A Phase 1, Randomized, Observer-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety, Tolerability, and Immunogenicity of Zika Vaccine mRNA-1893 in Healthy Flavivirus Seropositive and Seronegative Adults
Phase: PHASE1
Conditions: Zika Virus
Sponsor: ModernaTX, Inc.

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CLINICAL STUDY PROTOCOL 
A PHASE 1, RANDOMIZED, OBSERVER-BLIND, 
PLACEBO-CONTROLLED, DOSE-RANGING STUDY TO EVALUATE 
THE SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF ZIKA 
VACCINE mRNA-1893 IN HEALTHY FLAVIVIRUS SEROPOSITIVE 
AND SERONEGATIVE ADULTS 
PROTOCOL NO. mRNA-1893-P101 
Sponsor: 
ModernaTX, Inc. 
200 Technology Square 
Cambridge, MA 02139  
Sponsor Contact: 
 
 
ModernaTX, Inc. 
500 Technology Square 
Cambridge, MA 02139  
Telephone: 
 
Version of Protocol: 
Final 3.0 
Date of Protocol:  
17 March 2020 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without the expressed, 
written consent of ModernaTX, Inc. 
The study will be conducted according to the International Council for Harmonisation 
harmonized tripartite guideline E6(R2): Good Clinical Practice. 
NCT #: NCT04064905
PPD
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Signature Page 
 
PROTOCOL TITLE: 
A Phase 1, Randomized, Observer-Blind, Placebo-Controlled, 
Dose-Ranging Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of Zika Vaccine mRNA-1893 in Healthy 
Flavivirus Seropositive and Seronegative Adults 
PROTOCOL NUMBER: mRNA-1893-P101 
 
See eSignature and date signed on last page of document. 
 
 
ModernaTX, Inc. 
See eSignature and date signed on last page of document. 
 
Date 
 
 
ModernaTX, Inc. 
 
Date 
 
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Clinical Study Protocol Version 3.0 
 
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Investigator Protocol Agreement Page 
 
I agree to conduct the study as outlined in the protocol entitled “A Phase 1, Randomized, 
Observer-Blind, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety, Tolerability, 
and Immunogenicity of Zika Vaccine mRNA-1893 in Healthy Flavivirus Seropositive and 
Seronegative Adults” in accordance with the guidelines and all applicable government 
regulations including US Title 21 of the Code of Federal Regulations Part 54. I have read and 
understand all sections of the protocol. 
 
 
 
Signature of Investigator 
 
Date 
 
 
 
Printed Name of Investigator 
 
 
 
 

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Table of Contents 
Signature Page ................................................................................................................................ 2 
Investigator Protocol Agreement Page............................................................................................ 3 
Table of Contents ............................................................................................................................ 4 
List of Tables ................................................................................................................................... 7 
List of Figures ................................................................................................................................. 8 
Summary of Changes ...................................................................................................................... 9 
Protocol Synopsis.......................................................................................................................... 10 
List of Abbreviations..................................................................................................................... 20 
Glossary of Terms ......................................................................................................................... 22 
1 
INTRODUCTION ................................................................................................................ 24 
1.1 
Background ................................................................................................................. 24 
1.2 
Nonclinical Studies in Development of mRNA-1893 ................................................ 25 
1.3 
Clinical Studies With mRNA-1893 ............................................................................ 27 
1.4 
Rationale for Study ..................................................................................................... 27 
1.5 
Rationale for Dose Selection ...................................................................................... 28 
1.6 
Rationale for Study Design ......................................................................................... 28 
2 
STUDY OBJECTIVES ........................................................................................................ 30 
2.1 
Primary Objective ....................................................................................................... 30 
2.2 
Secondary Objectives.................................................................................................. 30 
2.3 
Exploratory Objectives ............................................................................................... 30 
3 
INVESTIGATIONAL PLAN ............................................................................................... 31 
3.1 
Study Design ............................................................................................................... 31 
3.2 
Selection of Study Population ..................................................................................... 34 
3.2.1 
Inclusion Criteria ........................................................................................... 35 
3.2.2 
Exclusion Criteria .......................................................................................... 36 
3.2.3 
Participant Restrictions During the Study ..................................................... 39 

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3.2.3.1 
General and Dietary ..................................................................... 39 
3.2.3.2 
Contraception and Pregnancy Avoidance Procedures ................. 39 
3.3 
Withdrawal of Participants From the Study or Study Dosing ..................................... 40 
3.3.1 
Participant Withdrawal From the Study......................................................... 40 
3.3.2 
Participant Withdrawal From Study Vaccine ................................................. 40 
3.3.3 
Handling of Withdrawals ............................................................................... 41 
3.3.4 
Replacements and Rescreening ..................................................................... 42 
3.4 
Study Dosing Groups .................................................................................................. 42 
3.4.1 
Method of Assigning Participants to Dosing Groups .................................... 42 
3.4.2 
Vaccination Administration ........................................................................... 43 
3.4.2.1 
Dose Escalation ........................................................................... 44 
3.4.2.2 
Pause Rules .................................................................................. 46 
3.4.2.3 
Contraindications to Subsequent Vaccination.............................. 49 
3.4.3 
Identity of Investigational Product ................................................................ 50 
3.4.4 
Management of Clinical Supplies .................................................................. 50 
3.4.4.1 
Study Vaccine Packaging and Storage ......................................... 50 
3.4.4.2 
Study Vaccine Accountability ...................................................... 51 
3.4.5 
Blinding ......................................................................................................... 51 
3.4.6 
Breaking the Blind ......................................................................................... 52 
3.4.7 
Dosing Compliance ....................................................................................... 53 
3.4.8 
Prior and Concomitant Medications .............................................................. 54 
3.4.8.1 
Prior Medications and Therapies ................................................. 54 
3.4.8.2 
Concomitant Medications and Therapies .................................... 54 
3.5 
Study Procedures ........................................................................................................ 55 
3.5.1 
Safety Telephone Calls .................................................................................. 56 
3.5.2 
Completion of Diary Card ............................................................................. 56 
3.5.3 
Immunogenicity Assessments ........................................................................ 58 
3.5.4 
Total Blood Volume ....................................................................................... 58 
3.5.5 
Safety Assessments ........................................................................................ 59 
3.5.6 
Solicited Safety Measurements ...................................................................... 60 
3.5.7 
Unsolicited Safety Measurements ................................................................. 61 
3.5.7.1 
Adverse Events ............................................................................ 61 

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3.5.7.2 
Eliciting and Documenting Adverse Events ................................ 65 
3.5.7.3 
Reporting Adverse Events ........................................................... 65 
3.5.7.4 
Assessment of Severity ................................................................ 66 
3.5.7.5 
Assessment of Causality .............................................................. 67 
3.5.7.6 
Follow-up of Adverse Events ...................................................... 67 
3.5.8 
Clinical Laboratory Testing ........................................................................... 68 
3.5.9 
Vital Sign Measurements ............................................................................... 69 
3.5.10 Physical Examinations ................................................................................... 70 
3.6 
Statistical Analysis Plans ............................................................................................ 70 
3.6.1 
Primary Endpoints ......................................................................................... 70 
3.6.2 
Secondary Endpoints ..................................................................................... 71 
3.6.3 
Exploratory Endpoints ................................................................................... 71 
3.6.4 
Sample Size Calculations .............................................................................. 73 
3.6.5 
Analysis Sets .................................................................................................. 73 
3.6.6 
Statistical Analysis ......................................................................................... 74 
3.6.6.1 
Immunogenicity Analyses ........................................................... 74 
3.6.6.2 
Safety Analyses ............................................................................ 76 
3.6.7 
Handling of Missing Data .............................................................................. 77 
3.6.8 
Interim Analyses ............................................................................................ 77 
3.7 
Data Quality Assurance............................................................................................... 77 
4 
INVESTIGATOR OBLIGATIONS ...................................................................................... 79 
4.1 
Confidentiality ............................................................................................................ 79 
4.2 
Institutional Review .................................................................................................... 79 
4.3 
Participant Consent ..................................................................................................... 80 
4.4 
Study Reporting Requirements ................................................................................... 80 
4.5 
Financial Disclosure and Obligations ......................................................................... 80 
4.6 
Investigator Documentation ........................................................................................ 81 
4.7 
Study Conduct ............................................................................................................. 82 
4.8 
Data Collection ........................................................................................................... 82 
4.8.1 
Case Report Forms and Source Documents .................................................. 82 
4.9 
Adherence to Protocol................................................................................................. 82 

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4.10 Reporting Adverse Events........................................................................................... 83 
4.11 Investigator’s Final Report ......................................................................................... 83 
4.12 Records Retention ....................................................................................................... 83 
4.13 Publications ................................................................................................................. 83 
5 
STUDY MANAGEMENT ................................................................................................... 84 
5.1 
Monitoring .................................................................................................................. 84 
5.1.1 
Monitoring of the Study ................................................................................. 84 
5.1.2 
Inspection of Records .................................................................................... 84 
5.2 
Management of Protocol Amendments and Deviations.............................................. 84 
5.2.1 
Modification of the Protocol .......................................................................... 84 
5.2.2 
Protocol Violations and Deviations ............................................................... 85 
5.3 
Study Termination ....................................................................................................... 85 
5.4 
Final Report ................................................................................................................ 86 
6 
APPENDICES ...................................................................................................................... 87 
6.1 
Appendix 1: Schedule of Events ................................................................................. 87 
6.2 
Appendix 2: Adverse Events of Special Interest......................................................... 92 
6.3 
Appendix 3: Toxicity Grading Scale Tables ............................................................... 96 
6.4 
Appendix 4: List of Hepatotoxic Drugs .................................................................... 104 
7 
REFERENCE LIST ............................................................................................................ 106 
 
List of Tables 
Table 1: 
Dose Group Assignment ....................................................................................... 43 
Table 2: 
Pause Rules Based on the Occurrence of a Single Adverse Event and Adjudicated 
by the SMC ........................................................................................................... 47 
Table 3: 
Pause Rules Based on the Occurrence of Adverse Events in a Proportion of 
Participants ............................................................................................................ 48 
Table 4: 
Total Blood Volume .............................................................................................. 59 

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Table 5: 
Schedule of Events ................................................................................................ 88 
Table 6: 
Tables for Clinical Abnormalities ......................................................................... 97 
Table 7: 
Tables for Laboratory Abnormalities .................................................................. 100 
List of Figures 
Figure 1: 
Dosing Schema by Cohort .................................................................................... 33 
 

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Summary of Changes 
New Version 
Number / Date 
Section(s) in Which 
Change(s) Occurred 
Brief Description of Change(s) 
Justification 
V2.0/17JUL2019 
3.2.3.2: Contraception and 
Pregnancy Avoidance 
Procedures 
Clarification of the requirements 
for male contraception timing to 
match eligibility requirements. 
Administrative 
Update 
V2.0/17JUL2019 
3.4.2.2 
Table 3 – Pause Rules 
Updated pause rule #6 to remove 
the timeframe around collection of 
any ≥ Grade 3 unsolicited adverse 
events and abnormal laboratory 
results  
Per FDA request 
V2.0/17JUL2019 
3.5.6: Solicited Safety 
Measurements 
Clarification of the number of days 
diary data will be collected post 
vaccination 
Administrative 
Update 
V2.0/17JUL2019 
Table 5 
Footnote i 
Clarification of collection of Diary 
Data 
Administrative 
Update 
V3.0/17MAR2020 
3.4.5: Blinding and 3.6.8:  
Interim Analysis  
Update Blinding section and 
Interim Analysis to clarify for 
whom and when unblinded data 
will be accessible 
Statistical Analysis 
Update 
V3.0/17MAR2020 
Synopsis; 3.6.2 Secondary 
Endpoints; 3.6.3 Exploratory 
Endpoints; 3.6.6.1 
Immunogenicity Analyses. 
Wording changes to take into 
consideration new level of Lower 
Limit of Quantification (LLOQ) 
during assay performance 
Change impacting 
data analysis  
V3.0/17MAR2020 
Table 5: Schedule of Events 
and throughout the document 
Day 29 and Day 57 Visit Windows 
Updated visit 
windows due to 
potential impact of 
COVID-19 
V3.0/17MAR2020 
3.5.8 Clinical Laboratory 
Testing 
Clarification of the requirements 
of when to repeat out of range lab 
testing  
Administrative 
Update 

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Protocol Synopsis 
Protocol Number: 
mRNA-1893-P101 
Title: 
A Phase 1, Randomized, Observer-Blind, Placebo-Controlled, 
Dose-Ranging Study to Evaluate the Safety, Tolerability, and 
Immunogenicity of Zika Vaccine mRNA-1893 in Healthy 
Flavivirus Seropositive and Seronegative Adults 
Study Phase: 
1 
Study Sites: 
Clinical sites in both endemic and nonendemic Zika regions of 
the United States or its territories. 
Objectives: 
Primary: 
 To evaluate the safety, tolerability, and reactogenicity of 
a 2-dose vaccination schedule of mRNA-1893 Zika 
vaccine, given 28 days apart, across a range of dose 
levels 
in 
flavivirus-seronegative 
and 
flavivirus-seropositive 
participants 
compared 
with 
placebo. 
Secondary: 
 To evaluate the immunogenicity of a 2-dose vaccination 
schedule of mRNA-1893 Zika vaccine, given 28 days 
apart as measured by Zika virus (ZIKV)-specific 
neutralization assay (Plaque Reduction Neutralization 
Test [PRNT]). 
Exploratory: 
 To evaluate the immunogenicity of a 2-dose vaccination 
schedule of mRNA-1893 Zika vaccine, given 28 days 
apart, as measured by enzyme-linked immunosorbent 
assay (ELISA) and additional neutralization assays. 
 To assess the occurrence of flavivirus infection 
throughout the course of participation in the trial.  

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Study Design and 
Methodology: 
This 
is 
a 
Phase 
1, 
randomized, 
observer-blind, 
placebo-controlled, dose-ranging study to evaluate the safety, 
tolerability, and immunogenicity of Zika vaccine mRNA-1893 
administered to healthy flavivirus-seropositive and seronegative 
adult participants (18 to 49 years of age, inclusive). The study 
will comprise a Screening Phase (up to 28 days), a Vaccination 
Phase (up to 57 days), and a Long-Term Follow-up Phase (up to 
12 months after last vaccination). Participants will have 
approximately 8 clinic visits with an additional 13 safety 
telephone calls. Study duration will be approximately 13 months 
for each participant. Participants will provide written informed 
consent before any study-specific procedures are performed. 
A total of 120 participants (30 participant per cohort) will be 
enrolled into 1 of 4 mRNA-1893 dose cohorts (10, 30, 100, or 
250 µg). Within each cohort, eligible participants will be 
randomly assigned to mRNA-1893 or placebo (4:1 mRNA-1893 
to placebo) and administered the study vaccine as a 0.5-mL 
intramuscular (IM) injection on a 2-dose vaccination schedule, 
28 days apart (Day 1 and Day 29). Participants will be stratified 
by baseline flavivirus serostatus (seropositive and seronegative).  
For each dose cohort (Cohorts 1 through 4), Safety Oversight 
will be performed 7 days after the first 5 participants (all 
seronegative) are randomly assigned and receive their first study 
vaccination (Day 1). Once safety is confirmed, the remaining 25 
participants in the dose level cohort will be randomly assigned to 
dosing. Seven days after all 30 participants in the cohort have 
received the first study vaccination, a blinded IST that is not 
directly involved in the day-to-day activities of the study, will 
review all available safety data for the currently dosed cohort 
and any cumulative safety data of all cohorts as the trial 
advances to determine the acceptability to escalate to the next 

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mRNA-1893 dose level. The 30 participants in the first cohort 
will continue to receive their second study vaccine dose on Day 
29 (+14 days).  
The blinded IST will oversee the safety of the trial and will 
review safety data to ensure adherence to the protocol, will 
monitor safety laboratory test results and reactogenicity, and 
may request input from the SMC should the study meet pause 
rules or for any other study events that could potentially affect 
participant safety. The IST will approve escalation to the next 
higher dosing cohort after review of blinded safety data of the 
currently dosed cohort through 7 days after the first vaccination 
and any cumulative safety data of all cohorts as the trial 
advances.  
At each vaccination visit (Day 1 and Day 29), a diary card will 
be provided to the participant and study staff will provide 
training on its proper use. Participants will record daily body 
temperature, any solicited local (injection site) and systemic AEs 
(solicited AEs), any unsolicited AEs, and any concomitant 
medications and vaccinations on the day of each vaccination and 
on 7 subsequent days. Participants will be instructed to return the 
completed diary card to the Investigator at the subsequent 
planned study visit (Day 8 and Day 36).  
Participants will record on the same diary card daily any 
unsolicited AEs experienced, daily body temperature, and 
concomitant medications and vaccinations (excluding vitamins 
and minerals) received from 7 through 28 days after each 
vaccination. Participants will be instructed to return the 
completed diary card to the Investigator at Day 29 and Day 57.  
All concomitant medications and vaccinations (excluding 
vitamins and minerals) received and SAEs, MAAEs, AESIs, and 

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AEs leading to withdrawal from vaccine dosing or from the 
study will be collected from Day 1 until Month 13 (EOS Visit). 
Other safety assessments will include clinical laboratory test 
results (hematology, serum chemistry, and coagulation); vital 
sign measurements; and physical examination findings. Blood 
samples for immunogenicity assessments will be collected the 
day of each vaccination (Days 1 and 29 before vaccination), 
28 (+14) days after each vaccination, and during the Long-Term 
Follow-up Phase at Month 7 (± 14 days) and Month 13 (± 14 
days). 
Once all subjects from a cohort have completed the Vaccination 
Phase through Day 57 (-7/+14 days), the database will be locked 
for that cohort and safety and immunogenicity data will be 
analyzed through 28 days following the second vaccination by 
an unblinded statistician. As dose escalation occurs, cumulative 
analyses will be included for each subsequent data lock to allow 
for all prior dosing cohorts to be analyzed by dose assignment, 
and in aggregate for mRNA-1893 exposure. Immunogenicity 
and safety data, including mean group analyses of change from 
baseline, where applicable, will be summarized for each dose 
group. These data are required to inform decisions on dose 
selection for this and other development programs using the 
same messenger RNA (mRNA) platform.  
When all participants have completed their final contact 
(approximately 
12 months 
after 
the 
last 
vaccination), 
immunogenicity testing is completed, and all queries resolved, 
the database will be locked and analyzed with a final clinical 
study report. 

