A Phase 2b, Double-blind, Randomized, Multi-site, Placebo-controlled Trial to Evaluate the Efficacy, Safety and Immunogenicity of Intramuscular HIL-214 Norovirus Vaccine in Healthy Children 5 Months of Age at Initial Vaccination
Phase: PHASE2
Conditions: Gastroenteritis
Sponsor: HilleVax

 
Title: A Phase 2b, Double-blind, Randomized, Multi-site, Placebo-controlled Trial to Evaluate the 
Efficacy, Safety and Immunogenicity of Intramuscular HIL-214 Norovirus Vaccine in Healthy Children 5 
Months of Age at Initial Vaccination 
Trial No.: NOR-212 
 
NCT: 05281094 

HIL-214 
 
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CONFIDENTIAL 
 
A Phase 2b, Double-blind, Randomized, Multi-site, Placebo-controlled Trial to Evaluate 
the Efficacy, Safety and Immunogenicity of Intramuscular HIL-214 Norovirus Vaccine 
in Healthy Children 5 Months of Age at Initial Vaccination 
(Efficacy and Safety of Two Doses of HIL-214 in Children) 
Sponsor: 
HilleVax 
 
Trial Identifier: 
NOR-212 
IND Number: 
014421 
EudraCT Number: 
Not Applicable 
Investigational 
Medicinal Product(s): 
• Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine 
• Placebo 
Protocol Date: 
1 September 2023 
Version: 
3.0 
CONFIDENTIAL PROPERTY OF HILLEVAX 
This document is a confidential communication of HilleVax. 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 except to the extent necessary to obtain informed consent from the legally 
authorized representative of those persons to whom the investigational product may be administered. 
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. 
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1.0 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
The list of contacts will be provided to the/each 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. 
SIGNATURES 
. 
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the investigator’s brochure (IB) 
[26], 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) 
 
 
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1.3 
Protocol Version V3.0 Summary of Changes 
This document describes the changes in reference to protocol version 2.0 (14 October 2022). 
The primary purpose of this amendment is to reduce the number of primary endpoint cases 
and to define the observation periods. 
 
. Full details on 
changes to the text are given in Section 1.3.2. 
1.3.1 Version History 
Table must include all approved versions, including the current version. 
Date 
Version 
Change Type 
Region 
6 October 2021 
1.0 
Not applicable 
Global 
14 October 2022 
2.0 
Substantial 
Global 
1 September 2023 
3.0 
Substantial 
Global 
1.3.2 Summary of Changes 
Summary of changes for protocol amendment 2 dated 1 September 2023 to protocol version 2.0 dated 
14 October 2022 
Section 
Description of Change 
Rationale for Change 
2.0 
Various changes. 
Consistent with the body of the 
protocol. 
2.1, 2.2, 
2.3 
4.2 
5.0 
Adjustment of the objectives and endpoint section for 
the primary endpoint cases, and analysis set and 
primary observation period definitions. 
Replace the expected number of 
endpoint cases (64), with the 
minimum number of cases for 80% 
power (24 cases). Define the 
analysis sets and the primary 
observation period. 
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6.1 
Arm 1 (N = 1500): One dose of HIL-214 onat Visit 1 
(Day 1) and one dose of HIL-214 between Day 29 and 
Day 57.at Visit 2 (28 to 56 days post dose 1). 
Arm 2 (N = 1500): One dose of placebo onat Visit 1 
(Day 1) and one dose of placebo between Day 29 and 
Day 57.at Visit 2 (28 to 56 days post dose 1). 
Change in the naming convention 
(applies throughout the protocol). 
 
The subject’s legally-authorized representative (LAR) 
(all subjects) will be contactedreceive weekly by 
phone, text messages or notifications via eDiary, or 
home visits by trained field workers for to complete the 
AGE surveillance, which should be made dailyreport if 
the subject has AGE is confirmed, and until the 
symptoms disappear.(episodes of vomiting and/or 
liquid stools). 
Correction to the description of 
method used for notifying subjects. 
 
The subject’s LARs will contact the site if the If the 
child has liquid/loose stools or vomiting, the LAR will 
enter the number of episodes in the eDiary to inform 
the site. The subject’s LARs will be requested to 
record AGE symptoms and their frequency, and body 
temperature in the eDiary (AGE symptoms log) from 
the first day of AGE onset until the symptoms have 
resolved. This log will be activated automatically if the 
number of episodes of vomiting and loose/liquid stools 
satisfies the AGE case definition. All subjects who 
meet the criteria for the AGE case definition will 
provide anone AGE onset stool sample. Subjects’ 
LARs and two AGE follow-on stool samples. AGE 
cases will be requested to enter the AGE into the 
Vigilant-e mobile appcollected starting from the first 
dayDay 1 (Dose 1 of AGE symptoms onsettrial 
vaccine) until the symptomsall subjects have 
resolved.reached 2 years of age (end of trial). The 
number of AGE cases including primary endpoint 
AGEs will be monitored during the trial in a blinded 
way. The process is described in the AGE monitoring 
charter. 
Clarification and further description 
of the process. 
 
• 
All AGE onset stool samples will be assayed 
for the presence of norovirus and norovirus-positive 
samples will be sequenced for genotype identification. 
Only norovirus-positive samples will be analyzed for 
the presence of co-pathogens. Follow-upon stool 
samples collected weekly for up to 2 and 3 weeks post-
onset will be analyzed for norovirus presence and 
genogroup only. 
Clarification. 
 
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6.2 
7.5 
‘There are circumstances … LAR is encouraged to 
allow the child to continue in trial participation for 
safety follow-up and efficacy and immunogenicity 
data collection.’ 
‘Early termination of a subject’s trial participation … 
may apply in which subjects may continue participating 
in the trial (e.g., contributing safety and other data 
according to protocol) but investigational vaccine 
administration is discontinued. Even if the subject is 
deemed ineligible to receive further doses of trial 
vaccine, all efforts should be made to continue the 
collection of safety data according to protocol.’ 
Clarification on the procedure for 
data collection if a subject 
terminates early. 
9.1.2 
Demographic information to be obtained will include 
age/date of birth (if applicable), sex, race (and 
ethnicity) as described by the subject’s LAR. 
All medications, vaccines and blood products taken or 
received by the subjects prior to Visit 1 (Day 1) are to 
be collected as prior and concomitant medications. 
a) 
Medications: 2 months prior to Visit 1 (Day 1, 
(day of vaccination). 
Clarification (stylistic change). 

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b) 
Vaccines: From birth up to Visit 1 (Day 1, 
(day of vaccination). 
c) 
Blood products: 3 months prior to Visit 1 (Day 
1, (day of vaccination). 
Concomitant medications and vaccines will be 
collected from Visit 1 (Day 1) to Visit 3 (28 days after 
the second dose). 
9.1.8 
Safety assessments are planned on at Visit 1 (Day 1,), 
Day 3 (phone contact), Day 8 (phone contact or visit), 
Day 29, 7Visit 2 (28 to 56 days post-Day 29 dose 1), 7 
days post dose 2 (phone contact) and Day 57Visit 3 (28 
days post dose 2), then when the subjects reach the age 
of 1 year, (Visit 4), 18 months (Visit 5) and 2 years. 
(Visit 6). The safety assessments will include 
collection and recording of solicited local (injection 
site) and systemic AEs (for 7 days post- vaccination), 
unsolicited AEs and AEs (serious and non-serious, for 
28 days followingpost vaccination).), and SAEs. Refer 
to Section 10.1 for safety definitions. Details on 
collection and reporting of AEs are in Section 10.5. 
Clarification (stylistic change). 
9.1.10 
9.3.3 
• 
The eDiary should be reviewed with bythe 
subject’s LAR site. 
Clarification and further description 
of the process. 
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• 
No corrections or additions to the eDiary will 
be allowed after it is reviewed with the 
investigator/designee. 
• 
Any the end of each day (midnight) in the 
solicited data that are identified as implausible or 
incorrect, and confirmed by the subject’s LAR to be an 
error should be corrected by the subject’s LAR on the 
eDiary. collection period (for 7 days post vaccination). 
• 
Any blank fields on the eDiary not otherwise 
corrected will be missing in the eCRF. 
• 
The site must enter all entries on the eDiary 
into the eCRF. 
• 
Any newly described solicited safety 
information should be added to the eDiary by the 
subject’s LAR. Any new unsolicited safety information 
would be recorded in the subject source document as a 
verbally reported event and therefore captured as an 
AE and recorded on the AE eCRF. 
• 
Starting on the day of vaccination, the 
subject’s LAR 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 
and body temperature will be recorded in the eDiary. 
Other symptoms and medications will be recorded in 
the memory aid section of the eDiary. Assessments 
should preferably take place in the evening. 
• 
Temperature measurement is to be performed 
daily using the thermometer provided by the site. If the 
subject feels unusually hot or cold during the day, the 
subject’s LAR should check their temperature. If the 
subject has fever, the highest body temperature 
observed that day should be recorded on the eDiary. 
• 
The collection on the eDiary of body 
temperature, solicited local (injection site) reactions, 
and solicited systemic AEs will continue for a total of 7 
days following vaccine administration (including day 
of administration). The collection recording of other 
symptoms on the eDiary of unsolicited AEs and 
medications in the memory aid section of the eDiary 
will continue for 28 days following vaccine 
administration by eDiary  (including day of 
administration). 
 
The subject’s LAR will receive a written reminder of 
the next planned trial activity. The subject’s LAR will 
be reminded to complete the eDiary daily and to 
contact the site if there are any questions and to contact 
the site immediately (or as soon as the subject is 
Clarification. 
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medically stable) if the subject has a medical condition 
that leads to a hospitalization or an emergency room 
visit. All site contact details will be provided to the 
subject’s LAR. 
9.3.5 
Site visits that do NOT include a vaccination will be 
performed on Day 57, age 1 year, age 18 months and 
age 2 years at Visit 3 (28 days post Dose 2), Visit 4 
(age 1 year), Visit 5 (age 18 months) and Visit 6 (age 2 
years). At the site visit, the eDiary will be reviewed. 
The healthcare professional reviewing these data will 
discuss the AEs (if any) reported by the subject’s LAR 
and will determine if any additional diagnoses and/or 
AEs are present and/or if concomitant medications 
have been used. 
The investigator will check vital signs and perform a 
physical examination at age 18 months and age 2 years. 
Blood (up toapproximately 5 mL) should be taken 
from the subject using an aseptic venipuncture 
technique for serological immunogenicity testing at 
Day 57, Visit 3 (28 days post dose 2), Visit 4 (age 1 
year, ), Visit 5 (age 18 months) and Visit 6 (age 2 
years.). 
Clarification for the blood volume. 
9.3.8 
The procedures for subjects who meet age case 
definition criteria and consenting symptomatic 
household members of AGE case are described in 
Section 2.2. The subject’s LAR will be requested to 
complete the healthcare resource utilization 
questionnaire 7 to 14 days after resolution of each AGE 
episode. 
Clarification and cross-referencing 
to the relevant section. 
9.3.9 
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9.4 
10.1.2 
Table 10.a 
Solicited Local (Injection Site) 
Reactions and Systemic AEs 
Inclusion of pain as a solicited 
reaction. 
10.4.1 
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 SAE form*, if 
necessary (see Section 10.4.4). All findings in subjects 
experiencing AEs must also be documented in the 
subject’s source documents. Any unsolicited AE will 
be collected by the subject’s LAR for 28 days via after 
each dose of trial vaccine. The subject's LAR will use 
the eDiary (usingmemory aid to record unsolicited 
symptoms for reporting to the Vigilant-e mobile 
app).site. AEs leading to discontinuation (from the trial 
or from the vaccination regimen) are collected 
throughout the trial. Even if the subject is deemed 
ineligible to receive further doses of trial vaccine, all 
efforts should be made to continue the collection of 
safety data according to protocol. 
Clarification and further description 
of the process. 
10.4.4 
Collection of SAEs will commence from the time that 
the subject is first administered the trial vaccine (Day 
1).subject’s LAR signs the ICF. Routine collection of 
SAEs will continue until the end of the trial (up to 2 
years of age). 
Clarification of when SAE 
collection actually begins. 
11.0 
A case adjudication committee (CAC) will assess the 
severity of individual confirmed AGE cases. Details 
are provided in the CAC charter. 
Removal of text concerning the 
CAC. A CAC will not be used for 
this trial. 
13.1 
A blinded data review will be conducted prior to 
unblinding of subject’s assignment to a trial arm. This 
review will assess the accuracy and completeness of 
the trial, database and subject evaluability, and 
appropriateness of the planned statistical methods. 
Text adjusted. 
13.1.1 
Safety Set (SAF): The SAF will consist of all subjects 
who are randomized and received at least one dose of 
HIL-214 or placebo. Subjects will be analyzed 
Inclusion of additional analysis sets. 
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according to the treatment which they actually 
received. 
Full-Analysis Set (FAS): The FAS will include all 
subjects who are randomized and received at least 1 
dose of HIL-214 or placebo. Subjects will be analyzed 
according to their randomized treatment. Modified 
Full-Analysis Set ([mFAS] – Efficacy-evaluable 
Ssubjects): The mFAS will include all subjects who are 
randomized and received 2 doses of HIL-214 or 
placebo. Subjects will be analyzed according to their 
randomized treatment. 
Efficacy Per-Protocol Analysis Set (PPS-E): The PPS 
will include all subjects in the FAS who have no 
majorimportant protocol deviations. The major which 
may affect the evaluation of efficacy. These important 
protocol deviation criteria will be defined as part of the 
blinded data review. prior to the unblinding of 
subject’s assignment to a trial arm. The categories of 
majorimportant protocol deviations include: (1) not 
meeting selected entry criteria, (2) receiving wrong or 
incomplete trial product (3) receiving prohibited 
therapies, and (4) other majorimportant protocol 
deviations that may impact the main efficacy endpoint. 
Subjects will be analyzed according to the treatment 
which they actually received. 
Immunogenicity Per-Protocol Analysis Set (PPS-I): 
The PPS-I will include all subjects in the FAS who 
have no important protocol deviations which may 
affect evaluation of immunogenicity. These important 
protocol deviation criteria will be defined as part of 
the blinded data review. The categories of important 
protocol deviations include: (1) not meeting selected 
entry criteria, (2) receiving wrong or incomplete trial 
product (3) receiving prohibited therapies, and (4) 
other important protocol deviations that may impact 
the immunogenicity endpoints. Subjects will be 
analyzed according to the treatment which they 
actually received. 
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13.1.2 
Age, sex, race, and other baseline characteristics will 
be summarized descriptively by trial arm for all 
randomized subjects for the FAS and mFAS. 
 
