose 
of vaccine to induce seroprotective level of anti-HBs.  
6.2. Study Design/Type 
This is an open label study of 18 patients taking long term immunosuppressive drug therapy. 
6.3. Randomization—Not applicable 
6.4. Maintenance – Not applicable 
6.5. Trial Treatment 
See Study Synopsis (2.0) and Figure 1 
6.6. Duration 
The protocol includes a 52 week observation period after two doses of vaccine. 
6.7. Premature Drug Discontinuation 
Further dosing of Heplisav-B will be withheld in the following situations: 
1. For all groups: A grade 3 AE or SAE that is considered to be possibly or definitely related 
to Heplisav-B.    
2. For Group A patients:  A significant clinical worsening of their inflammatory disorder or 
development of a new onset pIMMC after one or two doses of vaccine regardless of 
relatedness. 

17 
 
3. If the patient requests not to continue with dosing or if is the opinion of the investigator 
that further dosing should be withheld.  
4. If the patient develops transplant rejection that is possibly or definitely vaccine related. 
Indications for participant withdrawal in are further outlined in sections 7.3. 
6.8. Product Accountability 
All vaccine will be kept in a locked refrigerator to which only the principal investigator and clinical 
coordinator have access.  This refrigerator is immediately proximate to the clinic where patients 
will be seen.  A log of doses dispensed and those remaining will be kept for each patient by the 
study coordinator and will be made available to the principal investigator and sponsor upon 
request.  
6.9. Data Identification 
CRFs will include:  (a) patient age, sex, (b) Group (c) baseline serologic status, (d) results of anti-
HBs quantification, CRP, and AST and ALT levels, (e) immunosuppressant medications, and (f) 
any potential short or long term adverse events with plan of management.   Items (d), (e), and 
(f) will be recorded for each interval. 
7.0. SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. Inclusion Criteria 
1.) Age 18 or older and agree to adhere to the requirements of the study 
2.) Must be willing to provide informed consent 
3.) Serologic profile consistent with resolved hepatitis B (HBsAg negative but anti-HBc 
positive*)  
4.) Recipient of anti-HBc positive liver (Group C).  
5.) Chronic inflammatory disease requiring TNF or interleukin inhibitor therapy (Group A) 
6.) Solid organ malignancy that requires systemic cancer chemotherapy 
7.) Post liver transplant for chronic HBV infection (Group C). 
8.) Recipient of immunosuppressive drug medication as described above 
 
7.2. Exclusion Criteria 
1.) HBsAg positivity 
2.) Anti-HBs titer >  20 mIU/mL at baseline 
3.) HIV infection** 
4.) HCV infection** 
5.) Prior hepatitis B vaccination  
6.) Receipt of hepatitis B immune globulin during the past 4 months 
7.) Hematologic malignancy 

18 
 
8.) Hepatocellular carcinoma  
9.) Active alcohol use > 20 grams daily 
10.) Unstable underlying inflammatory disorder 
11.) Pregnancy or breast feeding 
12.) History of severe depression or other severe psychiatric disorder 
13.) Receipt of liver allograft < 3 years earlier 
14.) Transplant rejection within the past year 
15) Individuals having unstable or poorly responsive inflammatory disorders 
16) All persons who are judged by the investigator to have an unreasonable risk of 
complications  
17) Anticipated life expectancy less than one year 
 
Footnotes to Inclusion/Exclusion Criteria *There must be evidence of anti-HBc positivity at the 
screening visit and if so, documentation that this is chronic in nature will be obtained from a 
review of the electronic record (for example, history of past exposure, past serology 
documentations).   If documentation is lacking, however, then an IgM anti-HBc test will be at 
done at the screening visit to confirm that the patient has not recently acquired hepatitis B. 
 
**Serologic testing for HCV and HIV must be within 4 months of potential eligibility.  If this is 
not the case, the testing will be repeated at the screening visit.  
_____________________________________________________________________________ 
 
7.3  Vaccine Withdrawal  
Need for vaccine withdrawal and subject withdrawal (see Section 7.4 below)  will be assessed by 
application of the grading criteria for adverse events as described in the Common Terminology 
Criteria for Adverse Events as published by the US Department of Health and Human 
Services/National Institutes of Health, and the National Cancer Institute (version 5.0, November 
2017).  A three point scale will be used to judge relatedness: unrelated, possibly related, and 
definitely related.  Possibly related will be defined as any AE in which there is a reasonable time 
sequence to vaccination but the AE could be explained by another potential cause such as other 
drugs or events, patient noncompliance with immune suppression medication, or recent switch 
in immune suppression medication.   Definitely related will require a plausible time relationship 
to vaccine administration that cannot be explainable by other events and condition as described 
above.  Also, it will be further considered to be definitely related if there is a response to 
withholding further vaccination.  
1. Any patient in Group A who is deemed to have significant clinical worsening of their 
inflammatory disorder or develop a new onset pIMMC after one or two doses of vaccine will be 
withdrawn from further dosing regardless of relatedness to the vaccine.  However, the subject 
will be followed until week 60 to collect additional safety data.  During this time, additional 
immunogenicity data may be obtained if the patient had received at least two doses of vaccine 

