Phase 2 Study of a Live Attenuated Measles Virus-Vectored Chikungunya Vaccine in Previously Exposed Adults
Phase: PHASE2
Conditions: Chikungunya Virus Infection
Sponsor: Themis Bioscience GmbH

Official Protocol Title: 
NCT number: 
NCT03807843  
Document Date: 
23-Dec-2020
Phase 2 Study of a Live Attenuated Measles Virus-Vectored 
Chikungunya Vaccine in Previously Exposed Adults

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2 Protocol Synopsis 
TITLE: Phase 2 Study of a Live Attenuated Measles Virus-Vectored Chikungunya Vaccine in 
Previously Exposed Adults 
DESIGN: This will be a prospective randomized double-blind interventional clinical study. This study 
proposes to evaluate the safety and immunogenicity of an investigational live recombinant measles-
vectored chikungunya vaccine (MV-CHIK) delivered in 2 vaccinations, 28 days apart compared with 
saline placebo. After providing informed consent, individuals will be screened for eligibility including 
verification of previous exposure to chikungunya virus.  They will then be randomized in a double-blind 
fashion to receive either MV-CHIK or saline placebo in a 1:1 ratio.  This study will be conducted in two 
Steps, first in up to 30 individuals ages 21 to 50.  Then, pending a favorable review of the available 
vaccine safety data, in up to 30 individuals ages 51 to 65. 
OBJECTIVES:  
Primary: To determine the safety of MV-CHIK administered in 2 doses separated by 28 days in 
previously exposed individuals. 
Secondary: To determine the immunogenicity by a neutralization assay of MV-CHIK administered in 2 
doses separated by 28 days in previously exposed individuals. 
ENDPOINTS: 
Primary: Incidence of solicited and unsolicited adverse events.  
Secondary: Immunogenicity on Days 0, 28, 56, and at the end of the study measured as geometric 
mean titer (GMT) of neutralizing antibodies to chikungunya. 
Exploratory: Changes in acute phase reactant levels after each vaccination: C-reactive Protein at 3 
days and fibrinogen at 7 days post-vaccination; changes from baseline in scores on a quality-of-life 
survey (SF36) at 28 days after each vaccination and at the end of the study. 
POPULATION: The study population is from an area with a high seroprevalence of antibodies to 
chikungunya (San Juan, Puerto Rico). Chikungunya exposure status will be confirmed prior to 
randomization. Subjects who are seronegative to chikungunya or are still under treatment for 
symptoms attributed to a previous chikungunya virus infection will be excluded from the study. 
Subjects who attribute only mild and subjective symptoms such as fatigue to previous chikungunya 
infection will not be excluded. Subjects with acute chikungunya infection will be excluded but may be 
re-screened no sooner than 3 months after resolution of their symptoms.  The study will be conducted 
in two Steps, initially limited to those between ages 21-50.  Following a favorable review of available 
data on vaccine safety, individuals ages 51 to 65 will be enrolled. 
PHASE OF DEVELOPMENT: Phase 2. 
INTERVENTION(S): 
MV-CHIK is a recombinant live Schwarz-strain measles-vectored vaccine expressing chikungunya 
virus surface proteins. It is manufactured as a clear colorless to off-white opaque liquid without 
excipients in a single-use glass vial and must be stored at or below -65⁰C. The target dose is 5×105 
TCID50 per 0.4mL dose with a manufacture dependent window of ±0.5 log (1×105 to 1×106) and is 
delivered intramuscularly. 
Placebo: Intramuscular saline, 0.4mL, will be used as the placebo.   
Subjects will be randomized to these interventions in a 1:1 fashion. 
STUDY PERIOD: The study will be conducted in two Steps.  Step 1 will enroll up to 30 subjects ages 
21 to 50.  It is estimated that enrollment will take 6 months and the last subject in Step 1 will complete 
the study 13 months after study start.  Step 2 will begin after a favorable review of the safety data by a 
Data Safety Monitoring Board (DSMB).  The DSMB will convene after at least 20 volunteers in Step 1 
have been vaccinated.  Step 2 will enroll up to 30 subjects ages 51 to 65.  It is estimated that 
enrollment of this group will also take approximately 6 months.  The total duration of the study, from 
initial screening for Step 1, through DSMB review to final visit of the last subject in Step 2 is estimated 
to take a minimum of 24 months. 
 
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DURATION: The duration of participation for individual subjects from initial screening through the End-
of-Study visit is about 9 months.                                            
EVALUATIONS: 
Safety Variables: Solicited and unsolicited adverse events (AEs), serious adverse events (SAEs), and 
adverse events of special interest (AESIs). 
Immunogenicity Variable: Neutralization titers (chikungunya). 
Exploratory Variables: post- versus pre-vaccination C-reactive protein, fibrinogen, SF36 score. 
 
 
 
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3 Table of Contents 
 
1 
Signatures ................................................................................................................ 2 
2 
Protocol Synopsis .................................................................................................... 3 
3 
Table of Contents ..................................................................................................... 5 
4 
List of Tables and Figures ...................................................................................... 11 
4.1 
List of Tables .................................................................................................... 11 
4.2 
List of Figures ................................................................................................... 11 
5 
Definitions of Acronyms and Terms ....................................................................... 11 
5.1 
Definition of Acronyms ..................................................................................... 11 
5.2 
Definition of Terms ........................................................................................... 13 
6 
Ethics ..................................................................................................................... 14 
6.1 
Protocol Review Committees ........................................................................... 14 
6.1.1 
Institutional Review Board ......................................................................... 14 
6.1.2 
Human Research Protection Office ........................................................... 14 
6.2 
Informed Consent ............................................................................................. 15 
7 
Roles and Responsibilities ..................................................................................... 15 
7.1 
Sponsor ............................................................................................................ 15 
7.2 
Project Oversight Agency ................................................................................. 15 
7.2.1 
Protocol Chair ............................................................................................ 16 
7.2.2 
Sponsor Medical Expert (SME) ................................................................. 16 
7.2.3 
Compliance Management Unit .................................................................. 16 
7.3 
Clinical Trial Site .............................................................................................. 16 
7.4 
Clinical Research Organization ........................................................................ 16 
7.5 
Data Management and Statistical Analysis ...................................................... 17 
7.6 
Institutional Review Board of Record ............................................................... 17 
7.7 
Human Research Protection Office (HRPO) .................................................... 17 
7.8 
DoD Research Monitor ..................................................................................... 17 
7.9 
Aggregate Safety Reporting ............................................................................. 18 
7.10 
Clinical Laboratory ........................................................................................ 18 
7.11 
Screening Immunogenicity Laboratory .......................................................... 18 
7.12 
Endpoint Immunogenicity Laboratory ............................................................ 18 
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8 
Introduction ............................................................................................................ 19 
8.1 
Disease Review ............................................................................................... 19 
8.1.1 
Epidemiology and Transmission ................................................................ 19 
8.1.2 
Acute Chikungunya ................................................................................... 19 
8.1.3 
Chronic Chikungunya ................................................................................ 20 
8.2 
Investigational Vaccine .................................................................................... 21 
8.3 
Pre-Clinical Studies .......................................................................................... 22 
8.3.1 
Immunogenicity Studies............................................................................. 22 
8.3.2 
Toxicity Studies ......................................................................................... 22 
8.4 
Clinical Studies ................................................................................................. 23 
8.4.1 
Study MV-CHIK-101 .................................................................................. 23 
8.4.2 
Study MV-CHIK 202 .................................................................................. 24 
8.4.3 
Study DMID 15-0038 ................................................................................. 25 
8.4.4 
Study MV-CHIK 205 .................................................................................. 25 
8.4.5 
Study MV-CHIK 204 .................................................................................. 26 
8.5 
Military Relevance ............................................................................................ 28 
8.6 
Potential Benefits ............................................................................................. 28 
8.7 
Potential Risks ................................................................................................. 29 
8.7.1 
General ...................................................................................................... 29 
8.7.2 
MV-CHIK specific ...................................................................................... 29 
8.8 
Clinical Study Rationale ................................................................................... 29 
9 
Investigational Plan ................................................................................................ 31 
9.1 
Overall Study Design ....................................................................................... 31 
9.2 
Study Objectives and Endpoints ...................................................................... 32 
9.2.1 
Primary Objective ...................................................................................... 32 
9.2.2 
Secondary objectives ................................................................................ 33 
9.2.3 
Exploratory Objectives ............................................................................... 33 
9.3 
Study Population .............................................................................................. 33 
9.3.1 
Inclusion Criteria ........................................................................................ 34 
9.3.2 
Exclusion Criteria ....................................................................................... 34 
9.3.3 
Randomization ........................................................................................... 36 
9.3.4 
Blinding ...................................................................................................... 36 
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9.4 
Withdrawal of Subjects ..................................................................................... 37 
9.4.1 
Criteria for Subject Withdrawal from the Study .......................................... 37 
9.4.2 
Criteria for Discontinuing Individual Subjects from Further Vaccination .... 37 
9.4.3 
Evaluations at Withdrawal ......................................................................... 38 
9.4.4 
Replacement of Subjects ........................................................................... 38 
9.5 
Premature Termination or Suspension of the Study ......................................... 38 
9.5.1 
Study Stopping Criteria .............................................................................. 39 
9.5.2 
Interim Management of the Study Due to SARS-CoV-2 ............................ 39 
10 
Study Intervention ............................................................................................... 39 
10.1 
MV-CHIK ....................................................................................................... 39 
10.2 
Placebo ......................................................................................................... 40 
10.3 
Handling of the Investigational Vaccine Products ......................................... 41 
10.3.1 
Labelling ................................................................................................. 41 
10.3.2 
On-site storage ....................................................................................... 41 
11 
Study Events by Visit ........................................................................................... 42 
11.1 
Screening Visit S: Day -60 to -3 .................................................................... 45 
11.2 
Randomization Visit 1: Day 0 ........................................................................ 45 
11.3 
Visit 2: Day 3 (-1,+2 days) ............................................................................. 46 
11.4 
Visit 3: Day 7 (+5 days) ................................................................................. 46 
11.5 
Visit 4: Day 28 (-3,+7 days) ........................................................................... 47 
11.6 
Visit 5: Day 31 (3 [-1,+2] days post dose 2) .................................................. 48 
11.7 
Visit 6: Day 35 (7 [+5] days post dose 2) ...................................................... 48 
11.8 
Visit 7: Day 56 (±7 days) ............................................................................... 49 
11.9 
Visit 8: Day 84 (± 7 days) .............................................................................. 49 
11.10 
Visit 9: Day 140 (± 14 days) .......................................................................... 49 
11.11 
Visit 10: Day 196 (± 14 days) EOS visit ........................................................ 50 
11.12 
Early Termination Visit .................................................................................. 50 
11.13 
Study Visits During SARS-CoV-2 Pandemic ................................................. 51 
12 
Methods of Assessment ...................................................................................... 52 
12.1 
Vital Signs ..................................................................................................... 52 
12.2 
Physical Examination .................................................................................... 52 
12.3 
Medical History ............................................................................................. 53 
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12.3.1 
Subject Diaries ....................................................................................... 53 
12.3.2 
Medication History .................................................................................. 54 
12.4 
Quality-of-Life Surveys .................................................................................. 54 
12.5 
Routine Laboratory Tests of Vaccine Safety ................................................. 54 
12.6 
Samples for Future Research ....................................................................... 55 
12.6.1 
Serological Tests .................................................................................... 56 
12.6.2 
Acute phase reactants ............................................................................ 57 
13 
Adverse Event Reporting ..................................................................................... 58 
13.1 
Severity Assessment .................................................................................... 59 
13.2 
Causality Assessment ................................................................................... 59 
13.3 
Serious Adverse Events ................................................................................ 60 
13.3.1 
Definition of a Serious Adverse Event .................................................... 60 
13.3.2 
Reporting of Serious Adverse Events ..................................................... 60 
13.4 
Assessment of Subjects with Adverse Events .............................................. 62 
13.4.1 
Adverse events reported by history ........................................................ 62 
13.4.2 
Abnormal laboratory test results ............................................................. 62 
13.4.3 
Abnormal physical exam findings ........................................................... 63 
13.5 
Adverse Events of Special Interest ............................................................... 63 
13.5.1 
Definition ................................................................................................ 63 
13.5.2 
AESI Reporting ....................................................................................... 63 
13.6 
Aggregate Safety Monitoring ........................................................................ 63 
14 
Statistical Analysis ............................................................................................... 64 
14.1 
Database Management ................................................................................. 64 
14.2 
Sample Size Estimate ................................................................................... 64 
14.3 
Statistical Analysis Plan ................................................................................ 65 
14.4 
Analysis Populations ..................................................................................... 65 
14.4.1 
Intent-to-treat Population ........................................................................ 65 
14.4.2 
Per Protocol Population .......................................................................... 65 
14.5 
Statistical Methods ........................................................................................ 65 
14.5.1 
Missing Data........................................................................................... 66 
14.5.2 
Demographic and Baseline Clinical Data ............................................... 66 
14.5.3 
Subject Disposition ................................................................................. 66 
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14.5.4 
Vaccine Exposure .................................................................................. 66 
14.5.5 
Concomitant Medications ....................................................................... 66 
14.5.6 
Adverse Events ...................................................................................... 67 
14.5.7 
Safety Laboratory Tests including Acute Phase Reactants .................... 67 
14.5.8 
Vital signs and physical exam findings ................................................... 67 
14.5.9 
Immunogenicity ...................................................................................... 68 
15 
Study Monitoring Procedures .............................................................................. 68 
15.1 
DoD Research Monitor ................................................................................. 68 
15.2 
Sponsor Medical Expert ................................................................................ 69 
15.3 
Study Monitors .............................................................................................. 69 
15.3.1 
Blinded Study Monitor ............................................................................ 69 
15.3.2 
Unblinded Study Monitor ........................................................................ 70 
15.4 
Sponsor and Government Audits .................................................................. 70 
15.5 
Investigative Site Responsibilities ................................................................. 70 
15.6 
Data Safety Monitoring Board ....................................................................... 71 
16 
Data Management ............................................................................................... 71 
16.1 
Electronic Case Report Forms ...................................................................... 71 
16.2 
Data Collection.............................................................................................. 72 
16.3 
Clinical Database Management .................................................................... 72 
16.4 
Source Document Maintenance .................................................................... 73 
16.5 
Record Maintenance ..................................................................................... 73 
16.6 
Confidentiality ............................................................................................... 74 
17 
Administrative Procedures ................................................................................... 75 
17.1 
Regulatory Approval ..................................................................................... 75 
17.2 
Protocol Adherence ...................................................................................... 75 
17.3 
Protocol Amendments ................................................................................... 76 
17.4 
Specific Requirements of the Human Research Protection Office ................ 77 
17.4.1 
Unanticipated Problems Involving Risks to Self or Others ..................... 77 
17.4.2 
Subject Withdrawal of Consent Due to an Adverse Event ...................... 77 
17.4.3 
Protocol Modifications ............................................................................ 78 
17.4.4 
Change of IRB ........................................................................................ 78 
17.4.5 
Suspension or Termination of Research ................................................ 78 
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17.4.6 
Continuing IRB Review .......................................................................... 78 
17.4.7 
Pending Inspection ................................................................................. 78 
17.4.8 
Final Study Report .................................................................................. 79 
17.5 
Investigative Site File Management .............................................................. 79 
17.6 
Contract Requirements ................................................................................. 79 
17.7 
Insurance, Indemnity and Compensation ...................................................... 80 
17.8 
Clinical Study Report .................................................................................... 80 
17.9 
Publication Policy .......................................................................................... 80 
18 
References .......................................................................................................... 81 
19 
Appendices .......................................................................................................... 88 
19.1 
Appendix 1: Adverse Event grading scales ................................................... 88 
19.1.1 
Appendix Table A: Local Reaction to Injection ....................................... 89 
19.1.2 
Appendix Table B: Solicited Systemic Adverse Events .......................... 90 
19.1.3 
Appendix Table C: Unsolicited Adverse Events ..................................... 91 
19.1.4 
Appendix Table D: Vital Signs ................................................................ 92 
19.1.5 
Appendix Table E: Laboratory Results ................................................... 93 
19.2 
Appendix 2: SF-36 Quality of Life Survey ..................................................... 94 
19.2.1 
SF-36 Quality of Life Survey in English .................................................. 95 
19.2.2 
SF-36 Quality of Life Survey in Spanish ............................................... 105 
19.2.3 
Terms and Conditions for Using the SF-36 .......................................... 115 
 
 
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4 List of Tables and Figures 
 
4.1 List of Tables 
• Table 1: Treatment Assignments 
• Table 2: Schedule of Events 
 
4.2 List of Figures 
• Figure 1: Quality-of-Life survey results from French soldiers stationed on La 
Reunion during the 2006 epidemic 2.5 years later. 
• Figure 2: Study schematic. 
 
5 Definitions of Acronyms and Terms 
5.1 Definition of Acronyms 
acronym 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
Assign-DMB 
Assign Data Management and Biostatistics GmbH 
BMP 
Basic metabolic panel 
CBC 
Complete blood count 
CBER 
Center for Biologics Evaluation and Research of the FDA 
CD46 
Cluster of Differentiation-46, a cell surface molecule that confers 
susceptibility to measles virus infection 
CDC 
US Centers for Disease Control and Prevention 
CDMS 
Clinical Data Management System 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CMP 
Complete metabolic panel 
COVID 19 
Corona Virus Disease 2019 
CRA 
Clinical Research Associate (study monitor) 
CRF/eCRF 
Case report form/electronic case report form 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
DMID 
Division of Microbiology and Infectious Disease, conducts and 
supports extramural research for the NIAID 
DoD 
Department of Defense 
DoDI 
Department of Defense Instruction 
DSMB 
Data Safety Monitoring Board 
eCRF/CRF 
Electronic Case report form/case report form 
EDC 
Electronic Data Capture 
EIA 
Immunoassay 
ELISA 
Enzyme-linked immunosorbent assay 
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EOS 
End-of-study 
eTMF 
Electronic Trial Master File 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GmbH 
Gesellschaft mit beschränkter Haftung (German for Limited Liability 
Company) 
GMP 
Good Manufacturing Practice 
GMT 
Geometric Mean Titer 
HBsAg 
Hepatitis B Surface Antigen, a test for chronic Hepatitis B infection 
HCV 
Hepatitis C Virus 
HEENT 
Head, eyes, ears, nose and throat 
HHS 
US Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (of the MRMC) 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ID 
Identification 
IFA 
Immunofluorescence assay 
IgG 
Immunoglobulin class G 
IM 
Intramuscular 
IND 
Investigational New Drug application 
IFNAR 
Interferon-alpha receptor knock-out (a strain of mice that is 
susceptible to chikungunya infection) 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IVP 
Investigational vaccine product (used to indicate either MV-CHIK or 
placebo) 
IWRS 
Interactive web-based response system 
LLC 
Limited liability company 
MCAR 
Missing Completely at Random 
MD 
Doctor of Medicine 
mL 
milliliters 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
Measles, Mumps and Rubella vaccine 
MRMC 
US Army Medical Research and Materiel Command 
MV-1 F4 
An experimental measles-vectored vaccine for HIV infection 
MV-CHIK 
Measles-vectored chikungunya vaccine 
NC 
North Carolina 
NIAID 
US National Institute of Allergy and Infectious Disease 
NIH 
US National Institutes of Health 
NLM 
National Library of Medicine 
OHRP 
Office of Human Research Protections (of HHS) 
ORP 
Office of Research Protections (of the MRMC) 
PAHO 
Pan-American Health Organization 
PI 
Principal Investigator 
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PP 
Per-protocol 
PRNT, 
PRNT50 
Plaque-reduction neutralizing antibody test; the subscript refers to the 
percent of plaques reduced in order to conclude neutralization has 
occurred 
QoL 
Quality-of-life 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SF36 
Standardized quality-of-life questionnaire 
SL 
Sociedad Limitada (Spanish for Limited Liability Company) 
SME 
Sponsor Medical Expert 
SOC 
System-organ-class 
SOP 
Standard Operating Procedure 
SSP 
Study Specific Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBD 
To be determined 
TCID, TCID50 
Tissue culture infective dose; the subscript refers to the percent of 
cells in culture that are infected after inoculation. 
UPIRTSO 
Unanticipated Problem Involving Risk to Self or Others 
US, USA 
United States of America 
VLP 
Virus-like particles 
WHO 
World Health Organization 
WHODrug  
An international classification of medicines 
WRAIR 
The Walter Reed Army Institute of Research 
 
 
5.2 Definition of Terms 
Term 
Definition 
Adequate 
Contraception 
A contraceptive method with a failure rate of less than 1% per 
year when used consistently and correctly (when applicable, as 
mentioned in the product label).  This includes but is not limited to 
abstinence, combined or progestogen oral contraceptives, 
injectable progestogen, implants of levonorgestrel, estrogenic 
vaginal ring, percutaneous contraceptive patches or intrauterine 
device or intrauterine system, vasectomy with documented 
azoospermia of the sole male partner or male condom combined 
with a vaginal spermicide (foam, gel, film, cream or suppository) 
or male condom combined with a female diaphragm, either with 
or without a vaginal spermicide (foam, gel, film, cream, or 
suppository). 
Documented 
Azoospermia 
Documented azoospermia refers to the outcome of the 
investigator’s/designee’s medical examination of the subject or 
review of the subject’s medical history for study eligibility, as 
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obtained via a verbal interview with the subject or from the 
subject’s medical records.  
Childbearing 
potential 
All female subjects are considered to be of childbearing potential 
unless postmenopausal or surgically sterile and at least 3 months 
have passed since the sterilization procedure. 
Postmenopausal 
amenorrhea 
Amenorrhea for ≥12 months without an alternative medical cause. 
Permanent female sterilization procedures include tubal ligation, 
bilateral salpingectomy, hysterectomy, bilateral oophorectomy, or 
successful Essure placement. 
6 Ethics 
This study will be conducted in accordance with the Guidance for Industry on Good 
Clinical Practice (ICH Harmonised Tripartite Guideline E6 (R2); FDA CFR (21 CFR Part 
50, 56, 312), and all applicable regulatory requirements. 
 
6.1 Protocol Review Committees 
This study will be conducted in compliance with Institutional Review Board (IRB) and ICH 
GCP Guidelines - including Title 21 Part 56 of the US Code of Federal Regulations (CFR) 
relating to IRBs and GCP as described in the United States Food and Drug Administration 
(FDA) CFR (21 CFR Part 50, 56, 312) - in accordance with applicable ICH regulations 
regarding clinical safety data management (E2A, E2B(R3)), and with ICH regulations 
regarding scientific integrity (E4, E8, E9, and E10). In addition, this study will adhere to 
all local regulatory requirements and requirements for data protection. 
 
6.1.1 Institutional Review Board 
Before initiating this trial, the Investigator must have written and dated approval from the 
IRB for the study protocol, informed consent form, any consent form updates, subject 
recruitment materials (e.g., advertisements), and any written information to be provided 
to subjects. This approval should include a statement from the IRB that these documents 
pass both ethical and scientific review and comply with GCP requirements.  The approval 
letter must identify the documents and versions reviewed. 
 
6.1.2 Human Research Protection Office 
All United States Army Medical Research and Materiel Command (MRMC)-supported 
research involving humans, human data, human specimens, or cadavers must be 
reviewed for compliance with federal and Department of Defense (DoD) human subjects’ 
protection requirements and approved by the Office of Research Protections (ORP) 
Human Research Protection Office (HRPO) prior to initiation. The Project Oversight 
Agency is responsible for HRPO submissions and must ensure that documentation is 
complete and approvals received before trial initiation. See Section 17.4 for additional 
HRPO requirements. 
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6. 2  I nf or m e d C o n s e nt 
T h e I n v e sti g at or or d e si g n e e will e x pl ai n t h e b e n efit s a n d ri s k s of p arti ci p ati o n i n t h e st u d y 
t o e a c h s u bj e ct a n d o bt ai n writt e n i nf or m e d c o n s e nt. Writt e n i nf or m e d c o n s e nt m u st b e 
o bt ai n e d  b ef or e  i niti ati o n  of  a n y  st u d y -r el at e d  pr o c e d ur es (t o  i n cl u d e  s cr e e ni n g  a n d  
a d mi ni str ati o n of t h e i n v e sti g ati o n al v a c ci n e pr o d u ct  (I V P)).  
 
T h e i nf or m e d c o n s e nt f or m (I C F; fi n al, v er si o n d at e d) m u st b e a p pr o v e d b y t h e S p o n s or 
a n d t h e I R B a n d will c o nt ai n all el e m e nt s r e q uir e d b y r e g ul at or y a ut h o riti e s a n d G C P i n 
l a n g u a g e r e a dil y u n d er st o o d b y t h e s u bj e ct. E a c h s u bj e ct’ s ori gi n al c o n s e nt f or m, w hi c h 
will b e p er s o n all y si g n e d a n d d at e d b y t h e s u bj e ct a n d b y t h e p er s o n w h o c o n d u ct e d t h e 
i nf or m e d c o n s e nt di s c u s si o n, will b e r et ai n e d b y t h e I n v e sti g at or. T h e I n v e sti g at or will 
s u p pl y all e nr oll e d s u bj e ct s wit h a c o p y of t h eir si g n e d I C F.  
 
T h e  I C F  m a y n e e d t o b e r e vi s e d d uri n g  t h e  st u d y  s h o ul d i m p ort a nt  n e w  i nf or m ati o n 
b e c o m e a v ail a bl e t h at m a y b e r el e v a nt t o t h e s af et y of t h e s u bj e ct s. I n t hi s i n st a n c e,  
a p pr o v al  f or  t h e  r e vi si o n s  m u st  b e  gi v e n  b y  t h e  I R B  a n d  e xi sti n g  s u bj e ct s  m u st  b e  
i nf or m e d of t h e c h a n g e s a n d r e-c o n s e nt e d. T hi s i s d o c u m e nt e d i n t h e s a m e w a y a s 
pr e vi o u sl y d e s cri b e d.  I n t h e e v e nt s af et y i nf or m ati o n b e c o m e s a v ail a bl e aft er a s u bj e ct 
h a s  c o m pl et e d t h e  st u d y,  a n  i nf or m ati o n al  l ett er  will  b e  s e nt  vi a  c ertifi e d  m ail  t o  t h e 
s u bj e ct.   
 
7  R ol e s a n d R e s p o n si biliti e s 
 
7. 1  S p o n s or  
T h e mi s Bi o s ci e n c e G m b H  
Cli ni c al Pr oj e ct M a n a g er : 
 
M ut h g a s s e 1 1/ 2  
1 1 9 0 Vi e n n a  
A u stri a  
T el:  
 
E m ail: 
 
R ol e : V a c ci n e d e v el o p m e nt a n d m a n uf a ct uri n g, f ulfill m e nt of S p o n s or r e s p o n si biliti e s a s 
d e s cri b e d i n 2 1 C F R 3 1 2. 5 0, i nt er a cti o n wit h t h e F D A t hr o u g h t h eir A g e nt, cli ni c al tri al s 
r e gi str y p o sti n g a n d m aint e n a n c e , c o ntr a cti n g f or a n d f u n di n g p erf or m a n c e of 
c hi k u n g u n y a n e utr ali z ati o n a s s a y s, s el e cti o n a n d r ei m b ur s e m e nt of  s u bj e ct m att er 
e x p ert s f or t h e D at a S af et y M o nit ori n g B o ar d . 
 
7. 2  Pr oj e ct O v er si g ht A g e n c y  
W alt er R e e d Ar m y I n stit ut e of R e s e ar c h - Vir al Di s e a s e s Br a n c h  
5 0 3 R o b ert Gr a nt A v e n u e  
0 7 Z V H H
P P D
P P D
P P D
0 8 0 H 0 0

St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 1 6  of 1 1 6  
 
 
Sil v er S pri n g, M ar yl a n d  2 0 9 1 0  
U S A  
 
7. 2. 1  Pr ot o c ol C h air  
 
T el: 
 
E m ail: 
 
R ol e : S er v e a s t h e c e ntr al p oi nt of c o nt a ct f or s ci e ntifi c a n d pr ot o c ol q u e sti o n s fr o m t h e 
I n v e sti g at or( s) a n d sit e; r e vi e w m o nit ori n g r e p ort s a n d pr ot o c ol d e vi ati o n s ; i nt er a ct o n 
b e h alf of t h e st u d y t e a m wit h H R P O . 
 
7. 2. 2  S p o n s or M e di c al E x p ert ( S M E)  
  
T el: 
  
E m ail: 
  
R ol e: S er v e a s t h e c e ntr al p oi nt of c o nt a ct f or m e di c al q u e sti o n s fr o m t h e I n v e sti g at or( s) 
a n d sit e; r e vi e w d e -i d e ntifi e d ( c o d e d) r e p ort s of A E s a n d S A E s; dr aft n arr ati v e s of 
a d v er s e r e a cti o n s  t h at r e q uire e x p e dit e d r e p orti n g t o F D A  f or r e vi e w a n d s u b mi s si o n b y 
t h e S p o n s or. S e e S e cti o n 1 5. 2 . 
 