13.1.3 
AGE cases will be collected starting from the Day 1 
(Dose 1 of trial vaccine) until the 2nd birthday of 
each subject (end of trial). The number of AGE cases 
including primary endpoint AGEs will be monitored 
during the trial in a blinded way. The process is 
described in the AGE monitoring charter. 
The primary surveillance period will start 4 weeks after 
the second dose. The end of the surveillance period for 
the primary efficacy objective will be conditional on 
the number of primary endpoint cases and the subject’s 
age. If there are less than 64 primary endpoint cases 
then the surveillance period will finish at the end of the 
trial (i.e., when the last subject reaches 2 years of age). 
If the first 64 primary-endpoint cases are for subjects 
who have not reached 1 year of age then the 
surveillance period will finish when each subject 
reaches 1 year of age; otherwise, the surveillance 
period will finish when each subject has reached the 
age set by the maximum age of the first 64 primary-
endpoint cases (e.g. if the maximum age of the first 
AGE case is 15 months, the surveillance period will 
finish when all subjects have reached 15 months of 
age).The primary objective will be evaluated using 
primary endpoint cases which occurred during the 6-
month primary observation period starting at 28 days 
post-Dose 2. If the number of AGE events collected 
during the 6-month follow-up predicts less than 80% 
power (which translates into 24 predicted primary 
endpoint cases) for the evaluation of the primary 
objective, the primary observation period will be 
extended to 8 months, starting 28 days post-Dose 2. 
The event of interest for the primary endpoint is the 
first occurrence during the surveillance primary 
observation period, of a moderate/severe AGE case 
associated only with GI.1 or GII.4 norovirus genotypes 
for a subject. The primary endpoint Time-to-event will 
be computed from the start of the observation period 
until the date of AGE onset measured and analyzed by 
determining VE; defined as the date of last 
contact/discontinuation, the end date of the 
observation period, whichever is earlier. VE will be 
calculated as function 100%[1– (λV/λC)], where λV 
and λC denote the hazard rates for the HIL-214 and 
placebo arms, respectively. The primary analysis 
method will be a time-to-event Cox proportional 
hazards (CPH) model with trial arm as a factor and 
stratified by country, using the efficacy mFAS. 
Subjects without event will be censored at their last 
information date. The confidence interval (CI) for VE 
Adjustment made for 1) the change 
in number of primary endpoint cases 
from 64 to 30; 2) removal of the 
optional interim analysis and 3) 
clarification of the exploratory 
efficacy analyses. 
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will be derived from the CI of the hazard ratio obtained 
from the CPH model. 
The primary efficacy objective will be met if the lower 
bound of the 95.4% CI* for the VE is above 0%. 
The same model will be used to analyze the single 
event secondary and exploratory VE (only the event 
definition will be different). The proportional-hazards 
assumption will be testedassessed and an alternative 
method of analysis will be detailed in the SAP in the 
case of violation of this assumption.. A 
sensitivitysupplementary analysis based on the PPS-E 
will also be provided. Analyses for recurrent events 
(all primary endpoint AGEs, not only the first 
experienced by a subject) will be performed using 
proportional intensity (Andersen-Gill) models with 
treatment as a factor and stratified by country. 
Other sensitivity analysesThe same CPH model will be 
used to analyze the single event secondary and 
 (only the event definition will be 
different). will be described in the SAP, in order to 
handle subjects with only one vaccine dose or subjects 
having taken immunosuppressive drugs or blood 
products during the surveillance period. 
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13.1.4 
Immunogenicity results will be summarized using 
descriptive statistics including 95% CIs for all available 
assays at all relevant time points. These summaries 
will be provided for the FAS and PPS I. 
Clarification. 
13.1.5 
In general, data imputation will not be performed for 
any missing safety data. Any SAE or AE leading to 
trial vaccine dose withdrawal, and AEs leading to trial 
withdrawal collected throughout the trial for all 
subjects in the SAF will be included. All safety data 
summaries will be prepared using the SAF. 
Removal of redundant text and 
clarification. 
13.1.6 
Clarification of when the analyses 
will be performed and where they 
will be described in detail. 
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13.1.7 
Sequence of Analyses 
Primary and secondary efficacy objectives will be 
evaluated at the end of the primary observation 
period. Immunogenicity data collected up to Visit 4 
(subject aged 1 year) and safety data collected up to 
the end of the primary observation period will also be 
analyzed at this time point. 
Inclusion of an additional section 
describing the sequence of analyses. 
13.2 
The optional IA may occur at the time where a total of 
32 primary endpoint cases is expected to be observed 
according to the current accrual rate assumptions. 
Thirty-two available cases will provide a power of 
78.8% to rule out the null hypothesis of no effect of 
vaccine (with a one-sided significance level of 0.5%) 
on the primary endpoint. Only necessary staff will be 
unblinded, to make decisions on the phase 3 design. 
The final analysis for the main endpoint will be 
performed at alpha (Type I error) level of 4.6% 
(bilateral) in order to take into account the 0.1% alpha 
spent at the IA. The calculation uses gamma spending 
function (gamma = -3) for analyses at approximately 
half-information (32 cases/64 cases). 
Efficacy and futility rules are non-binding as the trial is 
expected to continue, in order to collect sufficient data 
for evaluation of all trial objectives. 
Clarification. 
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More details on the IA will be provided in the DMC 
charter and in the SAP. 
All calculations were performed using East® version 
6.5 (Cytel Inc., Boston, MA). 
Safety Interim Analysis (lead-in cohort) 
A safety data review will be performed by the DMC for 
the first 200 subjects based on 1) solicited events for 7 
days following the first dose of trial vaccine (first DMC 
analysis) and 2) unsolicited and all other safety data 
collected from Day 1 through Day 57 (28 days post-
dose 2) (second DMC analysis). Recruitment beyond 
200 subjects will be paused until both first and second 
DMC analyses for safety have been performed. 
Immunogenicity Interim Analysis (lead-in cohort) 
Immunogenicity data review will be performed when 
the pan-Ig data up to 28 days post-dose 2 for the first 
200 subjects is available. 
More details on the analyses will be provided in the 
SAP. 
A formal interim analysis (interim evaluation of the 
study objectives) is not planned for this trial. 
13.3 
It is anticipated that an enrolment of approximately 
3000 subjects (ratio 1:1) Collection of 24 primary 
endpoint cases will provide a power greater than 80% 
in comparing active vaccine versus placebo in the rate 
of evaluable first-confirmed AGE cases (moderate or 
severe) associated with norovirus GI.1 or GII.4 without 
co-pathogens during the 6 months period if the true VE 
is 70%. The underlying assumptions are a 7% annual 
incidence of moderate to severe AGE attributable to 
norovirus GI.1 or GII.4, hypothesizing that 40% of 
norovirus AGE cases are moderate to severe, and 30% 
are associated with norovirus GI.1 or GII.4 resulting in 
. Therefore, the 6-month incidence of evaluable 
primary endpoint AGE is cases of 3.5%, providing at 
the end of observation (6 months for all subjects) a 
target- events final number of 64 cases. The assumption 
is a 20% subject drop-out rate. 
It is expected that enrollment of 3000 subjects will 
provide sufficient number of cases to demonstrate 
efficacy, accounting for various rates of drop-
out/non-evaluable samples (20% to 30%), and 
possible lower incidence rate or underreporting of 
cases. 
Adjustment of the sample size 
calculation text. 
Appendices 
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Minor editorial changes were made throughout the document in light of the modifications made with this 
amendment. These include the naming convention for the timing of procedures (Visit/Day) and are not listed 
in each instance. 
 
Summary of changes for protocol amendment 1 dated 14 October 2022 to protocol version 1.0 dated 
6 October 2021 are provided in protocol version 2.0 dated 14 October 2023. 
Rationale for the amendment: 
• 
To update the protocol to address requests from the 
 
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION .................................................................. 2 
1.1 
Contacts.............................................................................................................. 2 
1.2 
Approval ............................................................................................................ 2 
1.3 
Protocol Version V3.0 Summary of Changes .................................................... 4 
1.3.1 
Version History ....................................................................................... 4 
1.3.2 
Summary of Changes .............................................................................. 4 
TABLE OF CONTENTS ................................................................................................... 18 
List of In-Text Tables .................................................................................................. 21 
List of In-Text Figures ................................................................................................. 21 
List of Appendices ....................................................................................................... 22 
2.0 
TRIAL SUMMARY .............................................................................................. 23 
2.1 
Trial Design Diagram ...................................................................................... 30 
2.2 
Schedule of Trial Procedures for all Subjects (N = 3000) ............................... 31 
2.3 
Schedule of Procedures for Consenting Symptomatic Household Members of 
an AGE Case - Ancillary Study (Panama and Peru) ........................................ 33 
2.4 
OBJECTIVES AND ENDPOINTS ................................................................. 34 
3.0 
TRIAL REFERENCE INFORMATION ............................................................... 38 
3.1 
Trial-Related Responsibilities .......................................................................... 38 
3.2 
Investigator/Principal Investigator/Coordinating Investigator ........................ 38 
3.3 
List of Abbreviations ....................................................................................... 39 
4.0 
INTRODUCTION ................................................................................................. 40 
4.1 
Background ...................................................................................................... 40 
4.2 
Rationale for the Proposed Trial ...................................................................... 40 
5.0 
OBJECTIVES AND ENDPOINTS ....................................................................... 42 
6.0 
TRIAL DESIGN AND DESCRIPTION ............................................................... 46 
6.1 
Trial Design ..................................................................................................... 46 
6.2 
Justification for Trial Design, Dose, and Endpoints ........................................ 48 
6.3 
Planned Duration of Subject’s Participation in the Trial ................................. 48 
6.4 
Premature Termination or Suspension of Trial or Investigational Site ........... 48 
6.4.1 
Criteria for Premature Termination or Suspension of the Trial ............ 48 
6.4.2 
Criteria for Premature Termination or Suspension of Investigational 
Sites ....................................................................................................... 49 
6.4.3 
Procedures for Premature Termination or Suspension of the Trial or the 
Participation of Investigational Site(s).................................................. 49 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ... 50 
7.1 
Inclusion Criteria ............................................................................................. 50 
7.2 
Exclusion Criteria ............................................................................................ 50 
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7.3 
Criteria for Delay of Investigational Medicinal Product Administration and/or 
Blood Sampling ............................................................................................... 51 
7.4 
Criteria for Early Termination of a Subject’s Trial Participation .................... 51 
7.5 
Criteria for Premature Discontinuation of Investigational Medicinal Product 
Administration ................................................................................................. 52 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ............................................. 54 
8.1 
Investigational Products ................................................................................... 54 
8.1.1 
Investigational Vaccine ......................................................................... 54 
8.1.2 
Placebo .................................................................................................. 54 
8.2 
Labeling ........................................................................................................... 54 
8.3 
Inventory and Storage ...................................................................................... 54 
8.4 
Dose and Regimen ........................................................................................... 55 
8.5 
Investigational Medicinal Product Assignment and Dispensing Procedures .. 55 
8.5.1 
Precautions to Be Observed When Administering the Investigational 
Medicinal Product ................................................................................. 55 
8.6 
Randomization Code Creation and Storage ..................................................... 56 
8.7 
Investigational Medicinal Product Blind Maintenance.................................... 56 
8.8 
Unblinding Procedure ...................................................................................... 56 
8.9 
Accountability and Destruction of Sponsor-Supplied Trial Vaccines, and 
Other Clinical Trial Materials .......................................................................... 57 
9.0 
TRIAL PLAN ........................................................................................................ 59 
9.1 
Trial Procedures ............................................................................................... 59 
9.1.1 
Informed Consent.................................................................................. 59 
9.1.2 
Demographics, Medical History and Prior Medications ....................... 59 
9.1.3 
Documentation of Trial Entry/Randomization ..................................... 60 
9.1.4 
Physical Examination............................................................................ 60 
9.1.5 
Vital Signs ............................................................................................. 60 
9.1.6 
Immunogenicity Assessments ............................................................... 60 
9.1.7 
Processing, Labeling and Storage of Biological Samples .................... 61 
9.1.8 
Safety Assessments ............................................................................... 61 
9.1.9 
Documentation of Subjects Who Are Not Randomized ....................... 61 
9.1.10 
...... 61 
9.2 
Monitoring Subject Compliance ...................................................................... 62 
9.3 
Schedule of Observations and Procedures ....................................................... 62 
9.3.1 
Pre-Vaccination Procedures (Day 1) .................................................... 62 
9.3.2 
Vaccination Procedures (Visit 1 [Day 1]; Visit 2 [28 to 56 days post 
dose 1]).................................................................................................. 62 
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9.3.3 
Post-vaccination Procedures (Visit 1 [Day 1]; Visit 2 [28 to 56 days 
post dose 1]) .......................................................................................... 63 
9.3.4 
Phone Contacts - Reminder Calls (2 and 7 days post dose 1 and dose 2 
and 7 days post dose 2) ......................................................................... 64 
9.3.5 
Site Visits After Vaccination (Visit 3 [28 days post dose 2], Visit 4 [age 
1 year], Visit 5 [age 18 months] and Visit 6 [age 2 years]) .................. 65 
9.3.6 
Final (End of Trial) Visit ...................................................................... 65 
9.3.7 
Post-Trial Care ...................................................................................... 65 
9.3.8 
Procedures for Subjects who Meet AGE Case Definition Criteria ....... 65 
9.3.9 
5 
9.4 
Biological Sample Retention and Destruction ................................................. 66 
10.0 
ADVERSE EVENTS ............................................................................................. 67 
10.1 
Definitions........................................................................................................ 67 
10.1.1 
Adverse Events ..................................................................................... 67 
10.1.2 
Solicited Adverse Events ...................................................................... 67 
10.1.3 
Adverse Events of Special Interest ....................................................... 69 
10.1.4 
Medically-attended Adverse Events ..................................................... 70 
10.1.5 
Serious Adverse Events ........................................................................ 70 
10.2 
Causality of Adverse Events ............................................................................ 70 
10.2.1 
Relationship to Trial Procedures ........................................................... 70 
10.2.2 
Outcome of Adverse Events ................................................................. 71 
10.3 
Additional Points to Consider for Adverse Events .......................................... 71 
10.4 
Collection and Reporting Procedures .............................................................. 72 
10.4.1 
Collection and Reporting of Adverse Events........................................ 72 
10.4.2 
Collection and Reporting of Solicited Adverse Events ........................ 73 
10.4.3 
Collection and Reporting of Adverse Events of Special Interest/ 
Medically-Attended Adverse Events .................................................... 73 
10.4.4 
Collection and Reporting of Serious Adverse Events........................... 73 
10.5 
Follow-up Procedures ...................................................................................... 74 
10.5.1 
Adverse Events ..................................................................................... 74 
10.5.2 
Serious Adverse Events ........................................................................ 74 
10.5.3 
Safety Reporting to Investigators, Independent Ethics Committees or 
Investigational Review Boards, and Regulatory Authorities ................ 74 
10.5.4 
Post-Trial Events ................................................................................... 75 
11.0 
TRIAL-SPECIFIC REQUIREMENTS ................................................................. 76 
12.0 
DATA HANDLING AND RECORD KEEPING ................................................. 77 
12.1 
Electronic CRFs ............................................................................................... 77 
12.2 
Record Retention ............................................................................................. 77 
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13.0 
STATISTICAL METHODS .................................................................................. 79 
13.1 
Statistical and Analytical Plans ........................................................................ 79 
13.1.1 
Analysis Sets ......................................................................................... 79 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ........... 80 
13.1.3 
Efficacy Analysis .................................................................................. 80 
13.1.4 
Immunogenicity Analysis ..................................................................... 81 
13.1.5 
Safety Analysis ..................................................................................... 81 
13.1.6 
Other Analyses ...................................................................................... 82 
13.1.7 
Sequence of Analyses ........................................................................... 83 
13.2 
Interim Analysis and Criteria for Early Termination ....................................... 83 
13.3 
Determination of Sample Size ......................................................................... 83 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................... 84 
14.1 
Trial-Site Monitoring Visits ............................................................................. 84 
14.2 
Protocol Deviations .......................................................................................... 84 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ...................... 84 
14.4 
Trial Risk Management.................................................................................... 84 
15.0 
ETHICAL ASPECTS OF THE TRIAL ................................................................. 86 
15.1 
Independent Ethics Committee and/or Institutional Review Board Approval 86 
15.2 
Subject Information, Informed Consent, and Subject Authorization .............. 87 
15.3 
Subject Confidentiality .................................................................................... 88 
15.4 
Clinical Trial Registration, Publication and Disclosure Policy ....................... 89 
15.4.1 
Clinical Trial Registration..................................................................... 89 
15.4.2 
Clinical Trial Results Disclosure .......................................................... 89 
15.4.3 
Publication of Trial Results .................................................................. 89 
15.5 
Insurance and Compensation for Injury ........................................................... 89 
16.0 
REFERENCES ...................................................................................................... 90 
 
