A Phase II Randomized, Double Blind, Parallel Group Dose-ranging Study of Oral RV3-BB Rotavirus Vaccine Administered at a High, Mid and Low Titre as a 3 Dose Neonate Schedule or Administered at a High Titre as a 3 Dose Infant Schedule.
Phase: PHASE2
Conditions: Rotavirus Infections
Sponsor: Murdoch Childrens Research Institute

 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase II randomised, double blind, parallel group 
dose-ranging study of oral RV3-BB Rotavirus Vaccine 
administered at a titre of 1x107, 3 x 106 or 1 x 106 as a 
3 dose neonate schedule or administered at a titre of 
1x107as a 3 dose infant schedule. 
Protocol Number: 
MCRI-RV3-BB-004 
Investigational Product: 
RV3-BB Rotavirus Vaccine 
Study Phase: 
II 
Indication: 
Prevention of rotavirus gastroenteritis in neonates and 
infants 
Sponsor: 
Murdoch Children’s Research Institute (MCRI) 
Royal Children’s Hospital 
Flemington Road 
Parkville, Victoria 3052, Australia 
Tel: 
 
Fax: 
 
Sponsor Protocol Approval: 
  
Principal Investigator: 
 
Version / Date: 
4.0 / 11 January 2019 
 
This document includes information and data that contain trade secrets and privileged or confidential information 
which is the property of Murdoch Childrens Research Institute.  This information must not be made public without 
written permission from Murdoch Childrens Research Institute.  These restrictions on disclosure will apply equally to 
all future information supplied to you.  This material may be disclosed to and used by your staff and associates as may 
be necessary to conduct the clinical study. 
 
 

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SPONSOR SIGNATURE PAGE 
 
 
 
Name: 
 
Title: 
 
 
Murdoch Children’s Research Institute 
Royal Children’s Hospital 
Flemington Road 
Parkville, Victoria, 3052 
Australia 
 
Signature:  
Date: 
 
 
 
Lead RV3 Rotavirus Vaccine Program

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INVESTIGATOR STATEMENT 
The undersigned Investigator agrees: 
1. 
To conduct the study in accordance with the study protocol, International Council on 
Harmonisation Good Clinical Practice and any national and local laws and 
regulations. 
2. 
That alteration of the procedures described in the study protocol, other than to 
protect participant safety, rights, or welfare, is not allowed without prior written 
approval MCRI and ethics committee approval. 
3. 
The study-specific data of the participants will be kept in the participants’ files and 
documented in the case report form in a complete and accurate manner.  All 
requested study-related records will be made available for direct access to MCRI 
representatives for monitoring or auditing the study. 
4. 
To allow authorised qualified delegates of MCRI to perform regular visits to monitor 
the study data. 
5. 
To dispose of used and unused Investigational Product and materials as instructed 
by MCRI. 
6. 
To ensure that all persons at their site assisting with the clinical study are 
adequately informed and trained about the study protocol, the Investigational 
Product and their study-related duties and functions. 
 
Name: 
 
 
Signature: 
 
 
Date: 
 
 
 

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TABLE OF CONTENTS 
1 
ABBREVIATIONS ..................................................................................................... 7 
2 
PROTOCOL SYNOPSIS ............................................................................................ 9 
3 
INTRODUCTION ..................................................................................................... 16 
3.1 
Rotavirus disease ........................................................................................... 16 
3.2 
The first licensed Rotavirus Vaccine ............................................................. 16 
3.3 
Current Globally Licensed Rotavirus Vaccines ............................................. 17 
3.4 
Current locally licensed Rotavirus vaccines .................................................. 18 
3.5 
Limitations of the current rotavirus vaccines ................................................. 19 
3.5.1 
Challenges to Rotavirus Vaccine Implementation ........... 20 
3.6 
Rationale for the development of Rotavirus Vaccine RV3-BB ..................... 20 
3.6.1 
Advantages of the birth dose strategy ............................... 21 
3.6.2 
Potential advantage of the P[6] genotype of RV3 ............ 22 
3.7 
Development of RV3 ..................................................................................... 22 
3.7.1 
Immunity Conferred by RV3 Infection ............................ 22 
3.8 
Development of RV3 Rotavirus Vaccine (RV3-BB) ..................................... 23 
3.8.1 
Phase I clinical study of RV3-BB ..................................... 23 
3.8.2 
Phase IIa immunogenicity study of RV3-BB ................... 24 
3.8.3 
Phase IIb efficacy study of RV3-BB ................................ 25 
3.9 
Dose and study rationale for current study .................................................... 26 
4 
STUDY OBJECTIVES ............................................................................................. 28 
4.1 
Primary Objective .......................................................................................... 28 
4.2 
Secondary Objectives .................................................................................... 28 
4.3 
Exploratory Objectives .................................................................................. 29 
5 
TRIAL PLAN ............................................................................................................ 30 
5.1 
Study Design .................................................................................................. 30 
5.2 
Study Population ............................................................................................ 32 
5.2.1 
Number of Participants and Study Sites ........................... 32 
5.2.2 
Trial Selection Record ...................................................... 32 
5.2.3 
Inclusion Criteria .............................................................. 32 
5.2.4 
Exclusion Criteria ............................................................. 32 
5.3 
Screening failures .......................................................................................... 33 
5.4 
Concomitant medications and vaccines ......................................................... 33 
6 
TRIAL PROCEDURES ............................................................................................ 34 
6.1 
Recruitment .................................................................................................... 36 
6.1.1 
Informed Consent ............................................................. 36 
6.2 
Birth Procedures ............................................................................................ 36 
6.3 
Visit 1 Procedures (0-5 days of age) .............................................................. 36 
6.4 
Visit 2 (7 ±1 days after Visit 1) ..................................................................... 38 
6.5 
Visit 3 (Week 6 +7 days) ............................................................................... 38 
6.6 
Visit 4 Procedure (7 ±1 days after Visit 3) .................................................... 38 
6.7 
Visit 5 (Week 10 ±7 days) ............................................................................. 39 
6.8 
Visit 6 (7 ±1 days after Visit 5) ..................................................................... 39 
6.9 
Visit 7 (Week 14 ±7 days) ............................................................................. 39 
6.10 
Visit 8 (7 ±1 days after Visit 7) ..................................................................... 40 
6.11 
Visit 9 (Week 18 ±7 days) ............................................................................. 40 
6.12 
Discontinuation of Participants ...................................................................... 41 
6.12.1 
Criteria for discontinuation ............................................... 41 
7 
TRIAL ENDPOINTS ................................................................................................ 42 
8 
TRIAL MEASUREMENTS AND OUTCOMES ..................................................... 42 
8.1 
Eligibility assessments ................................................................................... 42 
8.2 
Immunogenicity ............................................................................................. 43 
8.3 
Safety ............................................................................................................. 43 
8.4 
Diarrhoea capture ........................................................................................... 43 

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8.5 
Exploratory .................................................................................................... 44 
8.6 
Central laboratories ........................................................................................ 44 
9 
CONCOMITANT MEDICATIONS AND VACCINES ........................................... 45 
9.1 
Concomitant medications............................................................................... 45 
9.2 
Routine Concurrent Vaccines ........................................................................ 45 
10 INVESTIGATIONAL PRODUCT ........................................................................... 46 
10.1 
Special Warnings and Precautions for use of IP ............................................ 46 
10.2 
Labelling and Packaging ................................................................................ 47 
10.3 
Storage requirements ..................................................................................... 47 
10.4 
IP accountability ............................................................................................ 47 
10.5 
Doses and treatment regimens ....................................................................... 48 
10.6 
Method for Assigning Participants to Treatment Group ................................ 48 
10.7 
Blinding and procedures for breaking the blind............................................. 49 
10.8 
Preparation and Dispensing of IP .................................................................. 49 
10.9 
IP administration and treatment compliance .................................................. 49 
10.9.1 
Incomplete administration of IP ....................................... 50 
10.9.2 
Criteria for temporary delay of IP dose ............................ 50 
11 ADVERSE EVENTS ................................................................................................ 51 
11.1 
Adverse event definitions .............................................................................. 51 
11.2 
Serious Adverse Events ................................................................................. 52 
11.2.1 
SAE exceptions ................................................................ 52 
11.3 
Recording of AEs ........................................................................................... 52 
11.4 
Management and follow-up of AEs and SAEs .............................................. 53 
11.5 
Reporting of Serious Adverse Events ............................................................ 53 
12 STUDY OVERSIGHT .............................................................................................. 54 
12.1 
Medical Monitors ........................................................................................... 54 
12.2 
Steering Committee ....................................................................................... 54 
12.3 
Data Safety Monitoring Board ....................................................................... 54 
13 STATISTICS AND DATA EVALUATION ............................................................ 54 
13.1 
Sample Size Assumptions .............................................................................. 54 
13.2 
Analysis Sets .................................................................................................. 55 
13.3 
Data Analysis Considerations ........................................................................ 55 
13.3.1 
Demographics and Baseline Data ..................................... 56 
13.3.2 
Immunogenicity Analyses ................................................ 56 
13.4 
Safety Data ..................................................................................................... 56 
13.4.1 
Extent of exposure ............................................................ 56 
13.4.2 
Adverse events .................................................................. 56 
13.4.3 
Other safety measures ....................................................... 56 
14 DATA MANAGEMENT .......................................................................................... 57 
15 TRIAL MANAGEMENT .......................................................................................... 58 
15.1 
Contacts ......................................................................................................... 58 
15.2 
Quality control and Quality Assurance .......................................................... 58 
15.2.1 
Monitoring ........................................................................ 58 
15.2.2 
Audits and Inspections...................................................... 58 
15.3 
Training of Staff ............................................................................................. 59 
15.4 
Changes to the Protocol ................................................................................. 59 
15.5 
Trial Agreements ........................................................................................... 59 
15.6 
Trial Timetable and Termination ................................................................... 59 
15.7 
Ethics and regulatory review ......................................................................... 59 
15.8 
Ethical Conduct of the Trial ........................................................................... 60 
15.9 
Insurance and Liability .................................................................................. 60 
15.10 Participant Information and Consent ............................................................. 60 
15.11 Data Protection .............................................................................................. 60 
15.12 Archiving ....................................................................................................... 61 

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15.13 Emergency Procedures .................................................................................. 61 
15.14 Publication Policy .......................................................................................... 61 
16 REFERENCES .......................................................................................................... 62 
17 APPENDICES ........................................................................................................... 66 
17.1 
Appendix 1: Modified Vesikari Grading Scale for Gastroenteritis in Children
 ....................................................................................................................... 66 
 
List of In-text Figures 
Figure 1. Rotavirus Vaccine Introductions. ....................................................................... 19 
Figure 2. Study Design ...................................................................................................... 31 
 
List of In-text Tables 
Table 1:  Schedule of Procedures ....................................................................................... 34 
Table 2:  Identity of IP ....................................................................................................... 46 
 
 

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1 ABBREVIATIONS 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
BCG 
Bacillus Calmette-Guérin (vaccine) 
CPMP 
Committee for Proprietary Medicinal Products 
CRA 
Clinical Research Associate  
CRF 
Case Report Form 
D 
Day 
DMP 
Data Management Plan 
DSMB 
Data Safety Monitoring Board 
ELISA 
enzyme-linked immunosorbent assay 
EPI 
Expanded Programme on Immunisation 
FFU 
Fluorescing cell focus units 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GIT 
Gastro-intestinal tract (symptoms) 
GLP 
Good Laboratory Practice 
cGMP 
Current Good Manufacturing Practice 
HBGA 
Histo-blood group antigen 
HEENM 
Head, ears, eyes, nose and mouth 
HepB 
Hepatitis B 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IP 
Investigational Product 
IPV 
Inactivated polio vaccine 
ITT 
Intention-to-Treat 
kg 
Kilogram 
L 
Litre 
LLR 
Lanzhou Lamb Rotavirus Vaccine 
MCRI 
Murdoch Children’s Research Institute 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Millilitre 
mITT 
Modified Intention-to-treat 
NIP 
National Immunisation Programme  
NIS 
National Immunisation Schedule  
OPV 
Oral polio vaccine 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PICF 
Participant Information and Consent Form 
PP 
Per Protocol 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse transcription and polymerase chain reaction 
RV3 
RV3 (serotype G3) strain of rotavirus 
RV3-BB 
Second generation RV3 rotavirus vaccine 
SAE 
Serious adverse event 
SAGE 
Strategic Advisory Group of Experts (on Immunization) 

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SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SD 
Standard Deviation 
SNA 
Serum Neutralising Antibodies 
SOP 
Standard Operating Procedure 
SRM 
Study Reference Manual 
U 
Units 
ULN 
Upper limit of normal 
USA 
United States of America 
WHO 
World Health Organisation 
WHO-DD 
World Health Organisation - Drug Dictionary 
 
 

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2 PROTOCOL SYNOPSIS 
Title: 
A Phase II randomised, double blind, parallel group dose-ranging study of 
oral RV3-BB Rotavirus Vaccine administered at a titre of 1x107, 3 x 106 or 
1 x 106 as a 3 dose neonate schedule or administered at a titre of 1x107as a 
3 dose infant schedule. 
Indication: 
Prevention of rotavirus gastroenteritis in neonates and infants 
Sites: 
The study will be conducted at approximately four sites in Malawi. 
Duration: 
18 weeks per participant. 
The recruitment period is expected to be approximately 9 months, with total 
study duration of approximately 15 months. 
Objectives: 
Primary: 
• To assess a cumulative anti-rotavirus serum IgA response (defined as a 
≥3 fold increase from baseline) 4 weeks after 3 doses of RV3-BB 
administered in a neonatal schedule at a vaccine titre of 1x107, 3 x 106 
or 1 x 106. 
Secondary: 
• To assess the cumulative anti-rotavirus serum IgA response (defined as 
a ≥3 fold increase from baseline) 4 weeks after 3 doses of RV3-BB 
administered in an infant schedule at a vaccine titre of 1 x 107. 
• To assess cumulative vaccine take and components of vaccine take after 
three doses of RV3-BB (titre of 1 x 107) administered as a neonatal 
schedule versus three doses of RV3-BB (titre of 1 x 107) administered 
as an infant schedule.  
• To assess cumulative vaccine take and the components of RV3-BB 
vaccine take after 3 doses of RV3-BB administered as a neonatal 
schedule at a vaccine titre of 1 x 107, 3 x 106 or 1 x 106  
• To assess cumulative vaccine take and components of vaccine take after 
2 doses of RV3-BB administered as a neonatal schedule at a vaccine titre 
of 1 x 107, 3 x 106 or 1 x 106 or 2 doses as an infant schedule at a vaccine 
titre of 1 x 107, 
• To assess cumulative vaccine take and components of vaccine take after 
the first dose of RV3-BB administered as a neonatal schedule at a vaccine 
titre of 1 x 107, 3 x 106 or 1 x 106 compared to placebo (1st dose of IP in 
the infant schedule). 
• To assess cumulative vaccine take and components of vaccine take after 
the first dose of RV3-BB at a vaccine titre of 1 x 107, 3 x 106 or 1 x 106 
in the neonatal schedule compared with the first dose of RV3-BB at a 
vaccine titre of 1 x 107 in the infant schedule. 