19 
 
before clinical worsening became apparent and if seroprotective levels were observed when last 
tested. 
2. Regardless of which group a patient belongs to, any subject who has a Grade 3 AE or SAE will 
not receive further vaccination if the adverse event is considered to be possibly or definitely 
related to Heplisav-B.   Each of these patients will continue to be seen at the visits specified in 
the protocol until the end of the study (week 60) so that additional safety data may be collected. 
Additional immunogenicity data may be obtained if the patient had received two doses of vaccine 
before the AE became apparent and if seroprotective levels of anti-HBs were evident when last 
tested. 
3. Transplant rejection suspected by unexplainable increase in liver enzymes and proven by liver 
biopsy will be considered as a Grade 3 AE that requires medical intervention (MAAE).  Each 
patient with rejection will be withdrawn from further vaccination if the rejection is considered to 
be possibly or definitely related to the vaccine.     Such patients will be followed until the end of 
the study (week 60) so that additional safety data may be collected.  Additional immunogenicity 
data may be obtained if the patient had received at least two doses of vaccine before allograft 
rejection became apparent and if seroprotective levels were evident when last tested. 
7.4 Clinical Hold on Further Group Enrollment 
1. If at any time a Grade 3 AE or SAE develops that is considered to be definitely related to 
vaccination, then an immediate hold on further enrollment will be placed on the group the 
patient belongs to.  Also, neither the affected individual nor other participants in that group will 
be given further vaccine inoculations.  This applies to all groups.   
2. If transplant rejection develops that is considered to be definitely related to vaccination, this 
will be considered as an SAE that is medically attended (MAAE) and a clinical hold on further 
enrollment will be enacted for the group (C) the patient belongs to. In addition, no further 
vaccination will be given to the affected individual. 
3. Should 2 patients in any group have a grade 3 AE or SAE considered to be possibly related to 
vaccine, then an immediate hold on both further enrollment and repeat inoculations in that 
group will be enacted.  
7.5. Subject Withdrawal  
1. Patients with a Grade 4 adverse event that is possibly or definitely related will immediately be 
withdrawn from the study and followed clinically until resolution of the event occurs.  Every effort 
will be made to have the patient continue with the study visits to collect additional safety data 
up to 52 weeks after the last dose of vaccine. 
2. Patients will be withdrawn from the study if (a) it is the opinion of the investigator that further 
dosing or follow up should be withheld because of poor study compliance or (b) if the patient 

20 
 
wishes to end participation.  Patients who are excluded from further vaccine for reasons of safety 
will continue to meet study visit requirements to obtain additional safety data. 
8.0. TREATMENT OF SUBJECTS 
Patients will be given 0.5 ml of Heplisav-B in the clinic office on the 8th floor of the Sammons 
Cancer Center by skilled nursing staff.   It will be delivered by IM injection in the deltoid region. 
8.1. Medication 
The patient will continue to take all prescription drugs and may be on prophylactic nucleoside 
analogue therapy for HBV infection. 
8.2 Timing of Vaccine Initiation in Relation to Time of Initiation of Immune Suppressive 
Medication.   
Patients in Group A will be taking ISDT when seen at the screening visit. They must have stable 
underlying disease to be eligible for the study.  Provided they are eligible, the first vaccine 
inoculation will be 4 weeks after screening.   Patients with malignancy (Group B) will either be 
given vaccination prior to chemotherapy (depending on the planned schedule for initiation of 
chemotherapy) or alternatively as shortly as possible after chemotherapy has already begun.  
Patients who have been transplanted (Group C) will be receiving ISDT at the time they are first 
seen.   Those transplanted for hepatitis B will have been taking ISDT for three or more years when 
first vaccinated.  The same post-transplant interval will also apply to recipients of anti-HBc 
positive organs. 
8.3 Monitoring for Subject Compliance 
Patients will be called 24-48 hours before each visit to remind them.  A failure to appear will 
result in a call back by the principal investigator’s coordinator during work hours or at times by 
the principal investigator after work hours.   The patient will be offered a suitable time for 
reappearance within 3 to 5 working days of the initially scheduled visit.  This has proven to be 
successful in the investigator’s previous clinical research studies.   At each visit, the principal 
investigator will provide continuous education about the importance of continued participation 
to minimize noncompliance.  
9.0   ASSESSMENT OF EFFICACY 
9.1   Efficacy Parameters 
• Assessment of proportion of subjects with anti-HBs titers ≥ 10 mIU/ml at each study 
interval. 
• Assessment of percentage of subjects with anti-HBs titers ≥ 100 mIU/ml at each study 
interval. 