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Study Population: 
Participants (males and females 18 to 49 years of age, inclusive), 
will be included in the study if they are in good health as 
determined by medical history, clinical laboratory assessments, 
vital sign measurements, a physical examination at screening 
and per investigator judgement. Negative pregnancy tests will be 
required at screening and before vaccine administration for 
female participants of childbearing potential. Flavivirus 
serostatus (positive or negative) will be determined by ELISA or 
other commercially available serological assay. The full lists of 
inclusion and exclusion criteria are provided in Section 3.2.1 and 
Section 3.2.2, respectively. 
Safety Assessments: 
Safety assessments will include monitoring and recording of 
solicited AEs (local and systemic reactogenicity events) and 
unsolicited AEs, serious AEs (SAEs), AEs of special interest 
(AESIs), AEs leading to study withdrawal, medically attended 
AEs (MAAEs); clinical laboratory test results (hematology, 
serum chemistry, and coagulation); vital sign measurements; and 
physical examination findings. 
Immunogenicity 
Assessments: 
Immunogenicity assessments will include the following: 
 Serum neutralizing antibodies (nAb) against ZIKV 
 Serum binding antibodies (bAb) against ZIKV 
Vaccine, Dosage, 
and Route of 
Administration: 
mRNA-1893 is a novel lipid nanoparticle (LNP)-encapsulated 
mRNA-based vaccine encoding the full pre-membrane and 
envelope (prME) structural polyproteins of ZIKV. mRNA-1893 
consists of an mRNA Drug Substance formulated with LNPs. 
mRNA-1893 is provided as a sterile liquid for injection at a 
concentration of 0.5 mg/mL in 100 mM Tris buffer, 7% 
propylene glycol, and 1 mM diethylenetriamine-pentaacetic acid 
(DTPA).  

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mRNA-1893 (10, 30, 100, or 250 µg) and placebo will be 
prepared as outlined in the pharmacy manual and administered 
via IM injection (0.5 mL) into the deltoid muscle on designated 
vaccination days. The second dose of vaccine or placebo will be 
administered preferably in the same arm used for the first dose.  
The placebo is 0.9% sodium chloride injection, United States 
Pharmacopeia (USP) or British Pharmacopeia (BP).  
Sample Size: 
A total of 120 participants (30 participant per cohort) are planned 
for enrollment in the study and random assignment to study 
dosing. The sample size is considered sufficient to meet the 
study objective of identifying a dose and establishing initial 
safety results in a population of healthy adults in both endemic 
and nonendemic Zika regions. Formal sample size calculations 
were not performed. 
Statistical Methods: 
Safety: Reactogenicity will be summarized by dosing group (10, 
30, 100, or 250 µg mRNA-1893 or placebo), vaccination (first or 
second dose), duration, and severity. Adverse events will be 
coded by preferred term and system organ class using MedDRA 
and summarized by dose group, vaccination (first or second 
dose), and overall. Adverse events will also be summarized by 
severity and relationship to the study vaccine. Descriptive 
statistics will be presented, and the difference in the proportion 
of participants with AEs will be provided, comparing each dose 
level with placebo pooled across all cohorts. Individual 
participant listings will be provided for all AEs, AEs leading to 
study withdrawal, AESIs, MAAEs, and SAEs.  
Safety data from clinical laboratory test results and vital sign 
measurements will be graded by severity scoring and analyzed 
by dose group and vaccination (first or second). Absolute and 
change from baseline values will be provided according to the 

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toxicity table, along with mean, median, and standard deviation. 
Results of serology, urine drug screening, physical examinations, 
and pregnancy tests will be listed for all participants randomly 
assigned to receive study vaccine. 
Medical history data for all participants randomly assigned to 
receive study vaccine will be presented by participant in a 
listing. Baseline demographic and background variables will be 
summarized by dosing group for all randomly assigned 
participants. The number of participants who enroll in the study 
and the number and percentage of participants who complete the 
study will be presented. Frequency and percentage of 
participants who withdraw or discontinue from the study and the 
reason for withdrawal or discontinuation will also be 
summarized. 
Prior and concomitant medications will be listed (with start and 
stop dates) for each participant and summarized by common 
medical dictionary coding. Any vaccinations that occur during 
the trial will also be captured and summarized. 
Immunogenicity: The following secondary immunogenicity 
outcome measures and the 95% confidence intervals, where 
appropriate, will be summarized by dose group and by visit:  
 Serum neutralizing antibodies (nAb titers) against 
ZIKV by PRNT: 
 Geometric mean titer (GMT) of nAb against ZIKV at 
Day 1, Day 29, Day 57, Month 7, and Month 13 as 
measured by PRNT. 
 GMT of nAb in initially seronegative participants 
against ZIKV at Day 1, Day 29, Day 57, Month 7, 
and Month 13 as measured by PRNT. 

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 GMT of nAb in initially seropositive participants 
against ZIKV at Day 1, Day 29, Day 57, Month 7, 
and Month 13 as measured by PRNT. 
 Percentage of participants who seroconverted from 
Day 1 (baseline) to Day 29, from Day 1 to Day 57, 
from Day 1 to Month 7, and from Day 1 to Month 13. 
A seroconversion is defined as a change of PRNT 
from below the lower limit of quantification (LLOQ) 
to a PRNT equal to or above LLOQ, or a 
multiplication by at least 4 in subjects with 
pre-existing PRNT titers. 
 Proportion of initially seronegative participants with 
a seroresponse at Day 29, Day 57, Month 7, and 
Month 13 as measured by PRNT. 
 Proportion of initially seropositive participants with a 
2-fold or 4-fold increase in nAb titers as compared 
with baseline as measured by PRNT. 
The following exploratory immunogenicity outcome measures 
and the 95% confidence intervals, where appropriate, will be 
summarized by dosing group and by visit: 
 GMT of nAb against ZIKV at Day 1, Day 29, Day 
57, Month 7, and Month 13 as measured by 
additional neutralization assay. 
 GMT of nAb in initially seronegative participants 
against ZIKV at Day 1, Day 29, Day 57, Month 7, 
and 
Month 
13 
as 
measured 
by 
additional 
neutralization assay. 
 GMT of nAb in initially seropositive participants 
against ZIKV at Day 1, Day 29, Day 57, Month 7, 

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and 
Month 
13 
as 
measured 
by 
additional 
neutralization assay. 
 Percentage of participants who seroconverted from 
Day 1 (baseline) to Day 29, from Day 1 to Day 57, 
from Day 1 to Month 7, and from Day 1 to Month 13. 
A seroconversion is defined as change of nAb titer 
(by additional neutralization assay) from below the 
LLOQ to a titer equal to or above LLOQ, or a 
multiplication 
by 
at 
least 
4 
in 
pre-existing 
neutralizing titer. 
 Proportion of initially seronegative participants with 
a seroresponse at Day 29, Day 57, Month 7, and 
Month 13 as measured by additional neutralization 
assay. 
 Proportion of initially seropositive participants with a 
2-fold or 4-fold increase in nAb as compared with 
baseline as measured by additional neutralization 
assay. 
 GMT of bAb against ZIKV at Day 1, Day 29, Day 
57, Month 7, and Month 13 as measured by ELISA 
binding assay. 
 GMT of bAb in initially seronegative participants 
against ZIKV at Day 1, Day 29, Day 57, Month 7, 
and Month 13 as measured by ELISA binding assay. 
 GMT of bAb in initially seropositive participants 
against ZIKV at Day 1, Day 29, Day 57, Month 7, 
and Month 13 as measured by ELISA binding assay. 
 Percentage of participants that seroconverted from 
Day 1 (baseline) to Day 29, from Day 1 to Day 57, 

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from Day 1 to Month 7, and from Day 1 to Month 13. 
A seroconversion is defined as a change of binding 
antibody titer from below the LLOQ to a binding 
antibody titer equal or above the LLOQ, or a 
multiplication by at least 4 in pre-existing bAb titers. 
 Proportion of initially seronegative participants with 
a seroresponse at Day 29, Day 57, Month 7, and 
Month 13 as measured by ELISA binding assay. 
 Proportion of initially seropositive participants with a 
2-fold or 4-fold increase in bAb as compared with 
baseline as measured by ELISA binding assay. 
 IgG and IgM antibodies against envelope- and NS1- 
based antigens present in serum collected at baseline 
and at end of study measured as antibody binding by 
ELISA or equivalent methodology to flaviviruses.  
Date of Protocol: 
17 March 2020 

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List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
bAb 
serum binding antibodies 
BP 
British Pharmacopoeia 
CFR 
Code of Federal Regulations 
CRO 
contract research organization 
CS 
clinically significant  
DSPC 
1,2-distearoyl-sn-glycero-3-phosphocholine 
DTPA 
diethylenetriamine-pentaacetic acid 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunoabsorbent assay 
EOS 
end of study 
FDA 
Food and Drug Administration 
GLP 
Good Laboratory Practice 
GMT 
geometric mean titer 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
Ig 
immunoglobulin 
IM 
intramuscular 
IRB 
institutional review board 
IRT 
interactive response technology 
IST 
internal safety team 
IV 
intravenous 
LLOQ 
lower limit of quantification 
LNP 
lipid nanoparticle 
LOQ 
limit of quantification 
MAAE 
medically attended adverse event 
MedDRA 
Medical Dictionary for Regulatory Activities 

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Abbreviation 
Definition 
mRNA 
messenger RNA 
nAb 
serum neutralizing antibodies 
NCS 
not clinically significant 
NHP 
nonhuman primate 
PEG2000-DMG 
1-monomethoxypolyethyleneglycol-2,3-dimyristylglycerol with 
polyethylene glycol of average molecular weight 2000 
prME 
pre-membrane and envelope structural protein of ZIKV 
PRNT 
Plaque Reduction Neutralization Test 
SAE 
serious adverse event 
SM-102 
heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy) hexyl) 
amino)octanoate 
SMC 
Safety Monitoring Committee 
TEAE 
treatment-emergent adverse event 
ULOQ 
upper limit of quantification 
USP 
United States Pharmacopoeia 
WHO 
World Health Organization 
WNL 
within normal limits 
ZIKV 
Zika virus 
ZPIV 
Zika purified inactivated vaccine 

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Glossary of Terms 
Term 
Definition 
Adequate 
contraception  
Adequate contraception is defined as consistent and correct use of a Food 
and Drug Administration-approved contraceptive method in accordance with 
the product label. For example:  
 
Barrier method (such as condoms, diaphragm, or cervical cap) used in 
conjunction with spermicide  
 
Intrauterine device  
 
Hormonal contraceptive in the form of a pill or patch  
 
Medroxyprogesterone injection (Depo-Provera®) 
 
Etonogestrel implant (Nexplanon®) 
 
Sterilization of a female participant’s monogamous male partner prior to 
entry into the study 
 
Note: periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Grade 1 laboratory 
abnormality with 
potential clinical 
significance 
A Grade 1 laboratory parameter that cannot be explained or that is judged by 
the investigator to be potentially clinically significant. A list of 
laboratory-specific normal ranges and associated toxicity grades is provided 
in Appendix 3. 
Grade 1 laboratory 
abnormality without 
potential clinical 
significance 
A Grade 1 laboratory parameter that can be explained by a condition that is 
not related to vaccination and does not increase the risk for an adverse 
outcome of vaccination. A list of laboratory-specific normal ranges and 
associated toxicity grades is provided in Appendix 3. 
Menopause 
Natural menopause is defined as the permanent cessation of menstrual 
periods, determined retrospectively after a woman has experienced 
12 months of amenorrhea without any other obvious pathological or 
physiological cause. Menopause occurs at a median age of 51.4 years. 
Protocol amendment  The International Council for Harmonisation defines a protocol amendment 
as “A written description of a change(s) to or formal clarification of a 
protocol.” It may include a change that affects the safety of participants, 
scope of the investigation, study design, or scientific integrity of the study.  
Solicited adverse 
event 
Local and systemic reactogenicity events. 

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Term 
Definition 
Unsolicited adverse 
event 
Any adverse event (AE) reported by a participant that is either (1) not 
specified as a solicited AE in the protocol or (2) specified as a solicited AE 
in the protocol but its onset occurs outside of the protocol-defined 
post-vaccination period for reporting solicited AEs (i.e., for the 7 days after 
each vaccination). 
 

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1 
INTRODUCTION 
1.1 
Background 
Zika virus (ZIKV), first discovered in 1947, is a single-stranded RNA flavivirus, which is 
transmitted to humans by a mosquito vector (mainly Aedes aegypti but other Aedes 
mosquitoes are believed to be competent vectors) or by person-to-person spread, mainly 
through sexual transmission. In the 60 years after its discovery, ZIKV remained a relatively 
obscure pathogen, associated with only sporadic cases of human infection that were largely 
asymptomatic or resulted in a mild febrile illness (Weaver et al 2016). In the last decade, 
however, there has been rapid geographic spread into the Pacific Islands and South America, 
where ZIKV outbreaks have been larger, more frequent, and more severe (Lazear and 
Diamond 2016). Most concerning are infections in pregnant women, particularly during the 
first and second trimesters, which have resulted in a wide range of birth defects, including 
microcephaly, intrauterine growth restriction, and spontaneous abortion (Brasil et al 2016). 
The devastating consequences of ZIKV infection, including congenital Zika syndrome, 
pregnancy loss and complicated neurological sequelae such as Guillain-Barre syndrome, led 
the World Health Organization (WHO) to declare a Public Health Emergency of International 
Concern on 01 February 2016 (Heymann et al 2016) and to call on the global research and 
development community to prioritize the development of preventive and therapeutic 
solutions (WHO 2016a). Although the WHO declared an end to its global health emergency 
regarding the spread of ZIKV in November 2016, the long-term need for a ZIKV vaccine 
remains (WHO 2019) a priority need under the Blueprint Plan of Action (WHO 2016b). 
Currently, there is no approved vaccine to protect against this disease.  
ModernaTX, Inc. has developed a proprietary messenger RNA (mRNA)-based vaccine 
platform. This is based on the principle and observations that antigens can be produced in 
vivo by delivery and uptake of the corresponding mRNA by cells. The mRNA then 
undergoes intracellular ribosomal translation to endogenously express the protein antigen(s) 
encoded by the vaccine mRNA. This mRNA-based vaccine does not enter the cellular 
nucleus or interact with the genome and is nonreplicating, and expression is transient. mRNA 
vaccines thereby offer a mechanism to stimulate endogenous production of structurally intact 

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protein antigens in a way that mimics wild type viral infection and are able to induce highly 
targeted immune responses against infectious pathogens such as ZIKV.  
mRNA-1893 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine directed 
against the pre-membrane and envelope (prME) structural protein of ZIKV. mRNA-1893 
consists of an mRNA Drug Substance that is formulated with LNPs composed of 4 lipids: 
heptadecan-9-yl 
8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino) 
octanoate 
(SM-102); 
cholesterol; 
1,2-distearoyl-sn-glycero-3-phosphocholine 
(DSPC); 
and 
1-monomethoxypolyethyleneglycol-2,3-dimyristylglycerol with polyethylene glycol of 
average molecular weight 2000 (PEG2000-DMG). mRNA-1893 is provided as a sterile 
liquid for injection at a concentration of 0.5 mg/mL in 100 mM Tris buffer, 7% propylene 
glycol, and 1 mM diethylenetriamine-pentaacetic acid (DTPA).  
1.2 
Nonclinical Studies in Development of mRNA-1893 
In support of development of mRNA-1893 for prophylaxis against ZIKV infection, 
nonclinical immunogenicity, biodistribution, and safety studies have been completed with 
mRNA-1893 or similar mRNA-based vaccines formulated in SM-102-containing LNPs.  
In a non-Good Laboratory Practice (GLP) in vivo dose-range finding study, immunogenicity 
(binding and neutralizing antibody titers) to the mRNA-1893 encoded protein was evaluated 
in female C57BL/6 mice at 4 doses (15, 10, 2, and 0.4 µg) following intramuscular (IM) 
injection on Day 1 and Day 29. mRNA-1893 generated strong neutralizing and binding 
antibody titers at multiple doses. Mice dosed with 15 and 10 µg mRNA-1893 generated 
higher neutralizing and binding antibody titers than mice dosed with 0.4 µg mRNA-1893. 
Mice dosed with 15, 10, and 2 µg mRNA-1893 generated higher binding antibody titers 
compared with mice dosed with 0.4 µg mRNA-1893. 
The immunogenicity and efficacy of mRNA-1893 were evaluated in a non-GLP study in the 
rhesus macaque ZIKV infection model. A total of 40 monkeys were randomly assigned to 1 
of 7 groups to receive mRNA-1893 (200, 100, 50, 10, or 2 µg), Zika purified inactivated 
vaccine (ZPIV [400 antigenic units]), a formalin-inactivated ZIKV strain PRVABC59 shown 
to be immunogenic in human, or buffer control. Dose administration occurred via IM 
injection on Day 0 and Day 28. Following blood collections on Day 56, animals were 
challenged by subcutaneous injection with a target dose of 1 x 105 plaque-forming units of 

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ZIKV strain PRVABC59. Overall, administration of mRNA-1893 by IM injection (2 doses) 
was clinically well tolerated, with no mRNA-1893-related mortality, clinical observations, or 
changes in body weight. Animals in the buffer control group developed viremia that persisted 
for 3 to 7 days, whereas mRNA-1893– and ZPIV-treated animals were either negative for 
ZIKV RNA at all time points evaluated or had sporadic instances of low levels of ZIKV RNA 
at a single time point after ZIKV challenge. Detection of ZIKV RNA was inversely related to 
detection of ZIKV-neutralizing antibodies prior to ZIKV challenge. mRNA-1893 and/or 
ZPIV-treated animals had detectable neutralizing antibody titers in the ZIKV 
microneutralization assay at Days 28 and 56 as well as at the end of study (EOS; Day 77, 21 
days after ZIKV challenge), whereas animals in the buffer control group did not have ZIKV-
neutralizing titers until after ZIKV challenge on Day 77. 
Overall, these results demonstrate that mRNA-1893 generates strong immunogenic response 
in mice and nonhuman primates (NHPs) and prevents viremia, with either no or low levels of 
ZIKV RNA upon challenge in the rhesus macaque ZIKV infection model. 
To evaluate the generalized tissue distribution and tissue half-life of mRNA-1893, the 
biodistribution 
of mRNA-1647, a similar mRNA-based vaccine formulated in 
SM-102--containing LNPs, was evaluated in male rats. mRNA-1647 is a novel mRNA-based 
cytomegalovirus vaccine formulated in a mixture of the same 4 lipids as mRNA-1893. The 
biodistribution of mRNA-based vaccines formulated in LNPs is predicted to be driven by the 
LNP characteristics. Therefore, mRNAs that are within an LNP of the same composition (e.g., 
mRNA-1893 and mRNA-1647) are expected to distribute similarly. Overall, only a relatively 
small fraction of the administered mRNA-1647 dose distributed to distant tissues, and the 
mRNA constructs did not persist past 1 to 3 days in tissues other than the vaccination site, 
lymph nodes, and spleen.  
The safety and tolerability of 3 dose levels of mRNA-1893 administered by IM injection 
were evaluated in a GLP-compliant, repeat-dose (1 month; 3 doses) toxicity study in Sprague 
Dawley rats followed by a 2-week recovery period. Animals were administered mRNA-1893 
at doses of 10, 30, or 96 µg/dose or phosphate-buffered saline via IM injection on Days 1, 15, 
and 29. The results of this study indicated that administration of mRNA-1893 was clinically 
tolerated in rats up to 96 μg/dose with no mortality or changes in body weight or food 
consumption. 
Starting 
at 
10 μg/dose, 
dose-dependent 
clinical 
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(swelling/firmness/redness/scabs) at the injection site, changes in clinical pathology 
parameters and cytokines concentrations, and an increase in body temperature were observed 
and were consistent with an inflammatory reaction. Dose-dependent effects were observed at 
the vaccination site, spleen, liver, and seminal vesicle of animals given mRNA-1893. 
Additional microscopic findings in the iliac, inguinal, and popliteal lymph nodes or their 
perinodal tissue; perineural tissue of the sciatic nerve; spleen (extramedullary 
hematopoiesis); and bone marrow of animals given mRNA-1893 were considered to be an 
extension, a secondary response, or a reactive response to the vaccination site inflammation. 
At the end of the 2-week recovery period, all changes were partially or fully recovered.  
In GLP-compliant studies, SM-102, the novel lipid component of the LNP formulation, was 
not genotoxic when tested in a bacterial reverse mutation (Ames) test or an in vitro 
micronucleus test. An in vivo micronucleus study in Sprague Dawley rats showed that a 
similar mRNA-based vaccine formulated in SM-102-containing LNPs (mRNA-1706, which 
encodes the ZIKV pre-membrane and envelope polypeptide [different from the sequence 
encoded in mRNA-1893]), induced statistically significant increases in micronucleated 
immature erythrocytes in male rats at both 24 and 48 hours and in female rats at 48 hours 
only; however, there was no clear dose response, and the increases were generally weak and 
associated with minimal bone marrow toxicity. These observations indicate that the risk to 
humans after IM administration is low due to minimal systemic exposure.  
A detailed review of non-clinical experience with mRNA-1893 Zika vaccine is provided in 
the investigator’s brochure (IB).  
1.3 
Clinical Studies With mRNA-1893 
No clinical studies with mRNA-1893 have been conducted to date.  
1.4 
Rationale for Study 
No vaccines have yet been licensed for prophylaxis of ZIKV infection, although several 
vaccines have advanced to early clinical development with promising safety and 
immunogenicity data (Richner and Diamond 2018).  
The Sponsor previously advanced the ZIKV-vaccine mRNA-1325 to clinical testing. The 
mRNA-1325 trial enrolled 90 participants across 3 dose levels (74 participants received 

