Immunogenicity After a Prime Dose and Revaccination With Adjuvanted RSVPreF3 Vaccine in the Most Elderly and Frail Population - an Open-labeled Phase IIIb-trial
Phase: PHASE3
Conditions: RSV Immunisation
Sponsor: Karin Karin Loré

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 1 of 72 
 
 
CLINICAL TRIAL PROTOCOL 
Immunogenicity after a prime dose and 
revaccination with adjuvanted RSVPreF3 
vaccine in the most elderly and frail population – 
an open-labeled phase IIIb-trial 
RSV Immunogenicity Study in the Elderly (RISE) 
Trial ID:  
RISE  
EU Trial number:  
2024-520141-23-01  
Version number:  
2.0 
Date:  
12-June-2025 
Sponsor:  
 
Sponsor 
representative: 
 
 
 

 
 
 
 
 
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Table of Contents 
 
Table of Contents ................................................................................................ 2 
Revision history ................................................................................................... 6 
Signature page .................................................................................................... 7 
Contact information ............................................................................................. 9 
List of used acronyms and abbreviations ............................................................ 9 
1. Synopsis ..................................................................................................... 14 
2. Background and rationale ........................................................................... 18 
3. Benefit-risk evaluation ................................................................................ 20 
4. Trial objectives ............................................................................................ 21 
4.1. Primary objective................................................................................. 21 
4.2. Secondary objective(s) ........................................................................ 22 
4.3. Exploratory objective(s) ....................................................................... 22 
4.4. Primary endpoint ................................................................................. 23 
4.5. Secondary endpoint(s) ........................................................................ 23 
4.6. Exploratory endpoint(s) ....................................................................... 24 
5. Trial design and procedure ......................................................................... 26 
5.1. Overall trial design .............................................................................. 26 
5.2. Procedures and flow chart .................................................................. 27 
5.3. Biological sampling procedures .......................................................... 30 
5.3.1. Handling, storage, and destruction of biological samples ...........................30 
5.3.2. Total volume of blood per participant .........................................................32 
5.3.3. Laboratory assays .....................................................................................32 
5.3.4. Biobank .....................................................................................................34 
5.4. Start, end, temporary halt and early termination ................................. 34 
5.4.1. Start of the clinical trial ...............................................................................34 
5.4.2. Temporary halt or early termination ...........................................................34 
5.4.3. End of the clinical trial ................................................................................35 
6. Participant selection ................................................................................... 35 
6.1. Exclusion criteria ................................................................................. 36 
6.2. Screening and inclusion ...................................................................... 38 
6.3. Withdrawal criteria ............................................................................... 38 
7. Trial treatments ........................................................................................... 39 

 
 
 
 
 
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7.1. Description of investigational medicinal product(s) ............................. 39 
7.1.1. Dose and administration ............................................................................39 
7.1.2. Packaging, labelling, and handling of investigational medicinal product(s) .40 
7.1.3. Drug Accountability and treatment compliance ..........................................40 
7.1.4. Randomisation ...........................................................................................40 
7.1.5. Blinding ......................................................................................................40 
7.1.6. Code breaking ...........................................................................................41 
7.1.7. Destruction ................................................................................................41 
7.2. Auxiliary medicinal products ................................................................ 41 
7.2.1. Dose and administration ............................................................................41 
7.2.2. Drug accountability and treatment compliance ...........................................41 
7.3. Concomitant use of other medicinal products and treatments ............ 42 
7.4. Treatment after trial end ...................................................................... 42 
8. Methods for measurement of endpoints for clinical efficacy and safety ...... 42 
8.1. Methods for measurement of endpoints for clinical efficacy ................ 42 
8.1.1. Methods for the primary endpoint ..............................................................42 
8.1.2. Methods for the exploratory endpoints .......................................................43 
8.2. Methods for measurement of endpoints for clinical safety .................. 44 
9. Handling Adverse Events ........................................................................... 45 
9.1. Definitions ........................................................................................... 45 
9.1.1. Adverse Event (AE) ...................................................................................45 
9.1.2. Adverse Reaction (AR) ..............................................................................45 
9.1.3. Serious Adverse Event (SAE) ....................................................................45 
9.1.4. Suspected Unexpected Serious Adverse Reaction (SUSAR) ....................45 
9.1.5. Potential immune-mediated diseases (pIMD).............................................46 
9.2. Assessment of Adverse Events (AE) .................................................. 46 
9.2.1. Assessment of causal relationship .............................................................46 
9.2.2. Assessment of intensity .............................................................................46 
9.2.3. Assessment of seriousness .......................................................................47 
9.3. Reporting and registration of Adverse Events ..................................... 47 
9.3.1. Reporting of Adverse Events (AE) .............................................................48 
9.3.2. Reporting of Serious Adverse Events (SAE) ..............................................48 
9.3.3. Reporting of Suspected Unexpected Serious Adverse Reactions ..............49 
9.4. Follow-up of Adverse Events .............................................................. 49 
9.5. Independent Data Monitoring Committee ............................................ 49 

 
 
 
 
 
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9.6. Annual Safety Report (ASR) ............................................................... 50 
9.7. Procedures in case of emergencies .................................................... 50 
10. 
Statistics ................................................................................................. 50 
10.1. Analysis population ............................................................................. 50 
10.2. Statistical analyses .............................................................................. 51 
10.2.1. 
Statistical methods ...............................................................................51 
10.2.2. 
Drop-outs .............................................................................................52 
10.3. Adjustments of significance and confidence interval ........................... 52 
10.4. Sample size calculations ..................................................................... 52 
10.5. Interim analysis (if relevant) ................................................................ 52 
11. 
Quality Control and Quality Assurance ................................................... 53 
11.1. Quality Assurance and Sponsor oversight .......................................... 53 
11.2. Monitoring ........................................................................................... 53 
11.3. Source data ......................................................................................... 54 
11.4. Deviations, serious breaches and other reporting obligations ............. 54 
11.5. Audits and inspections ........................................................................ 55 
12. 
Ethics ...................................................................................................... 55 
12.1. Compliance to the protocol, ICH-GCP and regulations ....................... 55 
12.2. Ethical review of the trial ..................................................................... 56 
12.3. Procedures for obtaining informed consent ......................................... 56 
12.4. Data protection .................................................................................... 57 
12.5. Insurances .......................................................................................... 57 
13. 
Substantial changes to the trial .............................................................. 58 
14. 
Collection, handling and archiving of data .............................................. 58 
14.1. Case report form ................................................................................. 59 
15. 
Notification of trial completion, reporting, and publication....................... 59 
16. 
Appendix ................................................................................................ 59 
16.1. Laboratory Assay Description (refers to assays in 5.3.3) .................... 59 
17. 
References ............................................................................................. 64 
18. 
Attachments ........................................................................................... 67 
 
 
 

 
 
 
 
 
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Revision history 
Protocol version 
Date of Issue 
Summary of changes 
Describe all changes since the first final protocol. 
V1.0 
24-03-2025 
 
V2.0 
12-06-2025 
- 
Updated version number and EU clinical 
trial number 
- 
Updated pIMD list under section 18 
- 
More 
defined 
primary 
endpoint 
(measurement) 
- 
Clear mentioning of GSK subcontracted 
laboratories 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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Signature page 
Sponsor 
I am responsible for ensuring that this protocol includes all essential information 
to be able to conduct this trial. I will submit the protocol and all other important 
trial-related information to the responsible investigator(s) so that they can 
conduct the trial correctly. I am aware that it is my responsibility to hold the staff 
members who work with this trial informed and trained. 
Signature of sponsor’s representative 
Date 
 
Printed name 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 8 of 72 
Principal Investigator 
I have read this protocol and agree that it includes all essential information to be 
able to conduct the trial. By signing my name below, I agree to conduct the trial 
in compliance with this clinical trial protocol, the EU Regulation on clinical trials 
of medicinal products for human use (EU 536/2014), the Declaration of Helsinki, 
ICH-GCP (Good Clinical Practice) guidelines and the current national 
regulations governing the conduct of this clinical trial. 
I will submit this protocol and all other important trial-related information to the 
staff members and investigators who participate in this trial, so that they can 
conduct the trial correctly. I am aware of my responsibility to continuously keep 
the staff members and investigators who work with this trial informed and 
trained.  
I am aware that quality control of this trial will be performed in the form of 
monitoring and eventual audit and inspection. 
Principal Investigator’s signature  
Date 
 
Printed name 

 
 
 
 
 
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Contact information 
Responsibility in the clinical trial 
 
Sponsor representative 
Responsibility: 
• 
Ensure adherence to Good 
Clinical Practices and EMA 
regulatory requirements 
• 
Monitor trial progress to ensure 
compliance with study protocols 
and local regulations 
 
 
Principal Investigators  
 
 
 
 
 
 
 
 
 
 
 
Karolinska Trial Alliance (internal non-
profit facility for applications, CTIS 
submission and monitoring)  
 
 
 
 
 
List of used acronyms and abbreviations 
Abbreviation 
Term/Explanation 
AE 
Adverse Event = Any untoward medical occurrence in a 
participant to whom a medicinal product is administered and 
which does not necessarily have a causal relationship with this 
treatment. 