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• To describe the geometric mean titre of the anti-rotavirus serum IgA 
response after 3 doses of RV3-BB administered as a neonatal schedule or 
an infant schedule. 
• To describe the safety and tolerability of RV3-BB when administered as 
an infant or as a neonatal schedule.  
• To describe the occurrence of diarrhea episodes in participants, according 
to severity and detection of wild-type rotavirus. 
Exploratory: 
• To understand potential barriers to RV3-BB vaccine efficacy in the 
region: 
o To describe Histo-blood Group Antigens (Lewis and secretor) 
status of participants in association with anti-rotavirus sero-
conversion and cumulative vaccine take after 3 doses RV3-BB 
administered in either the neonatal schedule (any titre) or infant 
schedule.   
o To assess maternal anti-rotavirus IgA and IgG levels in 
association 
with 
anti-rotavirus 
IgA 
seroconversion 
and 
cumulative vaccine take in participants following receipt of RV3-
BB administered in either the neonatal schedule (at any vaccine 
titre) or infant schedule at a vaccine titre of 1 x 107.  
o To describe the gut microbiome in participants receiving RV3-
BB administered in the neonatal schedule (at any vaccine titre) or 
infant schedule at a vaccine titre of 1 x 107. 
o To describe innate and adaptive immune responses in infants 
vaccinated with RV3-BB administered in the neonatal vaccine 
schedule (any titre) or in the infant schedule at a vaccine titre of 
1 x 107. 
Design 
This is a Phase II, randomised, double blind, four arm parallel group study.  
Approximately 688 participants will be randomised 
Methodology 
The parents/guardians of potential study participants will be required to 
provide written informed consent prior to any study-specific procedures 
being performed. 
Antenatal recruitment: Pregnant women will be invited to provide 
preliminary consent for the study prior to labour and delivery, to provide 
them with adequate opportunity to consider the decision and to allow 
collection of a maternal blood sample and cord blood. Following delivery, 
parents/guardians who remain interested will be invited to provide written 
informed consent for their infant to participate in the study. 
Following the provision of consent and confirmation of eligibility for the 
trial, each participant will be randomly allocated in a blinded manner in a 

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1:1:1:1 ratio to one of the following four treatment arms. Each study 
participant will receive four oral doses of IP, with each administration 
consisting of 1 mL RV3-BB Rotavirus Vaccine at one of three different dose 
strengths or a dose of 1mL of placebo.  All participants will receive 4 doses 
in total, 3 of RV3-BB vaccine and one of placebo.  The first dose will be 
prior to 5 days (144 hours) of age, the second at approximately 6 weeks of 
age, the third at approximately 10 weeks of age and the final dose at 
approximately 14 weeks of age, according to the following treatment arms; 
• High dose neonatal RV3-BB vaccine schedule (1x107titre dose).  RV3-
BB Vaccine for doses 1, 2 and 3 and placebo for dose 4. 
• Mid dose neonatal RV3-BB vaccine schedule (3x106titre dose).  RV3-
BB Vaccine for doses 1, 2 and 3 and placebo for dose 4. 
• Low dose neonatal RV3-BB vaccine schedule (1x106titre dose).  RV3-
BB Vaccine for doses 1, 2 and 3 and placebo for dose 4. 
• Infant RV3-BB vaccine schedule (1x107titre dose).  Placebo for dose 1 
and RV3-BB Vaccine for doses 2, 3 and 4. 
All participants will also receive a single dose of oral Rotarix®, at 
approximately 18 weeks of age. 
A maternal blood sample, up to approximately 1.0mL, will be collected 
after preliminary consent, any time during the second or third trimester of 
pregnancy or after delivery of the placenta.  Cord blood, up to 
approximately 2.5mL, will be collected immediately following delivery of 
the placenta. Where cord blood is unavailable for collection a 1.0mL blood 
sample will be collected at Visit 1 prior to IP administration. 
A saliva sample will be collected on all randomised participants prior to the 
first administration of IP to determine histo-blood group antigen status 
(genotype) (Lewis and secretor). Saliva will also be collected at IP dosing 
visits prior to dosing to determine histo-blood group antigen to monitor 
changes in expression during the study. 
 
A baseline stool sample will be collected from pre-consented participants 
any time prior to the administration of the first dose of IP.  A Stool sample 
will be collected from randomised participants on day 3, 4 or 5 following 
each dose of IP. Samples will also be collected for any cases of diarrhoea 
(defined as 3 or more stools within a 24 hour period that are looser than 
normal for that participant). Up to two samples will be collected during 
each diarrhoea episode. Stool and diarrhoea samples will be tested at the 
local study laboratory for excretion of rotavirus using PCR. 
 
Up to approximately 1-2.5 mL venous blood will be collected from 
randomised participants within the 2 days prior to each IP dose and at 18 
weeks. 

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Participants will be followed up for the duration of the study, until 18 
weeks of age.  Face to face visits will be conducted at least monthly. 
Adverse events, including diarrhoea episodes, will be recorded for the 
duration of the study. 
Entry Criteria 
Inclusion criteria: 
• Neonate is less than 6 days (≤144 hours) of age at the time of first 
dose. 
• Neonate is in good health as determined by clinical judgment, 
including a medical history and physical exam, which confirms the 
absence of a current or past disease state considered significant by 
the investigator. 
• Neonate birth weight 2500-4000g inclusive or 2250-4000g inclusive 
at Visit 1. 
• Neonate’s parents/guardians expect to be available for the duration 
of the study, and agree to adhere to all protocol requirements. 
• Neonate’s parents/guardians have provided written informed 
consent prior to study-related procedures being performed. 
Exclusion criteria: 
• Any medical, psychiatric, or social condition of a parent/guardian 
that in the opinion of the investigator would prevent the neonate’s 
parents/guardians from giving proper informed consent or from 
complying with the study protocol. 
• Neonates with known or suspected major congenital malformations 
or genetically determined disease. 
• Neonates with intussusception. 
• Neonates with a known or suspected bleeding diathesis, or any 
condition that may be associated with a prolonged bleeding time. 
• Neonates who have ever received any blood products, including 
immunoglobulin, or for whom receipt of any blood product during 
the course of the study is anticipated. 
• Neonates in whom EPI vaccines or components are contraindicated. 
• Neonates who have received or who expect to receive during the 
study period, any rotavirus vaccine other than those which will be 
administered as part of this study. 
• Neonates who have ever received, or who are anticipated to receive 
during the study period, any investigational agent other than those 
which will be administered as part of this study  
• Neonates with a previous anaphylactic reaction to any drug, vaccine 
or vaccine component. 
• Neonates with a significant evolving neurological disorder. 

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• Neonates whose parents/guardians are site team employees with 
direct involvement with the investigators, or who are working on the 
study. 
• Neonates who have been exposed to immunosuppressive courses of 
glucocorticosteroids, cytotoxic drugs or blood products through 
prenatal exposure and/or breast milk in the four weeks prior to 
randomisation should be discussed with the Medical Monitor and 
sponsor and a decision on eligibility made on a case by case basis.  
• Neonates with diarrhoea or vomiting in the 24 hours preceding 
randomisation. 
• Neonates with any moderate or severe illness, and/or who have a 
temperature of ≥37.5˚C axillary/oral or ≥38˚C rectal/tympanic 
within the 48 hours preceding randomisation. 
IP, Dose and 
Mode of 
Administration 
Each active dose of RV3-BB will be given orally as 1 mL of RV3-BB 
Rotavirus Vaccine. 
The doses are as follows: 
• 1 x 107 FFU/mL 
• 3 x 106 FFU/mL 
• 1 x 106 FFU/mL 
Each dose of placebo will be given orally as 1 mL of cell culture 
medium/10% sucrose. 
The 2nd, 3rd and 4th doses of IP will be preceded by a 2 ml dose of antacid 
solution (Mylanta Original) to neutralise stomach acidity. 
Endpoints 
Immunogenicity will be assessed through: 
• Serum anti-rotavirus IgA response (defined as a ≥3 fold increase 
from baseline) at each serum collection time-point to 4 weeks 
after 3 doses of RV3-BB.  
• Vaccine take defined as at least a threefold increase in serum anti-
rotavirus immunoglobulin A (IgA) from baseline to post IP 
dosing, or detectable RV3 shedding in stools (by ELISA or PCR) 
any day from day 3 to 5 following administration of IP.  
• Cumulative vaccine take defined as vaccine take observed at the 
current assessment time point or following any previous dose. 
• Anti-rotavirus IgA response (defined as at least a threefold 
increase from baseline to post IP dosing) at each serum collection 
time point. 
• Presence of RV3 shedding in stools (by ELISA or PCR) from day 
3 to 7 following each dose of IP. 

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• Anti-rotavirus IgA titres defined as geometric mean titres at each 
serum collection time point. 
• Episodes of diarrhea, from the time of randomisation to 28 days 
following the last dose of IP. Episodes will be confirmed by 
Rotavirus antigen ELISA on samples. 
Safety and tolerability 
Safety and tolerability will be assessed through: 
• Unsolicited Adverse Events (AE) in the days 0-28 following each 
dose of IP. 
• Serious Adverse Events (SAE) from the first dose of IP until 28 
days post last dose of IP. 
• Review of episodes of blood in stool. 
Exploratory 
Exploratory endpoints will be assessed through: 
• HBGA Lewis and secretor status will be determined by 
ELISA/PCR on saliva collected at Visits 1, 3, 5 and 7 and using 
whole blood at week 18 for non secretors. 
• Maternal serum IgA and IgG response will be determined on 
maternal serum sample collected pre study or at Visit 1. 
• Bacterial taxonomic and genetic functional profiling of stool 
microbiome will be conducted on maternal stool samples and 
participant stool samples collected post administration of IP and 
at birth (prior to first IP dose). 
• B and T cell function will be measured by flow cytometry and 
innate and adaptive responses measured by whole killed pathogen 
assay and Toll like receptor ligand assays from whole blood 
collected at birth (cord), Visit 3 and Visit 9. 
Sample Size 
and Statistical 
Analyses 
With the high titre RV3-BB neonatal vaccine schedule as the active control 
arm, the sample size is calculated to demonstrate the non-inferiority of the 
lower titre vaccine arms with respect to the proportion of participants who 
have a serum IgA response 4 weeks after 3 doses of vaccine. A non-
inferiority margin of 20% for the difference between arms will be used. The 
primary analysis is based on the per protocol population defined as 
participants who receive all 3 doses and have no major protocol violations. 
Thirty percent of participants are expected to be excluded from the per 
protocol (PP) population due to death, study withdrawal, loss to follow-up, 
or study non-compliance. Among those in the PP population, a 50% 
response probability is assumed for the active controls. Based on a one-
sided 0.025 level score test with 90% power under the alternative of no 

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difference in response probabilities, 172 participants per arm are required 
for a total sample size of 688 participants. 
Non-inferiority of the lower titre vaccine will also be assessed in the 
intention to treat population (ITT). The cumulative probability of response 
by 18 weeks of age will be estimated by the Kaplan-Meier method for each 
vaccine arm. The difference between high and low titre arms in the 
cumulative probabilities and its 95% confidence interval will be calculated. 
If the upper bound of the confidence interval is below 20%, non-inferiority 
of the lower titre vaccine will be demonstrated. 

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3 INTRODUCTION 
Investigators should be familiar with the RV3-BB Investigator’s Brochure (IB). 
3.1 Rotavirus disease 
Rotavirus gastroenteritis results in more childhood deaths from diarrhoea than any other 
single agent (Vesikari, 1997).  Globally, rotavirus causes approximately 215,000 deaths 
annually in children under five years of age. The majority (56%) of these deaths occur in 
Sub-Saharan Africa; with 121,000 rotavirus deaths from rotavirus diarrhoea in 2013 
representing 38.9% of the global total for diarrheal deaths in this age group (Tate et al, 
2016).  
Children with severe rotavirus diarrhoea are at risk of dying from dehydration if they do 
not receive intravenous fluids urgently. In low-income countries, since many children do 
not readily have access to health care to administer this treatment, prevention of rotavirus 
diarrhoea is critically important. Primary rotavirus infection does not protect against re-
infection by this ubiquitous pathogen, however, does provide protection against severe 
disease on re-infection (Bishop et al., 1983; Velazquez et al., 1996)  
Vaccines are a key intervention for the prevention of rotavirus gastroenteritis morbidity 
and mortality, as the virus is largely transmitted from person to person, rather than 
contaminated food and water,  so improvements in hygiene, sanitation and drinking water 
do not adequately prevent rotavirus  (Glass et al., 1999; Tate et al., 2016).  
3.2 The first licensed Rotavirus Vaccine 
The first rotavirus vaccine licensed in the United States of America (USA) was a rhesus-
human reassortant tetra-valent vaccine (Rotashield®).  This was a live-attenuated vaccine 
given orally as a three dose regime starting in infancy and found to be highly efficacious 
for the prevention of severe diarrhoea and hospitalisation due to rotavirus infection (Bresee 
et al., 1999; Joensuu et al., 1997; Perez-Shael et al., 1997).  In 1998 the American Academy 
of Pediatrics recommended universal immunisation of all USA infants at two, four and six 
months of age.  However, nine months after licensure and after more than 500,000 of the 
3.8-4 million USA birth cohort had received at least one dose of Rotashield®, the 
programme was suspended (Smith et al., 2003).  This action was prompted by reports of 
intussusception in vaccine recipients (Bines, 2005).  In October 1999, recommendations 
for the programme were withdrawn and the manufacturer voluntarily withdrew the vaccine 
(Bines, 2006). 
 

