Phase 2, Single-arm, Open-label Trial for Serologic Assay Validation, Proficiency Testing, Safety and Immunogenicity of the Intramuscular HIL-214 Norovirus Vaccine in Adults Aged 18 to 49 Years
Phase: PHASE2
Conditions: Gastroenteritis
Sponsor: HilleVax

TITLE: Phase 2, Single-arm, Open-label Trial for Serologic Assay Validation, Proficiency Testing, 
Safety and Immunogenicity of the Intramuscular HIL-214 Norovirus Vaccine in Adults Aged 18 to 
49 Years 
NCT: NCT05972733 

HIL-214 
 
Trial No. NOR-215 
Page 1 of 63 
Protocol Version 3.0 
25 October 2023 
 
 
CONFIDENTIAL 
 
Phase 2, Single-arm, Open-label Trial for Serologic Assay Validation, Proficiency Testing, 
Safety and Immunogenicity of the Intramuscular HIL-214 Norovirus Vaccine in Adults 
Aged 18 to 49 Years 
(Serologic Assay Validation and Proficiency Testing of HIL-214 in Adults) 
Sponsor: 
HilleVax Inc. 
Trial Identifier: 
NOR-215 
IND Number: 
014421 
EudraCT Number: 
Not Applicable 
Trial Vaccine: 
Norovirus GI.1/GII.4c Bivalent Virus-like Particle Vaccine 
Protocol Date: 
25 October 2023 
Version: 
3.0 
CONFIDENTIAL PROPERTY OF HILLEVAX Inc. 
This document is a confidential communication of HilleVax Inc. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from HilleVax Inc. except to the extent necessary to obtain informed consent from those persons to 
whom the investigational product may be administered or their legally acceptable representatives. Furthermore, the 
information is only meant for review and compliance by the recipient, his or her staff, and applicable institutional 
review committees, and regulatory agencies to enable conduct of the trial. 
Effec
e

HIL-214 
 
Trial No. NOR-215 
Page 2 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
The list of contacts will be provided to the site. 
1.2 
Approval 
REPRESENTATIVES OF HILLEVAX 
This trial will be conducted with the highest respect for the individual subjects in accordance 
with the requirements of this clinical trial protocol and in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki [1]. 
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E6 (R2) Good Clinical Practice (GCP): Consolidated Guideline [2]. 
• All applicable laws and regulations, including, but not limited to those related to data privacy 
and clinical trial disclosure. 
 
Approvers: 
ctive

HIL-214 
 
Trial No. NOR-215 
Page 3 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure (IB), 
and any other product information provided by the sponsor. I agree to conduct this trial in 
accordance with the requirements of this protocol and protect the rights, safety, privacy, and 
well-being of trial subjects in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki [1]. 
• ICH, E6 (R2) GCP: Consolidated Guideline [2]. 
• All applicable laws and regulations, including, but not limited to those related to data privacy 
and clinical trial disclosure. 
• Regulatory requirements for reporting serious adverse events defined in Section 10.4.4 of this 
protocol. 
• Terms outlined in the clinical trial site agreement. 
• Appendix A – Responsibilities of the investigator. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix B of this protocol. 
 
 
 
 
 
 
Signature of the investigator 
 
Date 
 
 
 
 
 
 
Investigator name (print or type) 
 
 
 
 
 
 
 
 
Investigator’s title 
 
 
 
 
 
 
 
 
Location of Facility (City, State) 
 
 
 
 
 
 
 
 
Location of Facility (Country) 
 
 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 4 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
1.3 
Protocol Version Summary of Changes 
1.3.1 Version History 
Date 
Version 
Change Type 
Region 
17 November 2022 
1.0 
Not applicable 
Global 
31 May 2023 
2.0 
Non-substantial 
Global 
25 October 2023 
3.0 
Non-substantial 
Global 
1.3.2 Summary of Changes 
Summary of changes for protocol amendment 2 dated 25 October 2023 to protocol version 2.0 dated 
31 May 2023 
Rationale for the amendment: 
Alignment with provider procedures. 
Section 
Description of Change 
Rationale for Change 
2.2 
Indication that vital signs are to be collected during 
symptom-directed physical examinations. 
Clarification. 
7.3 
• 
Subjects who have used antipyretics and/or 
analgesic medications within 24 hours prior to trial 
vaccine administration. The reason for their use 
(prophylaxis versus treatment) must be documented. Trial 
vaccine administration should be delayed to allow for a 
full 24 hours to have passed between having used 
antipyretics and/or analgesic medications and trial vaccine 
administration. 
The reason for the use of antipyretics 
and/or analgesics will not be 
documented. 
9.3.3 
• 
The use of analgesic/antipyretic medications to 
treat symptoms associated with trial vaccine 
administration will be recorded in the diary card daily 
during the reporting period (Day 1 to Day 7). 
Antipyretics and/or analgesics will 
not be collected daily. 
9.3.4 
Site visits that do NOT include a vaccination will be 
performed on Day 8 and Day 29. Procedures include 
symptom-directed physical examination, vital signs, diary 
card review (Day 8 visit only solicited AEs) and blood 
draw. If applicable, a symptom-directed physical 
examination (including vital signs) may be performed. 
Information relating to unsolicited AEs will be obtained by 
interview at the Day 29 visit. The healthcare professional 
reviewing these data will discuss the AEs (if any) reported 
by the subject and will determine if any additional 
diagnoses and/or AEs are present and/or if concomitant 
medications and vaccines have been used. 
Clarification concerning the measure 
of vital signs during symptom-
directed physical examination. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 5 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
9.3.5 
These calls will follow a script, which will facilitate the 
collection of relevant safety information including 
concomitant medication, and any AEs/SAEs the subject 
may have experienced since receiving the trial vaccine. 
The subject will be interviewed according to the script, 
and information relating to AEs/SAEs, and concomitant 
medications or vaccinations associated with those events. 
All safety information described by the subject must be 
written down in a designated location within the source 
documents and not written on the script used for the 
telephone call. 
A telephone script will not be used 
for this trial. 
13.1.1 
The Per Protocol Set will consist of all subjects who 
received HIL-214 and did not have any major protocol 
deviations that impact immunogenicity. The Per Protocol 
Set will be used for supportive analyses of the 
immunogenicity data. 
Per Protocol set is included to see 
how the immunogenicity is impacted 
in subjects that complete procedures 
as planned. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 6 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................2 
1.3 
Protocol Version Summary of Changes .........................................................................4 
1.3.1 
Version History ...................................................................................................4 
1.3.2 
Summary of Changes ..........................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
List of In-Text Tables ................................................................................................................9 
List of Appendices .....................................................................................................................9 
2.0 
TRIAL SUMMARY ..........................................................................................................10 
2.1 
Trial Design Diagram ..................................................................................................15 
2.2 
Schedule of Trial Procedures .......................................................................................15 
3.0 
TRIAL REFERENCE INFORMATION ...........................................................................17 
3.1 
Trial-Related Responsibilities ......................................................................................17 
3.2 
Investigator ..................................................................................................................17 
3.3 
List of Abbreviations ...................................................................................................18 
4.0 
INTRODUCTION .............................................................................................................19 
4.1 
Background ..................................................................................................................19 
4.2 
Rationale for the Proposed Trial ..................................................................................19 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS ......................................................................21 
5.1 
Objectives ....................................................................................................................21 
5.2 
Endpoints .....................................................................................................................21 
6.0 
TRIAL DESIGN AND DESCRIPTION ...........................................................................22 
6.1 
Trial Design .................................................................................................................22 
6.2 
Justification for Trial Design, Dose, and Endpoints ....................................................22 
6.3 
Planned Duration of Subject’s Participation in the Trial .............................................22 
6.4 
Premature Termination or Suspension of Trial or Investigational Site .......................23 
6.4.1 
Criteria for Premature Termination or Suspension of the Trial ........................23 
6.4.2 
Criteria for Premature Termination or Suspension of the Investigational 
Site ....................................................................................................................23 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of the Investigational Site ............................................................23 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ...............24 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 7 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
7.1 
Inclusion Criteria .........................................................................................................24 
7.2 
Exclusion Criteria ........................................................................................................24 
7.3 
Criteria for Delay of Trial Vaccine Administration and/or Blood Sampling ..............26 
7.4 
Criteria for Early Termination of a Subject’s Trial Participation ................................26 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................28 
8.1 
Trial Vaccine ................................................................................................................28 
8.2 
Labeling .......................................................................................................................28 
8.3 
Inventory and Storage ..................................................................................................28 
8.4 
Dose and Regimen .......................................................................................................28 
8.5 
Trial Vaccine Assignment and Dispensing Procedures ...............................................29 
8.5.1 
Precautions to Be Observed When Administering the Trial Vaccine ...............29 
8.6 
Randomization Code Creation and Storage .................................................................29 
8.7 
Trial Vaccine Blind Maintenance ................................................................................29 
8.8 
Unblinding Procedure ..................................................................................................29 
8.9 
Accountability and Destruction of Sponsor-Supplied Clinical Trial Materials ...........29 
9.0 
TRIAL PLAN ....................................................................................................................31 
9.1 
Trial Procedures ...........................................................................................................31 
9.1.1 
Informed Consent..............................................................................................31 
9.1.2 
Demographics, Medical History, Prior Medications and Other Vaccinations ..31 
9.1.3 
Documentation of Trial Entry ...........................................................................32 
9.1.4 
Physical Examination........................................................................................32 
9.1.5 
Vital Signs .........................................................................................................32 
9.1.6 
Immunogenicity Assessments ...........................................................................33 
9.1.7 
Processing, Labeling and Storage of Biological Samples ................................33 
9.1.8 
Safety Assessments ...........................................................................................33 
9.1.9 
Contraception and Pregnancy Avoidance Procedure ........................................34 
9.1.10 
Pregnancy ..........................................................................................................34 
9.1.11 
Documentation of Subjects Who Are Not Randomized ...................................34 
9.2 
Monitoring Subject Compliance ..................................................................................34 
9.3 
Schedule of Observations and Procedures ...................................................................34 
9.3.1 
Pre-Vaccination Procedures (Day 1) ................................................................34 
9.3.2 
Vaccination Procedures (Day 1) .......................................................................35 
9.3.3 
Post-Vaccination Procedures (Day 1) ...............................................................35 
9.3.4 
Site Visits After Vaccination (Day 8 and Day 29) ...........................................37 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 8 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
9.3.5 
Phone Contact – Safety Call and Final Contact (Day 85) ................................37 
9.3.6 
Post-Trial Care ..................................................................................................37 
9.4 
Biological Sample Retention and Destruction .............................................................37 
10.0 
ADVERSE EVENTS .........................................................................................................39 
10.1 
Definitions....................................................................................................................39 
10.1.1 
Adverse Events .................................................................................................39 
10.1.2 
Solicited Adverse Events ..................................................................................39 
10.1.3 
Adverse Events of Special Interest ...................................................................42 
10.1.4 
Medically-Attended Adverse Events ................................................................42 
10.1.5 
Serious Adverse Events ....................................................................................42 
10.2 
Causality of Adverse Events ........................................................................................43 
10.2.1 
Relationship to Trial Procedures .......................................................................43 
10.2.2 
Outcome of Adverse Events .............................................................................43 
10.3 
Additional Points to Consider for Adverse Events ......................................................43 
10.4 
Procedures ....................................................................................................................45 
10.4.1 
Collection and Reporting Procedures ...............................................................45 
10.4.2 
Collection and Reporting of Solicited Adverse Events ....................................46 
10.4.3 
Collection and Reporting of Adverse Events of Special Interest/Medically-
Attended Adverse Events ..................................................................................46 
10.4.4 
Collection and Reporting of Serious Adverse Events.......................................46 
10.5 
Follow-up Procedures ..................................................................................................47 
10.5.1 
Adverse Events .................................................................................................47 
10.5.2 
Serious Adverse Events ....................................................................................47 
10.5.3 
Safety Reporting to Investigators, Institutional Review Boards, and 
Regulatory Authorities ......................................................................................47 
10.5.4 
Post-Trial Events ...............................................................................................47 
11.0 
TRIAL-SPECIFIC REQUIREMENTS .............................................................................48 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................49 
12.1 
Electronic CRFs ...........................................................................................................49 
12.2 
Record Retention .........................................................................................................49 
13.0 
STATISTICAL METHODS ..............................................................................................51 
13.1 
Statistical and Analytical Plans ....................................................................................51 
13.1.1 
Analysis Sets .....................................................................................................51 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics .......................51 
13.1.3 
Primary Analysis - Immunogenicity .................................................................51 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 9 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
13.1.4 
Secondary Analysis - Safety .............................................................................51 
13.1.5 
Exploratory Analyses ........................................................................................52 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................52 
13.3 
Determination of Sample Size .....................................................................................52 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................53 
14.1 
Trial-Site Monitoring Visits .........................................................................................53 
14.2 
Protocol Deviations ......................................................................................................53 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................53 
14.4 
Trial Risk Management................................................................................................53 
15.0 
ETHICAL ASPECTS OF THE TRIAL .............................................................................55 
15.1 
Institutional Review Board Approval ..........................................................................55 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................56 
15.3 
Subject Confidentiality ................................................................................................57 
15.4 
Clinical Trial Registration, Publication, and Disclosure Policy ..................................58 
15.4.1 
Clinical Trial Registration.................................................................................58 
15.4.2 
Clinical Trial Results Disclosure ......................................................................58 
15.4.3 
Publication of Trial Results ..............................................................................58 
15.5 
Insurance and Compensation for Injury .......................................................................58 
16.0 
REFERENCES ..................................................................................................................59 
 