21 
 
• Assessment of geometric mean titers for all subjects at each study interval. 
• Assessment of reasonable safety in patients who are medically immunosuppressed 
9.2 Method and Timing 
Assessment of efficacy will require quantitative anti-HBs assessments at each of the visits that 
are specified in Table 1.  This includes week 4,8,12, 24 and 60 week visits.   
10. 0.  ASSESSMENT OF SAFETY 
10.1   Safety Endpoints 
Patient safety is a co-primary objective of the study and the following endpoints will be 
considered and used for future reporting:  
1. Proportion of subjects with unsolicited AEs after inoculation. All adverse events 
including those that are unsolicited will be recorded for a period of 28 days after vaccine 
administration, and at each visit changes in the patient’s state of health will be recorded 
on the Appendix 1 (AE capture form) and as needed on the Appendix 2 form.  To facilitate 
accurate reporting in real time, patients will be questioned at a weekly telephone 
assessment and seen by the principal investigator should this appear warranted.  
Photographic evidence by the patient may be requested between visits for certain AEs. 
2. Proportion of subjects with SAEs.   The study will capture all SAEs (and Grade 3 AEs) 
that occur through one year after the last dose of vaccine.  To facilitate accurate reporting, 
all patients with these events will be seen within 48 to 72 hours and acted upon if needed.  
Follow up will continue until at least 52 weeks after the last dose of vaccination Data will 
be collected on the Appendix 1 safety form and in the case of Group A, Appendix 2 as 
well.  
3. Proportion of subjects with MAAEs.  All MAAEs that occur within one year of the last 
vaccine dose will be captured.   Patients will be handled as in 2 Above. 
4. Proportion of subjects with pIMMCs.  This will be captured for a period of 52 weeks 
after the last dose of vaccine.   Patients will be handled as in 2 and 3 above. Data will be 
reported on both the Appendix 1 and Appendix 2 safety forms. 
5. Proportion needing an increase in immune suppressive medication.  All concomitant 
medications used during the 28 day period following vaccination and those used to treat 
MMAEs or SAEs during a 12 month period after the last dose of vaccine will be recorded. 
Special attention will be given to new or dose adjusted immune suppressive medications 
that are needed to treat adverse events. Data will be captured in Appendix 1 (adverse 
event capture form) under the header “Type Intervention.” 
 

22 
 
10.2 Further Safety Considerations: 
a. C-reactive protein blood testing will be used to assess augmentation of inflammatory disease 
activity in Group A. 
b. Clinical assessment by principal investigator at each study visit.   A focused physical exam will 
be part of the safety data base.  Photographic evidence of underlying disorder in Group A patients 
may be obtained as needed for documentation.  
c. After vaccine administration, patients will be monitored for any immediate or unusual 
injection site reactions.  After leaving the clinic, reactions and AEs will be delineated by weekly 
post inoculation telephone assessment at which point photographic evidence of an underlying 
dermatologic disorder may be requested if deemed necessary. 
10.3 
Pregnancy Assessments.  Potentially child bearing females will have a serum pregnancy 
test at the screening visit.  If positive, they will be ineligible for the study.   A urine pregnancy 
test will be taken prior to vaccination at the visits in which vaccine administration is anticipated, 
including the visit for the week 12 dose.   Vaccine will be withheld if the test is positive at any 
time.   A urine pregnancy test will also be repeated at week 24.   Patients who are found to be 
pregnant after one or more doses have been given will be asked to continue with the per protocol 
visit schedule until week 60 so that additional safety data on pregnancy outcome can be collected 
 
10.4   Method and Timing. 
Each patient will be asked to report adverse events at the time of weekly telephone assessments 
or as needed after each dose of vaccine.   At each study visit, all relevant safety data will be 
captured and kept in a patient binder.  Data will be collected at each visit in regard to safety 
outcomes (AE Capture Form, Appendix 1, and Patient Related Outcome Assessment form, 
Appendix 2). 
 
10.5   Adverse Event Reporting 
All grade 3 or 4 adverse events will be reported simultaneously to the IRB and sponsor within 
one week and 72 hours, respectively.  Should a death occur, notification of the IRB will be 
within 24 -48 hours of receipt of this information.   Events will be conveyed to the IRB and if 
needed to the sponsor in both electronic and hard copy form along with whether or not the 
event was considered to be related to administration of the study drug.  All relevant lab studies 
will be included in the correspondence.  All Grade 1 and 2 AEs (for example, such as those 
related to reactogenicity of the vaccine) will be collected at each visit and reported to the 
sponsor in a yearly report. 
 

23 
 
10.6   Definitions 
An adverse event will be considered as “unexpected” if not included in the Investigator’s Drug 
Brochure (Feb, 2019) or not listed at the specificity or severity observed in the study (Code of 
Federal Regulations Title 21, April 1, 2018).    Definitions of grade severity of adverse events will 
be considered as follows:    
 
Grade 1: mild, asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not needed. 
Grade 2: Moderate; minimal local or noninvasive intervention indicated. 
Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care  
Grade 4: Life threatening; urgent intervention needed 
Grade 5: Death related to AE. 
 
Adverse event: any untoward medical occurrence associated with the use of the vaccine 
 
Serious adverse event: resulting in any of the following: death, potentially life-
threatening, resulting in hospitalization, prolongation of hospitalization, persistent 
incapacity, substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly. 
 
Medically attended adverse event (MAAE): any adverse event that leads to an evaluation 
by a healthcare professional. 
 
Potentially immune mediated medical conditions (pIMMC): A list of these provided by the 
FDA is included in Appendix 4. 
 
Grading of AEs will be according to Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0, November 27, 2017 by the U.S. Department of Health and Human Services/National 
Institute of Health/National Cancer Institute.   
10.7   Adverse Event Follow-up 
Patients with grade 3 or greater AEs and all with SAEs including MAAEs will be seen no later than 
48-72 hours of the time the event occurred.   The patient will be followed by the principal 
investigator and/or referring specialist until resolution has been documented (regardless of 
relatedness consideration).  Additional safety data will be included until at least week 52 after 
the last dose of vaccine.    
 