 
 
 
 
 
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SAE 
Serious Adverse Event = Any untoward medical occurrence that 
at any dose requires inpatient hospitalisation or prolongation of 
existing hospitalisation, results in persistent or significant 
disability or incapacity, results in a congenital anomaly or birth 
defect, is life-threatening, or results in death 
AESI 
 
Adverse Events of Special Interest 
AR 
Adverse Reaction = any unfavourable and unintended reaction to 
an investigational medicinal product, regardless of dose 
ASR 
Annual Safety Report = the annual safety report for reporting to 
authorities. In Sweden this is the Swedish Medical Products 
Agency via CTIS. 
ATCC 
 
American Type Culture Collection 
BCR 
 
B cell receptor 
CA 
 
Competent Authorities 
CD 
 
Cluster of Differentiation 
CFS 
 
Clinical Frailty Scale 
CIOMS 
 
Council for International Organizations of Medical Sciences 
CMI 
 
Cell-mediated immunity 
CRF/eCRF 
Case Report Form/electronic Case Report Form 
CTIS 
Clinical Trials Information System = Centralized EU 
database/portal for application and communication with 
authorities concerning clinical trials. In Sweden this includes the 
Swedish Medical Products Agency and the Swedish Ethical 
Review Authority. 
CTR 
EU Regulation 536/2014, also called CTR, Clinical Trials 
Regulation 
DOPC 
 
Dioleoyl phosphatidylcholine 
DSUR 
Development Safety Update Report = the standard which should 
be used for annual safety reporting to authorities 
ELISA 
 
Enzyme-linked immunosorbent assay 

 
 
 
 
 
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EMA 
 
European Medicines Agency 
EU/EEA 
 
European Union/European Economic Area 
FACS 
 
Fluorescence-activated cell sorting 
FDA 
 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
 
General Data Protection Regulation 
GMT 
 
Geometric mean titer 
GSK 
 
GlaxoSmithKline Biologicals S.A. 
GVHD 
 
Graft-versus-host disease  
 
 
 
HSCT 
Hematopoietic stem cell transplantation 
 
IB 
Investigator’s Brochure  
ICF 
 
Informed Consent Form 
ICH 
International Council for Harmonization  
IgG 
 
Immunoglobulin G 
IL 
 
Interleukin 
ITT 
Intention-to-treat = including all data from all participants who 
have participated in the trial 
Läkemedelsverket Swedish Medical Products Agency – the national authority 
responsible for regulation and surveillance of the development, 
manufacturing and sale of medicinal products.  
LFF 
 
Läkemedelsförsäkringen 
LÖF 
 
Landstingens Ömsesidiga Försäkringsbolag 
LRTD 
 
Lower Respiratory Tract Disease 
mAb/Ab 
 
Monoclonal antibody/Antibody 
MGI 
 
Mean geometric increase 

 
 
 
 
 
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Member State 
European Union (EU) Member state where an application for 
authorisation of a clinical trial or of a substantial modification has 
been submitted. 
MPL 
 
3-O-desacyl-4’-monophosphoryl lipid A 
mRNA/RNA 
Messenger ribonucleic acid/ribonucleic acid 
 
N/A 
 
Not applicable 
PBMC 
Peripheral blood mononuclear cell 
 
PI 
 
Principal Investigator 
pIMD 
 
Potential immune-mediated disease = autoimmune diseases and 
other inflammatory and/or neurologic disorders which may or 
may not have an autoimmune etiology 
 
postF 
 
Postfusion 
PP 
Per Protocol analysis = including only data from participants who 
have completed the trial in accordance with the protocol, with no 
deviations from the protocol  
preF 
 
Prefusion 
RSI  
Reference safety information = A list of all known serious 
adverse reactions for the investigational medicinal product, 
including severity and frequency of the adverse reaction. The 
RSI is contained in the Summary of Product Characteristics or IB 
and is used to determine which adverse reactions should be 
reported as suspected unexpected serious adverse reactions 
(SUSARs). 
RSV 
 
Respiratory syncytial virus 
RSVPreF3 
Vaccine antigen; recombinant RSV glycoprotein F stabilized in 
pre-fusion conformation 
SAP 
 
Statistical Analysis Plan 
SOP 
 
Standard Operating Procedure 
SPC or SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction = This is an 
event that is likely related to the investigational medicinal product 
but with unexpected occurrence. An adverse reaction is 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 13 of 72 
unexpected if its nature or seriousness is not consistent with the 
information on the product in the RSI.  
Tfh 
 
T follicular helper cell 
TMB 
 
3,3 ,5,5 -Tetramethylbenzidine 
TNF  
 
Tumor necrosis factor 
US 
 
United States 
USM 
 
Urgent Safety Measures 
VE 
 
Vaccine efficacy 
 
 
 

 
 
 
 
 
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1. Synopsis 
 
EU Trial number:  
2024-520141-23-01 
Title: 
Immunogenicity after a prime dose and revaccination with 
adjuvanted RSVPreF3 vaccine in the most elderly and 
frail population – an open-labeled phase IIIb trial 
RSV Immunogenicity Study in the Elderly (RISE) 
Trial ID: 
RISE 
Short background/ 
Rationale/Aim: 
Respiratory syncytial virus (RSV) is a common cause of 
respiratory tract infections leading to hospitalizations in 
infants and in elderly. Arexvy is an approved vaccine 
indicated for the prevention of RSV infections in older 
adults, however, there is yet limited information on the 
vaccine’s efficacy in individuals ≥80 years old. This study 
aims to investigate potential differences in the immune 
responses induced upon vaccination with Arexvy 
between individuals above 80 years of age and adults 
60-65 years old. 
Primary objective: 
To describe the induction of neutralizing antibodies 
against RSV A and B following the first dose of Arexvy in 
older adults aged 80 years and older and those aged 60 
to 65 years. 
Secondary 
objectives: 
To evaluate the reactogenicity of Arexvy by recording the 
occurrence of solicited adverse events (AEs) in the study 
participants.  
To evaluate the safety of Arexvy in terms of the incidence 
of unsolicited AEs, SAEs/pIMDs and fatal SAEs. 
Primary endpoint: 
 
To assess the neutralizing antibody geometric mean titers 
(GMTs) against RSV A and B one month after the prime 
dose (day 31) of Arexvy in study participants aged 60-65 
years and ≥80 years old, measured by a neutralization 
assay. Mean geometric increase (MGI), geometric 
increase (MGI) between day 0 and day 31 after prime will 
be calculated (equal to the geometric mean of the 
individual ratio). A more detailed description can be found 
in section 10.2.1. 

 
 
 
 
 
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Secondary 
endpoints: 
 
Occurrence, intensity and duration of solicited AEs in the 
study participants at the administration site and solicited 
systemic AEs with an onset during the 4-day follow-up 
period after each vaccination. 
Incidence of unsolicited AEs in the study participants with 
an onset during the 30-day follow-up period after each 
vaccination. 
Incidence of SAEs or pIMDs in the study participants from 
the day of vaccination until 6 months.  
Occurrence of any fatal SAEs from day 1 up to study end. 

 
 
 
 
 
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Trial design: 
 
Open-label phase IIIb trial where study participants will 
be vaccinated at study start and revaccinated 12 months 
after the first dose. The study period is 18 months. 
Trial population: 
 
Adults 60-65 years old and ≥80 years old. 
Number of 
participants: 
30 adults in the 60-65 years age group and 35-40 adults 
in the ≥80 years age group. 
Inclusion criteria: 
Male or female individuals who were born between 1965 
and 1960 or 1945 and before, who live in the community 
or in a long-term care facility. 
Individuals who can understand and read Swedish. 
Individuals who can provide written consent and agree 
(by written consent) to receive the Arexvy vaccine. 
Participants who, in the opinion of the investigator, can 
and will comply with the requirements of the protocol. 
Participants who are medically stable in the opinion of 
the investigator at the time of first vaccination. 
Participants with chronic stable medical conditions with 
or without specific treatment, such as diabetes, 
hypertension or cardiac disease, are allowed to 
participate if considered by the investigator as medically 
stable. 
Exclusion criteria: 
Individuals who are medically immunocompromised, less 
than 
2 
years 
since 
hematopoietic 
stem 
cell 
transplantation (HSCT) or graft-versus-host disease 
(GVHD), 
solid-organ 
transplanted, 
using 
immunosuppressive drugs for treatment of cancer and 
who have inflammatory mediated or autoimmune 
conditions, as judged by the Investigator. 
Individuals who have already received an RSV vaccine 
dose at any time in the past. 
Any known or suspected reaction, hypersensitivity or 
allergies to be exacerbated by any product or component 
included in the vaccine and trial. 
Mental inability, reluctance or language difficulties that 
result in difficulty understanding the meaning of 
participation in the trial. 
Treatment 
or 
disease 
which, 
according 
to 
the 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 17 of 72 
investigator, can affect treatment or trial results.  
 
Any of the following medical conditions:  
- 
Unstable chronic illness 
- 
Recurrent or un-controlled neurological disorders or 
seizures  
- 
Significant underlying illness that in the opinion of the 
investigator would be expected to prevent completion 
of the study 
- 
Any other medical condition that in the judgment of the 
investigator would make intramuscular injection unsafe 
- 
Any other clinical condition that, in the opinion of the 
investigator, might pose additional risk to the participant 
due to participation in the study  
- 
Any history of dementia or any medical condition that 
moderately 
or 
severely 
impairs 
cognition 
and 
understanding of the informed consent form and/or 
study procedures 
- 
History of chronic alcohol consumption and/or drug 
abuse as deemed by the investigator to render the 
potential participant unable/unlikely to provide accurate 
safety reports or comply with study procedures. 
 