List of In-Text Tables 
Table 9.a 
Blood Sampling Volumes ......................................................................................33 
Table 10.a 
Solicited Local and Systemic AEs .........................................................................40 
Table 10.b 
Solicited Safety Parameters ...................................................................................41 
 
List of Appendices 
Appendix A Responsibilities of the Investigator ...........................................................................61 
Appendix B Investigator Consent to use of Personal Information ................................................63 
 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 10 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
2.0 
TRIAL SUMMARY 
Name of Sponsor: 
HilleVax, Inc. 
Product Name: 
HIL-214 
Trial Title: Phase 2, Single-arm, Open-label Trial for Serologic Assay Validation, Proficiency Testing, Safety 
and Immunogenicity of the Intramuscular HIL-214 Norovirus Vaccine in Adults Aged 18 to 49 years. 
IND No.: 014421 
EudraCT No.: Not applicable 
Trial Identifier: NOR-215 
Phase: 2 
Blinding Schema: Open label 
Indication: Prevention of norovirus-associated acute gastroenteritis. 
Background and Rationale: 
Noroviruses have emerged as the single most significant cause of gastroenteritis in both middle-high income 
countries and low resource settings worldwide. Those most at risk of severe illness include the very young, the 
elderly, and immunocompromised individuals. Noroviruses are highly infectious, highly resistant to 
environmental conditions, and have multiple routes of transmission including person-to-person, food-borne, and 
contaminated surfaces. Noroviruses can cause acute, mild to severe illness characterized by vomiting, diarrhea, 
fever, dehydration, and abdominal pain, representing a significant burden to public health. The clinical 
presentation in adults and older children is similar. Acute gastroenteritis (AGE) caused by norovirus may 
sometimes lead to hospitalization and death. There is currently no vaccine against norovirus. 
Noroviruses are single-stranded, positive-sense RNA viruses that contain a non-segmented RNA genome and 
comprise a genetically diverse family consisting of at least 10 genogroups, 5 of which (GI, GII, GIV, GVIII, and 
GIX) cause human disease. Some norovirus strains drift from year to year, and although both GI and GII and 
numerous genotypes are reported, genotype II.4 (GII.4) causes the vast majority of norovirus cases in children 
worldwide. 
The trial vaccine, HIL-214 (previously called TAK-214), contains GI.1 virus-like particles (VLPs) and norovirus 
GII.4 consensus (GII.4c) VLPs which represents a consensus sequence of 3 GII.4 strains, as antigens. Norovirus 
VLPs are non-infectious because they do not contain viral RNA but are immunogenic because they preserve 
particulate antigen conformation and structure that mimic the functional interactions of the virus with cellular 
receptors. The trial vaccine used in this trial is adjuvanted with aluminum as aluminum hydroxide [Al(OH)3]. 
The clinical trials for different compositions of HIL-214 have so far been performed in Europe, the United States 
and several countries in South America. The composition of HIL-214 to be used in this phase 2 trial is 50/150 µg 
GI.I/GII.4c, which has been primarily tested in children below the age of 9 years and shown to be immunogenic 
and have a good safety profile in this population. This same dose level was tested in NOR-107 in adults aged 18 
to 64 years, and although 15/50 µg was considered the optimal dose, 50/150 µg was also immunogenic and had 
an acceptable safety profile in this population. 
This single-arm trial serves to obtain serum for proficiency testing to confirm assay validity is maintained. 
 Given the large volume of blood required, the pediatric dose 
will be tested in healthy adults. The main scientific rationale for the trial is to identify immune assays that can 
assess the generation of serum antibodies 
 
 
 
 
In this trial, the HBGA-blocking assay and total immunoglobulin (pan Ig) enzyme-linked immunosorbent assay 
(ELISA), for the measurement of titers specific to the strains represented in HIL-214 (GI.1 and GII.4c), will 
provide the positive-control benchmarks for the exploratory objectives, and with respect to comparisons with the 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 11 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
other clinical trials that have evaluated immunogenicity of HIL-214
 
 
 
 
 
 
 
The trial will be conducted in accordance with the protocol, International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH), Good Clinical Practice (GCP) Guidelines, 
and applicable regulatory requirements. 
Objectives of the Trial: 
Primary Objective 
• 
To assess the immunogenicity of HIL-214 in serum samples that will form a proficiency panel for further 
analysis. 
Secondary Objective 
• 
To assess the safety of HIL-214. 
Trial Design: 
This is a phase 2, single-arm, open-label trial for serologic assay validation, proficiency testing, safety and 
immunogenicity of HIL-214, in healthy adults aged 18 to 49 years. Vaccination with a single dose of HIL-214 
will occur on Day 1. 
There are 3 protocol-scheduled site visits (Day 1, Day 8, and Day 29) and 1 telephone contact (Day 85). Visits 1, 
2, and 3 involve blood draws. 
The final contact to collect safety data is scheduled on Day 85. 
The trial design diagram is shown in Section 2.1. The schedule of procedures is shown in Section 2.2. 
Safety assessments 
• 
For 7 days after vaccination (including the day of vaccination), solicited local adverse events (AEs; injection 
site: pain, erythema, induration and swelling); solicited systemic AEs (headache, fatigue, myalgia, 
arthralgia, vomiting, and diarrhea), and body temperature. 
• 
For 28 days after vaccination (including the day of vaccination), unsolicited AEs. 
• 
Throughout the trial, serious adverse events (SAEs), and AEs leading to withdrawal from the trial. 
Immunogenicity assessments 
• 
Blood for the primary endpoint (proficiency panel) will be collected from all 80 subjects at Day 1 and 
Day 29, corresponding to approximately 100 mL of serum from a total 200 mL of blood from an individual 
subject. 
• 
The blood sampling volumes are shown in Table S1. 
Eff
ve

HIL-214 
 
Trial No. NOR-215 
Page 12 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
Table S1: Blood Sampling Volumes 
Sample 
Day 1 
Day 8 
Day 29 
Total volume per Subject 
Blood for serum* and ** 
100 mL 
- 
100 mL 
200 mL blood 
 
10 mL 
- 
10 mL 
20 mL blood 
(total 110 mL) 
 
30 mL 
30 mL 
30 mL 
90 mL blood 
Total volume per blood draw 
140 mL 
30 mL 
140 mL 
310 mL blood 
Abbreviations:
 
. Notes: *serum-based assays include histoblood group antigen (HBGA)-blocking assay, pan-Ig enzyme-
linked immunosorbent assay (ELISA), and
 
 
Subject Population: 
Healthy Subjects: Yes. 
Age Range: 18 to 49 years. 
Planned Number of Subjects: 80. 
Planned Number of Trial Arms: 1. 
Inclusion Criteria: 
Subject eligibility is determined according to the following criteria: 
• 
Male or female subjects aged 18 to 49 years, inclusive. 
• 
Individuals who are in good health at the time of entry into the trial as determined by medical history, 
physical examination (including vital signs) and clinical judgment of the investigator. 
• 
The individual signs and dates a written, informed consent form and any required privacy authorization prior 
to the initiation of any trial procedures, after the nature of the trial has been explained according to 
regulatory requirements. 
• 
Individuals willing and able to comply with trial procedures and are available for the duration of follow-up. 
Key Exclusion Criteria: 
Any subject who meets any of the following criteria will not qualify for entry into the trial: 
• 
Females who are pregnant or breastfeeding. 
• 
Known hypersensitivity or allergy to any of the HIL-214 components (including excipients). 
• 
Known or suspected impairment/alteration of immune function, including history of any autoimmune 
disease or neuro-inflammatory disease. 
• 
Any serious chronic or progressive disease (including hepatitis B or C). 
• 
Previous exposure to an experimental norovirus vaccine. 
• 
Subject or subject’s first-degree relatives are involved in the trial conduct. 
Trial Vaccine: 
HIL-214 for injection is provided by HilleVax Inc. in single dose 1 mL pre-filled syringes as a 0.65 mL volume 
(to deliver a 0.5 mL dose). The trial vaccine contains 50 µg GI.1/150 µg GII.4c VLPs and 500 µg of aluminum 
as Al(OH)3. 
Route of administration: 
Intramuscular injection (deltoid muscle, preferably of the non-dominant arm). 
Duration of the Trial and Duration of Subject Participation: 
Up to 85 days. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 13 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
Criteria for Evaluation and Analyses: 
Primary Endpoints 
At Day 1 and Day 29, (i) HBGA-blocking titers and (ii) pan-Ig titers that are specific for: 
• 
GI.1 VLP. 
• 
GII.4c VLP. 
Secondary Endpoints 
• 
Solicited local AEs up to 7 days after the dose of trial vaccine. 
• 
Solicited systemic AEs up to 7 days after the dose of trial vaccine. 
• 
Unsolicited AEs for up to 28 days after the dose of trial vaccine. 
• 
AEs leading to the subject’s withdrawal from the trial from Day 1 to the end of the trial. 
• 
SAEs from Day 1 to the end of the trial. 
Exploratory Endpoints 
• 
 
Statistical Considerations: 
Analysis sets: 
Safety Set: The Safety Set will consist of all subjects who received HIL-214. The Safety Set will be used for the 
analyses of safety and immunogenicity data. 
Per-protocol Set: The Per Protocol Set will consist of all subjects who received HIL-214 and did not have any 
major protocol deviations that impact immunogenicity. The Per Protocol Set will be used for supportive analyses 
of the immunogenicity data. 
Analysis of demographics and baseline characteristics: Demographics, age, sex, race, and other baseline 
characteristics will be summarized descriptively for all subjects who received HIL-214. Summaries of 
continuous variables will include mean, standard deviation, median, minimum and maximum values. For 
categorical variables, count and percentage of subjects in each category will be computed. 
Primary analysis – immunogenicity: 
Descriptive statistics will be computed for HBGA-blocking titers and pan-Ig titers against GI.1 and GII.4c, 
measured at Day 1 and Day 29. These statistics will include the geometric mean titers (GMTs), geometric mean 
fold rise in titers (GMFR) from baseline (Day 1), and seroresponse rate (SRR). The SRR is defined as the 
percentage of subjects with a seroresponse, where seroresponse is a ≥4-fold rise in titer from baseline (Day 1). 
The 95% confidence intervals (CI) will be provided for geometric means and the SRRs. 
Secondary analysis – safety: 
Safety data will be summarized by computing number and percentage of subjects who experienced an AE. 
Solicited AEs 
Solicited AEs will be assessed 30 minutes after administration of trial vaccine then daily for 7 days (including 
the day of administration). Summaries will be provided for each solicited AE, daily from Day 1 to Day 7 after 
administration of trial vaccine (including the day of dose) and overall. Solicited local and systemic AEs will also 
be summarized by severity. For subjects with more than 1 episode of the same event within the Day 1 to Day 7 
period, the maximum severity will be used for overall tabulations. Body temperature measurements will be 
summarized in categories (including fever, defined as temperature ≥38°C). Summaries of the day of first onset of 
each event and the number of days subjects experienced each event will also be provided. Data from the 30-
minutes assessment will be summarized separately. 
Unsolicited AEs 
Unsolicited AEs, SAEs, and AEs leading to withdrawal from the trial will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and summarized by preferred term (PT) and system organ class (SOC). 
Subjects reporting more than 1 occurrence for the term (level) being summarized will be counted only once for 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 14 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
this term. Unsolicited AEs collected up to 28 days after administration (including the day of administration) of 
trial vaccine, will be summarized by severity (mild, moderate, severe) and relationship (not related, related) to 
trial vaccine or trial procedures. If a subject reported more than one AE within an SOC or PT then the event with 
the maximum severity and strongest relationship (causality) to trial vaccine or trial procedure will be included in 
the summaries. Any unsolicited AE will be summarized using the day of onset for the following 3 time intervals: 
1) Day 1 to Day 28, 2) Day 1 to Day 7, and 3) Day 8 to Day 28. 
SAEs and AEs leading to withdrawal from the trial will be summarized for Day 1 to Day 28, and overall (up to 
Day 85). 
Sample Size Justification: 
A sample size of 80 subjects will provide sufficient serum for the establishment of proficiency panels to confirm 
assay validation of the validated serology assays planned to support the clinical development plan for HIL-214. 
Interim Analysis: No interim analysis is planned for this trial. 
Data Monitoring Committee: An independent data monitoring committee (DMC) has been established for the 
HIL-214 clinical development program. The DMC will review the SAEs throughout the trial and convene as 
needed. 
NOR-215 Version 3.0 (25 October 2023) 
 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 15 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
2.1 
Trial Design Diagram 
 