7. 2. 3  C o m pli a n c e M a n a g e m e nt U nit  
Dir e ct or: 
 
T el: 
   
E m a il: 
 
R ol e : A s s e m bl y of kit s a n d l a b el s f or c oll e cti o n a n d pr o c e s si n g of bl o o d f or r e s e ar c h 
p ur p o s e s ; st or a g e a n d r etri e v al of s er a at W R AI R  f or f ut ur e u s e. 
 
7. 3  Cli ni c al Tri al Sit e  
S a n J u a n H o s pit al R e s e ar c h U nit  
3r d Fl o or R o o m F P -0 4  
S a n J u a n, P R 0 0 9 3 5  
T el: 
 
F a x: 
 
C ell p h o n e: 
 
 
7. 4  Cli ni c al R e s e ar c h Or g a ni z ati o n  
I nt e gr u m S ci e ntifi c, L L C 
Pr oj e ct M a n a g er: 
 
3 0 2 G alli m or e D air y R o a d  
Gr e e n s b or o, N ort h C ar oli n a  2 7 4 0 9  
U S A  
T el:  
 
0 7 Z V H H
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
0 8 0 H 0 0

St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 1 7  of 1 1 6  
 
 
E m ail:  
  
R ol e : St u d y M o nit ori n g, Cli ni c al Tri al M a n a g e m e nt, S eri o u s A d v er s e E v e nt R e p orti n g. 
 
7. 5  D at a M a n a g e m e nt a n d St ati sti c al A n al y si s  
D F/ N et R e s e ar c h, I n c.  
D at a M a n a g er: 
 
St ati sti c al Pr o gr a m m er :
 
1 4 0 L a k e si d e A v e n u e, S uit e 3 1 0  
S e attl e, W a s hi n gt o n  9 8 1 2 2  
U S A  
T el:
 
E m ail:
  
R ol e : D at a b a s e d e v el o p m e nt a n d m ai nt e n a n ce, S t ati sti c al A n al y si s, I nt eri m ( D S M B) 
a n d Fi n al D at a E x p ort s .  T hi s d at a b a s e will n ot c o nt ai n a n y p er s o n all y i d e ntif yi n g 
i nf or m ati o n. S e e S e cti o n 1 6. 3 . 
 
7. 6  I n stit uti o n al R e vi e w B o ar d of R e c or d 
S a n J u a n H o s pit al I n stit uti o n al R e vi e w B o ar d  
C e ntr o M e di c o, B o. M o n a cill o s, 2 n d  fl o or a n n e x 
Ri o Pi e dr a s, P u ert o R i c o 0 0 9 3 6  
U S A  
T el: 
 
R ol e : s ci e ntifi c a n d et hi c al r e vi e w. 
 
7. 7  H u m a n R e s e ar c h Pr ot e cti o n Offi c e ( H R P O)  
Offi c e of R e s e ar c h Pr ot e cti o n s  
U S Ar m y M e di c al R e s e ar c h a n d M at eri el C o m m a n d  
H u m a n S u bj e ct s Pr ot e cti o n S ci e nti st: 
 
1 1 0 1 W o ott o n P ar k w a y, S uit e 2 0 0  
R o c k vill e, M ar yl a n d 2 0 8 5 2  
U S A  
T el: 
 
E m ail: 
 
R ol e : H u m a n s u bj e ct’ s pr ot e cti o n r e vi e w a n d a p pr o v al; e n s uri n g a d h er e n c e t o et hi c al 
st a n d ar d s i n D o D -s u p p ort e d r e s e ar c h ; s e e S e cti o n 1 7. 4 . 
 
7. 8  D o D R e s e ar c h M o nit or  
 
C A P T,  U S N a v y 
N a v y M e di c al R e s e ar c h C o m m a n d  
5 0 3 R o b ert Gr a nt A v e n u e , R o o m 3 E1 9  
Sil v er S pri n g, M ar yl a n d 2 0 9 1 0  
0 7 Z V H H
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
0 8 0 H 0 0

St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 1 8  of 1 1 6  
 
 
U S A  
T el: 
 
E m ail:
 
R ol e : I n d e p e n d e nt a d v o c a c y f or s u bj e ct s af et y; m e m b er of t h e D S M B; s e e S e cti o n 1 5. 1 . 
 
7. 9  A g gr e g at e  S af et y R e p orti n g  
A s si g n D at a M a n a g e m e nt a n d Bi o st ati sti c s G m b H  ( A s si g n-D M B)  
St a dl w e g 2 3  
6 0 2 0 I n n s br u c k  
A u stri a  
T el: 
 
E m ail: 
 
R ol e: H ol d er of gl o b al M V -C HI K s af et y d at a b a s e ; e x p e dit e d a n d p eri o di c r e p orti n g t o 
r e g ul at or y a ut h oriti e s of a g gr e g at e s af et y  d at a  fr o m all cli ni c al tri al s wit h M V -C HI K . 
 
7. 1 0  Cli ni c al L a b or at or y   
S a n J u a n H o s pit al L a b or at or y  ( a n d ot h er l a b s c o ntr a ct e d or s u b c o ntr a ct e d a s 
n e c e s s ar y)  
C e ntr o M e di c o, B o. M o n a cill o s, 3r d fl o or a n n e x  
Ri o Pi e dr a s, P u ert o Ri c o  0 0 9 3 6  
U S A  
T el:  
 
R ol e: S af et y a n d s cr e e ni n g l a b or at or y t e sti n g  
 
7. 1 1  S cr e e ni n g I m m u n o g e ni cit y L a b or at or y  
I m m u n o R ef er e n c e L a b 
A v e. M u n o z Ri v er a # 5 6 2  
H at o R e y, P u ert o Ri c o 0 0 9 1 8  
U S A  
T el: 
 
F a x: 
 
R ol e: S cr e e ni n g i m m u n o g e ni cit y t e sti n g  
 
7. 1 2  En d p oi nt I m m u n o g e ni cit y L a b or at or y 
N e x eli s  
 
 
T o w n/ Cit y: 5 2 5 b o ul v . C arti er O u e st L a v al, Q C 
P o st c o d e : H 7 V 3 S 8  
C o u ntr y : C a n a d a  
T el e p h o n e n u m b er: 
 
R ol e : Pri m ar y e n d p oi nt i m m u n o g e ni cit y t e sti n g. 
0 7 Z V H H
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
0 8 0 H 0 0

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8 Introduction 
 
8.1 Disease Review 
 
8.1.1 Epidemiology and Transmission 
Chikungunya virus, a mosquito-borne pathogen that causes chikungunya fever, has re-
emerged since 2004, spreading through tropical areas worldwide [Silva, 2018].  Limited 
outbreaks have been reported in parts of Europe (Italy in 2007 and 2017; France in 2010, 
2014 and 2017) and the continental United States (Florida in 2014, Texas in 2015). Puerto 
Rico experienced a dramatic outbreak in 2014 with over 35,000 cases reported. Incidence 
then dropped off significantly with fewer than 10 confirmed cases in 2017 [Pan American 
Health Organization (PAHO) Website].  Herd immunity likely contributes to the current 
low incidence of disease [Staples 2009].  The seroprevalence of chikungunya in San Juan 
is approximately 23.5% [Simmons 2016].   
 
Chikungunya virus is transmitted to humans by the mosquitoes Aedes aegypti and Aedes 
albopictus, which are common in urban tropical areas worldwide [Vazeille 2007].  Sylvatic 
cycles involving other Aedes species and non-human primates have also been described 
[Silva 2018].  Vertical transmission may occur when mothers are viremic at the time of 
delivery and the resulting neonatal infection is typically severe and often fatal [Gerardin 
2008].  While viral RNA has been detected in breast milk and semen, human-to-human 
transmission by these routes has not yet been described [Silva 2018]. 
 
8.1.2 Acute Chikungunya 
The French Infectious Disease Society distinguishes three successive stages of 
chikungunya infection: acute, post-acute, and chronic [Simon 2015].  It appears that the 
majority of individuals who are infected with chikungunya virus develop symptomatic 
disease, though this may vary with location, possibly virus strain, and study methodology 
[Silva 2018].  A household contact study in Puerto Rico showed that while the majority of 
individuals who become infected report a compatible clinical syndrome, most do not seek 
healthcare [Sharp 2014].  Therefore it should be assumed that the number of reported 
cases underestimates the actual number significantly. 
 
Symptomatic disease that presents to healthcare providers generally occurs after an 
incubation period of 2 to 6 days and is characterized by the acute onset of fever and joint 
pain, lasting from several days to a week.  Joint symptoms usually involve multiple joints 
in a symmetric distribution.  Most commonly involved are wrists, elbows, fingers, knees, 
and ankles but also more proximal joints. Lower extremity joint pains can be particularly 
disabling, resulting in the inability to work or perform activities of daily living. Other 
common signs and symptoms commonly seen include rash, headache, diffuse back pain, 
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muscle aches, nausea, vomiting, and conjunctivitis [Weaver 2015]. Atypical presentations 
include hepatitis, Guillain-Barré syndrome, myocarditis, retinitis and nephritis [Rajapakse 
2010].   
 
Increases in all-cause mortality have been described in the wakes of several chikungunya 
epidemics [Brito 2017][Freitas 2018a].  In Puerto Rico the excess mortality was mostly 
attributed to chronic ischemic heart disease and diabetes mellitus [Freitas 2018b]. 
Therefore there is likely significant underestimation in both the number of clinical cases 
and the number of deaths due to chikungunya infection.  The overall case fatality ratio 
(CFR) of acute chikungunya is likely about 1:1000 (0.1%), with most deaths occurring in 
neonates, adults with underlying medical conditions and older persons [Staples 2009].  
Among patients admitted to one hospital in Puerto Rico for chikungunya, fatal cases 
tended to be older than non-fatal cases (78 versus 68 years) [Perti 2016], similar to trends 
reported elsewhere [Mavalankar 2008].  Studies of all-cause mortality following 
chikungunya epidemics have shown the greatest mortality increases occur in the older 
age groups defined as >60 [Beesoon 2008], >65 [Freitas 2018b], or >75 [Josseran 2006] 
though an excess all-cause mortality following the chikungunya epidemic in Puerto Rico 
was also seen in the 25-44 year age group [Freitas 2018b]. 
 
8.1.3 Chronic Chikungunya 
Following the acute phase, a majority of patients continue to experience prolonged 
symptoms, lasting several weeks to years [Edington 2018].  Chronic chikungunya is 
defined by the WHO as joint pain, rigidity, or edema that continue at least 12 weeks after 
the onset of acute chikungunya.  These symptoms may occur continuously or recurrently. 
[WHO 2015].  The French Infectious Disease Society defines chronic chikungunya as the 
absence of return to the pre-existing condition more than 3 months after the onset of 
chikungunya symptoms [Simon 2015].  Symptoms of chronic chikungunya range from 
non-specific local or generalized muscular discomfort to chronic inflammatory 
rheumatisms that meet diagnostic criteria for Spondyloarthritis (SA) or Rheumatoid 
Arthritis (RA) with positive tests for Rheumatoid Factor and Anti-Citrullinated Peptide 
Antibodies [Javelle 2015].  Post-chikungunya fibromyalgia is also described [Blettery 
2016].  In addition to joint symptoms, several components of quality-of-life surveys are 
consistently lower in patients with chronic chikungunya.  Fatigue, insomnia and 
depression that are coincident with acute infection are increasingly recognized [Elsinga 
2017][Bhatia 2015].   
 
Risk factors for chronic disease, in addition to the severity of the acute illness, are co-
morbidities such as diabetes [Van Aalst, 2017] and pre-existing joint conditions such as 
osteoarthritis. Multiple studies have documented an increased risk of chronic 
chikungunya with age using cutoffs of >35 [Schilte, 2013][Yaseen, 2014], >40 [Mohd Zim, 
2013],> 45 [Sissoko, 2009], >50 [Essackjee, 2013] and >60 years [Hoarau, 2010].   
 
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Figure 1: Quality-of-Life survey results from French soldiers stationed on La Reunion during the 
2006 epidemic 2.5 years later.  Note that soldiers who reported they had completely recovered 
(“Healed CHIKV+”) continued to have detectable decreases in most QoL parameters, including 
Bodily pain, more than 2 years later.  From [Marimoutou 2012]. 
 
The pathophysiology of chronic chikungunya is poorly understood.  Some authors use 
the 
term 
“post-chikungunya 
chronic 
inflammatory 
rheumatism” 
(pCHIK-CIR) 
synonymously with chronic chikungunya [Rodriguez Morales 2017] while others use it to 
describe only the minority of cases that meet specific diagnostic criteria for RA, SA or 
undifferentiated polyarthritis who have experienced symptoms continuously since the 
acute infection [Simon 2015], so it is difficult to know what proportion of chronic 
chikungunya cases result from synovial or systemic inflammation versus other 
mechanisms and if these proportions vary significantly between virus strains or epidemic 
locations.  Three mechanisms have been proposed to explain persistent symptoms: (1) 
persistence of infectious virus, (2) persistence of viral antigens, and (3) persistent immune 
activation after the virus has been cleared [Burt 2017].  For cases that meet diagnostic 
criteria for RA an autoimmune mechanism is suggested.  However RA following 
chikungunya infection is distinguished by its acute onset and increased risk in older 
subjects while RA that is not associated with chikungunya more often has a gradual onset 
in middle age.  Both conditions affect women more than men, have a predilection for small 
joints over large, and respond to treatment with methotrexate [Simon 2015].  As for other 
presentations of chronic chikungunya, the detection of cytokines or inflammatory markers 
is inconsistent [Dupuis-Maguiraga 2012] suggesting that pathogenic mechanisms vary.   
 
8.2 Investigational Vaccine 
MV-CHIK is a recombinant, live attenuated Schwarz strain measles virus-vectored 
vaccine in which the open reading frame of the entire structural gene of the chikungunya 
La Reunion strain 06-49 has been inserted [Brandler 2013].  Measles vector replication 
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and expression of the structural genes results in the formation of virus like particles (VLPs) 
in vivo. The advantage of VLPs is that structural proteins are expressed in their natural 
conformation without the risk of chikungunya replication in the host or transmission to 
mosquitoes. These VLPs are efficiently recognized by the immune system and elicit a 
high titer neutralizing antibody. In addition, live virus vectors elicit enduring cellular and 
humoral immune responses.  A further advantage of using this platform is that the 
methods for producing and up-scaling production of the measles vaccine are well 
established. See the Investigator’s Brochure for more information. 
 
MV-CHIK is manufactured as a colorless clear to off-white opaque liquid without 
excipients in a glass vial and must be stored at or below -65⁰C. The target dose is 5×105 
TCID50 per 0.4mL dose and is delivered intramuscularly.  See Section 10.3 for storage 
and handling requirements. 
 
8.3 Pre-Clinical Studies 
 
8.3.1 Immunogenicity Studies 
Preclinical evaluation of the MV-CHIK vaccine is described by Brandler et al [Brandler 
2013].  In CD46- interferon alpha/beta receptor knockout (IFNAR) mice, which express 
the human measles virus receptor, CD46, MV-CHIK induced high levels of chikungunya 
virus neutralizing antibodies. All immunized mice were protected from lethal challenge 
with chikungunya virus, even after a single immunization. Passive transfer of immune 
sera to highly susceptible IFNAR mice conferred protection from lethal challenge with 
homologous and heterologous strains of chikungunya. Importantly, pre-existing immunity 
to measles virus did not impair protection.  Immunogenicity as determined by a plaque 
reduction neutralization test (PRNT), has also been demonstrated in immunocompetent 
cynomolgus macaques receiving one or two immunizations. 
 
8.3.2 Toxicity Studies 
 
8.3.2.1 Biodistribution and Shedding profile 
A biodistribution and shedding study for MV-CHIK was performed in cynomolgus 
monkeys and is described in the Investigator’s Brochure. In brief, measles virus RNA was 
detected in the draining (iliac) lymph nodes up to 64 days post-inoculation and 
occasionally in a few other tissues (mandibular lymph node, tongue, popliteal lymph node 
and cervical lymph node), the same distribution seen with the non-recombinant parent 
Schwarz strain. All shedding levels were found to be at or below limit of detection (≤ 100 
genome equivalents per reaction). No recombinant virus was released into the 
environment.   
 
In clinical trial MV-CHIK 202 (described below) real-time PCR of urine and saliva samples 
was performed on a subset of participants at 0 7, 10, 14, 28 and 196 days after initial 
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vaccination.  MV-CHIK RNA was not detected in any of the samples analyzed [Reisinger 
2018].  In a biodistribution study of a similar measles-vectored vaccine, MV1-F4 for HIV, 
vaccine RNA was detected sporadically in feces, urine and vaginal secretions but no 
infective virus was recovered [Lorin 2012].   
 
8.3.2.2 Neurotoxicity 
A neurovirulence study in non-human primates was performed as requested by the 
European Pharmacopoeia and the World Health Organization (WHO) on measles vaccine 
seed lots. For this purpose, the MV-CHIK seed lot (MV-CHIK master virus seed stock) 
was inoculated into the thalamic region of each hemisphere of cynomolgus macaques. 
The study concluded that the MV-CHIK vaccine did not induce unexpected clinical or 
histopathological evidence of involvement of the central nervous system. 
 
8.4 Clinical Studies 
MV-CHIK has been evaluated in five Phase 1 and Phase 2 clinical trials enrolling over 
500 subjects. Safety data from all ongoing studies will be shared in real time with the 
Sponsor and communicated among all clinical trial sites to ensure that any safety signals 
that emerge are promptly addressed. 
 
8.4.1 Study MV-CHIK-101 
This first-in-human Phase 1 trial of MV-CHIK was conducted in 42 healthy adults (aged 
30.5±7.3 years) in Austria [Ramsauer 2015].  The vaccine induced neutralizing anti-
chikungunya antibodies even in the presence of pre-existing anti-measles immunity in all 
cohorts. The medium- and high-dose groups (7.5×104 and 3.0×105 TCID50 respectively) 
induced similar levels of neutralizing antibodies, which were significantly higher than the 
low-dose group (1.5×104 TCID50) and the MMR (Priorix®) comparator group. A second 
immunization at a 1- or 3-month interval boosted the neutralizing titers in all treatment 
groups. The seroconversion rate was 100% after the second immunization in all dose 
groups. Measles antibody titers were boosted in all dose groups after the first 
immunization. Overall, MV-CHIK induced a robust anti-chikungunya immune response. 
No immunological correlate of protection has been established, and the protective titer is 
still unknown. However, the highest dose induced the most persistent titer. 
 
The most frequent adverse events (AEs) encountered in this study were headache, 
injection site pain, influenza-like illness, fatigue, nausea, nasopharyngitis, and myalgia. 
Joint pain (arthralgia) was reported by 27.8% (10/36) of the subjects that received MV-
CHIK and in all cases was self-limited and accompanied by flu-like symptoms. The most 
frequent related AEs were injection site pain (18/36 [50.0%]), headache (12/36 [33.3%]), 
and fatigue (10/36 [27.8%]).  
 
Seven severe AEs occurred in six subjects who received MV-CHIK. One case of severe 
injection site induration and one case of severe injection site erythema were reported and 
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evaluated as definitely related to the study treatment. Injection site pain increased with 
dose, which was deemed related to the high inoculation volume (1 mL) and the 
formulation's salt buffer content rather than to the active ingredient. Of the first nine 
volunteers who received the highest dose, all reported significant pain, and three 
experienced vasovagal syncope. After decreasing the volume of injection by splitting it 
into two doses, the vaccine was much better tolerated. Subsequent lots of MV-CHIK, 
including those to be used in this study, were produced with a much lower salt 
concentration in the final product and were administered in a lower volume (0.4 mL) with 
much better tolerability. 
 
Three cases of severe headache after vaccination were reported; one was rated as 
probably related, and the other two cases were possibly related. One case of severe fever 
was documented and was evaluated as unlikely to be related to the study treatment. One 
subject with pre-existing alcohol dependence and depression attempted suicide and met 
the seriousness criterion “hospitalization” (severe and not related), which led to early 
termination. One other subject experienced a serious adverse event (SAE), a meniscus 
injury (moderate severity and determined to be not related).  
 
All AEs were recovered without any sequelae by study end. 
 
8.4.2 Study MV-CHIK 202 
Protocol MV-CHIK 202 (NCT02861586) was conducted in 263 adults at four sites in 
Austria and Germany [Reisinger 2018]. It compared two doses (5×104 or 5×105 TCID50) 
of MV-CHIK administered at two different intervals (one or six months). For each of these 
four cohorts subjects were randomized to receive either MV-CHIK or a licensed MMR 
comparator vaccine in a 6:1 ratio. In addition, two cohorts of 20 consented subjects each 
received the MMR either one or six months before a high-dose one month regimen of 
MV-CHIK to assess the effect of recently boosted immunity to measles on chikungunya 
immunogenicity.  
 
MV-CHIK showed an excellent safety profile with an overall incidence and severity of 
solicited and unsolicited AEs comparable to the MMR. The most frequent AEs were: 
headache (33% with MV-CHIK, 47% with MMR); fatigue (23% MV-CHIK, 24% MMR); flu 
like symptoms (18% MV-CHIK, 12% MMR); nausea (8% MV-CHIK, 18% MMR); and 
myalgia (15% MV-CHIK, 18% MMR). Arthralgia, regarded as an adverse event of special 
interest, was solicited and observed in 10% with MV-CHIK and in 15% of the MMR group. 
Injection site reactions were higher in the MV-CHIK group with induration (16% versus 
0%); and tenderness (52% versus 21%) being statistically significant.  Ten individuals 
reported severe adverse events after receiving MV-CHIK: one injection site pain, one 
injection site induration, four fatigue, two headache, two flu-like symptoms and one with 
nausea and vomiting.  All severe adverse events were resolved within 1 week.  No 
clinically relevant abnormalities were detected in hematology or chemistry laboratory 
tests.  No vaccine-related serious adverse events occurred.  
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The primary endpoint of the trial was immunogenicity on day 56 by the 50%-plaque 
reduction neutralization test (PRNT50). For the high-dose one-month interval to be used 
in this study, 95.7% seroconverted (defined as a PRNT50 > 10) at 28 days after the second 
dose and 87.2% remained positive seven months later.  Priming with the measles vaccine 
did not impair the rate of seroconversion or the GMT of the chikungunya vaccine. 
 
8.4.3 Study DMID 15-0038 
Protocol 15-0038 (NCT03028441) is sponsored by the Division of Microbiology and 
Infectious Diseases (DMID), National Institute of Allergy and Infectious Diseases (NIAID) 
of the National Institutes of Health (NIH) and is being conducted in Georgia, Iowa and 
Texas. This study compared two doses of MV-CHIK (5×104 and 5×105 TCID50) given at 
three different intervals (one month, three months, and six months). Each of these six 
cohorts contained 30 consented subjects of which 25 received MV-CHIK and 5 received 
saline placebo. 
 
Study enrollment and vaccination have been completed and the clinical phase should 
conclude by March 2019. After enrollment of 50 subjects, a Data and Safety Monitoring 
Board assessment was performed and did not raise any concerns for continuation of the 
study. The final data will be available by June 2019. 
 
8.4.4 Study MV-CHIK 205 
Protocol MV-CHIK 205 (NCT03635086) is an observer blinded, randomized study of 60 
healthy adults, ages 18 to 55 years, of the safety, tolerability and long-term 
immunogenicity of different formulations of MV-CHIK in healthy volunteers.  This study is 
being conducted in the United Kingdom.  The regimens under comparison are each of 
two injections 28 days apart of the following vaccine products: 
A. two doses of 5×104 TCID50 from a lyophilized formulation,  
B. two doses of 1×105 TCID50 in a liquid frozen formulation,  
C. two doses of 1×105 TCID50 in a liquid SPS® (Stabilizing and Protecting Solution), 
formulation,  
D. two doses of 1×106 TCID50 in a liquid frozen formulation, and  
E. one dose of 1×106 TCID50 in a liquid frozen formulation plus placebo.   
Subjects will return after 6 months and 1 year to follow up the durability of the immune 
response against chikungunya. 
 
Recruitment is completed. An interim analysis after all subjects have completed the 
primary endpoint visit will be available by mid-2019.  The final data will be available by 
the end of 2019.  The same lot of 1×106 TCID50 in a liquid frozen formulation will be used 
in the current study.  Post-manufacturing analyses have shown the actual concentration 
to be closer to 5×105 TCID50 as described in this protocol. 
 
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St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 2 6  of 1 1 6  
 
 
8. 4. 5  St u d y M V -C HI K 2 0 4  
Pr ot o c ol M V -C HI K 2 0 4  (N C T 0 3 1 0 1 1 1 1 ) i s a c o m p ani o n t o t h e c urr e nt st u d y a n d i s b ei n g 
c o n d u ct e d at t h e U ni v er sit y of P u ert o  Ri c o  M e di c al S ci e n c e s C a m p u s.  T hi s st u d y w a s 
d e si g n e d t o e x pl or e t h e s af et y of t h e M V -C HI K v a c ci n e i n pr e vi o u sl y e x p o s e d a d ult s a g e d 
2 1 t o 5 0 b y c o m p ari n g v ol u nt e er s w h o w er e s er o p o siti v e at b a s eli n e wit h t h o s e w h o w er e 
s er o n e g ati v e.  T h e r e a s o n f or st u d yi n g t h e eff e ct of M V -C HI K i n pr e vi o u sl y e x p o s e d 
i n di vi d u al s i s e x pl ai n e d i n S e cti o n 8. 7 .  E nr oll m e nt i n M V-C HI K 2 0 4 w a s si g nifi c a ntl y 
i m p e d e d f oll o wi n g H urri c a n e M ari a i n 2 0 1 7 a n d w a s st o p p e d aft er v a c ci n ati n g 3 4 of 1 0 0 
pl a n n e d s u bj e ct s.  A n u m b er of pr e vi o u sl y e x p o s e d i n di vi d u al s r e p ort e d j oi nt p ai n d uri n g 
t h e p o st-v a c ci n ati o n p eri o d, b ut it i s n ot cl e ar t h at t h e s e e v e nt s w er e tri g g er e d  b y t h e 
v a c ci n e.  T hi s tri al h a s n ot y et b e e n u n bli n d e d, b ut a t h or o u g h di s c u s si o n of e a c h A E SI 
i s a p pr o pri at e h er e. 
 
Fi v e a m o n g 1 6 s u bj e ct s w h o w er e s er o p o siti v e f or pr e vi o u s c hi k u n g u n y a i nf e cti o n at 
e nr oll m e nt  r e p ort e d si x  A E SI s : 
 
•  S u bj e ct  
 i s a
 w h o r e p ort e d o n 
, f o ur d a y s 
aft er t h e s e c o n d d o s e, m o d er at e l eft s h o ul d er p ai n.   
 t o o k a c et a mi n o p h e n o n 
1 7, 1 8 a n d 1 9 O ct o b er a n d i b u pr of e n o n 2 0, 2 1 a n d 2 2 O ct o b er.   
 al s o r e p ort e d 
di arr h e a fr o m 2 1 t o 2 3 O ct o b er.   
 s h o u l d er p ai n r e s ol v e d o n 
.    
 
 w hi c h m a y h a v e c o ntri b ut e d 
t o  
 s h o ul d er p ai n.  H o w e v er,  
 s p e cifi c all y c o m m e nte d t h at  
 s h o ul d er p ai n 
w a s si mil ar t o w h at  
 e x p eri e n c e d d uri n g  
 a c ut e c hi k u n g u n y a i nf e cti o n.   
 
C- r e a cti v e pr ot ei n w a s 0. 8 2 pri or t o i niti al v a c ci n ati o n, 1. 3 pri or t o  
 s e c o n d 
v a c ci n ati o n,  a n d  1. 1 8  t h e  d a y  pri or  t o  t h e  o n s et  of   
s y m pt o m s.   T h e 
i n v e sti g at or a s s e s s e d t hi s A E SI a s m o d er at e a n d p o s si bl y r el at e d t o t h e I V P. 
 