List of In-Text Tables 
Table 10.a 
Solicited Local (Injection Site) Reactions and Systemic AEs ................... 68 
Table 10.b 
Solicited Safety Parameters ....................................................................... 69 
 
List of In-Text Figures 
Figure 6.a: 
Schematic of Trial Design ......................................................................... 46 
Figure 16.a 
.
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List of Appendices 
Appendix A Responsibilities of the Investigator ............................................................... 93 
Appendix B Investigator Consent to use of Personal Information .................................... 95 
Appendix C Vesikari and Modified Vesikari Scoring ....................................................... 96 
Appendix D 
Appendix E 
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2.0 
TRIAL SUMMARY 
Name of Sponsor: 
HilleVax, Inc. 
Product Name: 
HIL-214 
Trial Title: A Phase 2b, Double-blind, Randomized, Multi-site, Placebo-controlled Trial to Evaluate the 
Efficacy, Safety and Immunogenicity of Intramuscular HIL-214 Norovirus Vaccine in Healthy Children 5 
Months of Age at Initial Vaccination 
IND No.: 014421 
EudraCT No.: Not applicable 
Trial Identifier: NOR-212 
Phase: 2b 
Blinding Schema: Double Blind 
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. While mortality due to acute gastroenteritis 
(AGE) caused by norovirus in the pediatric population is rare in industrialized countries, it is more common 
in developing countries. Although potentially a cause for hospitalization in very young children, there are 
fewer cases during the first 6 months of life possibly due to the protection offered by maternal antibodies 
from trans-placental transfer and in breast milk. In addition, norovirus infections have significant 
socioeconomic impact on hospitals, schools, day care centers and other closed settings. As the burden of 
rotavirus in children decreases due to successful rotavirus vaccination programs in infants, norovirus 
infections are increasingly recognized as the primary cause of AGE in many countries around the world. 
Currently, there is no available vaccine to counter the disease burden associated with 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, including Latin America, where this trial will be primarily performed. 
The investigational vaccine, HIL-214 (previously called TAK-214), contains GI.1 virus-like particles (VLPs) 
and norovirus GII.4 consensus VLPs (GII.4c) 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 investigational vaccine used in this trial is adjuvanted with 
aluminum as aluminum hydroxide [Al(OH)3]. 
The composition of HIL-214 (50/150 µg GI.I/GII.4) to be used in this phase 2b efficacy trial is based on the 
results of trial NOR-202, a phase 2 dose-finding, safety and immunogenicity trial in 840 children aged 
6 weeks to <9 years. The results of trial NOR-202 show that HIL-214 is immunogenic and had a generally 
good safety profile in children aged 6 weeks to <9 years for all GI.1/GII.4c VLP compositions adjuvanted 
with 500 µg of aluminum as Al(OH)3 as (1) a one or two-dose regimen in children aged 6 to 12 months, and 
(2) as a two or three-dose regimen in children aged 6 weeks to <6 months for the same composition. So far, 
7026 healthy volunteers have been dosed in Takeda Vaccines Inc.-sponsored HIL-214 trials and up to 4531 
have received different compositions of HIL-214, including 839 children aged 6 weeks to less than 9 years. 
The rationale for the inclusion of children 5 months (±14 days) of age at the time of initial vaccination is 
based on epidemiological data which shows that the risk of norovirus AGE increases in infants aged 
~6 months old and allows enrolment either before or after the required routine childhood vaccines in the 
participating countries per national guidelines. 
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Primary hypothesis: 
The primary hypothesis for this phase 2b proof-of-concept trial is that HIL-214, administered as 2-dose 
regimen, provides protection against moderate and severe AGE associated only with GI.1 or GII.4 vaccine-
represented norovirus genotypes in the targeted population of infants. 
This phase 2b trial aims to demonstrate the vaccine efficacy (VE) of two doses of HIL-214 administered up 
to 8 weeks apart, against moderate or severe AGE due to GI.1 or GII.4 norovirus genotypes in approximately 
3000 healthy children aged 5 months at the time of the first dose up to when they reach the age of 2 years, as 
well as the safety and immunogenicity of HIL-214. A placebo arm is included to allow an unbiased 
evaluation of efficacy and safety. Placebo will be used in this trial because there is no single active 
comparator vaccine that is available across all participating sites. 
The trial will be conducted in accordance with this 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: 
Objectives and endpoints are presented in Section 2.4. 
Trial Design: 
This is a phase 2b, double-blind, randomized, multi-site, placebo-controlled trial to evaluate the efficacy, 
safety, and immunogenicity of two doses of the IM HIL-214 vaccine compared to placebo in approximately 
3000 children, 5 months of age (-14/+14 days) at the time of the first dose of trial vaccine. 
The second dose of trial vaccine should be administered 28 days (and up to 56 days) after the first dose. Trial 
vaccine doses will be given at least 14 days before or after non-live and orally administered live vaccines, 
and at least 28 days before or after parenterally administered live vaccines which are given in accordance 
with country pediatric immunization guidelines. Subjects will be allocated (1:1) into 1 of 2 trial arms by 
interactive response technology (IRT) and stratified by country: 
• 
Arm 1 (N = 1500): One dose of HIL-214 at Visit 1 (Day 1) and one dose of HIL-214 at Visit 2 (28 
to 56 days post dose 1). 
• 
Arm 2 (N = 1500): One dose of placebo at Visit 1 (Day 1) and one dose of placebo at Visit 2 (28 to 
56 days post dose 1). 
The schematic of NOR-212 is shown in Section 2.1. 
• 
All subjects will be followed for solicited local and systemic adverse events (AEs) up to 7 days 
after each dose of trial vaccine (including day of dose) and unsolicited AEs for up to 28 days after 
each dose of trial vaccine (including day of dose). 
• 
All subjects will be followed throughout the trial (from Day 1) for serious adverse events (SAEs), 
AEs leading to trial vaccine dose withdrawal, and AEs leading to trial withdrawal. 
• 
The subject’s legally-authorized representative (LAR) (all subjects) will receive weekly 
notifications via eDiary to complete the AGE report if the subject has AGE symptoms (episodes of 
vomiting and/or liquid stools). 
• 
All subjects will have six blood draws (pre-dose 1 at Visit 1 [Day 1], pre-dose 2 at Visit 2 [28 to 56 
days post dose 1], at Visit 3 [28 days post dose 2], at Visit 4 [1 year of age], at Visit 5 [18 months of 
age] and at Visit 6 [2 years of age]), to measure anti-norovirus total immunoglobulin (pan-Ig) and 
histoblood group antigen (HBGA) blocking antibodies and 
 
 
• 
All subjects will have two safety phone/home contacts 2 days (Day 3) and 7 days (Day 8) post 
dose 1, and one safety phone/home contact 7 days post dose 2. 
• 
The first 200 subjects (cohort 1) will have a site visit on Day 8 post dose 1; the remaining subjects 
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(cohort 2) will have a safety phone/home contact on this trial day. 
• 
Enrolment beyond the first 200 subjects will be paused until safety data up to 28 days post dose 2 
has been analyzed by the sponsor and assessed to be satisfactory by the data monitoring committee 
(DMC). If applicable, the DMC will also evaluate immunogenicity data up to 28 days post dose 2 to 
support recommendation to continue enrolment. 
• 
If the child has liquid/loose stools or vomiting, the LAR will enter the number of episodes in the 
eDiary to inform the site. Subject’s LARs will be requested to record AGE symptoms and their 
frequency, and body temperature in the eDiary (AGE symptoms log) from the first day of AGE 
onset until the symptoms have resolved. This log will be activated automatically if the number of 
episodes of vomiting and loose/liquid stools satisfies the AGE case definition. All subjects who 
meet the criteria for the AGE case definition will provide one AGE onset stool sample and two 
AGE follow-on stool samples. AGE cases will be collected starting from the Day 1 (Dose 1 of trial 
vaccine) until all subjects have reached 2 years of age (end of trial). The number of AGE cases 
including primary endpoint AGEs will be monitored during the trial in a blinded way. The process 
is described in the AGE monitoring charter. 
• 
All AGE onset stool samples will be assayed for the presence of norovirus and norovirus-positive 
samples will be sequenced for genotype identification. Only norovirus-positive samples will be 
analyzed for the presence of co-pathogens. Follow-on stool samples collected 2 and 3 weeks post-
onset will be analyzed for norovirus presence and genogroup only. 
• 
• 
Trial procedures are shown in Section 2.2 
 
 
Subject Population: 
Healthy Subjects: Yes. 
Age at 1st vaccination: 5 months (-14/+14 days). 
Planned Number of Subjects: 3000. 
Planned Number of Trial Arms: 2. 
• 
Arm 1 (1500 subjects): HIL-214. 
• 
Arm 2 (1500 subjects): Placebo. 
Estimated total: 3000 randomized. 
Key Inclusion Criteria: 
• 
The subject is aged 5 months (-14/+14 days). 
• 
Male or female. 
• 
Children 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 subject’s LAR signs and dates a written ICF and any required privacy authorization prior to the 
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initiation of any trial procedures, after the nature of the trial has been explained according to local 
regulatory requirements. 
• 
Children whose LARs can and are willing to comply with trial procedures and are available for the 
duration of follow-up. 
Key Exclusion Criteria: 
• 
Clinically significant abnormality in growth by height, weight, or head circumference (according to 
local guidelines). 
• 
Gastrointestinal abnormalities or any chronic gastrointestinal disease, including any uncorrected 
congenital malformation of the gastrointestinal tract according to medical history and/or physical 
examination. 
• 
Known hypersensitivity or allergy to any of the investigational vaccine components (including 
excipients). 
• 
Any clinically significant active infection (as assessed by the investigator) or temperature ≥38.0°C 
(>100.4°F), within 3 days of intended trial vaccination. 
• 
Any serious chronic or progressive disease according to the judgment of the investigator (e.g., cardiac, 
renal or hepatic disease). 
• 
Individuals with history of, e.g., convulsions/febrile convulsions, or 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. 
• 
Known or suspected impairment/alteration of immune function. 
• 
Subjects with a known bleeding diathesis, or any condition that may be associated with a prolonged 
bleeding time. 
• 
Subjects who received or are scheduled to receive any routine or authorized vaccine within 14 days (for 
non-live or orally administered live vaccines) or 28 days (for parenterally administered live vaccines) 
before or after any dose of trial vaccine. 
• 
Subjects participating in any clinical trial with another investigational product 30 days prior to first trial 
visit or intend to participate in another clinical trial at any time during the conduct of this trial. 
• 
Subjects known to be positive for or in evaluation for possible human immunodeficiency virus infection. 
• 
Subject’s LAR or subject’s first-degree relatives involved in the trial conduct. 
The full list of exclusion criteria is included in the protocol (Section 7.2). 
Trial Vaccine and Placebo: 
Investigational 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 investigational vaccine contains 
50 µg GI.1/150 µg GII.4c VLPs and 500 µg of aluminum as Al(OH)3. 
Placebo: 0.9% sodium chloride (saline) for injection is provided by HilleVax Inc. or designated vendor in a 
container allowing delivery of a 0.5 mL dose. The placebo does not contain any preservatives. 
Route of administration: intramuscular (IM) injection (anterolateral thigh). 
Duration of the Trial and Duration of Subject Participation: 
The overall duration of the trial and subject participation will be up to 20 months. 
Criteria for Evaluation and Analyses: 
Objectives and endpoints are presented in Section 2.4. 
Statistical Considerations: 
Analysis sets 
Safety Set (SAF): The SAF will consist of all subjects who are randomized and received at least one dose of 
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HIL-214 or placebo. Subjects will be analyzed according to the treatment which they actually received. 
Full-Analysis Set (FAS): The FAS will include all subjects who are randomized and received at least 1 dose 
of HIL-214 or placebo. Subjects will be analyzed according to their randomized treatment. Modified Full-
Analysis Set ([mFAS] – Efficacy-evaluable subjects): The mFAS will include all subjects who are 
randomized and received 2 doses of HIL-214 or placebo. Subjects will be analyzed according to their 
randomized treatment. 
Efficacy Per-Protocol Analysis Set (PPS): The PPS will include all subjects in the mFAS who have no 
important protocol deviations which may affect the evaluation of efficacy. These important protocol 
deviation criteria will be defined as part of the blinded data review prior to the unblinding of subject’s 
assignment to a trial arm. The categories of important protocol deviations include: (1) not meeting selected 
entry criteria, (2) receiving wrong or incomplete trial product (3) receiving prohibited therapies, and (4) 
other important protocol deviations that may impact the main efficacy endpoint. Subjects will be analyzed 
according to the treatment which they actually received. 
Immunogenicity Per-Protocol Analysis Set (PPS-I): The PPS-I will include all subjects in the FAS who have 
no important protocol deviations which may affect evaluation of immunogenicity. These important protocol 
deviation criteria will be defined as part of the blinded data review. The categories of important protocol 
deviations include: (1) not meeting selected entry criteria, (2) receiving wrong or incomplete trial product 
(3) receiving prohibited therapies, and (4) other important protocol deviations that may impact the 
immunogenicity endpoints. Subjects will be analyzed according to the treatment which they actually 
received. 
Analysis of demographics and other baseline characteristics 
Age, sex, race, and other baseline characteristics will be summarized descriptively by trial arm for all 
randomized subjects for the FAS and mFAS. 
Efficacy analysis 
AGE cases will be collected starting from the Day 1 (Dose 1 of trial vaccine) until the 2nd birthday of each 
subject (end of trial). The number of AGE cases including primary endpoint AGEs will be monitored during 
the trial in a blinded way. The process is described in the AGE monitoring charter. 
The primary objective will be evaluated using primary endpoint cases which occurred during the 6-month 
primary observation period starting at 28 days post-Dose 2. If the number of AGE events collected during 
the 6-month follow-up predicts less than 80% power (which translates into 24 predicted primary endpoint 
cases) for the evaluation of the primary objective, the primary observation period will be extended to 
8 months, starting 28 days post-Dose 2. 
The event of interest for the primary endpoint is the first occurrence during the primary observation period, 
of a moderate/severe AGE case associated only with GI.1 or GII.4 norovirus genotypes. Time-to-event will 
be computed from the start of the observation period until the date of AGE onset, the date of last 
contact/discontinuation, the end date of the observation period, whichever is earlier. VE will be calculated as 
100%[1– (λV/λC)], where λV and λC denote the hazard rates for the HIL-214 and placebo arms, 
respectively. The primary analysis method will be a time-to-event Cox proportional hazards (CPH) model 
with trial arm as a factor and stratified by country, using the mFAS. The confidence interval (CI) for VE will 
be derived from the CI of the hazard ratio obtained from the CPH model. 
The primary efficacy objective will be met if the lower bound of the 95% CI for the VE is above 0%. 
The proportional-hazards assumption will be assessed and an alternative method of analysis will be detailed 
in the SAP. A supplementary analysis based on the PPS-E will also be provided. Analyses for recurrent 
events (all primary endpoint AGEs, not only the first experienced by a subject) will be performed using 
Ef
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proportional intensity (Andersen-Gill) models with treatment as a factor and stratified by country. 
The same CPH model will be used to analyze the single event secondary and
Missing data will be handled by the time to event analysis itself, as subjects prematurely withdrawn from the 
trial will be censored at their last information date. 
Immunogenicity analysis 
Immunogenicity results will be summarized using descriptive statistics including 95% CIs for all available 
assays at all relevant time points. These summaries will be provided for FAS and PPS I. 
Safety analysis 
In general, data imputation will not be performed for any missing safety data. All safety data summaries will 
be prepared using SAF. 
Solicited AEs 
Safety will be assessed daily for 7 days after each vaccination (including the day of vaccination) via 
collection of solicited local and systemic AEs. Body temperature by the actual route taken will be 
summarized with no adjustment or conversion for route of measurement. For each solicited AE, the 
percentage of subjects will be summarized by event intensity for each day from Day 1 to Day 7 (including 
the day of vaccination) and overall. Summaries of the day of first onset of each event and the number of days 
subjects reported experiencing each event will also be provided. For subjects with more than 1 episode of the 
same event, the maximum intensity will be used for tabulations. 
Unsolicited AEs 
Any unsolicited AEs up to 28 days after each vaccination (including the day of vaccination), SAEs and AEs 
leading to trial vaccine dose withdrawal and AEs leading to trial withdrawal (all subjects), will be coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA), and summarized by system organ 
class (SOC) and preferred term (PT) for each trial arm. In general, unsolicited AEs will be tabulated at each 
of the following levels: overall summary (subject with at least one AE), and by SOC and PT. Subjects 
reporting more than one occurrence for the term (level) being summarized will be counted only once with 
maximum intensity recorded. Unless otherwise specified, unsolicited AEs after each vaccination will be 
summarized in the following 3 ways: 1) overall for Day 1 (day of vaccination) to 28 after each vaccination, 
2) with onset between Day 1 (day of vaccination) and Day 7 after each vaccination, and 3) with onset 
between Day 8 and Day 28 after each vaccination. 
AEs leading to trial or trial dose discontinuation 
AEs leading to trial dose discontinuation collected up to the last planned trial dose administration and AEs 
leading to withdrawal from the trial collected throughout the trial will also be summarized. 
SAEs 
SAEs will be collected throughout the trial. SAEs will be coded using MedDRA and summarized by SOC 
and PT for each trial arm. 
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Sample Size Justification: 
Collection of 24 primary endpoint cases will provide a power greater than 80% in comparing active vaccine 
versus placebo in the rate of evaluable first-confirmed AGE cases (moderate or severe) associated with 
norovirus GI.1 or GII.4 without co-pathogens during the 6 months period if the true VE is 70%. The 
underlying assumptions are a 7% annual incidence of moderate to severe AGE attributable to norovirus GI.1 
or GII.4, hypothesizing that 40% of norovirus AGE cases are moderate to severe, and 30% are associated 
with norovirus GI.1 or GII.4 resulting in the 6-month incidence of evaluable primary endpoint AGE cases of 
3.5%. It is expected that enrollment of 3000 subjects will provide sufficient number of cases to demonstrate 
efficacy, accounting for various rates of drop-out/non-evaluable samples (20% to 30%), and possible lower 
incidence rate or underreporting of cases.. 
Interim Analyses: 
A formal interim analysis (interim evaluation of the study objectives) is not planned for this trial. 
Data Monitoring Committee: 
An independent DMC has been established for the HIL-214 clinical development program. The role and 
responsibilities of the DMC are presented in the DMC charter. 
NOR-212 Version 3.0 (1 September 2023) 
 