2.2 
Schedule of Trial Procedures 
Day 
Day 1 
Day 8 
Day 29 
Day 85 (a) 
Visit number 
1 
2 
3 
 
Visit window 
 
+2 days 
+3 days 
+ 14 days 
Site visit 
X 
X 
X 
 
Phone contact 
 
 
 
X 
Signed informed consent form 
X 
 
 
 
Pregnancy test (b) 
X 
 
 
 
Assessment of eligibility criteria (c) 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Prior medications 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
Physical exam 
Complete (d) 
X 
 
 
 
Symptom-directed 
 
X 
X 
 
Vital signs (e) 
X 
X (d) 
X (d) 
 
Vaccine administration 
X 
 
 
 
30 min post-vaccination observation period 
X 
 
 
 
Solicited AEs 
X 
X 
 
 
Unsolicited AEs 
X 
X 
X 
 
Diary card provision (f) 
X 
 
 
 
Diary card review (f) 
 
X (Days 1–7) 
 
 
Serious adverse events (g) 
X 
X 
X 
X 
AEs leading to withdrawal from trial 
X 
X 
X 
 
Blood draw (max. 140 mL) (h) 
X 
X 
X 
 
Notes on the next page. 
80 subjects 
18 to 49 years old
Blood draw #1 
Single dose of HIL-214 
(GI.1 [50 μg] / GII.4 [150 μg])
End of Study  Call
Blood draw #2
Blood draw #3 
Day 1
Day 8
Day 29
Day 85
Effective

HIL-214 
 
Trial No. NOR-215 
Page 16 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
Notes: 
(a) Day 85 corresponds to 84 days after trial vaccine administration at Day 1. 
(b) In women of childbearing potential, pregnancy tests (urine) will be performed on Day 1 before trial vaccine 
administration. 
(c) Assessment of eligibility criteria will be documented before trial vaccine administration. 
(d) Physical exam on Day 1 includes but is not limited to a check of general appearance, auscultation of heart and 
lungs, palpation of the abdomen, and inspection of extremities (including skin over the intended injection site), 
weight, and height. For any procedures at the site, the investigator shall follow his/her standard practice. If 
applicable, a symptom-directed physical examination (including vital signs) may be performed at the visits on Day 8 
and Day 29. 
(e) Vital signs include but are not limited to heart rate and temperature. 
(f) Daily diary of solicited local and systemic adverse events (AEs) for 7 days following the trial vaccine 
administration. 
(g) Serious adverse events (SAEs) will be collected from the time the subject is administered the trial vaccine 
(Day 1) up to the end of the trial (Day 85). 
(h) The maximum volume of blood taken at any single site visit is approximately 30 to 140 mL, and the approximate 
total volume of blood taken during the trial is maximum 310 mL for all subjects. Samples will be taken for all 
subjects prior to trial vaccine administration on Day 1. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 17 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
3.0 
TRIAL REFERENCE INFORMATION 
3.1 
Trial-Related Responsibilities 
The sponsor will perform all trial-related activities with the exception of those identified in the 
trial-related responsibilities form. The vendors identified in the template for specific trial-related 
activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Investigator 
Selection criteria for the investigator will include significant knowledge of the trial protocol, the 
trial vaccine, their expertise in the therapeutic area and the conduct of clinical research as well as 
trial participation. The investigator will be required to review and sign the clinical protocol. The 
investigator will also be required to review and sign the clinical study report (CSR) and by doing 
so agrees that it accurately describes the results of the trial. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 18 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
3.3 
List of Abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
AGE 
acute gastroenteritis 
Al(OH)3 
aluminum hydroxide 
CFR 
Code of Federal Regulations 
CSR 
clinical study report 
CTM 
clinical trial materials 
DMC 
data monitoring committee 
eCRF 
electronic case report form  
ELISA 
enzyme-linked immunosorbent assay 
GCP 
good clinical practice 
GI/GII 
genogroup I/genogroup II 
GI.1/GII.4 
genotype I.1/genotype II.4 
GII.4c 
GII.4 consensus 
HBGA 
histoblood group antigen 
IB 
investigator’s brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
institutional review board 
MAAE 
Medically-attended adverse events 
MedDRA 
Medical Dictionary for Regulatory Activities 
pan Ig 
total immunoglobulin 
PT 
Preferred Term 
QTL 
quality tolerance limit 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
System Organ Class 
SRR 
seroresponse rate 
SUSAR 
suspected unexpected serious adverse reaction 
HIL-214 
previously TAK-214 
VLP 
virus-like particle 
WHO 
World Health Organization 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 19 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
4.0 
INTRODUCTION 
4.1 
Background 
Noroviruses have emerged as the single most significant cause of gastroenteritis in both middle-
high income countries and low resource settings worldwide [3-6]. Those most at risk of severe 
illness include the very young, the elderly, and immunocompromised individuals [7-11]. 
Noroviruses are highly infectious, highly resistant to environmental conditions, and have 
multiple routes of transmission including person-to-person, food-borne, and contaminated 
surfaces. Noroviruses can cause acute, mild to severe illness characterized by vomiting, diarrhea, 
fever, dehydration, and abdominal pain, representing a significant burden to public health [7]. 
The clinical presentation in adults and older children is similar. Acute gastroenteritis (AGE) 
caused by norovirus may sometimes lead to hospitalization and death. There is currently no 
vaccine against norovirus. 
Noroviruses are single-stranded, positive-sense RNA viruses that contain a non-segmented RNA 
genome and comprise a genetically diverse family consisting of at least 10 genogroups, 5 of 
which (GI, GII, GIV, GVIII, and GIX) cause human disease [12-14]. Some norovirus strains 
drift from year to year, and although both GI and GII and numerous genotypes are reported, 
genotype II.4 (GII.4) causes the vast majority of norovirus cases in children worldwide [15-20]. 
The trial vaccine, HIL-214 (previously called TAK-214), contains GI.1 virus-like particles 
(VLPs) and norovirus GII.4 consensus (GII.4c) VLPs which represents a consensus sequence of 
3 GII.4 strains, as antigens. Norovirus VLPs are non-infectious because they do not contain viral 
RNA but are immunogenic because they preserve particulate antigen conformation and structure 
that mimic the functional interactions of the virus with cellular receptors. The trial vaccine used 
in this trial is adjuvanted with aluminum as aluminum hydroxide [Al(OH)3]. 
The clinical trials for different compositions of HIL-214 have so far been performed in Europe, 
the United States and several countries in South America. The composition of HIL-214 to be 
used in this phase 2 trial is 50/150 µg GI.I/GII.4c, which has been primarily tested in children 
below the age of 9 years and shown to be immunogenic and have a good safety profile in this 
population. This same dose level was tested in NOR-107 in adults aged 18 to 64 years, and 
although 15/50 µg was considered the optimal dose, 50/150 µg was also immunogenic and had 
an acceptable safety profile in this population [21]. 
More detailed information about the known and expected benefits and risks, and the reasonably 
expected adverse events (AEs) of the trial vaccine can be found in the current IB [21]. 
4.2 
Rationale for the Proposed Trial 
This single-arm trial serves to obtain serum for proficiency testing to confirm assay validity is 
maintained. 
 
. Given the large 
volume of blood required, the pediatric dose will be tested in healthy adults. The main scientific 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 20 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
rationale for the trial is to identify immune assays that can assess the generation of serum 
antibodies
 
 
 
The trial will be conducted in accordance with the protocol, International Council for 
Harmonisation of Technical Requirements for ICH-GCP Guidelines, and applicable regulatory 
requirements [2]. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 21 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
5.0 
TRIAL OBJECTIVES AND ENDPOINTS 
The trial objectives and endpoints are listed in the following sections. 
5.1 
Objectives 
The primary, secondary and exploratory objectives of this trial are: 
Primary Objective 
• To assess the immunogenicity of HIL-214 in serum samples that will form a proficiency 
panel for further analysis. 
Secondary Objective 
• To assess the safety of HIL-214. 
Exploratory Objectives 
 
 
5.2 
Endpoints 
Primary Endpoints 
At Day 1 and Day 29, (i) HBGA-blocking titers and (ii) total immunoglobulin (pan-Ig) titers that 
are specific for: 
• GI.1 VLP. 
• GII.4c VLP. 
Secondary Endpoints 
• Solicited local AEs up to 7 days after the dose of trial vaccine. 
• Solicited systemic AEs up to 7 days after the dose of trial vaccine. 
• Unsolicited AEs for up to 28 days after the dose of trial vaccine. 
• AEs leading to the subject’s withdrawal from the trial from Day 1 to the end of the trial. 
• Serious adverse events (SAEs) from Day 1 to the end of the trial. 
Exploratory Endpoints 
•
 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 22 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
6.0 
TRIAL DESIGN AND DESCRIPTION 
6.1 
Trial Design 
This is a phase 2, single-arm, open-label trial for serologic assay validation, proficiency testing, 
safety and immunogenicity of HIL-214, in healthy adults aged 18 to 49 years. Vaccination with a 
single dose of HIL-214 will occur on Day 1. 
There are 3 protocol-scheduled site visits (Day 1, Day 8, and Day 29) and 1 telephone contact 
(Day 85). Visits 1, 2, and 3 involve blood draws. 
The final contact to collect safety data is scheduled on Day 85. 
The trial design diagram is shown in Section 2.1. The schedule of procedures is shown in 
Section 2.2. 
6.2 
Justification for Trial Design, Dose, and Endpoints 
In this trial, the HBGA-blocking assay and pan-Ig enzyme-linked immunosorbent assay 
(ELISA), for the measurement of titers specific to the strains represented in HIL-214 (GI.1 and 
GII.4c), will provide the positive-control benchmarks for the exploratory objectives, and with 
respect to comparisons with the other clinical trials that have evaluated immunogenicity of 
HIL-214.
 