 
 
Planned move during the study period that will prohibit 
participating in the study until study end. 
Participation of any study personnel or their immediate 
dependents, family or household members as well as any 
family relations to Sponsor or PI. 
Co-administration of other vaccines less than 14 days 
before or after study vaccination. A period of less than 
30 days before or after study vaccination applies in the 
case of Shingrix. 
Intervention: 
 
Study participants will be vaccinated at study start and 
revaccinated 12 months after. The study period is 
approximately 18 months per study participant, during 
which 10 blood draws are planned.  
Investigational 
medicinal 
product(s), 
Adjuvanted RSVPreF3 vaccine (trade name Arexvy, 
manufactured by GSK). Arexvy is a sterile injectable 
suspension for intramuscular use (0.5 mL) containing 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 18 of 72 
dosage, 
administration: 
120 µg of recombinant RSVPreF3 adjuvanted with 
AS01E. 
Ethical 
considerations, 
benefit/risk: 
All study participants (60-65 years old and ≥80 years old) 
will be given Arexvy, an approved vaccine specifically 
indicated for preventing severe respiratory tract disease 
in this population. Arexvy has demonstrated a high 
protective efficacy, and an acceptable reactogenicity and 
safety profile. The overall benefit/risk balance is positive. 
Planned duration 
of the trial: 
Q3 2025 – Q2 2027 
 
 
2. Background and rationale 
Respiratory syncytial virus (RSV) is the primary cause of respiratory tract 
infections leading to hospitalizations in infants and in elderly (1,2). The two viral 
surface glycoproteins F and G are crucial for fusion and attachment to the 
respiratory cells. The F protein is the main target of neutralizing antibodies and 
hence pivotal for vaccine development (3). The infection spreads from 
contaminated nasal secretions via large droplets transferred via close human 
contact and contaminated surfaces. There is no lasting immunity after an RSV 
infection and the substantial burden of disease caused by RSV, in both infants as 
well as older adults, especially over the age of 75 or with certain underlying 
diseases, is well established and pose a large burden on the health care 
system (4).  
Progress towards RSV vaccines has been slow despite more than half a century 
of efforts and an enormous global need. One major challenge in vaccine 
development is the specificity, breadth, and longevity of antibody (Ab) responses 
needed for protection. Two vaccines were approved in 2023 and one in 2024 for 
use in both Europe and the United States (US) for the prevention of lower 
respiratory tract disease (LRTD) in individuals 60 years of age and older, as well 
as adults aged 50 to 59 years of age who are at increased risk for RSV disease 
(5–8).  

 
 
 
 
 
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Arexvy (developed and manufactured by GSK) is an adjuvanted RSV vaccine 
based on RSV’s F protein stabilized in its prefusion conformation (8). The 
AS01E-adjuvanted vaccine formulation was selected for Arexvy based on data 
from prior clinical studies (9). One dose of Arexvy was recently shown to be 
efficacious against LRTD over three RSV seasons in ≥60-year-olds. 
Revaccination one year after the first dose did not however appear to provide 
additional efficacy benefit (10,11). The vaccine has an acceptable reactogenicity 
and safety profile. So far, in the still ongoing large clinical trials there has been a 
limited number of individuals in the age group 80 years and older, as well as frail 
individuals, to conclude on the vaccine efficacy (VE) in this subgroup. Although 
there is some data available (12), we still lack substantial knowledge about the 
vaccine’s immunogenicity in a population that is markedly affected by severe RSV 
infections.  
For several years, our group has studied in detail the responses to immunization 
with the prototype RSV vaccine antigen preF (DS-Cav1) in non-human primates. 
We have established methods to dissect antibody specificities and affinity, 
including neutralization to live RSV  
 
 
 
 
(13,14). Additionally, we have a 
long-standing interest in studying mechanisms of action of vaccine adjuvants, 
since innate immune responses early after vaccination are critical for the 
subsequent adaptive responses. We therefore have developed expertise in 
methods to explore the immune activation induced by the AS01E adjuvant 
included in Arexvy. 
                                 
 
 
 
 (15–17).  
 
 
 

 
 
 
 
 
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3. Benefit-risk evaluation 
 
Expected therapeutic benefits to the individuals participating in the study 
 
Arexvy is a vaccine already approved by the regulatory authorities in the US 
(Food and Drug Administration [FDA]) and Europe (European Medicines Agency 
[EMA]). Arexvy is indicated for adults ≥60 years of age, and recently also for 
adults 50-59 years old with underlying conditions increasing the risk for severe 
disease upon RSV infection (8). In Sweden, RSV vaccination is recommended 
by the Public Health Agency (Folkhälsomyndigheten) since September 2023 to 
individuals ≥75 years of age and to the younger age group >60 years with 
increased risk of severe RSV-infection. The vaccination coverage is assumed to 
be overall low in these high-risk groups, although there is no vaccination 
registration done to confirm this. All participants in this study (grouped in 60-65 
years or ≥80 years age groups) will be offered Arexvy. In previous clinical studies 
the vaccine showed high protective efficacy. RSV vaccination is especially 
relevant for the older age group, given that the vaccine is recommended for them 
by national authorities and since additional knowledge about vaccine 
immunogenicity 
in 
the 
older 
group 
would 
be 
beneficial 
for 
future 
recommendations to this population. 
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 21 of 72 
Expected risks and inconvenience to the individuals participating in the 
study 
 
The most commonly reported adverse reactions (ARs) with Arexvy (≥10%) in 
individuals 60 years of age and older are injection site pain (60.9%), fatigue 
(33.6%), myalgia (28.9%), headache (27.2%) and arthralgia (18.1%) (8). The 
local adverse reactions reported with Arexvy had a median duration of 2 days, 
while the systemic adverse reactions had a median duration ranging between 
1 and 2 days. Based on currently available information, Arexvy shows an 
acceptable reactogenicity and safety profile (8). 
Concerning the interventions of the study, they consist of blood-sampling at 10 
different time points during a period of 13 months. Blood-sampling can cause a 
short-lived pain but is a standardized procedure of the routine healthcare, with no 
significant risks to the study participants given appropriate handling performed by 
adequately educated staff.  
 
To summarize, the expected risk-benefit balance for the study-participants, who 
will be offered an already approved and recommended vaccine, is positive. To 
mitigate potential risks for adverse events, the participating sites have 
experienced PI and study staff, as well as Standard Operating Procedures (SOP) 
to ensure safe study procedures. Details about how adverse events will be 
reported and registered throughout the study are described in section 9.3. 
 
 
4. Trial objectives 
4.1. 
Primary objective 
 
The primary objective of this study is to describe the induction of neutralizing 
antibodies following a first dose of Arexvy in older adults aged 80 years and older 
and those aged 60 to 65 years. We will descriptively compare the neutralizing 
antibody titers against RSV A and B one month (day 31) after a first dose in both 
groups. 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 22 of 72 
 
 
4.2. 
Secondary objective(s) 
 
The secondary objectives of this trial are to: 
• evaluate the reactogenicity of Arexvy by recording the occurrence of 
solicited adverse events (AEs) in the study participants during the 4-day 
follow-up period after each vaccination. Exact endpoints are described in 
section 4.5, while detailed information on recording AEs is described in 
section 9.2. 
• To evaluate the safety of Arexvy in terms of the incidence of unsolicited 
AEs, SAEs/pIMDs and fatal SAEs. Exact endpoints are described in 
section 4.5, while detailed methods to record any unsolicited AEs, 
SAE/pIMDs are described in section 9.2. The definition of SAEs and 
pIMDs are included in this study protocol in section 9.2. 
 
4.3. 
Exploratory objective(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 23 of 72 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4. 
Primary endpoint 
 
To assess the neutralizing antibody geometric mean titers (GMTs) against RSV 
A and B one month after the prime dose (day 31) of Arexvy in study participants 
aged 60-65 years and ≥80 years old, measured by a neutralization assay. Mean 
geometric increase (MGI), geometric increase (MGI) between day 0 and day 31 
after prime will be calculated (equal to the geometric mean of the individual ratio). 
A more detailed description can be found in section 10.2.1. 
 
 
4.5. 
Secondary endpoint(s) 
 
The secondary endpoints are: 
• Occurrence, intensity and duration of solicited AEs in the study 
participants at the administration site and solicited systemic AEs with an 
onset during the 4-day follow-up period after each vaccination (i.e., the day 
of vaccination and 3 subsequent days). 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 24 of 72 
• Occurrence of unsolicited AEs in the study participants with an onset 
during the 30-day follow-up period after each vaccination (i.e., the day of 
vaccination and 29 subsequent days). 
• Occurrence of SAEs in the study participants from the day of vaccination 
until 6 months. However, certain conditions will be excluded from this 
monitoring, to ensure that reporting is focused on relevant safety issues. 
The decision for this is based on the overall higher prevalence of certain 
conditions in the older age group. This includes but is not limited to falls, 
fractures, and the onset of tumors. A list of events that can be excluded is 
explicitly defined in the study protocol (see section 9.3.2). Such events are 
considered expected in an older patient population (>80 years). These do 
not need to be reported as SAEs unless there is an indication of a 
relationship with the investigational drug. 
• Occurrence of pIMDs in the study participants from the day of vaccination 
until 6 months. A list of possible conditions that could qualify as pIMDs is 
added in section 18. 
• Occurrence of any fatal SAEs in the study participants from Day 1 up to 
study end. 
 