24 
 
11.0.   STATISTICAL PLAN 
11.1. Statistical Methods 
The study is exploratory and as such descriptive statistics will be used.    Continuous variables 
will be expressed as median values, range of values, and mean ± standard deviation while 
categorical variables will be expressed as number (percentage).   Qualitative and quantitative 
differences between subgroups will be analyzed by Chi-square or Fisher’s Exact tests for 
categorical parameters and Student’s t test or Mann Whitney test for continuous parameters as 
appropriate.    Statistical significance will be taken as p < 0.05. 
11.2. Subject Population(s) for Analysis 
18 patients will be enrolled into 3 equally sized groups of 6.  This is deemed adequate to 
delineate whether further studies are warranted based on safety and efficacy observations 
made.  
11.3. Significance 
See above section 11.1 
11.4. Termination Criteria 
Termination of the study requires an assessment of the grade and number of SAEs, as well as 
their relatedness to the drug.  A three point scale will be used for relatedness: unrelated, possibly 
related, and definitely related.  Both sets of parameters are defined in Section 7.3, page 18.  
Definitely related will be assessed both temporally in relation to vaccine administration and will 
require the absence of other possible explaining factor(s). 
1. The study will be terminated if a Grade 4 AE or death occurs that is considered possibly 
or definitely related to vaccine. 
2. As previously mentioned in Section 7.4, page 19, a  hold will be placed on further 
enrollment into a group if a patient develops a Grade 3 or SAE that is considered to be 
definitely related to vaccine.  If this occurs, the study will be terminated if a second patient 
in a different group subsequently develops a grade 3 AE or SAE that is considered to be 
definitely related.   All patients will continue to be followed for at least 52 weeks after the 
last dose of vaccine to collect additional safety data. 
3. In the absence of a previous clinical hold on enrollment in any group, the study will be 
terminated if at any time two patients, one each from different groups, concurrently 
develop a Grade 3 AE or SAE both of which are considered definitely related.   Such 
patients will continue to be followed for at least 52 weeks after the last dose of vaccine 
to collect additional safety data.   

25 
 
11.5. Accountability Procedure 
All vaccine vials will be accountable in hard copy listings by the clinical coordinator using 
standardized good clinical practice procedures. 
11.6. Deviation Reporting 
Not applicable due to exploratory nature of the study 
12.0. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Periodic audits by vaccine manufacturer will be allowed if this is thought to be needed.  This will 
be formalized in a written agreement between Baylor Scott and White and Dynavax 
Technologies.  
13.0. QUALITY CONTROL AND QUALITY ASSURANCE 
Yearly submission of the findings of the study relevant to patient safety and overall study 
progress is required by the IRB. Annual reports to the FDA, including any pertinent case 
summaries, will be submitted under this IND # 18850 as required by 21CFR312.33.    The data on 
each participant will be recorded in separate patient binders to which only the principal 
investigator and study coordinator have access.  Also, periodic data monitoring will be conducted 
by an independent department through Baylor Scott and White Research Institute. 
14.0. ETHICAL CONSIDERATIONS 
This study will be conducted according to US and international standards of Good Clinical Practice 
(FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all studies. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB.  
The formal consent of a subject, using the IRB-approved consent form, will be obtained before 
that subject is submitted to any study procedure.  This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent. 
15.0. DATA HANDLING AND RECORD KEEPING 
Study binders for each patient kept in locked coordinator office.  Weekly review of all safety data 
by the principal investigator. 
16.0. PUBLICATION PLAN 
This will be specified in written form by Baylor Scott and White Research Institute. 