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3.3 Current Globally Licensed Rotavirus Vaccines 
Since 2006, two live oral attenuated rotavirus vaccines, RotaTeq® and Rotarix®, have 
been globally licensed for the prevention of rotavirus gastroenteritis.  Both RotaTeq® 
(pentavalent bovine-human reassortant vaccine: Merck/CSL) and Rotarix® (monovalent 
G1 human vaccine: GlaxoSmithKline) have been shown to be safe and efficacious in 
clinical trials of over 70,000 infants (Vesikari et al., 2006, Ruiz-Palacios et al., 2006).  Since 
initial licensure, rotavirus vaccines have been licensed in over 100 countries and >100 
million doses administered safely.  
Compared to the high vaccine efficacy found in developed countries (95-100% against 
severe disease (Buttery and Kirkwood, 2007) rotavirus vaccine efficacy against severe 
rotavirus disease was found to be significantly lower in clinical trials conducted in 
developing countries: 49% in Malawi, 48% in Bangladesh and Vietnam and 58% in 
Nicaragua (Madhi et al., 2010; Zaman et al., 2010; Patel et al., 2009).  The underlying 
reason for the suboptimal efficacy in high rotavirus disease burden countries is not yet 
completely understood but is suspected to be due to maternal and breast milk antibodies, 
characteristics of the gut microbiome, nutritional factors and genetic factors, including 
histo-blood group antigen (HBGA) status.  
Despite the low efficacy of the licensed rotavirus vaccines in low-income countries, they 
have achieved a substantial reduction in severe rotavirus gastroenteritis.  The phase III trial 
of Rotarix® conducted in both middle-income South Africa and low-income Malawi, 
demonstrated significant vaccine-attributable reduction in severe rotavirus episodes in the 
first year of life in both countries. The vaccine efficacy in Malawi of 49% was much lower 
than the efficacy of 77% for the same vaccine when studied in South Africa, however in 
Malawi the vaccine had a greater impact, preventing seven cases of severe rotavirus 
diarrhoea for every 100 Malawian infant-years, compared with four cases per 100 South 
African infant-years. The disease is transmitted year-round in Malawi and the country had 
a higher baseline rate of rotavirus (Madhi et al., 2010).  Diarrhoea is a leading killer of 
children in Malawi, causing approximately 11 percent of deaths in children under five years 
of age before vaccine introduction (Liu et al., 2012), with rotavirus infection causing an 
estimated one-third of diarrheal disease hospitalizations of Malawian children under five 
(Cunliffe et al., 2010).  
Similar effects of vaccination were demonstrated in a trial of Rotateq® in Ghana, Kenya 
and Mali, with an overall efficacy in the first year of life of 64% (Armah et al., 2010) 
In 2009 the World Health Organisation (WHO) made the following recommendation: 
“Rotavirus vaccines should be included in all national immunization programmes and 
considered a priority, particularly in countries with high rotavirus gastroenteritis associated 
fatality rates, such as in south and south-eastern Asia and sub-Saharan Africa.” (Rotavirus 
Vaccines WHO Position Paper January 2013). This decision was based on the high 

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rotavirus disease burden in low-income countries and the fact that a significant number of 
children would be saved by a rotavirus vaccine program despite the lower vaccine efficacy 
observed. 
Introduction of these vaccines into the routine immunisation schedule has proven effective 
in reducing both morbidity and mortality in early introducer countries.  In Brazil, a 22–
28% reduction in deaths and 21-25% reduction in hospital admissions due to rotavirus 
disease were found among children under two years of age (Patel et al., 2011) and in 
Mexican infants <11 months a 41% reduction in diarrhoea-related mortality was noted in 
2008/9 after rotavirus vaccine introduction in 2007 (Richardson et al., 2010). 
In October 2012, Malawi became the fourth Gavi-eligible country in Africa to introduce 
rotavirus vaccines into the national immunization programme.  A 43% reduction in 
rotavirus diarrhoea hospitalisation in infants (Bar-Zeev et al., 2016) and a vaccine 
effectiveness of 64% (Bar-Zeev et al., 2015), have been reported following vaccine 
introduction in Malawi.  Similarly, reductions in rotavirus diarrhoea hospitalisations in 
children <5y by 49% have also been observed in Ghana, after vaccine introduction in 2012; 
by 61-70% in Rwanda, after vaccine introduction in 2012; and by 32% in Togo, after 
vaccine introduction in 2014 (Armah et al., 2016; Ngabo et al., 2016; Tsolenyanu 2016). 
3.4 Current locally licensed Rotavirus vaccines 
In addition to the two current globally licensed vaccines, another three rotavirus vaccines 
are available in national markets only: Rotavac® in India; Lanzhou Lamb in China and 
Rotavin-M1 in Vietnam. These rotavirus vaccines have been developed by indigenous 
vaccine manufacturers with the primary aim to provide for their country’s own National 
Immunisation Programs. 
Rotavac® is manufactured by Bharat Biotech International Limited, licensed in India in 
2014 and planned to be introduced through a phased approach into India’s national 
immunization program, using an infant schedule, as the vaccine has not been tested in the 
neonatal age group. The vaccine demonstrated 56.4% efficacy in first year of life and 
48.9% efficacy in the second year of life (Bhandari et al., 2014). Importantly, the projected 
price US$1 per dose is substantially cheaper than the current globally licensed vaccines, 
Rotarix® and Rotateq®. Rotavac® contains a G9P[11] human rotavirus strain.  
Lanzhou Lamb Rotavirus Vaccine (LLR) is manufactured by Lanzhou Institute of 
Biological Products and licensed for use in China since 1998. The efficacy of LLR is yet 
to be established through a randomised clinical trial. LLR contains a G10P[12] lamb 
rotavirus strain 
Rotavin-M1 vaccine is manufactured by the Center for Research and Production of 
Vaccines and licensed for use in Vietnam. Rotavin-M1 contains a G1P[8] human rotavirus 

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strain. The efficacy of Rotavin-M1 is yet to be established through randomised controlled 
trials, however immunogenicity has been demonstrated with up to 73% IgA seroconversion 
in infants (Dang et al., 2012). 
3.5 Limitations of the current rotavirus vaccines 
Despite being heralded as a major breakthrough in the prevention of rotavirus disease 
burden, the commercially available rotavirus vaccines have their limitations. In particular, 
the high costs of the current vaccines, despite tiered pricing agreements, are a major barrier 
to rotavirus vaccine implementation to children in developing countries. 
Despite the WHO recommendation, by May 2016, only 41% countries had introduced 
rotavirus vaccines into their national immunization programmes, with the consequence that 
94 million infants still do not have access to this vaccine.  Unfortunately, countries with 
high child mortality in Africa and Asia have been particularly slow to introduce rotavirus 
vaccines (Figure 1) and therefore the promise of these vaccines for reduction in burden of 
disease has not fully been realised.   
Figure 1. Rotavirus Vaccine Introductions. 
 
 http://rotacouncil.org/toolkit/rotavirus-burden-vaccine-introduction-map/ 
 

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3.5.1 Challenges to Rotavirus Vaccine Implementation  
Besides affordability and supply limitations, there are some implementation challenges 
associated with the current globally licensed rotavirus vaccines. 
The volume of administration (Rotarix 1.5ml/dose; RotaTeq 2ml/dose) the volume 
required for storage and transport in the cold chain and the vaccine waste has been a major 
challenge for vaccine programs, particularly in remote, low resource settings.  Rotavirus 
vaccines currently take more space in the cold chain than all other EPI vaccines combined. 
This has required additional resources for transportation in cool boxes and additional 
refrigerators to keep the vaccine at 2-8oC. 
Safety concerns continue despite evidence of a positive risk-benefit in all studies conducted 
to date. It is acknowledged that there is a four to five-fold increased risk of intussusception 
in the one to seven days following the first dose of the two currently licensed rotavirus 
vaccines (Rotarix® and RotaTeq®) (Carlin et al., 2013, Buttery et al., 2011, Patel et al., 
2011).  This increased risk equated to approximately one to two additional cases of 
intussusception among every 100,000 infants vaccinated in Australia (Therapeutic Goods 
Administration, 2011; do Carmo et al., 2011).  WHO recommends that countries planning 
to introduce rotavirus vaccines into their NIPs enhance post-marketing surveillance 
activities in order to detect any increase in cases of intussusception that may occur after 
introduction. Vaccine providers are advised to inform all parents of the signs and symptoms 
of intussusception so that in the unlikely event of intussusception occurring post 
immunization, this can be identified and treated promptly. 
Because the risk of intussusception is highest following the first dose of a rotavirus vaccine 
and is highest if the first dose is delivered late, the WHO SAGE meeting initially 
recommended that the first dose of a rotavirus vaccine be restricted to < 6 months of age to 
limit the risk of intussusception. This provided a major challenge for the implementation 
of rotavirus vaccines in developing countries where timely administration of the current 
Expanded Program on Immunisation vaccines is often not achieved and the exact age of 
infants may be unknown (Buttery & Graham, 2009).  However, there are concerns that 
restrictions on the age of administration of the first and last dose of rotavirus vaccines has 
prevented vaccination of many vulnerable children in settings where the DTP doses are 
given late. In response to this concern the WHO have now relaxed age restrictions for 
rotavirus vaccination by allowing infants to receive rotavirus vaccines together with DTP 
regardless of the time of vaccination as long as this is after 6 weeks of age (WHO, 2013).  
3.6 Rationale for the development of Rotavirus Vaccine RV3-BB  
The RV3-BB live attenuated rotavirus vaccine has been developed from an unusual 
naturally occurring strain of rotavirus (RV3) found in healthy babies in obstetric hospital 

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nurseries in Melbourne between 1974 and 1983. Uniquely, it caused infection in babies, 
but did not cause disease.  These babies were followed-up for three years and found to be 
protected against subsequent severe gastroenteritis, a natural form of immunisation (Bishop 
et al., 1983). This unique rotavirus strain is the basis of the RV3-BB rotavirus vaccine. The 
goal of the RV3-BB Rotavirus Vaccine Program is to develop an effective, affordable 
rotavirus vaccine aimed at prevention of rotavirus disease from birth. Administration of the 
RV3-BB vaccine at birth has a number of potential advantages since it may offer earlier 
protection for infants in developing countries than the currently licensed rotavirus vaccines, 
and it may offer opportunity to achieve the timely implementation of rotavirus vaccines. 
The development strategy for RV3-BB involves the manufacture of the vaccine in 
collaboration with an emerging country vaccine manufacturer with the aim to provide a 
low-cost vaccine that is affordable for children in resource poor countries.  
3.6.1 Advantages of the birth dose strategy 
Rotavirus infection often occurs very early in life, particularly in developing countries. In 
Africa, 38% of hospitalisation due to rotavirus infection occurs in infants less than 6 months 
of age (Cunliffe, 1998). The rotavirus seropositivity rate among placebo recipients 1 month 
after the last dose had been given in a trial of Rotarix® was greater among Malawian infants 
than among South African infants (40.4% vs 16.7%) suggesting that Malawian infants have 
high exposure to wild-type rotavirus infection in the first 5 months of life (Cunliffe et al., 
2012). The current vaccines administered from 6 weeks of age, with completion of a 2- or 
3-dose course at 4–6 months may be too late to protect some infants. Neonatal vaccine 
administration offers the earliest possible protection.  
Providing a rotavirus vaccine at birth has the potential to address sub-optimal efficacy of 
rotavirus vaccination in high burden countries and improve safety concerns. It also may 
increase the proportion of infants living in remote regions completing a full course of a 
rotavirus vaccine.  
Birth dose administration may limit interference to vaccine take, as most newborns have a 
neutral gastric environment and minimal breast milk intake. The intestinal microbiota is 
not yet well established and intussusception is rare (Dennehy et al., 2007). Based on the 
unique structural and functional characteristics of neonatal rotavirus strains, it is proposed 
that RV3-BB is an ideal vaccine for a birth dose strategy. Natural infection with RV3 is 
associated with replication without symptoms but provides heterotypic protection against 
severe rotavirus disease for the first 3 years of life (Bishop et al., 1983). A birth dose of a 
rotavirus vaccine may also be safer as the natural intussusception risk is lowest in the 
neonatal period.  

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Neonatal rotavirus strains replicate well in the immature newborn intestine despite the 
presence of maternal and breast milk antibodies. They generally cause asymptomatic 
infections, but induce a protective immune response against rotavirus on re-infection 
(Bishop et al., 1983). The RV3-BB rotavirus vaccine based on a neonatal rotavirus strain 
may be the ideal candidate for a birth dose vaccine strategy.  
3.6.2 Potential advantage of the P[6] genotype of RV3 
The RV3-BB vaccine is the only rotavirus vaccine with a P[6]VP4 gene which may be 
advantageous in settings, including African countries, with a high proportion of Lewis and 
secretor – negative children. In US and Australia, the predominant circulating rotavirus 
strain are a P[8] strains. In contrast in Africa, a higher proportion of P[6] strains are 
observed. This could explain the lower efficacy to RotaTeq® and Rotarix®, vaccines that 
both have a P[8] genotype.  In addition, the frequency of Lewis phenotypes varies among 
populations, with the Le (a-b+) most common overall, identified in 75% of Europeans and 
Le (a-b-) phenotype more common in African (19%) populations. In vitro studies have 
demonstrated that the common human rotaviruses recognize the human HBGA in a P 
genotype specific manner. Specifically, P[8] rotavirus strains only infected Lewis-negative 
and secretor-negative children, whereas rotavirus strains with a P[6] VP4 genotype infected 
both Lewis-positive and- negative children. This may also, at least in part, explain why 
there is reduced vaccine efficacy of Rotarix® and Rotateq® in populations with a high 
percentage of Lewis-negative individuals (Nordgren et al., 2014). 
3.7 Development of RV3 
RV3 is a naturally attenuated strain of rotavirus isolated from newborn infants.  It is 
representative of a rotavirus strain that caused widespread endemic infections in newborn 
babies cared for in obstetrical hospital nurseries in Melbourne from 1974-1983.  
Asymptomatic neonatal infection was shown to be 100% protective against severe disease 
and 75% protective against moderate disease in the first three years of life (Bishop et al., 
1983).  Despite the strain being endemic in neonatal nurseries, it has never been detected 
in faeces from children admitted to hospital with severe gastroenteritis, despite active 
surveillance.  The natural attenuation of this strain is also supported by the observation that 
RV3 disease did not occur in the siblings of infants, even if the infants were still excreting 
at home following discharge from hospital. 
As a vaccine candidate, RV3-BB is a live attenuated vaccine being developed for 
administration at birth so as to prevent severe rotavirus disease in neonates and infants. 
3.7.1 Immunity Conferred by RV3 Infection 
RV3 is a G3P2A[6] strain containing neutralising epitopes on VP7 that react with 
monoclonal antibodies specific for G1, G3, G4 and G9 strains (Lazdins et al., 1995).  The 

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strain therefore has the potential to confer “heterotypic” protection against these four 
serotypes, based upon in vitro measures of protection.  In a three year infant cohort study 
following Melbourne infants infected as newborns, complete protection against severe 
rotavirus gastroenteritis was conferred by neonatal RV3 infection, observed during a period 
of four years when serotype G2P[4] infections comprised 80% of rotaviruses excreted by 
children admitted to hospital (Bishop, Unicomb & Barnes, 1991).  In addition, there is 
circumstantial evidence that neonatal infection with RV3 conferred widespread protection 
against severe rotavirus diarrhoea in the community (Bishop & Barnes, 1997).  The total 
number of Melbourne children under five years old admitted with severe diarrhoea was 
reduced by ~50% after 1975 when neonatal RV3 rotavirus infection was first recognised 
to be established in nurseries. 
Humoral immune responses were measured in the Melbourne cohort of children naturally 
infected with RV3 at birth and followed during their first three years of life.  Three months 
after neonatal infection with the RV3 strain, neutralising antibody to G1, G3 and G4 viruses 
persisted in 50-75% of sera.  Asymptomatic re-infection with G1, G2 or G4 rotaviruses 
induced strong heterotypic responses (Ruth Bishop, unpublished).  While neutralising 
antibody levels are not the primary serologic correlate of protection, the results support 
heterotypic priming of the humoral immune response by neonatal infection with a single 
rotavirus strain.   
3.8 Development of RV3 Rotavirus Vaccine (RV3-BB) 
The RV3-BB Rotavirus Vaccine has been successfully adapted to growth in the qualified 
Vero cell line ATTC TL-CCL-81.4.  The research seed stock was prepared in a dedicated 
room using dedicated equipment under Good Laboratory Practice (GLP) conditions at the 
MCRI and transferred to Meridian Life Sciences, USA, for preparation of a master seed lot 
and subsequent manufacture using current Good Manufacturing Practices (cGMP).  
In a preclinical oral toxicity study, conducted under GLP conditions, in juvenile rats, RV3-
BB was well tolerated throughout the duration of the study with no clinical signs considered 
to be treatment related.  Details of this study are provided in the IB. 
3.8.1 Phase I clinical study of RV3-BB 
This single-centre, double-blind, randomised placebo-controlled study evaluated the safety 
and tolerability of a single 1mL oral dose of RV3-BB in a total of 60 participants across 
three age groups (Protocol MCRI-RV3-BB-001). The study was completed in 2011 in 
Melbourne, Australia.  
A single dose of vaccine or placebo was administered initially to 20 adult males aged 18-
50 years (Cohort 1), progressing to 20 children aged 3-8 years (Cohort 2), then to 20 infants 
aged 6-8 weeks (Cohort 3).  Each cohort included 10 vaccine and 10 placebo recipients.  