 
4.6. 
Exploratory endpoint(s) 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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o  
o  
 
 
 
                
 
 
                 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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5. Trial design and procedure 
5.1. 
Overall trial design  
 
This is a phase IIIb open-label post-marketing clinical trial using an already 
approved vaccine in the targeted population group. The design will generate 
immunological data that will contribute to a better understanding of the induction 
and maintenance of RSV vaccine-induced immunity in the oldest vaccine 
recipients. The study includes a prime vaccination and revaccination after one 
year.  
                                                                                                   
                                                                                                 The study period is 
approximately 18 months per study participant. After screening and Informed 
Consent procedure, 10 visits are planned where one prime dose of vaccine 
Arexvy (GSK) 0.5 mL i.m is given at the first visit (V1) and a revaccination at the 
12-month timepoint (V7). The design and scheduled activities are shown in Figure 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 27 of 72 
1 and Table 1.  
 
 
 
Figure 1 Trial design 
D = day; m = month; w = weeks; B1 = revaccination 
 
 
5.2. 
Procedures and flow chart 
 
Table 1 summarizes the general procedures and visits at which they will be 
carried out. 
Table 1 Visit schedule and planned activities  
Procedure 
Inclusion/ 
exclusion 
criteria 
Informed 
consent 
Medical 
history/ 
concomitant 
medications 
Targeted 
physical 
examination° 
Vital 
signs‡ 
Blood 
draw 
Adverse 
Events 
Vaccine 
V0* 
√ 
√ 
√ 
√ 
 
 
 
 
V1(D0) 
(up to +10 
days to V0) 
 
 
 
√ 
√ 
√ (D0 of 
diary)§ 
√ 
V2 (D1) 
 
 
 
 
√ 
 
 
V3 (D7) 
(+/- 1 day) 
 
 
 
 
√ 
√ 
(collect 
diary) § 
 
V4 (D31) 
(+/- 3 days) 
 
 
 
√ 
√ 
 
V5 (3m) 
 
 
 
 
√ 
 
 
                                 
                   
                           
            
                             
                   
       
       
       
      
      
      
      
      
      
      
      
       
  
  
  
   
  
  
   
    
    
     
     
       
          
      
          
                    
            
         
                 
             

 
 
 
 
 
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(+/- 14 days) 
V6 (6m) 
(+/- 14 days) 
 
 
√ 
√ 
 
V7† (12m) 
(B1) 
(+/- 14 days) 
 
 
√ 
√ 
√ 
√ 
√ (D0 of 
diary) § 
√ 
V8 (B1D1) 
 
 
 
 
 
√ 
 
 
V9 (B1D7) 
(+/- 1 day) 
 
 
 
 
 
√ 
√ 
(collect 
diary) § 
 
V10 (B1D31) 
 (+/- 3 days) 
 
 
 
 
 
√ 
√ 
 
V11 (B1 6 m) 
(+/- 14 days) 
 
 
 
 
 
 
√ 
 
V = Visit; D = day; m = month; w = weeks; B1 = revaccination 
*V0 is the baseline visit: can be done at the same time as Visit 1(V1). Visit 1 will be the date of prime 
vaccination and start of the safety monitoring activity. V1 can be delayed to V0 for up to 10 days. 
°Targeted physical examination includes determination of frailty status of the patient, body weight and 
body height. 
†Visit 7 will be the date of the revaccination (B1) with sampling prior to vaccination (12-month prime 
vaccination timepoint).  
‡Vital signs that will be obtained include blood pressure, pulse and body temperature. 
§Diaries will be given to the study participants upon vaccination (V1 and V7) to note down any solicited 
AEs (local and systemic) for the 4-day follow-up period and will be recollected at the next study visit (V2 
and V8) 
 
For the trial, different medical parameters and vital signs will be measured at 
V0/V1 and V7. Medical history and concomitant medications will be noted to get 
an overview of the prevalence for certain co-morbidities. Targeted physical 
examination will include determination of a frailty index (using the Clinical Frailty 
Scale [CFS]), measurement of the body weight and the body height. Vital signs 
include blood pressure, pulse and body temperature. 
 
Table 2 Immunological read-outs at the different study visits  
Type of 
contact and 
time point 
Sampling time 
point 
No. of 
samples 
(Total) 
Component 
Priority 
rank 
Prime vaccination  
Visit 1 (D0) 
Pre-Dose 1 
~65-70 
RSV A neutralizing titers 
1  
RSV B neutralizing titers  
2  
RSVPreF3-specific IgG antibody 
3  
 
 
 
 
 
 

 
 
 
 
 
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Visit 2 (D1) 
Post Dose 1 
~65-70 
 
 
 
Visit 3 (D7) 
Post Dose 1 
~65-70 
 
 
 
RSV A neutralizing titers 
4 
RSV B neutralizing titers 
5 
RSVPreF3-specific IgG antibody 
6 
 
Visit 4 (D31) 
Post Dose 1 
~65-70 
RSV A neutralizing antibodies 
1  
RSV B neutralizing antibodies 
2  
RSVPreF3-specific IgG antibody 
3  
 
 
Visit 5 (3m) 
Post Dose 1 
~65-70 
RSV A neutralizing antibodies 
1  
RSV B neutralizing antibodies 
2  
RSVPreF3-specific IgG antibody 
3  
Visit 6 (6m) 
Post Dose 1 
~65-70 
RSV A neutralizing antibodies 
1  
RSV B neutralizing antibodies 
2  
RSVPreF3-specific IgG antibody 
3  
 
 
 
Revaccination  
Visit 7 (12m) 
 
Pre-Dose 2 
~65-70 
RSV A neutralizing antibodies 
1  
RSV B neutralizing antibodies 
2  
RSVPreF3-specific IgG antibody 
3  
 
 
 
 
 
 
 
 
 
 
Visit 8 
(B1D1) 
 
Post Dose 2 
~65-70 
 
 

 
 
 
 
 
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Visit 9 
(B1D7) 
 
Post Dose 2 
~65-70 
 
 
 
RSV A neutralizing antibodies 
4 
RSV B neutralizing antibodies 
5 
RSVPreF3-specific IgG antibody 
6 
 
 
 
Visit 10 
(B1D31) 
Post Dose 2 
~65-70 
RSV A neutralizing antibodies 
1  
RSV B neutralizing antibodies 
2  
RSVPreF3-specific IgG antibody 
3  
 
 
*Baseline measurement  
 
In case of insufficient blood sample volume to perform all assays, the samples 
will be analyzed according to the priority ranking provided in Table 2. 
 
 
5.3. 
Biological sampling procedures 
5.3.1. 
Handling, storage, and destruction of biological 
samples 
 
Detailed sampling and handling procedures are described in a separate 
document. Collected biological samples will be used for protocol-mandated 
research and purposes related to the improvement, development and quality 
assurance of the laboratory tests described in this protocol. Future findings may 
make it desirable to use the samples acquired in this study for future research 
not described in this protocol. Therefore, all participants will be asked to give a 
specific consent to allow the sponsor or a contracted partner to use the samples 
for future research. Sample testing will be done in accordance with the recorded 
consent of the individual participant.  
 
Throughout the trial 10 blood draws per participant are planned. Blood samples 

 
 
 
 
 
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(15-40 mL) will be collected at each time point (day 0, day 1, day 7, day 31, 
month 3, month 6, and month 12 after prime as well as day 1, day 7, and day 31 
after revaccination) by venipuncture at the authorized clinical trial site. For PBMC 
isolation up to 4 EDTA tubes (or similar) of 8 mL will be drawn at each timepoint. 
In addition, one serum tube with a volume of 5 ml will be drawn.  
 
 
 
 
 
 
 
 
A full overview of all 
samplings including volumes, types of samples and planned assays will be made 
available as an annex to this study protocol. 
 
The sampling will be carried out by trained and experienced personnel and in a 
specific sampling order. Samples will be labelled accordingly and transported to 
the principal investigator. SOPs for sampling and handling are in place and clearly 
communicated prior to study start. SOPs for sample processing and storage will 
be prepared and used throughout the trial. 
 
Serum and plasma samples will be used for enzyme-linked immunosorbent 
assay (ELISA)-based measurements of antibody titers against different 
pathogens. Appropriate methods are in place at the laboratory of the principal 
investigator. Approved and accredited methods from external laboratories might 
be used for validation.  
 
Measurements of neutralizing titers against RSV A and RSV B as well as serum 
levels of RSV preF3-specific IgG will be performed by GSK using validated 
methods. In addition, neutralization assays established in the laboratory of the 
principal investigator can be used for measurements of neutralizing antibody 
titers against other respiratory viruses. 
 