 
 
 
 
 
Please refer to the current IB [21]. 
6.3 
Planned Duration of Subject’s Participation in the Trial 
Expected duration of trial participation for each subject is up to 85 days. 
ffective

HIL-214 
 
Trial No. NOR-215 
Page 23 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
6.4 
Premature Termination or Suspension of Trial or Investigational Site 
6.4.1 Criteria for Premature Termination or Suspension of the Trial 
The trial will be completed as planned unless one or more of the following criteria that require 
temporary suspension or early termination of the trial are satisfied: 
• New information or other evaluation regarding the safety or efficacy of the trial vaccine that 
indicates a change in the known risk/benefit profile, such that the risk/benefit is no longer 
acceptable for subjects participating in the trial. 
• Significant deviation from GCP that compromises the ability to achieve the primary trial 
objectives or compromises subject safety. 
• The sponsor decides to terminate or suspend the trial. 
6.4.2 Criteria for Premature Termination or Suspension of the Investigational Site 
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant deviation from GCP, the trial protocol, or contractual agreement, is unable to 
ensure adequate performance of the trial, or as otherwise permitted by the contractual agreement. 
6.4.3 Procedures for Premature Termination or Suspension of the Trial or the 
Participation of the Investigational Site 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the trial or the participation of an investigational site, a trial-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will 
be followed by applicable investigational sites during the course of termination or trial 
suspension. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 24 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to trial vaccine 
administration. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. Male or female subjects aged 18 to 49 years, inclusive. 
2. Individuals who are in good health at the time of entry into the trial as determined by medical 
history, physical examination (including vital signs) and clinical judgment of the 
investigator. 
3. The individual signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any trial procedures, after the nature of the trial has 
been explained according to regulatory requirements. 
4. Individuals willing and able to comply with trial procedures and are available for the duration 
of follow-up. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the trial: 
1. Behavioral or cognitive impairment or psychiatric disease that, in the opinion of the 
investigator, may interfere with the subject’s ability to participate in the trial. 
2. History of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 
2 years prior to Visit 1. 
3. Female subjects who are pregnant or breastfeeding. 
4. Female subjects of child-bearing potential who are sexually active with men and have not 
used any of the acceptable contraceptive methods for at least 2 months prior to trial entry. 
a) Of childbearing potential is defined as status post-onset of menarche and not meeting any 
of the following conditions: menopausal for at least 2 years, status after bilateral tubal 
ligation for at least 1 year, status after bilateral oophorectomy, or status after 
hysterectomy. 
b) Acceptable birth control methods are defined as one or more of the following: 
I. 
Hormonal contraceptive (such as oral, injection, transdermal patch, implant, 
cervical ring). 
II. 
Double barrier methods (e.g., condom and cervical cap with spermicide or 
diaphragm with spermicide) every time during intercourse. 
III. 
Intrauterine device. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 25 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
IV. 
Monogamous relationship with vasectomized partner. The partner must have been 
vasectomized for at least six months prior to the subjects’ trial enrollment. 
5. Female subjects of childbearing potential who are sexually active and refuse to use an 
acceptable contraceptive method as outlined in the protocol, from the time of consent 
throughout the trial period for 6 months after the date of trial vaccine administration. 
6. Female subjects who plan to get pregnant or to donate ova before consent, during the trial 
period for 6 months after the date of trial vaccine administration. 
7. Any positive or indeterminate pregnancy test (Section 9.1.10). 
8. Chronic use of oral corticosteroids (equivalent to 20 mg/day prednisolone for ≥12 weeks / 
≥2 mg/kg body weight /day for ≥2 weeks) within 60 days prior to Visit 1 (use of inhaled, 
intranasal, or topical corticosteroids is allowed). 
9. Use of parenteral corticosteroids (equivalent to 20 mg/day prednisolone for ≥12 weeks / 
≥2 mg/kg body weight /day for ≥2 weeks. Use of inhaled, intranasal or topical corticosteroid 
is allowed) within 60 days prior to Visit 1. 
10. Receipt of immunostimulants within 60 days prior to Visit 1. 
11. Receipt of parenteral, epidural or intra-articular immunoglobulin (Ig) preparations, blood 
products, and/or plasma derivatives within 90 days prior to Visit 1 or planned during the full 
duration of the trial. 
12. Receipt of immunosuppressive therapy within 6 months prior to Visit 1. 
13. Known hypersensitivity or allergy to any of the trial vaccine components (including 
excipients). 
14. Any clinically significant active infection (as assessed by the investigator) or temperature 
≥38.0°C (100.4°F), regardless of method used, within 3 days prior to intended trial vaccine 
administration. 
15. Any serious chronic or progressive disease according to the judgment of the investigator 
(e.g., cardiac, neurological, renal, or hepatic disease). 
16. History of any illness, that, in the opinion of the investigator, might interfere with the results 
of the trial or pose additional risk to the subjects due to participation in the trial. 
17. Abnormalities of splenic or thymic function. 
18. Known or suspected impairment/alteration of immune function. 
19. Known bleeding diathesis, or any condition that may be associated with a prolonged bleeding 
time. 
20. Receipt or scheduled receipt of any approved or authorized vaccines within 14 days (all non-
live vaccines) or 28 days (for live vaccines) before or after trial vaccine administration. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 26 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
21. Previous exposure to an experimental norovirus vaccine. 
22. Participation in any clinical trial with another investigational product 30 days prior to first 
trial visit or intention to participate in another clinical trial at any time during the conduct of 
this trial. 
23. Seropositive for human immunodeficiency virus. 
24. Hepatitis B or C infection. 
25. Known or suspected impairment/alteration of immune function, including history of any 
autoimmune disease or neuro-inflammatory disease. 
26. Subject or subject’s first-degree relatives are involved in the trial conduct. 
There may be instances when individuals meet all entry criteria except one that relates to 
transient clinical circumstances (e.g., body temperature elevation or recent use of excluded 
medication[s] or vaccine[s]). Under these circumstances, eligibility for trial enrollment may be 
considered if the appropriate window for delay has passed, inclusion/exclusion criteria have been 
rechecked, and if the subject is confirmed to be eligible (Section 7.3). 
7.3 
Criteria for Delay of Trial Vaccine Administration and/or Blood Sampling 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in the 
administration of the trial vaccine. These situations are listed below. In the event that a subject 
meets a criterion for delay of trial vaccine administration, the subject may receive the trial 
vaccine once the window for delay has passed as long as the subject is otherwise eligible for trial 
participation: 
• Subjects with a clinically significant active infection (as assessed by the investigator). 
• Subjects with a body temperature ≥38.0°C (100.4°F), within 3 days of planned trial vaccine 
administration. 
• Subjects who received any approved or authorized vaccines within 14 days (all non-live 
vaccines) or 28 days (for live vaccines) prior to planned trial vaccine administration or blood 
sampling. 
• Subjects who have used antipyretics and/or analgesic medications within 24 hours prior to 
trial vaccine administration. Trial vaccine administration should be delayed to allow for a full 
24 hours to have passed between having used antipyretics and/or analgesic medications and 
trial vaccine administration. 
7.4 
Criteria for Early Termination of a Subject’s Trial Participation 
Under some circumstances, a subject’s trial participation may be terminated early. This means 
that no further trial procedures (including data collection) will be performed on that subject 
beyond the specific date of early termination of trial participation. The primary reason for early 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 27 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
termination of the subject’s trial participation should be documented using the following 
categories: 
1. Adverse Event: The subject has experienced an AE (irrespective of being related/unrelated 
to the trial vaccine or trial-related procedures) that requires early termination because 
continued participation imposes an unacceptable risk to the subject’s health and/or the 
subject is unwilling to continue participation because of the AE. The primary reason for early 
termination of trial participation in this case will be withdrawal due to AE and not 
withdrawal of consent, (see below). 
2. Lost to follow-up: The subject did not return to the clinic and at least three documented 
attempts to contact the subject were unsuccessful. 
3. Withdrawal of consent: The subject wishes to withdraw from the trial. The primary reason 
for early termination will be withdrawal of consent if withdrawal from participation is due to 
a non-medical reason (i.e., reason other than AE). While the subject has no obligation to 
provide a reason for withdrawing consent, attempts should be made to determine the 
underlying reason for the withdrawal and, where possible, the primary underlying reason 
should be documented. 
4. Premature trial termination by the sponsor, a regulatory agency, the IRB, or any other 
authority: If the clinical trial is prematurely terminated by the sponsor, the investigator is to 
promptly inform the trial subjects and the local IRB and should assure appropriate follow up 
for the subjects. The primary reason for early termination in this case will be trial 
termination. 
5. Subject’s death during trial participation. 
6. Other reason for early termination that is not captured by the above prespecified categories. 
For screen failure subjects, refer to Section 9.1.11. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 28 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding the trial vaccine (HIL-214) and materials provided 
directly by the sponsor, and/or sourced by other means, that are required by the trial protocol, 
including important sections describing the management of clinical trial materials (CTM). 
8.1 
Trial Vaccine 
HIL-214 for injection is provided by HilleVax, Inc. in single dose 1 mL pre-filled syringes as a 
0.65 mL volume (to deliver a 0.5 mL dose). HIL-214 contains 50 µg GI.1/150 µg GII.4c VLPs 
and 500 µg of aluminum as Al(OH)3.
 