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2.1 
Trial Design Diagram 
 
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2.2 
Schedule of Trial Procedures for all Subjects (N = 3000) 
Procedure 
Visit 1(a) 
Safety 
Contact 1(b) 
Safety 
Contact 2(b) 
Visit 2(a) 
Safety 
Contact 3(b)* 
Visit 3(a) 
Visit 4(a) 
Visit 5(a) 
Visit 6(a) (ET/ 
Trial End) 
Timing 
 
Dose 1 
+ 2d 
Dose 1 +7d 
Dose 1 
+ 28 to 56d 
Dose 2 + 7d 
Dose 2 
+ 28d 
Age: 1 
year 
Age: 18 
months 
Age: 2 years 
Visit/safety contact window 
 
+2 
+2 
+2 
+2 
±3 
±10 
±10 
±10 
Reminder via eDiary for AGE detection 
Weekly throughout the trial 
Signed informed consent(c) 
X 
 
 
 
 
 
 
 
 
Assessment of eligibility criteria(d) 
X 
 
 
X 
 
 
 
 
 
Assessment of criteria for delay of vaccination(e) 
X 
 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Medication/Vaccination history 
X 
 
 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Physical examination(f) 
X 
 
 
X 
 
 
 
 
X 
Vital signs(g) 
X 
 
 
X 
 
 
 
 
X 
Blood draw(h) 
X 
 
 
X 
 
X 
X 
X 
X 
Trial vaccine administration(i) 
X 
 
 
X 
 
 
 
 
 
eDiary training(j) 
X 
 
 
X 
 
 
 
 
 
Solicited AEs(k) 
X 
X 
X 
X 
X 
 
 
 
 
Unsolicited AEs(l) 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant medications(l) 
X 
 
X 
X 
X 
X 
 
 
 
SAEs(m) 
Throughout the trial 
AEs leading to trial vaccine withdrawal 
X 
X 
X 
X 
X 
 
 
 
 
AEs leading to withdrawal from trial 
Throughout the trial 
Assessments for AGE for subjects who meet AGE case definition criteria 
AGE onset stool 
Each new onset of AGE (as soon as possible after the start of the episode but up to 6 days after onset of AGE) 
Follow-on stool 
 
 
2 follow-on stool samples should be collected (7-14 days and 15-21 days after onset of AGE) 
AGE symptoms log(n) 
 
 
With each new onset of AGE (daily until resolution of the AGE episode) 
AGE-related healthcare provider visits and AGE treatment 
With each new onset of AGE (after resolution of the AGE episode) 
Abbreviations: AE, adverse event; AGE, acute gastroenteritis; d, day; ET, early termination; serious adverse event, SAE. 
Footnotes are on the following page. 
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Footnotes: 
(a) 
At each of the visits or phone contacts, the investigator should ask and record whether the child is breastfeeding or not. Home visits may be planned where local 
regulations and customs permit. 
(b) 
Safety phone/home contacts occur at 2 days (all subjects) and 7 days (the first 200 subjects) post dose 1, and 7 days post dose 2 (all subjects The subjects will be 
reminded of the next planned trial activity. The safety contact will be a visit for the first 200 subjects. 
(c) 
If the subject randomization visit is re-scheduled more than 15 days after the screening, then a new signed ICF should be obtained and eligibility criteria re-assessed. 
(d) 
Eligibility by review of all exclusion criteria or contraindications will be documented before trial vaccine dose administration at Visit 1 (Day 1). 
(e) 
Review of criteria for delay of trial vaccination will be documented before each trial vaccine dose administration. 
(f) 
Complete physical examination prior to trial vaccine dose administration will be performed for all subjects at Visit 1 (Day 1). Complete physical examination 
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, height/length, and head circumference. A targeted physical examination will be performed at Visit 2 (28 to 56 days post dose 1) prior to 
dose 2, and when the subject reaches 1 year of age (Visit 4) and 2 years of age (Visit 5). 
(g) 
Vital signs include (but are not limited to heart rate and temperature) prior to each trial vaccine dose administration and when the subject reaches 1 year of age 
(Visit 4) and 2 years of age (Visit 6). 
(h) 
The maximum volume of blood taken at any single visit is approximately 5 mL, and the approximate total volume of blood taken during the trial is maximum 30 mL 
for all subjects. Samples will be taken for all subjects prior to trial vaccine administration. 
(i) 
Administration of trial vaccine Dose 1 occurs at Visit 1 (Day 1; subject aged 5 months -14/+14 days) and trial vaccine Dose 2 occurs at Visit 2 (28 to 56 days post 
dose 1). Trial vaccine doses will not interfere with the timing of administration of the routine childhood vaccines per the national guidelines. Trial vaccine doses will be given 
at least 14 days before or after non-live and orally administered live vaccines, and at least 28 days before or after parenterally administered live vaccines. Subjects will be 
observed for at least 30 minutes following vaccine administration, including observation for unsolicited AEs, solicited local reactions and solicited systemic AEs. 
(j) 
Careful training of the subject’s legally-acceptable representative (LAR) on how to measure solicited local reactions, solicited systemic AEs and body temperature, 
how and how often to complete the eDiary for solicited AE and AGE data collection. 
(k) 
Solicited local reactions and solicited systemic AEs for 7 days following each trial vaccine dose administration will be recorded on the eDiary by the subject’s LAR. 
(l) 
Unsolicited AEs and concomitant medications for 28 days after each trial vaccine dose will be recorded on the memory aid section of the eDiary, and reviewed with 
the site staff/investigator. Full information on these AEs and medications will be collected and entered in the EDC by site staff/investigator. 
(m) 
SAEs must be reported to the sponsor as soon as possible but within 24 hours of the investigator becoming aware of the event. 
(n) 
AGE symptoms and body temperature measurements for all subjects with AGE to be entered in the eDiary by the subject’s LAR. 
(o) 
 
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CONFIDENTIAL 
Number: DOC-00351    Version: 3.0    Confidential    Status: Effective    Effective Date: 14 Sep 2023
NOR-212 Protocol V3.0
E

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2.4 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Endpoints  
Summary Statistics and Analysis Sets 
• 
To demonstrate the efficacy of HIL-214 
vaccine against mod/sev AGE associated only 
with GI.1 or GII.4 NoV genotypes. 
• 
Time to first occurrence during the primary 
observation period*, of mod/sev AGE case 
associated only with GI.1 or GII.4 NoV genotypes. 
• 
VE estimate** (VE; calculated as 100X [1 minus the 
risk ratio of AGE cases according to the endpoint 
definition in the vaccine group over that in the 
placebo group]) in the mFAS. 
Secondary Objectives 
 
 
Key Secondary Efficacy Objective 
• 
To evaluate the efficacy of HIL-214 vaccine 
against mod/sev AGE associated only with 
any NoV (GI or GII) genotypes. 
• 
Time to first occurrence during the primary 
observation period* of mod/sev AGE case 
associated only with any NoV (GI or GII) 
genotypes. 
• 
VE estimate according to the endpoint definition, in 
the mFAS. 
Secondary Efficacy Objectives 
• 
To evaluate the efficacy of HIL-214 vaccine 
against mod/sev AGE associated with GI.1 or 
GII.4 NoV genotypes, irrespective of other 
GE pathogens. 
• 
Time to first occurrence during the primary 
observation period* of mod/sev AGE case 
associated with GI.1 or GII.4 NoV genotypes, 
irrespective of other GE pathogens. 
• 
VE estimate according to the endpoint definition, in 
the mFAS. 
• 
To evaluate the efficacy of HIL-214 vaccine 
against mod/sev AGE associated with any 
NoV genogroup (GI or GII), irrespective of 
other GE pathogens. 
• 
Time to first occurrence during the primary 
observation period* of mod/sev AGE case 
associated with any NoV genogroup (GI or GII), 
irrespective of other GE pathogens. 
• 
VE estimate according to the endpoint definition, in 
the mFAS. 
Secondary Immunogenicity Objectives 
• 
To evaluate the immunogenicity of HIL-214. 
Pre-dose 1, 28 days post dose 1, and 
28 days post dose 2: 
• 
HBGA blocking antibody titers. 
• 
Pan-Ig antibody titers. 
• 
GI.1 GMTs, GMFRs and SRRs at relevant time 
points. 
• 
GII.4 GMTs GMFRs and SRRs at relevant time 
points. 
In the FAS and PPS-I. 
 
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OBJECTIVES AND ENDPOINTS (continued) 
Secondary Safety Objectives 
• 
To assess the safety of HIL-214 compared to 
placebo. 
• 
Solicited local AEs up to 7 days after each dose of 
trial vaccine. 
• 
Solicited systemic AEs up to 7 days after each 
dose of trial vaccine. 
• 
Unsolicited AEs for up to 28 days after each dose 
of trial vaccine. 
• 
AEs leading to trial vaccine dose withdrawal. 
• 
AEs leading to the subject’s withdrawal from the 
trial from Day 1 to the end of the trial. 
• 
SAEs throughout the trial. 
Proportion of subjects with, and number of: 
• 
Local reactions. 
• 
Systemic solicited AEs. 
• 
Unsolicited AEs. 
• 
AEs leading to trial vaccine dose withdrawal. 
• 
AEs leading to the subject’s withdrawal from the trial. 
• 
SAEs. 
In the SAF. 
Exploratory Objectives 
 
 
 
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OBJECTIVES AND ENDPOINTS (continued) 
Abbreviations: AE, adverse event; AGE, acute gastroenteritis; CI, confidence interval; FAS, Full-Analysis Set; GE, gastroenteritis; GMFR, geometric mean fold rise; GMT, 
geometric mean titer; HBGA, histoblood group antigen; 
; mod, moderate; mFAS, 
modified Full-Analysis set; NoV, norovirus; pan-Ig, total immunoglobulin; PPS, Per-Protocol set; SAE, serious adverse event; SAF, Safety-Analysis set; sev, severe; SRR, 
seroresponse rate. 
Notes on the next page. 

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CONFIDENTIAL 
Subject age at trial entry is 5 months (-14/+14 days). 
*The duration of the primary observation period is 6 months starting at 28 days post-Dose 2. Time-to-event will be computed from the start of the observation period until the 
date of AGE onset; the date of last contact/discontinuation; the end of the observation period, whichever is earlier. 
**Vaccine efficacy will be demonstrated if the lower limit of the 95.0% CI is above 0%. 
AGE Case Definition and Severity Assessment: 
All subjects meeting the following criteria indicating clinical illness (AGE) will be included in the efficacy analysis: 
• 
Individuals presenting with at least three loose or liquid stools OR at least two or more episodes of vomiting OR one or more loose or liquid stools plus one or more 
vomiting episodes in any 24-hour period. 
The severity assessment of AGE episodes will be determined based on a modified Vesikari score (MVS) [Appendix C]. 
Recurrent norovirus AGE in a subject is considered a new illness according to the clinical AGE definition if: 
• 
The subject has been free from clinical symptoms for at least 5 consecutive days. 
 