 
 

 
 
 
 
 
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5.3.2. 
Total volume of blood per participant 
A total of 10 blood draws per participant is planned for this clinical trial over the 
course of 13 months. Per timepoint a maximum volume of 40 mL blood will be 
taken. A blood sample will be taken from all participants at each visit. The overall 
volume of blood that will be collected during the entire study period is ~308 mL 
(4x ~40 mL, 2x ~37 mL, 2x 21 mL, 2x ~16 mL). 
 
Table 3 Overview of blood draws and planned volumes 
Prime 
Revaccination 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Time 
D0 
D1 
D7 
D31 
3m 
6m 
12m 
B1D1 
B1D7 
B1D31 
Blood 
32 mL 
8 mL 
32 mL 
32 mL 
16 mL 
16 mL 
32 mL 
8 mL 
32 mL 
32 mL 
Serum 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
5 mL 
 
 
 
 
 
 
 
 
 
 
 
Total 
40 mL 
16 mL 
40 mL 
37 mL 
21 mL 
21 mL 
40 mL 
16 mL 
40 mL 
37 mL 
 
 
5.3.3. 
Laboratory assays 
 

 
 
 
 
 
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Laboratory assays are summarized in Table 4. Please refer to section 8.1. for a 
brief description of the laboratory assays summarized here and performed in this 
study. 
 
Table 4 Laboratory assays planned in this study 
CMI = Cell-mediated immunity; GSK = GlaxoSmithKline Biologicals S.A.; ICS = Intracellular cytokine 
staining; N/A = Not applicable; PBMC = Peripheral blood mononuclear cell; PreF = prefusion protein; RSV 
= Respiratory syncytial virus. 
*Certain analyses will be carried out by subcontractors employed by GSK. 
A list of (clinical) laboratories used for sample analysis are provided in a separate document 
accompanying this study protocol, including address and information on analyses carried out by them. 
 
Additional exploratory testing on collected samples might be done to gain a better 
understanding of the vaccine, of the clinical study data and/or of the disease or 
other diseases, to inform the development of other investigational products or to 
support development of vaccine-related assays, should such assay(s) become 
available at Karolinska Institute’s laboratory, or a laboratory designated by 
Karolinska Institute. These assay(s) may not be represented in the 
objectives/endpoints of the protocol and will be described in ancillary study 
protocol(s), as needed. GSK clinical laboratories have established a Quality 
Test 
Classification 
System 
Component 
Challenge 
Method 
Laboratory1
Humoral 
immunity  
Serum 
RSV-A and RSV-B  
N/A 
Neutralization 
assay  
GSK* 
Serum 
Total IgG 
PreF3 
ELISA 
GSK* 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
l 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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System supported by procedures. The activities of GSK clinical laboratories are 
audited regularly for quality assessment by an internal but laboratory-
independent Quality Department. Certain assays will be carried out by 
subcontractors outside of the European Union that have been selected by GSK. 
The Informed Consent Form states that samples will be sent to collaboration 
partners outside the EU or EEC. 
GSK will be responsible for providing certain assay components including 
proteins such as RSVPreF3 for different assays including but not limited to 
antigen-specific cell probing and ELISA.  
 
 
5.3.4. 
Biobank 
 
All samples taken in this trial, covered by the Biobank Act, are registered in a 
biobank and handled according to the current national laws and regulations. The 
samples are coded to protect the participant´s identity. All samples and the 
identification/code list are stored securely and separately to prevent access by 
unauthorized persons. 
 
 
5.4. 
Start, end, temporary halt and early termination 
5.4.1. 
Start of the clinical trial 
 
The start of the trial is defined as the start of screening activities. Sponsor will 
report the start of the trial in Sweden through notification in the Clinical Trial 
Information System (CTIS) within 15 days. 
 
 
5.4.2. 
Temporary halt or early termination 
 
The trial may be prematurely terminated for safety reasons affecting the risk-
benefit balance or if the recruitment of participants cannot be completed within 
reasonable time. Decisions on premature termination are taken by the sponsor. 
The Competent Authorities (CA) should be informed as soon as possible via 

 
 
 
 
 
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CTIS, but no later than 15 days after trial suspension. 
If the trial is prematurely terminated or suspended, the investigator should 
immediately inform the participants and ensure appropriate treatment and follow-
up.  
 
 
5.4.3. 
End of the clinical trial 
 
The trial ends when the last participant has completed the last follow-up including 
the safety follow-up visit six months after revaccination.  
 
 
6. Participant selection 
 
Participants in the study will be enrolled as part of one of two age categories 
(60-65 years, and equal or older than 80 years). The goal is to have a similar ratio 
between male and female participants in both subgroups. Participants from both 
community dwelling and long-term care facilities will be enrolled in the study. 
Study participants will be enrolled at two different sites. The younger age group 
(60-65 years) representing community dwelling individuals will be enrolled at 
Studieenheten Akademiskt Specialistcentrum, Region Stockholm. Participants in 
the older age group (80 years and above) will be enrolled from long-term care 
facilities at Familjeläkarnas Särskilda boenden (SÄBO). 
 
Adherence to the inclusion criteria as specified in the protocol is essential. 
Inclusion criteria deviations are not allowed because they can jeopardize the 
scientific integrity or regulatory acceptability of the study or participant safety. All 
participants must satisfy all of the following criteria at study entry: 
• Male or female individuals who were born between 1965 and 1960 or 1945 
and before, who live in the community or in a long-term care facility. 
• Individuals who can understand and read Swedish. 

 
 
 
 
 
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• Individuals who can provide written consent and agree (by written consent) 
to receive the RSV vaccine. 
• Participants who, in the opinion of the investigator, can and will comply 
with the requirements of the protocol. 
• Participants who are medically stable in the opinion of the investigator at 
the time of first vaccination. Participants with chronic stable medical 
conditions with or without specific treatment, such as diabetes, 
hypertension or cardiac disease, are allowed to participate in this study if 
considered by the investigator as medically stable. 
 
 
6.1. 
Exclusion criteria 
 
Adherence to criteria specified in the protocol is essential. Exclusion criteria 
deviations are not allowed because they can potentially jeopardize the scientific 
integrity or regulatory acceptability of the study or safety of the participant. The 
following criteria should be checked at the time of study entry. 
Potential participants must not be included in this trial if any of the following 
exclusion criteria applies: 
• Individuals who are medically immunocompromised (definition of 
medications as separate list), less than 2 years since hematopoietic stem 
cell transplantation (HSCT) or graft-versus-host disease (GVHD), solid-
organ transplanted, other immunosuppressive drugs for treatment of 
cancer and inflammatory mediated or autoimmune conditions e.g. TNF-
inhibitors, anti-CD20 drugs, IL-inhibitors, methotrexate, cytostatics etc., as 
judged by the investigator. 
• Individuals who have already received an RSV vaccine dose at any time 
in the past. 
• Any known or suspected reaction, hypersensitivity or allergies to be 
exacerbated by any product or component included in the vaccine and 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 37 of 72 
trial. 
• Mental inability, reluctance or language difficulties that result in difficulty 
understanding the meaning of participation in the trial. 
• Treatment or disease which, according to the investigator, can affect 
treatment or trial results. However, if a participant begins a treatment 
during the study that could affect the immune system, they will not be 
discontinued from the study. In such cases, the details of the treatment will 
be documented appropriately. The participant will be followed for safety 
until the end of the safety follow-up period. If the participants continue the 
study, they will also receive the revaccination at one year. 
• Any of the following medical conditions: 
o Unstable chronic illness  
o Recurrent or un-controlled neurological disorders or seizures. 
o Significant underlying illness that in the opinion of the investigator 
would be expected to prevent completion of the study.  
o Any other medical condition that in the judgment of the investigator 
would make intramuscular injection unsafe 
o Any other clinical condition that, in the opinion of the investigator, 
might pose additional risk to the participant due to participation in 
the study.  
o Any history of dementia or any medical condition that moderately 
or severely impairs cognition and understanding of the informed 
consent form and/or study procedures.  
o History of chronic alcohol consumption and/or drug abuse as 
deemed by the investigator to render the potential participant 
unable/unlikely to provide accurate safety reports or comply with 
study procedures. 
•  
 
• Planned move during the study period that will prohibit participating in the 

 
 
 
 
 
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study until study end. 
• Participation of any study personnel or their immediate dependents, family 
or household members as well as any family relations to sponsor or PI. 
• Co-administration of other vaccines less than 14 days before or after study 
vaccination. A period of less than 30 days before or after study vaccination 
applies in the case of Shingrix. 
 
 
6.2. 
Screening and inclusion 
 
Participant eligibility (that participants fulfil all inclusion criteria and do not meet 
any exclusion criteria) is established at baseline visit before visit 1, or if these two 
visits are at the same time, before deciding to give the first dose of the study 
vaccine.  
 
Study vaccine administration may be postponed within the permitted timeframe 
for each study vaccination if a possible candidate cannot receive the vaccine at 
the baseline visit. Vaccination can be delayed for 10 days in case of: 
• Acute disease and/or fever at the time of vaccination. Fever is defined as 
a temperature ≥ 38.0°C/100.4°F by any route. The route for measuring 
temperature can be oral, axillary or tympanic. 
Participants with a minor illness (such as mild diarrhea, mild upper respiratory 
infection) without fever may be vaccinated at the discretion of the investigator. 
 