 HIL-214 does not contain a 
preservative. 
The syringe contents may appear biphasic with a clear upper layer and a white precipitate. After 
mixing by shaking, a uniformly turbid suspension should be observed. 
Each HIL-214 pre-filled syringe will be supplied in a tamper-evident, single dose carton. 
8.2 
Labeling 
A clinical label will be affixed to trial vaccine containers in accordance with local regulatory 
requirements. Trial vaccine identity (label text will state “HIL-214”) will be included on the trial 
vaccine container label. 
8.3 
Inventory and Storage 
Vaccines will be shipped in refrigerated, temperature-controlled containers with a temperature 
monitor. The trial vaccine must be stored, kept away from light, and maintained at a controlled 
temperature of 2°C to 8°C (36°F to 46°F), as specified on the label. The trial vaccine must be 
kept in an appropriate, limited access, secure place until it is used or returned to the sponsor or 
designee for destruction. The trial vaccine must not be frozen. Each kit is intended for single use 
only. 
Receipt and dispensing of trial vaccine must be recorded by authorized personnel at the trial site. 
All sponsor-supplied trial vaccine doses must be stored under the conditions specified on the 
label and remain in the original container until dispensed. A daily temperature log of the vaccine 
storage area must be maintained. Temperature excursions must be reported to the sponsor as 
soon as possible and use of these vaccines requires sponsor approval. Temperature excursion 
information can be found in the pharmacy manual. 
8.4 
Dose and Regimen 
The trial vaccine 50 µg GI.1/ 150 µg GII.4c VLPs and 500 µg of aluminum as Al(OH)3 will be 
administered intramuscularly as a single dose on Day 1 in the deltoid muscle, preferably of the 
non-dominant arm. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 29 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
8.5 
Trial Vaccine Assignment and Dispensing Procedures 
The investigator or designee will be responsible for overseeing the administration of the trial 
vaccine to subjects enrolled in the trial according to the procedures stipulated in this trial 
protocol. 
Expired trial vaccines must not be administered. 
8.5.1 Precautions to Be Observed When Administering the Trial Vaccine 
Prior to trial vaccine administration, a subject must be determined to be eligible to receive trial 
vaccine (Sections 7.1 and 7.2), and it must be clinically appropriate in the judgment of the 
investigator. 
Prior to trial vaccine administration, site staff must determine if the subject is eligible to receive 
the trial vaccine by evaluating the criteria listed in Sections 7.3 and 7.4. 
Standard vaccination practices are to be observed and care should be taken when administering a 
trial vaccine intramuscularly in the deltoid muscle. In addition, World Health Organization 
(WHO) recommendations to reduce anxiety and pain at the time of vaccination should be 
followed [24]. Before administration of the trial vaccine, the injection site must be disinfected 
with a skin disinfectant (e.g., 70% alcohol). Allow the skin to dry. Refer to the pharmacy manual 
for details on preparation and administration of trial vaccine. 
As with all injectable vaccines, trained medical personnel and appropriate medical treatment 
should be readily available in case of anaphylactic reactions following trial vaccine 
administration. For example, epinephrine 1:1000, diphenhydramine, and/or other medications for 
treating anaphylaxis should be available. 
8.6 
Randomization Code Creation and Storage 
Not applicable. 
8.7 
Trial Vaccine Blind Maintenance 
This is an open-label trial. 
8.8 
Unblinding Procedure 
This is an open-label trial. 
8.9 
Accountability and Destruction of Sponsor-Supplied Clinical Trial Materials 
The investigator or designee must ensure that the sponsor-supplied trial vaccine is used in 
accordance with the approved protocol and administered only to subjects enrolled in the trial. To 
document appropriate use of sponsor-supplied trial vaccine, the investigator must maintain 
records of all sponsor-supplied trial vaccine dose delivery to the site, site inventory, 
administration and use by each subject, and return to the sponsor or designee. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 30 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
Upon receipt of sponsor-supplied trial vaccine, the investigator or designee must verify the 
contents of the shipments against the packing list. The verifier should ensure that the quantity is 
correct, the trial vaccine is received within the labeled storage conditions (i.e., no cold chain 
break has occurred during transit), and is in good condition. If quantity and conditions are 
acceptable, investigator or designee will acknowledge receipt of the shipment. 
If there are any discrepancies between the packing list versus the actual product received, the 
sponsor or designee must be contacted to resolve the issue. The packing list should be filed in the 
pharmacy investigator site file. 
The investigator must maintain 100% accountability for all sponsor-supplied trial vaccine doses, 
and other CTM (including ancillary materials, as applicable) received and administered during 
their entire participation in the trial. Accountability includes, but is not limited to: 
• Verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the vaccine lot (or trial vaccine ID or job number) 
used to prepare the trial vaccine. 
• Verifying that all kits used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator must record the current inventory of all sponsor-supplied trial vaccine doses on 
a sponsor-approved accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, 
description of sponsor-supplied trial vaccine, date, and amount. The log should include all 
required information as a separate entry for each subject to whom sponsor-supplied trial vaccine 
is administered. 
The investigator will be notified of any expiry date or retest date extension of trial vaccine during 
the trial conduct. On expiry date notification from the sponsor or designee, the site staff must 
complete all instructions outlined in the notification, including segregation of expired CTM for 
return to the sponsor or designee for destruction. 
All CTM will be provided by the trial site, sponsor or designee, depending upon availability. The 
list of CTM and source information can be found in the pharmacy manual. Prior to site closure or 
at appropriate intervals throughout the trial, before any CTM are returned to the sponsor or 
designee for destruction, a representative from the sponsor will perform CTM accountability and 
reconciliation. The investigator will retain a copy of the documentation regarding CTM 
accountability, return, and/or destruction, and originals will be sent to the sponsor or designee. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 31 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
9.0 
TRIAL PLAN 
9.1 
Trial Procedures 
The following sections describe the trial procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
schedule of trial procedures is located in Section 2.2. All procedures must be performed by 
qualified and trained staff. Details about the trial procedures can be found in the procedures 
manual. All information collected should be recorded in the subject’s electronic case report 
forms (eCRFs). 
9.1.1 Informed Consent 
The requirements of the informed consent form (ICF) are described in Section 15.2. 
Informed consent must be obtained before any protocol-directed procedures are performed. 
A unique subject number will be assigned to each subject after informed consent is obtained. If 
all eligibility criteria are fulfilled (Sections 7.1 and 7.2), this subject number will be used 
throughout the trial. Subject numbers assigned to subjects who fail screening should not be 
reused (Section 9.1.11). 
9.1.2 Demographics, Medical History, Prior Medications and Other Vaccinations 
Demographic information to be obtained will include age/date of birth (if applicable), sex, race 
(and ethnicity) as described by the subject. 
Medical history will also be collected, including but not limited to any medical history that may 
be relevant to subject eligibility for trial participation such as prior vaccinations, concomitant 
medications, and previous and ongoing illnesses and/or injuries. Relevant medical history can 
also include any medical history that contributes to the understanding of an AE that occurs 
during trial participation if it represents an exacerbation of an underlying disease/preexisting 
problem. 
Medical history (including corresponding medication) to be obtained will include any significant 
conditions or diseases that have disappeared or resolved at or prior to signing of the ICF. 
Adverse medical occurrences emerging during the time between signing of the ICF and 
administration of trial vaccine will be recorded in the medical history eCRF page. If such an 
adverse medical occurrence is assessed as related to a screening procedure this should be 
recorded as an AE related to trial procedure in the eCRF. 
Details of all medications, vaccines and blood products administered or received by the subjects 
in the following timeframes will be collected as prior (prior to Day 1), or concomitant (from 
Day 1 to the end of the trial): 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 32 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
• Medications: from 2 months prior to Day 1 (day of trial vaccine administration), to the end of 
the trial. 
• Vaccines: within 14 days before or after trial vaccine administration, to the end of the trial. 
• Blood products: 90 days prior to Day 1 (day of trial vaccine administration), to the end of the 
trial. 
• Antipyretics and/or analgesic medications within 24 hours prior to trial vaccine 
administration and the reason for their use (prophylaxis versus treatment) must be 
documented. Administration of the trial vaccine should be delayed if the subject has received 
antipyretics within 24 hours prior to trial vaccine administration. 
Medications taken for prophylaxis are those intended to prevent the onset of AEs after trial 
vaccine administration. Medications taken for treatment are intended to reduce or eliminate the 
presence of symptoms that are present. 
These data must be recorded in the source documents. 
9.1.3 Documentation of Trial Entry 
Only subjects for whom there is a signed ICF, who meet all of the inclusion criteria (Section 7.1) 
and none of the exclusion criteria (Section 7.2) are eligible for entry into the trial. Trial entry will 
be recorded in the subject screening and enrolment log. 
9.1.4 Physical Examination 
Physical examinations must be performed by a qualified health professional in accordance with 
local regulations and as listed within the site responsibility delegation log. A physical 
examination includes but is not limited to the following: a check of general appearance, 
auscultation of heart and lungs, palpation of the abdomen, and inspection of extremities 
(including skin over the intended injection site). A complete physical exam will be performed on 
Day 1, prior to trial vaccine administration, according to the investigator’s standard practice. 
Additional symptom-directed physical examinations may be performed on Day 8 and Day 29 if 
indicated by review of the subject’s medical history or if deemed necessary. 
9.1.5 Vital Signs 
During the physical examination, a subject should have their vital signs measured. These will 
include (but are not limited to), heart rate and body temperature. The investigator will follow 
standard of care for trial population and operational feasibility. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 33 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
9.1.6 Immunogenicity Assessments 
The immunogenicity assessments will include: 
• Blood for the primary endpoint (proficiency panel) will be collected from all 80 subjects at 
Day 1 and Day 29, corresponding to approximately 100 mL of serum from a total 200 mL of 
blood from an individual subject. 
• 
 
The blood sampling volumes are shown in Table 9.a. 
Table 9.a 
Blood Sampling Volumes 
Sample 
Day 1 
Day 8 
Day 29 
Total volume per Subject 
Blood for serum* and ** 
100 mL 
- 
100 mL 
200 mL blood 
) ** 
10 mL 
- 
10 mL 
20 mL blood 
(total 110 mL) 
 
30 mL 
30 mL 
30 mL 
90 mL blood 
Total volume per blood draw 
140 mL 
30 mL 
140 mL 
310 mL blood 
Abbreviations: 
 
Notes: *serum-based assays include histoblood group antigen (HBGA)-blocking assay, pan-Ig enzyme-linked 
immunosorbent assay (ELISA
 
 
 