26 
 
17.0. LITERATURE 
1. Schillie S, Vellozzi C, Reingold A, et al.  MMWR Recomm Rep 2018; 67:1-31. Prevention of hepatitis B 
virus infection in the United States: recommendations of the Advisory Committee on Immunization 
Practices.   
2. Yang A, Guo Z, Ren Q, et al.  Active immunization in patients transplanted for hepatitis B virus 
related liver diseases: A prospective study.  PLOS ONE 2017; Nov, 1-13. 
3. Verma EC.  Vaccination to prevent de novo hepatitis B: are there patients who do not need anviral 
prophylaxis?  Liver Tranpl 2017; 1253-1254.[editorial review]. 
4. Nelson JC, Bittner RCL, Bounds L, et al.  Compliance with multiple-dose vaccine schedules among 
older children, adolescents, and adults: Results from a vaccine safety datalink study.  Am J Pub 
Health 2009; 99:S389-397. 
5. Heyward WL, Kyle M, Blumenau J, et al.  Immunogenicity and safety of an investigational hepatitis B 
vaccine with a toll-like receptor agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B 
vaccine in healthy adults 40-70 years of age.  Vaccine 2013; 31: 5300-5305 
6. Halperin SA, Ward B, Cooper C, et al.  Comparison of safety and immunogenicity of two doses of 
investigational hepatitis B virus surface antigen co-administered with an immunostimulatory 
phophorothioate oligodeoxyribonucleotide and three doses of a licensed hepatitis B vaccine in 
healthy adults 18-55 years of age.  Vaccine 2012; 30:2556-2563.  
7. Jackson S, Lentino J, Kopp J, et al.  Immunogenicity of a two dose investigational hepatitis B vaccine, 
HBsAg 1018, using a toll like receptor 9 agonist adjuvant compared with a licensed hepatitis B 
vaccine in adults.  Vaccine 2018; 36:668-674 
8. Janssen RS, Mangoo-Karim R, Pergola PE, et al.  Immunogenicity and safety of an investigational 
hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a 
licensed hepatitis B vaccine in patients with chroinc kidney disease.  Vaccine 2013; 31: 5306-5313. 
9. Perrillo RP, Gish R, Falck-Ytter YT.  American Gastroenterological Association Institute technical 
review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive 
drug therapy.  Gastroenterology 2015; 148:221-244. 
10. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter YT.  American Gastroenterological  
       Association Institute Guideline on the prevention and treatment of hepatitis B virus reactivation  
       during immunosuppressive drug therapy.  Gastroenterology 2015; 148:215-219. 
11. European Association for the Study of the Liver.  EASL 2017 clinical practice guidelines n the  
management of hepatitis B virus infection.  J Hepatol 2017; 67:370-398. 
12.  Perrillo RP.  Tumor necrosis factor inhibitor therapy for hepatitis B virus-infected individuals: How  
loud is the alarm bell?   Hepatology editorial 2015; 62:16-18.  
13.  Pei SN, Ma MC, Wang MC, et al.  Analysis of hepatitis B virus surface antibody titers in B cell  
        lymphoma patients after rituximab therapy.  Ann Hematol 2012; 91:1007-1012. 
14.  Sonali P, Dickstein A, Saxena A, et al.  Role of surface antibody in hepatitis B reactivation in patients      
        with resolved infection and hematologic malignancy: a meta-analysis.  Hepatology 2017; 66:379-      
        388. 
15.  Ayoub WS, Martin P, Bhamidimarri KR.  Hepatitis B virus infection and organ transplantation.         
        Gastroenterology and Hepatology 2018; 14:33-40 
16.  Perrillo R.  Hepatitis B virus prevention strategies for antibody to hepatitis B core antigen –positive   
        liver donation: a survey of North American, European and Asia-Pacific transplant programs. Liver  
        Transpl 2009; 15:223-232. 
17.  Wang SH, Loh PY, Lin TL, et al.  Active immunization for prevention of de novo hepatitis B virus  
        infection after adult liver donor liver transplantation with a hepatitis B core antigen positive graft.    
        Liver Transplantation 2017; 23:1266-1272. 

27 
 
18.  Lok AS, Lai CL, Wu PC.  Prevalence of isolated antibody to hepatitis B core antigen in an area  
        endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs.  Hepatology  
        8: 1988:766-770. 
19. Reddy KR, Beavers KL, Hammond SP, et al.  American Gastroenterological Association Institute  
       Guideline on the prevention and treatment of hepatitis B virus reactivation during  
       immunosuppressive drug therapy.  Gastroenterology 2015; 148:215-219. 
20. Sanchez-Fueyo A, Rimola A, Grande L, et. Al.  Hepatitis B immunoglobulin discontinuation followed  
       by hepatitis B vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver  
       transplantation.  Hepatology 2000; 31:496-501.  
21. data derived from www.cancer.gov/about -cancer/understanding /statistics.  Accessed, October  
       19, 2018. 
 

28 
 
Figure 1.   Flow Chart for Study of Immunologic Efficacy in Patients Undergoing Treatment with ISDT  
                           
                  Screening visit for reported anti-HBc pos.                                                                                  Recipient of anti-HBc  liver or                                                                              
                   patient on TNF/interleukin inhibitor                                                                                           or post transplant for chronic HBV 
                   therapy or to receive ca chemotherapy                                                                                           infection 
 
                        Test for HBsAg,                                                                                                                                     Test for HBsAg, 
                        anti-HBs (qual),              
 
 
 
 
                                       anti-HBs and               
                        confirm anti-HBc                                                                                                                             anti-HBc as needed* 
                                               Exclude if HBsAg positive                                                                                                                    Exclude if HBsAg positive or 
                                               or anti-HBc negative                                                                                                                            anti-HBs > 20 mIU/mL ** 
                                                              
 
       Exclude  if                     Determine anti-HBs level                                                                                                             Baseline visit (Time 0) 
 anti-HBs > 20 mIU                  if anti-HBs positive                                                                                                                                 
.                                                                                                                                                                                                    First dose of Heplisav-B + 
                                                                                                                                                                                                         Anti-HBs quantitation   
                                           
                                                                                        
 
                                                                                                
                      
                                     Baseline visit (Time 0) 
                                    First dose of Heplisav-B 
                                   +  anti -HBS   quantification                                                                            Week 4 visit --                     Week 8 visit--                      Week 12 visit--                  Week 24 visit-- 
                Second dose                       anti-HBs quant                      anti-HBs quant,                anti-HBs quant              
 
 
 
 
 
                of Heplisav-B + 
 
 
 
 
third dose as  
 
 
 
 
 
                            
 
anti-HBs quant 
 
 
 
 
needed #                       
                                   
 
 
 
                     
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                                                                       
Week 4 visit --                         Week 8 visit--                 Week 12 visit--                 Week 24 visit-- 
Week 60 visit-  
Second dose                          Anti-HBs quant                  Anti-HBs quant                  Anti-HBs quant               Final safety data 
 
of Heplisav-B  +                        
Third dose if                                                                  Anti-HBs quant 
Anti-HBs quant                                                                   needed  #                                                              
 