•  S u bj e ct  
 i s a 
 wit h a p a st hi st or y of c hi k u n g u n y a i nf e cti o n 
a n d ri g ht k n e e i nj ur y.  O n 
 ni n e d a y s aft er t h e fir st d o s e of 
st u d y  v a c ci n e  
 d e v el o p e d  bil at er al  k n e e  p ai n  f oll o wi n g  e x er ci s e  a n d  
h o u s e w or k.   
 di d n ot r e p ort t hi s t o t h e i n v e sti g at or u ntil aft er  
 r e c ei v e d t h e 
s e c o n d  d o s e  of  st u d y v a c ci n e.   M RI  r e v e al e d  o st e o art hriti c  c h a n g e s  i n  b ot h  
k n e e s a n d a t or n m e ni s c u s o n t h e ri g ht wit h eff u si o n.   
 w a s r ef err e d t o a n 
ort h o p e di c s ur g e o n a n d p h y si atri st.   
 s y m pt o m s c o nti n u e b ut n o c h a n g e i n 
t h e o v er all cli ni c al c o ur s e of t hi s d e g e n er ati v e di s e a s e i s attri b ut e d t o t h e st u d y 
v a c ci n e.   
 C -r e a cti v e pr ot ei n w a s 0. 1 m g/ L  pri or t o i n iti al v a c ci n ati o n, 0. 2 5 
t hr e e d a y s l at er, a n d 0. 1 1 pri or t o s e c o n d v a c ci n ati o n.  T h e i n v e sti g at or a s s e s s e d 
t hi s A E SI a s a n e x a c er b ati o n of a n o n-g oi n g a n d pr e vi o u sl y u nr e p ort e d c o n diti o n 
of m o d er at e s e v erit y a n d u nr el at e d t o t h e I V P. 
 
•  T w o  A E SI s  w er e  r e p ort e d  b y  S u bj e ct  
, a  
  
 
  O n 
, 3 1 d a y s aft er t h e s e c o n d d o s e of st u d y v a c ci n e,  
 
r e p ort e d ri g ht wri st art hr al gi a.  O n 
, 6 7 d a y s aft er t h e s e c o n d d o s e 
of st u d y v a c ci n e,  
r e p ort e d l eft wri st art hr al gi a.   
 w a s r ef err e d t o a p h y si atri st 
0 7 Z V H H
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
0 8 0 H 0 0

St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 2 7  of 1 1 6  
 
 
w h o  di a g n o s e d  t e n o s y n o viti s  of  t h e  e xt e n s or  of  t h e  5t h  fi n g er,  bil at er all y .  
S y m pt o m s  o c c urr e d  i nt er mitt e ntl y  u ntil  
   
b a s eli n e  C -r e a cti v e 
pr ot ei n w a s 0. 2 7  m g/ L , 0. 2 4 pri or t o s e c o n d v a c ci n ati o n a n d 0. 4 5 w h e n 
ri g ht 
wri st s y m pt o m s w er e r e p ort e d a b o ut o n e m o nt h l at er.  T h e i n v e sti g at or a s s e s s e d 
b ot h A E SI s a s mil d,  w or k -r el at e d a n d  u nr el at e d t o t h e I V P. 
 
•  S u bj e ct  
i s a 
 w h o o n 
, t hr e e d a y s aft er t h e 
s e c o n d d o s e of st u d y v a c ci n e, r e p ort e d p ai n i n  
ri g ht f o ot.   
 h a d i nj ur e d 
t hi s  f o ot  
 pr e vi o u sl y  w hi c h   
 tr e at e d  t o pi c all y  wit h 
B e n g a y ® wit h r e s ol uti o n of t h e p ai n .  
 di d n ot r e p ort p ai n o n t h e d a y of 
 
s e c o n d  v a c ci n ati o n.   T h e  p ai n  r e s ol v e d  b y  
.    
 C-r e a cti v e 
pr ot ei n w a s 0. 6 3 m g/ L pri or t o i niti al v a c ci n ati o n, 0. 8 5 pri or t o s e c o n d v a c ci n ati o n 
a n d  0. 8 2  w h e n   
 s y m pt o m s  w er e  fir st  r e p ort e d  t hr e e  d a y s  l at er.   T h e  
i n v e sti g at or  a s s e s s e d  t hi s  a s  A c hill e s  t e n di niti s c a u s e d  b y   
 pr e vi o u s  f all , 
m o d er at e a n d u nr el at e d t o t h e I V P. 
 
•  S u bj e ct  
 i s a
, s er o p o siti v e f or c hi k u n g u n y a, w h o r e p ort e d 
o n 
 n u m er o u s c o m pl ai nt s i n cl u di n g j oi nt p ai n t h at b e g a n o n 
 t hr e e d a y s aft er i niti al v a c ci n ati o n.  T h e s e c o m pl ai nt s w er e r ai s e d 
at a ti m e w h e n t h e s u bj e ct w a s b elli g er e nt a n d d e m a n di n g a d v a n c e d p a y m e nt 
f or  
 st u d y p arti ci p ati o n.   
 w a s s u s p e ct e d of dr u g a b u s e a n d r e m o v e d fr o m 
t h e st u d y b e c a u s e of a p er c ei v e d t hr e at t o st u d y sit e p er s o n n el.   
 C-r e a cti v e 
pr ot ei n w a s < 0. 1  m g/ L  pri or t o i niti al v a c ci n ati o n a n d < 0. 1 w h e n  
s y m pt o m s 
w er e  r e p ort e d.   T h e  i n v e sti g at or  a s s e s s e d   
 j oi nt  p ai n  a s  u n s u b st a nti at e d, 
p o s si bl y c o nf a b ul at e d a n d t h er ef or e u nr el at e d t o t h e  I V P. 
 
I n a d diti o n, t hr e e a m o n g 1 8 s u bj e ct s i n t h e s er o n e g ati v e gr o u p  r e p ort e d t hr e e A E SI s . 
 
•  S u bj e ct  
i s a 
 s er o n e g ati v e f or pr e vi o u s c hi k u n g u n y a 
i nf e cti o n.  O n e d a y aft er r e c ei vi n g t h e s e c o n d d o s e of t h e bli n d e d st u d y v a c ci n e 
o n 
,  
 r e p ort e d p ai n i n  
 ri g ht wri st 
.  
Si mil ar p ai n o c c urr e d i n  
 l eft wri st o n 
.  Wri st t e n o s y n o viti s wit h 
c ar p al t u n n el s y n dr o m e w a s di a g n o s e d a n d attri b ut e d t o  
o c c u p ati o n a s a 
.   
 w a s  r ef err e d  t o  a  p h y si atri st  a n d  i b u pr of e n  
pr e s cri b e d.  T h e c o n diti o n i s r e p ort e d a s r e s ol v e d a s of 
.   
 C-
r e a cti v e pr ot ei n w a s 0. 0 9 m g/ L  pri or t o i niti al v a c ci n ati o n, 0. 1 9 pri or t o s e c o n d 
v a c ci n ati o n a n d 0. 2 1 t hr e e d a y s l at er.  T h e i n v e sti g at or a s s e s s e d t hi s c o n diti o n 
a s mil d a n d u nr el at e d t o t h e I V P. 
 
•  S u bj e ct   
 i s  a  
 s er o n e g ati v e  f or  pr e vi o u s  c hi k u n g u n y a  
i nf e cti o n.  I n 
, a b o ut fi v e m o nt h s aft er t h e s e c o n d d o s e of t h e 
bli n d e d st u d y v a c ci n e, t h e s u bj e ct d e v el o p e d ri g ht ( d o mi n a nt) wri st t e n d er n e s s 
aft er a 
 pr oj e ct t h at r e q uir e d u s e of a pr e s s ur e  
.  It h a s 
i m pr o v e d  o v er  t h e  s u b s e q u e nt  f o ur  m o nt h s  b ut  n ot  f ull y  r e s ol v e d.   T h e  
i n v e sti g at or  a s s e s s e d  t hi s  c o n diti o n  a s  mil d  a n d  u nr el at e d  t o  t h e I V P. 
 
0 7 Z V H H
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
0 8 0 H 0 0

St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 2 8  of 1 1 6  
 
 
•  S u bj e ct  
 i s  a  
 s er o n e g ati v e  f or  pr e vi o u s  c hi k u n g u n y a  
i nf e cti o n.  I n 
 1 2 m o nt h s aft er t h e s e c o n d d o s e of t h e bli n d e d 
st u d y v a c ci n e, t h e s u bj e ct r e p ort e d ri g ht wri st p ai n  w h e n gr a s pi n g o bj e ct s .   
 
h a d  br o k e n  a  b o n e  i n  t hi s  h a n d  t w o  y e ar s  pr e vi o u sl y  a n d  h a d  d e cli n e d  
r e c o m m e n d e d s ur gi c al i nt er v e nti o n at t h at ti m e.  T h er e i s n o o b vi o u s r e a s o n f or 
t h e e x a c er b ati o n of s y m pt o m s t w o y e ar s aft er t h e fr a ct ur e a n d o n e y e ar aft er t h e 
s e c o n d  d o s e  of  I V P.   T h e  i n v e sti g at or  a s s e s s e d  t hi s  c o n diti o n  a s  mil d  a n d  
u nr el at e d t o t h e I V P.  
 
I n s u m m ar y, i n di vi d u al s pr e vi o u sl y e x p o s e d t o c hi k u n g u n y a r e p ort e d m or e j oi nt p ai n ( si x 
e v e nt s ,  o n e  of  w hi c h  w a s  c o n si d er e d  p o s si bl y  r el at e d  t o  t h e  I V P) t h a n  s er o n e g ati v e 
i n di vi d u al s  (t hr e e e v e nt s ,  n o n e  of w hi c h w a s c o n si d er e d p o s si bl y r el at e d t o t h e I V P) 
d uri n g M V -C HI K 2 0 4.  H o w e v er t h e t e m p or al r el ati o n s hi p of t h e s e e v e nt s  t o t h e I V P i n 
pr e -e x p o s e d s u bj e ct s  v ari e d wi d el y ( 3 a n d 9 d a y s aft er t h e fir st; 3, 4 , 3 1 a n d 6 7 d a y s aft er 
t h e s e c o n d v a c ci n ati o n) a n d i n e a c h c a s e ot h er c a u s ati v e or e x a c er b ati n g f a ct or s w er e 
i d e ntifi e d.   T h e  C-r e a cti v e  pr ot ei n  l e v el s  d o  n ot  s u g g e st  a n  i nfl a m m at or y  or  
i m m u n o p at h o g e ni c  b a si s  f or  t h e s e  a d v er s e  e v e nt s.   T h e  st u d y  h a s  n ot  y et  b e e n  
u n bli n d e d, s o it i s u n k n o w n w hi c h of t h e s e s u bj e ct s r e c ei v e d M V -C HI K v er s u s M M R.  It 
s h o ul d b e n ot e d t h at t hi s st u d y d e si g n, i n w hi c h pr e vi o u sl y e x p o s e d i n di vi d u al s w er e 
c o m p ar e d wit h pr e vi o u sl y u n e x p o s e d i n di vi d u al s, m a y h a v e b e e n i ntri n si c all y bi a s e d .  It 
h a s  b e e n o b s er v e d t h at i n di vi d u al s w h o r e p ort b ei n g i nf e ct e d b y c hi k u n g u n y a, e v e n t h o s e 
w h o r e p ort h a vi n g f ull y r e c o v er e d, c o nti n u e t o r e p ort s y m pt o m s at a hi g h er r at e t h a n t h eir 
u ni nf e ct e d p e er s (fi g ur e 1) [ M ari m o ut o u 2 0 1 2].  T h er ef or e a hi g h er r at e of a d v er s e e v e nt s 
i n cl u di n g j oi nt p ai n s h o ul d b e e x p e ct e d i n s er o p o siti v e s u bj e ct s i n d e p e n d e nt of t h e st u d y 
i nt er v e nti o n.  L e s s o n s l e ar n e d fr o m M V -C HI K 2 0 4  h a v e b e e n i n c or p or at e d i nt o t h e d e si g n 
of M V -C HI K 2 0 6.  
 
8. 5  Milit ar y R el e v a n c e  
T hi s st u d y will b e c o n d u ct e d i n a  n o n -milit ar y p o p ul ati o n of h e alt h y v ol u nt e er s u p t o a g e 
6 5, e x p a n di n g o n a pr e vi o u s st u d y t h at w e nt u p t o a g e 5 0. T hi s si m ul at e s a p orti o n of t h e 
d e pl o yi n g f or c e: M or e t h a n 5 % of s er vi c e m e m b er s w h o d e pl o y e d t o Ir a q or Af g h a ni st a n 
b et w e e n 2 0 0 1 a n d 2 0 1 0 ( o v er 1 0 0, 0 0 0 p e o pl e) w er e a g e 5 0 or ol d er [ R ut h erf or d, 2 0 1 3]. 
T h e n u m b er a n d pr o p orti o n of D o D ci vili a n s a n d c o ntr a ct or s i n c o m b at z o n e s o v er t h e 
a g e of 5 0 v ari e s, b ut i s al s o c o n si d er a bl e. H o w e v er, t h e p o p ul ati o n f or t h e pr o p o s e d st u d y 
w a s pri m aril y c h o s e n, n ot t o si m ul at e a milit ar y p o p ul ati o n, b ut t o s cr uti ni z e t h e p ot e nti al 
f or i m m u n o p at h o g e ni cit y t h at a n y v a c ci n e c o nt ai ni n g c hi k u n g u n y a a nti g e n s will h a v e t o 
a d dr e s s [ Y a n g, 2 0 1 7]. A v a c ci n e t h at i s n ot s af e i n t hi s a g e gr o u p d o e s n ot m e et t h e 
p u bli c h e alt h n e e d, i s n ot c o m m er ci all y vi a bl e a n d i s t h er ef or e u nli k el y t o e v er b e a v ail a bl e 
t o t h e W arfi g ht er. 
  
8. 6  P ot e nti al B e n efit s  
T h e p ot e nti al b e n efit of M V -C HI K v a c ci n ati o n f or t h o s e w h o h a v e n ot pr e vi o u sl y b e e n 
i nf e ct e d w o ul d b e pr ot e cti o n a g ai n st c hi k u n g u n y a i nf e cti o n if t h e v a c ci n e i s pr o v e n t o b e 
0 7 Z V H H
P P D
P P D
P P D
P P D
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efficacious. A boost in measles immunity may be an additional benefit.  For this study, in 
which all subjects have previously been infected with chikungunya and presumably 
therefore have lifelong immunity, there is no individual benefit to participation.  However 
the information to be gained will be vital to informing the consent of future participants in 
clinical trials conducted in areas of on-going transmission.   
 
8.7 Potential Risks 
 
8.7.1 General 
Potential risks that are frequently associated with any vaccine include injection site 
reactions such as edema, induration and erythema, transient local pain or tenderness.  
Adverse systemic events include mild to moderate headache, myalgia, arthralgia, flu-like 
symptoms, or fatigue. In addition, vaccines are reported to induce allergic and 
anaphylactic reactions at a rate of about 1 per million [Kelso 2012]. 
 
8.7.2 MV-CHIK specific 
As described above, AEs previously reported with MV-CHIK include injection site pain, 
headache, fatigue, and joint pain or arthralgia.  See Section 8.4.4 for a discussion of 
adverse events encountered in previously exposed individuals.   
 
8.8 Clinical Study Rationale 
The rationale for this study is to collect additional data on vaccine safety in individuals 
previously exposed to chikungunya virus. Although natural infection with chikungunya is 
thought to confer lifelong immunity, self-reporting of previous chikungunya infection is not 
reliable, particularly in areas where clinically similar arboviruses circulate.  Previously 
exposed persons will therefore inevitably receive the vaccine when field efficacy studies 
are conducted and when the vaccine is ultimately licensed for use in areas of ongoing 
transmission.  Because older individuals are at higher risk for developing chronic 
chikungunya, the risk of post-vaccination immunopathology may also be greater.  
Therefore this study will be conducted in two Steps in which individuals over the age of 
50 will not be enrolled until after a DSMB favorably reviews the accumulated safety data 
in younger subjects. 
 
 
There are two reasons to characterize the safety of MV-CHIK in previously exposed 
persons at this stage of product development.  First, some of the mechanisms of chronic 
chikungunya appear to be immunopathogenic responses to chikungunya antigens.  Any 
vaccine containing chikungunya antigens is therefore hypothetically capable of triggering 
or exacerbating such symptoms.  MV-CHIK has been shown to elicit both neutralizing 
humoral and cellular immune responses [unpublished data], the latter of which is 
associated with signs of chronic chikungunya in animal models [Lum 2015].  Because this 
live measles vectored vaccine bypasses anti-chikungunya immunity and results in in vivo 
production of chikungunya antigens, pathogenic responses to these antigens may result.  
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The second reason for assessing vaccine safety in previously exposed persons now is 
less tangible but possibly more important.  The fact that many of the manifestations of 
chikungunya infection are common and subjective (depression, fatigue, muscle and joint 
aches) there is a high risk that individuals who develop these symptoms for any reason 
will be inclined to attribute them to the vaccine.  A very similar situation occurred with, 
LYMErixTM, a vaccine for Lyme disease licensed by Smith Kline Beecham in the late 
1990s.  Lyme disease, similar to chikungunya, is associated with many chronic subjective 
complaints (depression, fatigue, muscle and joint aches).  LYMErix was shown to be safe 
and effective in clinical trials.  The presumed mechanism of action is that vaccine-induced 
antibodies are ingested by the vector and transmission is blocked without inducing any 
inflammation in the human host.  Nevertheless, this vaccine acquired a reputation for 
causing arthritis.  Despite the unanimous support of an FDA panel convened to address 
questions of vaccine safety, public confidence dissipated, demand dropped and the 
vaccine was withdrawn from the market in 2002 [Poland 2011].  Many experts feel that 
the prospects for any other vaccine for this particular disease are bleak [Shen 
2011][Plotkin 2011], citing issues that could easily arise following the licensure of any 
vaccine for chikungunya.   
 
One issue underlying the commercial failure of LYMErix was that it was not approved for 
use in the age group at highest risk of disease, namely those under the age of 15.  As a 
result, the public health impact of the vaccine was less perceptible and the tide of public 
opinion was more easily turned.  For chikungunya, the greatest public health impact will 
be in older individuals living in areas of on-going transmission.  Therefore studies 
specifically looking at vaccine safety in older adults are required prior to licensure and this 
study is required to appropriately inform the consent of older participants in those studies. 
 
A second, more important issue underlying the failure of LYMErix was a lack of consumer 
confidence in the vaccine industry and the vaccine licensure process.  According to a 
Senior Science Policy Advisor at the National Vaccine Program Office, the “key lesson 
learned from the LYMErix development story is that science and innovation are 
inadequate, by themselves, to assure that the public health value of a vaccine is 
realized… Communication, education, and transparency throughout the development 
and licensure process results in a deeper understanding of the vaccine. This 
understanding helps to inform attitudes about the vaccine not only among those 
individuals who are most vulnerable to Lyme disease but also among all of the other 
stakeholders who share a partnership role in vaccine development, licensing, distribution, 
and administration” [Shen 2011].   
 
Applying this lesson to chikungunya vaccine development requires acknowledgement of 
the high commercial risk of developing any vaccine against chikungunya and addressing 
this risk early and often.  It is entirely possible that MV-CHIK will induce some mild and 
transient symptoms in previously exposed persons.  And there will inevitably be 
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individuals destined to develop inflammatory arthritis or depression whose onset of 
symptoms will coincide with the receipt of a vaccine.  If this occurs with a vaccine whose 
path to licensure has included a cautious, deliberate and stepwise demonstration of 
vaccine safety in groups at hypothetical risk, subject matter experts will be in a position 
to lead public health authorities and consumers in an accurate assessment of the risks 
and benefits of vaccination.  This clinical trial is, therefore, on the critical path to both 
licensure and the long-term commercial viability of MV-CHIK. 
 
 
9 Investigational Plan 
 
9.1 Overall Study Design 
This will be a prospective randomized double-blind interventional clinical trial to evaluate 
the safety and immunogenicity of MV-CHIK in two intramuscular injections 28 days apart 
versus placebo.  Consented study subjects will be screened for baseline seropositivity to 
chikungunya virus where seropositivity is defined by a colorimetric capture ELISA 
(Novatec Immundiagnostica GmbH, Dietzenbach, Germany) as absorbance units 
exceeding that of the negative control by greater than 10%. Seropositive subjects are  
then randomized to receive either MV-CHIK (the experimental vaccine) or saline (the 
placebo) in a blinded fashion in a 1:1 ratio.  One dose level (5×105 TCID50) of MV-CHIK 
will be studied. Subjects will be followed for safety and immunogenicity for 24 weeks after 
completing the series. Because rheumatologic symptoms of chikungunya infection are 
more likely, more severe and more persistent in older patients, this study will initially be 
limited to adults aged 21 to 50 years of age (Step 1).  After at least 20 volunteers in Step 
1 have been vaccinated, a DSMB will review the safety data and, with their 
recommendation, the study will proceed to Step 2 and enroll subjects aged 51 to 65 years.  
The study schematic is shown as Figure 2. 
 
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Figure 2: Study schematic 
 
The trial will be registered online at the National Library of Medicine (NLM) public registry: 
http://www.ClinicalTrials.gov. 
 
 
9.2 Study Objectives and Endpoints 
 
9.2.1 Primary Objective 
The Primary Objective of this study is to determine the safety of MV-CHIK administered 
in two injections separated by 28 days in previously exposed individuals.  The following 
end-points will be used to assess safety in MV-CHIK versus placebo recipients: 
 
• solicited AEs (fever, fatigue, headache, malaise, myalgia, nausea/vomiting, joint 
pain 
or 
injection 
site 
itching, 
pain/tenderness, 
erythema/redness 
or 
induration/swelling occurring within 7 days of vaccination) 
• unsolicited AEs including the above signs or symptoms occurring more than 7 
days after vaccination, clinically significant abnormal safety laboratory results, 
vital signs, and physical examination findings  
• Solicited and unsolicited AEs of grade 2 and higher. 
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9.2.2 Secondary objectives 
The Secondary Objective of this study is to determine the Immunogenicity of MV-CHIK in 
previously exposed individuals.  The following end-points will be used to assess 
immunogenicity in MV-CHIK versus placebo recipients: 
 
• Fold-increase from Day 0 in geometric mean titer (GMT) of neutralizing antibodies 
to chikungunya on Days 28, 56, and at the end of the study. 
 
9.2.3 Exploratory Objectives 
As Exploratory Objectives, this study will assess the relationship of Quality-of-Life scores 
and acute phase reactants with adverse events experienced post-vaccination.  The 
following end-points will be used to assess these: 
 
• Change in serum C-reactive protein levels from pre-vaccination to three days post-
vaccination in recipients of MV-CHIK versus placebo. 
• Changes in plasma fibrinogen from pre-vaccination to seven days post-vaccination 
in recipients of MV-CHIK versus placebo. 
• Changes from baseline in Quality-of-Life survey (SF36) scores at four weeks post-
vaccination and at the end of the study in recipients of MV-CHIK versus placebo. 
 
9.3 Study Population 
 
The study will be conducted in Puerto Rico where a chikungunya epidemic occurred in 
2014 but where transmission is now negligible.  Individuals will be screened until 30 
subjects are vaccinated for each Step.  Subjects still under treatment for symptoms 
attributed to a previous chikungunya virus infection will be excluded from the study. 
Subjects who attribute only mild and subjective symptoms such as fatigue to previous 
chikungunya infection may be eligible at investigator discretion; subjects with acute 
chikungunya infection will be excluded but may re-screen no sooner than 3 months after 
symptoms (other than mild subjective symptoms not requiring treatment) have resolved.  
This study will measure, but not control for, baseline Quality-of-Life using the SF36 
questionnaire.  The seroprevalence of chikungunya in San Juan is approximately 23.5% 
[Simmons 2016].  Up to 500 subjects may be screened for each Step but it is hoped that 
existing databases of seropositive study volunteers will allow enrollment to be completed 
much more efficiently.   
 
Subjects will not be randomized unless all inclusion and no exclusion criteria, including 
lab test results, are met.  Subjects who fail to meet criteria because of an identifiable 
temporary condition or who cannot be randomized within the 60-day screening window 
may repeat the screening evaluation up to two times after the initial screening (total of 
three) at the discretion of the Investigator.  
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9.3.1 Inclusion Criteria 
Subjects MUST satisfy all of the following entry criteria before they will be allowed to 
participate in the study: 
1. Previous infection with chikungunya as verified by a serum immunoassay. 
2. Age appropriate for the Step being conducted: 
a. ≥21 to ≤50 years on the day of enrollment for Step 1. 
b. ≥51 to ≤65 years on the day of enrollment for Step 2. 
3. Able to provide informed consent. 
4. Available and accessible for the duration of the trial. 
5. Able and willing to comply with all requirements of the study. 
6. For women of childbearing potential, willing to practice adequate contraception 
(see Definition of Terms) for the duration of the study.  This is similar to 
recommendations following MMR vaccination [McLean 2013] but for a longer 
duration (six months versus one month) due to the higher concentration of 
measles virus and the lack of reproductive or developmental toxicology data on 
MV-CHIK. 
7. Medical history and physical examination findings are considered normal or not 
clinically significant in the opinion of the Investigator, which includes resolution 
of any arthralgias that may have occurred during prior chikungunya infection, 
as well as the absence of synovitis. 
8. Laboratory values are considered normal or not clinically significant in the 
opinion of the Investigator. If laboratory screening tests are out of the normal 
reference range and of potential clinical significance, the test(s) may be 
repeated up to 2 times (a total of 3 per screening evaluation) at the discretion 
of the Investigator, and the repeat values and their potential clinical significance 
will be used to determine eligibility. 
9. History of immunity to measles.  For persons born after 1957, this will be 
established by a history of compliance with vaccination policies that included 
measles vaccination or known vaccination as an adult at least one month 
before they are randomized.  Volunteers born before 1957 will be presumed to 
have immunity to measles based on natural exposure in accordance with CDC 
guidelines [McLean 2013]. 
 
9.3.2 Exclusion Criteria 
If any of the following apply, the subject MUST NOT be enrolled in the study: 
1. Taking medication or other treatment for unresolved symptoms attributed to a 
previous chikungunya virus infection. 
2. Prior receipt of any investigational chikungunya or other alphavirus vaccine.  To 
date, no alphavirus vaccines have been commercially available in the United 
States. 
3. Recent infection: 
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• 
self-limited upper respiratory infections until afebrile without medication 
for >1 week; 
• 
chikungunya unless/until asymptomatic (other than mild subjective 
symptoms not requiring treatment) for >3 months;  
• 
non-recurrent upper respiratory or urinary tract infections successfully 
treated with antibiotics, until asymptomatic for 1 month after full antibiotic 
course has been completed. 
4. History of an acute allergic or anaphylactic reaction to any vaccine. 
5. History of an immunosuppressive disorder (such as HIV infection, Common 
Variable Immune Deficiency), chronic infection (such as chronic hepatitis B or 
C), autoimmune disease (such as rheumatoid arthritis, systemic lupus 
erythematosus (SLE), autoimmune thyroid disease), or any medical condition 
that, in the opinion of the Investigator, could lead to an atypical immune 
response to the vaccine. 
6. History of moderate or severe non-traumatic arthritis or arthralgia within 3 
months of the Screening Visit. 
7. Recent (within 30 days), current or anticipated use of any immunosuppressive 
or immune modifying medication including corticosteroids (excluding nasal, 
ophthalmic, and other topical preparations). 
8. Other vaccination or planned vaccination within 4 weeks of either study dose 
(within 2 weeks for seasonal influenza vaccine).  
9. Receipt or planned receipt of blood products including immunoglobulins within 
120 days of the Screening Visit. 
10. Pregnant or lactating or planning pregnancy during the trial. 
11. Known alcohol or other substance abuse that in the opinion of the Investigator 
affects the ability or willingness of the subject to understand and comply with 
the study protocol.  
12. Participation in another clinical study within the past 30 days in which the 
subject was exposed to an investigational product (pharmaceutical product or 
placebo or device) or planned participation in another interventional clinical 
study while participating in this study.  
13. Relevant history of any medical condition that, in the opinion of the Investigator, 
may interfere with the safety of the subject or aims of the study.  
14. History of neoplastic disease (excluding successfully treated non-melanoma 
skin cancer or cervical intraepithelial neoplasia) within the past 5 years or a 
history of any hematological malignancy.  
15. Behavioral or psychiatric disease or cognitive impairment that in the opinion of 
the Investigator affects the ability or willingness of the subject to understand 
and comply with the study protocol.  
16. Non-consent to storage of blood specimens for future research. 
17. Persons in direct relationship with the Sponsor or its contracted service 
providers, the CRO or its subcontractors, the Investigator, or study site staff. 
Direct relationship includes first degree relatives or dependents (children, 
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spouse/partner, siblings or parents), as well as employees (site or Sponsor). 
Employees of the San Juan City Hospital not directly employed by the 
Research Unit will not be excluded. 
 