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The results demonstrate that the single dose of vaccine was well tolerated in adults, children 
and infants (Danchin et al., 2013).  Evaluation of vital signs revealed no clinically 
significant changes in any participant.  There were no clinically significant abnormalities 
in haematology.  Clinically significant increases in serum ALT above the upper limit of 
normal (ULN) were reported at the Day 28 time point for 5 participants in cohort 3 (4/10 
vaccine, 1/10 placebo).  All ALT abnormalities had resolved on follow up with no evidence 
of long-term consequences. No AEs were considered to have a definite or probable 
relationship to the study vaccine.  One SAE was reported in Cohort 3; this was an episode 
of pneumonia in the vaccine group that was assessed by an independent physician as 
unrelated to the IP. 
Vaccine response was a secondary objective in this trial, although it was expected that there 
would be limited immune response following a single dose of vaccine. In Cohort 3 a serum 
immune response (>3-fold increase in SNA and/or IgA from baseline) was identified in 5/9 
infants receiving RV3-BB (56%) compared to 2/7 placebo recipients (28%). A vaccine 
response, defined as evidence of RV3-BB -BB rotavirus replication detected in stool 
between day 3-6 and/or response of serum IgA or SNA, was observed in cohort 3 in 8/9 
infants receiving RV3-BB (89%) and 2/7 placebo recipients (28%). The data from the 
Phase I trial of RV3-BB are promising in that excretion consistent with viral replication 
occurred in the majority of infants after a single dose of RV3-BB. 
3.8.2 Phase IIa immunogenicity study of RV3-BB 
A phase IIa double-blind, randomised, placebo controlled study (Protocol MCRI-RV3-BB-
002) in 95 participants was completed in New Zealand in 2014.  This was a study of the 
immunogenicity, safety, tolerability and reactogenicity of three doses of oral RV3-BB 
Rotavirus Vaccine (8.3 x 106 FFU/mL), with the first dose of vaccine administered either 
at birth (0-5 days of age) or in infancy (8 weeks of age).  The results suggest that RV3-BB 
vaccine administered as three 1 mL oral doses was immunogenic and well tolerated (Bines 
et al., 2015). For both the Neonatal and Infant Vaccine schedules, solicited and unsolicited 
AE were similar across treatment groups and there was no evidence to suggest a 
relationship between the frequency of the events and treatment assignment.  There were no 
fatal SAE. 
Immunogenicity was the primary outcome and was measured by vaccine take after any of 
the three doses of RV3-BB vaccine.  Vaccine take was defined as ≥3 fold increase in serum 
anti-rotavirus IgA or SNA (at 28 days post dose) compared with baseline, and/or RV3-BB 
excretion in stool (measured by RT-PCR on days 3-7 post dose).  Over 90% of infants 
receiving RV3-BB as infant or neonate schedule had evidence of vaccine take compared 
with 13% (neonatal:placebo comparison) and 25% (infant:placebo comparison). 
For more information refer to the Investigators Brochure. 

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3.8.3 Phase IIb efficacy study of RV3-BB 
A phase IIb double-blind, randomised, placebo controlled study (Protocol MCRI-RV3-BB-
003) of 1649 participants was completed in Indonesia in 2016.  Participants received 3 
doses of RV3-BB vaccine as a neonate or an infant schedule, or placebo, and were followed 
to 18 months of age.  This study tested the hypotheses that RV3-BB Rotavirus Vaccine 
induces protective efficacy when given as either an infant or as a neonatal schedule, in a 
developing country setting. 
Two sub-studies were included:  Sub-study A assessed immunogenicity of RV3-BB when 
co-administered with the routine childhood vaccines, including inactivated polio vaccine 
(IPV), and Sub-study B assessed immunogenicity of oral polio virus (OPV) when co-
administered with RV3-BB. Limited biochemistry parameters were also assessed in a 
subset of 90 participants in each Sub-study. 
The primary outcome of the study was to assess the efficacy of three scheduled oral doses 
of RV3-BB vaccine in neonates and in infants against severe rotavirus gastroenteritis, up 
to 18 months of age, compared with placebo. This was measured using episodes of severe 
rotavirus gastroenteritis (defined as a modified Vesikari score ≥11 and rotavirus antigen 
detected in stool by ELISA) from 2 weeks after 4 doses of IP product to 18 months of age.  
Severe rotavirus gastroenteritis in the period from 2 weeks after the fourth dose of IP to 18 
months was identified in 28 of 504 participants in the placebo group (5.6%) as compared 
to 21 of 1009 participants in the combined vaccine group (2.1%), resulting in a vaccine 
efficacy of RV3-BB against the primary outcome of severe rotavirus gastroenteritis of 63% 
(95% confidence interval [CI], 34 to 80; p<0.001). When assessed with respect to each 
administration schedule, three doses of RV3-BB administered in the neonatal schedule was 
associated with a vaccine efficacy against severe rotavirus gastroenteritis from 2 weeks 
post dose three to 18 months of age of 75% (95% CI 44 to 91; p<0.001) and against any 
severity rotavirus gastroenteritis of 63% (95% CI 36 to 81; p<0.001). Three doses of RV3-
BB vaccine administered in the infant schedule was associated with a vaccine efficacy of 
51% (95% CI 7 to 76; p=0.027) severe rotavirus gastroenteritis from 2 weeks post dose 
four to 18 months of age.  RV3-BB vaccine demonstrated efficacy across the spectrum of 
severity of rotavirus gastroenteritis. Of note, only 2 episodes of very severe rotavirus 
gastroenteritis (Vesikari score ≥ 15) occurred in participants in the neonatal vaccine 
schedule group compared to 14 in the placebo group suggesting that the vaccine may 
particularly offer protection from the severest form of the disease. Of the 49 episodes of 
severe rotavirus gastroenteritis, 46 were due to the strain G3 P[8] (neonatal vaccine group 
7/7 G3 P[8]; infant vaccine group 13/14 G3 P[8] and 1 G3 P untypable; placebo group 
26/28 G3 P[8]; 2 P[8] untypable). 
Cumulative vaccine take following three doses of vaccine was identified in 78/83 (94%) of 
participants in the neonatal vaccine schedule and 83/84 (99%) of participants in the infant 
vaccine schedule in the PP population. Although cumulative vaccine take was identified in 
42% of the neonatal placebo schedule and 47% of the infant placebo schedule, there was a 

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significant difference in proportions between vaccine and placebo groups (neonatal vaccine 
schedule versus neonatal placebo schedule 0.52 [0.39, 0.64]: p<0.001; infant vaccine 
schedule versus infants placebo schedule 0.52 [0.40, 0.63]: p<0.001). After two doses in 
the infant vaccine schedule, cumulative vaccine take was identified in 73/84 (87%) 
compared to the infant placebo schedule in 22/79 (28%) (difference in proportions 0.59 
[0.45, 0.71]:  p<0.001). 
For both the Neonatal and Infant Vaccine schedules, SAE and non-serious solicited and 
unsolicited AE were similar between each vaccine schedule group compared with placebo 
and there was no evidence to suggest a relationship between the frequency of the events 
and treatment assignment. 
General disorders and administration site conditions were the most frequently reported 
solicited AEs; events included decreased activity, fever and irritable.  Gastrointestinal 
disorders were also reported including diarrhoea, loose stools and vomiting.  These events 
occur with similar frequency across all study groups (neonatal vaccine 16.7% vs neonatal 
placebo group 16.9%; infant vaccine group 15.6% vs infant placebo group 18.4%). 
There were 11 fatal events reported throughout the study period; ten events assigned as 
unrelated by the Investigator and one (neonatal aspiration; placebo group) was assigned as 
unlikely related to IP.  Six fatal events occurred in participants in the placebo group and 
five occurred in participants in the vaccine group. 
A single case of intussusception was reported in a participant in the infant vaccine schedule 
group. This SAE was reported 114 days after the last dose of IP and was assessed as not 
related to IP. The participant was successfully treated with surgery and recovered without 
sequelae. 
In summary, this Phase IIb study has demonstrated that administration of the RV3-BB 
vaccine (8.3 x 106 FFU/mL) was well tolerated, immunogenic and efficacious in infants 
when given as an infant or neonatal schedule. The data from this Phase IIb trial of the RV3-
BB vaccine support continued development of the vaccine. 
For more information refer to the Investigators Brochure. 
3.9 Dose and study rationale for current study 
This dose-ranging study of the RV3-BB vaccine in Malawi - a low income, high rotavirus 
disease burden region in Africa - aims to address an important “missing piece” in the 
development of the RV3-BB vaccine. 
This study will provide important information about the optimal titre of the RV3-BB 
vaccine required to produce an immune response needed to protect against severe rotavirus 
disease. This data will inform vaccine development and ensure that the vaccine is produced 

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efficiently and at the lowest possible cost by influencing the manufacturing costs and 
capacity. This study will also inform the ultimate dosage schedule of the RV3-BB vaccine.  
This project will address 3 key elements that are central to the development of the RV3-
BB vaccine: 
1. Can a lower titre of the RV3-BB vaccine (administered in a 3 doses schedule) 
produce an immune response that predicts protection from severe rotavirus 
disease? 
This information is critical to inform vaccine development. The titre of the RV3-BB 
vaccine used in the Phase I, IIa and IIb trials has been ~8.3x106. Reducing the titre of the 
final commercial vaccine would improve efficiencies in the manufacturing process as well 
as reduce cost of goods (the variable costs associated with each dose of vaccine) – 
impacting on final vaccine cost and vaccine manufacturing capacity.  
Even in highly competitive markets or tiered pricing arrangements, vaccine prices cannot 
fall below the floor which is set by manufacturing costs. Reducing the manufacturing costs 
significantly therefore has great potential to boost affordability of RV3-BB rotavirus 
vaccine, which will facilitate greater access to protection for more children globally, while 
also assisting an RV3-BB vaccine manufacturer to develop a sustainable business model 
for the vaccine.  
2. Is a neonatal administration schedule of the RV3-BB vaccine (first dose 0-5 days 
of birth) associated with a similar immune response to an infant schedule of the 
RV3-BB vaccine (first dose delivered at 6 weeks) in infants in Africa?  
There are a number of potential advantages of a birth dose strategy for a rotavirus vaccine, 
particularly in high burden regions where there are often challenges to ensuring complete 
vaccine coverage of a 3 dose infant vaccine schedule.  
The administration of vaccines under an infant schedule, with completion of a 2- or 3-dose 
course at 4–6 months may be too late to protect some infants. Neonatal vaccine 
administration may offer the earliest possible protection. 
The intrinsic characteristics of the RV3-BB vaccine may make it an ideal vaccine to deliver 
in a birth dose administration schedule. However, some countries may still prefer an infant 
dose schedule. Understanding how RV3-BB performs in a birth dose schedule or an infant 
schedule will assist the clinical development required for the regulatory submission and 
define the ideal schedule/s for the RV3-BB vaccine. 
3. Does RV3-BB rotavirus vaccine with a P[6]VP4 gene offer specific advantages in 
infants in Africa? 

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The RV3-BB vaccine is the only rotavirus vaccine with a P[6]VP4 gene which may be 
advantageous in settings, including African countries with a high proportion of Lewis and 
secretor – negative children 
With the high burden of rotavirus disease in low-income countries like Malawi, even 
modest gains in efficacy through alternative vaccine such as RV3-BB could have 
significant public health impact.  
4 STUDY OBJECTIVES 
4.1 Primary Objective 
The primary objective is to assess the cumulative anti-rotavirus serum IgA response 
(defined as a ≥3 fold increase from baseline) 4 weeks after 3 doses of RV3-BB 
administered in a neonatal schedule at a vaccine titre of 1x107, 3 x 106 or 1 x 106. 
4.2 Secondary Objectives 
The secondary objectives of the study are; 
• To assess the cumulative anti-rotavirus serum IgA response (defined as a ≥3 fold 
increase from baseline) 4 weeks after 3 doses of RV3-BB administered in an infant 
schedule at a vaccine titre of 1 x 107. 
• To assess cumulative vaccine take and components of vaccine take after 3 doses of 
RV3-BB (titre of 1 x 107) administered in a neonatal schedule versus three doses of 
RV3-BB in an infant schedule at a vaccine titre of 1 x 107. 
• To assess cumulative vaccine take and the components of RV3-BB vaccine take after 
3 doses of RV3-BB administered as a neonatal schedule at a vaccine titre of 1 x 107, 3 
x 106 or 1 x 106.  
To assess cumulative vaccine take and the components of vaccine take after 2 doses of 
RV3-BB administered as a neonatal schedule at a vaccine titre of 1 x 107, 3 x 106 or 1 
x 106 or 2 doses in the infant schedule at a vaccine titre of 1 x 107. 
• To assess cumulative vaccine take and components of vaccine take after the first dose 
of RV3-BB administered as a neonatal schedule at a vaccine titre of 1 x 107, 3 x 106 or 
1 x 106 compared to placebo (1st dose of IP in the infant schedule). 
• To assess cumulative vaccine take and components of vaccine take after the first dose 
of RV3-BB at a vaccine titre of 1 x 107, 3 x 106 or 1 x 106 in the neonatal schedule 
compared with the first dose of RV3-BB at a vaccine titre of 1 x 107 in the infant 
schedule. 
• To describe the geometric mean titre of the anti-rotavirus serum IgA response after 3 
doses of RV3-BB administered as a neonatal or an infant schedule 
• To describe the safety and tolerability of RV3-BB when administered as an infant or as 
a neonatal schedule.  
• To describe the occurrence of diarrhea episodes in participants, according to severity 
and detection of wild-type rotavirus. 

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4.3 Exploratory Objectives 
The basis of the exploratory objectives is to further understand potential barriers to 
rotavirus vaccine efficacy in the region. The exploratory objectives are;  
• To describe Histo-blood Group Antigens (Lewis and secretor) status of participants in 
association with anti-rotavirus sero-conversion and cumulative vaccine take after 3 
doses RV3-BB administered in either the neonatal schedule (any titre) or infant 
schedule. 
• To assess maternal anti-rotavirus IgA and IgG levels in association with anti-rotavirus 
IgA seroconversion and cumulative vaccine take in participants following receipt of 
RV3-BB administered in either the neonatal schedule (at any vaccine titre) or infant 
schedule at a vaccine titre of 1 x 107. 
• To describe the gut microbiome in participants receiving RV3-BB administered in the 
neonatal schedule (at any vaccine titre) or infant schedule at a vaccine titre of 1 x 107. 
• To describe innate and adaptive immune responses in infants vaccinated with RV3-BB 
administered in a neonatal vaccine schedule (any titre) or in the infant schedule at a 
vaccine titre of 1 x 107. 
 