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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/Principal Investigator/Coordinating Investigator 
Selection criteria for the investigator(s)/principal investigator(s) and/or coordinating investigator 
will include significant knowledge of the trial protocol, the investigational vaccine, their 
expertise in the therapeutic area and the conduct of clinical research as well as trial participation. 
HilleVax will select one or more signatory/signatories from the investigators who participate in 
the trial. The signatory investigator(s) will be required to review and sign the clinical protocol. 
The signatory investigator(s) will also be required to review and sign the clinical study report 
and by doing so agree(s) that it accurately describes the results of the trial. 
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3.3 
List of Abbreviations 
AESI 
adverse event of special interest 
AE 
adverse event 
AGE 
acute gastroenteritis 
Al(OH)3 
aluminum hydroxide 
CPH 
Cox proportional hazards 
CTM 
clinical trial material 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
eDiary 
electronic diary card 
FAS 
Full-Analysis Set 
FDA 
Food and Drug Administration 
GI 
genogroup (e.g., GI, GII, GIII, etc.) 
GI.1 
genotype (e.g., GI.1, GII.2, GII.4, etc.) 
GII.4c 
consensus GII.4 
GCP 
good clinical practice 
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 
IEC 
Independent Ethics Committee 
IM 
intramuscular 
IRB 
institutional review board 
IRT 
interactive response technology 
LAR 
legally authorized representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
pan Ig 
total immunoglobulin 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
QTL 
quality tolerance limits 
SAE 
serious adverse event 
SAF 
Safety-Analysis Set 
SAP 
statistical analysis plan 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
VE 
vaccine efficacy 
VLP 
virus-like particle 
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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 [4-6]. 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. While mortality due to acute 
gastroenteritis (AGE) caused by norovirus in the pediatric population is rare in industrialized 
countries, it is more common in developing countries [12,13]. Although potentially a cause for 
hospitalization in very young children, there are fewer cases during the first 6 months of life 
possibly due to the protection offered by maternal antibodies from trans-placental transfer and in 
breast milk [14]. In addition, norovirus infections have significant socioeconomic impact on 
hospitals, schools, day care centers and other closed settings [15]. As the burden of rotavirus in 
children decreases due to successful rotavirus vaccination programs in infants, norovirus 
infections are increasingly recognized as the primary cause of AGE in many countries around the 
world [16]. Currently, there is no available vaccine to counter the disease burden associated with 
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 [17-19]. 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, including Latin 
America, where this trial will be primarily performed [20-25]. 
The investigational vaccine, HIL-214 (previously called TAK-214), contains GI.1 virus-like 
particles (VLPs) and norovirus GII.4 consensus VLPs (GII.4c) 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 
investigational vaccine used in this trial is adjuvanted with aluminum as aluminum hydroxide 
[Al(OH)3]. 
Refer to the IB for a summary of known and potential risks and benefits [26]. 
4.2 
Rationale for the Proposed Trial 
The rationale for the proposed trial in children aged approximately 5 months is based primarily 
on epidemiological data which shows that the risk of norovirus AGE increases in infants aged ~6 
months old [14]. 
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CONFIDENTIAL 
The composition of HIL-214 (50/150 µg GI.I/GII.4) to be used in this phase 2b efficacy trial is 
based on the results of trial NOR-202, a phase 2 dose-finding, safety and immunogenicity trial in 
840 children aged 6 weeks to <9 years. The results of trial NOR-202 show that HIL-214 is 
immunogenic and had a generally good safety profile in children aged 6 weeks to <9 years for 
the 50/150 µg GI.1/GII.4c VLP composition adjuvanted with 500 µg of aluminum as Al(OH)3 as 
(1) a one or two-dose regimen in children aged 6 to 12 months, and (2) as a two or three-dose 
regimen in children aged 6 weeks to <6 months for the same composition. So far, 7026 healthy 
volunteers have been dosed in Takeda Vaccines Inc.-sponsored HIL-214 trials and up to 4531 
have received different compositions of HIL-214, including 839 children aged 6 weeks to less 
than 9 years. 
The rationale for the inclusion of children 5 months (±14 days) of age at the time of initial 
vaccination is based on epidemiological data which shows that the risk of norovirus AGE 
increases in infants aged ~6 months old and allows enrolment either before or after the required 
routine childhood vaccines in the participating countries per national guidelines. 
Primary hypothesis: 
The primary hypothesis for this phase 2b proof-of-concept trial is that HIL-214, administered as 
2-dose regimen, provides protection against moderate and severe AGE associated only with GI.1 
or GII.4 vaccine-represented norovirus genotypes in the targeted population of infants. 
This phase 2b trial aims to demonstrate the vaccine efficacy (VE) of two doses of HIL-214 
administered up to 8 weeks apart, against moderate or severe AGE due to GI.1 or GII.4 
norovirus genotypes in approximately 3000 healthy children aged 5 months at the time of the 
first dose up to when they reach the age of 2 years, as well as the safety and immunogenicity of 
HIL-214. A placebo arm is included to allow an unbiased evaluation of efficacy and safety. 
Placebo will be used in this trial because there is no single active comparator vaccine that is 
available across all participating sites. 
The trial will be conducted in accordance with this protocol, ICH and GCP Guidelines, and 
applicable regulatory requirements [2]. 
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CONFIDENTIAL 
5.0 
OBJECTIVES AND ENDPOINTS 
Primary Objective 
Endpoints  
Summary Statistics and Analysis Sets 
• 
To demonstrate the efficacy of HIL-214 
vaccine against mod/sev AGE 
associated only with GI.1 or GII.4 NoV 
genotypes. 
• 
Time to first occurrence during the primary 
observation period*, of mod/sev AGE case 
associated only with GI.1 or GII.4 NoV 
genotypes. 
• 
VE estimate** (VE; calculated as 100X [1 
minus the risk ratio of AGE cases according to 
the endpoint definition in the vaccine group 
over that in the placebo group]) in the mFAS. 
Secondary Objectives 
 
 
Key Secondary Efficacy Objective 
• 
To evaluate the efficacy of HIL-214 
vaccine against mod/sev AGE 
associated only with any NoV (GI or 
GII) genotypes. 
• 
Time to first occurrence during the primary 
observation period* of mod/sev AGE case 
associated only with any NoV (GI or GII) 
genotypes. 
• 
VE estimate according to the endpoint 
definition, in the mFAS. 
Secondary Efficacy Objectives 
• 
To evaluate the efficacy of HIL-214 
vaccine against mod/sev AGE 
associated with GI.1 or GII.4 NoV 
genotypes, irrespective of other GE 
pathogens. 
• 
Time to first occurrence during the primary 
observation period* of mod/sev AGE case 
associated with GI.1 or GII.4 NoV 
genotypes, irrespective of other GE 
pathogens. 
• 
VE estimate according to the endpoint 
definition, in the mFAS. 
• 
To evaluate the efficacy of HIL-214 
vaccine against mod/sev AGE 
associated with any NoV genogroup 
(GI or GII), irrespective of other GE 
pathogens. 
• 
Time to first occurrence during the primary 
observation period* of mod/sev AGE case 
associated with any NoV genogroup (GI or 
GII), irrespective of other GE pathogens. 
• 
VE estimate according to the endpoint 
definition, in the mFAS. 
Secondary Immunogenicity Objectives 
• 
To evaluate the immunogenicity of 
HIL-214. 
Pre-dose 1, 28 days post dose 1, and 
28 days post dose 2: 
• 
HBGA blocking antibody titers. 
• 
Pan-Ig antibody titers. 
• 
GI.1 GMTs, GMFRs and SRRs at relevant 
time points. 
• 
GII.4 GMTs GMFRs and SRRs at relevant 
time points. 
In the FAS and PPS-I. 
 
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CONFIDENTIAL 
OBJECTIVES AND ENDPOINTS (continued) 
Secondary Safety Objectives 
• 
To assess the safety of HIL-214 
compared to placebo. 
• 
Solicited local AEs up to 7 days after each dose of 
trial vaccine. 
• 
Solicited systemic AEs up to 7 days after each dose 
of trial vaccine. 
• 
Unsolicited AEs for up to 28 days after each dose 
of trial vaccine. 
• 
AEs leading to trial vaccine dose withdrawal. 
• 
AEs leading to the subject’s withdrawal from the 
trial from Day 1 to the end of the trial. 
• 
SAEs throughout the trial. 
Proportion of subjects with, and number of: 
• 
Local reactions. 
• 
Systemic solicited AEs. 
• 
Unsolicited AEs. 
• 
AEs leading to trial vaccine dose 
withdrawal. 
• 
AEs leading to the subject’s 
withdrawal from the trial. 
• 
SAEs. 
In the SAF. 
Exploratory Objectives 
 
 
 
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OBJECTIVES AND ENDPOINTS (continued) 

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Abbreviations: AE, adverse event; AGE, acute gastroenteritis; CI, confidence interval; FAS, Full-Analysis Set; GE, gastroenteritis; GMFR, geometric 
mean fold rise; GMT, geometric mean titer; HBGA, histoblood group antigen;
 
 mod, moderate; mFAS, modified Full-Analysis set; NoV, norovirus; pan-Ig, total immunoglobulin; PPS, Per-Protocol set; 
SAE, serious adverse event; SAF, Safety-Analysis set; sev, severe; SRR, seroresponse rate. Notes on the next page. 
Subject age at trial entry is 5 months (-14/+14 days). 
*The duration of the primary observation period is 6 months starting at 28 days post-Dose 2. Time-to-event will be computed from the start of the 
observation period until the date of AGE onset; the date of last contact/discontinuation; the end of the observation period, whichever is earlier. 
**Vaccine efficacy will be demonstrated if the lower limit of the 95.0% CI is above 0%. 
AGE Case Definition and Severity Assessment: 
All subjects meeting the following criteria indicating clinical illness (AGE) will be included in the efficacy analysis: 
• 
Individuals presenting with at least three loose or liquid stools OR at least two or more episodes of vomiting OR one or more loose or liquid 
stools plus one or more vomiting episodes in any 24-hour period. 
The severity assessment of AGE episodes will be determined based on a modified Vesikari score (MVS) [Appendix C]. 
Recurrent norovirus AGE in a subject is considered a new illness according to the clinical AGE definition if: 
• 
The subject has been free from clinical symptoms for at least 5 consecutive days. 
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6.0 
TRIAL DESIGN AND DESCRIPTION 
6.1 
Trial Design 
This is a phase 2b, double-blind, randomized, multi-site, placebo-controlled trial to evaluate the 
efficacy, safety, and immunogenicity of two doses of the intramuscular (IM) HIL-214 vaccine 
compared to placebo in approximately 3000 children, 5 months of age (-14/+14 days) at the time 
of the first dose of trial vaccine. 
The second dose of trial vaccine should be administered 28 days (and up to 56 days) after the 
first dose. Trial vaccine doses will be given at least 14 days before or after non-live and orally 
administered live vaccines, and at least 28 days before or after parenterally administered live 
vaccines which are given in accordance with country pediatric immunization guidelines. Subjects 
will be allocated (1:1) into 1 of 2 trial arms by interactive response technology (IRT) and 
stratified by country: 
• Arm 1 (N = 1500): One dose of HIL-214 at Visit 1 (Day 1) and one dose of HIL-214 at 
Visit 2 (28 to 56 days post dose 1). 
• Arm 2 (N = 1500): One dose of placebo at Visit 1 (Day 1) and one dose of placebo at Visit 2 
(28 to 56 days post dose 1). 
A schematic of the trial design is shown in Section 2.1 and included as Figure 6.a. 
Figure 6.a: 
Schematic of Trial Design 
 
• All subjects will be followed for solicited local and systemic adverse events (AEs) up to 
7 days after each dose of trial vaccine (including day of dose) and unsolicited AEs for up to 
28 days after each dose of trial vaccine (including day of dose). 
• All subjects will be followed throughout the trial (from Day 1) for serious adverse events 
(SAEs), AEs leading to trial vaccine dose withdrawal, and AEs leading to trial withdrawal. 
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• The subject’s legally-authorized representative (LAR) (all subjects) will receive weekly 
notifications via eDiary to complete the AGE report if the subject has AGE symptoms 
(episodes of vomiting and/or liquid stools). 
• All subjects will have six blood draws (pre-dose 1 at Visit 1 [Day 1], pre-dose 2 at Visit 2 [28 
to 56 days post dose 1], at Visit 3 [28 days post dose 2], at Visit 4 [1 year of age], at Visit 5 
[18 months of age] and at Visit 6 [2 years of age]), to measure anti-norovirus total 
immunoglobulin (pan-Ig) and histoblood group antigen (HBGA) blocking antibodies and 
 
• All subjects will have two safety phone/home contacts 2 days (Day 3) and 7 days (Day 8) 
post dose 1, and one safety phone/home contact 7 days post dose 2. 
• The first 200 subjects (cohort 1) will have a site visit on Day 8 post dose 1; the remaining 
subjects (cohort 2) will have a safety phone/home contact on this trial day. 
• Enrolment beyond the first 200 subjects will be paused until safety data up to 28 days post 
dose 2 has been analyzed by the sponsor and assessed to be satisfactory by the data 
monitoring committee (DMC). If applicable, the DMC will also evaluate immunogenicity 
data up to 28 days post dose 2 to support recommendation to continue enrolment. 
• If the child has liquid/loose stools or vomiting, the LAR will enter the number of episodes in 
the eDiary to inform the site. The subject’s LARs will be requested to record AGE symptoms 
and their frequency, and body temperature in the eDiary from the first day of AGE onset 
until the symptoms have resolved. This log will be activated automatically if the number of 
episodes of vomiting and loose/liquid stools satisfies the AGE case definition. All subjects 
who meet the criteria for the AGE case definition will provide one AGE onset stool sample 
and two AGE follow-on stool samples. AGE cases will be collected starting from the Day 1 
(Dose 1 of trial vaccine) until all subjects have reached 2 years of age (end of trial). The 
number of AGE cases including primary endpoint AGEs will be monitored during the trial in 
a blinded way. The process is described in the AGE monitoring charter. 
• All AGE onset stool samples will be assayed for the presence of norovirus and norovirus-
positive samples will be sequenced for genotype identification. Only norovirus-positive 
samples will be analyzed for the presence of co-pathogens. Follow-on stool samples 
collected 2 and 3 weeks post-onset will be analyzed for norovirus presence and genogroup 
only. 
• 
• 
 
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The trial procedures are described in Section 2.2, and procedures for the country-specific 
household transmission ancillary study are shown in Section 2.3 and Section 9.0. 
6.2 
Justification for Trial Design, Dose, and Endpoints 
Trial NOR-212 will be performed in children aged approximately 5 months at receipt of the first 
dose as this age corresponds to waning protection by maternal antibodies found in breast milk 
[14]. This phase 2b trial will evaluate the efficacy of HIL-214 against AGE associated with 
norovirus up to the time that the vaccinated subjects reach 2 years of age. Safety and 
immunogenicity will also be assessed throughout the trial. 
 