9.3.3 Randomization 
Initially, thirty (30) Step 1 subjects will be randomized at Visit 1, Day 0 using a Clinical 
Data Management System (CDMS). Subsequent to DSMB review, another thirty (30) 
Step 2 subjects will be enrolled and randomized at their Visit 1, Day 0. Visit 1 occurs after 
Screening (Visit S, Day -60 to -3) and includes enrollment, randomization and vaccine 
administration. At Visit 1 subjects will be randomized after enrollment and before vaccine 
administration. Subjects in each Step will be assigned to one of two groups, as shown in 
Table 1. Block randomization of appropriate size will accommodate balanced enrollment 
in ratio of 1:1 into each of the two treatment groups for the planned 30 Step 1 and 30 Step 
2 subjects. 
 
Table 1: Treatment Assignments 
Step 
N 
Treatment Assignment 
Study Days of 
Administration 
1 
15 
MV-CHIK 5×105 TCID50, 0.4mL IM injection 
0, 28 
15 
Saline, 0.4mL IM injection 
0, 28 
2 
15 
MV-CHIK 5×105 TCID50, 0.4mL IM injection 
0. 28 
15 
Saline, 0.4mL IM injection 
0, 28 
 
 
The list of randomized treatment assignments will be prepared by statisticians at DF/Net 
Research. The blinded randomization number will be provided through the randomization 
module in the data management system. The designated unblinded site personnel will be 
provided with the unblinded treatment key, which links the randomization number to the 
actual treatment assignment and should be securely stored. 
 
Instructions for use of the data management system for randomization will be included in 
the Pharmacy Manual. The Pharmacy Manual will also detail the manual back-up 
randomization procedures in the event that the site temporarily loses access to the 
internet or the randomization module is unavailable.  All documentation of the 
randomization procedure and output will be maintained by DF/Net until the end of the 
study.   
 
9.3.4 Blinding 
Vaccine administration will be double-blind, with the Investigator, study coordinator, all 
study personnel involved in assessing AEs and the subject being unaware of the 
treatment assignment. To achieve this, the thawed MV-CHIK vaccine and saline will be 
given the same wait time after procurement to allow both temperature equalization and 
non-discrepant wait times between treatments.  Furthermore, only designated site 
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personnel (pharmacist, etc.), unblinded CRAs and the unblinded biostatistician (at 
DF/Net) will have access to the treatment assignments. 
 
Unblinding will occur after the last subject’s last visit (Visit 10) and database lock, though 
the safety data may be unblinded upon Sponsor or DSMB request. 
 
9.4 Withdrawal of Subjects 
 
9.4.1 Criteria for Subject Withdrawal from the Study 
In accordance with the Declaration of Helsinki and applicable regulations, a subject has 
the right to withdraw from the study at any time and for any reason without prejudice to 
his or her future medical care by the physician or the institution. 
 
Subjects may also be withdrawn from the study if the Investigator determines that the 
subject should be withdrawn due to any unforeseen circumstance that may affect the 
safety of the subject, staff or the integrity of the study. 
 
The reason for early withdrawal will be recorded in the clinical records and the electronic 
case report form (eCRF). All subjects who are withdrawn prematurely from the study will 
undergo an early termination visit (see Section 11.12). However, it is acknowledged that 
a subject who is withdrawn from the study, might refuse to provide a reason for withdrawal 
and/or might refuse to return for an early termination visit. 
 
9.4.2 Criteria for Discontinuing Individual Subjects from Further Vaccination 
The following, in addition to the Exclusion Criteria listed above, are specific criteria for 
discontinuing individual subjects from further vaccination, but not from completing 
scheduled follow-up assessments, unless the subject is explicitly withdrawn from the 
study: 
 
• Anaphylaxis within 24 hours after administration of the study vaccine 
• Generalized urticaria within 72 hours after administration of the study vaccine 
• An SAE or AESI that is considered to be related to the study vaccine and, in 
the opinion of the Investigator, is likely to recur with repeat dosing. 
• A grade 3 or greater systemic or injection site AE that is considered to be 
related to the study vaccine that lasts longer than 3 days 
• A grade 3 or greater laboratory abnormality that is considered to be related to 
the study vaccine or that has not resolved prior to the next scheduled study 
vaccination 
 
If a subject withdraws consent or is discontinued from further vaccination or study 
participation because of an adverse event, appropriate measures to treat the subject will 
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be taken, and the IRB, Sponsor, SME, DoD Research Monitor and HRPO will be notified 
immediately. 
 
For safety reasons, all subjects who received at least one dose of study medication should 
not be withdrawn due to issues arising from the SARS-CoV-02 pandemic.  It is 
recommended that subjects withdrawals only occur under the existing conditions 
prescribed in the clinical protocol. 
 
If a subject received only a single vaccination prior to the SARS-CoV-02 pandemic and 
were unable to return for the second vaccination due to research site closure, a second 
vaccination will not be given.  The subject will receive a follow up telephone call to elicit 
general health status, new and existing adverse events and concomitant medications.  
The subject will be followed through all remaining visits per the original schedule of 
events. 
 
During a quality control check of the MV-CHIK TCB 001 03 18, Themis found some 
deficiencies in the prevention and detection of microbial and particulate contamination. 
Following notification of the research site PI of the concern, subjects who received only a 
single vaccination will not receive a second vaccination and will continue to be followed 
for remaining scheduled visits through Day 196. 
 
9.4.3 Evaluations at Withdrawal 
For any subject who is withdrawn before completing all study visits, the Investigator 
should: 
1. Perform an EOS visit (see Section 11.12). This assessment should be 
performed no later than 14 days after withdrawal/discontinuation. 
2. Complete all appropriate eCRF pages, providing the date of and explanation 
for the subject’s withdrawal/discontinuation. 
3. When indicated, arrange for appropriate follow-up and/or alternative medical 
care of the discontinued subject.  
If the subject fails to attend a scheduled follow-up or early termination visit, there will be 
at least two attempts to contact the subject via telephone and two written 
communications. If these receive no reply the subject will be considered lost to follow-up. 
 
9.4.4 Replacement of Subjects 
Once vaccinated, subjects will not be replaced. 
 
 
9.5 Premature Termination or Suspension of the Study 
 
The study may be temporarily suspended or prematurely terminated at any time if in the 
best interests of subjects and justified on either medical or ethical grounds. The Sponsor, 
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Investigator, IRB or DoD Research Monitor, acting in the interest of the study volunteers, 
are each empowered to suspend the study.  Written notification, documenting the reason 
for study suspension, will be provided by the suspending party to the Sponsor, 
Investigator, IRB and HRPO.   
 
9.5.1 Study Stopping Criteria 
The following study stopping criteria will suspend enrollment and study vaccinations 
pending review of available safety data and should result in Sponsor notification of the 
Center for Biologics Evaluation and Research (CBER): 
• Any subject experiences an SAE that is assessed as related to vaccination. 
• Three or more subjects experience the same or similar grade 3 or greater 
adverse events or clinically significant abnormal laboratory tests that are 
assessed as related to the vaccination. 
 
Regardless of how or by whom the study is suspended, the type of safety review or criteria 
required for study resumption will be determined by the Sponsor at the time of the 
suspension and will require approval by the IRB.  Whether the study is resumed or 
terminated, adequate consideration must be given to the protection of the subjects’ 
interests.  
 
9.5.2 Interim Management of the Study Due to SARS-CoV-2 
 
Due to the SARS-CoV-02 pandemic, social isolation has been imposed by the Puerto 
Ric0 Government which has resulted in the closure of the San Juan Research Unit.  
During this period of social isolation, active screening and enrollment will be suspended.  
It is understood, to protect subject safety and limit exposure to SARS-CoV-2 that the 
San Juan Research Unit may need to remain closed past the Puerto Rican 
Government’s regulatory period. Once the San Juan Research Unit re-opens and is fully 
functional, screening and enrollment will be re-started. 
 
Active subjects in the study with scheduled visits during the San Juan Research Unit 
closure will receive a follow up telephone call during the visit window or as soon as 
feasibly possible by the study staff.  Once the San Juan Clinical Research Unit re-opens 
subjects will be scheduled for their next follow up visits. 
 
10 Study Intervention 
 
10.1 MV-CHIK 
MV-CHIK is a recombinant live Schwarz-strain measles-vectored vaccine expressing 
chikungunya virus structural proteins. It is manufactured as a colorless clear to off-white 
opaque liquid without excipients and stored in a single-use glass vial at or below -65⁰C. 
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St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 4 0  of 1 1 6  
 
 
T h e t ar g et d o s e i s 5 × 1 0 5  T CI D 5 0  p er 0. 4 m L d o s e a n d i s d eli v er e d i ntr a m u s c ul arl y.   T h e 
s p e cifi c l ot t o b e u s e d i n t hi s st u d y h a s b e e n q u a ntifi e d a s  6. 3 4 × 1 0 5  T CI D 5 0  p er 0. 4 m L 
d o s e.  
 
M V -C HI K  w a s  m a n uf a ct ur e d  u n d er  r e s p o n si bilit y  of  T h e mi s  Bi o s ci e n c e  a n d  will  b e  
s u p pli e d a s a fr o z e n li q ui d. M V -C HI K / dr u g s u b st a n c e w a s m a n uf a ct ur e d, q u alit y c o ntr ol 
c h e c k e d a n d r el e a s e d i n a c c or d a n c e wit h G o o d M a n uf a ct uri n g P r a cti c e ( G M P)  
 
 
 T h e dr u g s u b st a n c e 
 
 a n d m a n uf a ct uri n g, q u alit y c o ntr ol, a n d r el e a s e 
w a s  p erf or m e d  i n  a c c or d a n c e  wit h  G M P.  N o  e x ci pi e nt s  w er e  a d d e d.  F ull  d et ail s  o n  
m a n uf a ct uri n g ar e gi v e n i n t h e “ M a st er Fil e T y p e II – C h e mi str y, M a n uf a ct ur e a n d C o ntr ol 
of C hi k u n g u n y a Vir u s -R e c o m bi n a nt M e a sl e s Vir u s ( S c h w ar z Str ai n) -V e ct or e d V a c ci n e”, 
M F # 1 7 1 4 3).  
 
T h e si n gl e u s e vi al s will b e r e m o v e d fr o m t h e fr e e z er  a n d sit at r o o m t e m p er at ur e f or  at 
l e a st 3 0 mi n ut e s b ef or e 0. 4 m L i s dr a w n i nt o a s yri n g e .  Th e v a c ci n e will b e i nj e ct e d I M 
i m m e di at el y or t h e s yri n g e will b e pl a c e d i n t h e r efri g er at or f or u p t o o n e h o ur a n d i nj e ct e d 
n ot l at er t h a n 9 0  mi n ut e s aft er t h e vi al w a s r e m o v e d fr o m t h e fr e e z er.   F or m or e d et ail s 
s e e t h e P h ar m a c y M a n u al.  
 
T h e  M V -C HI K  v a c ci n e  will  b e  s hi p p e d  a s  a  h a z ar d o u s  m at eri al a n d  l a b el e d  a s  li v e  
att e n u at e d m e a sl e s v a c ci n e e x pr e s si n g f or ei g n a nti g e n s o n dr y i c e. T h e bi o s af et y l e v el 
( B S L) / Ri s k Gr o u p i s 2.  
 
D uri n g a q u alit y c o ntr ol c h e c k of t h e M V -C HI K T C B 0 0 1 0 3 1 8, T h e mi s  f o u n d s o m e 
d efi ci e n ci e s i n t h e pr e v e nti o n a n d d et e cti o n of mi cr o bi al a n d p arti c ul at e c o nt a mi n ati o n . 
A m e di c al a s s e s s m e nt h a s b e e n c o m pl et e d i n cl u di n g r e vi e w of h e alt h c h a n g e s f or t h e 
st u d y. T h er e h a v e b e e n n o s eri o u s h e alt h c h a n g e s attri b ut e d t o t h e v a c ci n e t o d at e. 
N o n -s eri o u s h e alt h c h a n g e s h a v e b e e n o b s er v e d a n d a p p e ar c o n si st e nt wit h v a c ci n e 
a d mi ni st r ati o n. T h er e i s n o e vi d e n c e t h at t h e s e h e alt h c h a n g e s h a v e r e s ult e d fr o m 
tr a n s mi s si o n of i nf e cti o u s a g e nt a n d/ or i nj e cti o n of p arti c ul at e m att er a n d t h e ri s k of 
h ar m i s r e d u c e d b y t h e cl o s e f oll o w -u p of st u d y p arti ci p a nt s.  T h e M V -C HI K T C B 0 0 1 
0 3 1 8 h a s b e e n s e gr e g at e d fr o m cli ni c al s u p pli e s a n d will b e m ai nt ai n e d u n d er t h e 
l a b el e d st or a g e c o n diti o n s u ntil it i s r et ur n e d p er t h e s p o n s or’ s i n str u cti o n s. 
 
 
 
1 0. 2  Pl a c e b o  
S ali n e pl a c e b o will b e k e pt  i n a m o nit or e d r efri g er at or ( 2- 8⁰ C) .  W h e n r e a d y f or u s e, t h e 
si n gl e u s e vi al will b e tr a n sf err e d t o r o o m t e m p er at ur e f or at l e a st 3 0 mi n ut e s b ef or e 0. 4 
m L i s b e dr a w n i nt o a s yri n g e  a n d  i nj e ct e d I M i m m e di at el y or t h e s yri n g e will b e r et ur n e d 
t o t h e r efri g er at or a n d i nj e ct e d n ot l at er t h a n 6 0  mi n ut e s  aft er  dr a wi n g it u p .  F or m or e 
d et ail s s e e t h e P h ar m a c y M a n u al.  
0 7 Z V H H
P P D
P P D
P P D
P P D
P P D
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10.3 Handling of the Investigational Vaccine Products  
 
10.3.1 Labelling 
Both MV-CHIK and the saline placebo will be supplied as a liquid in single-use vials. The 
vials and carton labels will include the following information: 
 
• Product manufacturer name (carton) 
• Sponsor name (carton) 
• Vaccine name (carton and vial) 
• Dosage form (carton and vial) 
• Concentration of vaccine (carton and vial) 
• Lot (batch) number (carton and vial) 
• Route of administration (carton and vial) 
• Storage conditions (carton and vial) 
• “For clinical trial use only” (carton and vial) 
 
The target dose at the time of manufacture was 1×106 (±0.5log) TCID50, which appears 
as the concentration of vaccine on the label.  The vaccine lot to be used in this study has 
been quantified as 6.34×105 TCID50.  This value is in the same range as some cohorts in 
other clinical trials of this vaccine (5×105 (±0.5log) TCID50), including the companion 
study, MV-CHIK 204. With the exception of the vaccine label, this latter value is used 
throughout the documentation for this study to clarify which cohorts in other studies 
received the directly comparable dose. 
 
10.3.2 On-site storage 
MV-CHIK will be stored on-site in monitored freezers at or below -65⁰C. 
 
All supplies of MV-CHIK and saline placebo will be accounted for in accordance with 
GCP. An individual study IVP accountability record will be kept for each subject, and the 
Investigator will keep and maintain accurate records of the disposition of all IVP (MV-
CHIK and placebo) received during the study. These records should include the amounts 
and dates supplies were received, administered to the subject, or returned to the Sponsor. 
If errors or damages in the vaccine supply shipments occur, the Investigator should 
contact the Integrum project manager immediately for information on how the error or 
damage will be handled. Copies of the investigational vaccine accountability records will 
be provided by the Investigator for inclusion in the Trial Master File after database lock. 
The Clinical Research Associate (CRA) will periodically check the supplies of IVP held by 
the Investigator or pharmacist to verify accountability of all IVP used. 
 
The Investigator will only approve administration of the IVP to the identified subjects of 
this study, according to the procedures described in this protocol. After the end of the 
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study, all unused IVP and all containers can be destroyed on site as long as proper 
documentation is provided. If destruction on site is not possible or at the discretion of the 
Sponsor, investigational vaccine and all containers may be returned to the Sponsor for 
destruction. The Sponsor or CRO designee will verify that a final report of IVP 
accountability is prepared and maintained in the Investigator’s file and the electronic Trial 
Master File (eTMF). 
 
11 Study Events by Visit 
The Schedule of Events (Table 2) shows which procedures/assessments are to be 
performed at each scheduled visit for the screening, vaccination, and follow-up periods. 
Prior to conducting any procedures, the subject will provide informed consent (see 
Section 6.2).
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Table 2: Schedule of Events 
 
 
Screening 
Vaccination Period 
Post-Vaccination Follow-up Period 
Day -60 to 
Day-3 
Day 0 
Day 3 
(-1,+2 days) 
Day 7 
(+5 days) 
Day 28 
(-3,+7 
days) 
Day 31 
(3 [-1,+2] 
days post 
dose 2) 
Day 35 
(7 [+5] days 
post dose 2) 
Day 56 
(±7 days) 
Day 84 
(± 7 days) 
Day 140 
(±14 days) 
Day 196 
(±14 days) 
EOS visit 
Visit 
S 
1 
2 
3 
4 
5 
6 
7 
8 
9  
10 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
Medical & medication history  
X 
 
 
 
 
 
 
 
 
 
 
SF36 Questionnaire 
 
X 
 
 
X 
 
 
X 
 
 
X 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
 
Directed physical examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense diary b 
 
X 
 
 
X 
 
 
 
 
 
 
Collect and/or review diaries 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Review concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Interim history/adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review inclusion/exclusion 
criteria 
X 
X 
 
 
X 
 
 
 
 
 
 
Laboratory Assessments c 
 
 
 
 
 
 
 
 
 
 
 
Serology: chikungunya d, 
HBsAg, anti-HCV, anti-HIV-1 
and -2 
X 
 
 
 
 
 
 
 
 
 
 
Complete blood count e  
X 
X 
 
X 
X 
 
X 
 
 
 
 
Complete metabolic panel e 
X 
 
 
 
 
 
 
X 
 
 
 
Basic metabolic panel e 
 
X 
X 
 
X 
X 
 
 
 
 
 
Urinalysis (clean catch)  
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test f 
X 
X 
 
 
X 
 
 
 
 
 
X 
Neutralizing antibody to 
chikungunya 
 
X 
 
 
X 
 
 
X 
 
 
X 
Sera for future 
immunogenicity studies g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-reactive protein 
 
X 
X 
 
X 
X 
 
X 
 
 
 
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Screening 
Vaccination Period 
Post-Vaccination Follow-up Period 
Day -60 to 
Day-3 
Day 0 
Day 3 
(-1,+2 days) 
Day 7 
(+5 days) 
Day 28 
(-3,+7 
days) 
Day 31 
(3 [-1,+2] 
days post 
dose 2) 
Day 35 
(7 [+5] days 
post dose 2) 
Day 56 
(±7 days) 
Day 84 
(± 7 days) 
Day 140 
(±14 days) 
Day 196 
(±14 days) 
EOS visit 
Visit 
S 
1 
2 
3 
4 
5 
6 
7 
8 
9  
10 
Fibrinogen 
 
X 
 
X 
X 
 
X 
 
 
 
 
Ferritin 
X 
 
 
 
 
 
 
 
 
 
 
Vaccination  
Blinded vaccination 
 
X 
 
 
X 
 
 
 
 
 
 
Abbreviations: AE, adverse event; EOS, end of study; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus. 
Note: See Section 9.4.3 for Early Termination Visit procedures/assessments. 
a: To include body temperature, pulse rate, systolic and diastolic blood pressure. 
b: The paper subject diary will assess solicited local injection site reactions (erythema/redness, induration/swelling, itching, and pain/tenderness) after each 
injection for up to 7 days. Systemic signs and symptoms (fever, fatigue, headache, malaise, myalgia, nausea/vomiting, and joint pain) will also be solicited for 
7 days. The diary will include a section for recording unsolicited AEs and concomitant medications. 
c: The cumulative total of blood drawn in this study is approximately 300 mL per subject. 
d: Determine chikungunya exposure status using an enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin G 
(IgG). 
e: See Section 12.5 for individual tests performed. 
f:Urine pregnancy testing will be done on women of childbearing potential at Screening, on vaccination days and at the EOS visit. 
g: On Day 0, an 80-mL blood sample will be collected for sera; on other collection days, 10 mL will be collected for sera. These samples will be shipped to the 
Viral Diseases Branch of WRAIR for storage pending future testing and analysis. Refer to the Investigator Site File for sample preparation, handling, and 
shipping instructions. 
 
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11.1 Screening Visit S: Day -60 to -3 
 
At the time of screening the following assessments/procedures will be performed: 
• Medical and medication history 
• Physical examination to include vital signs 
• Review of inclusion/exclusion criteria 
• Chikungunya serology to determine the subject’s serostatus (seropositive or 
seronegative) 
using 
enzyme 
immunoassay 
(EIA) 
or 
enzyme-linked 
immunosorbent assay (ELISA) to detect immunoglobulin G (IgG) 
• Hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti-HCV), 
anti-HIV-1/2 serologies 
• Complete blood count 
• Comprehensive Metabolic Panel 
• Urinalysis (clean catch) 
• Ferritin 
• Pregnancy test (urine, women of child bearing potential only) 
 
11.2 Randomization Visit 1: Day 0 
The following assessments/procedures will be performed: 
• Pregnancy test (urine, women of childbearing potential only) 
• Review of inclusion/exclusion criteria 
• Directed physical examination and vital signs 
• Interim history 
• Concomitant medication review 
• SF36 Questionnaire 
• Baseline immunogenicity test samples 
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o 
Neutralizing antibody to chikungunya  
o 
Sera for future immunogenicity analyses (from 80 mL of whole blood) 
• Complete blood count 
• Basic metabolic panel 
• Acute phase reactants (C-reactive protein and fibrinogen) 
• Randomization (via CDMS) to receive either MV-CHIK or Placebo 
• Vaccine administration (IM) in a blinded fashion 
• Monitor for at least 30 minutes post-vaccination 
• Dispense diary and instruct on its use 
 
11.3 Visit 2: Day 3 (-1,+2 days) 
 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• Diary review 
• Basic metabolic panel 
• Sera for future immunogenicity analyses (from 10cc of whole blood) 
• Acute phase reactant blood sample (C-reactive protein only) 
 
11.4 Visit 3: Day 7 (+5 days) 
The following assessments will be evaluated: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
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• Concomitant medication review 
• Diary review 
• Complete blood count 
• Sera for future immunogenicity analyses (from 10 mL of whole blood) 
• Acute phase reactant blood sample (fibrinogen only) 
 
11.5 Visit 4: Day 28 (-3,+7 days) 
 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• SF36 Questionnaire 
• Collect and review first diary 
• Pregnancy test (urine, women of childbearing potential only) 
• Review of inclusion/exclusion criteria 
• Immunogenicity Test Samples 
o 
Neutralizing antibody to chikungunya 
o 
Sera for future immunogenicity analyses (from 10mL whole blood) 
• Complete blood count 
• Basic metabolic panel 
• Acute phase reactants (C-reactive protein and fibrinogen) 
• Vaccine administration in a blinded fashion 
• Monitor for at least 30 minutes post-vaccination 
• Dispense second diary  
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11.6 Visit 5: Day 31 (3 [-1,+2] days post dose 2) 
This visit is not required unless or until after the subject receives Dose 2. 
 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history 
• Concomitant medication review 
• Diary review 
• Basic metabolic panel 
• Sera for future immunogenicity analyses (from 10 mL whole blood) 
• Acute phase reactant (C-reactive protein only) 
 
11.7 Visit 6: Day 35 (7 [+5] days post dose 2) 
The following assessments will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• Diary review 
• Complete blood count 
• Sera for future immunogenicity analyses (from 10 mL of whole blood) 
• Acute phase reactant blood sample (fibrinogen only) 
 
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11.8 Visit 7: Day 56 (±7 days) 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• Collect and review diary 
• SF36 Questionnaire 
• Immunogenicity Test Samples 
o 
Neutralizing antibody to chikungunya 
o 
Sera for future immunogenicity analyses (from 10 mL of whole blood) 
• Complete blood count 
• Comprehensive metabolic panel 
• Acute phase reactants (C-reactive protein only) 
 
11.9 Visit 8: Day 84 (± 7 days) 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• Immunogenicity Test Samples 
o 
Sera for future immunogenicity analyses (from 10mL whole blood) 
 
11.10 Visit 9: Day 140 (± 14 days) 
 
The following assessments/procedures will be performed: 
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• Brief physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• Immunogenicity Test Samples 
o 
Neutralizing antibody to chikungunya 
o 
Sera for future immunogenicity analyses (from 10mL whole blood) 
 
11.11 Visit 10: Day 196 (± 14 days) EOS visit 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• SF36 Questionnaire 
• Pregnancy test (urine, women of childbearing potential only) 
• Immunogenicity Test Samples 
o 
Neutralizing antibody to chikungunya 
o 
Sera for future immunogenicity analyses (from 10mL whole blood) 
 
11.12 Early Termination Visit 
The early termination visit should occur within 14 days of subject withdrawal. 
The following assessments/procedures will be performed: 
• Focused physical examination and vital signs 
• Interim history/adverse events 
• Concomitant medication review 
• Pregnancy test (urine, women of childbearing potential only) 
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• Collect and review the diary if termination is prior to Day 56 
• SF36 Questionnaire 
• Immunogenicity Test Samples 
o 
Neutralizing antibody to chikungunya 
o 
Sera for future immunogenicity analyses (from 10mL whole blood) 
 
11.13 Study Visits During SARS-CoV-2 Pandemic 
 
Due to the SARS-CoV-02 pandemic, social isolation has been imposed by the Puerto 
Rico Government which has resulted in the closure of the San Juan Research Unit. 
Active subjects in the study with scheduled visits during the San Juan Research Unit 
closure period will receive a follow up telephone call during the visit window or as soon 
as feasibly possible by the study staff.  At the time of the telephone call the following 
information will be elicited:  
• 
general health status,  
• 
new and existing adverse events,  
• 
concomitant medications.    
Data collected will be recorded on a Subject Encounter Source Document and entered 
into the study database.  Subjects will be reminded to follow current country protocol if 
experiencing symptoms of COVID-19 and to follow up at the hospital emergency room 
for medical emergencies. 
 
Clinical activities which will not be completed during the San Juan Research Unit 
closure include the following:  
• Focused physical exam and vital signs 
• Blood and urine collection for protocol scheduled tests 
• SF 36 Questionnaire 
• Review and collection of diary 
 
Once the San Juan Clinical Research Unit re-opens subjects will be scheduled for their 
follow up visits. 
 
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For Day 196 visits which were not conducted due to social isolation, subjects will be 
invited to return to the research site for the following: 
• Completion of the SF-36  
• Blood collection neutralizing antibody to chikungunya and sera for future use 
studies.   
 
12 Methods of Assessment 
During each study visit, the Investigator will maintain progress notes in the subject’s study 
records to document all significant observations. 
 
12.1 Vital Signs 
Vital signs will be assessed by the Investigator or a qualified designee. Clinically 
significant abnormal findings after the IVP is administered will be reported as AEs as 
determined by the Investigator. 
Systolic and diastolic blood pressure will be assessed by sphygmomanometer 
measurement after the subject has been in a supine or sitting position for at least 5 
minutes. On vaccination days, the blood pressure will be taken prior to injecting the 
vaccine.  Pulse and temperature will also be assessed. 
The measurement of vital signs may be repeated at the discretion of the Investigator as 
needed for improved accuracy or to monitor the subject for safety reasons. 
 
12.2 Physical Examination 
A complete physical examination will be performed by a clinical Investigator at the 
Screening Visit and will include the following: general appearance, head, ears, eyes, 
nose, throat (HEENT), neck, skin, musculoskeletal (especially joints and movement), 
cardiovascular system, respiratory system, abdominal system and nervous system (with 
an assessment of the reflexes, motor and sensory nerve assessment, sensory checks of 
the extremities and mental status assessment). 
A focused physical examination will be performed at all subsequent visits during the study 
and will include mental status, musculoskeletal (joints and movement) and any additional 
systems as per the Investigator’s judgment. 
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Findings at the Screening Visit and before the first dose of IVP will be recorded as medical 
history.  Findings after the first dose of IVP is administered will be recorded as AEs. 
 
12.3 Medical History 
 
A complete medical history will be taken by a clinical Investigator at the screening visit 
with a view to identifying past, chronic or recurring problems that would result in exclusion 
from the study.  In particular, any recalled symptoms of chikungunya infection will be 
documented. 
Interim medical history will be reviewed at subsequent visits to identify any adverse 
events and to verify eligibility on vaccination days. 
12.3.1 Subject Diaries 
In order to facilitate a discussion between the investigator and the subject, diaries will be 
dispensed on each vaccination day and reviewed and collected according to the study 
events schedule. 
 