 

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5 TRIAL PLAN 
5.1 Study Design 
This is a Phase II, randomised, double-blind, placebo-controlled, four-arm parallel group 
study of two different dosing schedules of oral RV3-BB, and placebo. 
Approximately 688 participants will be randomised to the study; 172 to each treatment arm. 
Pregnant women will be invited to provide preliminary consent for the study prior to 
labour and delivery. A maternal blood sample and a stool sample will be collected. 
Following delivery, those who remain interested will be invited to provide written 
informed consent for their baby to participate in the study. 
Following confirmation of eligibility for the trial post-birth, participants will be randomised 
in a 1:1:1:1 ratio to one of four treatment arms; high-dose, mid-dose or low-dose neonatal 
schedule, or a high-dose infant schedule.  Each study participant will receive four oral doses 
of IP, with each administration consisting of 1 mL RV3-BB Rotavirus Vaccine or 1mL of 
placebo.  All participants will receive a total of 3 doses of RV3-BB vaccine, one dose of 
placebo, and one dose of Rotarix®. 
A baseline stool sample will be collected prior to the administration of the first dose of IP.  
A stool sample will also be collected on either Day 3, 4 or 5 following each dose of IP. 
Samples will also be collected for any cases of diarrhoea (defined as 3 or more stools that 
are looser than normal for that participant). 
A saliva sample will be collected at birth and prior to IP doses 2, 3 and 4. 
Cord blood will be collected at birth, and blood samples taken prior to IP doses 1 (if cord 
blood not collected) 2, 3 and 4, and prior to the Rotarix® dose. 
Participants will be followed until 18 weeks of age.  Face to face visits will be conducted 
at least monthly. Adverse events, including blood-in-stool occurrences, and diarrhoea 
episodes will be recorded for the duration of the study. 
The recruitment period is estimated at 9 months.  The study period for each participant will 
be 18 weeks, and the total duration of the study approximately 15 months. 
An independent Data Safety Monitoring Board (DSMB) will review safety data at agreed 
recruitment and progression milestones throughout the study, as agreed and documented in 
the DSMB Charter.  The DSMB will recommend whether the study continues unchanged, 
continues with amendments, or is stopped.  Recruitment will continue during the DSMB 
review periods. 
 
 

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Figure 2. Study Design 
 
 

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5.2 Study Population 
5.2.1 Number of Participants and Study Sites 
Approximately 688 babies will be randomised across approximately four sites in Malawi.  
Study visits will be conducted at the sites or at participant homes. 
5.2.2 Trial Selection Record 
Investigators must keep a record of those who were considered for the study but were not 
enrolled.  This information is necessary to establish that the patient population was selected 
without bias. 
Only babies who meet all of the inclusion and none of the exclusion criteria will be eligible 
to participate in the study.  No protocol waivers for eligibility will be allowed. 
5.2.3 Inclusion Criteria 
• Neonate is less than 6 days (≤144 hours) of age at the time of first dose. 
• Neonate is in good health as determined by clinical judgment, including a medical 
history and physical exam, which confirms the absence of a current or past disease 
state considered significant by the investigator. 
• Neonate birth weight 2500-4000g inclusive or 2250-4000g inclusive at Visit 1. 
• Neonate’s parents/guardians expect to be available for the duration of the study, 
and agree to adhere to all protocol requirements. 
• Neonate’s parents/guardians have provided written informed consent prior to 
study-related procedures being performed. 
5.2.4 Exclusion Criteria 
• Any medical, psychiatric, or social condition of a parent/guardian that in the 
opinion of the investigator would prevent the neonate’s parents/guardians from 
giving proper informed consent or from complying with the study protocol. 
• Neonates with known or suspected major congenital malformations or genetically 
determined disease. 
• Neonates with intussusception. 
• Neonates with a known or suspected bleeding diathesis, or any condition that may 
be associated with a prolonged bleeding time. 
• Neonates who have ever received any blood products, including immunoglobulin, 
or for whom receipt of any blood product during the course of the study is 
anticipated. 
• Neonates in whom EPI vaccines or components are contraindicated. 
• Neonates who have received or who expect to receive during the study period, any 
rotavirus vaccine other than those which will be administered as part of this study. 
• Neonates who have ever received, or who are anticipated to receive during the 
study period, any investigational agent other than those which will be 
administered as part of this study.  

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• Neonates with a previous anaphylactic reaction to any drug, vaccine or vaccine 
component. 
• Neonates with a significant evolving neurological disorder. 
• Neonates whose parents/guardians are site team employees with direct 
involvement with the investigators, or who are working on the study. 
• Neonates who have been exposed to immunosuppressive courses of 
glucocorticosteroids, cytotoxic drugs or blood products through prenatal exposure 
and/or breast milk in the four weeks prior to randomisation should be discussed 
with the Medical Monitor and sponsor and a decision on eligibility made on a case 
by case basis. 
• Neonates with diarrhoea or vomiting in the 24 hours preceding randomisation. 
• Neonates with any moderate or severe illness, and/or who have a temperature of 
≥37.5˚C axillary/oral or ≥38˚C rectal/tympanic within the 48 hours preceding 
randomisation. 
5.3 Screening failures 
A screening failure is a participant for whom informed consent is obtained and documented 
in writing from the legally authorised representative, but who is deemed ineligible for the 
trial and is therefore not randomised.  Reasons for screening failure include conditions 
detected on history or during the screening examination that deem the participant ineligible.   
Records will be kept of screening failures, including reasons. 
5.4 Concomitant medications and vaccines 
The following medications are contraindicated for use at any time during the study period: 
• Immunosuppressive therapy, including immunosuppressive courses of systemic 
corticosteroids 
• Immunoglobulins (antibodies) or other blood products; 
• Other investigational products 
• Other rotavirus vaccines; 
• Aspirin or aspirin-containing medications 
• Medications that may affect the liver, for example, chloramphenicol including eye 
drops.  A list of other drugs will be provided in the Study Reference Manual 
(SRM). 
If a contraindicated medication is administered, future IP dosing of the participant will be 
decided by MCRI (or designee) on a case-by-case basis. 
All participants will receive EPI vaccines during the study at scheduled time points.  
Standard vaccines approved for use in Malawi will be administered by study staff during 
the study but will be provided via usual channels, not provided by the study.  The 
exceptions are polio vaccine, which will be provided by the study as IPV rather than the 
usual OPV, and Rotarix® which will only be administered at Visit 9.  
 

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6 TRIAL PROCEDURES 
Table 1:  Schedule of Procedures 
Visit 
Pre-study 
1 
2 
3 
4 
5 
6 
7 
8 
99 
Timing 
Second 
trimester to 
birth 
Day 1 
Day 8 
Week 6 
Week 7 
Week 10 
Week 
11 
Week 14 
Week 
15 
Week 18 
Window 
Birth to 
144 hrs 
old 
7±1 
days 
post V1 
+7 days 
7±1 
days 
post V3 
±7 days and 
at least 21 
days post 
V3 
7±1 
days 
post V5 
±7 days and 
at least 21 
days post 
V5 
7±1 
days 
post V7 
±7 days and 
at least 21 
days post 
V7 
Preliminary consent 
X 
 
 
 
 
 
 
 
 
 
Cord blood collection 
X 
 
 
 
 
 
 
 
 
 
Maternal blood sample 
X 
 
 
 
 
 
 
 
 
 
Maternal stool sample 
X 
 
 
 
 
 
 
 
 
 
Study consent 
 
X 
 
 
 
 
 
 
 
 
Eligibility confirmation 
 
X 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
 
X 
 
 
 
 
 
 
 
 
Physical exam 
 
X 
 
 
 
 
 
 
 
 
Vital signs1 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool sample 
X5 
X 6 
 
X6 
 
X6 
 
X6 
 
 
Saliva sample 
 
X 
 
X 
 
X 
 
X 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
IP administration 
 
X 
 
X 
 
X 
 
X 
 
 
Antacid administration2 
 
 
 
X 
 
X 
 
X 
 
 
EPI vaccine administration9 
 
X 
 
X 
 
X 
 
X 
 
X 
IPV administration 
 
 
 
X 
 
X 
 
X 
 
 
Rotarix® administration 
 
 
 
 
 
 
 
 
 
X7 
Pre dose blood sample 
 
X10 
 
X 
 
X 
 
X 
 
X 
Issue/review diarrhoea log3 
 
X 
 
X 
 
X 
 
X 
 
X 
Issue/review study reminder 
Card3 
 
X 
 
X 
 
X 
 
X 
 
X 
Issue stool sample kits3 
 
X 
 
X 
 
X 
 
X 
 
 
Feeding review4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Con med recording 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Follow up contacts 
 
 
Weekly contact (clinic, home or telephone) throughout the study 
1.   Temperature, pulse rate, respiratory rate.  At dosing visits vital signs will be measured within one hour pre dose and 15 and 30 mins post 
dose. 
2.  2mL of Mylanta Original® will be administered within the 10 minutes prior to the IP dose. 
3.  Logs, reminder card and kits will be issued and reviewed as required. 
4.  Record if baby receiving breast milk, formula, or other. 
5.  A pre dose stool sample will be collected at any time from birth before the first dose of IP. 
6.  A stool sample will be collected 3 – 5 days post IP dose. 
7.  If the participant withdraws prior to receiving all IP doses they will be given a Rotarix® dose one month following their last dose of IP. 
8.  Day 1 pre dose sample will be cord blood. 
9.  EPI vaccines will be provided via usual supplier (not study) but may be administered by study staff at appropriate time points according to 
standard schedule.  The exceptions are OPV and other rotavirus vaccines, which will not be given (see Section 5.4). 
10. A 1.0mL blood sample will be collected if cord blood is not able to be collected. 

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6.1 Recruitment 
Sites will have information about the study on display and pregnant women will be 
identified at the time of antenatal care.  During the second or third trimester, pregnant 
women will be approached by a member of the study team who will describe the study to 
them, provide written information and, if they are interested, arrange to discuss the study 
in more detail at a later time.  Expectant women will be encouraged to discuss the study 
with their partner, usual doctor, midwife, and family members. 
6.1.1 Informed Consent 
The investigator or delegate must obtain the written informed consent according to local 
laws and requirements before any study-related procedures are performed, including any 
study specific screening procedures. 
A two-stage consent process will be followed: 
• Pregnant women who are interested in participating will be invited to provide 
preliminary consent during the second or third trimester and prior to going into labour.  
This consent is to allow a pre-birth maternal blood sample (taken any time from consent 
until Visit 1), collection of cord blood at the birth, and collection of their baby’s stool 
(taken from birth up to Visit 1).  Consent for a stool sample from the pregnant woman 
will also be requested. 
• Post birth, the parents/guardians will be invited to provide consent for their baby to 
participate in the study. 
6.2 Birth Procedures 
An approximate 2.5 mL cord blood sample will be taken immediately following delivery, 
after the umbilical cord has been cut. A baseline stool sample will also be collected from 
the baby.  Inability to collect a baseline stool sample does not exclude the baby from further 
trial participation.  
If not previously obtained, a maternal blood sample (approximately 1mL) will also be 
collected.  Inability to collect a maternal blood sample does not exclude the baby from 
further trial participation.  
If not previously obtained, a maternal stool sample will also be collected.  Inability to 
collect a maternal stool sample does not exclude the baby from further trial participation 
6.3 Visit 1 Procedures (0-5 days of age) 
After consent for the baby to participate in the study is obtained, the following will be 
conducted/recorded at any time up to and including 5 days (144 hours) of age; 
• Demographic data including date of birth, gender, ethnicity, gestational age and birth 
weight, current weight and height/length. 
• Medical history. 
• Feeding status (breast milk and/or formula). 

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• All medications, supplements, traditional/complementary/herbal products and 
immunisations administered to the baby since birth. 
• All medications, supplements, traditional/complementary/herbal products and 
immunisations administered to the mother from 4 weeks pre-delivery. 
• Physical examination (see section 8.1). 
• Vital signs (see section 8.3). 
• Collection of a pre dose stool sample from the baby (inability to collect a stool sample 
does not exclude the baby from further trial participation).  
• Collection of a saliva sample from the baby. 
• Collection of a 1.0mL pre dose blood sample from the baby (when cord blood is not 
collected) 
Confirmation of eligibility must be completed within the 24 hours prior to administration 
of the first dose of IP.  If the administration of the dose is delayed, assessments must be 
repeated. 
Eligible participants will be randomised and the following procedures performed pre dose; 
• Vital signs (see section 8.3) within the 60 minutes pre dose. 
IP will be administered.  A dose of 1 ml will be given orally from a syringe (see section 
10.9).   
The following procedures will be performed post dose; 
• Administer any scheduled EPI vaccines other than OPV and rotavirus vaccines 
according to local guidelines (see section 9.2). 
• Vital signs (see section 8.3) will be measured at 15 minutes and 30 minutes post dose 
(±5 minutes). 
• Record any AE. 
• Issue the parents/guardians with the Study reminder card and provide instructions for 
its completion (see section 8.3). 
• Issue the parents/guardians with the Diarrhoea Log and provide instructions for its 
completion (see section 8.4) and for notifying the site of any episodes of diarrhoea. 
• Issue kits and containers for stool and diarrhoea samples, and instructions for 
collection and storage of samples (see section 8.4). 
• Explain the definition of diarrhoea (three or more stools in a 24 hour period that are 
looser than normal for that child). 
• Issue thermometer and instructions for measuring temperature (see section 8.3) and 
for notifying the study staff if the participant develops a temperature 37.5C. 
• Remind the parents/guardians of potential AEs and to contact the study staff 
immediately if any illness or hospitalisation occurs during the study period. 
Study staff will contact the parents/guardians (clinic or home visit) the day following 
dosing, and on day 3, 4 or 5 following dosing, to review AEs and medications, and collect 
stool and diarrhoea samples. 

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6.4 Visit 2 (7 ±1 days after Visit 1) 
The following will be performed/recorded: 
• Vital signs (see section 8.3).  
• Review AEs. 
• Review concomitant medications (participant, and mother if breastfeeding). 
• Review feeding status. 
• Review Diarrhoea Log and study reminder card. 
Throughout the remainder of the study, study staff will contact the parents/guardians at 
least weekly via telephone, home visit, or clinic visit, to review AEs, medications, and 
diarrhoea episodes. If the baby has a diarrhoea episode a sample will be collected. 
6.5 Visit 3 (Week 6 +7 days) 
The following will be performed/recorded at the trial site no earlier than 6 weeks of age: 
• Review AEs. 
• Review concomitant medication. 
• Review feeding status. 
• Review Diarrhoea Log and study reminder card. 
• Collect a pre dose blood sample. 
• Collect a saliva sample. 
• Vital signs (see section 8.3) within the 60 minutes pre dose. 
• Administer 2mL of Mylanta Original® antacid formulation within the 10 minutes pre 
dose. 
• Administer the IP dose. 
The following procedures will be performed post dose; 
• Administer IPV and any scheduled EPI vaccines other than OPV and rotavirus 
vaccines according to local guidelines (see section 9.2). 
• Vital signs (see section 8.3) will be measured at 15 minutes and 30 minutes post dose 
(±5 minutes). 
• Record any AEs. 
• Issue kits and containers for stool and diarrhoea samples, and instructions for 
collection and storage of samples (see section 8.4). 
Study staff will contact the parents/guardians (clinic or home visit) the day following 
dosing, and once on day 3, 4 or 5 following dosing, to review AEs and medications, and 
collect stool and diarrhoea samples. 
6.6 Visit 4 Procedure (7 ±1 days after Visit 3) 
The following will be performed/recorded: 
• Vital signs (see section 8.3).  
• Review AEs. 
• Review concomitant medications (participant, and mother if breastfeeding). 