*If not available in patient record 
** 5% of recipients of anti-HBc donor liver are anticipated to be anti-HBc positive.  These patients will be excluded if anti-HBs also > 20 mIU/ml.   Patients transplanted for HBV 
infection are anticipated to be anti-HBc positive  
#  If anti-HBs level remains < 10 mIU/ml 

29 
 
TABLE 1.  Study Participation Table 
 
 
Visit 1: 
Screening 
Visit 2 
Enrollment/ 
Baseline 
Visit 3 
4 Week 
Follow up 
(+/- 3-5 d) 
Visit 4 
8 Week 
Follow up 
(+/- 3-5 d) 
Visit 5: 
12 Week 
Follow Up 
(+/- 3-5 d) 
 Visit 6: 
24 Week 
Follow Up 
(+/- 1 week) 
Visit 7: 
60 Week 
Follow Up 
(+/- 1 week) 
Read and Sign Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
X 
Review of Immunosuppresants 
X 
X 
X 
X 
X 
X 
X 
Interview, brief physical 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (heart rate, blood 
pressure, temperature) 
X 
X 
X 
X 
X 
X 
X 
Missing HBV blood testing* 
X 
 
 
 
 
 
 
Quant anti-HBs 
X≠ 
X 
X 
X 
X 
X 
X 
CRP** 
 
X 
X 
X 
X 
X 
X 
Pregnancy test¥ 
X 
X 
X 
   
X 
X∞ 
 
Hepatic function panel 
 
X 
X 
X 
X 
X 
X 
Patient Related Outcome Form for 
Inflammatory Disorder 
 
X 
X 
X 
X 
X 
 
X 
Repository Blood Sample (for 
repeat antibody test) 
 
X 
X 
X 
X 
X 
X 
Vaccine Administration, with 
observation for reactions 
 
X 
X 
 
X*** 
 
 
Adverse effects form± 
 
 
X 
X 
X 
X 
X 
*   Test for anti-HBs, anti-HBc, or HBsAg if not in the medical record or > one year previously.   Test for HIV and HCV antibody is not within 4 months of screening. 
≠    Only done at this visit if medical record indicates patient is anti-HBs positive by qualitative testing. 
**  This will only be done in patients taking TNF or interleukin inhibitor therapy for chronic inflammatory  disorders. 
¥      If potentially child bearing female.  Patients who are positive will not be eligible. 
*** A 3rd dose will be offered to those participants who lack seroprotection (>10 mIU/ml) at week 8. 
±   Observation for adverse events includes weekly telephone calls for 4 weeks after each vaccine dose. 
∞  If patient requires third dose of vaccine as per protocol. 
 
 

30 
 
Appendix 1.  Form to Capture All Adverse Events 
 
Participant Number ______________          Date __________________               Visit Number _____________ 
 
System 
Involved 
Description of Event  HHS* 
Grade  
Unexpected** 
 
 
 
    Yes        No 
Relatedness 
a. Unrelated 
b. Possibly  
c. Definitely    
     
Time 
Relationship 
to Dose 1 
Time 
Relationship 
to Dose 2 
MAAE, 
pIMMC, 
and/or SAE 
(specify) 
 
Yes      No 
  Type 
Intervention 
Participant 
Withdrawal 
Needed 
 
Yes        No 
Time to  
Resolution 
 
PI 
Initials 
& Date 
Local 
reaction 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
 
 
 
 
 
 
 
 
Systemic 
 
 
 
 
 
 
 
 
 
 
 
 
Lab 
Abnormality 
 
 
 
 
 
 
 
 
 
 
 
 
HEENT 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac 
 
 
 
 
 
 
 
 
 
 
 
 
Lung 
 
 
 
 
 
 
 
 
 
 
 
 
Abdomen 
 
 
 
 
 
 
 
 
 
 
 
 
Muscular/ 
skeletal 
 
 
 
 
 
 
 
 
 
 
 
 
Neuro 
 
 
 
 
 
 
 
 
 
 
 
 
Skin 
 
 
 
 
 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
 

31 
 
 
Footnotes to Appendix 1   
*As defined in Common Terminology Criteria for Adverse Events (CTCAE).  Version 5.0, November 27, 2017).   U.S. Department of Health and 
Human Services/National Institute of Health/National Cancer Institute 
 
Grade 1: mild, asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not needed. 
Grade 2: Moderate; minimal local or noninvasive intervention indicated. 
Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care  
Grade 4: Life threatening; urgent intervention needed 
Grade 5: Death related to AE. 
 
** Unexpected indicates that the adverse event if not listed in the investigator’s brochure or is not listed at the specificity or severity observed as indicated in CFR 
312.32. Revised as of April 1, 2018. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

32 
 
Appendix 2 A.  Psoriasis Patient Related Outcome Measurement [Data Collected at Each Study Visit] 
 Patient Study Number _______Date _______   Visit Number  ______   Visit in Between Those Specified?--    Yes       No 
 
 
Skin  related 
 
 
 
 
 
 
Areas 
affected 
Arms  
Legs 
Back 
Neck 
Scalp 
Feet 
 
New areas 
Since last 
visit 
YES/NO 
Arms 
 
Legs 
Back 
Neck  
Scalp 
Feet 
 
Eye 
Redness 
Pain  
Sensitivity 
to light 
Blurred 
vision 
 
 
 
 
Joint related 
YES/NO 
If so, 
where? 
(see below) 
 
 
 
 
 