Diary Day 0 – 7 entries: 
• The following solicited injection site adverse reactions will be assessed and 
entered: erythema/redness, induration/swelling, itching, and pain/tenderness 
after each injection (See Appendix 1 for the Toxicity Grading Scale, Table A, 
Local Reactions to Injectable Product). 
• Solicited systemic symptoms to be recorded are fatigue, headache, malaise, 
myalgia, nausea/vomiting and joint pain. (See Appendix 1, Toxicity Grading 
Scale, Appendix Table B, Solicited Systemic Adverse Events). 
• This diary will also include a section for recording temperature daily and if the 
subject feels feverish and entering unsolicited AEs and concomitant medications. 
 
Diary Day 8 – 28 entries: 
• This diary will include a section for recording temperature if the patient feels 
feverish and entering unsolicited AEs and concomitant medications. 
 
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12.3.2 Medication History 
Concomitant medications will be reviewed to identify any interventions that resulted from 
adverse events and to verify eligibility on vaccination days.  Medications will be coded by 
WHODrug. The number and percentage of subjects receiving each category of 
medication will be summarized by IVP administered. 
 
12.4 Quality-of-Life Surveys 
The SF36 Quality-of-Life survey has been used in several studies to assess longitudinal 
function in patients with a history of chikungunya infection.  [Marimoutou 2012] 
[Marimoutou 2015][Rodriguez-Morales 2017].  This tool was developed by the RAND 
Corporation and is in the public domain.  Non-English versions of the SF36 are widely 
used but have not been validated.  The use of SF36 scores in this study will be 
exploratory.  The test will be given to subjects to self-administer on study days 0, 28, 56 
and at the end of the study.  Scoring of results will be done in accordance with RAND 
Corporation instructions.  See Appendix 2. 
 
12.5 Routine Laboratory Tests of Vaccine Safety 
In accordance with routine practice in early phase clinical trials, several clinical lab tests 
of a general nature will be monitored according to the schedule indicated in the Study 
Events Schedule.  Venous blood samples will be taken by a trained phlebotomist or 
qualified designee.  Subjects will be provided with instructions on submission of clean-
catch urine specimens.  Additional and repeat laboratory safety testing may be performed 
at the discretion of the Investigator. 
 
12.5.1.1 Complete Blood Count (CBC) 
white blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils), hemoglobin, hematocrit, platelet count. 
12.5.1.2 Basic Metabolic Panel (BMP) 
glucose, sodium, potassium, carbon dioxide, chloride, urea nitrogen, and creatinine. 
12.5.1.3 Comprehensive Metabolic Panel (CMP) 
BMP analytes plus calcium, albumin, total protein, ALP (alkaline phosphatase), ALT 
(alanine amino transferase), AST (aspartate aminotransferase), and bilirubin. 
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12.5.1.4 Ferritin 
Ferritin may be used to indicate iron-deficiency anemia.  Ferritin will be checked at 
baseline as a means of identifying subjects who may benefit from iron supplementation 
during the study.  For use of serum ferritin as an acute phase reactant see Section 
12.6.2.3. 
12.5.1.5 Urinalysis 
protein, glucose, hemoglobin, erythrocytes, and leukocytes.  The screening urinalysis can 
be repeated twice if necessary to ensure there is no clinically significant underlying 
medical condition.  No other urine samples will be collected except at the discretion of the 
Investigator. 
12.5.1.6 Pregnancy Testing 
Pregnancy will be determined by evaluation of β-human chorionic gonadotrophin (HCG) 
in urine for all women of childbearing potential. All female subjects are considered of 
childbearing potential unless postmenopausal or surgically sterile and at least 3 months 
have passed since the sterilization procedure. Postmenopausal is defined as amenorrhea 
for ≥12 months without an alternative medical cause. Permanent female sterilization 
procedures include tubal ligation, bilateral salpingectomy, hysterectomy, bilateral 
oophorectomy, or successful Essure placement. Subjects with a positive pregnancy test 
will be excluded from further vaccinations and study-related blood draws. 
The Investigator will inform the Sponsor immediately of any case of pregnancy during the 
study and collect information on any female subject who becomes pregnant while 
participating in this study. If the subject consents, she will continue to be followed and the 
outcome of the pregnancy will be documented. 
 
12.6 Samples for Future Research 
At the end of the study, the site(s) will ship any remaining sera to the Viral Diseases 
Branch of WRAIR for storage and/or future research. The blood samples will be de-
identified, shipped and stored in accordance with applicable regulations and approved 
Study Specific Procedures (SSPs). For samples stored at WRAIR, protection of subject 
confidentiality during any future research with the stored specimens will be guaranteed 
by labeling samples with a unique tracking number to protect confidentiality.  
Personnel at the WRAIR Viral Diseases Branch will not know any personally identifying 
information corresponding to the subject ID code. Any further research will be done in 
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accordance with a WRAIR IRB-approved laboratory protocol(s). Specimens will be 
retained under the supervision of the Compliance Management Unit of the Viral Diseases 
Branch, WRAIR. No identifying information will be available for use in the reporting or 
publication of any results. Refer to the Investigator Site File for more detailed information. 
Samples from subjects who withdraw consent for future use will be destroyed after all 
protocol-specified assays, including immunogenicity assays, are completed. 
 
12.6.1 Serological Tests 
12.6.1.1 Chikungunya serology  
A commercial laboratory will test subjects for chikungunya antibodies at baseline. The 
IgG antibody test will be performed via EIA or ELISA to determine the subject’s pre-
vaccination chikungunya serostatus and will be interpreted according to the laboratory’s 
guidance.  
12.6.1.2 HBsAg, anti-HCV, anti HIV-1 and -2 
Baseline screening for HBsAg, anti-HCV, anti-HIV-1/2 will require one blood sample to 
be sent to the local laboratory for analysis.  Subjects incidentally found to be positive to 
any of these viruses will be notified in a manner consistent with local practice and will be 
excluded from study participation. 
12.6.1.3 Neutralizing Antibody to Chikungunya 
Subjects will be tested for neutralizing anti-chikungunya virus antibodies in order to 
determine the response to vaccination. Immunogenicity samples will be sent for testing 
(Days 0, 28, 56, and 196) to NEOMED Labs. The assay will be an immunofocus 
microneutralization assay based on chikungunya strain 181/25.  
12.6.1.4 Future immunogenicity testing 
Subjects will be required to agree to the future use of blood specimens as specified in the 
ICF.  On Day 0, 80mL of sera will be collected for future immunogenicity testing.  This 
large volume will provide baseline samples for future studies comparing results at multiple 
time points post-vaccination.  In addition, these samples may be used in passive transfer 
studies as a control for naturally acquired immunity.  On other sera collection days, 10-
mL blood will be collected for future immunogenicity studies.  These samples will be 
stored at WRAIR. 
 
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12.6.2 Acute phase reactants 
Chikungunya infection is associated with both acute and chronic joint symptoms. Different 
pathophysiological mechanisms appear to cause these symptoms in different people, with 
one possible mechanism related to an aberrant host immune response to the virus or 
virus antigens [Javelle, 2015]. Because of this possibility, safety studies of vaccines that 
contain chikungunya antigens in previously exposed subjects are necessary before large 
scale efficacy studies or vaccination campaigns can be conducted in areas of on-going 
transmission. In the current study, joint pain will be solicited as an adverse event, and 
non-traumatic joint pain or stiffness that persists for more than 24 hours or is associated 
with objective findings of effusion or soft tissue swelling will be considered an AESI. 
However, assessing joint symptoms is complicated by the fact that they can be subjective 
and are regularly reported in the placebo arms of vaccine studies [Steere, 1998]. 
Arthralgia(s) were reported by nearly 20% of adult volunteers in a clinical trial of a 
conjugated meningococcal vaccine, yet post-licensure studies have not shown this to be 
a significant side effect [Sanofi Pasteur, 2016] suggesting that soliciting this symptom in 
early phase clinical trials can be misleading. To add clarity and objectivity to the 
assessment of arthralgia reported in this trial, and to help determine if joint symptoms that 
study participants report are due to an immunological or inflammatory mechanism, acute 
phase reactants will be included in the laboratory tests assessed routinely to monitor 
participant safety. 
 
12.6.2.1 C-reactive Protein  
C-reactive protein (CRP) is a blood biomarker signifying an inflammatory process. CRP 
is produced in the liver, and levels increase in response to inflammation. CRP levels are 
frequently used to monitor rheumatologic diseases [NCCCC, 2009] and also correlate 
with viremia in acute chikungunya infection [Anfasa, 2017]. Even in the absence of 
arthralgia or infection, CRP increases after influenza vaccination [Liuba, 2007]. The 
rationale for routinely testing CRP in this study is to provide Investigators with an objective 
assessment of systemic inflammation to aid in assigning causality to arthralgia(s) or other 
potentially inflammatory symptoms.  The timing of collection (3 days post-vaccination) 
was chosen based on a study of CRP levels following an inactivated (influenza) vaccine   
[McDade 2015]. 
 
Because so little is known about how CRP responds to vaccination, and because it can 
be expected that values will be increased at Day 3 post-vaccination, abnormal lab values 
will not be considered AEs. However, levels that are particularly high or more persistent 
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compared to other study participants may be considered by the Investigators as evidence 
that the vaccine or other inflammatory stimulus plays a causal role in the development of 
some AEs. Blood samples will be obtained on Days 0, 3, 28, 31, and 56 and at additional 
time points in individual subjects at the discretion of the Investigators.  
 
12.6.2.2 Fibrinogen  
Fibrinogen has not been shown to correlate with chronic chikungunya [Hoarau 2010] but 
has been shown to increase mildly following vaccination with other live [van der Beek 
2002] and inactivated [Liuba 2007] vaccines.  Collection of these samples for this study 
is exploratory.  The timing of collection (7 days post-vaccination) was chosen based on a 
study of fibrinogen levels following another live (Yellow Fever) vaccine [Verschuur, 2004].  
Blood samples will be obtained on Days 0, 7, 28, 35, and 56 and at additional time points 
at the discretion of the investigators. 
 
12.6.2.3 Ferritin 
Ferritin is a blood cell protein containing iron that increases in inflammatory conditions. 
Ferritin has been shown to correlate with chronic arthralgia in chikungunya infection 
[Anfasa, 2017]. Prospective collection of ferritin was performed in MV-CHIK 204 without 
any clear benefit.  In this study, ferritin will be collected at baseline so that, at the discretion 
of the Investigator, future values can be checked and compared. 
 
13 Adverse Event Reporting 
 
Adverse event (AE) definitions and reporting procedures provided in this protocol comply 
with current 21 CFR Part 312. An AE is any untoward medical occurrence temporally 
associated with the use of an IVP that does not necessarily have a causal relationship 
with the IVP. An AE can therefore be any unfavorable or unintended sign, abnormal 
laboratory finding, symptom, or disease whether or not considered related to the IVP. 
 
Adverse events will be monitored throughout the entire study. The Investigator will review 
the subject diary (if applicable) and ask subjects at each visit if they have experienced 
any untoward effects since the last study visit. All AEs will be recorded on the 
corresponding eCRF page: a description of the event, severity, time of occurrence, 
duration, any action (e.g., treatment or follow-up tests) and the outcome should be 
provided along with the Investigator’s assessment of the relationship to the IVP. 
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Adverse events will be recorded from the time subjects receive their first Day 0 
vaccination through the last study follow-up visit on Day 196 (±14 days).  If known, the 
name of the illness should be recorded, in preference to the listing of individual signs or 
symptoms. 
 
13.1 Severity Assessment 
Adverse events must be graded as being mild, moderate, or severe and their approximate 
duration given. Definitions of severity are as follows: 
 
Mild:   
an AE that does not interfere with normal activities; 
Moderate:  
an AE that is sufficiently discomforting to interfere with normal activities; 
Severe:  
an AE that is incapacitating or prevents normal activities. 
 
Even if the Investigator judges there is no relationship to the IVP, all AEs must be 
recorded in the eCRF.  
 
See Appendix 1 for grading scales to be used for local reactions to injectable product 
(Table A), solicited systemic adverse events (Table B), unsolicited systemic adverse 
events (Table C), and vital signs (Table D). For clinical laboratory test results outside of 
the normal range the FDA toxicity scale will be used to assign AE severity.  The 
Investigator will assign the grade of severity and document in the eCRF. 
 
13.2 Causality Assessment 
The Investigator is obligated to assess the relationship between the IVP and the 
occurrence of each AE/SAE. The Investigator will use clinical judgment to determine the 
relationship. Alternative plausible causes, underlying medical conditions, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the IVP will be 
considered and investigated. The Investigator will also consult the Investigator’s Brochure 
in the determination of his/her assessment. 
 
All solicited local (injection site) AEs will be considered causally related to vaccination.  
Causality of all other AEs should be assessed by the Investigator using the following 
question: “Is there at least a reasonable possibility that the AE may be related to the IVP?”  
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NO: 
The AE is not causally related to administration of IVP. There are other, 
more likely causes and administration of the IVP is not suspected to have 
contributed to the AE. 
YES: There is at least a reasonable possibility that the IVP may be related to the 
AE.  
 
13.3 Serious Adverse Events 
 
13.3.1 Definition of a Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence or effect that fulfills 
the following criteria: 
 
• results in death; 
• is life threatening; 
• requires hospital admission or prolongation of  an on-going hospitalization; 
• results in persistent or significant disability or incapacity; 
• is a congenital abnormality/birth defect; 
• is an important medical event not captured by the preceding criteria but which may 
require medical intervention to prevent one of the preceding outcomes. 
 
Events associated with hospitalization for the following will not be considered SAEs: 
 
• Evaluation or treatment of a pre-existing or recurring condition as long as the 
condition: 
o is recorded in the subject’s medical history as documented in the eCRF 
(e.g., degenerative disease) 
o has not worsened in severity or frequency during the subject’s exposure to 
the IVP 
o has not required a change in treatment management during the subject’s 
exposure to the IVP 
• Treatment that is elective or due to a pre-existing condition. 
 
13.3.2 Reporting of Serious Adverse Events 
Themis will be responsible for reporting of SAEs to the regulatory authorities as required. 
The Investigator is responsible for reporting SAEs to the DoD Research Monitor and the 
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St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 6 1  of 1 1 6  
 
 
I R B a s r e q uir e d a n d m ai nt ai ni n g all I R B c orr e s p o n d e n c e s o n fil e at t h e sit e a n d i n t h e 
e T M F.  R ef er t o t h e I n v e sti g at or Sit e Fil e f or f ull d et ail s of t h e pr o c e d ur e s a d o pt e d a n d 
a p pr o v e d  b y r e s p o n si bl e p arti e s, i n bri ef:  
•  A n y S A E t h at o c c ur s t o a n y s u bj e ct aft er e nt eri n g i nt o i nt er v e nti o n i n t hi s st u d y 
t hr o u g h t h e l a st st u d y f oll o w-u p vi sit o n D a y 1 9 6 ( ± 1 4 d a y s) m u st b e r e p ort e d b y 
t h e I n v e sti g at or t o t h e S M E , D o D R e s e ar c h M o nit or, C R O a n d S p o n s or r e g ar dl e s s 
of w h et h er or n ot t h e S A E i s c o n si d er e d r el at e d t o t h e I V P,  
•  S A E s t h at o c c ur aft er t h e l a st st u d y f oll o w -u p vi sit a n d t h at ar e d e e m e d t o b e 
r el at e d t o t h e I V P m u st al s o b e r e p ort e d b y t h e I n v e sti g at or t o t h e S p o n s or.  If 
p o s si bl e, t h e S M E , D o D R e s e ar c h M o nit or, a n d C R O s h o ul d al s o b e n otifi e d.   
•   All s u bj e ct s wit h S A E s m u st b e f oll o w e d f or o ut c o m e. 
 
All S A E s m u st b e r e p ort e d b y t h e In v e sti g at or  t o t h e S M E , C R O a n d S p o n s or wit hi n 2 4 
h o ur s of l e ar ni n g a b o ut t h e e v e nt. T hi s c a n b e d o n e b y s e n di n g a c o m pl et e d S af et y 
R e p ort  F or m  vi a  e m ail.  All  f oll o w -u p  i nf or m ati o n  p ert ai ni n g  t o  a n  S A E  m u st  al s o  b e  
r e p ort e d wit hi n 2 4 h o ur s of k n o wl e d g e of t h e f oll o w-u p i nf or m ati o n.  
 
C o nt a ct i nf or m ati o n f or t h e I nt e gr u m Dr u g S af et y C e nt er (i n cl u d e s v a c ci n e r e p orti n g):  
 
I nt e gr u m Dr u g S af et y C e nt er 
E m ail: 
  
T el e p h o n e: 
 
 
T h e  i niti al  r e p ort  s h o ul d  b e  pr o m ptl y  f oll o w e d  b y  d et ail e d,  writt e n  r e p ort s,  w hi c h  will  
i n cl u d e  c o pi e s  of  h o s pit al  c a s e  r e p ort s,  a ut o p s y  r e p ort s  a n d  ot h er  d o c u m e nt s  w h e n  
r e q u e st e d a n d a p pli c a bl e. T hi s a d diti o n al i nf or m ati o n will b e r e q u e st e d, if n e c e s s ar y, b y 
t h e S M E  or  C R A  wit hi n 5 d a y s of r e c ei pt of t h e al ert r e p ort.  Aft er t h e i niti al S A E r e p ort, 
t h e I n v e sti g at or i s r e q uir e d t o f oll o w u p pr o a cti v el y wit h t h e  s u bj e ct a n d pr o vi d e f urt h er 
i nf or m ati o n o n t h e s u bj e ct’ s c o n diti o n  a s it b e c o m e s a v ail a bl e . 
 
I nt e gr u m, i n c o n s ult ati o n wit h t h e S M E  a n d S p o n s or , will a s s e s s i niti al a n d f oll o w-u p S A E 
r e p ort s fr o m t h e sit e f or e x p e ct e d n e s s, w hi c h will b e d et er mi n e d b a s e d o n t h e m o st r e c e nt 
e diti o n of t h e I n v e sti g at or’ s Br o c h ur e. C o m pl et e d S af et y R e p ort  F or m s will b e pr o vi d e d 
t o t h e S p o n s or f or s u b mi s si o n t o r e g ul at or y a ut h oriti e s.  T h e S p o n s or will e x p e dit e r e p ort s 
of S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s ( S U S A R s) a s a n I n v e sti g ati o n al 
N e w Dr u g (I N D) S af e t y R e p ort wit hi n t h e r e q uir e d ti m e fr a m e. 
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The Integrum safety team may collect further information for final evaluation of the SAE 
case and for submitting an updated Safety Report Form to the Sponsor for submission to 
the regulatory authorities. 
 
See Section 17.4 for HRPO reporting requirements. 
 
13.4 Assessment of Subjects with Adverse Events 
Each subject must be carefully assessed for AEs by the Principal or designated 
Subinvestigator. This includes review of symptoms reported in the diary or at follow-up 
visits, physical findings, and laboratory results. Assessments must be made of the 
seriousness, severity, and relationship to the IVP. During the study all AE/SAEs should 
be followed to resolution or stabilization unless the event is considered by the Investigator 
to be unlikely to resolve or stabilize or the subject is lost to follow-up. 
 
13.4.1 Adverse events reported by history 
Throughout the duration of the study, SAEs and AESIs will be reported. See Appendix 1, 
Table C for the Toxicity Grading Scale: Unsolicited Systemic Adverse Events.  Subject 
diaries will not be considered source documents, but rather memory aids.  They should 
facilitate a discussion between the investigator and the subject, but the investigator is not 
compelled to regard each entry as an AE or accept the subject’s assessment of severity. 
 
13.4.2 Abnormal laboratory test results 
Abnormalities in laboratory parameters that are not present at screening will, if considered 
clinically significant in the judgment of the Investigator, be recorded in the eCRF as AEs. 
All clinically significant abnormal lab values will also be assigned a severity grade by the 
Investigator according to the Toxicity Grading Scale for Healthy Adult Volunteers Enrolled 
in Preventive Vaccine Clinical Trials; FDA/CBER Guidance, September 2007. The grade 
will be either: 1, mild; 2, moderate; 3, severe; or 4 potentially life threatening, and will be 
entered in the eCRF.  Abnormal laboratory tests should be repeated and followed up until 
they have returned to the normal range or an adequate explanation of the abnormality is 
found. 
 
An exception is made for CRP and fibrinogen in which abnormal values are expected. 
These tests will be used to aid in assigning causality to AEs that are potentially due to 
inflammatory causes, but abnormal values will not be considered AEs in themselves. 
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13.4.3 Abnormal physical exam findings 
Physical examination findings that were not present at screening and, in the judgment of 
the Investigator, are clinically significant will be recorded as AEs. 
 
13.5 Adverse Events of Special Interest 
 
13.5.1 Definition 
An AESI is an adverse event of scientific and medical concern specific to the Sponsor’s 
product or program, which requires additional monitoring and rapid communication. Such 
an event might warrant further investigation, including unblinding the treatment allocation 
of the subject, in order to better characterize and understand it. 
 
In this study, the AESI for MV-CHIK vaccine will be defined as: non-traumatic joint pain 
or stiffness that persists for more than 24 hours or is associated with objective findings of 
joint effusion or soft tissue swelling. For the purposes of this definition, “joint” includes all 
structures associated with the joint including ligaments and tendons.  Overuse of a joint 
should not be considered “traumatic” and joint pains resulting from overuse should not be 
excluded from this definition.  To characterize these symptoms, additional serologic, 
immunologic, and radiographic data may need to be obtained and other etiologies ruled 
out. The basis for selection of persistent joint symptoms as an AESI is discussed in 
Section 8.7. If the Investigator has any question about a case of persistent joint symptoms 
being an AESI, the SME should be contacted. 
 
13.5.2 AESI Reporting 
An AESI should be reported by the Investigator to Integrum, the SME and the Sponsor 
within 24 hours of learning about the event by completing the Safety Report Form and 
sending via email.  
 
13.6 Aggregate Safety Monitoring 
Assign-DMB will review de-identified safety data generated in this and other trials of 
MV-CHIK in order to keep the global MV-CHIK safety database up to date and 
consequently to detect any emerging safety signals in a timely fashion. Assign DMB and 
the Sponsor will ensure that applicable information will  be reported to concerned 
authorities and communicated to the individual sites as appropriate.  Assign-DMB will 
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incorporate data from this and all other trials into the development safety update report 
(DSUR) of MV-CHIK for annual submission to regulatory authorities. 
 
14 Statistical Analysis 
Data management, analysis, and reporting will be performed by DF/net. 
 
14.1 Database Management 
An electronic CRF and electronic data capture (EDC) will be used for this study, and a 
Data Management Plan will be prepared.  See Section 16.3. 
 
 
14.2 Sample Size Estimate 
A formal sample size calculation was not conducted for this study. The sample size was 
determined based on prior experience in evaluating the safety and immunogenicity of 
vaccines and is typical for early phase clinical studies.  In previous studies MV-CHIK was 
associated with joint pain in about 4% of previously unexposed recipients.  The largest 
study to date is MV-CHIK 202 in which 9/229 reported joint pain (95% confidence interval: 
1.8 to 7.3%).  A higher risk of joint pain in previously exposed individuals would be 
suggested if 4/15 individuals who receive MV-CHIK in either Step 1 or 2 of the current 
study develop joint pain (95% confidence interval: 7.8% to 55.1%) while the placebo 
group develops none.      
 
It is not possible to define a statistical threshold of safety that will rule out any increased 
risk of this vaccine in previously exposed individuals or guarantee market acceptance of 
this or any vaccine for an infection associated with joint pain, as demonstrated by the 
experience with LYMErix (see Section 8.7).  This study is not expected to provide a final 
answer on whether or not to continue development of this vaccine candidate, but rather 
contribute to the incremental gathering of information on vaccine safety.  In this regard, 
the details of individual cases including the time course and severity of their symptoms 
and the associated changes in their acute phase reactants and quality of life scores, will 
have to be examined individually.  A qualitative description of these events to include their 
assessed causality, severity, duration, and association with evidence of inflammation and 
immunopathology will provide critical data to inform the consent of participants in field 
trials conducted in areas of on-going transmission.   
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14.3 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the study 
database. The SAP will provide a detailed description of the statistical methods and 
expand on the details provided in the protocol. Additional analyses may be added. The 
SAP will include templates for the report tables, listings, and figures. 
 
14.4 Analysis Populations 
All of the analysis populations will be identified and finalized before the blind is broken for 
the study. The primary and exploratory analyses of safety will use the intent-to-treat (ITT) 
population. The per-protocol (PP) population will be used for secondary analyses of 
immunogenicity.  Analysis of the study Steps will be conducted separately. 
 
14.4.1 Intent-to-treat Population 
The ITT population will include all subjects who receive at least one dose of vaccine and 
will be the population for the safety analyses. 
 
14.4.2 Per Protocol Population 
The PP population is a subset of the ITT population that includes subjects who received 
both doses of IVP, have at least one post-vaccination immunogenicity assessment, and 
do not experience a protocol deviation that would affect their evaluation for 
immunogenicity. The protocol deviations that affect evaluation for immunogenicity will be 
determined based on a blinded data review prior to database lock. 
 
14.5 Statistical Methods 
Statistical methodology including hypotheses and all analyses will be provided in the 
Statistical Analysis Plan (SAP). Categorical variables will be summarized using the 
number frequency and percentage by Step, treatment and overall of subjects falling into 
each category. Continuous variables will be summarized using mean, standard error or 
standard deviation, median, minimum, maximum, and number of subjects with 
observations by Step of subjects falling into each category. Continuous variables will be 
summarized using mean, standard error or standard deviation, median, minimum, 
maximum, and number of subjects with observations treatment and overall. 
 
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14.5.1 Missing Data 
The intervention is not expected to have any effect on missing data. As such, any missing 
data will be considered Missing Completely At Random (MCAR) and will be assumed to 
have no effect on the analysis and no imputations will be performed. All attempts will be 
made to prevent missing data. An observed cases approach will be applied for all 
endpoints. 
 
14.5.2 Demographic and Baseline Clinical Data 
Demographics will be summarized by age (in years, at time of signing informed consent), 
gender and ethnicity. Baseline characteristics and medical history will also be 
summarized by relevant characteristics and classifications. 
 
14.5.3 Subject Disposition 
The following will be summarized categorically: 
• Subjects in each of the populations.  
• Subjects randomized and who received at least one dose of IVP.  
• Subjects with protocol deviations and reason for deviation. 
• Subjects who discontinued the study early along with the reasons for 
discontinuation.  
• Screen failures and reasons for screen failure.  
• Subjects at each study visit, and the number of subjects with important protocol 
deviations (defined in Section 17.2). 
 
 
14.5.4 Vaccine Exposure 
The number and percentage of subjects who receive only one of the IVP doses and the 
number and percentage of subjects who receive both of the IVP doses will be 
summarized. 
 
14.5.5 Concomitant Medications 
Concomitant medications will be coded by WHODrug. The number and percentage of 
subjects who received each category of medication will be summarized by IVP 
administered. 
 
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14.5.6 Adverse Events 
All verbatim terms for any reported AEs will be coded to the appropriate system organ 
class and preferred term according to the current version of MedDRA and graded by the 
Investigator for severity as per the FDA Guidance for Industry: Toxicity Grading Scale for 
Healthy Adults Enrolled in Vaccine Clinical Trials; 2007. The number and percentage of 
subjects experiencing an AE (all, serious, and vaccine-related) will be reported. 
 
All AEs will be summarized by IVP received according to the MedDRA system organ class 
(SOC) and preferred term. An additional summary will be provided for the incidence of all 
AEs by severity. Summaries will be presented for SAEs, AEs of grade 2 (moderate) and 
higher, IVP-related AEs, AESIs, and AEs where an action was taken. All AE data will be 
listed by subject, and a separate listing will include all SAEs, including any deaths on 
study. 
 
Adverse events will also be summarized separately for solicited and unsolicited events. 
Specific local injection site reactions (erythema/redness, induration/swelling, itching, and 
pain/tenderness) will be solicited using the subject diary from 0 to 7 days after each 
injection and Investigator interviews at follow-up visits. Specific systemic AEs (fever, 
fatigue, headache, malaise, myalgia, nausea/vomiting and joint pain) will be solicited 
using the subject diary from 0 to 7 days and Investigator interviews at follow-up visits. 
Unsolicited AEs will be all of those excluding the preferred terms of solicited AEs. Similar 
summaries will be presented for solicited and unsolicited AEs as noted above. 
 
14.5.7 Safety Laboratory Tests including Acute Phase Reactants 
Clinical laboratory test results and changes from baseline will be summarized by time 
point. Clinically significant abnormal laboratory results will also be captured as AEs.  
Abnormal results of CRP, fibrinogen or ferritin will not be captured as AEs. 
 