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• Review feeding status. 
6.7 Visit 5 (Week 10 ±7 days) 
The following will be performed/recorded at the trial site, no sooner than 21 days after the 
previous dose of IP (Visit 3): 
• Review AEs. 
• Review concomitant medication. 
• Review feeding status. 
• Review Diarrhoea Log and study reminder card. 
• Collect a pre dose blood sample. 
• Collect a saliva sample. 
• Vital signs (see section 8.3) within the 60 minutes pre dose. 
• Administer 2mL of Mylanta Original® antacid formulation within the 10 minutes pre 
dose. 
• Administer the IP dose. 
The following procedures will be performed post dose; 
• Administer IPV and any scheduled EPI vaccines other than OPV and rotavirus 
vaccines according to local guidelines (see section 9.2). 
• Vital signs (see section 8.3) will be measured at 15 minutes and 30 minutes post dose 
(±5 minutes). 
• Record any AEs. 
• Issue kits and containers for stool and diarrhoea samples, and instructions for 
collection and storage of samples (see section 8.4). 
Study staff will contact the parents/guardians (clinic or home visit) the day following 
dosing, and once on day 3, 4 or 5 following dosing, to review AEs and medications, and 
collect stool and diarrhoea samples. 
6.8 Visit 6 (7 ±1 days after Visit 5) 
The following will be performed/recorded: 
• Vital signs (see section 8.3).  
• Review AEs. 
• Review concomitant medications (participant, and mother if breastfeeding). 
• Review feeding status. 
6.9 Visit 7 (Week 14 ±7 days) 
The following will be performed/recorded at the trial site, no sooner than 21 days after the 
previous dose of IP (Visit 5): 
• Review AEs. 
• Review concomitant medication. 
• Review feeding status. 

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• Review Diarrhoea Log and study reminder card. 
• Collect a pre dose blood sample  
• Collect a saliva sample 
• Vital signs (see section 8.3) within the 60 minutes pre dose. 
• Administer 2mL of Mylanta Original® antacid formulation within the 10 minutes pre 
dose. 
• Administer the IP dose. 
The following procedures will be performed post dose; 
• Administer IPV and any scheduled EPI vaccines other than OPV and rotavirus 
vaccines according to local guidelines (see section 9.2). 
• Vital signs (see section 8.3) will be measured at 15 minutes and 30 minutes post dose 
(±5 minutes). 
• Record any AE. 
• Issue kits and containers for stool and diarrhoea samples, and instructions for 
collection and storage of samples (see section 8.4). 
Study staff will contact the parents/guardians (clinic or home visit) the day following 
dosing, and once on day 3, 4 or 5 following dosing, to review AEs and medications, and 
collect stool and diarrhoea samples. 
6.10 
Visit 8 (7 ±1 days after Visit 7) 
The following will be performed/recorded: 
• Vital signs (see section 8.3).  
• Review AEs. 
• Review concomitant medications (participant, and mother if breastfeeding). 
• Review feeding status. 
6.11 
Visit 9 (Week 18 ±7 days) 
The following will be performed/recorded at the trial site, no sooner than 21 days after the 
previous dose of IP (Visit 7): 
• Review AEs. 
• Review concomitant medication. 
• Review feeding status. 
• Review Diarrhoea Log.  
• Collect a pre dose blood sample. 
• Vital signs (see section 8.3) within the 60 minutes pre dose. 
• Administer Rotarix®. 
• Administer any scheduled EPI vaccines according to local guidelines (see section 
9.2). 
Study staff will contact the parents/guardians (clinic or home visit) the day following 
dosing.  

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6.12 
Discontinuation of Participants 
6.12.1 Criteria for discontinuation 
The participant may be discontinued from the trial at any time at the discretion of the 
investigator(s). 
Specific reasons for withholding further doses or discontinuing a participant in this trial 
may include: 
• Withdrawal of informed consent by parents/guardians. 
• Participant lost to follow-up. 
• Protocol non-compliance. 
• Investigator considers that it is not in the interest of the participant to continue. 
• MCRI terminates the study for administrative, financial or other reasons. 
If a participant is discontinued from dosing, unless they withdraw consent they should 
continue to have blood samples collected at the scheduled time points and continue to 
collect diarrhoea samples and complete the Diarrhoea Log. Investigators are encouraged to 
discuss possible treatment discontinuations and withdrawals with the Medical Monitor, if 
appropriate, prior to ceasing treatment or withdrawing the infant.  The decision to replace 
withdrawn subjects will be made on a case by case basis.  Participants withdrawn due to 
AEs will not be replaced. 
All withdrawn participants should be seen and assessed approximately 28 days after their 
last dose of IP, primarily for the purposes of monitoring participant safety.  Wherever 
possible, AEs should be followed up until resolution.  Parents/guardians who withdraw 
consent should be asked whether they agree to this follow up. 
Participants who withdraw from study or IP will continue to receive IPV until the course is 
complete.  They will receive Rotarix® at standard scheduled time points according to the 
National Immunisation Program. 
 
 

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7 TRIAL ENDPOINTS 
Immunogenicity will be assessed through: 
• Serum anti-rotavirus IgA response (defined as a ≥3 fold increase from baseline) at 
each serum collection time-point to 4 weeks after 3 doses of RV3-BB.  
• Serum anti-rotavirus IgA levels at each serum collection time point. 
• Vaccine take defined as at least a threefold increase in serum anti-rotavirus 
immunoglobulin A (IgA) from baseline to post IP dosing, or detectable RV3 
shedding in stools (by ELISA or PCR) any day from day three to day five 
following administration of IP. 
• Cumulative vaccine take defined as vaccine take observed at the current 
assessment time point or following any previous dose. 
• Anti-rotavirus IgA response (defined as at least a threefold increase from baseline 
to post IP dosing) at each serum collection time point. 
• Anti-rotavirus IgA titres defined as geometric mean titres at each serum collection 
time point. 
• Presence of RV3 shedding in stools (by ELISA or PCR) from day 3 to day 5 
following each dose of IP. 
Safety and tolerability will be assessed through: 
• Adverse Events (AE) in the 28 days following each dose of IP. 
• Serious Adverse Events (SAE) during the study. 
• Review of episodes of blood in stool. 
The exploratory objectives will be assessed through: 
• HBGA Lewis and secretor status will be determined by ELISA/PCR on Saliva 
collected at Visits 1, 3, 5 and 7 and whole blood collected at Visit 9 for non 
secretor participants. 
• Maternal serum IgA and IgG responses will be determined by ELISA on Maternal 
Serum sample collected pre study or at Visit 1. 
• Bacterial taxonomic and genetic functional profiling of stool microbiome will be 
conducted by 16s rRNA or shotgun sequencing on maternal stool and stool 
samples collected post administration of IP and at birth (prior to first IP dose). 
• B and T cell function will be measured by Flow cytometry and innate and 
adaptive responses measured by whole killed pathogen assay and Toll like 
receptor ligand assays from whole blood collected at birth (cord), Visit 3 and Visit 
9. 
8 TRIAL MEASUREMENTS AND OUTCOMES 
8.1 Eligibility assessments 
A full physical examination will be performed at study entry by a clinician prior to 
randomisation at Visit 1, according to common medical practice.  The examination will 
include assessment of general appearance, HEENM (head, ears, eyes, nose and mouth), 

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skin, cardiovascular system, musculoskeletal system, respiratory system, gastrointestinal 
system and nervous system.  Length (height) and weight will be measured.  New findings 
or clinically significant changes noted in any physical examinations conducted post dosing 
will be recorded as AEs. 
8.2 Immunogenicity 
Faecal samples will be collected from participants following each dose of IP.  One sample 
will be collected during the day 3 – 5 post dose period.  These samples will be tested at the 
study central laboratories for shedding of rotavirus. 
Serum samples will also be tested at the central laboratories, for anti-rotavirus IgA. 
See Section 8.6 for testing at each laboratory. 
Faecal and serum samples collected for this study may be stored for up to 4 years post-
study, and if consent has been obtained from the parents/guardians, may be used for 
additional testing outside of this protocol.  Stored samples will be labelled with the 
participants study number.  Any additional testing would be performed under a protocol 
approved by an ethics committee, and would maintain strict confidentiality. 
8.3 Safety 
Safety will be assessed by recording of AEs, vital signs, and occurrence of blood in stool 
throughout the study. 
• Parents/guardians will be questioned and monitored throughout the study with regard 
to any AEs their baby may have experienced.  See Section 11 for further details on 
recording AEs. 
• Vital signs will be measured at each site visit and will include pulse rate, respiratory 
rate and temperature. 
• Parents/guardians will be issued with thermometers and will be instructed on how to 
take the participant’s axillary temperature, which should be measured and recorded if 
the baby has a diarrhoea episode. 
• Parents/guardians will be instructed to immediately contact study staff if the participant 
has any episode of blood in stool during the study.  A doctor will assess the participant 
for each case of blood in stool. An abdominal ultrasound may be conducted, including 
if intussusception is suspected.  Blood in stool and any ultrasound findings will be 
recorded as AEs. 
8.4  Diarrhoea capture 
Incidence of diarrhoea will be assessed by recording and grading of diarrhoea episodes 
during the study.  For this study the definition of diarrhoea is three or more stools in a 24 
hour period that are looser than normal for that child. 
A Diarrhoea Log will be completed by the parents/guardians throughout the study.  For 
each diarrhoea episode the date, participant’s temperature, time of first and last loose stool 
of the diarrhoea episode, number of loose stools in each 24-hour period, time of first and 

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last vomit of any vomiting associated with the diarrhoea episode, and number of vomits in 
each 24-hour period will be recorded. 
Parents/guardians will be instructed to contact the study staff to notify them of each episode 
of diarrhoea.  The study staff will record the participant’s symptoms, including degree of 
dehydration, treatment, duration of illness and outcome. 
Two faecal samples should be collected per diarrhoea episode, from separate stools.  Faecal 
samples will be tested at the study central laboratories for presence and strain of rotavirus.  
Instructions for sample collection, transport, processing and storage are contained in the 
SRM. 
The details of the diarrhoea episode will be scored in the study database using a modified 
version of the Vesikari clinical score for gastroenteritis in infants (Appendix 1). 
Episodes of diarrhoea will also be recorded as AE. 
Analysis of separate faecal samples by stool microscopy and stool culture for identification 
of an underlying causative agent besides rotavirus may be done in the hospital or MLW 
Laboratory, Blantyre for cases where a participant is admitted to hospital with diarrhoea 
(or for other cases if clinically indicated or if requested by the investigator and/or Medical 
Monitor). 
See Section 8.6 for testing at each laboratory. 
8.5 Exploratory 
A saliva sample will be collected from participants at Visit 1. The sample will be tested at 
the laboratory to determine the Lewis and secretor histo-blood group antigen status.  A 
saliva sample will be collected at all IP dosing visits, to determine the phenotypic 
expression of the Lewis and secretor histo-blood group antigen status of participants. 
The maternal serum sample will be tested for serum IgA as per Section 8.2, and for anti-
rotavirus IgG. 
Bacterial taxonomic and genetic functional profiling of stool microbiome will be conducted 
on a maternal stool sample and stool samples collected post administration of IP and at 
birth (prior to first IP dose) by 16S and shotgun sequencing.  Assessment of T cell and B 
cell function will be completed by flow cytometric assays on whole blood (cord blood, 
Week 6 and Week 18).  Innate and adaptive immunity will be assessed by in vitro reactivity 
in toll-like receptor ligand assays and whole killed pathogen assays by measurement of 
cytokines in supernatants collected from whole blood cultures with TLR agonists and whole 
killed pathogens. 
See Section 8.6 for testing at each laboratory. 
8.6 Central laboratories 
Central laboratories for this study, and the tests they are performing, are; 
• MLW Laboratory, Blantyre, Malawi: 
o Immunogenicity endpoints:  shedding of rotavirus in post dose stool samples. 

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o Diarrhoea endpoint:  presence and strain of rotavirus in diarrhoea samples. 
o Exploratory endpoints:  Lewis and secretor histo-blood group antigen status and 
phenotypic expression from saliva sample and whole blood. 
o  T and B cell function from cord and blood samples, and innate and adaptive 
immunity from cord and blood samples. 
• Enteric Viruses Research Laboratory, MCRI, Melbourne, Australia 
o Immunogenicity endpoints:  sequence analysis of faecal samples for shedding, 
and serum sample (including maternal) testing for immunogenicity. 
o Exploratory endpoints:  IgA and IgG in maternal serum sample, maternal and 
stool microbiome testing and cytomegalovirus and Epstein-Barr virus testing of 
serum for the assessment of the immune development exploratory endpoint.  
Instructions for sample collection, transport, processing and storage are contained in the 
SRM. 
9 CONCOMITANT MEDICATIONS AND VACCINES 
9.1 Concomitant medications 
All prescription and non-prescription medication including traditional, herbal and 
complementary medicines given to the participant from birth until end of study will be 
recorded. 
In addition, prescription and non-prescription medication including traditional, herbal and 
complementary medicines taken by the mother will be recorded from 4 weeks prior to 
delivery, during delivery, and post-delivery until end of study (or until cessation of 
breastfeeding). 
Concomitant medications records will include the drug name, total daily dose, route of 
administration, start and stop date of administration, and indication (for participants only). 
9.2 Routine Concurrent Vaccines 
During the study period, all trial participants should continue to receive standard EPI 
immunisations in accordance with the routine schedule and local recommendations, with 
the following exceptions; 
• All study participants will be administered IPV by study staff at weeks 6, 10 and 
14, rather than OPV, as a transition from OPV to IPV in Malawi is planned during 
the period of the trial 
• Participants will not receive the standard Rotarix® schedule of vaccines during the 
study.  As RV3-BB vaccine efficacy is not yet established, all participants will be 
administered a single dose of Rotarix® approximately one month after their final 
dose of IP. 
Additional licensed vaccines may be administered as appropriate for the participant. 
Commercial name, batch number, and date of administration will be recorded for all 
vaccinations. 

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10 INVESTIGATIONAL PRODUCT 
The RV3-BB Rotavirus Vaccine and placebo will be manufactured, packaged and labelled 
by Meridian Life Sciences, USA. 
Table 2:  Identity of IP 
Name: 
RV3-BB Rotavirus Vaccine 
Placebo 
Formulation: 
Each dose is a cell free solution containing 
attenuated rotavirus particles 
• High dose at a concentration of 1.0 x 107 
FFU/ml) in 10% sucrose/cell culture 
medium.   
• Mid dose at a concentration of 3.0 x 106 
FFU/ml) in 10% sucrose/cell culture 
medium.   
• Low dose at a titre of 1 x 106 FFU/ml) in 
10% sucrose/cell culture medium 
Sterile solution of 
cell culture medium 
and 10% sucrose 
Route of 
administration: 
Oral 
Oral 
Dosage: 
1 mL  
1 mL 
Dosage form: 
Single dose sterile aqueous solution for oral 
administration 
Single dose sterile 
aqueous solution for 
oral administration 
10.1 
Special Warnings and Precautions for use of IP 
RV3-BB Rotavirus Vaccine 
Please see the Investigator Brochure for detail. 
Based on data preclinical animal testing, the two clinical trials of the first generation RV3 
Rotavirus Vaccine, and data from the RV3-BB clinical trials conducted to date (Danchin et 
al, 2013, Bines et al, 2015), side effects from RV3-BB candidate could include 
gastrointestinal events (for example: vomiting, diarrhoea/loose bowel motions and 
abdominal discomfort). 
Although no previous recipient of either the first or second generation RV3 Rotavirus 
Vaccine experienced an anaphylactic reaction there is a low risk of a generalised 
anaphylactic reaction to the IP. 
 
As for any study in neonates, particularly in low-income settings, the Investigator 
should be aware of the following:  
• Jaundice is not uncommon in the neonatal period and is usually self-limited often 
occurring in association with establishment of breast feeding. Jaundice was 
observed in infants in both the vaccine and placebo groups in the Phase IIa and IIb 
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• Sepsis is an important cause of death and illness in the neonatal period, 
particularly in low income settings. Neonatal Sepsis occurred in infants in both the 
neonatal and infant vaccine schedule in the Phase IIa and IIb study. 
 