All samples must be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood taken at any single site visit is approximately 140 mL, and the 
approximate total volume of blood for the trial is maximum 310 mL. 
9.1.7 Processing, Labeling and Storage of Biological Samples 
All biological samples (e.g., blood and serum) will be processed, labeled, and stored according to 
the laboratory manual or other appropriate guideline provided to the site (Section 9.4). 
9.1.8 Safety Assessments 
Safety assessments will include: 
• For 7 days after vaccination (including the day of vaccination), solicited local AEs (injection 
site: pain, erythema, induration and swelling); solicited systemic AEs (headache, fatigue, 
myalgia, arthralgia, vomiting, and diarrhea), and body temperature. 
• For 28 days after vaccination (including the day of vaccination), unsolicited AEs. 
• Throughout the trial, SAEs and AEs leading to withdrawal from the trial. 
Refer to Section 10.1 for safety definitions. Details on collection and reporting of AEs are in 
Section 10.5. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 34 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
9.1.9 Contraception and Pregnancy Avoidance Procedure 
For female subjects of childbearing potential, pregnancy testing (urine) will be performed on 
Day 1 prior to trial vaccine administration. All subjects will be provided with information on 
acceptable methods of contraception as part of the subject informed consent process and will be 
asked to sign a consent form stating that they understand the requirements for avoidance of 
pregnancy and donation of ova. In each case of delayed menstrual period (over one month 
between menstruations) confirmation of absence of pregnancy is strongly recommended. 
Refer to Section 7.2. 
9.1.10 Pregnancy 
To ensure subject safety and the safety of the unborn child, each pregnancy occurring during the 
trial in a subject having received the trial vaccine must be reported to the sponsor promptly. If 
the subject agrees, the pregnancy must be followed to determine outcome, including spontaneous 
or voluntary termination, details of birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. If the subject agrees, this 
follow-up should occur even if the intended duration of safety follow-up for the trial has ended. 
Any pregnancy occurring following trial vaccine administration should be reported immediately, 
using the paper pregnancy report form, to the contact listed in the investigator site file. 
Should the pregnancy occur after administration of the trial vaccine, the investigator must inform 
the subject of their right to receive information concerning the trial vaccine. 
Any SAE occurred during pregnancy should be reported throughout the trial as per timelines and 
procedures described in Section 10.4.4. 
9.1.11 Documentation of Subjects Who Are Not Randomized 
This trial is open-label. 
Subject numbers assigned to subjects who fail screening should not be re-used. 
9.2 
Monitoring Subject Compliance 
The investigator will record the injection of trial vaccine given to the subject. 
9.3 
Schedule of Observations and Procedures 
The schedule for all trial-related procedures for all evaluations is shown in Section 2.2. 
Assessments should be completed at the designated site visit(s)/time point(s). 
9.3.1 Pre-Vaccination Procedures (Day 1) 
The following procedures must be performed before trial vaccine administration: 
1. Informed consent (ICF) (Section 9.1.1). 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 35 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
2. Assessment of eligibility criteria (Section 7.1 and Section 7.2). 
3. Demographics (Section 9.1.2). 
4. Medical history (Section 9.1.2). 
5. Medication/vaccination history (Section 9.1.2). 
6. Concomitant medications and vaccines (Section 9.1.2). 
7. Documentation of trial entrance (Section 9.1.3). 
8. Complete physical examination (Section 9.1.4). 
9. Vital signs (Section 9.1.5). 
10. Blood sampling (~ 140 mL) (Section 9.1.6). 
11. Pregnancy test (Section 9.1.10). 
9.3.2 Vaccination Procedures (Day 1) 
After completing all pre-vaccination procedures (Section 9.3.1) and assessing the criteria for the 
delay of trial vaccine administration, the investigator will administer the trial vaccine according 
to the procedures described in Section 8.5. 
9.3.3 Post-Vaccination Procedures (Day 1) 
The following post-vaccination procedures will be performed on Day 1: 
• Training of the subject on how to measure solicited local AEs and body temperature, how to 
complete the diary card and how often to complete the diary card. Training should be 
directed at the individual(s) who will perform the measurements of solicited local AEs and 
those who will enter the information into the diary card. This individual may or may not be 
the subject, but if a person other than the subject enters information into the diary card, this 
person’s identity must be documented in the source and this person must receive training on 
the diary card. Training of the subject on how to measure an injection site AE and how to 
take their temperature, as well as how to record the information in the diary card, should be 
performed while the subject is under observation after vaccination. 
Diary card instructions must include the following: 
The individual(s) who will enter the information in the must understand that timely completion 
of the diary card on a daily basis is a critical component of trial participation. 
Please note: 
The diary card will be the only source document allowed for remote collection of solicited local 
and systemic AEs (including body temperature measurements). The following additional rules 
apply to the documentation of safety information collected by diary card: 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 36 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
• The diary card should be reviewed with the subject. 
• No corrections or additions to the diary card will be allowed after it is reviewed with the 
investigator/designee. 
• Any data that are identified as implausible or incorrect, and confirmed by the subject to be an 
error should be corrected by the subject on the diary card. 
• Any blank fields on the diary card not otherwise corrected as above will be missing in the 
eCRF. 
The site must enter all readable entries on the diary card into the eCRF. 
• Any newly-described solicited safety information should be added to the diary card by the 
subject. Any new unsolicited safety information would be recorded in the subject’s source 
document as a verbally-reported event and therefore captured as an AE and recorded in the 
AE eCRF. 
• Starting on the day of trial vaccine administration, the subject will check for specific types of 
events at the injection site, any specific generalized symptoms (solicited systemic AEs), body 
temperature (any method), any other symptoms or change in the subject’s health status, and 
any medications taken (excluding vitamins and minerals). These solicited AEs, body 
temperature, other symptoms and medications will be recorded in the diary card. 
Assessments should preferably take place in the evening. 
• Temperature measurement is to be performed using the thermometer provided by the site. If 
the subject feels unusually hot or cold during the day, the subject should check their 
temperature. If the subject has fever, the highest body temperature observed that day should 
be recorded in the diary card. 
• The measurements of solicited local AEs are to be performed using the ruler provided by the 
site. 
• The collection in the diary card of body temperature, solicited local AEs, and solicited 
systemic AEs will continue for a total of 7 days after trial vaccine administration (Day 1). 
• The use of analgesic/antipyretic medications to treat symptoms associated with trial vaccine 
administration will be recorded in the diary card during the reporting period (Day 1 to 
Day 7). 
After trial vaccine administration, the subject will be observed for at least 30 minutes including 
observation for unsolicited AEs, solicited local AEs, solicited systemic AEs, and body 
temperature measurement. Information should be recorded in the eCRF. The investigator or 
delegate will take the opportunity to remind the subject how to measure solicited local AEs and 
body temperature as part of this observation period. All safety data will be collected in the 
subject’s source documents. 
The site staff should schedule the next trial activity reminder call or site visit. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 37 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
The subject will receive a written reminder of the next planned trial activity. The subject will be 
reminded to complete the diary card daily and to contact the site if there are any questions and to 
contact the site immediately (or as soon as the subject is medically stable) if the subject has a 
medical condition that leads to a hospitalization or an emergency room visit. All contact details 
will be provided to the subject. 
9.3.4 Site Visits After Vaccination (Day 8 and Day 29) 
Site visits that do NOT include a vaccination will be performed on Day 8 and Day 29. 
Procedures include diary card review (Day 8 visit only solicited AEs) and blood draw. If 
applicable, a symptom-directed physical examination (including vital signs) may be performed. 
Information relating to unsolicited AEs will be obtained by interview at the Day 29 visit. The 
healthcare professional reviewing these data will discuss the AEs (if any) reported by the subject 
and will determine if any additional diagnoses and/or AEs are present and/or if concomitant 
medications and vaccines have been used. 
Blood (30-140 mL/visit) should be taken from the subject using an aseptic venipuncture 
technique for serological immunogenicity testing. 
The site should schedule the next site visit or other trial activity with the subject. 
The subject will receive a written reminder of the next planned trial activity. The subject will be 
reminded to contact the site if there are any questions and to contact the site immediately (or as 
soon as the subject is medically stable) if the subject has a medical condition that leads to a 
hospitalization or an emergency room visit. 
9.3.5 Phone Contact – Safety Call and Final Contact (Day 85) 
The final (end of trial) contact will be a phone contact on Day 85. 
These calls will facilitate the collection of relevant safety information including concomitant 
medication, and any AEs/SAEs the subject may have experienced since receiving the trial 
vaccine. All safety information described by the subject must be written down in a designated 
location within the source documents. 
The investigator must complete the end of trial eCRF page for all subjects who received trial 
vaccine. 
9.3.6 Post-Trial Care 
No post-trial care will be provided. 
9.4 
Biological Sample Retention and Destruction 
In this trial, specimens for immune response testing will be collected as described in 
Section 9.1.6. After blood draw and serum processing, the serum samples will be preserved and 
retained at a central laboratory that was contracted by the sponsor for this purpose for up to but 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 38 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
not longer than 20 years or as required by applicable law. The sponsor has put into place a 
system to protect the subject’s personal information to ensure optimal confidentiality and defined 
standard processes for sample and data collection, storage, analysis, and destruction. 
Serum samples will be used for the analyses defined in this protocol, but can also, with 
permission from the subject, be used to assess, improve, or develop tests related to norovirus or 
the investigational vaccine that will allow more reliable measurement of the response to the 
investigational vaccine. Serum samples could also be used for further exploratory testing. If the 
subject does not consent to future testing of samples on the ICF, the subject can still participate 
in the trial. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 39 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a trial vaccine; it does not necessarily have to have a causal relationship with trial 
vaccine administration. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the administration 
of a trial vaccine whether or not it is considered related to the trial vaccine. 
AEs will be graded by the investigator in the following manner: 
Mild 
Grade 1 
• 
Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities. Relieved with or without 
symptomatic treatment. 
Moderate 
Grade 2 
• 
Sufficient discomfort is present to cause interference with normal activity. 
Only partially relieved with symptomatic treatment. 
Severe 
Grade 3 
• 
Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities. Not relieved with 
symptomatic treatment. 
10.1.2 Solicited Adverse Events 
The occurrence of selected indicators of safety will be measured/collected for 7 days after trial 
vaccine administration (including the day of administration) and will be recorded on the local 
and systemic AEs eCRF page as applicable and as listed in Table 10.a. 
Any solicited local or systemic AEs observed as continuing on Day 8 trial vaccine administration 
will be recorded as an AE on the AE eCRF for follow-up. For these persistent/prolonged 
solicited AEs the end date will be captured on the AE eCRF to permit a separate analysis from 
the unsolicited AEs (see Section 10.4.2). 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 40 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
Table 10.a 
Solicited Local and Systemic AEs 
Solicited local AEs: 
Erythema 
Induration 
Swelling 
Pain 
Systemic AEs: 
Headache 
Fatigue 
Myalgia 
Arthralgia 
Vomiting 
Diarrhea 
Fever* 
Body temperature will be collected and recorded. *Fever is defined as body temperature ≥38°C (100.4°F) regardless 
of method used [25]. 
The severity of solicited safety parameters will be assessed as described in Table 10.b. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 41 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
Table 10.b 
Solicited Safety Parameters 
Adverse Event 
Severity 
Grade 
Intensity 
Pain at injection site 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without treatment 
3 
Severe: Prevents daily activity with or without treatment 
Erythema at injection site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Induration at injection site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤50 mm 
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Swelling at injection site (a) 
0 
<25 mm 
1 
Mild: >25 – ≤50 mm  
2 
Moderate: >50 – ≤100 mm 
3 
Severe: >100 mm 
Headache 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity with or without treatment 
3 
Severe: Prevents daily activity with or without treatment 
Fatigue 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Myalgia  
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe: Prevents daily activity 
Arthralgia 
0 
None 
1 
Mild: No interference with daily activity 
2 
Moderate: Interference with daily activity 
3 
Severe Prevents daily activity 
Vomiting 
0 
None 
1 
Mild: No interference with activity or 1 – 2 episodes/24h 
2 
Moderate: Some interference with activity or >2 episodes/24h 
3 
Severe: Prevents activity, requires outpatient IV hydration 
Diarrhea 
0 
None 
1 
Mild: 2 – 3 loose stools/24h 
2 
Moderate: 4 – 5 loose stools/24h 
3 
Severe: ≥6 watery stools/24h or requires outpatient IV hydration 
Fever (b) 
Record body temperature in °C/°F 
Abbreviations: h, hour; IV, intravenous. 
(a) Subjects are to record greatest surface diameter in mm on the diary. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 42 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
(b) Fever is defined as body temperature greater than or equal to 38°C (100.4°F) regardless of method used [25]. 
10.1.3 Adverse Events of Special Interest 
Not applicable. No adverse event of special interest (AESI) has been identified for this trial. 
10.1.4 Medically-Attended Adverse Events 
No medically-attended adverse events (MAAEs) will be collected in this trial. 
10.1.5 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• The term life threatening refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT in the offspring of a subject. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 to 5 above. 
• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 43 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
10.2 
Causality of Adverse Events 
Relationship (causality) to the trial vaccine will also be assessed by the investigator. The 
relationship of each AE to the trial vaccine, including solicited systemic AEs (solicited local AEs 
are considered as related by default) will be assessed using the following categories: 
Related: 
There is suspicion that there is a relationship between the trial vaccine and 