14.5.8 Vital signs and physical exam findings 
Vital signs results (including blood pressure, heart rate, and body temperature) and 
changes from baseline will be summarized by time point. Abnormal vital signs will be 
graded (see Appendix Table D) and findings from physical examinations will be assessed 
for clinical significance and included in the tabular summaries and by-subject AE listings. 
 
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14.5.9 Immunogenicity 
Analyses of immunogenicity will be conducted in the PP population according to IVP 
received.  The analysis of immunogenicity will be measured as GMTs of neutralizing 
antibodies on Days 0, 28, 56, and at EOS. The GMT will be calculated using a mixed 
effects model  with IVP (MV-CHIK versus placebo), visit and study Step (age group) ) and 
treatment visit interaction as fixed factors and subject as a random effect. The analysis of 
variance will be fit using log10 transformed data. The estimates for the least squares 
means and corresponding 95% confidence intervals (CIs) will be back-transformed by 
taking the anti-log to obtain the GMTs and CIs. 
 
15 Study Monitoring Procedures 
The Sponsor has ethical, legal, and scientific obligations to conduct this study in 
accordance with established research principles and ICH GCP guidelines. As such, in 
order to fulfill these obligations, a DoD Research Monitor, a SME, and blinded and 
unblinded CRAs will be employed for the duration of the study.  In addition, this study will 
include an interim review of data by a DSMB. 
 
15.1 DoD Research Monitor 
The DoD Research Monitor is a physician independent of the Sponsor responsible for 
serving as advocate for the medical safety of volunteers in accordance with Department 
of Defense Instruction (DoDI) 3216.02. As such, they may: 
• Perform oversight functions and report their observations to the IRB or other 
designated officials on recruitment/enrollment procedures, the consent process, 
other study interventions and interactions, data matching, data collection, and 
analysis. 
• Review ‘unanticipated problem involving risk to subjects or others’ (UPIRTSO) 
reports. 
• Review all SAEs, deviations and other unanticipated problems and provide an 
independent assessment/report of these events. 
 
The DoD Research Monitor is authorized to: 
• Interview and examine subjects and their clinical data. 
• Remove individual subjects from the study. 
• Stop the research protocol in progress. 
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• Promptly report their observations and findings to the IRB or other designated 
official and the HRPO as required. 
• Take any other steps necessary to protect the safety and well-being of human 
subjects until the IRB can assess their report. 
 
15.2 Sponsor Medical Expert 
The SME will review monitoring plans and serve as the central point of contact for medical 
questions from the site and Investigator(s).  They will review all AE and SAE reports on 
behalf of the Sponsor using de-identified (coded) information only.  They will also receive 
notifications from the site of any adverse events that require time-sensitive reporting to 
FDA or HRPO to include Serious and Unexpected Suspected Adverse Reactions 
(SUSARs) and adverse events that meet study stopping criteria.  For SUSARs, the SME 
will draft a narrative of the event for the Sponsor to review prior to reporting to FDA.  The 
SME will also communicate adverse events directly with HRPO in accordance with their 
requirements.  The SME will not interact with study subjects nor obtain their personally 
identifying information.   
 
15.3 Study Monitors 
Clinical Research Associates (CRAs), both blinded and unblinded, will monitor study 
progress by scheduling and performing on-site study visits throughout the study. 
 
15.3.1 Blinded Study Monitor 
A blinded CRA will conduct a site initiation visit, several interim monitoring visits and a 
site close out visit. The blinded CRA will also communicate with the site via phone, email 
and formal visit confirmation and follow-up letters. The blinded CRA will be responsible 
for 100% source document verification of study data, to include reviewing all UPIRTSOs 
associated with the protocol. The CRA may escalate any critical subject safety or GCP 
finding to the Investigator, Sponsor and SME and direct the site to contact the IRB 
immediately and the DoD Research Monitor if required. Regular inspection of the eCRFs 
will be conducted by the CRA in order to assess subject enrollment, compliance with 
protocol procedures, completeness and accuracy of data entered on the eCRFs, 
verification of eCRF data against original source documents, and occurrence of AEs. A 
full description of the responsibilities of the CRA, which will include reviewing the 
Investigational Site File on a routine basis, will be documented in the Monitoring Plan. 
 
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15.3.2 Unblinded Study Monitor 
An unblinded CRA will also be assigned to verify appropriate accountability and storage 
of the IVP and ensure site pharmacy staff understand and conduct their IVP preparation 
and administration procedures according to protocol.   
 
15.4 Sponsor and Government Audits 
The purpose of an audit is to assess whether ethical, regulatory and quality requirements 
are met.  The Sponsor may conduct an audit at the investigative site at any time. In 
addition, representatives from the Project Oversight Agency (WRAIR) may conduct 
inspections at the investigative site in order to assess contractor and subcontractor 
performance. The HRPO also conducts site visits as part of its responsibility for 
compliance oversight.  These visits may include but are not limited to, inspection of the 
IVP supply, required documents, the informed consent process, and comparison of CRFs 
with source documents.  
 
Government regulatory authorities may also inspect the Investigative site during or after 
the study. The Investigator or designee should contact the Sponsor/CRO and SME/HRPO 
immediately if this occurs. He/she must cooperate fully with regulatory authorities or other 
audits conducted in a reasonable manner. 
 
15.5 Investigative Site Responsibilities 
All study records including progress notes must be available for audit. The Investigator 
agrees to participate with audits conducted in a reasonable manner.  The Investigator 
must provide monitors/auditors with full access to all source and study documents and 
clinical study facilities and equipment (vaccine storage and reconstitution areas, freezers, 
centrifuges, calibration logs, monitors, and laboratory equipment). Adequate time and 
space for monitoring visits should be made available by the Investigator. 
 
The site must complete the eCRFs in a timely manner and on an ongoing basis to allow 
regular review by the CRAs, who will verify entries made in the eCRF. Whenever a subject 
name is revealed on a document that is to be collected for the Sponsor the name must 
be blacked out (for paper source) or encrypted (for electronic source) permanently by the 
site personnel, leaving the initials visible, and annotated with the subject code as 
identification. 
 
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15.6 Data Safety Monitoring Board 
Following vaccination of at least 20 volunteers in Step 1, an independent DSMB will be 
convened to review safety data and provide recommendations to the Sponsor. The DSMB 
will review unblinded cumulative study data to evaluate safety, performance parameters, 
study conduct, and the scientific validity and integrity of the trial. Data from MV-CHIK 204 
will also be made available to the DSMB by the Sponsor.  The DSMB will specifically 
address the question of whether or not it is safe to proceed to Step 2 of the study in which 
previously exposed volunteers ages 51 to 65 will receive this vaccine.  The DSMB will 
provide recommendations only; final decisions regarding study conduct rest with the 
Sponsor.  Members of the DSMB serve in an individual capacity, the DSMB has no 
protocol enforcement authority.  Refer to the DSMB Charter for detailed information on 
the DSMB. 
 
16 Data Management 
Clinical data (including AEs, concomitant medications and clinical laboratory data) will be 
entered into a 21 CFR Part 11-compliant validated computerized EDC system. Clinical 
data will be entered directly from the source documents at the investigational site. The 
EDC system includes password protection and internal quality checks, such as automatic 
edit checks, to identify data that appear inconsistent, incomplete, or inaccurate. 
 
16.1 Electronic Case Report Forms 
An eCRF will be used to store and transmit subject information. The file structure and 
format for the eCRF will be provided by the DF/net and should be handled in accordance 
with the instructions provided.  The eCRF must be reviewed and electronically signed and 
dated by the Investigator. 
 
Access to the eCRF will be strictly password protected and limited to authorized 
personnel directly participating in the study. Data should be entered into the eCRF 
completely by examining personnel or the study coordinator. The eCRF must be 
completed as soon as possible after any subject evaluation or communication. If data is 
to be changed due to erroneous input or other reason, an electronic audit trail will track 
these changes. The eCRFs and computers that store them must be accessible to the 
CRAs and to any regulatory auditor.   
 
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16.2 Data Collection 
During each study visit, the Investigator will maintain progress notes in the subject’s study 
record to document all significant observations. At a minimum, these notes will contain: 
• The date of the visit and the corresponding day or visit in the study schedule (eg, 
screening, Day 0, Day 28, and so forth). 
• General condition including subjective complaints, any significant medical findings, 
discussion of any documentation in the diaries, the severity, frequency, duration, 
and resolution of any reported AEs, and the Investigator's assessment as to 
whether or not the reported AE is IVP-related. 
• Changes in concomitant medications or dosages. 
• Documentation of the procedures performed. 
• The signature or initials of all Investigators making an entry in the medical record 
via the progress notes. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the study record (progress 
notes). Information from the study records (progress notes) and other source documents 
will be promptly entered in the appropriate section of the eCRF. 
 
Changes to information in the study record (progress notes) and other source documents 
will be initialed and dated on the day the change is made by the Investigator or designee. 
Changes to information in an electronic record will be handled per DF/Net SOPs. If the 
reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change. 
 
16.3 Clinical Database Management 
An electronic CRF and electronic data capture (EDC) will be used for this study, and a 
Data Management Plan will be prepared.  The EDC system will be hosted by DF/Net.  
Note that the EDC system will not contain any of the subjects’ personally identifying 
information: only de-identified (coded) data will be entered. DF-Net will not have access 
to any of the subjects’ personally identifying information. 
 
Previous and concomitant medications will be coded using version Global B3 September 
1, 2018 WHO Drug Reference Dictionary. The same WHO Drug version will be used 
throughout the study even though a new release is expected by March 2019.  Coexistent 
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diseases and AEs will be coded using version 21.1 of MedDRA (Medical Dictionary for 
Regulatory Activities) as documented in the Data Management Plan.  The same version 
of MedDRA will be used throughout the study even though a new release is expected by 
March 2019. 
 
Data cleaning will be an ongoing process throughout the trial. Specific reviews and 
processes used to clean the data are described in the Data Management Plan.  External 
data sources and reconciliation processes are documented in the Data Management 
Plan. Vendor contact information and information regarding data formats and transfer 
frequency is provided in the Data Transfer Specifications. External data will be reconciled 
with CDMS data in accordance with DF/Net SOP 3.13 version 6 “Data Transfer from 
External Sources”.  When the database has been declared to be complete and accurate, 
the database will be locked. Any changes to the database after that time can only be 
made by written agreement between the Investigator and DF/Net. 
 
16.4 Source Document Maintenance 
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, study records (progress 
notes), computer printouts, screening logs and recorded data from automated 
instruments. Diaries provided to subjects will be used as a memory aid to inform 
Investigator documentation in the progress notes, but will not themselves be considered 
source documents. 
 
All source documents from this study will be maintained by the Investigator and made 
available for inspection by authorized persons. The original signed informed consent for 
each subject shall be filed with records kept by the Investigator and a copy shall be given 
to the subject. 
 
16.5 Record Maintenance 
Records will be retained in accordance with the current ICH Guidelines. All essential study 
documents including records of subjects, source documents, eCRFs and IVP inventory 
will be maintained in the eTMF.  US FDA regulations (21 CFR 312.62[c]) require that 
records and documents pertaining to the conduct of this study and the distribution of IVP, 
including eCRFs, consent forms, laboratory test results, and medical source documents, 
be retained by the PI for 2 years after marketing application approval. If no application is 
filed, DoD regulations (32 CFR 219.115[b]) require these records to be kept 3 years after 
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the investigation is discontinued and the US FDA and the applicable national and local 
Health Authorities are notified. The Sponsor or their representative will notify the PI of 
these events. 
 
If an application is filed and approved, essential documents should be retained until at 
least 2 years after the last approval and until there are no pending or contemplated 
marketing applications in an ICH region, or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of MV-CHIK. However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the Sponsor. The Sponsor is responsible for informing 
the Investigator when these documents need no longer be retained. 
 
The Investigator will not dispose of any records relevant to this study without written 
permission from the Sponsor, and will provide the Sponsor the opportunity to collect such 
records. The Investigator shall take responsibility for maintaining adequate and accurate 
hard copy source documents of all observations and data generated during this study. 
Such documentation is subject to inspection by the Sponsor, its representatives, and 
regulatory authorities. 
 
If an Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person who will accept 
responsibility. Notice of transfer must be made to and agreed by the Sponsor. 
 
Data property rights are as specified in the trial contracts/agreements. 
 
16.6 Confidentiality 
All information obtained during the conduct of the study with respect to the subject’s state 
of health will be regarded as confidential. The Investigator must ensure that each 
subject’s anonymity is maintained. On CRFs and other documents submitted to the SME, 
Sponsor or the CRO, subjects must not be identified by name. Instead, subjects will only 
be known by the unique subject number allocated to them in order to ensure 
confidentiality on all study documentation. Subjects will retain this unique number 
throughout the study. The Investigator will keep a separate paper log of these codes in 
the Investigator Site File. 
 
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In order to comply with government regulatory guidelines and to ensure subject safety, it 
may be necessary for the Sponsor or representative, the DoD, the CRO, the IRB, or the 
FDA to review subjects’ medical records as they relate to this study. Only the subject’s 
unique number on the CRFs will identify him/her, but their full names may be made known 
to a pharmaceutical regulatory authority or other authorized government or health care 
officials, if necessary, and to personnel designated by the Sponsor. 
 
Documents that are not for submission to the Sponsor or the CRO (eg, consent forms) 
will be maintained by the Investigator in strict confidence, except to the extent necessary 
to allow checking by study monitors, and auditing by the Sponsor, the Project Oversight 
Agency, or regulatory authorities. No documents identifying subjects by name will leave 
the investigative site, and subject identity will remain confidential in all reports or 
publications related to the study. 
 
For any request to disclose the subject’s identity, an agreement among the subject, 
Investigator, and the Sponsor or designee will be obtained in writing. 
 
17 Administrative Procedures 
 
17.1 Regulatory Approval 
Themis Bioscience GmbH or their appointed agents will be responsible for ensuring that 
appropriate regulatory authority approvals are obtained, in accordance with FDA and DoD 
requirements.  No subject may enter the study until this approval has been obtained. A 
copy of the FDA IND application approval will be provided to the Investigator and to the 
IRB. 
 
17.2 Protocol Adherence 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, Standard 
Operating Procedures (SOPs) or Study Specific Procedures (SSPs). The noncompliance 
may be either on the part of the subject, the Investigator, or the study site staff. As a result 
of deviations, corrective actions are to be developed by the site and implemented 
promptly. These practices are consistent with ICH E6 (R2): 
• Compliance with Protocol, Section 4.5, 
• Quality Assurance and Quality Control, Section 5.1, 
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• Noncompliance, Sections 5.20. 
 
The protocol must be read thoroughly, and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety, and well-
being of the subject requires immediate intervention based on the judgment of the 
Investigator or a responsible appropriately trained and credentialed professional(s) 
designated by the Investigator as a Subinvestigator. 
 
Important protocol deviations are a subset of protocol deviations that might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject’s rights, safety, or well-being.  In the event of an important 
protocol deviation due to an emergency, accident, or error, the Investigator or designee 
must contact the Sponsor, CRO and SME at the earliest possible time by telephone or 
email. This allows for an early joint decision to be made as to whether and to what extent 
the involved subject(s) should continue in the study.  
 
It is the responsibility of the site to use continuous vigilance to identify and report protocol 
deviations to the CRA within 5 working days of identification of the protocol deviation or 
within 5 working days of the scheduled protocol-required activity. 
 
17.3 Protocol Amendments 
In accordance with ICH E6 (R2) Guideline for GCP, the Investigator should not implement 
any deviation from or changes to the protocol without agreement by the Sponsor and 
documented approval from the IRB, except where necessary to eliminate an immediate 
hazard(s) to study subjects, or when the change(s) involve(s) only logistical or 
administrative aspects of the study (e.g., change in contact information or correction of 
typographical errors). 
 
Substantive changes to the protocol must be handled as a protocol amendment. Any 
potential amendment must be approved by the Sponsor. A written amendment must be 
submitted to the appropriate regulatory authorities and to the IRB. The Investigator must 
await IRB approval of protocol amendments before implementing the changes, except 
where necessary to eliminate apparent immediate hazard to subjects. In these cases, the 
IRB must be notified within 5 days of the change. 
 
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St u d y Pr ot o c ol: M V -C HI K -2 0 6 , W R AI R # 2 6 2 9    
  
 
V er si o n 2. 1 , 2 3  D e c e m b er 2 0 2 0  
 
 
 
P a g e 7 7  of 1 1 6  
 
 
All a m e n d m e nt s t o t h e pr ot o c ol m u st b e a p pr o v e d i n writi n g b y b ot h t h e a p pr o pri at e 
r e g ul at or y a ut h oriti e s a n d t h e I R B, e x c e pt f or a d mi ni str ati v e a m e n d m e nt s, w hi c h r e q uir e 
n otifi c ati o n b ut n ot writt e n a p pr o v al. O n c e a p pr o v e d, t h e pr ot o c ol a m e n d m e nt will b e 
di stri b ut e d  t o  all  r e ci pi e nt s  of  t h e  ori gi n al  pr ot o c ol,  wit h  i n str u cti o n s  t o  a p p e n d  t h e  
a m e n d m e nt t o t h e pr ot o c ol.  
 
If, i n t h e o pi ni o n of t h e I R B, I n v e sti g at or, a n d/ or S p o n s or, t h e pr ot o c ol  a m e n d m e nt alt er s 
t h e st u d y d e si g n or pr o c e d ur e s a n d/ or i n cr e a s e s t h e p ot e nti al ri s k s t o t h e s u bj e ct s, t h e 
c urr e ntl y a p pr o v e d writt e n I C F will r e q uir e m o difi c ati o n. T h e m o difi e d I C F m u st al s o b e 
r e vi e w e d a n d a p pr o v e d b y t h e S p o n s or, a p pr o pri at e r e g ul at or y a ut h oriti e s, a n d t h e I R B. 
I n s u c h c a s e s, r e p e at i nf or m e d c o n s e nt m u st b e o bt ai n e d fr o m s u bj e ct s still e nr oll e d i n 
t h e st u d y b ef or e p arti ci p ati o n c o nti n u e s. 
 
1 7. 4  S p e cifi c R e q uir e m e nt s of t h e H u m a n R e s e ar c h Pr ot e cti o n Offi c e  
T h e H u m a n R e s e ar c h Pr ot e cti o n Offi c e ( H R P O) of t h e U S Ar m y M e di c al R e s e ar c h a n d 
M at eri el C o m m a n d ( M R M C) m u st pr o vi d e writt e n a p pr o v al b ef or e t h e st u d y c a n b e gi n.  
T h e H R P O m a y st o p or s u s p e n d t h e u s e of t h e I V P i n D o D -s u p p ort e d st u di e s at a n y ti m e.   
A c c or di n gl y, H R P O a p pr o v al i s c o nti n g e nt u p o n t h e f oll o wi n g r e p orti n g r e q uir e m e nt s:  
 
1 7. 4. 1  U n a nti ci p at e d Pr o bl e m s I n v ol vi n g Ri s k s t o S elf or Ot h er s  
All u n a nti ci p at e d pr o bl e m s i n v ol vi n g ri s k t o s u bj e ct s or ot h er s m u st b e pr o m ptl y r e p ort e d 
b y
 t el e p h o n e
  
 
 b y
 e m ail
 
 or b y f a c si mil e 
 t o t h e H R P O. A c o m pl et e 
writt e n  r e p ort  will  f oll o w  t h e  i niti al  n otifi c ati o n.  I n  a d diti o n  t o  t h e  m et h o d s  a b o v e,  t h e 
c o m pl et e r e p ort c a n b e s e nt t o t h e U S Ar m y M e di c al R e s e ar c h a n d M at eri el C o m m a n d, 
A T T N: M C M R -R P, 8 1 0 S c hr ei d er Str e et, F ort D etri c k, M ar yl a n d 2 1 7 0 2 -5 0 0 0.  T h e I R B 
a n d t h e H R P O will, i n c o or di n ati o n wit h t h e S p o n s or, e n s ur e u p w ar d r e p orti n g of t h e 
u n a nti ci p at e d pr o bl e m s i n v ol vi n g ri s k t o s u bj e ct s or ot h er s t o t h e a p pr o pri at e r e g ul at or y 
offi c e s. 
 
1 7. 4. 2  S u bj e ct Wit h dr a w al of C o n s e nt D u e t o a n A d v er s e E v e nt  
A E -r el at e d  wit h dr a w al s  of  c o n s e nt  f or  eit h er  t h e  s e c o n d  v a c ci n e  d o s e  or  f or  st u d y  
p arti ci p ati o n i n g e n er al n e e d n ot b e r e p ort e d t o t h e H R P O.  N otifi c ati o n of t h e S p o n s or, 
t h e C R A, t h e S M E  a n d t h e I R B s h o ul d b e d o n e i n a c c or d a n c e wit h S e cti o n 9. 4 .  N ot e t h at 
r e p orti n g t o H R P O of A E s, i n cl u di n g S A E s, i s n ot r e q uir e d. 
 
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17.4.3 Protocol Modifications 
Substantive modifications to the research protocol and any modifications that could 
potentially increase risk to subjects must be submitted to the HRPO for approval prior to 
implementation. The HRPO defines a substantive modification as a change in PI, change 
or addition of an institution, elimination or alteration of the consent process, change to the 
study population that has regulatory implications (such as adding children, adding active 
duty population), significant change in study design (ie, that would prompt additional 
scientific review), or a change that could potentially increase risks to subjects. 
 
17.4.4 Change of IRB 
Any changes of the IRB used to review and approve the research will be promptly 
reported to the HRPO. 
 
17.4.5 Suspension or Termination of Research 
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by 
the IRB, Investigator, Sponsor, DoD Research Monitor or regulatory authorities will be 
promptly reported to the HRPO. 
 
17.4.6 Continuing IRB Review  
A copy of continuing review approvals by the IRB must be submitted to the HRPO as 
soon as possible after receipt. For greater than minimal risk research, a copy of the 
continuing review report approved by the IRB must also be provided. Please note that the 
HRPO also conducts random audits at the time of continuing review. Additional 
information and documentation may be requested at that time. 
 
17.4.7 Pending Inspection 
The knowledge of any pending compliance inspection/visit by the FDA, Office for Human 
Research Protections (OHRP) of the U.S. Department of Health and Human Services 
(HHS), or other government agency concerning clinical investigation or research, the 
issuance of Inspection Reports, FDA Form 483, warning letters, or actions taken by any 
regulatory agency including legal or medical actions and any instances of serious or 
continuing noncompliance with the regulations or requirements will be reported 
immediately to the IRB and HRPO. 
 
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17.4.8 Final Study Report 
The final study report and supporting documents, including any acknowledgement 
documentation, must be submitted to the IRB and HRPO when available. 
 
17.5 Investigative Site File Management 
The Investigator is responsible for assuring that the Investigational Site File is maintained. 
The Investigational Site File will contain, but will not be limited to, the information listed 
below: 
 
1. Investigator’s Brochure, 
2. Current, signed version of the protocol and any previous versions of the protocol, 
3. Protocol amendment(s), 
4. Current ICF (blank) and any previous versions of the ICF, 
5. Curricula Vitae of the PI, Subinvestigator(s), and photocopies of their respective 
professional license(s) where required by law; original US FDA Form 1572 signed 
by the PI at each site. The names of any Subinvestigators should appear on this 
form. The Investigator must also complete all regulatory documentation as 
required ICH GCP and by local or national regulations, 
6. Documentation of IRB approval of the protocol, the ICF, any protocol amendments, 
and any ICF revisions, 
7. All correspondence between the Investigator, IRB, and the Sponsor/CRO relating 
to study conduct, 
8. Lab certification(s), 
9. Monitoring log, 
10. IVP shipment invoices, 
11. Signature list of all staff completing the eCRF pages, 
12. Site Delegation Log, which will include delegation of tasks or functions (including 
eCRF entry, IVP accountability, and other tasks) from PI to qualified staff and 
signatures of these staff members acknowledging their role(s), 
13. Current Safety Report Form, Pregnancy Report Form (blank), and corresponding 
completion guidelines and any previous versions of the aforementioned forms and 
guidelines. 
 
17.6 Contract Requirements 
The Investigator and the Geneva Foundation will sign a Clinical Trial Agreement prior to 
the start of the study outlining overall Sponsor and Investigator responsibilities in relation 
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to the study. The contract should describe whether costs for pharmacy, laboratory, and 
other protocol-required services are being paid directly or indirectly. Financial Disclosure 
Statements will need to be completed, as required by 21 CFR part 54. 
 
17.7 Insurance, Indemnity and Compensation 
Themis Bioscience GmbH maintains an appropriate liability insurance policy. Deviations 
from the study protocol, such as the administration of a dose other than that scheduled in 
the study protocol or another route of administration, are not permitted and will not be 
covered by the subject insurance scheme. 
 
17.8 Clinical Study Report 
A final clinical study report will be prepared according to the ICH E3 guideline on Structure 
and Contents of Clinical Study Reports. A final clinical study report will be prepared 
regardless of whether the study is completed or prematurely terminated. 
 
17.9 Publication Policy 
After completion of the study, the Investigator may prepare a joint publication with the 
Sponsor and Project Oversight Agency. The Investigator must not submit any part of the 
data from this protocol for publication without the prior consent of the Sponsor and Project 
Oversight Agency. 
 
 
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18 References 
 
Anfasa F, Provacia L, Kessel CG, et al. Hyperferritinemia is a potential marker of chronic 
chikungunya: A retrospective study on the Island of Curacao during the 2014–2015 
outbreak. J Clin Virology. 2017;86:31-38. 
 
Beesoon S, Funkhouser E, Kotea N, Spielman A, Robich RM. Chikungunya fever, 
Mauritius, 2006. Emerg Infect Dis. 2008 Feb;14(2):337-8. 
 
Blettery M, Brunier L, Polomat K, et al. Brief Report: Management of Chronic Post-
Chikungunya Rheumatic Disease: The Martinican Experience. Arthritis Rheumatol. 2016 
Nov;68(11):2817-2824. 
 
Brandler S, Ruffié C, Combredet C, et al.  A recombinant measles vaccine expressing 
chikungunya virus-like particles is strongly immunogenic and protects mice from lethal 
challenge with chikungunya virus. Vaccine. 2013 Aug 12;31(36):3718-25. 
 
Brito CAA, Teixeira MG. Increased number of deaths during a chikungunya epidemic in 
Pernambuco, Brazil. Mem Inst Oswaldo Cruz. 2017 Sep;112(9):650-651 
 
Burt FJ, Chen W, Miner JJ, et al. Chikungunya virus: an update on the biology and 
pathogenesis of this emerging pathogen. Lancet Infect Dis. 2017 Apr;17(4):e107-e117. 
 
Dupuis-Maguiraga L, Noret M, Brun S, et al. (2012) Chikungunya Disease: Infection-
Associated Markers from the Acute to the Chronic Phase of Arbovirus-Induced Arthralgia. 
PLoS Negl Trop Dis 6(3): e1446. 
 
Edington F, Varjão D, Melo P. Incidence of articular pain and arthritis after chikungunya 
fever in the Americas: A systematic review of the literature and meta-analysis. Joint Bone 
Spine. 2018 Jul 24. pii: S1297-319X(18)30145-3. 
 
Elsinga J, Gerstenbluth I, van der Ploeg S, et al. Long-term Chikungunya Sequelae in 
Curaçao: Burden, Determinants, and a Novel Classification Tool. J Infect Dis. 2017 Sep 
1;216(5):573-581. 
 
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Essackjee K, Goorah S, Ramchurn SK, Cheeneebash J, Walker-Bone K. Prevalence of 
and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years 
after infection with chikungunya virus.  Postgrad Med J. 2013 Aug;89(1054):440-7. 
 
FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). 
 
Freitas ARR, Alarcón-Elbal PM, Donalisio MR. Excess mortality in Guadeloupe and 
Martinique, islands of the French West Indies, during the chikungunya epidemic of 2014. 
Epidemiol Infect. 2018 Aug 28:1-7. 
 
Freitas ARR, Donalisio MR, Alarcón-Elbal PM. Excess Mortality and Causes Associated 
with Chikungunya, Puerto Rico, 2014-2015. Emerg Infect Dis. 2018 Dec 17;24(12). 
 
Gerardin P, Barau G, Michault A, et al. Multidisciplinary prospective study of mother-to-
child chikungunya virus infections on the island of La Réunion. PLoS Med 5: e60. (2008) 
doi:10.1371/journal.pmed.0050060. 
 
Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, Das T, Li-Pat-Yuen G, Dassa B, et al. 
Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in 
spite of a robust host immune response. J Immunol. 2010 May 15;184(10):5914-27. 
 
Javelle E, Ribera A, Degasne I, Gaüzère BA, Marimoutou C, Simon F. Specific 
management of post-chikungunya rheumatic disorders: a retrospective study of 159 
cases in Réunion Island from 2006-2012. PLoS Negl Trop Dis. 2015 Mar 
11;9(3):e0003603. 
 