In the phase IIb study, one participant developed intussusception, although this was 114 
days after the final dose of IP.  As intussusception is a known rare side-effect of other 
rotavirus vaccines, the cautious approach is to assume it may be a class effect and 
parents/guardians will be advised of potential symptoms of intussusception. 
Placebo 
The Placebo contains only cell culture medium and 10% sucrose.  There are no known 
warnings or risks associated with the use of the Placebo. 
10.2 
Labelling and Packaging 
IP will be supplied as 1 mL single doses in prefilled plastic cryovials, which will be packed 
and stored in bulk outer boxes.  Each box of IP will contain up to 81 vials of either RV3-
BB or placebo. 
The IP will be labelled according to local legal requirements and GMP guidelines. 
Syringe labels 
IP will be thawed and drawn into polypropylene syringes for dispensing and administration.  
The syringe will be labelled by the pharmacist indicating protocol number, randomisation 
number, date and time of thawing, and time by which IP must be administered (expiry 
time). 
10.3 
Storage requirements 
Vaccine and placebo vials will be stored at –70°C ±10°C in a temperature-monitored and 
alarmed freezer.  The IP will be stored in a secure and access-restricted location, isolated 
from any potential sources of contamination. 
Once thawed, IP must not be refrozen but may be stored at 2-10°C for a maximum of 6 
hours until time of administration. 
Following removal from 2-10°C storage, the IP should be administered as soon as possible, 
within a maximum of 20 minutes at room temperature. 
10.4 
IP accountability 
All material supplied is for use only in this clinical study and should not be used for any 
other purpose. 
The PI or designee is responsible for IP accountability, reconciliation and record 
maintenance.  The PI or designated site staff must maintain IP accountability records 
throughout the course of the study including records of the amount of IP received, the 
identification of the participant for whom it was dispensed, and the date(s) and quantity of 
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The IP and records must be available for inspection by a study monitor during the study.  
IP supplies, including unused, partially used or empty vials and syringes, must be retained 
and will either be returned by the site to MCRI or designee, or destroyed on site if written 
approval to do so is given by MCRI and appropriate facilities and procedures are available.  
Records shall be maintained by the PI of any disposition of the IP.  These records must 
show the identification and quantity of IP disposed of, the method of destruction, and the 
person who disposed of the IP. 
10.5 
Doses and treatment regimens 
Approximately 688 participants will be prospectively randomised to one of the following 
four treatment groups in a 1:1:1:1 ratio. 
• High dose neonatal RV3-BB vaccine schedule (1x107titre dose).  RV3-BB Vaccine 
for doses 1, 2 and 3 and placebo for dose 4 
• Mid dose neonatal RV3-BB vaccine schedule (3x106titre dose).  RV3-BB Vaccine for 
doses 1, 2 and 3 and placebo for dose 4. 
• Low dose neonatal RV3-BB vaccine schedule (1x106titre dose).  RV3-BB Vaccine for 
doses 1, 2 and 3 and placebo for dose 4. 
• High dose Infant RV3-BB vaccine schedule (1x107titre dose).  Placebo for dose 1 and 
RV3-BB Vaccine for doses 2, 3 and 4 
Participants will also receive a dose of commercially available Rotarix® at 18 weeks of 
age. 
10.6 
Method for Assigning Participants to Treatment Group  
Participant eligibility will be established before randomisation.  Eligible participants will 
be assigned to a treatment arm according to the randomisation schedule. 
At each site, a unique Screening Number will be allocated to each pregnant woman who 
provides preliminary informed consent, so that potential participants can be identified 
without making assumptions about their subsequent eligibility for the main trial.  From 
birth, the baby will have the same Screening Number as their mother. 
Randomisation will be stratified by birth multiple (single vs multiple), to minimise 
imbalance across the treatment arms.  Multiple births will be randomised to the same 
treatment arm to avoid potential contamination across treatment arms. 
Eligible participants will be randomised at V1 following confirmation of eligibility.  The 
pharmacist will assign the next available Randomisation Number and prepare the IP dose. 
The Randomisation Number will be used to identify the participant throughout the study 
period and on all study-related documentation. 
If study consent is not given, or a participant fails screening, the Screening Number will 
not be reused.  If a participant is discontinued after randomisation, the Randomisation 
Number will not be reallocated. 

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10.7 
Blinding and procedures for breaking the blind 
This is a double-blind study; only the pharmacists dispensing the IP and the unblinded CRA 
will know the treatment allocation of the participants.  The site staff, parents/guardians of 
participants, sponsor, and monitoring personnel will be blind to treatment arm allocations. 
To maintain the blind, the identity of the IP in each dispensed syringe will not be indicated 
on the label. 
The laboratory personnel completing assays on routine stool samples will have potential 
deductive knowledge of the participants’ treatment allocation as a result of conducting 
assays.  For this reason, communication will be restricted between the laboratory personnel 
and blinded study personnel, until after final database lock. 
Only in a medical emergency, when the investigator determines that adequate medical care 
cannot be provided without knowing the treatment assignment, the blind may be broken.  
In this instance the Investigator may contact the Pharmacy to obtain the treatment identity.  
If possible, such emergencies should be discussed with the Medical Monitor before 
breaking the blind.  Details for contacting the Medical Monitor will be provided in the 
SRM. 
If the blind has been broken, the investigator must document the date and the reason the 
blind was broken in the participant’s notes and CRF. 
The study monitor should be notified if the blind is broken.  MCRI or designee will decide 
on a case-by-case basis whether unblinded infants will receive further doses of IP. 
10.8 
Preparation and Dispensing of IP 
The pharmacist will prepare and dispense the appropriate dose of IP, according to the 
participant’s allocated treatment schedule. 
Dose preparation and transport to sites is described in the Pharmacy Manual and SRM. 
10.9 
IP administration and treatment compliance 
Prior to administration of the second, third and fourth doses of IP, participants will be given 
a 2ml oral dose of an antacid solution (Mylanta® Original), using a syringe without a 
needle.  The antacid solution is administered to help neutralise stomach acid to ensure 
vaccine stability when administered to infants.  The neonatal stomach is less acidic, so the 
antacid solution is not required for the first dose of IP. 
The investigator or designee will administer the IP to the participant within 10 minutes after 
administering the antacid (where applicable).  The participant should be held in a supine 
position, and the entire contents of the syringe administered orally to the inside of the cheek 
in small aliquots, taking care that the participant does not spit the IP out. 
The participant must remain under supervision at the clinic for at least 30 minutes after 
administration of the IP. 
A participant will be considered compliant with study treatment if they received the 
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10.9.1 Incomplete administration of IP 
Participants who do not ingest the full 1 mL dose of IP (e.g. due to spitting out the IP or 
vomiting within the 30 minutes following administration) will not receive any further IP at 
that visit.  The participant will however, continue to receive subsequent doses of the IP as 
per protocol. 
Any incomplete administration of IP will be recorded in the participant notes and the CRF.  
10.9.2 Criteria for temporary delay of IP dose 
Administration of any dose of IP can be delayed at the discretion of the investigator or 
Medical Monitor. 
For the second, third and fourth doses, if a participant has a fever (paediatrics: 37.5°C 
axillary/oral or 38.0°C rectal/tympanic) and/or acute illness that contraindicates 
vaccination, dosing will be delayed until the participant is afebrile.  If the dose then falls 
outside of the protocol specified window it will be recorded as a protocol deviation. 

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11 ADVERSE EVENTS 
The definitions of AEs and SAEs are given below.  It is extremely important that all staff 
involved in the trial are familiar with the content of this section.  The PI is responsible for 
ensuring this. 
11.1 
Adverse event definitions 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment.  An 
AE can therefore be any unfavourable and unexpected sign, symptom, or disease 
temporally associated with the use of an IP, whether or not related to the IP. 
Pre-existing diseases are not considered AEs unless there is a change in frequency or 
severity.  This change has to be reflected in the reported term.  Lack of efficacy is not 
considered an AE, per se. 
Parents/guardians must be instructed to inform the Investigator about all participant AEs 
and these must be documented in the participant records and Case Report Form (CRF) 
together with their intensity; 
• Mild (Grade 1) AEs do not impact normal daily routine. 
• Moderate (Grade 2) AEs impact the normal daily routine 
• Severe (Grade 3) are those AEs which make normal daily routine impossible. 
• Life Threatening (Grade 4) 
• Fatal (Grade 5) 
An AE that is assessed as severe should not be confused with a SAE.  Severity is a category 
utilised for rating the intensity of an event, and both AEs and SAEs can be assessed as 
severe.  An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as 
described in Section 11.2. 
The Investigator must assign causality to each adverse event in relation to RV3-BB based 
on the following scale: 
• Not related:  AE for which there is evidence of another explanation, e.g. the adverse 
event is obviously explained by a concurrent disease(s), is in accordance with the 
known effect of a concomitant medication, or has occurred prior to first administration 
of IP. 
• Unlikely related:  AE with a time to IP administration that makes a relationship 
improbable (but not impossible), and disease or other drugs provide plausible 
explanations. 
• Possibly related:  AE with a reasonable time relationship to IP administration, but which 
could also be explained by disease or other drugs. 
• Probably related:  AE with reasonable time relationship to IP administration that is 
unlikely to be attributed to disease or other drugs. 
• Definitely related:  AE with plausible time relationship to IP administration which 
cannot be explained by disease or other drugs, and event is definitive pharmacologically 

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or phenomenologically (i.e. an objective and specific medical disorder or a recognised 
pharmacological phenomenon). 
All AEs must be documented by the Investigator, regardless of causality. 
Expected AEs are defined as all AEs stated as such in the IB.  If an AE has not been 
previously reported as expected (including type, degree, or frequency) in the IB, it is an 
unexpected adverse event.  MCRI or designee is responsible for determining the 
expectedness of an AE. 
If an AE leads to premature discontinuation of the study, the appropriate pages of the CRF 
must be completed. 
11.2 
Serious Adverse Events 
An AE shall be defined as serious if it: 
• results in death; 
• is life-threatening; 
o Life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event, it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalisation or prolongation of an existing hospitalisation; 
o Hospitalisation is defined as in-patient admission or care regardless of 
duration. 
o Out-patient treatment in an emergency room is not in itself an SAE, although 
the reasons for it may be (e.g. bronchospasm, laryngeal oedema).  Elective 
surgery, hospitalisation for social reasons (with no causal AE), or hospital 
admissions and/or surgical operations planned before or during this study are 
not considered AEs if the illness or disease existed before the participant was 
enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
• results in a persistent or significant disability or incapacity; 
• is an important medical event 
o This includes events that may not be immediately life-threatening or result in 
death or hospitalisation but may jeopardise the participant or may require 
intervention to prevent one of the other outcomes listed above. 
11.2.1 SAE exceptions 
Conditions identified as a congenital anomaly or birth defect, regardless of when the 
condition is identified, will not be recorded as SAEs unless the condition 
progresses/worsens or is fatal.  These conditions should be recorded as medical history, 
even if they are identified/diagnosed after randomisation. 
11.3 
Recording of AEs 
AEs will be captured from the time of first dose of IP until the final study visit.  
Parents/guardians will be asked at each visit whether their baby has experienced any AEs.  

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SAEs that are at least possibly or definitely related to IP occurring to a study participant 
after the AE reporting period will be reported to the sponsor if the Investigator becomes 
aware of them. 
It is preferable that AEs are reported as diagnoses if one is able to be made, rather than 
individual signs and symptoms.  The AE description, start and stop dates, severity, causality 
and outcome must be recorded, as well as any actions taken. 
Unless a diagnosis is made, or signs and symptoms are present, an abnormal laboratory 
value or vital sign should only be reported as AEs if they cause the participant to 
discontinue from the trial, the investigator feels they are clinically significant, or they meet 
a criterion for a SAE. 
11.4 
Management and follow-up of AEs and SAEs 
Medical follow-up (such as history, physical examination, laboratory testing and/or 
treatment) may be necessary if a participant experiences an AE. 
All AEs and SAEs recorded for this study, regardless of relationship to IP, should be 
followed until resolution or stabilisation. 
Participants experiencing SAEs should be followed clinically until their health has returned 
to baseline status or until all parameters have returned to normal, are stabilised, or have 
otherwise been explained. 
11.5 
Reporting of Serious Adverse Events 
Investigators and other site personnel must report SAEs to MCRI’s representative within 
24 hours of becoming aware of the SAE, regardless of causality. 
STUDY CONTACTS AND PROCESSES FOR REPORTING 
SERIOUS ADVERSE EVENTS ARE DESCRIBED IN THE 
STUDY REFERENCE MANUAL. 
 
Follow-up information on SAEs must also be reported by the investigational site within the 
same time frame.  If a non-serious AE becomes serious, this and other relevant follow-up 
information must also be provided within 24 hours. 
All SAEs will be recorded in the participant records and the CRF.  MCRI or designee is 
responsible for informing the regulatory authorities of the SAE as appropriate. 
The investigator must notify their Independent Ethics Committee (IEC) of any SAEs within 
the time period specified by the IEC.  MCRI or designee is responsible for informing other 
relevant IECs. 

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12 STUDY OVERSIGHT 
12.1 
Medical Monitors 
The Medical Monitor is an appropriately qualified, designated physician who will be 
available to advise on trial related medical questions or problems, without other direct 
involvement with trial participants.  The Medical Monitor will be available to respond to 
questions from the investigators about study eligibility, abnormal assessments, participant 
follow-up, assistance with AE and SAE assessment, concomitant medications and criteria 
for delay of IP.  The contact details for the Medical Monitor are available in the SRM. 
12.2 
Steering Committee 
The Steering Committee (SC) is a MCRI group and may include non-MCRI personnel as 
invited.  The SC will provide oversight of the trial to review recruitment rates, site progress, 
and protocol compliance.  The SC’s responsibilities will be documented and will include 
input into protocol amendments, contact with study investigators to promote recruitment 
and high quality data, review, recommendation and implementation of major protocol 
changes, and implementation of DSMB recommendations. 
12.3 
Data Safety Monitoring Board 
An independent DSMB will be established prior to recruitment start, with appropriate 
charter that defines its roles and responsibilities.  The DSMB will monitor accruing trial 
safety results at intervals throughout the study.  The main purpose of the DSMB will be to 
protect the interests of the participants included in the trial.  
The charter will specify the intervals for formal DSMB meetings. 
The DSMB will convey to MCRI their recommendations as to whether the trial may 
continue as planned or if the trial should be modified or stopped.  The final decision on 
whether the study should be modified or stopped will be the responsibility of MCRI.  Any 
decision to modify or stop will be communicated to investigators and regulatory agencies 
by MCRI (or their representatives). 
13 STATISTICS AND DATA EVALUATION 
The statistical analysis principles described below will be supplemented by a 
comprehensive statistical analysis plan (SAP) which will be finalised before the database 
is locked.  Any changes to the statistical plans will be described and justified in the final 
report. 
13.1 
Sample Size Assumptions 
With the high titre RV3-BB neonatal vaccine schedule as the active control arm, the sample 
size is calculated to demonstrate the non-inferiority of the lower titre vaccine arms with 
respect to the proportion of participants who have a serum IgA response 4 weeks after 3 
doses of vaccine. A non-inferiority margin of 20% for the difference between arms will be 
used. The primary analysis is based on the per protocol population defined as participants 
who receive all 3 doses and have no major protocol violations. Thirty percent of participants 

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are expected to be excluded from the PP population due to death, study withdrawal, loss to 
follow-up, or study non-compliance. Among those in the PP population, a 50% response 
probability is assumed for the active controls. Based on a one-sided 0.025 level score test 
with 90% power under the alternative of no difference in response probabilities, 172 
participants per arm are required for a total sample size of 688 participants. 
Non-inferiority of the lower titre vaccine will also be assessed in the intention to treat 
population. The cumulative probability of response by 18 weeks of age will be estimated 
by the Kaplan-Meier method for each vaccine arm. The difference between high and low 
titre arms in the cumulative probabilities and its 95% confidence interval will be calculated. 
If the upper bound of the confidence interval is below 20%, non-inferiority of the lower 
titre vaccine will be demonstrated. 
13.2 
Analysis Sets 
The following sets will be used for the statistical analyses: 
Full analysis set (FAS):  All participants randomised into the study.  Participants 
will be analysed according to treatment to which they were randomised.  
Immunogenicity analyses performed in the FAS are considered supportive. 
Safety set:  All randomised participants who received at least one dose of IP.  
Participants will be analysed according to the treatment received. 
Intention-to-treat (ITT) set:  All randomised participants who received at least 
one dose of IP and have an evaluable baseline and post-baseline blood sample.  
Participants will be analysed according to the treatment to which they were 
randomised.  Supportive immunogenicity analysis will be performed in the ITT set. 
Per-protocol (PP) set:  All participants from the ITT population who completed 
the study in compliance with the protocol and who reported no major violation of 
the study protocol.  Participants will be analysed according to the treatment to which 
they were randomised.  The final decision to exclude a participant from the PP set 
will be taken during a blinded data review meeting before database lock.  Primary 
analyses are performed on the PP set. 
13.3 
Data Analysis Considerations 
All immunogenicity and safety data will be listed and summarised using descriptive 
statistics by treatment group and nominal time.  The descriptive summary for the 
categorical variables will include counts and percentages.  The descriptive summary for the 
continuous variables will include means, medians, standard deviations and minimum and 
maximum values.  Where possible, data from participants who withdraw prematurely from 
the study will be included in any analysis.  Further details on the handling of withdrawals 
and/or missing data will be specified in the SAP. 
All statements of statistical significance will be based on a two-sided test at the 5% level 
of significance, unless stated otherwise.  Further details will be specified in the SAP. 
The baseline value for each clinic assessment will be the last pre dose value obtained. 