the AE (without determining the extent of probability); there is a reasonable 
possibility that the trial vaccine contributed to the AE. 
Not Related: 
There is no suspicion that there is a relationship between the trial vaccine 
and the AE; there are other more likely causes and administration of the 
trial vaccine is not suspected to have contributed to the AE. 
10.2.1 Relationship to Trial Procedures 
Relationship (causality) to trial procedures should be determined for all AEs. 
The relationship should be assessed as related to trial procedure if the investigator considers that 
there is a reasonable possibility that an event is due to a trial procedure. Otherwise, the 
relationship should be assessed as not related. 
10.2.2 Outcome of Adverse Events 
The outcome of AEs can be described as follows: 
Resolved: 
The subject has fully recovered from the event or the condition has 
returned to the level observed at baseline. 
Resolving: 
The event is improving but the subject is still not fully recovered. 
Not resolved: 
The event is ongoing at the time of reporting and the subject has 
still not recovered. 
Resolved with sequelae: 
As a result of the AE, the subject suffered persistent and significant 
disability/incapacity (e.g., became blind, deaf or paralysed). 
Fatal: 
The subject died due to the event. If the subject died due to other 
circumstances than the event, the outcome of the event per se 
should be stated otherwise (e.g., not resolved or resolving). 
Unknown: 
If outcome is not known or not reported. 
10.3 
Additional Points to Consider for Adverse Events 
An untoward occurrence generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. Intermittent 
events for pre-existing conditions or underlying disease should not be considered as AEs. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 44 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require a change in concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
Diagnoses vs. signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, signs or symptoms should be recorded appropriately as AEs. 
Worsening of AEs: 
• If the subject experiences a worsening or complication of an AE after administration of the 
trial vaccine, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
worsening of…). 
• If the subject experiences a worsening or complication of an AE, the worsening or 
complication should be recorded as a new AE. Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., worsening of…). 
Changes in severity of AEs: 
• If the subject experiences changes in severity of an AE, the event should be captured once 
with the maximum intensity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of the 
ICF are not considered as AEs. Complications resulting from any planned surgery should be 
reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs, but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs. 
Trial procedures: 
• Adverse occurrences related to trial procedures after signing of the ICF are considered as 
AEs and should be reported as AEs. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 45 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
AEs occurring during pregnancy: 
• AEs that are associated with the pregnancy, or worsened by the pregnancy should be 
reported, as clinically indicated, using the appropriate pregnancy related terms or indicating 
the AE is during pregnancy by adding ‘during pregnancy’, ‘in pregnancy’ or ‘antepartum’. 
Other: 
• If possible, include anatomical location to the AE verbatim. 
• Death is the outcome of an AE, not the AE term. 
• Cause of death is the AE term. 
10.4 
Procedures 
10.4.1 Collection and Reporting Procedures 
All AEs, whether considered related to the use of the trial vaccine or not, must be monitored by 
the investigator until symptoms subside and any abnormal laboratory values have returned to 
baseline, or until there is a satisfactory explanation for the changes observed, or until death, in 
which case a full autopsy report should be supplied, if possible. All findings must be reported on 
the AE eCRF and on the paper SAE report form*, if necessary (see Section 10.4.4). All findings 
in a subject experiencing an AE must also be documented in that subject’s source documents. 
Any unsolicited AE will be collected by the subject for 28 days post-dose. AEs leading to 
withdrawal from the trial are collected throughout the trial. 
The following information will be documented for each event: 
• Reported term for the AE. 
• Start and end date, duration. 
• Serious (Y/N). 
• Intensity. 
• Investigator’s opinion of the causality (relationship) between the event and administration of 
trial vaccine (related or not related). 
• Investigator’s opinion of the causality (relationship) to trial procedure(s), including the 
details of the suspected procedure. 
• Outcome of event. 
*SAE reporting will be done with a paper SAE form emailed (encrypted) or faxed 
: 
 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 46 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
10.4.2 Collection and Reporting of Solicited Adverse Events 
The occurrence of selected indicators of safety will be collected in the diary card by the subject 
for 7 days after administration of the trial vaccine (including the day of administration, 
corresponding to Day 1 and will be recorded on the local and systemic AEs eCRF, as applicable. 
These will be summarized in the final CSR under the category solicited AEs to differentiate them 
from unsolicited AEs. Any solicited local (injection site) or systemic AE observed as continuing 
on Day 8 after the trial vaccine administration will be recorded as an AE on the AE eCRF for 
follow-up. For these persistent/prolonged solicited AEs, the end date will be captured on the AE 
eCRF to permit a separate analysis from the unsolicited AEs. 
Any solicited AE that meets any of the following criteria must be entered as an AE on the AE 
eCRF page: 
• Solicited local or systemic AEs that lead the subject to withdraw from the trial. 
• Solicited local or systemic AEs that lead to the subject being withdrawn from the trial by the 
investigator. 
• Solicited local and systemic AEs that otherwise meet the definition of an SAE 
(see Section 10.1.2). 
10.4.3 Collection and Reporting of Adverse Events of Special Interest/Medically-
Attended Adverse Events 
AESIs and MAAEs will not be collected. 
10.4.4 Collection and Reporting of Serious Adverse Events 
Collection of SAEs will commence from the time that the subject is administered the trial 
vaccine (Day 1). Routine collection of SAEs will continue until the end of the trial (Day 85). 
SAEs should be reported according to the following procedure: 
A paper SAE report form must be completed, in English, and signed by the investigator 
immediately or within 24 hours of first onset or notification of the event. The information should 
be completed as fully as possible but contain, at a minimum: 
• A short description of the event and the reason the event is categorized as serious. 
• Causality assessment. 
• Protocol number. 
• Subject identification number. 
• Investigator’s name. 
The paper SAE form must be transmitted within 24 hours to 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 47 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
10.5 
Follow-up Procedures 
10.5.1 Adverse Events 
All AEs will be monitored until resolution or a stable status is reached, or until a formal 
diagnosis can be made or until the end of the trial, whichever occurs first. 
10.5.2 Serious Adverse Events 
If information is not available at the time of the first report becomes available later, the 
investigator should complete a paper follow-up SAE report form and provide relevant source 
documentation immediately. Copies of any relevant data from the hospital notes (e.g., laboratory 
tests, discharge summary, postmortem results) should be sent to the sponsor after redaction of 
any personal information for privacy. All SAEs should be followed up within the trial until 
resolution, permanent outcome of the event, or are otherwise explained. The timelines and 
procedure for follow-up reports are the same as those for the initial report. 
10.5.3 Safety Reporting to Investigators, Institutional Review Boards, and Regulatory 
Authorities 
The sponsor or designee will be responsible for the reporting of all suspected unexpected serious 
adverse reactions (SUSARs) and any other SAEs to regulatory authorities, investigators and IRB, 
as applicable, in accordance with national guidelines and regulations. Relative to the first 
awareness of the event by/or further provision to the sponsor or designee, SUSARs will be 
submitted within 7 days for fatal and life-threatening events and 15 days for other SUSARs, 
unless otherwise required by national regulations. The sponsor will also prepare an expedited 
report for other safety issues where these might materially alter the current benefit-risk 
assessment of the trial vaccine, or that would be sufficient to consider changes in the trial 
vaccine administration or in the overall conduct of the trial. The investigational site will also 
forward a copy of all expedited reports to its IRB in accordance with national guidelines and 
regulations. 
10.5.4 Post-Trial Events 
Any SAE that occurs outside of the protocol-specified observation period or after the end of the 
trial, but is considered to be caused by the trial vaccine must be reported to the sponsor. These 
SAEs will be processed by the sponsor or designee. Instructions for how to submit these SAEs 
will be provided in a handout in the investigator site file. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 48 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
11.0 
TRIAL-SPECIFIC REQUIREMENTS 
An independent DMC has been established for the HIL-214 clinical development program. The 
DMC will review the SAEs throughout the trial and convene as needed. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 49 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
12.0 
DATA HANDLING AND RECORD KEEPING 
The full details of procedures for data handling will be documented in the data management plan. 
AEs, medical history, and concurrent medical conditions will be coded using the current Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the current 
WHO Drug Dictionary. 
12.1 
Electronic CRFs 
Completed eCRFs are required for each subject for whom there is a signed ICF. 
The sponsor or designee will supply the investigative site with access to eCRFs. The sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this trial to the sponsor and regulatory 
authorities. eCRFs must be completed in English. Data entered onto the eCRFs must be checked 
against the source documents. 
After completion of the entry process, computer logic checks will be run to identify erroneous 
items, such as inconsistent dates, missing data, and questionable values. Queries may be issued 
by sponsor personnel (or designee) and will be answered by the site. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for the change. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the trial site during periodic visits 
by trial monitors. The sponsor or designee will be permitted to review the subject’s medical and 
hospital records pertinent to the trial to ensure accuracy of the eCRFs. The completed eCRFs are 
the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator must agree to keep the records stipulated in Appendix A and those documents 
that include (but are not limited to) the trial-specific documents, and the log that identifies all the 
medical records of the participating subjects. The investigator must also agree to keep temporary 
media, such as thermal sensitive paper (which should be copied and certified), source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICF), eCRFs, including the audit trail, and 
detailed records of vaccine disposition, to enable evaluations or audits from regulatory 
authorities, the sponsor or designee. Furthermore, ICH E6 Section 4.9.5 [2] requires the 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 50 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
investigator to retain essential documents specified in ICH E6 (Section 8) until at least 2 years 
after the last approval of a marketing application for a specified vaccine indication being 
investigated or, if an application is not approved, until at least 2 years after the investigation is 
discontinued and regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that 
the trial records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the clinical trial site agreement between the investigator 
and sponsor. 
Refer to the clinical trial site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 51 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
13.0 
STATISTICAL METHODS 
The statistical considerations for NOR-215 are described in the following sections. 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all trial objectives. 
13.1.1 Analysis Sets 
Analyses will be performed on the Safety Set. 
The Safety Set will consist of all subjects who received HIL-214. The Safety Set will be used for 
the analyses of safety and immunogenicity data. 
The Per Protocol Set will consist of all subjects who received HIL-214 and did not have any 
major protocol deviations that impact immunogenicity. The Per Protocol Set will be used for 
supportive analyses of the immunogenicity data. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographics, age, sex, race, and other baseline characteristics will be summarized 
descriptively for all subjects who received HIL-214. Summaries of continuous variables will 
include mean, standard deviation, median, minimum and maximum values. For categorical 
variables, count and percentage of subjects in each category will be computed. 
13.1.3 Primary Analysis - Immunogenicity 
Descriptive statistics will be computed for HBGA-blocking titers and pan-Ig titers against GI.1 
and GII.4c, measured at Day 1 and Day 29. These statistics will include the geometric mean 
titers (GMTs), geometric mean fold rise in titers (GMFR) from baseline (Day 1), and 
seroresponse rate (SRR). The SRR is defined as the percentage of subjects with a seroresponse, 
where seroresponse is a ≥4-fold rise in titer from baseline (Day 1). The 95% confidence intervals 
(CI) will be provided for geometric means and the SRRs. 
13.1.4 Secondary Analysis - Safety 
Safety data will be summarized by computing number and percentage of subjects who 
experienced an AE. 
Solicited AEs 
Solicited AEs will be assessed 30 minutes after administration of trial vaccine then daily for 7 
days (including the day of administration). Summaries will be provided for each solicited AE, 
daily from Day 1 to Day 7 after administration of trial vaccine (including the day of dose) and 
overall. Solicited local AEs and systemic AEs will also be summarized by severity. For subjects 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 52 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
with more than 1 episode of the same event within the Day 1 to Day 7 period, the maximum 
severity will be used for overall tabulations. Body temperature measurements will be 
summarized in categories (including fever, defined as temperature ≥38°C). Summaries of the day 
of first onset of each event and the number of days subjects experienced each event will also be 
provided. Data from the 30-minutes assessment will be summarized separately. 
Unsolicited AEs 
Unsolicited AEs, SAEs, and AEs leading to withdrawal from the trial will be coded using the 
MedDRA and summarized by preferred term (PT) and system organ class (SOC). Subjects 
reporting more than 1 occurrence for the term (level) being summarized will be counted only 
once for this term. Unsolicited AEs collected up to 28 days after administration (including the 
day of administration) of trial vaccine, will be summarized by severity (mild, moderate, severe) 
and relationship (not related, related) to trial vaccine or trial procedures. If a subject reported 
more than one AE within an SOC or PT then the event with the maximum severity and strongest 
relationship (causality) to trial vaccine or trial procedure will be included in the summaries. Any 
unsolicited AE will be summarized using the day of onset for the following 3 time intervals: 1) 
Day 1 to Day 28, 2) Day 1 to Day 7, and 3) Day 8 to Day 28. 
SAEs and AEs leading to withdrawal from the trial will be summarized for Day 1 to Day 28, and 
overall (up to Day 85). 
13.1.5 Exploratory Analyses 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned for this trial. 
13.3 
Determination of Sample Size 
A sample size of 80 subjects will provide sufficient serum for the establishment of proficiency 
panels to confirm assay validation of the validated serology assays planned to support the clinical 
development plan for HIL-214. 
E ective