 The sample size calculation for this efficacy trial considers the number of subjects 
required for the primary endpoint (Section 13.3). 
HIL-214 will be administered intramuscularly as previously done in the NOR-202 pediatric trial. 
Based on NOR-202, the dose used during NOR-212 will be 50/150 GI.1/GII4c adjuvanted with 
500 µg Al(OH)3, administered as two doses, 28 days apart (at Day 1 and between Day 29 and 
Day 57). HIL-214 and placebo will be administered separately from the routine infant/childhood 
vaccines. Placebo will be used in this trial because there is no single active comparator vaccine 
that is available across all participating sites. 
Please refer to the IB for further details [26]. 
6.3 
Planned Duration of Subject’s Participation in the Trial 
The overall duration of the trial and subject participation will be up to 20 months. 
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. 
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• New information or other evaluation regarding the safety or efficacy of the investigational 
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 Investigational Sites 
A trial site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant deviation from GCP, 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 Investigational Site(s) 
In the event that the sponsor, an Independent Ethics Committee (IEC)/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. 
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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria: 
1. The subject is aged 5 months (-14/+14 days). 
2. Male or female. 
3. Children 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. 
4. The subject’s LAR signs and dates a written ICF and any required privacy authorization prior 
to the initiation of any trial procedures, after the nature of the trial has been explained 
according to local regulatory requirements. 
5. Children whose LARs can and are willing 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. Clinically significant abnormality in growth by height, weight, or head circumference 
(according to local guidelines). 
2. Gastrointestinal abnormalities or any chronic gastrointestinal disease, including any 
uncorrected congenital malformation of the gastrointestinal tract according to medical history 
and/or physical examination. 
3. Known hypersensitivity or allergy to any of the investigational vaccine components 
(including excipients). 
4. Any clinically significant active infection (as assessed by the investigator) or temperature 
≥38.0°C (>100.4°F), within 3 days of intended trial vaccination. 
5. Any serious chronic or progressive disease according to the judgment of the investigator 
(e.g., cardiac, renal or hepatic disease). 
6. Individuals with history of, e.g., convulsions/febrile convulsions, or 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. 
7. Known or suspected impairment/alteration of immune function. 
8. Subjects with a known bleeding diathesis, or any condition that may be associated with a 
prolonged bleeding time. 
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9. Subjects who received or are scheduled to receive any routine or authorized vaccine within 
14 days (for non-live or orally administered live vaccines) or 28 days (for parenterally 
administered live vaccines) before or after any dose of trial vaccine. 
10. Subjects participating in any clinical trial with another investigational product 30 days prior 
to first trial visit or intend to participate in another clinical trial at any time during the 
conduct of this trial. 
11. Subjects known to be positive for or in evaluation for possible human immunodeficiency 
virus infection. 
12. Subject’s LAR or subject’s first-degree relatives 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 Investigational Medicinal Product Administration and/or 
Blood Sampling 
After enrollment, subjects may encounter clinical circumstances that warrant a delay in the 
administration of 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 other vaccines within 14 days (for non-live or orally administered 
live vaccines) or 28 days (for parenterally administered live vaccines) prior to planned trial 
vaccine administration or blood sampling. 
• Subjects who have been given antipyretics and/or analgesic medications within 24 hours 
prior to vaccination. The reason for their use (prophylaxis versus treatment) must be 
documented. Investigational medicinal product administration should be delayed to allow for 
at least 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 
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termination of the subject’s trial participation should be documented using the following 
categories. 
For screen failure subjects, refer to Section 9.1.9. 
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’s LAR is unwilling to allow the child to continue participation because of the AE. If 
the subject’s LAR is unwilling to allow the child to continue 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 attempts to 
contact the subject’s LAR were unsuccessful. 
3. Withdrawal of consent: The subject’s LAR wishes to withdraw the child from the trial. The 
primary reason for early termination will be withdrawal of consent if the subject’s LAR 
withdraws the child from participation due to a non-medical reason (i.e., reason other than 
AE). While the subject’s LAR 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 IEC/IRB, or any other 
authority. 
If the clinical trial is prematurely terminated by the sponsor, the investigator is to promptly 
inform the subject’s LAR and local IEC/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. 
7.5 
Criteria for Premature Discontinuation of Investigational Medicinal Product 
Administration 
There are circumstances under which receipt of a further trial vaccine dose is a contraindication 
in this trial. These circumstances include anaphylaxis or severe hypersensitivity reactions 
following the initial vaccination. If these reactions occur, the subject must not receive additional 
trial vaccine but the subject’s LAR is encouraged to allow the child to continue in trial 
participation for safety follow-up and efficacy and immunogenicity data collection. 
Early termination of a subject’s trial participation will by default prevent the subject from 
receiving further doses of investigational vaccine, as the subject will no longer be participating in 
the trial. In addition to criteria for early termination of a subject’s participation (see Section 7.4), 
other situations may apply in which subjects may continue participating in the trial (e.g., 
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contributing safety and other data according to protocol) but investigational vaccine 
administration is discontinued. Even if the subject is deemed ineligible to receive further doses 
of trial vaccine, all efforts should be made to continue the collection of data according to 
protocol. 
In addition, the primary reason for premature discontinuation of trial vaccine administration 
should be recorded in the (electronic) case report form (eCRF, end of trial vaccine administration 
page) 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) for which subsequent trial vaccine 
administration(s) pose an unacceptable risk to the subject’s health, but the subject will 
continue trial participation for safety, or for a subset of other trial procedures. 
2. Lost to follow-up: The subject did not return to the clinic and at least three attempts to 
contact the subject were unsuccessful. 
3. Withdrawal of consent: The subject’s LAR wishes to withdraw the child from the trial. The 
primary reason for early termination will be withdrawal of consent if the subject’s LAR 
withdraws the child from participation due to a non-medical reason (i.e., reason other than an 
AE). The reason for withdrawal, if provided, should be recorded in the eCRF. 
4. Premature trial termination by sponsor, a regulatory agency, the IEC/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 local IEC/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 prior to the next trial vaccine administration. 
6. Protocol deviation: A protocol deviation is any change, divergence, or departure from the 
trial design or procedures of a trial protocol. The subject may remain in the trial unless 
continuation in the trial jeopardizes the subject’s health, safety or rights (see Section 7.4). 
7. Other reason for early termination that is not captured by the above prespecified categories. 
For criteria which also lead to early termination of a subject’s trial participation, please refer to 
Section 7.4. 
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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all investigational vaccines, placebo, 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 
Investigational Products 
Descriptions for the investigational vaccine and the placebo are provided in the following 
sections. 
8.1.1 Investigational 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 investigational vaccine contains 50 µg 
GI.1/150 µg GII.4c VLPs and 500 µg of aluminum as Al(OH)3. 
 
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. 
8.1.2 Placebo 
Placebo [0.9% sodium chloride (saline)] for injection is provided by HilleVax, Inc. or designated 
vendor, in a container allowing delivery of a 0.5 mL dose). The placebo does not contain any 
preservatives. 
The contents of the placebo container will appear clear and therefore, distinguishable from the 
vaccine. 
Each placebo container 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. 
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 
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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 and placebo 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 every day. 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 dose of 50 µg GI.1/ 150 µg GII.4c VLPs and 500 µg of aluminum as Al(OH)3 
or placebo will be administered intramuscularly at Visit 1 (Day 1) and Visit 2 (28 to 56 days 
after the first dose) in the anterolateral thigh muscle. 
8.5 
Investigational Medicinal Product Assignment and Dispensing Procedures 
The vaccine identification number of the kit to be administered will be assigned by the IRT. 
The vaccine and placebo are visually distinguishable and therefore, to maintain the blind, the 
trial vaccine doses will be prepared and administered by the unblinded designee according to the 
instructions in the Pharmacy Manual. 
The investigator or designee will be responsible for overseeing the administration of vaccine to 
subjects enrolled in the trial according to the procedures stipulated in this trial protocol. All 
vaccines will be administered only by unblinded personnel who are qualified to perform that 
function under applicable laws and regulations for that specific trial. 
Expired vaccines must not be administered. 
If sponsor-supplied kit is lost or damaged, the site can request a replacement from the IRT (refer 
to IRT manual supplied separately). At the subsequent dose-administration visit, the investigator 
or designee will again contact the IRT to request an additional kit for a subject. 
8.5.1 Precautions to Be Observed When Administering the Investigational Medicinal 
Product 
Prior to trial vaccine administration, a subject must be determined to be eligible to receive trial 
vaccine (Sections 7.1and 7.2), and it must be clinically appropriate in the judgment of the 
investigator to administer the HIL-214 or placebo. 
Prior to subsequent trial vaccine administration, site staff must determine if the subject is eligible 
to receive vaccination by evaluating the criteria outlined in Sections 7.3, 7.4 and 7.5. 
Standard immunization practices are to be observed and care should be taken when 
administering a trial vaccine intramuscularly. In addition, World Health Organization (WHO) 
recommendations to reduce anxiety and pain at the time of vaccination should be followed [27]. 
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Before administration of trial vaccine/placebo, the vaccination 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 post vaccination. For example, 
epinephrine 1:1000, diphenhydramine, and/or other medications for treating anaphylaxis should 
be available. 
8.6 
Randomization Code Creation and Storage 
The investigator or investigator’s designee will access the IRT at Visit 1 (Day 1) to obtain the 
subject number. 
The investigator or investigator’s designee will utilize the IRT to randomize all subjects into 
either the HIL-214 or placebo arms. During this contact, the investigator or designee will provide 
the necessary subject identifying information. 
Randomization information will be stored in a secured area, accessible only by authorized 
personnel. 
8.7 
Investigational Medicinal Product Blind Maintenance 
The blind will be maintained by the unblinded designee. 
This is a double-blind trial; the investigator and subject’s LAR are blinded to trial vaccine 
assignment. Trial vaccine identity (label text as HIL-214 or placebo) will be included on the trial 
vaccine container label. 
8.8 
Unblinding Procedure 
The trial vaccine blind shall not be broken by the investigator unless information concerning the 
HIL-214 is necessary for the medical treatment of a subject. In the event of a medical 
emergency, if possible, the medical monitor should be contacted before the trial vaccine blind is 
broken to discuss the need for unblinding. For unblinding a subject, the trial vaccine blind can be 
obtained by the investigator, by accessing the IRT. 
The sponsor’s pharmacovigilance department must be notified as soon as possible if the trial 
vaccine blind is broken by the investigator and the completed SAE form, if applicable, must be 
sent within 24 hours. The date, time, and reason the blind is broken must be recorded in the 
source document and the same information (except the time) must be recorded on the eCRF. 
If any subject is unblinded, the subject must be withdrawn from the trial and their data no longer 
evaluated. Subjects should continue to be monitored for safety follow-up. 
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8.9 
Accountability and Destruction of Sponsor-Supplied Trial Vaccines, and Other 
Clinical Trial Materials 
The investigator or designee must ensure that the sponsor-supplied trial vaccines and placebo are 
used in accordance with the approved protocol and is/are administered only to subjects enrolled 
in the trial. To document appropriate use of sponsor-supplied trial vaccine or placebo, the 
investigator must maintain records of all sponsor-supplied trial vaccine or placebo delivery to the 
site, site inventory, administration and use by each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied trial vaccines or placebo, 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 or placebo 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 by 
recording in IRT. 
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 vaccines and 
placebo, 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/placebo ID or job 
number) used to prepare each dose. 
• 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 vaccines or 
placebo (list all that apply) on a sponsor-approved trial vaccine 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 vaccines or placebo, date, and 
amount. The log (IRT) should include all required information as a separate entry for each 
subject to whom sponsor-supplied trial vaccine or placebo is administered. 
Include the following if manual system is used for vaccine shipment. 
The investigator will be notified of any expiry date or retest date extension of trial vaccine or 
placebo during the trial conduct. On expiry date notification from the sponsor or designee, the 
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site 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. 
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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 and Section 2.3. 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 eCRFs. 
9.1.1 Informed Consent 
The requirements of the 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 by the IRT after informed consent is 
obtained. If all eligibility criteria are fulfilled (Section 7.1and 7.2, this subject number will be 
used throughout the trial. Subject numbers assigned to subjects who fail screening should not be 
reused (Section 9.1.9). 
9.1.2 Demographics, Medical History and Prior Medications 
Demographic information to be obtained will include date of birth, sex, race (and ethnicity) as 
described by the subject’s LAR. 
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 informed consent 
and the first 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. 
All medications, vaccines and blood products taken or received by the subjects prior to Visit 1 
(Day 1) are to be collected as prior medications. 
a) Medications: 2 months prior to Visit 1 (Day 1, day of vaccination). 
b) Vaccines: From birth up to Visit 1 (Day 1, day of vaccination). 
c) Blood products: 3 months prior to Visit 1 (Day 1, day of vaccination). 
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Concomitant medications and vaccines will be collected from Visit 1 (Day 1) to Visit 3 (28 days 
after the second dose). 
The use of antipyretics and/or analgesic medications within 24 hours prior to vaccination must be 
identified and the reason for their use (prophylaxis versus treatment) must be documented. 
Administration of the trial vaccine should be delayed if subjects have received antipyretics 
within 24 hours prior to vaccine administration. 
Medications taken for prophylaxis are those intended to prevent the onset of AEs post 
vaccination. Medications taken for treatment are intended to reduce or eliminate the presence of 
symptoms that are present. 
These data must be written in the source documents. 
9.1.3 Documentation of Trial Entry/Randomization 
Only subjects who’s LAR have a signed ICF and meet all of the inclusion criteria (Section 7.1) 
and none of the exclusion criteria (Section 7.2) will be eligible for randomization/entry into the 
active phase. The randomization schedule will be created and controlled by the IRT provider. 
The randomization specification will be approved by the sponsor’s trial statistician, or designee. 
If the subject is ineligible for randomization, the investigator should record the primary reason 
for failure on 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: 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/length and head circumference. A complete physical 
exam will be performed at Visit 1 (Day 1) according to the investigator’s standard practice. 
Additional physical examinations may be performed if indicated by review of the subject’s 
medical history. The findings should be documented in the subject’s source document. 
Symptom-directed physical examination may be performed 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. Follow standard of care for trial 
population and operational feasibility. 
9.1.6 Immunogenicity Assessments 
Subjects in all trial arms will undergo blood sampling for serological immunogenicity testing at 
Visit 1 (Day 1), Visit 2 (28 to 56 days post dose 1 - prior to dose 2) and Visit 3 (28 days post 
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dose 2); then when the subjects reach the age of 1 year (Visit 4), 18 months (Visit 5) and 2 years 
(Visit 6). All samples must be collected in accordance with acceptable laboratory procedures. 
The maximum volume of blood taken at any single visit is approximately 5 mL, and the 
approximate total volume of blood for the trial is maximum 30 mL. 
9.1.7 Processing, Labeling and Storage of Biological Samples 
All biological samples (e.g., blood, serum, and stool) 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 are planned at Visit 1 (Day 1), Day 3 (phone contact), Day 8 (phone contact 
or visit), Visit 2 (28 to 56 days post dose 1), 7 days post dose 2 (phone contact) and Visit 3 (28 
days post dose 2), then when the subjects reach the age of 1 year (Visit 4), 18 months (Visit 5) 
and 2 years (Visit 6). The safety assessments will include collection and recording of solicited 
local (injection site) and systemic AEs (for 7 days post vaccination), unsolicited AEs and AEs 
(serious and non-serious, for 28 days post vaccination), and SAEs. Refer to Section 10.1 for 
safety definitions. Details on collection and reporting of AEs are in Section 10.5. 
9.1.9 Documentation of Subjects Who Are Not Randomized 
Investigators must account for all subjects for whom there is a signed an ICF. If the subject is 
found to be not eligible at this visit, the investigator should complete the eCRF. 
The primary reason for non-randomization is recorded in the eCRF using the following 
categories: 
• Screen failure (did not meet one or more inclusion criteria or did meet one or more exclusion 
criteria). 
• Withdrawal by subject’s LAR. 
• Trial terminated by the sponsor. 
Subject numbers assigned to subjects who fail screening will not be re-used. 
9.1.10 
 