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mRNA-1325, 16 participants received placebo). While the vaccine was well tolerated, the 
immunogenicity objective at doses up to 100 µg was not met. Despite a safety profile that 
permitted additional dose escalation, current development efforts are focused on the next 
generation vaccine, mRNA-1893, that contains an engineered sequence shown to be 20 times 
more potent in NHP Zika challenge studies (data on file).  
The Sponsor believes that on the basis of preclinical data, mRNA-1893 has the potential to 
achieve safety and efficacy levels comparable to virus-like particle or live-attenuated vaccine 
approaches, with the additional benefit of a rapid and scalable manufacturing platform.  
The purpose of this Phase 1, first-in-human, randomized, placebo-controlled, dose-ranging 
study is to evaluate the safety, tolerability, and immunogenicity of mRNA-1893 Zika vaccine 
in healthy adult participants in endemic and nonendemic Zika regions. The primary objective 
of this study is to assess the safety, tolerability, and reactogenicity profile of a range of doses 
of mRNA-1893 Zika vaccine compared with placebo. The study will also evaluate 
immunogenicity by assessing changes from baseline in ZIKV-specific neutralizing antibody 
titers. The safety profile and immune response(s) will be compared between 
flavivirus-seropositive and flavivirus-seronegative participants to indicate the ability of the 
selected dose to safely protect populations in both endemic and nonendemic Zika regions.  
1.5 
Rationale for Dose Selection 
Doses of mRNA-1893 ranging from 10 to 250 µg will be tested in a dose-escalating fashion 
starting with 10 µg (Cohort 1), then moving to 30 µg (Cohort 2), then 100 µg (Cohort 3), and 
eventually 250 µg (Cohort 4). This dose selection is based on preclinical data and clinical 
experience with other infectious disease programs. A dose as low as 2 µg has been shown to 
be protective in a NHP challenge model.  
1.6 
Rationale for Study Design 
The study is designed to generate the safety and immunogenicity data required to select the 
optimal dose of mRNA-1893 for further development in both endemic and nonendemic 
populations. Preclinical and clinical data support the expectation that a 2-dose vaccination 
schedule, 1 month apart, will induce a protective immune response. The 2-dose schedule will 
be explored at a range of doses in 2 subpopulations: endemic and nonendemic. The 

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nonendemic population will be represented by participants recruited from the general 
population who are flavivirus seronegative. The endemic population will be represented by 
participants recruited from endemic Zika regions who are seropositive for flavivirus 
(including dengue, West Nile, and Zika).  
In order to explore vaccine safety, dosing will begin with 10 µg (Cohort 1) and escalate to 30, 
100, and 250 µg. For each dose cohort, 5 flavivirus seronegative participants will be 
randomly assigned to dosing (4:1 mRNA-1893 to placebo) and followed for 7 days after the 
first vaccination, with safety oversight to confirm no pause rules were met (Section 3.4.2.2; 
Section 3.5.6) before randomly assigning the remaining 25 participants in the cohort. In 
addition, starting with the 10 µg-dose cohort, 7 days after all participants have received the 
first study vaccination, a blinded internal safety team (IST) will review all safety data for the 
cohort and determine the acceptability of escalating to the next mRNA-1893 dose level. The 
IST will approve escalation to the next higher dosing cohort after review of blinded safety 
data of the currently dosed cohort participants through 7 days after the first vaccination and 
any cumulative safety data of all cohorts as the trial advances.  
Pause rules have been pre-established to trigger ad hoc unblinded Safety Monitoring 
Committee (SMC) reviews. The SMC is composed of independent experts with relevant 
expertise that will meet upon request of the IST, if required.  
Immunogenicity against ZIKV will be assessed before vaccination (baseline; Day 1) and 
28 (+14) days after each vaccination and assessed for persistence at Month 7 and at Month 13 
(12 months after the last vaccination) with assays that are relevant for the field, in particular, 
neutralization assays that may correlate with protection. A 12-month Long-Term Follow-up 
Phase after the last vaccine administration will be performed to assess if any serious AEs 
(SAEs), medically attended AEs (MAAEs), and AEs of special interest (AESIs) have 
occurred during the study. This is comparable to the assessments performed by the Sponsor 
across its mRNA vaccine candidates in early development.  

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the safety, tolerability, and reactogenicity of 
a 2-dose vaccination schedule of mRNA-1893 Zika vaccine, given 28 days apart, across a 
range of dose levels in flavivirus-seronegative and flavivirus-seropositive participants 
compared with placebo.  
2.2 
Secondary Objectives 
The following is the secondary objective of the study:  
 To evaluate the immunogenicity of a 2-dose vaccination schedule of mRNA-1893 
Zika vaccine, given 28 days apart as measured by ZIKV-specific neutralization assay 
(Plaque Reduction Neutralization Test [PRNT]). 
2.3 
Exploratory Objectives 
The following are the exploratory objectives of the study:  
 To evaluate the immunogenicity of a 2-dose vaccination schedule of mRNA-1893 
Zika vaccine, given 28 days apart, as measured by enzyme-linked immunoabsorbent 
assay (ELISA) and additional neutralization assays. 
 To assess the occurrence of flavivirus infection throughout the course of participation 
in the trial. 

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3 
INVESTIGATIONAL PLAN 
3.1 
Study Design 
This is a Phase 1, randomized, observer-blind, placebo-controlled, dose-ranging study to 
evaluate the safety, tolerability, and immunogenicity of Zika vaccine mRNA-1893 
administered to healthy flavivirus-seropositive and seronegative adult participants (18 to 
49 years of age, inclusive). A total of 120 participants (30 participants per cohort) will be 
enrolled into 1 of 4 mRNA-1893 dose cohorts (10, 30, 100, or 250 µg). Within each cohort, 
eligible participants will be randomly assigned to mRNA-1893 or placebo (4:1 mRNA-1893 
to placebo) and administered the study vaccine as an IM injection on a 2-dose vaccination 
schedule, 28 days apart (Day 1 and Day 29). Participants will be stratified by baseline 
flavivirus serostatus (seropositive and seronegative).  
The study will comprise a Screening Phase (up to 28 days), a Vaccination Phase (up to 
57 days), and a Long-Term Follow-up Phase (up to 12 months after last vaccination) 
(Table 5). Participants will have approximately 8 clinic visits with an additional 13 safety 
telephone calls. Study duration will be approximately 13 months for each participant. 
Participants will provide written informed consent before any study-specific procedures are 
performed.  
Study vaccine dosing will begin with Cohort 1 (10 µg mRNA-1893 or placebo), followed 
sequentially by Cohort 2 (30 µg mRNA-1893 or placebo), Cohort 3 (100 µg mRNA-1893 or 
placebo), and Cohort 4 (250 µg mRNA-1893 or placebo). Vaccine accountability, dose 
preparation, and vaccine administration will be performed by unblinded pharmacy personnel, 
who will not participate in any other aspects of the study. The remainder of the study staff 
and all participants will remain blinded to dosing assignment.  
For each dose cohort (Cohort 1 through 4), Safety Oversight will be performed 7 days after 
the first 5 participants (all seronegative) are randomly assigned and receive the first study 
vaccination (Day 1). Once safety is confirmed, the remaining 25 participants in the dose level 
cohort will be randomly assigned to dosing. Seven days after all 30 participants in the cohort 
have received the first study vaccination, a blinded IST that is not directly involved in the 
day-to-day activities of the study, will review all available safety data for the currently dosed 

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cohort and any cumulative safety data of all cohorts as the trial advances to determine the 
acceptability to escalate to the next mRNA-1893 dose level. The 30 participants in the first 
cohort will continue to receive their second study vaccine dose on Day 29 (+14 days). 
The blinded IST will oversee the safety of the trial and will review safety data to ensure 
adherence to the protocol, will monitor safety laboratory test results and reactogenicity, and 
may request input from the SMC should the study meet pause rules or for any other study 
events that could potentially affect participant safety. The IST will approve escalation to the 
next higher dosing cohort after review of blinded safety data of the currently dosed cohort 
through 7 days after the first vaccination and any cumulative safety data of all cohorts as the 
trial advances.  
A diagram of the dosing schema by cohort is shown in Figure 1.  

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Figure 1: 
Dosing Schema by Cohort 
 
Abbreviations: IST = internal safety team; S- = flavivirus seronegative; S+ = flavivirus seropositive. 
Note: For each dose cohort (Cohorts 1 through 4), Safety Oversight will be performed 7 days after the first 
5 participants (all flavivirus-seronegative) are randomly assigned and receive their first study vaccination 
(Day 1) before randomly assigning the remaining 25 participants in the cohort. Seven days after all 
30 participants in the cohort have received the first study vaccination and review of all available safety data 
has been performed (ie, no safety concerns and pause rules have not been met), the IST will determine the 
acceptability to escalate to the next mRNA-1893 dose level. 
During the Vaccination Phase, participants will be instructed to contact the Investigator 
immediately should they develop any untoward signs or symptoms or any medical 
occurrence that leads to an unplanned visit to a health care practitioner, hospitalization, or an 
emergency room visit. In case of MAAEs, if the participant presents with clinical symptoms 

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that may suggest a dengue infection, a blood sample should be collected for testing of dengue 
infection. In addition, participants will be instructed to contact the site within 24 hours, in the 
event of any severe Grade 3 local and systemic reactogenicity AE (solicited AEs; Section 
3.5.6) or any episode of rash within 6 days after study vaccination.  
At each vaccination visit (Day 1 and Day 29), a diary card will be provided to the participant 
and study staff will provide training on its proper use. Participants will record daily body 
temperature, any solicited local (injection site) and systemic AEs (solicited AEs), any 
unsolicited AEs, and any concomitant medications and vaccinations on the day of each 
vaccination and on 6 subsequent days. Participants will be instructed to return the completed 
diary card to the Investigator at the subsequent planned study visit (Day 8 and Day 36).  
Participants will record on the same diary card daily any unsolicited AEs experienced and 
concomitant medications and vaccinations (excluding vitamins and minerals) received from 
7 through 28 days after each vaccination. Participants will be instructed to return the 
completed diary card to the Investigator at Day 29 and Day 57.  
All concomitant medications and vaccinations (excluding vitamins and minerals) received, 
and SAEs, MAAEs, AESIs, and AEs leading to withdrawal from vaccine dosing or from the 
study will be collected from Day 1 until Month 13 (EOS Visit). Other safety assessments will 
include clinical laboratory test results (hematology, serum chemistry, and coagulation); vital 
sign measurements; and physical examination findings.  
Blood samples for immunogenicity assessments will be collected the day of each vaccination 
(Days 1 and 29 before vaccination), 28 (+14) days after each vaccination, and during the 
Long-Term Follow-up Phase (Month 7 and Month 13).   
Detailed information on all statistical analysis of data is presented in Section 3.6.6.  
The complete Schedule of Events is shown in Table 5.  
3.2 
Selection of Study Population 
Healthy male or female participants will be enrolled at clinical sites in both endemic and 
nonendemic Zika regions of the United States or its territories. A total of 120 participants 
(30 participants per cohort) are planned to be randomly assigned to receive study dosing.  

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3.2.1 
Inclusion Criteria 
Each participant must meet all of the following criteria during the Screening Phase and at 
Day 1, unless noted otherwise, to be enrolled in this study:  
1. Male or female 18 to 49 years of age, inclusive. 
2. Understands and agrees to comply with the study procedures and provides written 
informed consent. 
3. In the opinion of the investigator, can and will comply with the requirements of the 
protocol (e.g., complete diary cards, return for follow-up visits, be available for safety 
telephone calls).  
4. Is in good general health, as determined by medical history, clinical laboratory 
assessments, vital sign measurements, and physical examination at screening. 
5. For flavivirus-seropositive group, has positive flavivirus test results (including dengue, 
West Nile, and Zika) as determined by ELISA or other commercially available 
serological assay. 
6. For flavivirus-seronegative group, has negative flavivirus test results (including dengue, 
West Nile, and Zika) as determined by ELISA or other commercially available 
serological assay. 
7. Female participants of childbearing potential may be enrolled in the study, if the 
participant: (1) has a negative urine pregnancy test at Screening, Day 1, and before 
second vaccine administration, (2) has practiced adequate contraception (Glossary of 
Terms) or is abstaining from all activities that could lead to pregnancy for 30 days before 
the first vaccination, and (3) has agreed to continue adequate contraception through 
3 months after the last vaccination. 
8. Female participants of nonchildbearing potential may be enrolled in the study. 
Nonchildbearing potential is defined as bilateral tubal ligation > 1 year before screening, 
bilateral oophorectomy, hysterectomy, or menopause (Glossary of Terms). The 

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follicle-stimulating hormone level may be measured at the discretion of the investigator 
to confirm menopausal status. 
9. Male participants must agree to practice adequate contraception (Glossary of Terms) from 
the time of the first vaccination and through 3 months after the last vaccination. Males 
must also agree to refrain from donation of sperm from the time of first vaccination until 
3 months following the last vaccination.  
3.2.2 
Exclusion Criteria 
Participants meeting any of the following criteria during the Screening Phase and at Day 1, 
unless noted otherwise, will be excluded from the study:  
1. Has any acute or chronic, CS disease, as determined by medical history, physical 
examination, 
clinical 
laboratory 
assessments, 
and 
vital 
sign 
measurements. 
Asymptomatic conditions or findings (e.g., mild hypertension or dyslipidemia) are not 
exclusionary if they are being appropriately managed, are clinically stable, and are 
unlikely to progress within the study period, in the opinion of the investigator. 
2. Has received (at any time) a vaccine for dengue, Japanese encephalitis, tick-borne 
encephalitis, West Nile, Yellow Fever, or Zika. 
3. Has a neurologic disorder (e.g., history of seizures, Guillain-Barré syndrome, dementia, 
vasculitis, or any known congenital or acquired disorder). 
4. Has a body mass index that is ≤ 18 or ≥ 35 kg/m2. 
5. If female of childbearing potential, is pregnant or lactating or has not adhered to an 
adequate contraception method from at least 30 days before the first dose of study 
vaccine through 3 months after the last vaccination. 
6. Has elevated liver function tests, defined as aspartate aminotransferase, alanine 
aminotransferase, or alkaline phosphatase with a toxicity score of Grade ≥ 1 at Screening 
(Appendix 3). Retesting of these parameters is not allowed. 

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7. Has clinical laboratory test results (hematology, serum chemistry, or coagulation) with a 
toxicity score of Grade ≥ 1 at Screening (Appendix 3). Retesting of these parameters is 
allowable once, but the results must be within normal limits (WNL). If results are not 
WNL, the participant will be excluded from the study. 
8. Has a bleeding disorder that would contraindicate IM injections or phlebotomy. 
9. Reports a diagnosis of congenital or acquired immunodeficiency (including human 
immunodeficiency virus [HIV] infection), or autoimmune disease. 
10. Has a history of hypersensitivity or severe reactions (e.g., anaphylaxis, urticaria, other 
significant event requiring medical intervention) to previous vaccinations or any 
component of the study vaccine. 
11. Has a history of idiopathic urticaria. 
12. Reports a previous diagnosis of hematologic malignancy or pre-malignancy (leukemia, 
lymphoma, or lymphoproliferative disorders) or a diagnosis of any other malignancy 
within the previous 10 years (excluding nonmelanoma skin cancer). 
13. Has a medical, psychiatric, or occupational condition that, in the opinion of the 
investigator, might pose an additional risk to the participant due to participation in the 
study or would interfere with the evaluation of the study vaccines or the interpretation of 
study results. 
14. Is acutely ill or febrile on the day of screening (Day 0) or randomization (Day 1). Fever is 
defined as a temperature ≥ 38.0°C/100.4°F by the oral, axillary, or tympanic route. 
Participants meeting this criterion may be rescheduled for screening at a later date. 
Afebrile participants with minor illnesses can be enrolled at the discretion of the 
investigator. 
15. Has a history of inflammatory arthritis. 
16. Has a history of febrile disease with arthritis or arthralgia within 2 weeks of 
administration of any study vaccine. 

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17. Has received an investigational or nonregistered product (drug or vaccine) within 30 days 
before the first dose of study vaccine or has plans for administration during the study 
period. 
18. Has received or is scheduled to receive an inactivated vaccine within the period from 
14 days before, or through 14 days after, administration of any study vaccination. 
19. Has received or is scheduled to receive a live virus vaccine administered within the 
period from 28 days before, or through 28 days after, any dose of study vaccine. 
20. Has received chronic administration (defined as > 14 total days) of immunosuppressants 
or other immune-modifying drugs within 6 months before the first study vaccine dose 
(for corticosteroids: prednisone ≥ 20 mg/day or equivalent is not permitted). Inhaled, 
nasal, and topical steroids are allowed. 
21. Has received immunoglobulins and/or blood products within the 3 months before the first 
study vaccine dose or has plans for administration during the study period. 
22. Has a positive test result at the Screening Visit for hepatitis B surface antigen, hepatitis C 
virus antibody, or HIV type 1 or 2 antibodies.  
23. Has donated > 450 mL of whole blood or blood products within 30 days of enrollment or 
plans to do so during the study period. 
24. Is an immediate family member or household member of study personnel. 
25. Previously participated in an investigational study involving LNPs.  
26. Has a positive urine drug screen result at Screening for any of the following 
nonprescription drugs of abuse: amphetamines, benzodiazepines, cocaine, methadone, 
opiates, and phencyclidine. A positive test result for any other drug will require 
investigator approval prior to inclusion of the participant. Positive urine drug screens for 
amphetamines, benzodiazepines, or opiates will not be exclusionary if the positive result 
is due to a prescribed concomitant medication, in the opinion of the investigator. 