HIL-214 
 
Trial No. NOR-215 
Page 53 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Trial-Site Monitoring Visits 
Monitoring visits to the trial site will be made periodically during the trial to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or designee 
(clinical research organization [CRO]) and by the IRB. 
All aspects of the trial and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the investigator site file, trial vaccine records, subject 
medical records, ICF documentation, documentation of subject authorization to use personal 
health information (if separate from the ICF), and review of eCRFs and associated source 
documents. It is important that the investigator and other trial personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the medical 
monitor (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospective approved deviation) from the inclusion or exclusion criteria. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The trial site also may be subject to quality assurance audits by the sponsor or designee. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the vaccine is stored and prepared, and any other facility used during the trial. In addition, 
there is the possibility that this trial may be inspected by regulatory agencies, including those of 
foreign governments. If the trial site is contacted for an inspection by a regulatory body, the 
sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all trial documents as described in Section 14.1. 
14.4 
Trial Risk Management 
The ICH E6 addendum (R2) guidance [2] encourages a risk-based approach to the management 
of clinical trials and includes requirements for risk control and risk reporting. Before initiation of 
the trial, the sponsor or designee will establish quality tolerance limits (QTL) taking into 
consideration the medical and statistical characteristics of the variables and the statistical design 
of the trial. This process will be performed according to the sponsor internal procedures. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 54 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
At the end of the trial, the quality management approach implemented will be described in the 
CSR. If applicable, the CSR will summarize important deviations from the predefined QTL and 
the remedial actions taken. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 55 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
15.0 
ETHICAL ASPECTS OF THE TRIAL 
This trial will be conducted with the highest respect for the trial subjects according to the 
protocol, the ethical principles that have their origin in the Declaration of Helsinki [1], and the 
ICH Harmonized Tripartite Guideline for GCP E6 (R2) [2]. Each investigator will conduct the 
trial according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the Responsibilities of the Investigator that are listed in Appendix A. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
15.1 
Institutional Review Board Approval 
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct participation in 
this trial, written notification regarding his or her abstinence from voting must also be obtained. 
Those US sites unwilling to provide names and titles of all members due to privacy and conflict 
of interest concerns should instead provide a Federal Wide Assurance Number or comparable 
number assigned by the Department of Health and Human Services. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if applicable, 
subject recruitment materials and/or advertisements and other documents required by all 
applicable laws and regulations, must be submitted to a central or local IRB for approval. The 
IRB’s written approval of the protocol and subject ICF must be obtained and submitted to the 
sponsor or designee before commencement of the trial (i.e., before shipment of the trial vaccine 
or trial specific screening activity). The IRB approval must refer to the trial by exact protocol 
title, number, and version date; identify versions of other documents (e.g., the ICF) reviewed; 
and state the approval date. The sponsor will notify the site once the sponsor has confirmed the 
adequacy of site regulatory documentation and, when applicable, the sponsor has received 
permission from the competent authority to begin the trial. Until the site receives 
notification/approval no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, recruitment materials 
intended for viewing by the subject, local safety reporting requirements, reports and updates 
regarding the ongoing review of the trial at intervals specified by the respective IRB, and 
submission of the investigator’s final status report to the IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or designee. 
Incentives should not be used to exert undue influence on the subject for participation. Payments 
to subjects must be approved by the IRB and sponsor. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 56 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki [1] and the ICH Guidelines for GCP [2] and will be in accordance with 
all applicable laws and regulations. The ICF, subject authorization form (if applicable), and 
subject information sheet describe the planned and permitted uses, transfers, and disclosures of 
the subject’s personal and personal health information for the purpose of conducting the trial. 
The ICF and the subject information sheet further explain the nature of the trial, its objectives, 
and potential risks and benefits, as well as the date informed consent is given. The ICF will detail 
the requirements of the subject and the fact that the subject is free to withdraw at any time 
without giving a reason and without prejudice to the subject’s further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF and if 
applicable, the subject authorization form. The ICF, subject authorization form (if applicable), 
and subject information sheet must be approved by both the IRB and the sponsor prior to use. 
The ICF, subject authorization form (if applicable), and subject information sheet must be 
written in a language fully comprehensible to the prospective subject. It is the responsibility of 
the investigator to explain the detailed elements of the ICF, subject authorization form (if 
applicable), and subject information sheet (if applicable) to the subject. Information should be 
given in both oral and written form whenever possible and in the manner deemed appropriate by 
the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the trial and (2) 
decide whether or not to (allow the child to) participate in the trial. If the subject determines he 
or she will participate in the trial, then the ICF and subject authorization form (if applicable) 
must be signed and dated by the subject, at the time of consent and prior to the subject entering 
into the trial. The subject should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the ICF and subject 
authorization (if applicable) at the time of consent and prior to the subject entering into the trial; 
however, the sponsor may allow a designee of the investigator to sign to the extent permitted by 
applicable law. 
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet will be stored in the investigator’s site file. The investigator must document the date the 
subject signs the ICF in the subject’s medical record and eCRF. Copies of the signed ICF, the 
signed subject authorization form (if applicable), and subject information sheet (if applicable) 
shall be given to the subject. 
All revised ICFs must be reviewed and signed by the subject in the same manner as the original 
ICF. The date the revised consent was obtained should be recorded in the subject’s medical 
record and eCRF, and the subject should receive a copy of the revised ICF. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 57 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
15.3 
Subject Confidentiality 
The sponsor and designee affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this trial, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee, representatives from any 
regulatory authority, the sponsor’s designated auditors, and the appropriate IRBs to review the 
subject’s original medical records (source data or documents), including, but not limited to, 
laboratory test result reports, electrocardiogram (ECG) reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s trial participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the ICF process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 58 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
15.4 
Clinical Trial Registration, Publication, and Disclosure Policy 
15.4.1 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, the sponsor will, as a minimum register all 
clinical trials conducted in subjects that it sponsors anywhere in the world, on publicly accessible 
websites such as ClinicalTrials.gov, according to local requirements, before trial initiation. The 
sponsor contact information, along with the investigator’s city, country, and recruiting status will 
be registered and available for public viewing. 
15.4.2 Clinical Trial Results Disclosure 
The sponsor’s clinical trial disclosure policy aims to comply with the clinical trial data disclosure 
requirements of all relevant regions. The sponsor will post the results of this clinical trial 
regardless of outcome, on publicly accessible websites such as ClinicalTrials.gov, as required by 
applicable laws and/or regulations. 
Completion of trial corresponds to the date on which the final subject was examined or received 
an intervention for the purpose of final collection of data (usually corresponds to last subject last 
visit ([LSLV]). 
15.4.3 Publication of Trial Results 
The results of this trial are expected to be published in a peer-reviewed scientific journal 
Publication of trial results will follow the sponsor’s publication policies, applicable international 
standards and guidelines for good publication practice, applicable laws, and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the trial must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical trial insurance against the risk of injury to clinical trial subjects. 
Refer to the clinical trial site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 59 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
16.0 
REFERENCES 
1. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects. https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-
for-medical-research-involving-human-subjects/ (accessed 20 October 2023). 
2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH). ICH harmonized guideline. Integrated Addendum to ICH E6 (R2): 
Guideline for Good Clinical Practice E6. 
3. Mans J. Norovirus Infections and Disease in Lower-Middle- and Low-Income Countries, 
1997–2018. Viruses. 2019;11(4):341. 
4. Glass RI, Parashar UD, Estes MK. Norovirus gastroenteritis. N Engl J Med. 
2009;29;361(18):1776-85. 
5. Lopman B, Gastañaduy P, Park GW, Hall AJ, Parashar UD and Vinjé J. Environmental 
transmission of norovirus gastroenteritis. Curr Opin Virol. 2012;2(1):96-102. 
6. Cannon JL, Bonifacio J, Bucardo F, Buesa J, Bruggink L, Chan MC et al. Global Trends in 
Norovirus Genotype Distribution among Children with Acute Gastroenteritis. Emerg Infect 
Dis. 2021 May;27(5):1438-1445. 
7. Hall AJ, Lopman BA, Payne DC, Patel MM, Gastañaduy PA, Vinjé J et al. Norovirus disease 
in the United States. Emerg Infect Dis. 2013;19(8):1198-205. 
8. Lopman B. Vennema H, Kohli E, Pothier P, Sanchez A, Negredo A et al. Increase in viral 
gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant. Lancet. 
2004;363(9410):682-688. 
9. Bernard H, Höhne M, Niendorf S, Altmann D and Stark K. Epidemiology of norovirus 
gastroenteritis in Germany 2001-2009: eight seasons of routine surveillance. Epidemiol 
Infect. 2014;142(1):63-74. 
10. Trivedi TK, Desai R, Hall AJ, Patel M, Parashar UD and Lopman BA. Clinical 
characteristics of norovirus-associated deaths: a systematic literature review. Am J Infect 
Control. 2013;41(7):654-7. 
11. van Asten L, van den Wijngaard C, van Pelt W, van de Kassteele J, Meijer A, van der Hoek 
W et al. Mortality attributable to 9 common infections: significant effect of influenza A, 
respiratory syncytial virus, influenza B, norovirus, and parainfluenza in elderly persons. J 
Infect Dis. 2012;206(5):628-39. 
12. Tan M and Jiang X. Association of histo-blood group antigens with susceptibility to 
norovirus infection may be strain-specific rather than genogroup dependent. J Infect Dis. 
2008;198(6):940-1; author reply 942-3. 
13. https://www.cdc.gov/norovirus/downloads/global-burden-report.pdf. (accessed 6 August 
2022). 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 60 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
14. Chhabra P, de Graaf M, Parra GI, Chan MC, Green K, Martella V, Wang Q, White PA, 
Katayama K, Vennema H, Koopmans MPG, Vinjé J. Updated classification of norovirus 
genogroups and genotypes. J Gen Virol. 2019;100(10):1393-1406. 
15. Siebenga JJ, Vennema H, Zheng DP, Vinjé J, Lee BE, Pang XL et al. Norovirus illness is a 
global problem: emergence and spread of norovirus GII.4 variants, 2001-2007. J Infect Dis. 
2009;200(5):802-12. 
16. Siebenga JJ. Vennema H, Renckens B, de Bruin E, van der Veer B, Siezen RJ et al. Epochal 
evolution of GGII.4 norovirus capsid proteins from 1995 to 2006. J. Virol. 2007;81(18): 
9932-41. 
17. Ferreira MS, Victoria M, Carvalho-Costa FA, Vieira CB, Xavier MP, Fioretti JM et al. 
Surveillance of norovirus infections in the state of Rio De Janeiro, Brazil 2005-2008. J Med 
Virol. 2010;82(8):1442-8. 
18. Estévez A, Arvelo W, Hall AJ, López MR, López B, Reyes L et al. Prevalence and genetic 
diversity of norovirus among patients with acute diarrhea in Guatemala. J Med Virol. 
2013;85(7):1293-8. 
19. Cannon JL, Bonifacio J, Bucardo F, Buesa J, Bruggink L, Chan MC et al. Global Trends in 
Norovirus Genotype Distribution among Children with Acute Gastroenteritis. Emerg Infect 
Dis. 2021;27(5):1438-1445. 
20. Safadi MA, Riera-Montes M, Bravo L, Tangsathapornpong, Lagos R, Thisyakorn et al. The 
burden of norovirus disease in children: a multi-country study in Chile, Brazil, Thailand and 
the Philippines. Int J Infect Dis. 2021;109:77-84. 
21. Current Global Investigator’s Brochure - Candidate Norovirus Bivalent GI.1/GII.4c Virus-
Like Particle Vaccine (HIL-214). 
22. Vesikari T, Saez-Llorens X, Blazevic V, Lopez P, Lopez E, Masuda T. Immunogenicity of a 
bivalent virus-like particle norovirus vaccine in children from 1 to 8 years of age: A phase 2 
randomized, double-blind study. Vaccine. 2022;40(26):3588-3596. 
23. Treanor J, Sherwood J, Cramer JP, Le Cam Bouveret N, Lin S, Baehner F, Borkowski A; 
NOR-204 investigators. A phase 2 study of the bivalent VLP norovirus vaccine candidate in 
older adults; impact of MPL adjuvant or a second dose. Vaccine. 2020;38(36):5842-5850. 
24. WHO 2015. Reducing pain at the time of vaccination: WHO position paper. Weekly 
Epidemiological Record. 2015, 90, 505-516. https://www.who.int/publications/i/item/who-
wer9039 (accessed 20 October 2023). 
25. Kohl KS, Marcy M, Blum M, Jones MC, Dagan R, Hansen J. et al. Fever after immunization: 
current concepts and improved future scientific understanding. Clin Infect Dis. 
2004;39(3):389-94. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 61 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
APPENDIX A RESPONSIBILITIES OF THE INVESTIGATOR 
Clinical research trials sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities: 
1. Conduct the trial in accordance with this protocol. 
2. Personally conduct or supervise the staff that will assist in the protocol. 
3. Ensure that trial related procedures, including trial specific (non-routine/non-standard panel) 
screening assessments, are NOT performed on potential subjects prior to the receipt of 
written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the trial are informed of 
these obligations. 
5. Secure prior approval of the trial and any changes by an appropriate IRB that conforms to 
Code of Federal Regulations (CFR) Part 6, ICH, and local regulatory requirements. 
6. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB all changes in research activity and all anticipated 
risks to subjects. Make at least yearly reports on the progress of the trial to the IRB, and issue 
a final report within 3 months of trial completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the trial, and document 
the date of consent in the subject’s medical chart. The valid ICF is the most current version 
approved by the IRB. Each ICF should contain a subject authorization section that describes 
the uses and disclosures of a subject’s personal information (including personal health 
information) that will take place in connection with the trial. If an ICF does not include such 
a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject. 
9. Prepare and maintain adequate case histories of all persons entered into the trial, including 
eCRFs, hospital records, laboratory results, etc., and maintain these data for a minimum of 
2 years after notification by the sponsor that all investigations have been discontinued or that 
the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of CTM, and return 
all unused CTM to the sponsor. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 62 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
12. Report AEs to the sponsor promptly. In the event of an SAE, notify PPD Safety within 24 
hours. 
13. Report pregnancies to PPD Safety promptly. 
14. Review and provide a signature as approval of the content of the clinical study report, if 
needed. 
Effective

HIL-214 
 
Trial No. NOR-215 
Page 63 of 63 
Protocol Version 3.0 
25 October 2023 
 
CONFIDENTIAL 
APPENDIX B INVESTIGATOR CONSENT TO USE OF PERSONAL INFORMATION 
The sponsor will collect and retain personal information of the investigator, including his or her 
name, address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (e.g., 
the United Kingdom, United States, and Japan), including the following: 
• The sponsor, its affiliates, and licensing partners. 
• Business partners assisting the sponsor, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs. 
The investigator’s personal information may be retained, processed, and transferred by the 
sponsor and these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the trial and/or other clinical trials. 
• Management, monitoring, inspection, and audit of the trial. 
• Analysis, review, and verification of the trial results. 
• Safety reporting and pharmacovigilance relating to the trial. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the trial. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other vaccines used in other clinical trials that may contain the 
same chemical compound present in the investigational vaccine. 
• Inspections and investigations by regulatory authorities relating to the trial. 
• Self-inspection and internal audit within the sponsor, its affiliates, and licensing partners. 
• Archiving and audit of trial records. 
• Posting investigator site contact information, trial details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the 
investigator’s own country. The investigator acknowledges and consents to the use of his or her 
personal information by the sponsor and other parties for the purposes described above. 
Effective

Eff