Fingers 
Back 
Neck 
Shoulder 
Hips 
Ankles 
 
 
Systemic 
 
 
 
 
 
 
Fever or 
feeling 
feverish? 
YES/NO 
99-100 F 
101-103 F 
>103 F 
 
 
 
Fatigue 
YES/NO  
Minimal  
Moderate 
Severe 
 
 
 
Overall 
assessment* 
No change 
Feel slightly 
worse 
Feel 
moderately 
worse 
Feel much 
worse 
 
 
 
 
 
Comments__________________________________________________________________________________________________________________________ 
 
___________________________________________________________________________________________________________________________________ 
 
________________________________________________________________________________________________________________________ 
 

33 
 
Appendix 2B.  Rheumatoid Arthritis/Ankylosing Spondylitis Patient Related Outcome Measurement [Data Collected at Each Study Visit] 
 
Patient Study Number ______  Date _________ Visit Number _______  Visit  in Between Those Specified?--    Yes       No 
Joint related 
 
 
 
 
 
 
Number affected 
< 2 
≥2 , ≤ 5 
≥ 5 
 
 
 
Location  
Hands 
Wrists 
Elbows 
Shoulder 
Hips 
Ankles 
Joint Pain 
On a scale 1-10 (with 
10 being the worst) 
 
1   2   3   4   5  6  7  8  9  10 
On a scale 1-10 (with 
10 being the worst) 
 
1  2  3  4  5  6  7  8  9  10 
On a scale 1-10 (with 
10 being the worst) 
 
1  2  3  4  5  6  7  8  9  10 
On a scale 1-10 (with 
10 being the worst) 
 
1  2  3  4  5  6  7  8  9  10 
On a scale 1-10 (with 
10 being the worst) 
 
1  2  3  4  5  6  7  8  9  10 
On a scale 1-10 (with 
10 being the worst) 
 
1  2  3  4  5  6  7  8  9  10 
Stiffness 
Mild  
Moderate 
Severe 
 
 
 
Swelling 
None 
Mild 
Moderate 
Severe 
 
 
New joint 
location 
YES/NO 
If so, where? (see 
below) 
 
 
 
 
 
Hands 
Wrists 
Elbows 
Shoulder 
Hips 
Ankles 
Systemic 
 
 
 
 
 
 
Fever or feeling 
feverish? 
YES/NO 
99-101  F 
> 101-103  F 
>103  F 
 
 
Muscle aching  
YES/NO 
If so, where? 
 
 
 
 
Fatigue 
YES/NO  
Minimal  
Moderate 
Severe 
 
 
Overall 
assessment* 
No change 
Feel slightly worse 
Feel moderately 
worse 
Feel much worse 
 
 
Function related 
 
 
 
 
 
 
Difficulty with 
dressing 
YES/NO  
Minimal  
Moderate 
Severe 
 
 
Difficulty with 
driving 
YES/NO  
Minimal  
Moderate 
Severe 
 
 
Difficulty with 
grasping 
YES/NO 
Minimal 
Moderate 
Severe 
 
 
Difficulty with 
walking 
YES/NO 
Minimal  
Moderate 
Severe 
 
 

34 
 
Appendix 2 C.  Inflammatory Bowel Disease Patient Related Outcome Measurement [Data Collected at Each Study Visit] 
 
Patient Study Number _____ Date _______ Visit Number _____  Visit  in Between Those Specified?--    Yes       No 
 
 
Bowel related 
 
 
 
 
 
Number stools/ 24 hr 
< 2 
>2 but  < 5 
> 5 
 
 
Blood in stools 
None 
Occasional (1-3 times 
Weekly) 
Most days (4-6) 
Daily 
 
   Amount        
   of blood  
 
Minimal 
(teaspoonful mixed with stool) 
Moderate 
(More than teaspoonful, but 
less than cupful) 
Severe 
(Cupful or more) 
 
Abdominal Pain  
None 
On a scale 1-10 (with 10 being 
the worst) 
 
1   2   3   4   5   6   7   8   9   10 
On a scale 1-10 (with 10 
being the worst) 
 
1   2   3   4   5   6   7   8   9   10 
On a scale 1-10 (with 10 
being the worst) 
 
1   2   3   4   5   6   7   8   9   10 
 
Systemic 
 
 
 
 
 
Fever  
YES/NO 
99-101 F 
> 101 to 103 F 
> 103 
 
Fatigue 
YES/NO 
Minimal  
Moderate 
Severe 
 
Overall assessment* 
No change 
Feel slightly worse 
Feel moderately worse 
Feel much worse 
 
Social Function  
 
 
 
 
 
 
Normal 
Occasional limitation 
Several times weekly 
Absence from work  
Home ridden 
 
Food tolerability 
No problem 
Minimally affected  
Moderately affected  
Severely affected  
 
          
Comments_________________________________________________________________________________________________________ 
____________________________________________________________________________________________________________________ 
____________________________________________________________________________________________________________________ 
 