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3.2.3 
Participant Restrictions During the Study 
3.2.3.1 
General and Dietary 
To avoid false positive results for drugs of abuse tested at the Screening Visit, participants 
should refrain from food or drink containing poppy seeds (e.g., specialty breads and muffins) 
for 72 hours before the Screening Visit.  
3.2.3.2 
Contraception and Pregnancy Avoidance Procedures 
Female participants who are not of childbearing potential (defined as any female who has 
experienced menarche and who is NOT permanently sterile or postmenopausal) must be 
postmenopausal, as defined in Glossary of Terms, or surgically sterile (e.g., hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy). NOTE: These procedures and/or 
laboratory test results must be confirmed by physical examination or be provided through 
medical documentation. If of childbearing potential, female participants must be practicing a 
medically approved and highly effective method of contraception (Glossary of Terms).  
All female participants of childbearing potential must have a negative urine pregnancy test 
result at the Screening Visit and before vaccine administration. Women of childbearing 
potential must agree to be heterosexually inactive or to consistently use acceptable methods 
of contraception, as defined in Glossary of Terms, from at least 30 days before the first 
vaccination through 3 months after the last vaccination.  
Male participants must agree to practice adequate contraception (Glossary of Terms) from the 
time of first vaccination through 3 months after the last vaccination. Males must also agree to 
refrain from donation of sperm from the time of first vaccination through 3 months after the 
last vaccination.  
Periodic abstinence, declaration of abstinence for the duration of the study, and withdrawal 
are not acceptable methods of contraception for male or female participants.  
Female participants of childbearing potential and male participants will be provided with 
information on acceptable methods of contraception as part of the participant informed 
consent process and will be asked to sign a consent form stating that they understand the 
requirements for avoidance of pregnancy.  

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3.3 
Withdrawal of Participants From the Study or Study Dosing 
3.3.1 
Participant Withdrawal From the Study 
Participants can withdraw consent and discontinue from the study at any time, for any reason, 
without prejudice to further treatment the participant may need to receive.  
If participant desires to withdraw from the study because of an AE, the investigator will try to 
obtain agreement to follow up with the participant until the event is considered resolved or 
stable and will then complete the EOS electronic case report form (eCRF).  
Potential reasons for withdrawing a participant from the study include the following:  
 SAE 
 AE (non-SAE) 
 Protocol violation (specify) 
 Consent withdrawal (document the reason) 
 Lost to follow-up 
 Other (specify)  
Participants who are withdrawn from the study will be requested to complete the EOS 
(Visit 20 [Month 13]) assessments. The reason for participant withdrawal or lost to follow-up 
will be documented, as detailed in Section 3.3.3.  
3.3.2 
Participant Withdrawal From Study Vaccine 
Every reasonable attempt will be made to follow up with participants for safety throughout 
the entire study period, even if further vaccination is withheld or the participant misses one or 
more visits.  
Unless consent is withdrawn, a participant who discontinues from receiving the second dose 
of study vaccine will remain in the study and complete all safety and immunogenicity 
procedures required through 1 month after the last vaccination received per the Schedule of 
Events (i.e., up to Visit 5/Day 29 for subjects receiving only the first dose of vaccine). 

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Subjects will then enter the 12-month Long-Term Follow-up Phase per the Schedule of 
Events (Table 5).  
The investigator, in consultation with the Sponsor’s medical monitor, may withhold a 
participant from further vaccination if the participant experiences any of the following:  
 Becomes pregnant 
 Develops, during the course of the study, symptoms or conditions listed in the 
exclusion criteria 
 Experiences an AE (other than reactogenicity) after vaccination that is considered by 
the investigator to be possibly or probably related to vaccine and is of Grade 3 
(severe) or greater severity (Appendix 3) 
 Experiences an AE or SAE that, in the judgment of the investigator, requires study 
vaccine withdrawal due to its nature, severity, or required treatment, regardless of the 
causal relationship to vaccine 
 Experiences a CS change in clinical laboratory test results, vital sign measurements, 
or general condition that, in the judgment of the investigator, requires vaccine 
withdrawal 
 Experiences anaphylaxis clearly attributed to study vaccine 
 Experiences generalized urticaria related to the study vaccine 
The reason(s) for withdrawing further vaccination will be recorded.  
3.3.3 
Handling of Withdrawals 
When a participant withdraws from the study, the reason(s) for withdrawal will be recorded 
by the investigator on the relevant page of the eCRF. These participants will also be 
requested to complete the EOS (Visit 20 [Month 13]) assessments.  
Any participant who fails to return for final assessments will be contacted by the site with a 
minimum of 3 documented telephone calls, faxes, text messages, or emails and 1 registered 
mail letter. If participant is not reached, the participant will be defined as lost to follow-up. 
All attempts to contact the participant must be documented in the participant’s source 

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documents. After the final attempt, the participant will be declared “lost to follow-up” at the 
EOS Visit.  
3.3.4 
Replacements and Rescreening 
Any participant who is withdrawn, who is significantly outside the allowed vaccination 
window, or who is lost to follow-up from the study may be replaced at the Sponsor’s 
discretion. Rescreening of an eligible subject is allowed if their originally intended dose level 
closes and their 28-day screening window is surpassed before another dose level opens. The 
participant will be assigned a new screening number and all screening procedures will be 
repeated. 
3.4 
Study Dosing Groups 
3.4.1 
Method of Assigning Participants to Dosing Groups 
Participants will be randomly assigned (Day 1) in a blinded manner using the centralized 
Interactive Response Technology (IRT), with approximately 30 participants assigned to each 
cohort. Study vaccine dosing will begin with Cohort 1 (10 µg mRNA-1893 or placebo), 
followed sequentially by Cohort 2 (30 µg mRNA-1893 or placebo), Cohort 3 (100 µg 
mRNA-1893 or placebo), and Cohort 4 (250 µg mRNA-1893 or placebo). Within each cohort, 
participants will be randomly assigned in a blinded manner to receive either mRNA-1893 
vaccine or placebo (4:1 mRNA-1893 vaccine to placebo) using the centralized IRT. 
Participants will be stratified according to flavivirus baseline serostatus.  
In each cohort, the initial 5 participants (all seronegative) will be randomly assigned to 
vaccine or placebo (4:1 mRNA-1893 vaccine to placebo) before the remaining participants 
(n=25, 20 seronegative and 5 seropositive) are enrolled in the cohort.  
Randomization by the centralized IRT will be in accordance with pre-generated 
randomization schedules, with only the unblinded pharmacy personnel having controlled 
access.  
Dose group assignment in each cohort and stratification within each cohort is summarized in 
Table 1.  

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Table 1: 
Dose Group Assignment 
Cohort 
Dose Group 
Assignment 
n 
Flavivirus Status 
Stratificationa 
Total 
(Ratio) 
Status 
n 
1 
mRNA-1893 
10 µg 
24 
+ 
4 
30 
(4:1) 
- 
20 
Placebo 
6 
+ 
1 
- 
5 
2 
mRNA-1893 
30 µg 
24 
+ 
4 
30 
(4:1) 
- 
20 
Placebo 
6 
+ 
1 
- 
5 
3 
mRNA-1893 
100 µg 
24 
+ 
4 
30 
(4:1) 
- 
20 
Placebo 
6 
+ 
1 
- 
5 
4 
mRNA-1893 
250 µg 
24 
+ 
4 
30 
(4:1) 
- 
20 
Placebo 
6 
+ 
1 
- 
5 
Total 
120 
Abbreviations: - = flavivirus seronegative; + = flavivirus seropositive. 
a 
In each cohort, the initial 5 participants enrolled will be flavivirus seronegative and randomly assigned to vaccine or 
placebo (4:1 mRNA-1893 to placebo) before the remaining participants (n=25, 20 seronegative and 5 seropositive) are 
enrolled in the cohort.  
3.4.2 
Vaccination Administration 
Vaccine dosing will begin with Cohort 1 (10 µg mRNA-1893 or placebo), followed 
sequentially by Cohort 2 (30 µg mRNA-1893 or placebo), Cohort 3 (100 µg mRNA-1893 or 
placebo), and Cohort 4 (250 µg mRNA-1893 or placebo).  
The vaccine will be administered as an IM injection into the deltoid muscle on a 2-dose 
vaccination schedule at Day 1 and Day 29 (e.g., at least a 28-day interval between dosing). 

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Each vaccination will contain 0.5 mL of 10, 30, 100, or 250 μg mRNA-1893 or 0.5 mL of 
placebo. Preferably, the second dose of vaccine should be administered in the same arm used 
for the first dose.  
The vaccine will be prepared as detailed in the Pharmacy Manual. Unblinded pharmacy 
personnel, who will not participate in any other aspect of the study, will perform vaccine 
accountability, dose preparation, and vaccine administration. The investigator or designee 
will be responsible for oversight of the administration of vaccine according to the procedures 
stipulated in this study protocol and the Pharmacy Manual.  
At each visit when vaccines are administered, participants will be monitored for 60 minutes 
after vaccine administration; assessments will include vital sign measurements and 
monitoring for local or systemic reactions (Schedule of Events, Table 5).  
Eligibility for subsequent study vaccination is determined by following the criteria outlined 
in Section 3.4.2.3.  
The clinic will be appropriately staffed, will be trained on emergency resuscitation, and will 
have stocked available rescue medications (such as epinephrine, steroids, antihistamines, and 
IV fluids) should any severe reaction (e.g., anaphylaxis or urticaria) occur that requires 
immediate intervention.  
Details regarding safety oversight of within-cohort dosing and dose escalation are provided 
in Section 3.4.2.1. The rules for pausing dosing are provided in Section 3.4.2.2.  
3.4.2.1 
Dose Escalation 
For each dose cohort (Cohorts 1 through 4), Safety Oversight will be performed 7 days after 
the first 5 participants (all seronegative) are randomly assigned and receive their first study 
vaccination (Day 1) before randomly assigning the remaining participants in the cohort. Once 
safety is confirmed (i.e., no safety concerns and pause rules as defined in Section 3.4.2.2 
have not been met), the study medical monitor will authorize the random assignment of the 
remaining 25 participants in the cohort. Seven days after all 30 participants in the cohort have 
received the first study vaccination, a blinded IST that is not directly involved in the 
day-to-day activities of the study, will review all available safety data for the currently dosed 
cohort and any cumulative safety data of all cohorts as the trial advances to determine the 

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acceptability to escalate to the next mRNA-1893 dose level. The 30 participants in the first 
cohort will continue to receive their second study vaccine dose on Day 29 (+14 days).  
Oversight of safety will be performed in a blinded manner by the contract research 
organization’s (CRO’s) medical monitor, the Sponsor’s medical monitor, and the individual 
site principal investigators throughout the study for all participants.  
The blinded IST will oversee the safety of the trial and will review safety data to ensure 
adherence to the protocol, monitor safety laboratory test results and reactogenicity, and they 
may request input from the SMC should the study meet pause rules (Section 3.4.2.2) or for 
any other study events that could potentially affect participant safety. The IST will approve 
escalation to the next higher dosing cohort after review of blinded safety data of the currently 
dosed cohort through 7 days following the first vaccination and any cumulative safety data of 
all cohorts as the trial advances.   
The IST is composed of 3 Sponsor clinicians who are not directly involved in the day-to-day 
conduct of the study and who are the voting members for decision for dose escalation. 
Additionally, the investigator, the CRO medical monitor, and the Sponsor medical lead will 
be nonvoting extended members. A Biomedical Advanced Research and Development 
Authority representative may also join these meetings as an observer. Details regarding 
composition, responsibilities, and procedures of the IST are presented in the IST charter.  
An independent, unblinded SMC will be consulted at the discretion of the IST or if a pause 
rule is met (Section 3.4.2.2). The SMC will review all available safety data to adjudicate any 
potential study pauses and make recommendations on further study conduct, including 
requesting additional information, recommending stopping the study, recommending changes 
to study conduct and/or the protocol, or recommending additional operational considerations 
due to safety issues that arise during the study.  
The SMC will be comprised of external independent consultants with relevant expertise. 
Details regarding composition, responsibilities, and procedures of the SMC are presented in 
the SMC charter.  

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3.4.2.2 
Pause Rules 
Study pause rules will be continuously monitored during all phases of the study by the 
investigators, study medical monitor, Sponsor medical lead, IST, and SMC (as warranted). If 
the investigator, study medical monitor, Sponsor medical lead, IST, or SMC request that the 
study be paused due to a safety concern, further study vaccine administration in the affected 
cohort and at higher dose levels will be suspended, but all other planned procedures relating 
to safety, reactogenicity, and immunogenicity assessments will continue as described in the 
protocol.  
The occurrence of any of the events listed in Table 2, regardless of dosing group, will result 
in immediate suspension of dosing and enrollment in the cohort. An unscheduled meeting of 
the SMC will be convened to assess specific data concerns and to make recommendations.  
The Sponsor will notify the Center for Biologics Evaluation and Research within 48 hours in 
the event of a study pause.  

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Table 2: 
Pause Rules Based on the Occurrence of a Single Adverse Event and 
Adjudicated by the SMC 
Pause 
Rule 
Adverse Event 
Number of Participants 
per Dose Cohort 
1 
Any serious adverse event that cannot be reasonably 
attributed to a cause other than vaccination 
≥ 1 
2 
Any Grade 4 adverse event that cannot be reasonably 
attributed to a cause other than vaccination 
≥ 1 
3 
Any systemic immediate hypersensitivity reaction 
within 60 minutes after the study vaccination 
≥ 1 
Abbreviation: SMC = Safety Monitoring Committee.  
Table 3 summarizes safety events that will pause study dosing based on defined threshold 
levels, which are aggregate incidences relative to the number of exposed participants within a 
dosing group. An unblinded statistician may be consulted to determine if a pause rule has 
been met.  

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Table 3: 
Pause Rules Based on the Occurrence of Adverse Events in a Proportion 
of Participants 
Pause 
Rule 
Adverse Event 
Number of Participants 
per Dose Cohorta 
4 
Any Grade 3 solicited local adverse event lasting more than 
24 hours in an mRNA-1893 cohortb within the 7-day 
(Days 1-8) post-vaccination period 
≥ 20% and 
≥ 2 participants/group 
5 
Any Grade 3 solicited general adverse event lasting more 
than 24 hours in an mRNA-1893 cohortb that cannot be 
reasonably attributed to a cause other than vaccination, 
within the 7-day (Days 1-8) post-vaccination period 
≥ 20% and 
≥ 2 participants/group 
6 
Any ≥ Grade 3 unsolicited adverse event in an mRNA-1893 
cohortb that cannot be reasonably attributed to a cause other 
than vaccination 
OR 
Any ≥ Grade 3 laboratory abnormalityc in an mRNA-1893 
cohortb that cannot reasonably be attributed to a cause other 
than vaccination 
≥ 20% and 
≥ 2 participants/group 
a 
For the first 5 participants in each dose level cohort, the pause rule will be considered met if 2 of the first 5 participants 
experience the same event regardless of dosing group. 
b 
The rate of adverse events and laboratory abnormalities will be computed based on the number of exposed participants 
who have provided safety data (i.e., have completed a post-dosing visit for assessment of safety). 
c 
Grading of laboratory parameters will be based on the US Food and Drug Administration Guidance for Industry 
“Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials” 
(DHHS 2007). 
If a pause is triggered in the study, each participant’s clinic visits will continue until the next 
scheduled vaccination visit. If a pause affects a participant’s vaccination visit, the window for 
that participant’s vaccination visit will be suspended until the pause is lifted and vaccination 
can resume. Once the pause is lifted at a site, vaccination should be reinstated as soon as 
possible. Clinic visits should thereafter (Day 36 [+3 days], Day 57 [-7/+14 days], Month 7 
[± 14 days], and Month 13 [± 14 days]) be scheduled as if participants had received their 
second vaccination within the 28 (+14) day window. The Dose 2 window may be extended to 
28 (+14) days at the discretion of the principal investigator and with approval of the study 
medical monitor on a case by case basis for participants whose window is affected by a study 
pause.   