 
6.3. 
Withdrawal criteria 
 
Participants can discontinue their participation in the trial at any time without any 
consequence to his/her continued treatment. The investigator/sponsor can at any 
time terminate the trial for a participant due to, e.g., unacceptable AEs/ARs or 
because the participant does not follow the procedures in the clinical trial protocol. 

 
 
 
 
 
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If a participant prematurely discontinues the trial, a safety follow-up visit will be 
performed (at 6 months following prime vaccination or revaccination). If the 
participant does not want to attend the follow-up visit or if it is not possible to 
establish contact, this will be recorded.  
No replacement of discontinued participants will be done. Data from participants 
who discontinue the trial prematurely can be included in the analysis, provided 
the participant has given consent for such use. 
 
 
 
 
7. Trial treatments 
7.1. 
Description of investigational medicinal product(s) 
 
Arexvy (manufactured by GSK) is a sterile injectable suspension for 
intramuscular use (8). The vaccine comes as a vial of lyophilized recombinant 
RSV glycoprotein F stabilized in pre-fusion conformation (RSVPreF3) as the 
antigen component, which must be reconstituted at the time of use with the 
accompanying vial of AS01E as the adjuvant suspension component. AS01E is 
composed of 3-O-desacyl-4’-monophosphoryl lipid A [MPL] from Salmonella 
minnesota and QS-21, a saponin purified from plant extract Quillaja saponaria 
Molina, combined in a liposomal formulation. The liposomes are composed of 
dioleoyl phosphatidylcholine (DOPC) and cholesterol in a phosphate-buffered 
saline solution containing disodium phosphate anhydrous, potassium dihydrogen 
phosphate, sodium chloride and water for injection. Each dose also contains 
trehalose, dipotassium phosphate and polysorbate 80 as formulation excipients. 
 
 
7.1.1. 
Dose and administration 
 
Two doses of the EMA-approved study vaccine (Arexvy, 0.5mL, intramuscular) 
will be administered 12 months apart. Vaccine preparation and administration will 
be done by authorized medical personnel who will not participate in any of the 
study clinical evaluation assays. Vaccination will be performed under medical 

 
 
 
 
 
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supervision.  
 
 
7.1.2. 
Packaging, labelling, and handling of 
investigational medicinal product(s) 
 
Arexvy is procured via a medicinal product vendor and therefore labelled and 
packaged as commercially available. The integrity of the cold chain for vaccine 
storage will be maintained through temperature logs during transportation and 
continuous monitoring of refrigerators used for vaccine storage. Site staff will be 
trained in proper procedures for vaccine handling, including the safe disposal of 
vaccines when necessary. 
 
7.1.3. 
Drug Accountability and treatment compliance 
 
The clinical sites will maintain an inventory log to track the receipt, storage and 
use of the vaccines. The lot number, expiration date and condition of the vials 
upon arrival will be documented. 
 
 
7.1.4. 
Randomisation 
 
This is an open label study, and no randomisation will be performed. Participants 
are included, and allocated to the respective age group, consecutively as they 
are found to be eligible for inclusion in the trial. If a participant discontinues their 
participation, the participant’s trial-specific code will not be reused, and the 
participant will not be allowed to re-enter the trial again. In this trial, no 
replacement will be recruited for any participant that discontinues their 
participation in the trial. 
 
 
7.1.5. 
Blinding 
 
This is an open trial, however each participant who consents to participate in the 
study will be assigned a unique identification number. This number will be used 

 
 
 
 
 
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to label all study-related data and biological samples to ensure confidentiality. 
Laboratory testing in this trial will be partially blinded. For laboratory tests carried 
out by GSK laboratories, data will be collected in an observer-blind manner, only 
the sample ID and date of the sampling will be made available. The laboratory in 
charge of the sample testing will be blinded to the intervention assignment. Codes 
will be used to link the participant and study (without any link to the intervention 
attributed to the participant) to each sample. 
The sponsor’s lab personnel will be aware of the specific site in which a sample 
was obtained and thereby also have knowledge about the respective allocation 
in an age group. 
 
 
 
 
7.1.6. 
Code breaking 
 
Not applicable. 
 
 
7.1.7. 
Destruction 
 
If needed, destruction of vaccine doses will follow standard practice at each trial 
site. The number of vials and their lot numbers will be documented. 
 
 
7.2. 
Auxiliary medicinal products 
 
Not applicable. 
 
 
7.2.1. 
Dose and administration 
 
Not applicable. 
 
 
7.2.2. 
Drug accountability and treatment compliance 
 

 
 
 
 
 
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Not applicable. 
 
 
7.3. 
Concomitant use of other medicinal products and 
treatments 
 
Medications considered necessary for the safety and well-being of the participant 
may be provided at the discretion of the investigators, unless otherwise specified 
in the exclusion criteria. Concomitant medication should be recorded in the Case 
Report Form (CRF). 
 
 
7.4. 
Treatment after trial end 
 
Not applicable. 
 
 
 
8. Methods for measurement of endpoints for clinical efficacy 
and safety 
8.1. 
Methods for measurement of endpoints for clinical 
efficacy 
 
An overview of all planned laboratory assays can be found in section 5.3.3. 
(Table 4). 
 
 
8.1.1. 
Methods for the primary endpoint 
 
The primary endpoint of this trial is defined as the descriptive analysis of the 
differences in RSV A and B neutralizing antibodies at D31 after prime vaccination 
in the two age groups enrolled in this study. The primary endpoint will be 
measured in serum by an established neutralization assay. The assays will be 
performed at accredited laboratories of GSK. The analysis will be performed after 
the collection of all D31 samples. A short description of the method can be found 
in section 16. 
 

 
 
 
 
 
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8.1.2. 
Methods for the exploratory endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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8.2. 
Methods for measurement of endpoints for clinical 
safety 
 
To assess reactogenicity of the vaccine, all solicited AEs will be recorded over 
the 4-day follow-up period after each vaccination. The AEs will be reported by the 
study participants on standardized diary cards and information will be collected 
by the respective study personnel. Solicited AEs include: 
• Injection site pain 
• Injection site erythema 
• Injection site swelling 
• Fever (similar definition as described in section 6.2.) 
• Headache 
• Fatigue 
• Myalgia 
• Arthralgia 
Grading of intensity of solicited AEs will follow the description in section 18.2. 
 
To assess safety, all unsolicited AEs with an onset during the 30-day follow-up 
period after each vaccination (i.e., the day of vaccination and 29 subsequent 
days) will be recorded.  
 
To assess safety, any SAEs or pIMD will be recorded from the day of vaccination 
until up to 6 months after vaccination.  
 
Fatalities will be recorded throughout the whole study period. 
 

 
 
 
 
 
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9. Handling Adverse Events 
9.1. 
Definitions 
9.1.1. 
Adverse Event (AE) 
 
Any untoward medical occurrence in a participant to whom a medicinal product 
is administered and which does not necessarily have a causal relationship with 
this treatment. 
 
 
9.1.2. 
Adverse Reaction (AR) 
 
The phrase “reaction” to a medicinal product means that the causal relationship 
between the medical product and an adverse event is at least a reasonable 
possibility, that is the relationship cannot be ruled out. 
 
 
9.1.3. 
Serious Adverse Event (SAE) 
 
Any untoward medical occurrence that at any dose requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability or incapacity, results in a congenital anomaly or birth defect, 
is life-threatening, or results in death.  
Medical and scientific assessment will be made to determine if an event is 
serious. A list of SAEs that have been excluded from reporting in this study are 
registered in section 9.3.  
 
 
9.1.4. 
Suspected Unexpected Serious Adverse Reaction 
(SUSAR) 
 
An adverse reaction/event that is unexpected, serious, and suspected to be 
caused by the treatment, i.e. adverse reactions/events that are not included in 
the RSI section of the Investigator’s Brochure (IB) or SmPC. 
 

 
 
 
 
 
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9.1.5. 
Potential immune-mediated diseases (pIMD) 
 
Adverse events of special interest (AESIs) collected during this study include 
potential immune-mediated diseases (pIMDs). No other AESIs will be collected. 
pIMDs are a subset of AESIs that include autoimmune diseases and other 
inflammatory and/or neurologic disorders of interest which may or may not have 
an autoimmune etiology. AEs that need to be recorded and reported as pIMDs 
include those listed in Table 5 (see section 18). 
 
 
9.2. 
Assessment of Adverse Events (AE) 
9.2.1. 
Assessment of causal relationship 
 
The investigator is responsible for determining whether there is a causal 
relationship between the AE/SAE and use of the investigational medicinal 
product. 
Consideration should be given to whether there is a reasonable possibility of 
establishing a causal relationship between the adverse event and the 
investigational medicinal product based on the analysis of the available evidence. 
All AEs can be categorized as either related (yes) or not related (no).  
Those AEs which are suspected of having a causal relationship to the 
investigational medicinal product will be followed up until the participant has 
recovered or is stabilized and on the way to good recovery (see also section 9.3.).  
If the reporting investigator does not provide any information on causality, the 
sponsor should consult with the reporting investigator and encourage the 
expression of a position on this issue. The sponsor must take into account the 
assessment of causality provided by the investigator. If the sponsor disagrees 
with the investigator's assessment of causality, both the investigator's and the 
sponsor's views should be included in the report. 
 