Josseran L, Paquet C, Zehgnoun A, et al. Chikungunya disease outbreak, Reunion 
Island. Emerg Infect Dis. 2006 Dec;12(12):1994-5. 
 
Kelso JM, Greenhawt MJ, Li JT, Nicklas RA, et al. Adverse reactions to vaccines practice 
parameter 2012 update. J Allergy Clin Immunol. 2012 Jul;130(1):25-43. 
 
Liuba P, Aburawi EH, Pesonen E, et al. Residual adverse changes in arterial endothelial 
function and LDL oxidation after a mild systemic inflammation induced by influenza 
vaccination. Ann Med. 2007;39(5):392-399. 
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Lorin C, Segal L, Mols J, et al. Toxicology, biodistribution and shedding profile of a 
recombinant measles vaccine vector expressing HIV-1 antigens, in cynomolgus 
macaques. Naunyn. Schmiedebergs. Arch. Pharmacol. 2012;385:1211-1225. Published 
online: DOI 10.1007/s00210-012-0793-4. 
 
Lum FM, Ng LF. Cellular and molecular mechanisms of chikungunya pathogenesis. 
Antiviral Res. 2015 Aug;120:165-74. 
 
Marimoutou C, Vivier E, Oliver M, Boutin JP, Simon F. Morbidity and impaired quality of 
life 30 months after chikungunya infection: comparative cohort of infected and uninfected 
French military policemen in Réunion Island. Medicine (Baltimore). 2012 Jul;91(4):212-
219. 
 
Marimoutou C, Ferraro J, Javelle E, Deparis X, Simon F. Chikungunya infection: self-
reported rheumatic morbidity and impaired quality of life persist 6 years later.  Clin 
Microbiol Infect. 2015 Jul;21(7):688-93. 
 
McDade TW, Borja JB, Kuzawa CW, Perez TL, Adair LS. C-reactive protein response to 
influenza vaccination as a model of mild inflammatory stimulation in the Philippines. 
Vaccine. 2015 Apr 21;33(17):2004-8. 
 
McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS; Centers for Disease Control and 
Prevention.  Prevention of measles, rubella, congenital rubella syndrome, and mumps, 
2013: summary recommendations of the Advisory Committee on Immunization Practices 
(ACIP).  
 
Mavalankar D, Shastri P, Bandyopadhyay T, Parmar J, Ramani KV. Increased mortality 
rate associated with chikungunya epidemic, Ahmedabad, India. Emerg Infect Dis. 2008 
Mar;14(3):412-5. 
 
Mohd Zim MA, Sam IC, Omar SF, Chan YF, AbuBakar S, Kamarulzaman A. Chikungunya 
infection in Malaysia: comparison with dengue infection in adults and predictors of 
persistent arthralgia. J Clin Virol. 2013 Feb;56(2):141-5. 
 
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NCCCC (National Collaborating Centre for Chronic Conditions). Rheumatoid arthritis: 
national clinical guideline for management and treatment in adults. London: Royal College 
of Physicians, February 2009. 
 
PAHO 
Web 
site: 
http://www.paho.org/hq/index.php?option=com_topics&view=article&id=343&Itemid=40
931&lang=en 
 
Plotkin SA. Correcting a public health fiasco: The need for a new vaccine against Lyme 
disease. Clin Infect Dis. 2011 Feb;52 Suppl 3:s271-5. 
 
Poland GA. Vaccines against Lyme disease: What happened and what lessons can we 
learn? Clin Infect Dis. 2011 Feb;52 Suppl 3:s253-8. 
 
Rajapakse S, Rodrigo C, Rajapakse A. Atypical manifestations of chikungunya infection. 
Trans R Soc Trop Med Hyg. 2010 Feb;104(2):89-96. 
 
Ramsauer K, Schwameis M, Firbas C, et al. Immunogenicity, safety, and tolerability of a 
recombinant measles-virus-based chikungunya vaccine: a randomized, double-blind, 
placebo-controlled, active- comparator, first-in-man trial. Lancet Infect Dis. 2015;15:519-
527. 
 
Reisinger EC, Tschismarov R, Beubler E, et al. Immunogenicity, safety, and tolerability 
of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, 
randomised, placebo-controlled and active-controlled phase 2 trial. Lancet. 2018 Nov 5. 
pii: S0140-6736(18)32488-7. 
 
Rodriguez-Morales AJ, Restrepo-Posada VM, Acevedo-Escalante N, et al. Impaired 
quality of life after chikungunya virus infection: a 12-month follow-up study of its chronic 
inflammatory rheumatism in La Virginia, Risaralda, Colombia. Rheumatol Int. 2017 
Oct;37(10):1757-1758 
 
Rutherford GW (chair), Committee on the Assessment of Readjustment Needs of Military 
Personnel, Veterans and their Families, Returning Home from Iraq and Afghanistan: 
Assessment of the readjustment needs of veterans, service members, and their families.  
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Institue of Medicine. Washington, DC: National Academies Press, 2013. Chapter 3, 
“Characteristics of the Deployed,” accessed on 20 March 2019 at: 
https://www.ncbi.nlm.nih.gov/books/NBK206861/table/tab_3_4/?report=objectonly. 
 
Sanofi Pasteur, 284 Menactra package insert, v0.18, 16 September 2016, available at 
http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UC
M131170.pdf .  
 
Schilte C, Staikowsky F, Couderc T, Madec Y, Carpentier F, Kassab S, et al.  
Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal 
study.  PLoS Negl Trop Dis. 2013;7(3):e2137 
 
Sharp TM, Roth NM, Torres J, et al; Centers for Disease Control and Prevention (CDC).  
Chikungunya cases identified through passive surveillance and household investigations-
-Puerto Rico, May 5-August 12, 2014. MMWR Morb Mortal Wkly Rep. 2014 Dec 
5;63(48):1121-8. 
 
Shen AK, Mead PS, Beard CB. The Lyme disease vaccine--a public health perspective. 
Clin Infect Dis. 2011 Feb;52 Suppl 3:s247-52. 
 
Silva JVJ Jr, Ludwig-Begall LF, Oliveira-Filho EF, et al. A scoping review of Chikungunya 
virus infection: epidemiology, clinical characteristics, viral co-circulation complications, 
and control. Acta Trop. 2018 Dec;188:213-224. 
 
Simmons G, Brès V, Lu K, et al. High incidence of chikungunya virus and frequency of 
viremic blood donations during epidemic, Puerto Rico, USA, 2014. Emerg Infect Dis. 
2016;22(7):1221-1228. 
 
Simon F, Javelle E, Cabie A,et al. French guidelines for the management of chikungunya 
(acute and persistent presentations). November 2014. Med Mal Infect. 2015 
Jul;45(7):243-63. 
 
Sissoko D, Malvy D, Ezzedine K, Renault P, Moscetti F, Ledrans M, Pierre V. Post-
epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations 
and associated factors over a 15-month period. PLoS Negl Trop Dis. 2009;3(3):e389. 
 
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Staples JE, Breiman RF, Powers AM. Chikungunya fever: an epidemiological review of a 
re-emerging infectious disease. Clin Infect. Dis. 2009;49:942-948. 
 
Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with 
recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease 
Vaccine Study Group. N Engl J Med. 1998 Jul 23;339(4):209-215. 
 
van Aalst M, Nelen CM, Goorhuis A, Stijnis C, Grobusch MP. Long-term sequelae of 
chikungunya virus disease: A systematic review. Travel Med Infect Dis. 2017 Jan - 
Feb;15:8-22. 
 
van der Beek MT, Visser LG, de Maat MP. Yellow fever vaccination as a model to study 
the response to stimulation of the inflammation system. Vascul Pharmacol. 2002 
Aug;39(3):117-21. 
 
Vazeille M, Moutailler S, Coudrier D, et al. Two Chikungunya isolates from the outbreak 
of La Réunion (Indian Ocean) exhibit different patterns of infection in the mosquito, Aedes 
albopictus. PLoS ONE 2: (2007) e1168. doi:10.1371/journal.pone.0001168. 
 
Verschuur M, van der Beek MT, Tak HS, Visser LG, de Maat MP. Interindividual variation 
in the response by fibrinogen, C-reactive protein and interleukin-6 to yellow fever 
vaccination. Blood Coagul Fibrinolysis. 2004 Jul;15(5):399-404. 
 
Weaver SC, Lecuit M. Chikungunya Virus Infections. N Engl J Med. 2015 Jul 2;373(1):94-
5. 
 
WHO, Chikungunya: case definitions for acute, atypical and chronic cases: Conclusions 
of an expert consultation, Managua, Nicaragua, 20–21 May 2015, Weekly 
Epidemiological Record. 2015, Aug 14; 33(90): 409–420. 
 
Yang S, Fink D, Hulse A, Pratt RD. Regulatory considerations in development of vaccines 
to prevent disease caused by Chikungunya virus. Vaccine. 2017 Sep 5;35(37):4851-
4858. 
 
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Yaseen HM, Simon F, Deparis X, Marimoutou C. Identification of initial severity 
determinants to predict arthritis after chikungunya infection in a cohort of French 
gendarmes.  BMC Musculoskelet Disord. 2014 Jul 24;15:249. 
 
 
 
 
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19 Appendices 
 
19.1 Appendix 1: Adverse Event grading scales 
 
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19.1.1 Appendix Table A: Local Reaction to Injection 
 
Local Reaction to 
Injectable 
Product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain/Tenderness 
Does not interfere with 
activity 
Interferes with activity 
or repeated use of non- 
narcotic pain reliever 
 
Prevents daily 
activity or any use 
of narcotic pain 
reliever  
Emergency room 
(ER) visit or 
hospitalization 
Erythema/Redness 
2.5 - 5 cm 
5.1 – 10 cm  
> 10 cm  
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling 
≤ 5 cm and does not 
interfere with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or prevents 
daily activity 
Necrosis 
Itching 
Does not interfere 
with activity  
Interferes with 
activity or 
repeated use of 
non-narcotic pain 
reliever  
Prevents daily 
activity or repeated 
use of anti-
inflammatory, pain-
relieving ointment  
Emergency room (ER) 
visit or hospitalization  
 
 
 
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19.1.2 Appendix Table B: Solicited Systemic Adverse Events 
 
Systemic (General) 
Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening  
(Grade 4) 
Nausea/Vomiting 
No interference 
with activity or 1 – 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 
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 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Malaise  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents daily 
activity  
ER visit or hospitalization  
Myalgia  
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
ER visit or 
hospitalization 
Joint Pain*  
No interference with 
activity  
Some interference with 
activity  
Significant; prevents daily 
activity  
ER visit or hospitalization  
Fever 
(°C)  
(°F)  
 
38.0-38.4 
100.4-101.1 
 
38.5-38.9 
101.2-102.0 
 
39.0-40.0 
102.1-104.0 
 
>40.0 
>104.0 
*Non-traumatic joint pain or stiffness that persists for more than 24 hours, or is associated with objective findings of effusion or soft tissue swelling, will be 
considered an AESI. See the protocol Section 13.5 and the Investigator Site File for this study for additional reporting requirements. 
 
 
 
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19.1.3 Appendix Table C: Unsolicited Adverse Events 
 
Systemic Adverse Event 
(for solicited AEs 
occurring at other than 
solicited times, see Table 
B) 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Illness or Clinical 
Adverse Event (as 
defined according to 
applicable regulations) 
No interference with 
activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
ER visit or 
hospitalization 
 
 
 
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19.1.4 Appendix Table D: Vital Signs 
 
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 
Fever 
(°C)  
(°F)  
 
38.0-38.4 
100.4-101.1 
 
38.5-38.9 
101.2-102.0 
 
39.0-40.0 
102.1-104.0 
 
>40.0 
>104.0 
* Subjects should be at rest for all vital sign measurements. 
** Use clinical judgment to characterize bradycardia among some healthy populations, for example, conditioned athletes. 
 
 
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19.1.5 Appendix Table E: Laboratory Results 
 
 Laboratory test 
Mild (Grade 1)  
Moderate (Grade 2)  
Severe (Grade 3)  
Potentially Life Threatening (Grade 4)** 
Sodium – Hyponatremia mEq/L  
132 – < LLN***  
130 – 131  
125 – 129  
< 125  
Sodium – Hypernatremia mEq/L  
> ULN*** – 145  
146 – 147  
148 – 150  
> 150  
Potassium – Hyperkalemia mEq/L  
> ULN – 5.2  
5.3 – 5.4  
5.5 – 5.6  
> 5.6  
Potassium – Hypokalemia mEq/L  
3.5 – < LLN  
3.3 – 3.4  
3.1 – 3.2  
< 3.1  
Glucose – Hypoglycemia mg/dL  
65 – < LLN  
55 – 64  
45 – 54  
< 45  
Glucose – Hyperglycemia  
  Fasting – mg/dL  
Random – mg/dL  
 
> ULN – 110  
> ULN – 125  
 
111 – 125  
126 – 200  
 
> 125  
> 200  
 
Insulin requirements or hyperosmolar coma  
Blood Urea Nitrogen mg/dL  
> ULN– 26  
27 – 31  
> 31  
Requires dialysis  
Bilirubin – when Liver Function 
Test is normal; increase by factor  
1.1 – 1.5 x ULN  
1.6 – 2.0 x ULN  
2.0 – 3.0 x ULN  
> 3.0 x ULN  
Hemoglobin (Female) - gm/dL  
11.0 – < LLN  
9.5 – 10.9  
8.0 – 9.4  
< 8.0  
Hemoglobin (Female)  
decrease from baseline - gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
Hemoglobin (Male) - gm/dL  
12.5 to < LLN  
10.5 – 12.4  
8.5 – 10.4  
< 8.5  
Hemoglobin (Male)  
decrease from baseline – gm/dL  
Any decrease – 1.5  
1.6 – 2.0  
2.1 – 5.0  
> 5.0  
WBC Increase - cell/mm3  
> ULN – 15,000  
15,001 – 20,000  
20,001 – 25, 000  
> 25,000  
WBC Decrease - cell/mm3  
2,500 – < LLN  
1,500 – 2,499  
1,000 – 1,499  
< 1,000  
Lymphocytes Decrease - cell/mm3  
750 – < LLN  
500 – 749  
250 – 499  
< 250  
Neutrophils Decrease - cell/mm3  
1,500 – < LLN  
1,000 – 1,499  
500 – 999  
< 500  
Eosinophils - cell/mm3  
> ULN – 1500  
1501 - 5000  
> 5000  
Hypereosinophilic  
Platelets Decreased - cell/mm3  
125,000 – < LLN  
100,000 – 124,000  
25,000 – 99,000  
< 25,000  
** 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 subject had a new seizure associated with the low sodium value.  
*** LLN=lower limit of the normal range; ULN=upper limit of the normal range. 
 
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19.2 Appendix 2: SF-36 Quality of Life Survey  
 
 
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19.2.1 SF-36 Quality of Life Survey in English
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This 36-Item Health Survey (SF-36) was developed by RAND as part of the Medical Outcomes Study. 
For more information see their web-site: https://www.rand.org. 
 
SF-36 Quality of Life Survey 
 
 
 
 
Choose one option for each questionnaire item. 
 
 
1. In general, would you say your health is: 
 
 
  
 
 
 
 
 
 
2. Compared to one year ago, how would you rate your health in general now? 
 
 
 
 
 
 
 
 
 
The following items are about activities you might do during a typical day. Does your 
health now limit you in these activities? If so, how much? 
 
3. Vigorous activities, such as running, lifting heavy objects, participating in strenuous 
sports? 
 
 
 
 
 
 
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For more information see their web-site: https://www.rand.org. 
 
4. Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or 
playing golf? 
 
 
 
 
 
 
5. Lifting or carrying groceries? 
 
 
 
 
 
 
6. Climbing several flights of stairs? 
 
 
 
 
 
 
7. Climbing one flight of stairs? 
 
 
 
 
 
 
8. Bending, kneeling, or stooping? 
 
 
 
 
 
 
9. Walking more than a mile? 
 
 
 
 
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10. Walking several blocks? 
 
 
 
 
 
  
11. Walking one block (about 100 meters)? 
 
 
 
 
 
 
12. Bathing or dressing yourself? 
 
 
 
 
 
 
 
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of your physical health? 
 
 
13. Cut down the amount of time you spent on work or other activities? 
 
 
 
 
 
14. Accomplished less than you would like? 
 
 
 
 
 
15. Were limited in the kind of work or other activities? 
 
 
 
 
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16. Had difficulty performing the work or other activities (for example, it took extra 
effort)? 
 
 
 
 
  
During the past 4 weeks, have you had any of the following problems with your work or 
other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
 
17. Cut down the amount of time you spent on work or other activities? 
 
 
 
 
18. Accomplished less than you would like? 
 
 
 
 
 
19. Didn't do work or other activities as carefully as usual? 
 
 
 
 
 
 
20. During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, neighbors, or 
groups? 
 
 
 
 
 
 
 
 
 
 
 
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For more information see their web-site: https://www.rand.org. 
21. How much bodily pain have you had during the past 4 weeks? 
 
 
 
 
 
 
 
 
 
22. During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
 
 
 
 
 
 
 
 
 
These questions are about how you feel and how things have been with you during the 
past 4 weeks. For each question, please give the one answer that comes closest to the 
way you have been feeling.   
 
How much of the time during the past 4 weeks... 
 
23. Did you feel full of pep? 
 
 
 
 
 
 
 
 
  
 
 
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24. Have you been a very nervous person? 
 
 
 
 
 
 
 
 
 
25. Have you felt so down in the dumps that nothing could cheer you up? 
 
 
 
 
 
 
 
 
 
26. Have you felt calm and peaceful? 
 
 
 
 
 
 
 
 
  
27. Did you have a lot of energy? 
 
 
 
 
 
 
 
 
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28. Have you felt downhearted and blue? 
 
 
 
 
 
 
 
 
 
29. Did you feel worn out? 
 
 
 
 
 
 
 
 
 
30. Have you been a happy person? 
 
 
 
 
 
 
 
 
  
31. Did you feel tired? 
 
 
 
 
 
 
 
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32. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with friends, 
relatives, etc.)? 
 
 
 
 
 
 
 
 
 
How TRUE or FALSE is each of the following statements for you. 
 
33. I seem to get sick a little easier than other people. 
 
 
 
 
 
 
 
 
34. I am as healthy as anybody I know. 
 
 
 
 
 
 
 
  
35. I expect my health to get worse. 
 
 
 
 
 
 
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36. My health is excellent. 
 
 
 
 
 
 
 
 
 
 
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19.2.2 SF-36 Quality of Life Survey in Spanish
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Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
 
Encuesta de Calidad de Vida SF-36 
 
 
 
 
 
Marque una sola respuesta: 
 
1. En general, usted diría que su salud es: 
 
 
 
  
 
 
 
 
 
 
2. En comparación con hace un año, ¿cómo diría que es su salud actualmente? 
 
 
 
 
 
 
 
 
Las siguientes preguntas se refieren a actividades o cosas que usted podría hacer en 
un día normal. Su salud actual, ¿le limita en estas actividades?  Si es así, ¿cuánto? 
 
3. ¿Actividades intensas, tales como correr, levantar objetos pesados, o participar en 
deportes agotadores? 
 
 
 
 
 
 
 
 
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Study Protocol: MV-CHIK-206, WRAIR #2629  
 
 
Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
4. ¿ Actividades moderadas, como mover una mesa, pasar la aspiradora, jugar a los 
bolos o jugar al golf? 
 
 
 
 
 
 
5. ¿Levantar o llevar comestibles? 
  
 
 
 
 
 
6. ¿Subir varios pisos por la escalera? 
 
 
 
 
 
 
7. ¿Subir un solo piso por la escalera? 
 
 
 
 
 
 
8. ¿Doblar, arrodillarse o agacharse? 
 
 
 
 
 
 
9. ¿Caminar más de una milla? 
 
 
 
 
 
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Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
10. ¿Caminar varias cuadras? 
 
 
 
 
 
  
11. ¿Caminar una cuadra (unos 100 metros)? 
 
 
 
 
 
 
12. ¿Bañarse o vestirse por sí mismo? 
 
 
 
 
 
 
 
Durante las últimas 4 semanas, ¿ha tenido usted alguno de los siguientes problemas 
con su trabajo u otras actividades diarias regulares como resultado de su salud 
física? 
 
13. ¿Tuvo que reducir el tiempo dedicado al trabajo o a sus otras actividades? 
 
 
 
 
 
14.¿Hizo menos de lo que hubiera querido hacer? 
 
 
 
 
 
15.¿Estuvo limitado en el tipo de trabajo o otras actividades? 
 
 
 
 
 
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Study Protocol: MV-CHIK-206, WRAIR #2629  
 
 
Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
16.¿Tuvo dificultad para hacer su trabajo o sus actividades (por ejemplo, le costó más 
esfuerzo)? 
 
 
 
 
 
 
Durante las últimas 4 semanas, ¿ha tenido alguno de los siguientes problemas con su 
trabajo u otras actividades diarias regulares como resultado de cualquier problema 
emocional (como sentirse deprimido o ansioso)? 
  
 
17.¿Tuvo que reducir el tiempo dedicado al trabajo o a otras actividades? 
 
 
 
 
 
18.¿Hizo menos de lo que hubiera querido hacer? 
 
 
 
 
 
19.¿No hizo su trabajo o otras actividades tan cuidadosamente como de costumbre? 
 
 
 
 
 
20. Durante las 4 últimas semanas, ¿hasta qué punto su salud física o los problemas 
emocionales han interferido con sus actividades sociales habituales con familiares, 
amigos, vecinos o grupos? 
 
 
 
 
 
 
 
 
21. ¿Cuánto dolor de cuerpo ha tenido durante las 4 últimas semanas? 
 
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Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
 
 
 
 
 
 
 
 
 
22. Durante las 4 últimas semanas, ¿hasta qué punto el dolor le ha dificultado su 
trabajo habitual (incluido el trabajo fuera de casa y las tareas domésticas)? 
 
 
 
 
 
 
 
 
 
Las preguntas que siguen se refieren a cómo se ha sentido y cómo le han ido las cosas 
durante las 4 últimas semanas.  En cada pregunta responda lo que se parezca más a 
cómo se ha sentido usted. Durante las 4 últimas semanas, ¿cuánto tiempo… 
 
23. ¿Se sintió lleno de vitalidad? 
 
 
 
 
 
 
 
 
  
 
 
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Study Protocol: MV-CHIK-206, WRAIR #2629  
 
 
Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
24. ¿Ha sido usted una persona muy nerviosa? 
 
 
 
 
 
 
 
 
 
25. ¿Se ha sentido tan bajo en ánimo que nada podía animarle? 
 
 
 
 
 
 
 
 
 
26. ¿Se ha sentido calmado y tranquilo? 
 
 
 
 
 
 
 
 
  
27. ¿Tuvo mucha energía? 
 
 
 
 
 
 
 
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Study Protocol: MV-CHIK-206, WRAIR #2629  
 
 
Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
28. ¿Se sintió desanimado y triste? 
 
 
 
 
 
 
 
 
 
29. ¿Se sintió agotado? 
 
 
 
 
 
 
 
 
 
30. ¿Ha sido una persona feliz? 
 
 
 
 
 
 
 
 
  
31. ¿Se sintió cansado? 
 
 
 
 
 
 
 
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Study Protocol: MV-CHIK-206, WRAIR #2629  
 
 
Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
 
32. Durante las 4 últimas semanas, ¿con qué frecuencia su salud física o los 
problemas emocionales han interferido con sus actividades sociales (como visitar a 
los amigos o familiares, etcétera)? 
 
 
 
 
 
 
 
 
Diga si le parece CIERTA o FALSA cada una de las siguientes frases. 
 
 
33. Parece que me pongo enfermo más fácilmente que otras personas. 
 
 
 
 
 
 
 
 
34. Estoy tan saludable como cualquier persona que conozco. 
 
 
 
 
 
 
 
 
35. Creo que mi salud va a empeorar. 
 
 
 
 
 
 
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Version 2.1, 23 December 2020 
 
Esta encuesta de salud de 36 artículos (SF-36) fue desarrollada por RAND como parte del estudio, “the 
Medical Outcomes Study” y fue traducido por el equipo de estudio MV CHIK 206. 
Para obtener más información, consulte su sitio web: https://www.rand.org. 
 
 
36. Mi salud es excelente. 
 
 
 
 
 
 
 
 
 
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19.2.3 Terms and Conditions for Using the SF-36
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DF/Net Research Inc. 
Building Relationships  
With People And Their Data 
140 Lakeside Avenue, Suite 310 
Seattle, WA 98122 USA 
1-206-322-5931 / phone 
1-206-322-5932 / fax 
www.dfnetresearch.com 
 
 
CLINICAL STATISTICAL ANALYSIS PLAN 
DF/Net Research, Inc. 
 
 
PHASE 2 STUDY OF A LIVE ATTENUATED MEASLES VIRUS-VECTORED CHIKUNGUNYA VACCINE IN 
PREVIOUSLY EXPOSED ADULTS
 
Client: Themis 
Protocol: MV-CHIK-206 Version 2.1, 23DEC2020 
 
 
SAP Version: 2 
Date of Version: 20AUG2021 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or institutional 
review boards.  The contents of this document shall not be disclosed to others without written 
authorization from Themis (or others, as applicable), unless it is necessary to obtain informed consent 
from potential study subjects. 
 