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If a pause is prolonged such that the second vaccination takes place outside the 28 (+14) day 
window, the Sponsor has the option to add additional participants in a dosing cohort to 
achieve the original number of participants planned for dosing within the 28 (+14) day 
window. If a participant is in the Screening Phase for more than 28 days as the result of a 
pause, the participant may be rescreened for study eligibility (and will receive a new 
screening number) as long as the participant continues to provide consent to participate in the 
study.  
3.4.2.3 
Contraindications to Subsequent Vaccination 
Prior to receiving a second vaccination, participants will be reassessed to ensure that they 
continue to meet eligibility requirements as outlined below.  
The following events constitute absolute contraindications to any further administration of 
study vaccines. If any of these events occur during the study, the participant must not receive 
additional doses of vaccine but will be encouraged to continue study participation for safety 
through 12 months following last vaccination (Section 3.3.2).  
 Anaphylaxis or systemic hypersensitivity reaction following the administration of 
vaccine  
 Any SAE judged to be related to study vaccine 
 Any AESI related to study vaccine (Appendix 2) 
 Pregnancy 
 Any CS medical condition that, in the opinion of the Investigator, poses an additional 
risk to the participant if he/she continues to participate in the study 
The following events constitute contraindications to administration of study vaccine at 
certain points in time, and if any of these events occur at the time scheduled for vaccination, 
the participant may be vaccinated at a later date, within the time window specified in the 
Schedule of Events (Table 5), or the participant may be withdrawn from dosing at the 
discretion of the Investigator (Section 3.3):  
 Acute moderate or severe infection with or without fever at the time of vaccination 
 Fever, defined as body temperature ≥ 38.0°C (100.4°F) at the time of vaccination 

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Participants with a minor illness without fever, as assessed by the investigator, can be 
administered study vaccines. Participants with a fever of 38.0°C (100.4°F) or higher will be 
recontacted within the time window acceptable for participation and reevaluated for 
eligibility. 
3.4.3 
Identity of Investigational Product 
mRNA-1893 is a novel LNP-encapsulated mRNA-based vaccine directed against the prME 
structural protein of ZIKV. mRNA-1893 consists of CX-005809, an mRNA Drug Substance 
that is formulated into LNPs composed of 4 lipids: SM-102; cholesterol; DSPC; and 
PEG2000-DMG. mRNA-1893 is provided as a sterile liquid for injection at a concentration 
of 0.5 mg/mL in 100 mM Tris buffer, 7% propylene glycol, and 1 mM DTPA. 
The placebo is 0.9% sodium chloride injection, United States Pharmacopeia (USP) or British 
Pharmacopeia (BP).  
3.4.4 
Management of Clinical Supplies 
3.4.4.1 
Study Vaccine Packaging and Storage 
The Sponsor will provide the investigator and study site with adequate quantities of 
mRNA-1893. The placebo (0.9% sodium chloride injection, USP or BP) is commercially 
available and will be supplied by the Sponsor or CRO. mRNA-1893 will have all required 
labeling per regulations. mRNA-1893 will be supplied to the pharmacy in an unblinded 
manner. Each vial will be individually labeled for future participant identification purposes.  
mRNA-1893 will be supplied as a sterile liquid for injection at a concentration of 0.5 mg/mL. 
The sterile product will be provided in 2-mL glass vials with a 0.85-mL fill volume. The 
unblinded study site pharmacy personnel will prepare a single dose (0.5 mL) for each 
participant based on the cohort and randomization assignment. A pharmacy manual will be 
available, and training provided.  
mRNA-1893 vaccine must be stored in a secure area with limited access (unblinded 
pharmacy staff only), protected from moisture and light, and be stored at -20°C ± 5°C. The 
freezer should have an automated temperature recording and alert system. There must be an 
available back-up freezer. The freezers must be connected to a back-up generator. The 

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pharmacy must have in place a 24-hour alert system that allows for rapid response in case of 
freezer malfunctioning. In addition, vaccine accountability study staff (e.g., the unblinded 
pharmacy personnel) are required to keep a temperature log to establish a record of 
compliance with these storage conditions. The placebo will be stored according to the 
instructions on the product label and must also comply with storage in a restricted access area. 
Only vaccine accountability study staff (e.g., unblinded pharmacy personnel) should have 
access to the products used in this study.  
The site is responsible for reporting any mRNA-1893 vaccine that was not temperature 
controlled during shipment or during storage to the unblinded site (pharmacy) monitor. Such 
mRNA-1893 will be retained for inspection by the unblinded monitor and disposed of 
according to approved methods.  
3.4.4.2 
Study Vaccine Accountability 
It is the investigator’s responsibility that the unblinded pharmacy personnel maintain accurate 
records of receipt of all mRNA-1893 vaccine, including dates of receipt. In addition, accurate 
records will be kept regarding when and how much mRNA-1893 is dispensed and used by 
each participant in the study. Reasons for departure from the expected dispensing regimen 
must also be recorded. To satisfy regulatory requirements regarding vaccine accountability, 
all mRNA-1893 vaccine will be reconciled and retained until study conclusion. At that time, 
mRNA-1893 vaccine will be destroyed or returned to the Sponsor according to applicable 
regulations.  
3.4.5 
Blinding 
This is an observer-blind study. The Sponsor, investigator, study participants, site monitors, 
and study staff will be blinded to the study vaccine administered until trial end, with the 
following exceptions:  
 Unblinded pharmacy personnel (of limited number) will be assigned to vaccine 
accountability procedures and will prepare and administer mRNA-1893 (or placebo) 
to all participants. The designee(s) will have no study functions other than study 
vaccine management, documentation, accountability, preparation, and administration. 
They will not be involved in participant evaluations and will not reveal the study 

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vaccine identity to either the participant or the study site personnel involved in the 
conduct of the study unless this information is necessary in the case of an emergency. 
 An unblinded study monitor, not involved in other aspects of monitoring, will be 
assigned as the vaccine accountability monitor. They will have responsibilities to 
ensure that the site is following all proper vaccine accountability, preparation, and 
administration procedures. 
 An unblinded statistician will provide a descriptive analysis of safety and 
immunological endpoints after the completion of each dosing cohort, including 
evaluation of the pause rules criteria summarized in Table 3 (Section 3.4.2.2). The 
interim analyses of immunogenicity data will be performed as outlined in 
Section 3.6.8. 
 The Sponsor will remain blinded to individual treatment assignment throughout the 
Vaccination Phase through Visit 9 (28 days post last vaccination) for each vaccine 
cohort/dose level of the study. Once the Vaccination Phase for each vaccine 
cohort/dose level is completed, at the time of the Day 57 Interim Analysis pre-
identified Sponsor team members will be unblinded to review treatment level results 
and individual listings and will remain unblinded. Study sites will remain blinded to 
individual treatment assignments until trial end. 
The dosing assignment will be concealed by having the unblinded designee(s) 
(e.g., unblinded pharmacy personnel) prepare the study vaccine in a secure location that 
is not accessible to other study staff. The syringe used for administration will maintain 
the blind at the time of vaccination (i.e., a sleeve will be used, as the vaccine substance 
will be distinguishable in appearance between the mRNA-1893 and placebo). Only 
pharmacy staff will conduct the vaccination procedure. Once the vaccination is 
completed, the blinded study staff will perform further assessments and interact with the 
participants. Access to the randomization code will be strictly controlled at the pharmacy.  
3.4.6 
Breaking the Blind 
A participant or participants may be unblinded in the event of an SAE or other severe event, 
or if there is a medical emergency requiring the identity of the product to be known to 

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properly treat a participant. If a participant becomes seriously ill or pregnant during the study, 
the blind will be broken if knowledge of the administered vaccine will affect that 
participant’s dosing options. In the event of a medical emergency requiring identification of 
the vaccine administered to an individual participant, the investigator will make every 
attempt to contact the Sponsor medical lead to explain the need for opening the code within 
24 hours of opening the code. The investigator will be responsible for documenting the time, 
date, reason for the code break, and the names of the personnel involved.  
In addition to the aforementioned situations where the blind may be broken, the data will also 
be unblinded to a statistical team at specified time points for interim analyses as outlined in 
Section 3.6.8.  
3.4.7 
Dosing Compliance 
All doses of vaccine will be administered at the study site under direct observation of 
unblinded pharmacy personnel and appropriately recorded (date and time) in the eCRF. 
Unblinded pharmacy personnel will confirm that the participant has received the entire dose 
of vaccine. If a participant does not receive vaccine or does not receive all of the planned 
doses, the reason for the missed dose will be recorded.  
Participants who miss the second vaccination due to noncompliance with the visit schedule 
and not due to a cohort pause will still be required to follow the original visit and testing 
schedule as described in the protocol. Unless consent is withdrawn, a participant who 
discontinues from receiving the second dose of study vaccine will remain in the study and 
complete all safety and immunogenicity procedures required through 1 month after the last 
vaccination received per the Schedule of Events (i.e., up to Day 29 for subjects receiving 
only the first dose of vaccine). Subjects will then enter the 12-month Long-Term Follow-up 
Phase per the Schedule of Events (Table 5).  
Subjects will enter the Long-Term Follow-up Phase starting at Month 3 and will complete 
protocol-specified procedures, including further blood sampling for immunogenicity at 
Month 7 and Month 13 (Table 5).  
The study site is responsible for ensuring participants comply with the study windows 
allowed. If a participant misses a visit, every effort should be made to contact the participant 
and complete a visit within the defined visit window. If a participant exceeds their 

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post-vaccination visit in excess of 28 days from the scheduled visit or misses a vaccination 
schedule by more than 28 days (i.e., 28 days beyond the scheduled time of vaccination), then 
that visit will be classified as a missed visit and the participant will continue with subsequent 
study visits. All safety requirements of the missed visit will be captured and included in the 
subsequent visit (e.g., clinical laboratory testing, diary card review for reactogenicity, 
immune testing, as applicable).  
3.4.8 
Prior and Concomitant Medications 
3.4.8.1 
Prior Medications and Therapies 
Information about prior medications (including any prescription or over-the-counter 
medications, vaccines, or blood products) taken by the participant within the 30 days before 
providing informed consent (or as designated in the inclusion/exclusion requirements) will be 
recorded in the participant’s eCRF.  
3.4.8.2 
Concomitant Medications and Therapies 
Concomitant medications include all medications (including vaccinations received outside of 
the study) that the participant takes from the time of signing the informed consent form (ICF) 
through the follow-up visit at Month 13. At each study visit, the site personnel should 
question the participant about concomitant medications use, including any vaccinations 
received, and record use in the eCRF.  
The use of the following concomitant medications and/or vaccines will not require 
withdrawal of the participant from the study but may determine a participant’s evaluability in 
the per-protocol analysis (analysis sets are described in Section 3.6.5):  
 Any investigational or nonregistered product (drug or vaccine) other than the study 
vaccine used during the study period. 
 Immunosuppressants or other immune-modifying drugs administered chronically (i.e., 
more than 14 days in total) during the study period. For corticosteroids, this will mean 
that prednisone ≥ 20 mg/day or the equivalent is not permitted. Inhaled, nasal, and 
topical steroids are allowed.  

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 Long-acting immune-modifying drugs administered at any time during the study 
period (e.g., infliximab). 
 A vaccine not foreseen by the study protocol administered during the period from 
30 days before through 30 days after each study vaccination, except for any licensed 
influenza vaccine that was administered ≥ 15 days before or after any study 
vaccination. 
 Immunoglobulins and/or any blood products administered during the study period. 
 Any hepatotoxic drugs administered chronically (i.e., more than 14 days in total) 
(Appendix 4).  
 Analgesics/antipyretics may be used post-vaccination for symptomatic relief of 
reactogenicity symptoms. 
Concomitant medications (including vaccinations) will be coded using the WHO Drug 
Dictionary. If a participant takes a prohibited drug therapy, the investigator and the CRO 
medical monitor will make a joint decision about continuing or withholding further 
vaccination of the participant based on the time the medication was administered, the drug’s 
pharmacology and pharmacokinetics, and whether use of the medication will compromise the 
participant’s safety or interpretation of the data. It is the investigator’s responsibility to 
ensure that details regarding the concomitant medications are adequately recorded in the 
eCRF.  
3.5 
Study Procedures 
Before performing any study procedures, all potential participants will sign an ICF (as 
detailed in Section 4.3). Participants will undergo study procedures at the time points 
specified in the Schedule of Events (Table 5).  
A participant also can be seen for an unscheduled visit at any time during the study. An 
unscheduled visit may be prompted by reactogenicity issues, new or ongoing AEs, or 
abnormal clinical laboratory test results. The site also has the discretion to make reminder 
telephone calls or send text messages to inform the participant about visits, request further 
laboratory assessments, review diary card content requirements, or follow up on ongoing or 
outstanding issues.  

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3.5.1 
Safety Telephone Calls 
A safety telephone call is a telephone call made to the participant by trained site personnel. 
This call will follow a script, which will facilitate the collection of relevant safety 
information. The participant will be interviewed according to the script, about occurrence of 
AEs, MAAEs, SAEs, AESI, or AEs leading to study withdrawal and concomitant 
medications associated with those events will be collected.  
Additionally, in the Vaccination Phase of the study, the site will telephone the participant for 
safety monitoring on each of the 2 days after study vaccination (i.e., Day 2 and Day 3 after 
the first vaccination and Day 30 and Day 31 after the second vaccination). The purpose of 
this safety telephone call is to identify any rash or Grade 3 local and systemic reactogenicity 
AEs (solicited AEs) that may occur within 48 hours after study vaccination and to ensure that 
they are recorded in the eCRF and reported to the medical monitor in a timely manner.  
The timing of the safety telephone calls is provided in Table 5.  
All safety information described by the participant must be documented in source documents 
and not documented on the script used for the safety telephone contact.  
3.5.2 
Completion of Diary Card 
At each vaccination visit (Day 1 and Day 29), study staff will provide a diary card to 
participants and training on its proper use. The participant will use the diary card for 
recording AE information; this information will be subject to potential change based on 
further questioning and/or follow-up by study staff.  
Each participant will be instructed to complete the diary card to including the following:  
 Solicited local and systemic reactogenicity AEs, as defined in Section 3.5.6, that 
occur on the day of each vaccine administration and during the 7 days after vaccine 
administration, with appropriate documentation to allow severity scoring by the 
investigator. 
 Daily oral body temperature measurement should be performed at approximately the 
same time each day using the thermometer provided by the study site. If body 

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temperature is taken more than once in a given day, only the highest temperature 
reading should be recorded. 
 Measurement, as applicable, for solicited local AEs; the size measurements will be 
performed using the ruler provided by the study site. 
 All medications (excluding vitamins and minerals) taken on the day of each vaccine 
administration and during the 28 days after vaccine administration. 
 Any unsolicited AE (Section 3.5.7) during the 28 days after each vaccine 
administration 
During clinic visits, study staff will review the diary card information regarding solicited and 
unsolicited AEs, body temperature, and concomitant medications. This information will be 
recorded in the participant’s source documents and the eCRF.  
Diary cards will be the only source documents allowed for solicited systemic and local AEs 
(including body temperature measurements). The following additional rules apply to 
documentation of safety information collected using Diary Cards: 
 No corrections or additions to the Diary Card will be allowed after it is delivered to 
the site. 
 Any blank or illegible fields on the Diary Card must be described as missing data. 
 The site staff must enter all readable entries in the Diary Cards into the eCRF. 
 Any new safety information reported during the site visit (including a solicited 
reaction) must not be written into the Diary Card and must be described in the source 
documents as verbally reported event. Any adverse reaction reported in this manner 
must be described as an unsolicited reaction and therefore entered on the adverse 
event eCRF.  
Any unreturned Diary Cards will be requested from the subject through telephone call(s) or 
other suitable method. 

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3.5.3 
Immunogenicity Assessments 
Blood samples for the following immunogenicity assessments will be collected at the time 
points indicated in the Schedule of Events (Table 5):  
 Serum neutralizing antibodies (nAb) against ZIKV 
 Serum binding antibodies (bAb) against ZIKV 
Sample aliquots will be designed to ensure that backup samples are available and that 
adequate vial volumes may allow further testing needs. The actual time and date of each 
sample collected will be recorded in the eCRF, and unique sample identification will be 
utilized to maintain the blind at the laboratory at all times and to allow for automated sample 
tracking and housing. Handling and preparation of the samples for analysis, as well as 
shipping and storage requirements, will be provided in a separate laboratory manual.  
3.5.4 
Total Blood Volume 
The approximate blood volumes to be collected from each participant during the study are 
provided in Table 4.  

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Table 4: 
Total Blood Volume 
Assessment 
Blood Volume per 
Sample 
Scheduled Number of 
Collectionsa 
Total Amount 
of Scheduled 
Blood 
Clinical Laboratory Assessments 
Hematology 
2 mL 
6 
12 mL 
Serum chemistry 
6.5 mL 
6 
39 mL 
Coagulation 
3 mL 
6 
18 mL 
Flavivirus screening by ELISAb 
12 - 16 mL 
1 
12 - 16 mL 
Serologyc 
6 mL 
1 
6 mL 
Immunogenicity Assessments 
Serum neutralizing antibodies 
against Zika by neutralization 
assays 
8 mL 
5 
40 mL 
Serum binding antibodies 
against Zika by ELISA 
4 mL 
5 
20 mL 
IgG and IgM antibodies against 
envelope- and NS1-based 
antigens by ELISA 
4 mL 
5 
20 mL 
Participant Total 
167 - 171 mL 
Abbreviations: IgG = immunoglobulin G; IgM = immunoglobulin M; ELISA = enzyme-linked immunosorbent assay; 
HIV = human immunodeficiency virus; NSI = nonstructural protein 1. 
a 
Additional blood collections may be required at the discretion of the investigator to follow up on abnormal results. 
b 
Flavivirus testing by ELISA will include testing for dengue, West Nile, and Zika. 
c 
Serology testing will include hepatitis B surface antigen, hepatitis C virus antibody, HIV virus type 1 and 2, Separate 
counseling and consent will be provided for HIV testing. 
3.5.5 
Safety Assessments 
Safety assessments will include monitoring and recording of solicited AEs (local and 
systemic reactogenicity events) and unsolicited AEs, SAEs, AESI, AEs leading to study 
withdrawal, and MAAEs; clinical laboratory test results (hematology, serum chemistry, and 
coagulation); vital sign measurements; and physical examination findings. If an MAAE 
occurs that evokes clinical symptomatology consistent with a flavivirus infection, serology 
and polymerase chain reaction testing against dengue will be uniformly collected.  

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3.5.6 
Solicited Safety Measurements 
The term “reactogenicity” refers to selected signs and symptoms (AEs) occurring after 
vaccine administration that the participants are systemically asked to record. Participants will 
record such occurrences in a diary card (Section 3.5.2) on the day of each vaccine 
administration and for the 6 days after vaccine administration. Participants will be instructed 
to call or return to the clinic within 24 hours if a reactogenicity score reaches Grade 3 or 
greater during the first 6 days after vaccination.  
The following AEs are included on the diary card:  
 Solicited local AEs: 
 Injection site pain 
 Injection site erythema 
 Injection site induration/swelling 
 Solicited systemic AEs: 
 Body temperature (oral) 
 Generalized myalgia (muscle ache or pain) 
 Generalized arthralgia (joint ache or pain) 
 Headache 
 Fatigue/malaise (unusual tiredness) 
 Nausea/vomiting 
 Chills 
 Rash 
Appropriate reactogenicity measurements will be taken using the tools provided by Sponsor 
(oral thermometer and measuring device; Section 3.5.2). The investigator will later review, 
confirm, and grade reactogenicity according to the Guidance for Industry: Toxicity grading 
scale for healthy adult and adolescent volunteers enrolled in preventative vaccine clinical 
trials (DHHS 2007; Table 6).  

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In case of any rash episode observed within 6 days after study vaccination, the participants 
will be instructed to contact the study site within 24 hours. During subject evaluation, the 
investigator should categorize the rash as one of the following: 
 Rash no longer present and history not consistent with urticaria. 
 Rash no longer present but history is consistent with urticaria. 
 Rash present but clinical findings are not consistent with urticaria. Alternative 
diagnosis should be specified as an AE. 
 Rash present and clinical findings consistent with urticaria. 
If a solicited local or systemic reactogenicity AE continues beyond 7 days after vaccine 
administration, it will also be recorded as an AE in the eCRF from 8 days after vaccination 
until the AE has resolved or stabilized (Section 3.5.7.1.1).  
Other solicited reactions will include the following:  
 Use of analgesics and/or antipyretics will be recorded as absent or present, and 
participant will indicate if use was for treatment or prophylaxis. 
 To improve recall before the next visit, participants will record the incidence of 
unsolicited AEs and any medication (prescription and over the counter [excluding 
vitamins and minerals]) using the diary card during the 28 days after each vaccine 
administration. 
All AEs necessitating an unscheduled physician visit or medical attention or leading to 
withdrawal from the study will also be collected throughout the study, as detailed in 
Section 3.5.7.  
3.5.7 
Unsolicited Safety Measurements 
3.5.7.1 
Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to vaccine or their clinical significance. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported.  

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3.5.7.1.1 
Definitions 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Participants will be instructed to record any 
AEs (solicited or unsolicited) in the diary card.  
A treatment-emergent AE (TEAE) is defined as any event not present before exposure to 
vaccine or any event already present that worsens in intensity or frequency after exposure.  
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
vaccine caused the AE. For the purposes of investigational new drug safety reporting, 
“reasonable possibility” means that there is evidence to suggest a causal relationship between 
the vaccine and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a vaccine. Adverse 
reactions are a subset of all suspected adverse reactions for which there are reasons to 
conclude that the drug caused the event.  
An unsolicited AE is any AE reported by the participant that is either (1) not specified as a 
solicited AE in the protocol or (2) specified as a solicited AE in the protocol, but its onset 
occurs outside of the protocol-defined post-vaccination period for reporting solicited AEs 
(i.e., for the 7 days after each vaccination; Section 3.5.6 for additional information on 
solicited safety measures).  
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the IB or 
is not listed at the specificity or severity that has been observed with the vaccine being tested 
or, if an IB is not required or available, it is not consistent with the risk information described 
in the general investigational plan or elsewhere in the current application. For example, under 
this definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the IB 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism 
and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the IB listed 
only cerebral vascular accidents. “Unexpected,” as used in this definition, also refers to AEs 
or suspected adverse reactions that are mentioned in the IB as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug but are not specifically 
mentioned as occurring with the particular drug under investigation.  