 
9.2.2. 
Assessment of intensity  
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 47 of 72 
Each adverse event shall be classified by an investigator as mild, moderate or 
severe. Assessment of intensity of solicited AEs is described further in section 
18.2. 
 
Mild: The adverse event is relatively tolerable and transient in its nature but does 
not affect the participant’s normal life. 
 
Moderate: The adverse event causes deterioration of function but does not affect 
health. The event can be sufficiently unpleasant and interferes with normal 
activities but does not completely obstruct them. 
 
Severe: The adverse event causes deterioration of function or work ability or 
poses a health risk to the participant. 
 
 
9.2.3. 
Assessment of seriousness 
 
The investigator is responsible for assessing the seriousness (serious or non-
serious). If the adverse event is considered serious, this should be reported as a 
serious adverse event (SAE) by the investigator to the sponsor.  
 
 
9.3. 
Reporting and registration of Adverse Events 
 
Reporting of AEs will follow standard procedures, including follow-up on 
reactogenicity for 4 days after each vaccination for systemic and local solicited 
adverse events. Unsolicited AEs are reported for 30 days following each 
vaccination while SAEs are reported for 6 months following each vaccination. 
Follow-up of fatalities is carried out throughout the whole study period. 
AEs that occur during the trial and not excluded from follow-up, which are 
observed by the investigator/trial nurse or reported by the participant will be 
registered in the CRF regardless of whether they are assessed as related to the 
investigational medicinal product or not. Assessment of causal relationship, 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 48 of 72 
severity, and whether the AE is considered to be an SAE will be made by the 
investigator directly in the CRF (RedCap) or on a trial-specific worksheet. At 
minimum, for each AE/SAE, a description of the event is recorded 
(diagnosis/symptom if diagnosis is missing), start and stop dates, causal 
relationship, severity, if the AE is considered to be an SAE, measures and 
outcome. 
 
 
9.3.1. 
Reporting of Adverse Events (AE) 
All AEs shall be registered in the CRF within 3 days as indicated above (section 
9.3, Reporting and registration of Adverse Events). 
 
 
9.3.2. 
Reporting of Serious Adverse Events (SAE) 
 
 
Serious Adverse Events (SAE) are reported to the sponsor on a special SAE form 
within 24 hours of the investigator being informed of the SAE. 
 
Follow-up information describing the outcome and handling of the SAE is 
reported as soon as this information is available. The original SAE form should 
be kept in the Investigator Site File. 
Duplicate reporting will be avoided by reporting to one of the entities. This process 
will be conducted according to the standard clinical routine. 
Reporting of the following list of conditions will not be recorded as these 
conditions are commonly occurring in the studied age group: 
o Falls and fractures even if they would, by definition, qualify as SAE 
(i.e. if they would lead to hospitalization, prolonged hospitalization 
or disability) 
o Onset of cancers and tumors 
o Dementia and dementia related delirium or confusion unless they 
are related to AEs following vaccination (e.g. in case of fever-
induced delirium) and would qualify as SAE 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 49 of 72 
o Bacterial or fungal infections 
To assess safety, any fatal SAEs will be recorded from the day of vaccination 
until the end of the study period. 
 
 
9.3.3. 
Reporting of Suspected Unexpected Serious 
Adverse Reactions 
 
Those SAE which are assessed by sponsor to be SUSAR are to be reported to 
the EudraVigilance database. The completed CIOMS form will be the basis for 
the reporting, by the Swedish Medical Products Agency in the EudraVigilance 
database according to the specified time frames.  
 
Any SAE/pIMD must be reported to the sponsor as soon as possible and not later 
than 24 h after the site has become aware of the SAE. SUSAR that are fatal or 
life-threatening are reported as soon as possible and no later than 7 days after 
the SAE/pIMD has become known to the sponsor. Relevant follow-up information 
is sent thereafter within an additional 8 days. Other SUSAR are reported as soon 
as possible and no later than 15 days after they have come to the sponsor’s 
knowledge. 
 
 
9.4. 
Follow-up of Adverse Events 
 
Study participants who have been reported with AE/SAE/SUSAR or AESI will 
be followed up until the condition has resolved or remains stable/persistent and 
even if the study period has ended. 
 
 
 
 
9.5. 
Independent Data Monitoring Committee 
 
Not applicable. 
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 50 of 72 
 
9.6. 
Annual Safety Report (ASR) 
 
Since the sponsor is non-commercial and the marketing authorization holder of 
the investigational medicinal product is within the EU/EEA the SPC is used as 
RSI. The simplified template of Annual Safety Report will be used for the ASR 
reporting.  
 
 
9.7. 
Procedures in case of emergencies 
 
Medication errors and use of other medicinal products than those specified in the 
protocol, including misuse and abuse of the investigational medicinal product, 
shall be subject to the same reporting obligations as adverse events, as 
described more detailed in section 9.3. Any failure to produce the expected 
benefits would also lead to reporting. This would include RSV infection or RSV-
related disease. Since no active follow-up for infections is carried out, this aspect 
is only relevant if any study participant reports such an incident.  
 
If an unforeseen event is likely to have a serious impact on the benefit/risk 
relationship of the trial, the sponsor and investigator should take appropriate 
Urgent Safety Measures (USM) necessary to protect the participants. Examples 
of such measures are to temporarily halt the clinical trial or to introduce 
supplementary monitoring measures. The sponsor should, via CTIS, inform the 
concerned Member States about the event and the measures taken. Notification 
must be made as soon as possible, but no later than seven days after the 
measures have been taken. 
 
 
 
 
 
10. 
Statistics 
10.1. 
Analysis population 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 51 of 72 
 
The trial intends to include all participants into the analysis for the primary 
endpoint. A primary per-protocol analysis will be performed and can be 
complemented by a secondary analysis including all enrolled participants that 
have received at least one dose of Arexvy.  
 
 
10.2. 
Statistical analyses 
10.2.1. 
Statistical methods 
 
Descriptive statistics for the primary endpoint will include reporting the geometric 
mean neutralizing titers (GMTs) against RSV A and B one month (D31) after the 
prime dose with Arexvy with their corresponding standard deviations for both 
study groups. In addition, the sero-response rate, defined as the percentage of 
participants with at least a 4-fold increase from baseline to D31, and the mean 
geometric increase (MGI) between D31 and D0 after prime will be calculated 
(equal to the geometric mean of the individual ratio).  
The same analysis will be applied to the neutralizing titers for RSV A and B 
following revaccination, which includes calculation of the sero-response rate 
following revaccination after one year as well as MGI between D31 after 
revaccination compared to m12 and the MGI between D31 after revaccination 
over D31 after prime. Statistical analysis will also include the width of the 
confidence interval around the GMT.  
Safety measurements, such as occurrence of solicited AEs, unsolicited AEs, 
SAEs or any pIMDs will be reported as frequency counts and percentages in both 
age groups. Analysis of the intensity, relationship and duration will be performed.  
Any analysis of other parameters and experimental outcomes will be outlined in 
a separate statistical analysis plan (SAP).  
The results of this study will be interpreted in the context of its exploratory nature 
and aligned with the descriptive study objectives. 
 
 

 
 
 
 
 
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10.2.2. 
Drop-outs 
 
A 10-20% of dropouts in the older adult cohort (80+ years) is expected during the 
study based on previous experience. Enrollment of participants will therefore 
intend to account for this, including 65-70 participants in total, with 30 participants 
in the 60-65 years age group and 35-40 participants in the 80+ older adult cohort. 
The extent of missing data will be reported. 
 
 
10.3. 
Adjustments of significance and confidence interval 
 
Not applicable 
 
 
10.4. 
Sample size calculations 
 
This study is primarily designed to gather descriptive immunogenicity data in 
older adults upon vaccination with Arexvy, including adults of 80 years of age and 
older for which data is currently limited. As the study objective is purely 
descriptive rather than to demonstrate efficacy or test a hypothesis, no formal 
power-based sample size calculation has been made.  
A sample size of 30 individuals in the 60-65 years group and of 35-40 individuals 
in the 80+ years group was chosen based on feasibility of recruitment, clinical 
judgement and a 10-20% drop-out expected in the older age group. This sample 
size of approximately 30 individuals per age group is expected to generate 
valuable immunogenicity data in an otherwise understudied population and to 
allow for exploratory comparisons between age groups. Given the descriptive 
nature of the study, its findings will be interpreted as preliminary.  
 
 
10.5. 
Interim analysis (if relevant) 
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 53 of 72 
Given the exploratory nature of the study objectives and that this study employs 
a licensed vaccine under already approved conditions, no formal interim analysis 
will be performed. Analysis of the different endpoints and study outcomes will be 
conducted as the samples are collected and following the priority list given in 
Table 2 (see section 5.2.). 
The primary endpoint will be analysed once all study participants have completed 
their D31 follow-up visit after prime vaccination. Secondary endpoints regarding 
safety after prime vaccination can be completed once the 6-month follow-up data 
has been collected.  
 
 
 
For the revaccination timepoints a similar approach will be applied, including a  
final analysis after reaching the end of the trial. 
 
 
11. 
Quality Control and Quality Assurance 
11.1. 
Quality Assurance and Sponsor oversight 
 
The sponsor's quality-related work is based on a risk analysis of the trial as a 
whole: design, conduct, data collection, evaluation, reporting and archiving. The 
sponsor will perform quality assurance and quality control activities for the trial; 
however, responsibility for the accuracy, completeness, and reliability of the trial 
data presented to the sponsor lies with the PI (and delegate(s)) generating the 
data. 
 