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Full details of the statistical analyses will be presented in the SAP.  Any deviations from 
the planned analyses detailed in the protocol will be documented in the SAP and final study 
report.  If the study is prematurely discontinued, all available data will be listed and a review 
will be carried out to determine which statistical analyses are considered appropriate. 
13.3.1 Demographics and Baseline Data 
Demographic and baseline characteristics will be listed and summarised by treatment arm. 
13.3.2 Immunogenicity Analyses 
13.3.2.1 
Definition of baseline IgA for the calculation of vaccine take  
Due to the timing of the blood tests, baselines for serum anti-rotavirus IgA are defined 
differently for participants in the neonatal vaccine schedule and the infant vaccine schedule.  
Baseline serum anti-rotavirus IgA in the neonatal vaccine schedule is defined as the 
measurement from the cord blood. In the infant vaccine schedule baseline is defined as the 
measurement from analysis of serum collected prior to the second dose, although the 
measurement from the cord blood may be used if there are no data on IgA following the 
first dose of IP.   
Further details of the analysis of secondary endpoints will be described in the SAP.  Details 
about multiplicity and Type I error for secondary endpoints will be included in the SAP. 
13.4 
Safety Data 
13.4.1 Extent of exposure 
The number of participants exposed to study treatment will be summarised by treatment 
received. 
13.4.2 Adverse events 
AE data will be listed individually and incidence of AEs summarised by system organ class 
and preferred terms within a system organ class for each treatment group.  When calculating 
the incidence of AEs, each AE, based on preferred terminology defined by Medical 
Dictionary for Regulatory Activities (MedDRA; Version 13.1, or later), will be counted 
only once for a given participant.  A summary of the number and percent of participants 
with the following treatment emergent AEs will be displayed by treatment groups: 
• All AEs 
• IP related AEs 
• Severe AEs 
• SAEs 
• AEs leading to permanent discontinuation of IP. 
13.4.3 Other safety measures 
Continuous variables will be summarised along with the change from baseline at each time 
point by treatment group.  Other variables will be summarised as appropriate to the data. 

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14 DATA MANAGEMENT 
Data collection and entry into the CRF will be completed by authorised study site personnel 
designated by the Investigator.  Appropriate training and security measures will be 
completed with the Investigator and all authorised study site personnel prior to the study 
being initiated and any data being entered into the system for any study participants. 
All data must be entered in English.  The CRFs should always reflect the latest observations 
on the participants participating in the trial; therefore, the CRFs are to be completed as soon 
as possible after the participant’s visit.  The Investigator must verify that all data entries in 
the CRFs are accurate and correct.  If some assessments are not done, or if certain 
information is not available or not applicable or unknown, this should be indicated in the 
CRF.  The Investigator will be required to sign off on the clinical data. 
The study monitor/Clinical Research Associate (CRA) will review the CRFs and evaluate 
them for completeness and consistency, and compare them to the source documents to 
ensure that there are no discrepancies between critical data.  All entries, corrections and 
alterations are to be made by the responsible Investigator or designee.  The CRA cannot 
enter data into the CRFs.  Once data in the CRF have been entered, corrections to the data 
fields will be audit trailed, meaning that the reason for change, the name of the person who 
performed the change, together with time and date of the change, will be logged.  Roles 
and rights of the site personnel responsible for entering the clinical data into the CRF will 
be determined in advance.  If additional corrections are needed, the responsible CRA or 
Data Manager will raise a query.  The appropriate investigational staff will answer queries.  
This will be audit trailed, as described above. 
The CRF is essentially a data entry form and should not constitute the original, or source 
document.  Source documents are all documents used by the Investigator or hospital that 
relate to the participant’s medical history, that verify the existence of the participant, the 
inclusion and exclusion criteria and all records covering the participant’s participation in 
the study.  They may include, but are not limited to, laboratory reports, ECG results, 
imaging reports, pharmacy dispensing records, hospital records, participant files, etc.   For 
this study, Study Reminder Card and Diarrhoea Logs will be considered source documents. 
The Investigator is responsible for maintaining source documents.  These will be made 
available for inspection by the CRA at each monitoring visit. 
A CRF will be completed for all participants who are screened. 
 
 

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15 TRIAL MANAGEMENT 
15.1 
Contacts 
Details of study sites, investigators, Medical Monitors, CRAs, and MCRI and designee 
contacts can be found in the SRM. 
15.2 
Quality control and Quality Assurance 
15.2.1 Monitoring 
Study monitoring will be performed in accordance with applicable regulations, 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), and 
MCRI and designee SOPs. 
Before the start of the trial, a representative of MCRI or designee will contact the 
investigational site to ensure facilities are adequate and discuss responsibilities with the site 
staff with regards to following the protocol and regulatory and ethical requirements. 
During the trial, a CRA from MCRI or its designee will regularly contact and visit the site 
to monitor study progress, confirm protocol, regulatory and ethical adherence, confirm data 
accuracy and provide information and support. 
A separate unblinded study monitor will conduct monitoring visits at the pharmacy.  This 
monitor will be unblinded to the treatment allocation of participants through their contact 
with pharmacy personnel and records.  The nominated unblinded monitor will ensure that 
accountability and dispensing records are adequately maintained and ensure that 
appropriate storage conditions for the vaccine are maintained. 
The PI agrees to allow the CRA direct access to all relevant documents, including electronic 
records, and to allocate their time and the time of their staff to the CRA to discuss findings 
and any relevant issues. 
Site staff will be provided with CRA and back up contact details in the event they have 
queries or require assistance. 
15.2.2 Audits and Inspections 
An audit is a systematic and independent examination of trial related activities and 
documents to determine whether the evaluated trial related activities were conducted, and 
the data were recorded, analysed and accurately reported according to the protocol, MCRI’s 
SOPs and those of MCRI’s designees, GCP and the applicable regulatory requirements. 
Authorised representatives of MCRI, its designee, a regulatory authority, or the IEC may 
visit the centre to perform audits or inspections.  The investigator should contact MCRI or 
designee immediately if they are contacted by a regulatory agency about an inspection at 
their centre.  If an audit or inspection occurs, the PI, site coordinating investigators, and 
institutions agree to allow the auditor/inspector direct access to all relevant documents and 
allocate their time and the time of their staff to the auditor/inspector to discuss findings and 
any relevant issues. 

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15.3 
Training of Staff 
Each individual involved in this trial should be qualified by education, training, and 
experience to perform his or her respective tasks. 
Site staff may be trained for this study at investigator meetings and initiation visits by 
MCRI, or their designees. 
The PI will maintain a record of all staff involved in the trial at each site.  The PI will ensure 
that appropriate training relevant to the trial is given to all these staff, and that they will 
receive any new information relevant to the performance of this trial. 
15.4 
Changes to the Protocol 
Trial procedures will not be changed without the agreement of MCRI. 
If it is necessary for the trial protocol to be amended, the amended protocol must be 
approved by the IEC, unless the immediate safety of participants is involved. 
If a protocol amendment requires a change to the PICF, approval of the revised PICF by 
MCRI or their designee and by the IEC is required before the revised form can be used. 
MCRI or their designee will distribute amendments and new versions of the protocol to the 
PI.  The PI will be responsible for submitting to the IEC. 
MCRI or their designee will also distribute amendments and new versions of the protocol 
to the regulatory agencies.  Regulatory approval must be obtained prior to implementation. 
15.5 
Trial Agreements 
The PI and site coordinating investigator at each centre must comply with all the terms, 
conditions and obligations of the trial agreement for this trial. In the event of any 
inconsistency between this protocol and the trial agreement, the trial agreement shall 
prevail. 
15.6 
Trial Timetable and Termination 
The planned start date for this trial is mid to late-2017.  The proposed completion date is in 
2019. 
MCRI reserves the right to terminate the trial at any stage for any reason including 
commercial considerations.  In the event of early termination, MCRI and designees will 
work with the PI and site staff to ensure all participants are appropriately discontinued and 
follow up for safety. 
15.7 
Ethics and regulatory review 
The protocol, PICF, and other patient-facing documents will be submitted for approval to 
the IEC and regulatory agency, and must be approved or given a favourable opinion in 
writing as appropriate.  The investigator must submit written approval to MCRI or designee 
before they can commence recruitment or enrol any participants into the trial. 
Any amendment to the protocol will be sent to the IEC and regulatory agency.  No 
deviations from or changes to the protocol will be implemented without documented 

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approval/favourable opinion from the IEC and regulatory agency of an amendment, except 
where necessary to eliminate an immediate hazard to a trial participant, or when the changes 
involve only logistical or administrative aspects of the trial. 
The deviations from or changes to the protocol which were implemented to eliminate an 
immediate hazard to a trial participant and the proposed amendment, if appropriate, should 
be submitted to the IEC and regulatory agency for review and approval as soon as possible. 
The PI must submit progress reports to the IEC according to local regulations and 
guidelines.  The PI must also provide the IEC with any reports of SAEs from the trial site 
in accordance with the IEC requirements and timelines. 
MCRI or designee will report to the regulatory agency as required. 
15.8 
 Ethical Conduct of the Trial 
The trial will be performed in accordance with the ethical principles in the Guidelines of 
the World Medical Association's Declaration of Helsinki in its revised edition (Fortaleza, 
Brazil, October 2013), ICH GCP, the approved study protocol, and applicable regulatory 
requirements. 
15.9 
Insurance and Liability 
Liability and insurance for this study are addressed in the Clinical Trial Agreement. MCRI 
will not, under any circumstances, have any responsibility or liability regarding any injury 
to, or death of, an infant or infant’s mother arising from or in connection with delivery or 
birth of a potential research participant. 
15.10 Participant Information and Consent 
The investigator at each centre will ensure that the participant’s parents/guardians are given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the trial prior to obtaining both preliminary and final study consent.  
Parents/guardians must also be notified that they are free to discontinue their child from the 
trial at any time.  The parents/guardians should be given the opportunity to ask questions 
and should be allowed time to consider the information provided. 
The participant’s parents/guardians’ signed and dated informed consent must be obtained 
before conducting any procedure specifically for the trial.  The PI must store the original, 
signed PICFs.  A copy of the signed and dated PICFs must be given to the 
parents/guardians. 
15.11 Data Protection 
The PICF will explain that trial data will be stored in a computer database, maintaining 
confidentiality of participants.  Participants in this database will be identified by Screening 
and Randomisation Number only.  The PICF will also explain that for data verification 
purposes, authorised representatives of MCRI or their designees, regulatory authorities, 
IECs or sites may require direct access to parts of the hospital or site records relevant to the 
trial, including the participant’s and mother’s personal information. 

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15.12 Archiving 
The PI is responsible for the archiving of the trial records for their site.  Trial records 
include the participant files as well as the source data, the Investigator Site File, pharmacy 
records, and other study documents.  Trial records must be archived for at least 15 years 
(or at least 2 years after the formal discontinuation of clinical development of RV3-BB 
vaccine). 
However, these documents should be retained for a longer period if specified by 
regulatory requirements or by an agreement with MCRI.  It is the responsibility of MCRI 
to inform the PI/institution as to when these documents no longer need to be retained.  
Records may not be destroyed without prior written consent from MCRI. 
If the PI leaves the investigational site for any reason, the responsibility for all study 
related records must be transferred to another person at site. 
15.13 Emergency Procedures 
The PI is responsible for ensuring that procedures and expertise are available to cope with 
medical emergencies during the trial. 
If emergency unblinding is required, the site should contact the study Medical Monitor.  
Contact details are provided in the SRM. 
15.14 Publication Policy 
The publication policy for the study will be specified in a separate contract(s) between 
MCRI, and other relevant parties involved with the clinical study. 
 

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Perez-Schael I., Guntinas M. J., Perez M., Pagone V., Rojas A. M., Gonzalez R., Cunto W., 
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Aug 6. 
 
 

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17 APPENDICES 
17.1 
Appendix 1: Modified Vesikari Grading Scale for Gastroenteritis in Children 
Non severe diarrhoea < 11 points 
Severe diarrhoea  
≥11 points 
 
        Points 
Value 
Symptom 
1 
2 
3 
Duration of diarrhoea 
(days) 
1-4 
5 
≥6 
Max. 
number 
of 
diarrhoea stools/24hrs 
1-3 
4-5 
≥6 
Duration of vomiting 
(days) 
1 
2-4 
≥5 
Max. 
number 
of 
vomiting episodes/24hrs 
1 
2-5 
≥6 
Temperature 
(degrees 
C)* 
37.1 – 38.4 
38.5 – 38.9 
≥39.0 
Dehydration 
- 
Some (1-5%) 
Severe (≥6%) 
Treatment 
Rehydration 
Hospitalisation 
- 
Reference: (Ruuska ,1990) 
*Temperature measurements will be entered into the CRF as axillary measurements and 
converted at the database level to rectal equivalent temperatures, which are standard for 
Vesikari scoring. 
Modifications 
Children who receive oral rehydration solution prior to the dehydration assessment AND 
who have at least one of the signs of “some” dehydration according to the Integrated 
Management of Childhood Illness dehydration criteria at the initial clinic assessment 
receive a score of 2 for ‘Dehydration’ 
Use of NG, IV or six hours of supervised oral rehydration is scored as hospitalisation (score 
of 2) for ‘Treatment’ 
 
Reference: 
Lewis, K. Vesikari Clinical Severity Scoring System Manual. Seattle: PATH; Version 1.3, 
2 May 2011.