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Unsolicited AEs will also be evaluated by the investigator for the coexistence of any of the 
other following conditions:  
 Medically attended AE, defined as an AE that leads to an unscheduled visit to a 
healthcare practitioner 
Any solicited AE (Section 3.5.6) that meets any of the following criteria must be entered as 
an AE in the eCRF:  
 Solicited local or systemic AE leading to the participant withdrawing from the study 
or the participant being withdrawn from the study by the investigator 
 Solicited local or systemic AE lasting beyond 7 days post-vaccination 
 Solicited local or systemic AE that leads to participant withdrawal from vaccine 
 Solicited local or systemic AE that otherwise meets the definition of an SAE 
 Laboratory test result or vital sign measurements with a toxicity score of Grade 3 or 
greater 
3.5.7.1.2 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” (SAE) if, in the view of either 
the investigator or Sponsor, it results in any of the following outcomes:  
 Death 
 Is life-threatening  
 Inpatient hospitalization or prolongation of existing hospitalization 
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 Congenital anomaly or birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical events 

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include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the investigator or Sponsor, its occurrence places the participant at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death. The reporting requirements for SAEs are discussed in 
Section 3.5.7.3.  
3.5.7.1.3 
Adverse Events of Special Interest 
Adverse events of special interest are a subset of AEs that include potentially 
immune-mediated medical conditions (autoimmune or auto-inflammatory diseases) that may 
have the theoretical potential for association with novel vaccines. All participants enrolled in 
the study will be monitored for new onset of AESI from Day 1 through Month 13. The 
occurrence of any of these AEs will be treated as an SAE, meeting the criterion of a 
“medically important event.”  
The list of AESI is presented in Appendix 2.  
A diagnosis of an AESI will be reported to the Sponsor in an expedited manner, similar to an 
SAE (Section 3.5.7.3). The AESI diagnosis, as well as any medications taken to treat the 
condition, will be recorded in the participant’s eCRF.  
3.5.7.1.4 
Pregnancy 
To ensure participant safety, each pregnancy in a participant after study vaccination must be 
reported to the Sponsor or designee within 72 hours of the site learning of its occurrence. If 
the participant agrees to submit this information, the pregnancy must be followed to 
determine the outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. This follow-up should occur even if intended duration of the Long-
Term Follow-up Phase for the study has ended.  
Pregnancy report forms will be distributed to the study site to be used for this purpose.  

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The investigator must immediately (within 24 hours of awareness) report to the Sponsor any 
case of pregnancy resulting in an abnormal outcome (miscarriage or newborn with congenital 
abnormality and/or stillbirth) according to the procedures described for SAEs.  
3.5.7.2 
Eliciting and Documenting Adverse Events 
The investigator is responsible for ensuring that all AEs, SAEs and AESI are recorded in the 
eCRF and reported to the Sponsor. Unsolicited AEs will be assessed during the Vaccination 
Phase from the time of the first dose administration at Day 1 through Day 57 (±7 days). 
Serious AEs, MAAEs, and AESI will be assessed from Day 1 through Month 13 (EOS Visit), 
as specified in the Schedule of Events (Table 5). Any AEs occurring before receipt of the 
vaccine will be analyzed separately from TEAEs.  
At every clinic visit or telephone contact, participants will be asked a standard question to 
elicit any medically-related changes in their well-being according to the scripts provided. 
Participants will also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (both prescription and 
over-the-counter medications).  
In addition to participant observations, data from clinical laboratory test results, physical 
examination findings, or other documents relevant to participant safety classified as an AE 
will be documented on the AE page of the eCRF.  
3.5.7.3 
Reporting Adverse Events 
All unsolicited AEs reported or observed during the study will be recorded on the AE page of 
the eCRF. Information to be collected includes dose group assignment and dose, type of 
event, time of onset, investigator-specified assessment of severity and relationship to vaccine, 
time of resolution of the event, seriousness, as well as any required treatment or evaluations, 
and outcome. The unsolicited AEs resulting from concurrent illnesses, reactions to concurrent 
illnesses, reactions to concurrent medications, or progression of disease states must also be 
reported. All AEs will be followed until they are resolved or stable or judged by the 
investigator to be not clinically significant (NCS). The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all unsolicited AEs.  

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Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should not be reported as an unsolicited AE. However, if it deteriorates at any 
time during the study, it should be recorded as an unsolicited AE.  
Any AE or AESI considered serious by the investigator or that meets SAE criteria 
(Section 3.5.7.1.2) must be reported to the Sponsor immediately (within 24 hours of 
becoming aware of the SAE or AESI). The investigator will assess whether there is a 
reasonable possibility that the vaccine caused the SAE or AESI. The Sponsor will be 
responsible for notifying the relevant regulatory authorities of any SAE or AESI as outlined 
in the 21 US Code of Federal Regulations (CFR) Parts 312 and 320. The investigator is 
responsible for notifying the institutional review board (IRB) directly.  
If the eCRF is unavailable at the time of the SAE or AESI, the following contact information 
is to be used for SAE reporting:  
SAE Mailbox: 
 
SAE Hotline (USA and Canada): 
 
SAE Fax line (USA and Canada): 
 
3.5.7.4 
Assessment of Severity  
The severity (or intensity) of an AE refers to the extent to which it affects the participant’s 
daily activities. When applicable, the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials (DHHS 2007) will be 
used to categorize local and systemic reactogenicity events (solicited AEs), clinical 
laboratory test results, and vital sign measurements observed during this study. Specific 
criteria for clinical and laboratory abnormalities are presented in Appendix 3 (Table 6 and 
Table 7, respectively) and will be graded if outside of the reference range for the laboratory 
utilized.  
The determination of severity for all unsolicited AEs not listed in Toxicity Grading Scale 
should be made by the investigator based upon medical judgment and the definitions of 
severity as follows:  
 Mild: These events do not interfere with the participant’s daily activities. 
PPD
PPD
PPD

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 Moderate: These events cause some interference with the participant’s daily activities 
but do not require or require limited medical intervention. 
 Severe: These events prevent the participant’s daily activity and require intensive 
therapeutic intervention. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. An AE characterized as 
intermittent requires documentation of onset and duration of each episode. 
In the case where an AE meets the definition of a serious AE (SAE), refer to Section 3.5.7.1.2.  
3.5.7.5 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to vaccine is part of the documentation 
process but is not a factor in determining what is or is not reported in the study.  
The investigator will assess causality (i.e., whether there is a reasonable possibility that the 
vaccine caused the event) for all AEs, AESIs, and SAEs. The relationship will be 
characterized using the following classification:  
 Not related: There is not a reasonable possibility a relationship to the investigational 
product. Participant did not receive the investigational product OR temporal sequence 
of the AE onset relative to administration of the investigational product is not 
reasonable OR the AE is more likely explained by another cause than the 
investigational product.  
 Related: There is a reasonable possibility of a relationship to the investigational 
product. There is evidence of exposure to the investigational product. The temporal 
sequence of the AE onset relative to the administration of the investigational product 
is reasonable. The AE is more likely explained by the investigational product than by 
another cause. 
3.5.7.6 
Follow-up of Adverse Events 
All AEs, SAEs, and AESI must be reported in detail on the appropriate page of the eCRF and 
followed until the event is resolved or stable or judged by the investigator to be NCS.  

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3.5.8 
Clinical Laboratory Testing 
Clinical laboratory tests will be performed by the central laboratory, unless otherwise 
specified. Blood and urine will be collected at the time points indicated in the Schedule of 
Events (Table 5). Fasting is not required before collection of laboratory samples.  
Clinical laboratory results will be scored for toxicity using the grading scale provided in 
Appendix 3 (Table 7). Of note, the laboratory test value itself may not be the AE 
classification. Each AE will be classified by its most specific term (e.g., renal insufficiency, 
bronchitis) and supporting evidence (e.g., laboratory test value) will not be classified as an 
AE. The following hematology, serum chemistry, and coagulation assessments will be 
performed: 
Hematology: 
Hemoglobin, platelet count, red blood cell count, and total and 
differential white blood cell count 
Serum 
chemistry: 
Alanine aminotransferase, albumin, alkaline phosphatase, aspartate 
aminotransferase, bilirubin (total and direct), blood urea nitrogen, 
creatinine, random glucose, and total protein 
Coagulation: 
Prothrombin time and partial thromboplastin time 
Additional tests include the following:  
 Urine pregnancy testing will be performed on site by the local laboratory for all 
female participants of childbearing potential. Testing will be performed at the 
Screening Visit, before each vaccine administration, and as needed at unscheduled 
visits.  
 If not documented in a female participant’s medical records, a follicle-stimulating 
hormone test may be performed at the Screening Visit, as necessary and at the 
discretion of the investigator, to confirm postmenopausal status. 
 Hepatitis B surface antigen, Hepatitis C virus antibody, and HIV virus (types 1 and 2) 
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 Flaviviruses as determined by ELISA (including dengue, West Nile, and Zika) at 
screening 
 A urine screen for drugs of abuse performed by the local laboratory for amphetamines, 
benzodiazepines, cocaine, methadone, opiates, and phencyclidine (Exclusion 
Criterion 26; Section 3.2.2).  
Should clinical laboratory testing at 7 days post-vaccination result in a Grade 2 or greater 
toxicity score, then repeat testing must be performed within the next 7 days and may include 
an unscheduled visit. Should the participant’s laboratory test value not return to baseline (i.e., 
toxicity grade at Visit Day 1), then periodic testing may be needed until the abnormality is 
deemed to be associated with a new stable AE or determined to be NCS by the investigator.  
Values that fall within the normal laboratory range will automatically be classified as normal 
and receive a toxicity score of zero. All values that have a toxicity score of Grade 1 or greater 
will also be evaluated by the investigator and classified as CS or NCS (Glossary of Terms for 
the definition of laboratory abnormalities with and without potential clinical significance). 
Investigators should use their clinical judgment when considering the clinical significance of 
any abnormal laboratory findings. All laboratory test values with a toxicity score of Grade 3 
or greater will be entered as AEs.  
Any additional laboratory test value that is determined to be CS will also be recorded as an 
AE, should the test result be considered the primary diagnosis. In such instances, the 
abnormal value and grade will be documented on the AE page of the eCRF. The investigator 
will continue to monitor the participant with additional assessments until the value has 
reached the reference range or the value at baseline (i.e., toxicity grade at Visit Day 1) or 
until the investigator determines that follow-up is no longer medically necessary. The only 
exception to this rule would be a laboratory test value that is associated with an identified 
ongoing AE where that event would be the classifying AE.  
3.5.9 
Vital Sign Measurements 
Vital sign measurements will include systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature (preferred route is oral). The participant will be seated 
for at least 5 minutes before all measurements are taken. Vital signs will be measured at the 
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sign measurements will be collected once before vaccine administration and at least 1 hour 
after vaccine administration (before participants are discharged from the clinic).  
When procedures overlap and are scheduled to occur at the same time point, the order of 
procedures should be vital sign measurements and then the blood collection.  
If any of the vital sign measurements meet the toxicity grading criteria for clinical 
abnormalities (Table 6) of Grade 3 or greater, the abnormal value and grade will be 
documented on the AE page of the eCRF (unless there is another known cause of the 
abnormality that would result in an AE classification). The investigator will continue to 
monitor the participant with additional assessments until the vital sign value has reached the 
reference range, the vital sign value at baseline, is considered stable, or until the investigator 
determines that follow-up is no longer medically necessary.  
3.5.10 
Physical Examinations 
A full physical examination will be performed at the Screening Visit and a symptom-directed 
(targeted) physical examination will be performed at all other scheduled time points as 
indicated in the Schedule of Events (Table 5). The full examination will include assessment 
of skin, head, ears, eyes, nose, throat, neck, thyroid, lungs, heart, cardiovascular, abdomen, 
lymph nodes, and musculoskeletal system/extremities. Interim physical examinations will be 
performed at the discretion of the investigator, if necessary, to evaluate AEs or abnormal 
clinical laboratory test results. Before vaccination and at 7 days post-vaccination, a physical 
evaluation of the arm that was vaccinated and the associated lymph nodes should be 
evaluated.  
Height and weight will be measured, and body mass index calculated, at screening only.  
3.6 
Statistical Analysis Plans 
3.6.1 
Primary Endpoints 
The following are the primary endpoints of the study:  
 Frequency and grade of each solicited local and systemic reactogenicity AE during a 
7-day follow-up period after each vaccination  

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 Frequency and grade of any unsolicited AEs during the 28-day follow-up period after 
each vaccination 
 Frequency of any MAAE, SAE, and AESI from Day 1 to the EOS Visit at Month 13 
3.6.2 
Secondary Endpoints 
The following are the secondary endpoints of the study:  
 Serum nAb titers against ZIKV by PRNT: 
 GMT of nAb against ZIKV at Day 1, Day 29, Day 57, Month 7, and Month 13 as 
measured by PRNT. 
 GMT of nAb in initially seronegative participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by PRNT. 
 GMT of nAb in initially seropositive participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by PRNT. 
 Percentage of participants who seroconverted from Day 1 (baseline) to Day 29, 
from Day 1 to Day 57, from Day 1 to Month 7, and from Day 1 to Month 13. A 
seroconversion is defined as a change of PRNT from below the LLOQ to a PRNT 
equal to or above LLOQ, or a multiplication by at least 4 in subjects with pre-
existing PRNT titers. 
 Proportion of initially seronegative participants with a seroresponse at Day 29, 
Day 57, Month 7, and Month 13 as measured by PRNT. 
 Proportion of initially seropositive participants with a 2-fold or 4-fold increase in 
nAb titers as compared with baseline as measured by PRNT. 
3.6.3 
Exploratory Endpoints 
The following are the exploratory endpoints of the study:  
 Geometric mean titer (GMT) of nAb against ZIKV at Day 1, Day 29, Day 57, 
Month 7, and Month 13 as measured by additional neutralization assay. 

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 GMT of nAb in initially seronegative participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by additional neutralization assay. 
 GMT of nAb in initially seropositive participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by additional neutralization assay. 
 Percentage of participants who seroconverted from Day 1 (baseline) to Day 29, from 
Day 1 to Day 57, from Day 1 to Month 7, and from Day 1 to Month 13. A 
seroconversion is defined as change of nAb titer (by additional neutralization assay) 
from below the LLOQ to a titer equal to or above LLOQ, or a multiplication by at 
least 4 in pre-existing neutralizing titer. 
 Proportion of initially seronegative participants with a seroresponse at Day 29, Day 
57, Month 7, and Month 13 as measured by additional neutralization assay. 
 Proportion of initially seronegative participants with a 2-fold or 4-fold increase in 
nAb as compared with baseline as measured by additional neutralization assay. 
 GMT of bAb against ZIKV at Day 1, Day 29, Day 57, Month 7, and Month 13 as 
measured by ELISA binding assay. 
 GMT of bAb in initially seronegative participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by ELISA binding assay. 
 GMT of bAb in initially seropositive participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by ELISA binding assay. 
 Percentage of participants that seroconverted from Day 1 (baseline) to Day 29, from 
Day 1 to Day 57, from Day 1 to Month 7, and from Day 1 to Month 13. A 
seroconversion is defined as a change of binding antibody titer from below LLOQ to 
a binding antibody titer equal or above the LLOQ, or a multiplication by at least 4 in 
pre-existing bAb titers. 
 Proportion of initially seronegative participants with a seroresponse at Day 29, Day 
57, Month 7, and Month 13 as measured by ELISA binding assay. 
 Proportion of initially seropositive participants with a 2-fold or 4-fold increase in bAb 
as compared with baseline as measured by ELISA binding assay. 

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 IgG and IgM antibodies against envelope- and NS1- based antigens present in serum 
collected at baseline and at end of study measured as antibody binding by ELISA or 
equivalent methodology to flaviviruses. 
3.6.4 
Sample Size Calculations 
A total of 120 participants (30 participant per cohort) are planned for enrollment in the study 
and random assignment to study dosing. The sample size is considered sufficient to meet the 
study objective of identifying a dose and establishing initial safety results in a population of 
healthy adults in both endemic and nonendemic Zika regions. With 24 subjects receiving 
mRNA-1893 in each dose level, there is a 92% probability to observe at least 1 subject with 
an AE if the true incidence of the AE is 10% and a 70.8% probability if the true incidence of 
the AE is 5%. 
3.6.5 
Analysis Sets 
The All Enrolled Participants Set will include all participants who signed the ICF.  
The Safety Set will include all participants who received at least 1 dose of vaccine 
(mRNA-1893 or placebo). Participants will be analyzed according to the vaccine actually 
received.  
The Per-Protocol Set will be determined for each visit and will include all participants who 
did not have a major protocol violation, received vaccine within the acceptable vaccination 
window (i.e., received full dose[s] of assigned vaccine), had blood collection within 
acceptable visit windows, and had a pre-vaccination and at least 1 post-vaccination serum 
sample available for testing. All participants in the Per-Protocol Set will be analyzed 
according to the vaccine the participant was randomly assigned to receive and not according 
to vaccine actually received. Participants who missed the second vaccination may still be 
included in the Per-Protocol Set for Visit 5 immunogenicity data analysis. If the second 
vaccination occurred outside of the window, the subsequent data may need to be excluded 
from the Per-Protocol Set analysis.  
The Intent-to-Treat Set will include all participants who were randomized to the study, 
regardless of protocol violations, unacceptable visit windows, missed vaccination, or missing 
data. The Intent-to-Treat Set will used for supportive analyses.  

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3.6.6 
Statistical Analysis 
Details of all statistical analyses will be described in a statistical analysis plan. All data 
collected will be presented in data listings. Data from participants excluded from an analysis 
set will be presented in the data listings but not included in the calculation of summary 
statistics.  
Data from participants who received placebo will be pooled across cohorts for all dosing.  
For categorical variables, frequencies and percentages will be presented. Continuous 
variables will be summarized using descriptive statistics (number of participants, mean, 
median, standard deviation, minimum, and maximum).  
3.6.6.1 
Immunogenicity Analyses 
The following secondary immunogenicity outcome measures and the 95% confidence 
intervals, where appropriate, will be summarized by dose group and by visit:  
 Serum neutralizing antibodies (nAb titers) against ZIKV by PRNT: 
 GMT of nAb against ZIKV at Day 1, Day 29, Day 57, Month 7, and Month 13 as 
measured by PRNT. 
 GMT of nAb in initially seronegative participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by PRNT. 
 GMT of nAb in initially seropositive participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by PRNT. 
 Percentage of participants who seroconverted from Day 1 (baseline) to Day 29, 
from Day 1 to Day 57, from Day 1 to Month 7, and from Day 1 to Month 13. A 
seroconversion is defined as a change of PRNT from below LLOQ to a PRNT 
equal to or above LLOQ, or a multiplication by at least 4 in subjects with 
pre-existing PRNT titers. 
 Proportion of initially seronegative participants with a seroresponse at Day 29, 
Day 57, Month 7, and Month 13 as measured by PRNT. 