 
 
 
Page 1 of 22
0806B2

V ersi o n 2 ( 2 0 2 1- 0 8- 2 0)
T h e mis M V- C HI K- 2 0 6 
Pr ot oc ol V ersi o n 2. 1 ( 2 0 2 0- 1 2- 2 3)
S h ar e P oi nt/ T e a m Sit e/S O Ps/S O P 4. 0 1 
T e m pl at e V ersi o n D at e: 2 0 1 9- 0 2- 1 5
P a g e 2 of 2 0
S P O N S O R A P P R O V AL
B y si g ni n g b el o w, I c ertif y t h at I a p pr ov e of t h e St atistic al A n al ysis Pl a n f or t his pr oj ect.
Pri nt e d N a m e a n d Titl e:
, T h e mis Bi osci e nc e G m b H
Si g n at ur e a n d A p pr o v al D at e:
D F/ N E T A P P R O V AL
B y si g ni n g b el o w, I c ertify t h at I a p pr ov e of t h e St atistic al A n al ysis Pl a n f or t his pr oj ect. I als o c ertify t h at 
t h e a n al ys es will b e p erf or m e d i n acc or d a nc e wit h t his St atistic al A n al ysis Pl a n.
Pri nt e d N a m e a n d Titl e:
 D F/ N et R es e arc h I nc.
Si g n at ur e a n d A p pr o v al D at e:
P a g e 2 of 2 2
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P P D
P P D
0 8 0 6 B 2

V ersi o n 2 ( 2 0 2 1- 0 8- 2 0) 
T h e mis M V- C HI K- 2 0 6  
Pr ot oc ol V ersi o n 2. 1 ( 2 0 2 0- 1 2- 2 3) 
S h ar e P oi nt/ T e a m Sit e/S O Ps/S O P 4. 0 1  
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R e visi o n Hist or y 
 
V ersi o n  
D at e  
A ut h or(s)  
Or g a niz ati o n(s)  
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D F/ N et R es e arc h, I nc.  
N e w d oc u m e nt  
2. 0  
2 0 A U G 2 0 2 1  
 
D F/ N et R es e arc h, I nc.  
U p d at es m a d e t o b e 
c o nsist e nt wit h t h e u p d at e d 
v ersi o n 2. 1 of t h e pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS  
1-INTRODUCTION .............................................................................................. 5 
2-STUDY OBJECTIVES ......................................................................................... 5 
2.1 
Primary Objective ............................................................................................... 5 
2.2 
Secondary Objectives .......................................................................................... 5 
2.3 
Exploratory Objectives ........................................................................................ 5 
3-STUDY ENDPOINTS ......................................................................................... 6 
3.1 
Primary Endpoint ................................................................................................ 6 
3.2 
Secondary Endpoints .......................................................................................... 6 
3.3 
Exploratory Endpoints ......................................................................................... 6 
4-DEFINITIONS .................................................................................................. 6 
5-STUDY DESIGN................................................................................................ 7 
6-STUDY POPULATION ....................................................................................... 8 
6.1       Inclusion Criteria ................................................................................................. 8 
6.2 
Exclusion Criteria ................................................................................................ 9 
6.3 
Withdrawal of Study Subject ............................................................................. 10 
6.4 
Randomization and Blinding ............................................................................. 10 
6.5 
 Schedule of Events ........................................................................................... 11 
7-SAMPLE SIZE................................................................................................. 12 
7.1 
Determination of Sample Size ........................................................................... 12 
8-STATISTICAL CONSIDERATIONS ..................................................................... 12 
8.1 
Demographic and Other Baseline Characteristics .............................................. 13 
8.2        Study Objective Analyses .................................................................................. 13 
8.2.1 Primary Endpoints ..............................................................................................13 
8.2.2 Secondary Endpoints ..........................................................................................13 
8.2.3 Exploratory Endpoints ........................................................................................14 
8.3 
Subject Disposition ........................................................................................... 14 
8.4
Vaccine Exposure.............................................................................................. 14
8.5 
Concomitant Medications ................................................................................. 14 
8.6 
Safety Laboratory Tests ..................................................................................... 14 
8.7 
Vital Signs and Physical Exam Findings .............................................................. 15 
8.8 
Missing Values .................................................................................................. 15 
9-STUDY DISCONTINUATION ............................................................................ 15 
10-SUGGESTED TABLES/LISTINGS/FIGURES ...................................................... 16 
APPENDIX I: ABBREVIATIONS ........................................................................... 19 
 
 
 
 
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1-INTRODUCTION 
The purpose of this document is to describe the reporting and statistical analyses that will guide 
the preparation of the clinical portion of the final study report for Themis study MV-CHIK-206.  
The study report will be prepared after all data in the database have been reviewed, all data 
queries have been resolved and the database has been locked.  
All individual subject listings, summary tables, and statistical analyses described below will be 
provided in separate appendices to the study report. Unless other indicated, all listings and 
summary tables will be provided by treatment assignment, subject identifier and visit. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials [ICH 1998] and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports [ICH 1995].  
2-STUDY OBJECTIVES 
The main objective of this trial is to evaluate the safety and immunogenicity of an investigational 
live recombinant measles-vectored chikungunya vaccine (MV-CHIK) delivered in 2 vaccinations, 
28 days apart compared with saline placebo.  
2.1 Primary Objective 
To determine the safety of MV-CHIK administered in 2 doses separated by 28 days in previously 
exposed individuals. 
2.2 Secondary Objectives 
To determine the immunogenicity by a neutralization assay of MV-CHIK administered in 2 doses 
separated by 28 days in previously exposed individuals. 
2.3 Exploratory Objectives 
To assess the relationship of Quality-of-Life scores and acute phase reactants with adverse events 
experienced post-vaccination. 
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3-STUDY ENDPOINTS 
3.1 Primary Endpoint 
 Solicited AEs (fever, fatigue, headache, malaise, myalgia, nausea/vomiting, joint pain or 
injection site itching, pain/tenderness, erythema/redness or induration/swelling)  
 Unsolicited AEs including clinically significant abnormal safety laboratory results, vital 
signs, and physical examination findings 
 Solicited and unsolicited AEs of grade 2 and higher. 
3.2 Secondary Endpoints 
 Fold-increase from Day 0 in geometric mean titer (GMT) of neutralizing antibodies to 
chikungunya on Days 28, 56, and at the end of the study. 
3.3 Exploratory Endpoints 
 Change in serum C-reactive protein levels from pre-vaccination to three days 
postvaccination in recipients of MV-CHIK versus placebo. 
 Changes in plasma fibrinogen from pre-vaccination to seven days post-vaccination in 
recipients of MV-CHIK versus placebo. 
 Changes from baseline in Quality-of-Life survey (SF36) scores at four weeks post-
vaccination and at the end of the study in recipients of MV-CHIK versus placebo. 
4-DEFINITIONS 
The following definitions apply to the summary tables and statistical analyses planned for the 
study report: 
Screened population: All subjects who signed informed consent. 
Intent-to-treat (ITT) population: Subjects who receive at least one dose of vaccine and will be the 
population for the safety analyses. 
Per-Protocol (PP) population: A subset of the ITT population that includes subjects who received 
both doses of IVP, have at least one post-vaccination immunogenicity assessment, and do not 
experience a protocol deviation that would affect their evaluation for immunogenicity. The 
protocol deviations that affect evaluation for immunogenicity will be determined based on a 
blinded data review prior to database lock.  
Baseline value: Endpoint value at Day 0 
Visit Day: Planned visit based on schedule of events, each visit day has a range of allowed days 
from previous visit. 
Study Day: Number of days from Visit Day 0, with day on Day 0 equal to 1 and the day before Day 
0 equal to -1. 
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Protocol Deviation: Any noncompliance with the clinical trials protocol, Good Clinical Practice 
(GCP), or SOP requirements. Noncompliance may be either on the part of the subject, the 
investigator, or the study site staff.  
5-STUDY DESIGN 
This will be a prospective randomized double-blind interventional clinical trial to evaluate the 
safety and immunogenicity of MV-CHIK in two intramuscular injections 28 days apart versus 
placebo. Consented study subjects will be screened for baseline seropositivity to chikungunya 
virus, with or without a clinical history of chikungunya infection, and then randomized to receive 
either MV-CHIK (the experimental vaccine) or saline (the placebo) in a blinded fashion in a 1:1 
ratio. One dose level (5×105 TCID50) of MV-CHIK will be studied. Subjects will be followed for 
safety and immunogenicity for 24 weeks after completing the series. Because rheumatologic 
symptoms of chikungunya infection are more likely, more severe and more persistent in older 
patients, this study will initially be limited to adults aged 21 to 50 years of age (Step 1). After at 
least 20 volunteers in Step 1 have been vaccinated, a DSMB will review the safety data and, with 
their recommendation, the study will proceed to Step 2 and enroll subjects aged 51 to 65 years. 
The study schematic is: 
 
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6-STUDY POPULATION 
The study will be conducted in Puerto Rico where a chikungunya epidemic occurred in 2014 but 
where transmission is now negligible. Individuals will be screened until 30 subjects are vaccinated 
for each Step. Subjects still under treatment for symptoms attributed to a previous chikungunya 
virus infection will be excluded from the study. Subjects who attribute only mild and subjective 
symptoms such as fatigue to previous chikungunya infection may be eligible at investigator 
discretion; subjects with acute chikungunya infection will be excluded but may re-screen no 
sooner than 3 months after symptoms (other than mild subjective symptoms not requiring 
treatment) have resolved. This study will measure, but not control for, baseline Quality-of-Life 
using the SF36 questionnaire. The seroprevalence of chikungunya in San Juan is approximately 
23.5% [Simmons 2016]. Up to 500 subjects may be screened for each Step but it is hoped that 
existing databases of seropositive study volunteers will allow enrollment to be completed much 
more efficiently. 
Subjects will not be randomized unless all inclusion and no exclusion criteria, including lab test 
results, are met. Subjects who fail to meet criteria because of an identifiable temporary condition 
or who cannot be randomized within the 60-day screening window may repeat the screening 
evaluation up to two times after the initial screening (total of three) at the discretion of the 
Investigator. 
6.1 Inclusion Criteria 
1. Previous infection with chikungunya as verified by a serum immunoassay. 
2. Age appropriate for the Step being conducted: 
a. 
enrollment for Step 1. 
b. 
 
3. Able to provide informed consent. 
4. Available and accessible for the duration of the trial. 
5. Able and willing to comply with all requirements of the study. 
6. For women of childbearing potential, willing to practice adequate contraception (see 
Definition of Terms) for the duration of the study. This is similar to recommendations 
following MMR vaccination [McLean 2013] but for a longer duration (six months versus 
one month) due to the higher concentration of measles virus and the lack of reproductive 
or developmental toxicology data on MV-CHIK. 
7. Medical history and physical examination findings are considered normal or not clinically 
significant in the opinion of the Investigator, which includes resolution of any arthralgias 
that may have occurred during prior chikungunya infection, as well as the absence of 
synovitis. 
8. Laboratory values are considered normal or not clinically significant in the opinion of the 
Investigator. If laboratory screening tests are out of the normal reference range and of 
potential clinical significance, the test(s) may be repeated up to 2 times (a total of 3 per 
screening evaluation) at the discretion of the Investigator, and the repeat values and their 
potential clinical significance will be used to determine eligibility. 
9. History of immunity to measles. For persons born after 1957, this will be established by a 
history of compliance with vaccination policies that included measles vaccination or 
known vaccination as an adult at least one month before they are randomized. Volunteers 
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born before 1957 will be presumed to have immunity to measles based on natural 
exposure in accordance with CDC guidelines [McLean 2013]. 
6.2 Exclusion Criteria  
1. Taking medication or other treatment for unresolved symptoms attributed to a previous 
chikungunya virus infection. 
2. Prior receipt of any investigational chikungunya or other alphavirus vaccine. To date, no 
alphavirus vaccines have been commercially available in the United States. 
3. Recent infection: 
a. self-limited upper respiratory infections until afebrile without medication for >1 
week; 
b. chikungunya unless/until asymptomatic (other than mild subjective symptoms not 
requiring treatment) for >3 months; 
c. non-recurrent upper respiratory or urinary tract infections successfully treated 
with antibiotics, until asymptomatic for 1 month after full antibiotic course has 
been completed. 
4. History of an acute allergic or anaphylactic reaction to any vaccine. 
5. History of an immunosuppressive disorder (such as HIV infection, Common Variable 
Immune Deficiency), chronic infection (such as chronic hepatitis B or C), autoimmune 
disease (such as rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune 
thyroid disease), or any medical condition that, in the opinion of the Investigator, could 
lead to an atypical immune response to the vaccine. 
6. History of moderate or severe non-traumatic arthritis or arthralgia within 3 months of the 
Screening Visit. 
7. Recent (within 30 days), current or anticipated use of any immunosuppressive or immune 
modifying medication including corticosteroids (excluding nasal, ophthalmic, and other 
topical preparations). 
8. Other vaccination or planned vaccination within 4 weeks of either study dose (within 2 
weeks for seasonal influenza vaccine). 
9. Receipt or planned receipt of blood products including immunoglobulins within 120 days 
of the Screening Visit.
10. Pregnant or lactating or planning pregnancy during the trial. 
11. Known alcohol or other substance abuse that in the opinion of the Investigator affects the 
ability or willingness of the subject to understand and comply with the study protocol. 
12. Participation in another clinical study within the past 30 days in which the subject was 
exposed to an investigational product (pharmaceutical product or placebo or device) or 
planned participation in another interventional clinical study while participating in this 
study. 
13. Relevant history of any medical condition that, in the opinion of the Investigator, may 
interfere with the safety of the subject or aims of the study. 
14. History of neoplastic disease (excluding successfully treated non-melanoma skin cancer or 
cervical intraepithelial neoplasia) within the past 5 years or a history of any hematological 
malignancy. 
15. Behavioral or psychiatric disease or cognitive impairment that in the opinion of the 
Investigator affects the ability or willingness of the subject to understand and comply with 
the study protocol. 
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16. Non-consent to storage of blood specimens for future research. 
17. Persons in direct relationship with the Sponsor or its contracted service providers, the 
CRO or its subcontractors, the Investigator, or study site staff. Direct relationship includes 
first degree relatives or dependents (children, spouse/partner, siblings or parents), as well 
as employees (site or Sponsor). Employees of the San Juan City Hospital not directly 
employed by the Research Unit will not be excluded. 
6.3 Withdrawal of Study Subject  
A subject has the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or the institution. 
Subjects may also be withdrawn from the study if the Investigator determines that the subject 
should be withdrawn due to any unforeseen circumstance that may affect the safety of the 
subject, staff or the integrity of the study. 
6.4 Randomization and Blinding 
Initially, thirty (30) Step 1 subjects will be randomized at Visit 1, Day 0 using a Clinical Data 
Management System (CDMS). Subsequent to DSMB review, another thirty (30) Step 2 subjects 
will be enrolled and randomized at their Visit 1, Day 0. Visit 1 occurs after Screening (Visit S, Day -
60 to -3) and includes enrollment, randomization and vaccine administration. At Visit 1 subjects 
will be randomized after enrollment and before vaccine administration. Subjects in each Step will 
be assigned to one of two groups. Block randomization of appropriate size will accommodate 
balanced enrollment in ratio of 1:1 into each of the two treatment groups for the planned 30 
Step 1 and 30 Step 2 subjects. 
 
 
 
The list of randomized treatment assignments will be prepared by statisticians at DF/Net 
Research. The blinded randomization number will be provided through the randomization 
module in the data management system. The designated unblinded site personnel will be 
provided with the unblinded treatment key, which links the randomization number to the actual 
treatment assignment and should be securely stored.  
Instructions for use of the data management system for randomization will be included in the 
Study Specific Procedures (SSP) Manual. The SSP will also detail the manual backup 
randomization procedures in the event that the site temporarily loses access to the internet or 
the randomization module is unavailable. All documentation of the randomization procedure and 
output will be maintained by DF/Net until the end of the study. 
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Vaccine administration will be double-blind, with the Investigator, study coordinator, all study 
personnel involved in assessing AEs and the subject being unaware of the treatment assignment. 
To achieve this, the thawed MV-CHIK vaccine and saline will be given the same wait time after 
procurement to allow both temperature equalization and non-discrepant wait times between 
treatments. Furthermore, only designated site personnel (pharmacist, etc.), unblinded CRAs and 
the unblinded biostatistician (at DF/Net) will have access to the treatment assignments. 
 the 
safety data may be unblinded upon Sponsor or DSMB request. 
6.5  Schedule of Events 
 
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7-SAMPLE SIZE
7.1 Determination of Sample Size 
60 subjects are intended to be enrolled in the study. A formal sample size calculation was not 
conducted for this study. The sample size was determined based on prior experience in 
evaluating the safety and immunogenicity of vaccines and is typical for early phase clinical 
studies. In previous studies MV-CHIK was associated with joint pain in about 4% of previously 
unexposed recipients. The largest study to date is MV-CHIK 202 in which 9/229 reported joint 
pain (95% confidence interval: 1.8 to 7.3%). A higher risk of joint pain in previously exposed 
individuals would be suggested if 4/15 individuals who receive MV-CHIK in either Step 1 or 2 of 
the current study develop joint pain (95% confidence interval: 7.8% to 55.1%) while the placebo 
group develops none. 
It is not possible to define a statistical threshold of safety that will rule out any increased risk of 
this vaccine in previously exposed individuals or guarantee market acceptance of this or any 
vaccine for an infection associated with joint pain, as demonstrated by the experience with 
LYMErix. This study is not expected to provide a final answer on whether or not to continue 
development of this vaccine candidate, but rather contribute to the incremental gathering of 
information on vaccine safety. In this regard, the details of individual cases including the time 
course and severity of their symptoms and the associated changes in their acute phase reactants 
and quality of life scores, will have to be examined individually. A qualitative description of these 
events to include their assessed causality, severity, duration, and association with evidence of 
inflammation and immunopathology will provide critical data to inform the consent of 
participants in field trials conducted in areas of on-going transmission. 
8-STATISTICAL CONSIDERATIONS
SAS® version 9.3 or higher will be used for statistical analyses and the production of tables, 
listings, and figures (TLFs). 
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Categorical variables will be summarized using the number frequency and percentage by Step, 
treatment and overall of subjects falling into each category. Continuous variables will be 
summarized using mean, standard error or standard deviation, median, minimum, maximum, and 
number of subjects with observations by Step of subjects falling into each category. Continuous 
variables will be summarized using mean, standard error or standard deviation, median, 
minimum, maximum, and number of subjects with observations treatment and overall. 
8.1 Demographic and Other Baseline Characteristics 
Demographics will be summarized by age (in years, at time of signing informed consent), gender 
and ethnicity. Baseline characteristics and medical history will also be summarized by relevant 
characteristics and classifications. 
8.2 Study Objective Analyses 
8.2.1 Primary Endpoints  
All verbatim terms for any reported AEs will be coded to the appropriate system organ class and 
preferred term according to the current version of MedDRA and graded by the Investigator for 
severity as per the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adults Enrolled 
in Vaccine Clinical Trials; 2007. The number and percentage of subjects experiencing an AE (all, 
serious, and vaccine-related) will be reported. 
All AEs will be summarized by IVP received according to the MedDRA system organ class (SOC) 
and preferred term. An additional summary will be provided for the incidence of all AEs by 
severity. Summaries will be presented for SAEs, AEs of grade 2 (moderate) and higher, IVP-
related AEs, AESIs, and AEs where an action was taken. All AE data will be listed by subject, and a 
separate listing will include all SAEs, including any deaths on study. 
Adverse events will also be summarized separately for solicited and unsolicited events. Specific 
local injection site reactions (erythema/redness, induration/swelling, itching, and 
pain/tenderness) will be solicited using the subject diary from 0 to 7 days after each injection and 
Investigator interviews at follow-up visits. Specific systemic AEs (fever, fatigue, headache, 
malaise, myalgia, nausea/vomiting and joint pain) will be solicited using the subject diary from 0 
to 7 days and Investigator interviews at follow-up visits. Unsolicited AEs will be all of those 
excluding the preferred terms of solicited AEs. Similar summaries will be presented for solicited 
and unsolicited AEs as noted above. 
8.2.2 Secondary Endpoints 
Analyses of immunogenicity will be conducted in the PP population according to IVP received. 
Chikungunya virus neutralizing antibody titer values which are less than the assay cut-off of 10 
ED50 titer will be replaced with half the assay cut-off (i.e. 5 ED50 titer). The analysis of 
immunogenicity will be measured as GMTs of neutralizing antibodies on Days 0, 28, 56, and at 
EOS. The GMT will be calculated using a mixed effects model with IVP (MV-CHIK versus placebo), 
visit and study Step (age group) and treatment visit interaction as fixed factors and subject as a 
random effect. The analysis of variance will be fit using log10 transformed data. The estimates for 
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the least squares means and corresponding 95% confidence intervals (CIs) will be back-
transformed by taking the anti-log to obtain the GMTs and CIs. 
The following will be summarized quantitatively: 
 Fold-increase from Day 0 in geometric mean titer (GMT) of neutralizing antibodies to 
chikungunya on Days 28, 56, and at the end of the study. 
8.2.3 Exploratory Endpoints 
The following will be summarized quantitatively: 
 Change in serum C-reactive protein levels from pre-vaccination to three days 
postvaccination in recipients of MV-CHIK versus placebo. 
 Changes in plasma fibrinogen from pre-vaccination to seven days post-vaccination in 
recipients of MV-CHIK versus placebo. 
 Changes from baseline in Quality-of-Life survey (SF36) scores at four weeks 
postvaccination and at the end of the study in recipients of MV-CHIK versus placebo. 
8.3 Subject Disposition 
The following will be summarized categorically: 
 Subjects in each of the populations. 
 Subjects randomized and who received at least one dose of IVP. 
 Subjects with protocol deviations and reason for deviation. 
 Subjects who discontinued the study early along with the reasons for discontinuation. 
 Screen failures and reasons for screen failure. 
 Subjects at each study visit, and the number of subjects with important protocol 
deviations. 
8.4 Vaccine Exposure 
The number and percentage of subjects who receive only one of the IVP doses and the number 
and percentage of subjects who receive both of the IVP doses will be summarized. 
8.5 Concomitant Medications 
Concomitant medications will be coded by WHODrug. The number and percentage of subjects 
who received each category of medication will be summarized by IVP administered. 
8.6 Safety Laboratory Tests 
Clinical laboratory test results and changes from baseline will be summarized by time point. 
Clinically significant abnormal laboratory results will also be captured as AEs. Abnormal results of 
CRP, fibrinogen or ferritin will not be captured as AEs. 
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8.7 Vital Signs and Physical Exam Findings
Vital signs results (including blood pressure, heart rate, and body temperature) and changes from 
baseline will be summarized by time point. Abnormal vital signs will be graded and findings from 
physical examinations will be assessed for clinical significance and included in the tabular 
summaries and by-subject AE listings.
8.8 Missing Values 
The intervention is not expected to have any effect on missing data. As such, any missing data will 
be considered Missing Completely At Random (MCAR) and will be assumed to have no effect on 
the analysis and no imputations will be performed. All attempts will be made to prevent missing 
data. An observed cases approach will be applied for all endpoints. 
9-STUDY DISCONTINUATION
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the IRB, 
Investigator, Sponsor, DoD Research Monitor or regulatory authorities will be promptly reported 
to the HRPO.  
 
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10-SUGGESTED TABLES/LISTINGS/FIGURES 
Type 
Title 
Population 
Listing
L16.2.1.1- Patient Disposition: Screen Failures, Patients Enrolled and 
Eligibility 
Screened 
Listing
L16.2.1.2- Patient Disposition: Study Summary 
ITT 
Listing
L16.2.1.3- Patient Disposition: Visit Summary 
ITT 
Listing
L16.2.1.3- Patient Disposition: Patients Who Discontinued or Were Lost 
to Follow-Up 
ITT 
Listing
L16.2.2.1-Inclusion/Exclusion Criteria 
Screen 
Failures 
Listing
L16.2.2.2-Protocol Deviations
ITT 
Listing
L16.2.3-Patients Excluded from the Per-Protocol Population
ITT
Listing
L16.2.4.1-Demographics 
ITT 
Listing
L16.2.4.2-Medical History 
ITT 
Listing
L16.2.5.1-Vaccine Exposure 
ITT 
Listing
L16.2.5.2-Concomitant Medications 
ITT 
Listing
L16.2.6.1-Chikungunya Serology 
ITT 
Listing
L16.2.6.2-Neutralizing Antibody to Chikungunya 
ITT 
Listing
L16.2.6.3-C-Reactive Protein 
ITT 
Listing
L16.2.6.4-Fibrinogen 
ITT 
Listing
L16.2.6.5-SF-36 Quality of Life Scores 
ITT 
Listing
L16.2.7.1-Adverse Events
ITT 
Listing
L16.2.7.2-Serious Adverse Events 
ITT 
Listing
L16.2.7.3-Adverse Events of Grade 2 or Higher 
ITT 
Listing
L16.2.7.4-Study Injection-Related Adverse Events 
ITT 
Listing
L16.2.7.5-Adverse Events of Special Interest 
ITT 
Listing
L16.2.7.6-Adverse Events with an Action Taken 
ITT 
Listing
L16.2.7.7-Solicited Adverse Events 
ITT 
Listing
L16.2.7.8-Unsolicited Adverse Events 
ITT 
Listing
L16.2.8.1-Ferritin 
ITT 
Listing
L16.2.8.2-Serology Laboratory Results 
ITT 
Listing
L16.2.8.3-Urinanalysis Laboratory Results 
ITT 
Listing
L16.2.8.4-Pregnancy Test Laboratory Results 
ITT 
Listing
L16.2.8.5-Complete Blood Count Laboratory Results 
ITT 
Listing
L16.2.8.6-Metabolic Panel Laboratory Results 
ITT 
Listing
L16.2.9-Vital Signs 
ITT 
Listing
L16.2.10-Physical Examination Findings 
ITT 
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Listing
L16.2.11-Pregnancy Report 
ITT 
Table 
T14.1.1.1-Disposition Summary of Screen Failures 
Screened 
Table 
T14.1.1.2-Disposition Summary 
Screened 
Table 
T14.1.1.3-Protocol Deviation Summary 
ITT 
Table 
T14.1.1.4-Visit Summary 
ITT 
Table 
T14.1.2-Demographic Summary 
ITT 
Table 
T14.2.1.1-Neutralizing Antibodies to Chikungunya Summary 
PP 
Table 
T14.2.1.2-Fold-increase from Baseline in Neutralizing Antibodies to 
Chikungunya Summary 
PP 
Table 
T14.2.1.3-Statistical Analysis of Neutralizing Antibodies to Chikungunya
Summary 
PP 
Table 
T14.2.2-Change in Serum C-reactive Protein Levels (mg/L) Summary 
PP 
Table 
T14.2.3-Change in Plasma Fibrinogen (mg/dL) Summary
PP 
Table 
T14.2.4-Change in SF-36 Quality of Life Scores Summary 
PP 
Table 
T14.3.1.1.1-Adverse Events Summary 
ITT 
Table 
T14.3.1.1.2-Incidence of Adverse Events by System Organ Class and 
Preferred Term Summary 
ITT 
Table 
T14.3.1.1.3- Incidence of Serious Adverse Events by System Organ Class 
and Preferred Term Summary 
ITT 
Table 
T14.3.1.1.4- Incidence of Adverse Events of Grade 2 or Higher by 
System Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.1.5- Incidence of Adverse Events of Special Interest by System 
Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.1.6- Incidence of Adverse Events by System Organ Class and 
Preferred Term, by Severity 
ITT 
Table 
T14.3.1.1.7- Incidence of Adverse Events by System Organ Class and 
Preferred Term, by Relationship to Study Injection 
ITT 
Table 
T14.3.1.1.8- Incidence of Adverse Events with an Action Taken by 
System Organ Class and Preferred Term 
ITT 
Table 
T14.3.1.2.1-Solicited Adverse Events Summary 
ITT 
Table 
T14.3.1.2.2-Incidence of Solicited Adverse Events by System Organ 
Class and Preferred Term Summary
ITT 
Table 
T14.3.1.2.3- Incidence of Solicited Serious Adverse Events by System 
Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.2.4- Incidence of Solicited Adverse Events of Grade 2 or Higher 
by System Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.2.5- Incidence of Solicited Adverse Events of Special Interest by 
System Organ Class and Preferred Term Summary 
ITT 
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Table 
T14.3.1.2.6- Incidence of Solicited Adverse Events by System Organ 
Class and Preferred Term, by Severity 
ITT 
Table 
T14.3.1.2.7- Incidence of Solicited Adverse Events by System Organ 
Class and Preferred Term, by Relationship to Study Injection 
ITT 
Table 
T14.3.1.2.8- Incidence of Solicited Adverse Events with an Action Taken 
by System Organ Class and Preferred Term 
ITT 
Table 
T14.3.1.3.1-Unsolicited Adverse Events Summary 
ITT 
Table 
T14.3.1.3.2-Incidence of Unsolicited Adverse Events by System Organ 
Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.3.3- Incidence of Unsolicited Serious Adverse Events by System 
Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.3.4- Incidence of Unsolicited Adverse Events of Grade 2 or 
Higher by System Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.3.5- Incidence of Unsolicited Adverse Events of Special Interest 
by System Organ Class and Preferred Term Summary 
ITT 
Table 
T14.3.1.3.6- Incidence of Unsolicited Adverse Events by System Organ 
Class and Preferred Term, by Severity 
ITT 
Table 
T14.3.1.3.7- Incidence of Unsolicited Adverse Events by System Organ 
Class and Preferred Term, by Relationship to Study Injection 
ITT 
Table 
T14.3.1.3.8- Incidence of Unsolicited Adverse Events with an Action 
Taken by System Organ Class and Preferred Term 
ITT 
Table 
T14.3.4.1-Serology Laboratory Results at Screening Summary 
ITT 
Table 
T14.3.4.2-Urinalysis Laboratory Results Summary at Screening
ITT 
Table 
T14.3.4.3-Pregnancy Test Laboratory Results Summary 
ITT 
Table 
T14.3.4.4-Complete Blood Count Laboratory Results Summary 
ITT 
Table 
T14.3.4.5-Metabolic Panel Laboratory Results Summary 
ITT 
Table 
T14.3.5.1-Vaccine Exposure Summary 
ITT 
Table 
T14.3.5.2-Incidence of Concomitant Medications by ATC Level 4 and 
Preferred Drug Name
ITT 
Table 
T14.3.5.3-Vital Signs Summary
ITT 
Table 
T14.3.5.4-Physical Examination Summary 
ITT 
 
 
 
 
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APPENDIX I: ABBREVIATIONS 
 Abbreviation 
Meaning 
AE 
Adverse event  
AESI 
Adverse event of special interest 
BMP 
Basic metabolic panel 
CBC 
Complete blood count 
CDC 
US Centers for Disease Control and Prevention 
CDMS 
Clinical Data Management System 
CI 
Confidence Interval
CRA 
Clinical Research Associate (study monitor) 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
DoD 
Department of Defense 
DSMB 
Data Safety Monitoring Board 
EOS 
End-of-study 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GmbH 
Gesellschaft mit beschränkter Haftung (German for Limited Liability 
Company) 
GMT 
Geometric Mean Titer 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (of the MRMC) 
ICH 
International Conference on Harmonization 
ID 
Identification 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IVP 
Investigational vaccine product (used to indicate either MV-CHIK or 
placebo) 
MCAR 
Missing Completely at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
Measles, Mumps and Rubella vaccine 
MRMC 
US Army Medical Research and Materiel Command 
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MV-CHIK
Measles-vectored chikungunya vaccine 
PP 
Per-protocol 
QoL 
Quality-of-life
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SF36 
Standardized quality-of-life questionnaire 
SOC 
System-organ-class 
SOP 
Standard Operating Procedure 
SSP 
Study Specific Procedure 
TCID, TCID50
Tissue culture infective dose; the subscript refers to the percent of cells 
in culture that are infected after inoculation. 
US, USA 
United States of America 
WHO 
World Health Organization 
WHODrug 
An internal classification of medicines 
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