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9.2 
Monitoring Subject Compliance 
The investigator will record all injections 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 and 
Section 2.3. Assessments should be completed at the designated time points. 
9.3.1 Pre-Vaccination Procedures (Day 1) 
1. Informed consent or ICF (Section 9.1.1). 
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. Randomization (Section 8.5). 
7. Concomitant medications (Section 9.1.2). 
8. Documentation of trial entrance/randomization (Section 9.1.3). 
9. Complete physical examination (Section 9.1.4). 
10. Vital signs (Section 9.1.5). 
11. Blood sampling (~ 5 mL) (Section 9.1.6). 
9.3.2 Vaccination Procedures (Visit 1 [Day 1]; Visit 2 [28 to 56 days post dose 1]) 
After confirming eligibility and randomizing the subject (on Day 1) and blood sampling, perform 
trial vaccine administration according to the procedures described in Section 8.5. At the next 
clinic visit that involves vaccination (Visit 2 - between Day 29 and Day 57), confirm that the 
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subject does not meet any criteria for delaying, or premature discontinuation of, additional trial 
vaccine administration, as described in Section 7.3. 
9.3.3 Post-vaccination Procedures (Visit 1 [Day 1]; Visit 2 [28 to 56 days post dose 1]) 
The following post-vaccination procedures will be performed at Visit 1 (Day 1) and Visit 2 
(28 to 56 days post dose 1): 
• Training of the subject’s LAR on how to measure solicited local (injection site) reactions and 
body temperature, how to complete the electronic diary card (eDiary) and how often to 
complete the eDiary. Training should be directed at the individual(s) who will perform the 
measurements of solicited local (injection site) reactions and those who will enter the 
information into the eDiary. This individual may or may not be the subject’s LAR, but if a 
person other than the subject’s LAR enters information into the eDiary, this person’s identity 
must be documented in the source and this person must receive training on the eDiary. 
Training of the subject’s LAR on how to measure an injection site reaction and how to take 
their temperature, as well as how to record the information in the eDiary, should be 
performed while the subject is under observation after vaccination. 
The eDiary instructions must include the following: 
• The individual(s) who will enter the information into the eDiary must understand that timely 
completion of the eDiary on a daily basis is a critical component of trial participation. 
Please note: 
The eDiary will be the only source document allowed for remote collection of solicited local 
(injection site) reactions and systemic AEs (including body temperature measurements). The 
following additional rules apply to the documentation of safety information collected by eDiary: 
• The eDiary should be reviewed by the site. 
• No corrections or additions to the eDiary will be allowed after the end of each day (midnight) 
in the solicited data collection period (for 7 days post vaccination). 
• Any blank fields on the eDiary will be missing in the eCRF. 
• Any new unsolicited safety information would be recorded in the subject source document as 
a verbally reported event and therefore captured as an AE and recorded on the AE eCRF. 
• Starting on the day of vaccination, the subject’s LAR 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 and body 
temperature will be recorded in the eDiary. Other symptoms and medications will be 
recorded in the memory aid section of the eDiary. Assessments should preferably take place 
in the evening. 
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• Temperature measurement is to be performed daily using the thermometer provided by the 
site. If the subject feels unusually hot or cold during the day, the subject’s LAR should check 
their temperature. If the subject has fever, the highest body temperature observed that day 
should be recorded on the eDiary. 
• The measurements of solicited local (injection site) reactions are to be performed using the 
ruler provided by the site. 
• The collection on the eDiary of body temperature, solicited local (injection site) reactions, 
and solicited systemic AEs will continue for a total of 7 days following vaccine 
administration (including day of administration). The recording of other symptoms and 
medications in the memory aid section of the eDiary will continue for 28 days following 
vaccine administration (including day of administration). 
After vaccination, the subject will be observed for at least 30 minutes including observation for 
unsolicited AEs, solicited local (injection site) reactions, and body temperature measurement. 
Information should be recorded in the eCRF. The investigator or delegate will take the 
opportunity to remind the subject’s LAR how to measure solicited local (injection site) reactions 
and body temperature as part of this observation period. All safety data will be collected in the 
subject’s source documents. 
The site should schedule the next trial activity reminder call or visit. 
The subject’s LAR will receive a written reminder of the next planned trial activity. The 
subject’s LAR will be reminded to complete the eDiary 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 
site contact details will be provided to the subject’s LAR. 
9.3.4 Phone Contacts - Reminder Calls (2 and 7 days post dose 1 and dose 2 and 7 days 
post dose 2) 
All subjects will have two safety phone/home contacts 2 days (Day 3) and 7 days (Day 8) post 
dose 1, and one safety phone/home contact 7 days post dose 2. The contact on these days may be 
a home visit if needed. The purpose is to remind the subject’s LAR about completion of the 
eDiary. If the subject’s LAR wishes to describe safety information, this information should only 
be collected by a trained healthcare professional at the site, and the safety data described must be 
written down in source documents. The subject’s LAR should be reminded to enter the 
information in the eDiary and to contact the site via the telephone number provided in the ICF to 
discuss medical questions. The subject’s LAR will be asked on Day 8 about any concomitant 
medications being administered to the child. 
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9.3.5 Site Visits After Vaccination (Visit 3 [28 days post dose 2], Visit 4 [age 1 year], 
Visit 5 [age 18 months] and Visit 6 [age 2 years]) 
Site visits that do NOT include a vaccination will be performed at Visit 3 (28 days post dose 2), 
Visit 4 (age 1 year), Visit 5 (age 18 months) and Visit 6 (age 2 years). At the site visit, the eDiary 
will be reviewed. The healthcare professional reviewing these data will discuss the AEs (if any) 
reported by the subject’s LAR and will determine if any additional diagnoses and/or AEs are 
present and/or if concomitant medications have been used. 
The investigator will check vital signs and perform a physical examination at age 18 months and 
age 2 years. 
Blood (approximately 5 mL) should be taken from the subject using an aseptic venipuncture 
technique for serological immunogenicity testing at Visit 3 (28 days post dose 2), Visit 4 (age 
1 year), Visit 5 (age 18 months) and Visit 6 (age 2 years). 
The site investigator/personnel should ask and record whether the child is breastfeeding or not. 
The site should schedule the next site visit or other trial activity (except at the final visit) with the 
subject’s LAR. 
The subject or the subject’s LAR will receive a written reminder of the next planned trial 
activity. The subject or the subject’s LAR 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. 
9.3.6 Final (End of Trial) Visit 
The final (end of trial) visit will be performed when the subject has reached 2 years of age. If a 
subject terminates earlier, the final (end of trial) visit procedures (Section 9.3.5) should be 
performed at their last trial visit, if possible. The investigator must complete the End of Trial 
eCRF page for all subjects who received trial vaccine. 
9.3.7 Post-Trial Care 
No post-trial care will be provided. 
9.3.8 Procedures for Subjects who Meet AGE Case Definition Criteria 
The procedures for subjects who meet AGE case definition criteria are described in Section 2.2. 
9.3.9 
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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 
not longer than 20 years or as required by applicable law. Stool samples will also be stored at a 
central repository after the trial has ended for up to but not longer than 20 years or as required by 
applicable law. The sponsor has put into place a system to protect the subjects’ personal 
information to ensure optimal confidentiality and defined standard processes for sample and data 
collection, storage, analysis, and destruction. 
Serum and stool samples will be used for the analyses defined in this protocol, but can also, with 
permission from the subject’s LAR, 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 and stool samples could also be used for further 
exploratory testing. If the subject’s LAR does not consent to future testing of samples on the 
ICF, the subject can still participate in the trial. 
The same applies to samples collected from consenting symptomatic household members. 
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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 investigational 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 following 
administration of each dose of investigational vaccine (including the day of administration) and 
will be recorded on the Local and Systemic Reactions eCRF page as applicable and as listed in 
Table 10.a. 
Any solicited local or systemic AEs observed as continuing on Day 8 following each trial 
vaccination 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). 
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Table 10.a 
Solicited Local (Injection Site) Reactions and Systemic AEs 
Solicited local (injection site) reactions: 
Erythema 
Induration 
Pain 
Swelling 
Systemic adverse events: 
Drowsiness 
Irritability/fussiness 
Loss of appetite 
Fever* 
Vomiting 
Diarrhea 
Body temperature will be collected and recorded. *Fever is defined as body temperature greater than or equal to 
38°C (100.4°F) regardless of method used [28]. 
The intensity of solicited safety parameters will be assessed as described in Table 10.b. 
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Table 10.b 
Solicited Safety Parameters 
Adverse Event 
Intensity Grade 
Intensity 
Pain at injection site 
0 
None 
1 
Mild: Minor reaction to touch 
2 
Moderate: Cries/protests on touch 
3 
Severe: Cries when limb is moved/spontaneously painful 
Erythema at injection site(a) 
0 
≤10 mm 
1 
Mild: >10 – ≤20 mm 
2 
Moderate: >20 – ≤40 mm 
3 
Severe: >40 mm 
Induration at injection site(a) 
0 
≤10 mm 
1 
Mild: >10 – ≤20 mm 
2 
Moderate: >20 – ≤40 mm 
3 
Severe: >40 mm 
Swelling at injection site(a) 
0 
≤10 mm 
1 
Mild: >10 – ≤20 mm  
2 
Moderate: >20 – ≤40 mm 
3 
Severe: >40 mm 
Drowsiness 
0 
Behavior as usual 
1 
Mild: Drowsiness easily tolerated 
2 
Moderate: Drowsiness that interferes with normal activity 
3 
Severe: Drowsiness that prevents normal activity 
Irritability/fussiness 
0 
Behavior as usual 
1 
Mild: Crying more than usual/no effect on normal activity 
2 
Moderate: Crying more than usual/interferes with normal activity 
3 
Severe: Crying that cannot be comforted/prevents normal activity 
Loss of appetite 
0 
Appetite as usual 
1 
Mild: Eating less than usual/no effect on normal activity 
2 
Moderate: Eating less than usual/interferes with normal activity 
3 
Severe: Not eating at all 
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. 
(b) Fever is defined as body temperature greater than or equal to 38°C (100.4°F) regardless of method used [28]. 
10.1.3 Adverse Events of Special Interest 
Not applicable. No adverse event of special interest (AESI) has been identified for this trial. 
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10.1.4 Medically-attended Adverse Events 
Not applicable. 
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 through 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. 
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 Yes 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 No. 
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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. 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require trial vaccine discontinuation or 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…). 
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• 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 severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 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 ICF are considered as AEs 
and should be reported as AEs. 
10.4 
Collection and Reporting Procedures 
10.4.1 Collection and Reporting of Adverse Events 
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 SAE form*, if necessary (see Section 10.4.4). All findings in subjects 
experiencing AEs must also be documented in the subject’s source documents. Any unsolicited 
AE will be collected for 28 days after each dose of trial vaccine. The subject's LAR will use the 
eDiary memory aid to record unsolicited symptoms for reporting to the site. AEs leading to 
discontinuation (from the trial or from the vaccination regimen) are collected throughout the 
trial. Even if the subject is deemed ineligible to receive further doses of trial vaccine, all efforts 
should be made to continue the collection of safety data according to protocol. 
The following information will be documented for each event: 
• Reported term for the AE. 
• Start and end date, duration. 
• Serious (Y/N). 
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• Severity. 
• 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. 
• Action taken with the trial vaccine. 
• Outcome of event. 
*SAE reporting will be done by eCRF. If the eCRF system is unavailable, a paper sponsor SAE 
form/paper CRF should be completed and the event must be entered into the eCRF once access 
is restored. 
10.4.2 Collection and Reporting of Solicited Adverse Events 
The occurrence of selected indicators of safety will be collected on eDiary by the subject’s LAR 
for 7 days following administration of each trial vaccine dose (including the day of 
administration) and will be recorded on the Local and Systemic AEs eCRF, as applicable. These 
will be summarized in the final clinical study report 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 following each trial vaccination will be additionally 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 (injection site) reactions or systemic AEs that lead the subject to withdraw 
from the trial. 
• Solicited local (injection site) reactions or systemic AEs that lead to the subject being 
withdrawn from the trial by the investigator. 
• Solicited local (injection site) reactions 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 medically-attended AEs (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’s LAR signs the ICF. Routine 
collection of SAEs will continue until the end of the trial (up to 2 years of age). 
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SAEs should be reported according to the following procedure: 
A sponsor SAE 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 SAE form should be transmitted within 24 hours to 
 