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 Proportion of initially seropositive participants with a 2-fold or 4-fold increase in 
nAb titers as compared with baseline as measured by PRNT. 
The following exploratory immunogenicity outcome measures and the 95% confidence 
intervals, where appropriate, will be summarized by dosing group and by visit: 
 GMT of nAb against ZIKV at Day 1, Day 29, Day 57, Month 7, and Month 13 as 
measured by additional neutralization assay. 
 GMT of nAb in initially seronegative participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by additional neutralization assay. 
 GMT of nAb in initially seropositive participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by additional neutralization assay. 
 Percentage of participants who seroconverted from Day 1 (baseline) to Day 29, from 
Day 1 to Day 57, from Day 1 to Month 7, and from Day 1 to Month 13. A 
seroconversion is defined as change of nAb titer (by additional neutralization assay) 
from below the LLOQ to a titer equal to or above LLOQ, or a multiplication by at 
least 4 in pre-existing neutralizing titer. 
 Proportion of initially seronegative participants with a seroresponse at Day 29, Day 
57, Month 7, and Month 13 as measured by additional neutralization assay.  
 Proportion of initially seropositive participants with a 2-fold or 4-fold increase in nAb 
as compared with baseline as measured by additional neutralization assay.  
 GMT of bAb against ZIKV at Day 1, Day 29, Day 57, Month 7, and Month 13 as 
measured by ELISA binding assay. 
 GMT of bAb in initially seronegative participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by ELISA binding assay.  
 GMT of bAb in initially seropositive participants against ZIKV at Day 1, Day 29, 
Day 57, Month 7, and Month 13 as measured by ELISA binding assay.  
 Percentage of participants that seroconverted from Day 1 (baseline) to Day 29, from 
Day 1 to Day 57, from Day 1 to Month 7, and from Day 1 to Month 13. A 
seroconversion is defined as a change of binding antibody titer from below LLOQ to 

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a binding antibody titer equal or above the LLOQ, or a multiplication by at least 4 in 
pre-existing bAb titers.  
 Proportion of initially seronegative participants with a seroresponse at Day 29, Day 
57, Month 7, and Month 13 as measured by ELISA binding assay.  
 Proportion of initially seropositive participants with a 2-fold or 4-fold increase in bAb 
as compared with baseline as measured by ELISA binding assay.  
 IgG and IgM antibodies against envelope- and NS1- based antigens present in serum 
collected at baseline and at end of study measured as antibody binding by ELISA or 
equivalent methodology to flaviviruses.  
3.6.6.2 
Safety Analyses 
Reactogenicity will be summarized by dosing group (10, 30, 100, or 250 µg mRNA-1893 or 
placebo), vaccination (first or second dose), duration, and severity. Adverse events will be 
coded by preferred term and system organ class using MedDRA and summarized by dose 
group, vaccination (first or second dose), and overall. Adverse events will also be 
summarized by severity and relationship to the study vaccine. Descriptive statistics will be 
presented, and the difference in the proportion of participants with AEs will be provided, 
comparing each dose level with placebo pooled across all cohorts. Individual participant 
listings will be provided for all AEs, AEs leading to study withdrawal, AESI, MAAEs, and 
SAEs.  
Safety data from clinical laboratory test results and vital sign measurements will be graded 
by severity scoring and analyzed by dose group and vaccination (first or second). Absolute 
and change from baseline values will be provided according to the toxicity table, along with 
mean, median, and standard deviation. Results of serology, urine drug screening, physical 
examinations, and pregnancy tests will be listed for all participants randomly assigned to 
receive study vaccine.  
Medical history data for all participants randomly assigned to receive study vaccine will be 
presented by participant in a listing.  
Baseline demographic and background variables will be summarized by dosing group for all 
randomly assigned participants. The number of participants who enroll in the study and the 

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number and percentage of participants who complete the study will be presented. Frequency 
and percentage of participants who withdraw or discontinue from the study and the reason for 
withdrawal or discontinuation will also be summarized.  
Prior and concomitant medications will be listed (with start and stop dates) for each 
participant and summarized by common medical dictionary coding. Any vaccinations that 
occur during the trial will also be captured and summarized.  
3.6.7 
Handling of Missing Data 
For GMT calculation, antibody values reported as below the lower LOQ (LLOQ) will be 
replaced by 0.5 × LLOQ. Values that are greater than the upper LOQ (ULOQ) will be 
converted to the ULOQ. Missing data will not be imputed.  
3.6.8 
Interim Analyses 
Once all subjects from a cohort have completed the Vaccination Phase through Visit 9, the 
database will be locked for that cohort and safety and immune test results will be analyzed 
through 28 days following the second vaccination by an unblinded statistician. As dose 
escalation occurs, cumulative analyses will be included for each subsequent data lock to 
allow for all prior dosing cohorts to be analyzed by dose assignment, and in aggregate for 
mRNA-1893 exposure. Immunogenicity and safety data, including mean group analyses of 
change from baseline, where applicable, will be summarized for each dose group. These data 
are required to inform decisions on dose selection for this and other development programs 
using the same mRNA platform. Participant-level dose assignment will not be released to the 
participants or to those individuals involved directly in managing or assessing safety until the 
study is completed.  
Additional information can be found in the statistical analysis plan.  
3.7 
Data Quality Assurance 
All aspects of the study will be monitored for compliance with applicable government 
regulations with respect to current International Council for Harmonisation (ICH) 
harmonized tripartite guideline E6(R2): Good Clinical Practice and current standard 
operating procedures. The eCRFs will be utilized and accessed through iMedidata® via the 

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internet. This electronic data capture system is validated and compliant with US Title 21 of 
CFR Part 11. Each person involved with the study will have an individual identification code 
and password that allow for record traceability. There may be an internal quality review audit 
of the data and additional reviews by the clinical monitor.  
Due to safety review requirements, no more than 3 business days should transpire between 
participant data availability (visits, laboratory test results, etc.) and data entry. As a quality 
measure, timeliness of data entry and data query resolution will be reported to the IST. Other 
issues of data quality that may hinder safety review or pose a concern with patient safety will 
also be reported to the IST with appropriate awareness to the SMC if needed.  

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4 
INVESTIGATOR OBLIGATIONS 
The following administrative items are meant to guide the investigator in the conduct of the 
study and may be pursuant to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Changes will be reported to the IRB 
but will not result in protocol amendments.  
4.1 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant, except as necessary for monitoring and auditing by the Sponsor, 
its designee, relevant regulatory authority, or the IRB.  
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the Sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties.  
4.2 
Institutional Review 
Federal regulations and the ICH E6(R2) guidelines require that approval be obtained from an 
IRB before participation of human participants in research studies. Before study onset, the 
protocol, informed consent, advertisements to be used for the recruitment of study 
participants, and any other written information regarding this study to be provided to the 
participant must be approved by the IRB. Documentation of all IRB approvals and of the IRB 
compliance with the ICH E6(R2) guidelines will be maintained by the site and will be 
available for review by the Sponsor or its designee.  
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address, the clinical protocol by title or protocol number or both, and the date 
approval or a favorable opinion was granted.  

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4.3 
Participant Consent 
Written informed consent in compliance with US Title 21 CFR Part 50 shall be obtained from 
each participant before he or she enters the study or before any unusual or nonroutine 
procedure that involves risk to the participant is performed. If any institution-specific 
modifications to study-related procedures are proposed or made by the site, the consent 
should be reviewed by the Sponsor or its designee or both before IRB submission. Once 
reviewed, the investigator will submit the ICF to the IRB for review and approval before the 
start of the study. If the ICF is revised during the course of the study, all active participating 
participants must sign the revised form.  
Before recruitment and enrollment, each prospective participant will be given a full 
explanation of the study and be allowed to read the approved ICF. Once the investigator is 
assured that the participant understands the implications of participating in the study, the 
participant will be asked to give his or her consent to participate in the study by signing the 
ICF. Separate counseling and consent will be provided for HIV testing.  
The ICF will also explain that excess serum from immunogenicity testing may be used for 
future research, which may be performed at the discretion of the Sponsor to further 
characterize the immune response to the ZIKV, additional assay development, and the 
immune response across flaviviruses.  
The investigator or designee will provide a copy of the ICF to the participant. The original 
form shall be maintained in the participant’s medical records at the site.  
4.4 
Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of SAEs and AESI 
according to the timeline and method outlined in this protocol. In addition, the investigator 
agrees to submit annual reports to his or her IRB as appropriate.  
4.5 
Financial Disclosure and Obligations 
The investigator is required to provide financial disclosure information to allow the Sponsor 
to submit the complete and accurate certification or disclosure statements required under 
21 CFR 54. In addition, the investigator must provide to the Sponsor a commitment to 

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promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study.  
Neither the Sponsor, PPD, nor the study site is financially responsible for further testing or 
treatment of any medical condition that may be detected during the screening process. In 
addition, in the absence of specific arrangements, neither the Sponsor, PPD, nor the study site 
is financially responsible for further treatment of the disease under study.  
4.6 
Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R2) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to:  
 IRB approval, 
 An original investigator-signed investigator agreement page of the protocol, 
 Form FDA (Food and Drug Administration) 1572, fully executed, and all updates on a 
new fully executed Form FDA 1572, 
 Curriculum vitae for the principal investigator and each subinvestigator listed on 
Form FDA 1572. Current licensure must be noted on the curriculum vitae. The 
curriculum vitae will be signed and dated by the principal investigators and 
subinvestigators at study start-up, indicating that they are accurate and current, 
 Financial disclosure information to allow the Sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR 54. In addition, 
the investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and 
for 1 year after the completion of the study, 
 An IRB-approved ICF, samples of site advertisements for recruitment for this study, 
and any other written information about this study that is to be provided to the 
participant, and 
 Laboratory certifications and reference ranges for any local laboratories used by the 
site, in accordance with 42 CFR 493. 

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4.7 
Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6(R2). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. The study will be conducted in compliance with 
the protocol, current Good Clinical Practice guidelines – adopting the principles of the 
Declaration of Helsinki – and all applicable regulatory requirements.  
4.8 
Data Collection 
4.8.1 
Case Report Forms and Source Documents 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for participants treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include laboratory reports and similar 
sources.  
Electronic case report forms are accessed through iMedidata® via the internet. This electronic 
data capture system is validated and compliant with 21 CFR 11. Each person involved with 
the study will have an individual identification code and password that allows for record 
traceability. Thus, the system, and subsequently any investigative reviews, can identify 
coordinators, investigators, and individuals who have entered or modified records, as well as 
the time and date of any modifications. There may be internal quality review audit of the data 
and additional reviews by the clinical monitor.  
Each eCRF is presented as an electronic copy, allowing data entry by site personnel, who can 
add and edit data, add new participants, identify and resolve discrepancies, and view records. 
This system provides immediate direct data transfer to the database, as well as immediate 
detection of discrepancies, enabling site coordinators to resolve and manage discrepancies in 
a timely manner.  
4.9 
Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R2) and all applicable guidelines and regulations.  

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4.10 
Reporting Adverse Events 
By participating in this study, the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in this protocol. In addition, the investigator agrees to 
submit annual reports to his or her IRB as appropriate. The investigator also agrees to 
provide the Sponsor with an adequate report, if applicable, shortly after completion of the 
investigator’s participation in the study.  
4.11 
Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the study’s 
outcome, and the Sponsor and regulatory authority(ies) with any reports required.  
4.12 
Records Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the vaccine. These documents should be retained 
for a longer period, however, if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. It is the Sponsor’s responsibility to inform the 
investigator/institution as to when these documents no longer need to be retained.  
4.13 
Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the Sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The Sponsor has final approval authority over all 
such issues.  
Data are the property of the Sponsor and cannot be published without their prior 
authorization, but data and publication thereof will not be unduly withheld.  

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5 
STUDY MANAGEMENT 
5.1 
Monitoring 
5.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of the Sponsor, is obligated to follow the study 
closely. In doing so, the monitor will visit the investigator and study facility at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and staff. The monitor will be blinded to dose assignment. A separate unblinded 
study monitor will be responsible for vaccine accountability.  
All aspects of the study will be carefully monitored by the Sponsor or its designee for 
compliance with applicable government regulation with respect to current ICH E6(R2) 
guidelines and standard operating procedures.  
5.1.2 
Inspection of Records 
The investigator and institution involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study records. 
In the event of an audit, the investigator agrees to allow the Sponsor, their representatives, 
the FDA, or other regulatory agency access to all study records.  
The investigator should promptly notify the Sponsor of any audits scheduled by any 
regulatory authorities and promptly forward copies of any audit reports received to the 
Sponsor.  
5.2 
Management of Protocol Amendments and Deviations 
5.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the participant, must be reviewed and approved by the Sponsor or 

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designee. Amendments to the protocol must be submitted in writing to the investigator’s IRB 
for approval before participants are enrolled into an amended protocol.  
5.2.2 
Protocol Violations and Deviations 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard to study 
participants without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol amendments 
should be submitted to the IRB for review and approval, to the Sponsor for agreement, and to 
the regulatory authorities, if required.  
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the Sponsor and the IRB and agreed to by the 
investigator. Deviations usually have an impact on individual participants or a small group of 
participants and do not involve inclusion/exclusion or primary endpoint criteria. A protocol 
violation occurs when the participant or investigator does not adhere to the protocol, resulting 
in a significant additional risk to the participant. Protocol violations can include 
nonadherence to inclusion or exclusion criteria, enrollment of the participant without prior 
Sponsor approval, or nonadherence to FDA regulations or ICH E6(R2) guidelines.  
Protocol violations and deviations will be documented by the clinical monitor throughout the 
course of monitoring visits. The investigator will be notified in writing by the monitor of 
violations and deviations. The IRB should be notified of all protocol violations and 
deviations, if appropriate, in a timely manner.  
5.3 
Study Termination 
Although the Sponsor has every intention of completing the study, they reserve the right to 
discontinue it at any time for clinical or administrative reasons.  
The EOS is defined as the date on which the last participant completes the last visit (includes 
the EOS Visit and any additional long-term follow-up). Any additional long-term follow-up 
that is required to monitor the resolution of a finding or AE may be reported through an 
amendment to the clinical study report.  

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5.4 
Final Report 
Whether the study is completed or prematurely terminated, the Sponsor will ensure that 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The Sponsor will also ensure that clinical study 
reports in marketing applications meet the standards of the ICH harmonized tripartite 
guideline E3: Structure and content of clinical study reports.  
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review complete study results.  
A final clinical study report will contain all data collected through the Long-Term Follow-up 
Phase.  
Upon completion of the clinical study report, the Sponsor will provide the investigator(s) 
with the final approved clinical study report.  

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6 
APPENDICES 
6.1 
Appendix 1: Schedule of Events  
The Schedule of Events is presented in Table 5.  
 

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Table 5: 
Schedule of Events  
Procedure 
Screening 
Phase 
Vaccination Phase 
Long-Term Follow-up Phase 
Study Visit 
Screening 
Day 1 
Day 2 
Day 3 
Day 8 
Day 29 
Day 30 
Day 31 
Day 36 
Day 57 
(Month 2) 
Months 3, 
4, 5, 6
Month 7 
Months 8, 
9, 10, 11, 12 
Month 13  
(EOS)a 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10-
14 
15-19 
20 
Type of Visit 
C 
C 
SC 
SC 
C 
C 
SC SC 
C 
C 
SC 
C 
SC 
C 
Window Allowance 
-28/0 
0 
0 
0 
+3 
+14 
0 
0 
+3 
-7/+14 
±7 
±14 
±7 
±14 
Informed consent 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Inclusion/exclusion criteria 
X 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Baseline demographics 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Medical and prior medication 
history 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Concomitant medications, 
including vaccinations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurementsb 
X 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
Physical examinationc 
X 
X 
– 
– 
X 
X 
– 
– 
X 
X 
– 
(X) 
– 
(X) 
Serology screeningd 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Serology flavivirus screening by 
ELISAe 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Urine drug screenf 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 

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Procedure 
Screening 
Phase 
Vaccination Phase 
Long-Term Follow-up Phase 
Study Visit 
Screening 
Day 1 
Day 2 
Day 3 
Day 8 
Day 29 
Day 30 
Day 31 
Day 36 
Day 57 
(Month 2) 
Months 3, 
4, 5, 6
Month 7 
Months 8, 
9, 10, 11, 12 
Month 13  
(EOS)a 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10-
14 
15-19 
20 
Type of Visit 
C 
C 
SC 
SC 
C 
C 
SC SC 
C 
C 
SC 
C 
SC 
C 
Window Allowance 
-28/0 
0 
0 
0 
+3 
+14 
0 
0 
+3 
-7/+14 
±7 
±14 
±7 
±14 
Urine pregnancy testg 
X 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
Assessment of 
eligibility/contraindications for 
subsequent vaccinationh 
– 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
Randomization 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Blood sample for clinical 
laboratory tests (hematology, 
serum chemistry, and 
coagulation) (Section 3.5.8) 
X 
X 
– 
– 
X 
X 
– 
– 
X 
X 
– 
– 
– 
– 
Diary card training 
– 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
Distribute diary card for 
collection of solicited and 
unsolicited AEsi 
– 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
Vaccination administration 
– 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 
60-minute post-vaccination 
assessmentj 
– 
X 
– 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
– 