35 
 
Appendix 3.  Quick View Table of Criteria for Subject Withdrawal, Vaccine Withdrawal, and Study Termination 
Adverse Event 
Relatedness 
Not   Poss   Def 
Subject  
withdrawal 
Vaccine 
Withdrawal 
              Anticipated Follow up 
               Study Termination 
Death 
Not 
- 
- 
- 
No* 
Possibly 
- 
- 
- 
Yes 
Definitely 
- 
- 
- 
Yes 
Grade 4  
No 
No 
No 
Until 52 weeks after last vaccine dose 
No* 
Possibly 
Yes 
Yes 
Until 52 weeks after last vaccine dose 
Yes 
Definitely 
        Yes 
Yes 
Until 52 weeks after last vaccine dose 
Yes 
Worsened underlying 
disease in Group A patient 
  Regardless of    
  relatedness 
Yes 
Yes 
Until 52 weeks after last vaccine dose 
No, but hold on further enrollment & vac-
cine in group A if AE is definitely related** 
Grade 3 AE or SAE in any 
patient group 
Not 
No 
No 
Until 52 weeks after last vaccine dose 
No 
Possibly 
     No*** 
Yes 
Until 52 weeks after last vaccine dose 
No 
Definitely 
     No*** 
Yes 
Until 52 weeks after last vaccine dose 
Yes, if a second patient in different group 
has a Grade 3 AE or SAE that is also 
definitely related to vaccineΩ      If this does 
not occur, a hold on further enrollment & 
vaccine in the group the patient belongs to  
Liver allograft rejection 
 
Possibly 
    No***  
Yes 
Until 52 weeks after last vaccine dose 
No 
Definitely 
    No*** 
Yes 
Until 52 weeks after last vaccine dose 
Yes, if a second patient in different group 
has a Grade 3 AE or SAE that is also 
definitely related to vaccineΩ      If this does 
not occur, a hold on further enrollment & 
vaccine in group C will be enacted. 
*The finding of a death or Grade 4 AE that is considered unrelated to vaccine will not be considered sufficient to terminate the study nor place a hold on further 
enrollment in that group. 
**The finding of a Grade 3 AE or SAE that is considered definitely related to vaccine will place a hold on further enrollment in Group A and all other groups (B and 
C).  Should two subjects in one group have the same or similar Grade 3 AE or SAE assessed as possibly related, then enrollment and vaccination in that group will 
also be put on hold. 
*** If patient meets criteria for vaccine withdrawal they will still be followed for safety until week 60.  
Ω Study termination will occur if two patients, one each from two different groups, develop a Grade 3 AE or SAE considered to be definitely related to vaccine.      

36 
 
Appendix 4.  List of Potentially Immune-Mediated Medical Conditions 
 
Gastrointestinal  disorders 
• 
Celiac disease 
• 
Crohn's disease 
• 
Ulcerative colitis 
• 
Ulcerative proctitis 
Liver disorders 
• 
Autoimmune cholangitis 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing cholangitis 
 
Metabolic diseases 
• 
Addison's disease 
• 
Autoimmune thyroiditis (including Hashimotothyroiditis) 
• 
Diabetes mellitus type I 
• 
Grave's or Basedow's disease 
 
Musculoskeletal disorders 
• 
Antisynthetase syndrome 
• 
Dermatomyositis 
• 
Juvenile chronic arthritis (including Still's disease) 
• 
Mixed connective tissue disorder 
• 
Polymyalgia  rheumatic 
• 
Polymyositis 
• 
Psoriatic arthropathy 
• 
Relapsing  polychondritis 
• 
Rheumatoid arthritis 
• 
Scleroderma, including diffuse systemic form and CREST syndrome 
• 
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter's Syndrome) and undifferentiated spondyloarthritis 
• 
Systemic lupus erythematosus 
• 
Systemic sclerosis 
 

37 
 
 
Neuroinflammatory disorders 
• 
Acute disseminated encephalomyelitis, including site specific variants (e.g., non­ infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis) 
• 
Cranial nerve disorders, including paralyses/paresis (e.g., Bell's palsy) 
• 
Guillain-Barre syndrome, including Miller Fisher syndrome and other variants 
• 
Immune-mediated peripheral neuropathies and plexopathies, including chronic inflammatory demyelinating polyneuropathy, multifocal 
motor neuropathy and polyneuropathies associated with monoclonal gammopathy 
• 
Multiple sclerosis 
• 
Narcolepsy 
• 
Optic neuritis 
• 
Transverse myelitis 
• 
Myasthenia gravis, including Eaton-Lambert syndrome 
 
Skin disorders 
• 
Alopecia areata 
• 
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and dermatitis herpetiformis 
• 
Cutaneous lupus erythematosus 
• 
Erythema nodosum 
• 
Morphoea 
• 
Lichen planus 
• 
Psoriasis 
• 
Rosacea 
• 
Sweet's syndrome 
• 
Vitiligo 
 
Vasculitides 
• 
Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and temporal arteritis 
• 
Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg­ Strauss syndrome (allergic granulomatous angiitis), Buerger's disease thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil 
cytoplasmic antibody (ANCA) positive vasculitis (type unspecified),  Henoch­ Schonlein purpura,  Behcet's syndrome, leukocytoclastic  
vasculitis 
 
 

38 
 
Others 
• 
Antiphospholipid syndrome 
• 
Autoimmune hemolytic anemia 
• 
Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative glomerulonephritis) 
• 
Autoimmune myocarditis/ cardiomyopathy 
• 
Autoimmune thrombocytopenia 
• 
Goodpasture syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Pernicious anemia 
• 
Raynaud's phenomenon  
• 
Sarcoidosis 
• 
Sjogren's syndrome 
• 
Stevens-Johnson syndrome 
• 
Uveitis