If the eCRF system is unavailable, a paper sponsor SAE form/paper CRF should be completed 
and the event must be entered into the eCRF once access is restored. 
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 not available at the time of the first report becomes available later, the investigator 
should complete a follow-up SAE form or provide other written 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 until resolution, permanent outcome of the event, or is 
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, Independent Ethics Committees or 
Investigational Review Boards, and Regulatory Authorities 
The sponsor or designee will be responsible for the reporting of all suspected unexpected serious 
adverse reactions (SUSAR) and any other SAEs to regulatory authorities, investigators and 
IEC/IRB, as applicable, in accordance with national regulations in the countries where the trial is 
conducted. 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 
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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 an investigational 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 their IEC/IRB in 
accordance with national 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. 
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11.0 
TRIAL-SPECIFIC REQUIREMENTS 
An independent DMC has been established for the HIL-214 clinical development program. The 
role and responsibilities of the DMC are presented in the DMC charter. 
The DMC will be composed with a minimum of 2 members with pediatric infectious disease 
and/or vaccine expertise, a clinician and statistician. 
Two safety data reviews will be performed by the DMC for the first 200 subjects at: 
1. Safety Contact 2 (7 days post dose 1) for safety data collected up to 7 days following the first 
dose of trial vaccine (solicited local reactions and systemic events), and 
2. Visit 3 (28 days post dose 2) for safety data collected up to 28 days following the second 
dose of trial vaccine (unsolicited AEs). 
Enrolment beyond the first 200 subjects will be paused until safety data up to 28 days post dose 2 
has been analyzed by the sponsor and assessed to be satisfactory by the DMC. If applicable, the 
DMC will also evaluate immunogenicity data up to 28 days post dose 2 to support the 
recommendation to continue enrolment. 
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC can conduct additional analyses of the safety data. 
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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 World 
Health Organization (WHO) Drug Dictionary. 
12.1 
Electronic CRFs 
Completed eCRFs are required for each subject for who there is a signed ICF. 
The sponsor or designee will supply investigative sites 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 items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by sponsor 
personnel (or designee[s]) 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 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 agrees to keep the records stipulated in Appendix A and those documents that 
include (but are not limited to) the trial-specific documents, the identification log of all 
participating subjects, medical records. Temporary media such as thermal sensitive paper should 
be copied and certified, source worksheets, all original signed and dated informed consent forms, 
subject authorization forms regarding the use of personal health information (if separate from the 
informed consent), electronic copy of eCRFs, including the audit trail, and detailed records of 
vaccine disposition to enable evaluations or audits from regulatory authorities, the sponsor or 
designee. Furthermore, International Council on Harmonisation (ICH) E6 [2] Section 4.9.5 
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requires the 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. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
trial arm. This document will provide further details regarding the definition of analysis variables 
and analysis methodology to address all trial objectives. 
A blinded data review will be conducted prior to unblinding of subject’s assignment to a trial 
arm. This review will assess the accuracy and completeness of the trial, database and subject 
evaluability. 
13.1.1 Analysis Sets 
Safety Set (SAF): The SAF will consist of all subjects who are randomized and received at least 
one dose of HIL-214 or placebo. Subjects will be analyzed according to the treatment which they 
actually received. 
Full-Analysis Set (FAS): The FAS will include all subjects who are randomized and received at 
least 1 dose of HIL-214 or placebo. Subjects will be analyzed according to their randomized 
treatment. Modified Full-Analysis Set ([mFAS] – Efficacy-evaluable subjects): The mFAS will 
include all subjects who are randomized and received 2 doses of HIL-214 or placebo. Subjects 
will be analyzed according to their randomized treatment. 
Efficacy Per-Protocol Analysis Set (PPS): The PPS-E will include all subjects in the mFAS who 
have no important protocol deviations which may affect the evaluation of efficacy. These 
important protocol deviation criteria will be defined as part of the blinded data review prior to 
the unblinding of subject’s assignment to a trial arm. The categories of important protocol 
deviations include: (1) not meeting selected entry criteria, (2) receiving wrong or incomplete trial 
product (3) receiving prohibited therapies, and (4) other important protocol deviations that may 
impact the main efficacy endpoint. Subjects will be analyzed according to the treatment which 
they actually received. 
Immunogenicity Per-Protocol Analysis Set (PPS-I): The PPS-I will include all subjects in the 
FAS who have no important protocol deviations which may affect evaluation of 
immunogenicity. These important protocol deviation criteria will be defined as part of the 
blinded data review. The categories of important protocol deviations include: (1) not meeting 
selected entry criteria, (2) receiving wrong or incomplete trial product (3) receiving prohibited 
therapies, and (4) other important protocol deviations that may impact the immunogenicity 
endpoints. Subjects will be analyzed according to the treatment which they actually received. 
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13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Age, sex, race, and other baseline characteristics will be summarized descriptively by trial arm 
for all randomized subjects for the FAS and mFAS. 
13.1.3 Efficacy Analysis 
AGE cases will be collected starting from the Day 1 (Dose 1 of trial vaccine) until the 2nd 
birthday of each subject (end of trial). The number of AGE cases including primary endpoint 
AGEs will be monitored during the trial in a blinded way. The process is described in the AGE 
monitoring charter. 
The primary objective will be evaluated using primary endpoint cases which occurred during the 
6-month primary observation period starting at 28 days post dose 2. If the number of AGE events 
collected during the 6-month follow-up predicts less than 80% power (which translates into 24 
predicted primary endpoint cases) for the evaluation of the primary objective, the primary 
observation period will be extended to 8 months, starting 28 days post-Dose 2. 
The event of interest for the primary endpoint is the first occurrence during the primary 
observation period, of moderate/severe AGE associated only with GI.1 or GII.4 norovirus 
genotypes. Time-to-event will be computed from the start of the observation period until the date 
of AGE onset, the date of last contact/discontinuation, the end date of the observation period, 
whichever is earlier. VE will be calculated as 100%[1– (λV/λC)], where λV and λC denote the 
hazard rates for the HIL-214 and placebo arms, respectively. The primary analysis method will 
be a time-to-event Cox proportional hazards (CPH) model with trial arm as a factor and stratified 
by country, using the mFAS. The confidence interval (CI) for VE will be derived from the CI of 
the hazard ratio obtained from the CPH model. 
The primary efficacy objective will be met if the lower bound of the 95% CI for the VE is above 
0%. 
The proportional-hazards assumption will be assessed and an alternative method of analysis will 
be detailed in the SAP. A supplementary analysis based on the PPS-E will also be provided. 
Analyses for recurrent events (all primary endpoint AGEs, not only the first experienced by a 
subject) will be performed using proportional intensity (Andersen-Gill) models with treatment as 
a factor and stratified by country. 
The same CPH model will be used to analyze the single event secondary and exploratory VE 
(only the event definition will be different). 
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Missing data will be handled by the time to event analysis itself, as subjects prematurely 
withdrawn from the trial will be censored at their last information date. 
Further details on efficacy analyses will be provided in the SAP. 
13.1.4 Immunogenicity Analysis 
Immunogenicity results will be summarized using descriptive statistics including 95% CIs for all 
available assays at all relevant time points. These summaries will be provided for the FAS and 
PPS-I. 
13.1.5 Safety Analysis 
In general, data imputation will not be performed for any missing safety data. All safety data 
summaries will be prepared using the SAF. 
Solicited AEs 
Safety will be assessed daily for 7 days after each vaccination (including the day of vaccination) 
via collection of solicited local and systemic AEs. Body temperature by the actual route taken 
will be summarized with no adjustment or conversion for route of measurement. For each 
solicited AE, the percentage of subjects will be summarized by event intensity for each day from 
Day 1 to Day 7 (including the day of vaccination) and overall. Summaries of the day of first 
onset of each event and the number of days subjects reported experiencing each event will also 
be provided. For subjects with more than 1 episode of the same event, the maximum intensity 
will be used for tabulations. 
Unsolicited AEs 
Any unsolicited AEs up to 28 days after each vaccination (including the day of vaccination), 
SAEs and AEs leading to trial vaccine dose withdrawal and AEs leading to trial withdrawal (all 
subjects), will be coded according to the MedDRA, and summarized by system organ class 
(SOC) and preferred term (PT) for each trial arm. In general, unsolicited AEs will be tabulated at 
each of the following levels: overall summary (subject with at least one AE), and by SOC and 
PT. Subjects reporting more than one occurrence for the term (level) being summarized will be 
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counted only once with maximum intensity recorded. Unless otherwise specified, unsolicited 
AEs after each vaccination will be summarized in the following 3 ways: 1) overall for Day 1 
(day of vaccination) to 28 days after each vaccination, 2) with onset between Day 1 (day of 
vaccination) and Day 7 after each vaccination, and 3) with onset between Day 8 and Day 28 after 
each vaccination. 
AEs leading to trial or trial dose discontinuation 
AEs leading to trial dose discontinuation collected up to the last planned trial dose administration 
and AEs leading to withdrawal from the trial collected throughout the trial will also be 
summarized. 
SAEs 
SAEs will be collected throughout the trial. SAEs will be coded using MedDRA and summarized 
by SOC and PT for each trial arm. 
13.1.6 Other Analyses 
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No imputation will be performed for missing data. 
13.1.7 Sequence of Analyses 
Primary and secondary efficacy objectives will be evaluated at the end of the primary 
observation period. Immunogenicity data collected up to Visit 4 (subject aged 1 year) and safety 
data collected up to the end of the primary observation period will also be analyzed at this time 
point. 
13.2 
Interim Analysis and Criteria for Early Termination 
A formal interim analysis (interim evaluation of the study objectives) is not planned for this trial. 
13.3 
Determination of Sample Size 
Collection of 24 primary endpoint cases will provide a power greater than 80% in comparing 
active vaccine versus placebo in the rate of evaluable first-confirmed AGE cases (moderate or 
severe) associated with norovirus GI.1 or GII.4 without co-pathogens during the 6 months period 
if the true VE is 70%. The underlying assumptions are a 7% annual incidence of moderate to 
severe AGE attributable to norovirus GI.1 or GII.4, hypothesizing that 40% of norovirus AGE 
cases are moderate to severe, and 30% are associated with norovirus GI.1 or GII.4 resulting in 
the 6-month incidence of evaluable primary endpoint AGE cases of 3.5%. 
It is expected that enrollment of 3000 subjects will provide sufficient number of cases to 
demonstrate efficacy, accounting for various rates of drop-out/non-evaluable samples (20% to 
30%), and possible lower incidence rate or underreporting of cases. 
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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 IEC or IRB. 
All aspects of the trial and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator Site File, 
trial vaccine records, subject medical records, ICF documentation, documentation of 
authorization to use personal health information (if separate from the ICFs) by the subject’s 
LAR, 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 IEC or 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 [e.g., Medicines and Healthcare products Regulatory Agency (MHRA), 
Pharmaceuticals and Medical Devices Agency (PMDA)]. 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, sponsor or designee will establish quality tolerance limits (QTL) taking into 
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consideration the medical and statistical characteristics of the variables and the statistical design 
of the trial. This process will be performed according to sponsor internal procedures. 
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. 
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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 
Independent Ethics Committee and/or Institutional Review Board Approval 
IECs and 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 IEC or IRB. If any member of the IEC or IRB has 
direct participation in this trial, written notification regarding his or her abstinence from voting 
must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IEC or 
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 IEC or IRB for 
approval. The IEC’s or 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 IEC or IRB approval must refer to the 
trial by exact protocol title, number, and version date; identify versions of other documents (e.g., 
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 IEC or IRB. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports and 
updates regarding the ongoing review of the trial at intervals specified by the respective IEC or 
IRB, and submission of the investigator’s final status report to IEC or IRB. All IEC and 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 subjects for participation. Payments to 
subjects must be approved by the IEC or IRB and sponsor. 
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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’s LAR is free to withdraw their child 
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 IEC or IRB approval of the ICF 
and if applicable, the subject authorization form. The informed consent form, subject 
authorization form (if applicable), and subject information sheet must be approved by both the 
IEC or 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’s LAR. 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’s 
LAR. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IEC or IRB. 
The subject’s LAR 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’s LAR, 
determines their child will participate in the trial, then the ICF and subject authorization form (if 
applicable) must be signed and dated by the subject’s LAR, at the time of consent and prior to 
the subject entering into the trial. The subject’s LAR 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 informed consent, 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’s LAR signs the ICF in the subject’s medical record and eCRF. 
Copies of the signed informed consent, 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’s LAR in the same manner as the 
original informed consent/ form. The date the revised consent was obtained should be recorded 
in the subject’s medical record and eCRF, and the subject’s LAR should receive a copy of the 
revised ICF. 
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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 (e.g., FDA), the sponsor’s designated auditors, and the appropriate 
IECs/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’s LAR 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). 
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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 correspond to last subject last 
visit (LSLV)]. 
In line with EC Regulation N° 1901/2006 [3], the sponsor will submit a summary of the results 
of a pediatric trial within six months of completion and irrespective of whether it is part of a 
pediatric investigational plan (PIP) (completed or not yet completed) or not, or whether it is 
intended for submission later on as part of a variation, extension or new stand-alone marketing 
authorization application or not. 
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. 
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16.0 
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13. Hoa Tran TN, Trainor E, Nakagomi T, Cunliffe NA and Nakagomi O. Molecular 
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25. 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 
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26. Current Global Investigator’s Brochure - Candidate Norovirus Bivalent GI.1/GII.4c Virus-
Like Particle Vaccine (HIL-214). 
27. WHO 2015. Reducing pain at the time of vaccination: WHO position paper. Vaccine. 
2015;90:505-516. 
28. 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;39:389-
94. 
29. Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for 
clinical severity of diarrhoeal episodes. Scand J Infect Dis 1990;22:259-67. 
30. Clark HF, Bernstein DI, Dennehy PH, Dennehy PH, Offit P, Pichichero M et al. Safety, 
efficacy, and immunogenicity of a live, quadrivalent human-bovine reassortant rotavirus 
vaccine in healthy infants. J Pediatr. 2004;144(2):184 –190. 
31. Freedman SB, Eltorky M, Gorelick M. Evaluation of a gastroenteritis severity score for use 
in outpatient settings. Pediatrics 2010;125:e1278-e1285. 
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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 IEC/IRB that conforms 
to 21 CFR Part 56, ICH, and local regulatory requirements. 
6. Ensure that the IEC/IRB will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research activity and 
all anticipated risks to subjects. Make at least yearly reports on the progress of the trial to the 
IEC/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 the LAR of 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 IEC/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’s LAR. 
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 following 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 sponsor-supplied 
vaccines, and return all unused sponsor-supplied vaccines to the sponsor. 
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12. Report AEs to the sponsor promptly. In the event of an SAE, notify the sponsor within 24 
hours. 
13. Review and provide a signature as approval of the content of the clinical study report, if 
needed. 
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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. 
• IECs or 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. 
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APPENDIX C VESIKARI AND MODIFIED VESIKARI SCORING 
 
Vesikari Clinical Severity Scoring System
(a) 
Modified Vesikari Score
(b) 
 
Score 
Points 
 
1 
2 
3 
0 
1 
2 
3 
Diarrhea duration, days 
1-4 
5 
≥6 
0 
1-4 
5 
≥6 
Max. n° of diarrheal stools/24h 
1-3 
4-5 
≥6 
0 
1-3 
4-5 
≥6 
Vomiting duration, days 
1 
2 
≥3 
0 
1 
2 
≥3 
Max. n° of vomiting episodes/24h 
1 
2-4 
≥5 
0 
1 
2-4 
≥5 
Max. recorded body temperature, °C 
37.1-38.4 
38.5-38.9 
≥39.0 
≤37.0 
37.1-38.4 
38.5-38.9 
≥39.0 
Dehydration 
N/A 
1-5% 
≥6% 
- 
- 
- 
- 
Health care provider visits 
- 
- 
- 
None 
- 
Outpatient
(c) 
ED
(d) 
Treatment 
Rehydration 
Hospitalization 
N/A 
None 
Rehydration 
Hospitalization 
- 
(a) Adapted from rotavirus clinical trials using the Vesikari clinical scoring system [29,30]. Mild: <7; Moderate: 7-10; Severe: ≥11; Maximum score: 20; 
(b) Adapted from Freedman et al [31]. Mild: <9; Moderate: 9-10; Severe: ≥11 Maximum score: 20; 
(c) Community-based health care provider visit related to vomiting, diarrhea, fever or fluid refusal; 
(d) Emergency room health care provider visit related to vomiting, diarrhea, fever or fluid refusal. 
 
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