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Procedure 
Screening 
Phase 
Vaccination Phase 
Long-Term Follow-up Phase 
Study Visit 
Screening 
Day 1 
Day 2 
Day 3 
Day 8 
Day 29 
Day 30 
Day 31 
Day 36 
Day 57 
(Month 2) 
Months 3, 
4, 5, 6
Month 7 
Months 8, 
9, 10, 11, 12 
Month 13  
(EOS)a 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10-
14 
15-19 
20 
Type of Visit 
C 
C 
SC 
SC 
C 
C 
SC SC 
C 
C 
SC 
C 
SC 
C 
Window Allowance 
-28/0 
0 
0 
0 
+3 
+14 
0 
0 
+3 
-7/+14 
±7 
±14 
±7 
±14 
Blood sample collection for 
vaccine-induced 
immunogenicity assayk 
– 
Xl 
– 
– 
– 
Xl 
– 
– 
– 
X 
– 
X 
– 
X 
Post-vaccination SCm 
– 
– 
X 
X 
– 
– 
X 
X 
– 
– 
X 
– 
X 
– 
Return and review diary card 
– 
– 
– 
– 
X 
X 
– 
– 
X 
X 
– 
– 
– 
– 
Record unsolicited AEs 
– 
X 
X 
X 
X 
X 
X 
X 
X 
X 
– 
– 
– 
– 
Record SAEs, MAAEs, and AEs 
of special interestn 
– 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Abbreviations: –, not collected; AE, adverse event; C, clinic visit; AE, adverse event; AESI, adverse event of special interest; ELISA, enzyme-linked immunosorbent assay; 
EOS, end of study; IgG, immunoglobulin G; IgM, immunoglobulin M; MAAE, medically attended adverse event; NA, not applicable; SAE, serious adverse event; SC, 
safety telephone call; SOE, schedule of events. 
a 
Unless consent is withdrawn, a participant who discontinues from receiving the second dose of study vaccine will remain in the study and complete all safety and 
immunogenicity procedures required through 1 month after the last vaccination received per the SOE (i.e., up to Day 29 for subjects receiving only the first dose of 
vaccine). Subjects will then enter the 12‑month Long-Term Follow-up Phase per the SOE. 
b 
Vital sign measurements will include systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature. Oral temperature is preferred route. The 
participant will be seated for at least 5 minutes before all measurements are taken. Vital sign measurements will be collected once before dose administration and at least 
1 hour after dose administration (before participants are discharged from the clinic) on Visits Day 1 and Day 29. When procedures overlap and are scheduled to occur at 
the same time point, the order of procedures should be vital sign measurements and then the blood collection. 
c 
A full physical examination, including height and weight (and body mass index calculation), will be performed at screening (Section 3.5.10); symptom-directed 
(targeted) physical examinations will be performed at all other scheduled time points. Interim physical examinations will be performed at the discretion of the 
investigator. Investigator may perform targeted physical examinations at Month 7 and Month 13 at their discretion. A physical examination of the arm that was 
vaccinated and the associated lymph nodes should be evaluated before each vaccination and at 7 days post-vaccination. 
d 
Serology testing will include hepatitis B virus surface antigen, hepatitis C virus antibody, human immunodeficiency virus type 1 and 2 antibodies. 
e 
Flavivirus screening by ELISA will include screening for dengue, West Nile, and Zika. 
f 
Urine drug screen will include amphetamines, benzodiazepines, cocaine, methadone, opiates, and phencyclidine (Exclusion Criterion 26, Section 3.2.2). 
g 
Urine pregnancy testing only for women of childbearing potential (performed at the local laboratory) at the Screening Visit, prior to vaccination administration and as 
needed at unscheduled visits. 
h 
Participants are assessed for eligibility/contraindications for second vaccination (Section 3.4.2.3).  
i 
At each vaccination visit (Day 1 and Day 29), study staff will provide a diary card to participants and training on its proper use. The participant will use the diary card 
(Section 3.5.2) for recording information on solicited AEs (Section 3.5.6) during the 6 days after vaccine administration, unsolicited AEs (Section 3.5.7) during the 28 
days after each vaccination.  
j 
At each visit when vaccine injections are administered, participants will be monitored for 60 minutes after vaccine administration; assessments will include vital sign 
measurements and monitoring for local or systemic reactions. 
k 
For all participants, blood samples for immunogenicity testing will be collected for the analysis of vaccine-induced immunogenicity (Section 3.5.3). At EOS, blood 
samples will also be used to test for flavivirus seroconversion. 
l 
Sample collection before study vaccination. 
m 
During the Vaccination Phase, all participants will receive a post-vaccination safety telephone call at 24 hours and 48 hours after vaccinations (Day 2 and Day 3 after 
first vaccination and Day 30 and Day 31 after second vaccination). Trained site personnel will inquire about the presence of solicited and unsolicited AEs and 
concomitant medication use and will remind participants to keep their diary cards up to date (Section 3.5.2). 
n 
The investigator must report all SAEs, MAAEs, and AESI within 24 hours of awareness (Section 3.5.7.3).  

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6.2 
Appendix 2: Adverse Events of Special Interest 
The following is a list of AESI:  
Gastrointestinal disorders:  
 Celiac disease 
 Crohn’s disease 
 Ulcerative colitis 
 Ulcerative proctitis 
Liver disorders:  
 Autoimmune cholangitis 
 Autoimmune hepatitis 
 Primary biliary cirrhosis 
 Primary sclerosing cholangitis 
Metabolic diseases:  
 Addison’s disease 
 Autoimmune thyroiditis (including Hashimoto thyroiditis) 
 Diabetes mellitus type I 
 Grave's or Basedow’s disease 
Musculoskeletal disorders:  
 Antisynthetase syndrome 
 Dermatomyositis 
 Juvenile chronic arthritis (including Still’s disease) 
 Mixed connective tissue disorder 
 Polymyalgia rheumatic 

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 Polymyositis 
 Psoriatic arthropathy 
 Relapsing polychondritis 
 Rheumatoid arthritis 
 Spondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter’s 
Syndrome), and undifferentiated spondyloarthritis 
 Systemic lupus erythematosus 
 Systemic sclerosis (with limited or diffuse cutaneous involvement) 
Neuroinflammatory disorders:  
 Acute 
disseminated 
encephalomyelitis, 
including 
site-specific 
variants 
(e.g., encephalitis, encephalomyelitis, myelitis, myeloradiculoneuritis, cerebellitis) 
 Cranial nerve disorders, including paralyses/paresis (e.g., Bell’s palsy) 
 Immune-mediated peripheral neuropathies and plexopathies, including Guillain-Barré 
syndrome, Miller Fisher syndrome and other variants, chronic inflammatory 
demyelinating polyneuropathy, multifocal motor neuropathy, and polyneuropathies 
associated with monoclonal gammopathy 
 Multiple sclerosis 
 Myasthenia gravis (including Lambert-Eaton myasthenic syndrome) 
 Narcolepsy 
 Optic neuritis 
 Transverse myelitis 
Skin disorders:  
 Alopecia areata 
 Autoimmune bullous skin diseases, including pemphigus, pemphigoid, and dermatitis 
herpetiformis 

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 Cutaneous lupus erythematosus 
 Erythema nodosum 
 Morphea 
 Lichen planus 
 Psoriasis 
 Sweet’s syndrome 
 Vitiligo 
Vasculitides:  
 Large vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and 
temporal arteritis 
 Medium-sized and/or small vessels vasculitis including the following: polyarteritis 
nodosa, Kawasaki’s disease, microscopic polyangiitis, Wegener’s granulomatosis, 
Churg-Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease 
(thromboangiitis obliterans), necrotizing vasculitis and anti-neutrophil cytoplasmic 
antibody positive vasculitis (type unspecified), Henoch-Schönlein purpura, Behcet’s 
syndrome, and leukocytoclastic vasculitis 
Other:  
 Antiphospholipid syndrome 
 Autoimmune hemolytic anemia 
 Autoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis 
rapidly 
progressive, 
membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and mesangioproliferative glomerulonephritis) 
 Autoimmune myocarditis/cardiomyopathy 
 Autoimmune thrombocytopenia 
 Goodpasture syndrome 

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 Idiopathic pulmonary fibrosis 
 Pernicious anemia 
 Raynaud’s phenomenon 
 Sarcoidosis 
 Sjögren’s syndrome 
 Stevens-Johnson syndrome 
 Uveitis 
 
Abbreviations: AESI, adverse event of special interest; IgA, immunoglobulin A.  
Source: Tavares Da Silva et al 2013 
 

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6.3 
Appendix 3: Toxicity Grading Scale Tables 
The toxicity grading scales for clinical and laboratory abnormalities are presented in Table 6 and 
Table 7, respectively. Note that for laboratory abnormalities, grading only occurs if the values are 
outside of the normal values established by the clinical laboratory. For study-specific laboratory 
normal ranges and associated toxicity grades, refer to the laboratory manual. 

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Table 6: 
Tables for Clinical Abnormalities 
Local Reaction to Injectable 
Product 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Pain  
Does not 
interfere with 
activity 
Repeated use of 
non-narcotic pain 
reliever > 24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Tenderness  
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness * 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling ** 
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Abbreviation: ER = emergency room. 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded 
as a continuous variable.  
** Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
Source: Guidance for industry – Toxicity grading scale for heathy adult and adolescent volunteers enrolled in preventative 
vaccine clinical trials; Tables for clinical abnormalities (DHHS 2007). 
 

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Vital Signs * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Tachycardia (beats per minute) 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia (beats per 
minute)** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) 
(mm Hg) 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) 
(mm Hg) 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension (systolic) 
(mm Hg)  
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive 
shock 
Respiratory rate (breaths per 
minute) 
17 – 20 
21 – 25 
> 25 
Intubation 
Abbreviation: ER = emergency room. 
Note that fever is classified under systemic reactions for grading purposes. 
* 
Participant should be at rest for all vital sign measurements.  
** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgment when characterizing bradycardia 
among some healthy participant populations, for example, conditioned athletes. 
Source: Guidance for industry – Toxicity grading scale for heathy adult and adolescent volunteers enrolled in preventative 
vaccine clinical trials; Tables for clinical abnormalities (DHHS 2007). 
 

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Systemic (General) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4) 
Fever (°C) * 
(°F) * 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Nausea/vomiting  
No interference with 
activity or 1 to 
2 episodes/ 24 hours 
Some interference 
with activity or 
> 2 episodes/ 
24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea  
2 – 3 loose stools or 
< 400 g/ 24 hours 
4 – 5 stools or 400 – 
800 g/ 24 hours 
6 or more watery 
stools or > 800 g/ 
24 hours or 
requires outpatient 
IV hydration 
ER visit or 
hospitalization 
Headache  
No interference with 
activity 
Repeated use of non-
narcotic pain 
reliever > 24 hours 
or some interference 
with activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue/Malaise 
(unusual tiredness) 
No interference with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Generalized myalgia 
(muscle ache or pain) 
No interference with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Generalized arthralgia 
(joint ache or pain) 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
Abbreviations: ER = emergency room; IV = intravenous. 
* 
Oral temperature; no recent hot or cold beverages or smoking. 
Sources: Guidance for industry – Toxicity grading scale for heathy adult and adolescent volunteers enrolled in preventative 
vaccine clinical trials; Tables for clinical abnormalities (DHHS 2007). Division of AIDS Grading the Severity of Adult 
and Pediatric Adverse Events (DHHS 2014). 
 

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Table 7: 
Tables for Laboratory Abnormalities 
Serum Chemistry*  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially 
Life-threatening 
(Grade 4)** 
Sodium – hyponatremia (mEq/L) 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – hypernatremia (mEq/L) 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – hyperkalemia (mEq/L)  
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – hypokalemia (mEq/L) 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – hypoglycemia (mg/dL) 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – hyperglycemia  
Fasting (mg/dL) 
Random (mg/dL) 
100 - 110 
110 – 125 
111 - 125 
126 – 200 
>125 
> 200 
Insulin requirements or 
hyperosmolar coma 
Blood urea nitrogen (mg/dL)  
23 – 26 
27 – 31 
> 31 
Requires dialysis 
Creatinine (mg/dL) 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires dialysis 
Calcium – hypocalcemia (mg/dL)  
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – hypercalcemia (mg/dL) 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – hypomagnesemia 
(mg/dL) 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – hypophosphatemia 
(mg/dL) 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK (mg/dL) 
1.25 – 1.5X 
ULN 
1.6 – 3.0X 
ULN 
3.1 – 10X 
ULN 
> 10X ULN 
Albumin – hypoalbuminemia (g/dL) 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
– 
Total protein – hypoproteinemia 
(g/dL) 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
– 
Alkaline phosphate; increase by factor  
1.1 – 2.0 × 
ULN 
2.1 – 3.0 × 
ULN 
3.1 – 10 × 
ULN 
> 10 × ULN 
Liver function tests – ALT and AST; 
increase by factor  
1.1 – 2.5 x 
ULN 
2.6 – 5.0 × 
ULN 
5.1 – 10 × 
ULN 
> 10 × ULN 
Bilirubin – when accompanied by any 
increase in liver function test; increase 
by factor  
1.1 – 1.25 × 
ULN 
1.26 – 1.5 × 
ULN 
1.51 – 1.75 
× ULN 
> 1.75 × ULN 
Bilirubin – when liver function test is 
normal; increase by factor  
1.1 – 1.5 × 
ULN 
1.6 – 2.0 × 
ULN 
2.0 – 3.0 × 
ULN 
> 3.0 × ULN 
Cholesterol 
201 – 210 
211 – 225 
> 226 
- 
Pancreatic enzymes – amylase and 
lipase  
1.1 – 1.5 × 
ULN 
1.6 – 2.0 × 
ULN 
2.1 – 5.0 × 
ULN 
> 5.0 × ULN 

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Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of the normal range. 
* 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
** The clinical signs or symptoms associated with laboratory abnormalities might result in characterization of the 
laboratory abnormalities as potentially life threatening (Grade 4). For example, a low sodium value that falls within a 
Grade 3 parameter (125 – 129 mEq/L) should be recorded as a Grade 4 hyponatremia event if the participant had a new 
seizure associated with the low sodium value. 
Source: Guidance for industry – Toxicity grading scale for heathy adult and adolescent volunteers enrolled in preventative 
vaccine clinical trials; Tables for laboratory abnormalities (DHHS 2007). 
 

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Hematology * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Hemoglobin (female) (g/dL) 
11.0 – 12.0 
9.5 – 10.9 
8.0 – 9.4 
< 8.0 
Hemoglobin (female) change 
from baseline value (g/dL) 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
Hemoglobin (male) (g/dL) 
12.5 – 13.5 
10.5 – 12.4 
8.5 – 10.4 
< 8.5 
Hemoglobin (male) change 
from baseline value (g/dL) 
Any decrease – 
1.5 
1.6 – 2.0 
2.1 – 5.0 
> 5.0 
WBC increase (cell/mm3) 
10,800 – 15,000 
1,5001 – 20,000 
20,001 – 25,000 
> 25,000 
WBC decrease (cell/mm3) 
2,500 – 3,500 
1,500 – 2,499 
1,000 – 1,499 
< 1,000 
Lymphocytes decrease 
(cell/mm3) 
750 – 1,000 
500 – 749 
250 – 499 
< 250 
Neutrophils decrease 
(cell/mm3) 
1,500 – 2,000 
1,000 – 1,499 
500 – 999 
< 500 
Eosinophils (cell/mm3) 
650 – 1,500 
1,501 – 5,000 
> 5,000 
Hypereosinophilic 
Platelets decreased 
(cell/mm3) 
125,000 – 
140,000 
100,000 – 124,000 
25,000 – 99,000 
< 25,000 
PT; increase by factor  
1.0 – 1.10 × ULN 
1.11 – 1.20 × ULN 
1.21 – 1.25 × ULN 
> 1.25 × ULN 
PTT; increase by factor  
1.0 – 1.2 × ULN 
1.21 – 1.4 × ULN 
1.41 – 1.5 × ULN 
> 1.5 × ULN 
Fibrinogen increase (mg/dL) 
400 – 500 
501 – 600 
> 600 
- 
Fibrinogen decrease (mg/dL) 
150 – 200 
125 – 149 
100 – 124 
< 100 or associated 
with gross bleeding 
or disseminated 
intravascular 
coagulation (DIC) 
Abbreviations: PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal; WBC = white blood 
cell. 
* 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
Source: Guidance for industry – Toxicity grading scale for heathy adult and adolescent volunteers enrolled in preventative 
vaccine clinical trials; Tables for laboratory abnormalities (DHHS 2007). 
 

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Urine * 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Protein  
Trace 
1+ 
2+ 
Hospitalization or 
dialysis 
Glucose  
Trace 
1+ 
2+ 
Hospitalization for 
hyperglycemia 
Blood (microscopic) – red 
blood cells per high power 
field  
1 – 10 
11 – 50 
> 50 and/or gross 
blood 
Hospitalization or 
packed red blood 
cells transfusion 
* 
The laboratory values provided in the tables serve as guidelines and are dependent upon institutional normal parameters. 
Institutional normal reference ranges should be provided to demonstrate that they are appropriate. 
Source: Guidance for industry – Toxicity grading scale for heathy adult and adolescent volunteers enrolled in preventative 
vaccine clinical trials; Tables for laboratory abnormalities (DHHS 2007). 
 

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6.4 
Appendix 4: List of Hepatotoxic Drugs 
Cardiovascular  
 
Amiodarone 
 Atorvastatin 
 Hydralazine 
 Methyldopa 
 Quinidine 
 Simvastatin 
 Ticlopidine 
Antimicrobial 
 
Amoxicillin-clavulanate 
 Didanosine 
 Efavirenz 
 Erythromycin 
 Flucloxacillin 
 Interferon alpha/Peginterferon 
 Isoniazid 
 Ketoconazole 
 Minocycline 
 Nevirapine 
 Nitrofurantoin 
 Pyrazinamide 
 Rifampin 
 Sulfamethoxazole/Trimethoprim 
 Sulfasalazine 
 Sulfonamides 
 Telithromycin 

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Antineoplastic/Immunosuppressives 
 
Azathioprine/6-Mercaptopurine 
 Busulfan 
 Floxuridine 
 Flutamide 
 Gold salts 
 Infliximab 
 Interferon beta 
 Methotrexate 
 Propylthiouracil 
 Thioguanine 
Neurologic 
 
Carbamazepine 
 Chlorpromazine 
 Dantrolene 
 Disulfiram 
 Phenytoin 
 Valproate 
Nonsteroidal antiinflammatory 
 
Diclofenac 
 
Ibuprofen 
 Nimesulide 
 Sulindac 
Miscellaneous 
 
Allopurinol 
 Anabolic steroids 
 Contraceptives 
 Halothane 
Source: Björnsson 2016 

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7 
REFERENCE LIST 
Björnsson ES. Hepatotoxicity by drugs: the most common implicated agents. Int J Mol Sci. 
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Zika virus infection in pregnant women in Rio de Janeiro. N Engl J Med. 
2016;375(24):2321-34. 
Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Biologics Evaluation and Research (US). Guidance for industry: Toxicity grading scale 
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September 2007 [cited 2019 Apr 10] [10 screens]. Available from: 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
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Department of Health and Human Services (DHHS), National Institutes of Health, National 
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and microcephaly: why is this situation a PHEIC? Lancet. 2016;387(10020):719-21. 
Lazear HM, Diamond MS. Zika virus: new clinical syndromes and its emergence in the 
Western Hemisphere. J Virol. 2016;90(10):4864-75. 
Richner JM, Diamond MS. Zika virus vaccines: immune response, current status, and future 
challenges. Curr Opin Immunol. 2018;53:130-6. 
Tavares Da Silva F, De Keyser F, Lambert PH, Robinson WH, Westhovens R, Sindic C. 
Optimal approaches to data collection and analysis of potential immune mediated disorders 
in clinical trials of new vaccines. Vaccine. 2013;31(14):1870-6. 
Weaver SC, Costa F, Garcia-Blanco MA, Ko AI, Ribeiro GS, Saade G, et al. Zika virus: 
history, emergence, biology, and prospects for control. Antiviral Res. 2016;130:69-80. 

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Clinical Study Protocol Version 3.0 
 
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World Health Organization [Internet]. WHO and experts prioritize vaccines, diagnostics and 
innovative vector control tools for Zika R&D. 09 March 2016a [cited 2019 April 12]; 
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2019 April 12]. Available from: https://www.who.int/emergencies/diseases/zika/en/. 

Signature Page for VV-CLIN-000302 v4.0
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