 
11.2. 
Monitoring 
 
The trial will be monitored by an independent monitor before the trial begins, 
during the conduct of the trial, and after the trial has been completed. This is to 
ensure that the trial is carried out according to the protocol, that data are reliable 
and collected, documented, and reported according to ICH-GCP and applicable 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 54 of 72 
ethical and regulatory requirements. Monitoring will be risk-based, which means 
that the extent of the monitoring is based on the sponsor`s risk-assessment and 
is performed as per the trial’s monitoring plan. The monitoring is intended to 
ensure that the participant’s rights, safety, and well-being are met and that data 
in the CRF are complete, correct, and consistent with the source data.  
 
 
11.3. 
Source data 
 
The investigator must keep source documents for each participant in the trial. A 
document describing what has been classified as source data in the trial (source 
data reference document) should be included in the Investigator Site File (ISF). 
The investigator must ensure that all source documents are accessible for 
monitoring and other quality control activities. 
 
Source data is defined before trial start at each individual site and can, in cases 
where source data is not registered in another document, consist of the CRF. 
This should be decided in consultation with the monitor and clearly stated in the 
source data reference document. 
 
Access to trial-related documentation, such as participants' medical records, 
CRFs, other source data and other trial documentation will be provided for 
monitoring and auditing purposes. Access to participants' medical records will 
require a confidentiality agreement to be signed by the person in charge of the 
medical records at the trial site and by the monitor and auditor, if applicable. 
Access will also be granted in the context of regulatory inspections. 
 
 
11.4. 
Deviations, serious breaches and other reporting 
obligations 
 
The responsible investigator and/or any involved service provider shall, without 
delay, report to the sponsor any suspected serious breaches from the trial 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 55 of 72 
protocol, the CTR, ICH-GCP and other regulations that are likely to affect the 
safety, rights of the participants and/or the data reliability and robustness to a 
significant degree. The sponsor should assess the suspected serious breach, the 
consequences of the deviations and without undue delay, but no later than 7 days 
(from knowledge), report these to the CAs via CTIS. 
 
Other unexpected events that may affect the benefit/risk relationship for the 
clinical trial must be reported via CTIS without undue delay, but no later than 15 
days after the sponsor becomes aware of the event. 
 
Minor deviations that do not affect participants’ integrity or safety, nor significantly 
affect the trial’s scientific value, are documented in the trial documentation of the 
principal investigator and the sponsor and appropriate measures shall be taken. 
The deviations, including minor deviations, must be recorded in the clinical trial 
report. 
 
 
11.5. 
Audits and inspections 
 
The purpose of an audit or inspection is to review trial-related activities and 
documents systematically and independently, to determine whether these 
activities were performed, registered, analyzed and reported correctly according 
to the protocol, ICH-GCP and applicable regulations. 
Authorized representatives for the sponsor and CAs may carry out audits or 
inspections at the trial site, including source data verification. The investigator 
must ensure that all source documents are available for audits and inspections.  
 
 
12. 
Ethics 
12.1. 
Compliance to the protocol, ICH-GCP and regulations 
 
The trial will be performed in compliance with this clinical trial protocol, the EU 
regulation on clinical trials on medicinal products for human use (536/2014), the 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 56 of 72 
Declaration of Helsinki, ICH-GCP, and current national regulations governing this 
clinical trial. This is to ensure the safety and integrity of the trial participants as 
well as the quality of the data collected. 
 
 
 
 
 
12.2. 
Ethical review of the trial 
 
The final protocol for clinical trials on medicinal products must be approved, as a 
part of the application for a permit for clinical trials via CTIS, by the CAs, before 
the trial can be conducted. The authorities must be informed via CTIS of any 
changes in the trial protocol in accordance with current requirements. See also 
section 13.  
 
 
12.3. 
Procedures for obtaining informed consent 
 
The principal investigator at each site shall ensure that the participant is given full 
and adequate oral and written information about the trial, its purpose, any risks 
and benefits as well as inclusion and exclusion criteria. Participants must also be 
informed that they are free to discontinue their participation in the trial at any time 
without having to provide a reason. Participants should be given the opportunity 
to ask questions and be allowed time to consider the provided information. If the 
participant chooses to participate, both the participant and the investigator shall 
sign the informed consent form. A copy of the participant information as well as 
the informed consent form shall be provided to the participant. The participant’s 
signed and dated informed consent must be obtained before any trial-specific 
activity is performed. Each participant who participates in the trial will be identified 
by a participant number on a participant identification list. The participant agrees 
that monitors, auditors, and inspectors may have access to the participants’ 
medical records and other source data. If new information is added to the trial, 
the participant has the right to reconsider whether he/she will continue their 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 57 of 72 
participation. 
 
 
12.4. 
Data protection 
 
Data protection takes into account the General Data Protection Regulation 
(GDPR) (EU) 2016/679. In case data will be handled, stored or transferred 
outside the EU, a level of data protection similar to the GDPR is taken into 
account. When study data is compiled for transfer to the sponsor and other 
authorized parties, participant names, address, and other identifiable data will be 
replaced by a numerical code consisting of a numbering system provided by the 
sponsor in order to de-identify the study participant. The study site will maintain 
a confidential list of participants linking their numerical code to the participant’s 
actual identity. In case of data transfer, the sponsor will maintain high standards 
of confidentiality and protection of participant personal data consistent with 
applicable privacy laws. 
 
In the information provided to the participants, they will be fully informed about 
how their trial data will be collected, used and disclosed. The content of the 
informed consent form complies with relevant integrity and data protection 
legislation. The participant information and the informed consent form will explain 
how trial data are stored to maintain confidentiality in accordance with national 
data legislation.  
The informed consent form will also explain that for verification of the data, 
representatives delegated by the sponsor, as well as relevant authorities, may 
require access to parts of medical records or trial records that are relevant to the 
trial, including the participant’s medical history. 
 
 
12.5. 
Insurances 
 
All participants taking part in the trial are covered by the Swedish Patient 
Insurance 
(patientförsäkringen) 
through 
Regionernas 
Ömsesidiga 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 58 of 72 
Försäkringsbolag, LÖF, and by the Swedish Pharmaceutical Insurance 
(Läkemedelsförsäkringen) through LFF.  
 
 
13. 
Substantial changes to the trial 
 
Substantial changes to the signed clinical trial protocol are only possible through 
approved protocol amendments.  
 
In the event that substantial changes to the protocol need to be implemented 
during the course of the trial which may affect the safety, rights of participants or 
the reliability and robustness of data generated, permission from the relevant 
authority via application in CTIS should be obtained before implementing the 
change. This includes the addition of a new trial site or a change of the principal 
investigator at the trial site.  
 
Non-substantial amendments are entered into the CTIS in the next substantial 
amendment application concerning the same part. If the non-substantial change 
is relevant to the Authority's oversight (e.g. contact details), the CTIS should be 
updated on an ongoing basis. 
 
 
14. 
Collection, handling and archiving of data 
 
Participants who participate in the trial are coded with a trial-specific identification 
number. All participants are registered in a participant identification list 
(participant enrolment and identification list) that connects the participant’s name 
and personal number with a participant number/trial identification number. 
All data will be registered, managed, and stored in a manner that enables correct 
reporting, interpretation, and verification. The complete Trial Master File with 
essential documents will be archived for at least 25 years. The content of the 
Clinical Trial Master file will be archived in a way that ensures that it is readily 
available and accessible upon reasonable request. Source data in the medical 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 59 of 72 
records system are stored and archived in accordance with national regulations. 
 
 
14.1. 
 Case report form 
 
An electronic Case Report Form (eCRF) is used for data collection (RedCap). 
The investigator must ensure that data are registered and any corrections in the 
eCRF are made as stated in the clinical trial protocol and in accordance with the 
instructions. The investigator must ensure that the registered data is consistent 
with the source documents, and that reporting takes place according to the 
timelines that have been predefined and agreed. In the event of discrepancies, 
these must be explained. The principal investigator signs the completed eCRF. 
A copy of the completed eCRF will be archived at the site. 
 
 
15. 
Notification of trial completion, reporting, and 
publication 
 
End of recruitment of participants and end of the trial is reported in CTIS, within 
15 days from occurrence in the Member state. Within one year of trial completion 
in all Member states a summary of the clinical trial results must be reported in 
CTIS, including a summary for lay people. In addition, a full clinical trial report 
with individual data is to be completed and archived in the trial master file by 
sponsor and in the ISFs at each site. 
 
 
16. 
Appendix 
16.1. 
Laboratory Assay Description (refers to assays in 5.3.3) 
 
RSVPreF3 ELISA 
The principle of these assays has been previously described by Papi et. al. (2023) 
(19). Shortly, the method works as follows: RSVPreF3 protein antigen will be 
adsorbed onto a 96-well polystyrene microplate. After washing and blocking 
steps, dilutions of serum samples, controls and standards will be added to the 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 60 of 72 
coated microplate. A reference standard curve will be prepared using a pool of 
commercial human serum containing anti-RSV antibodies. After incubation, the 
microplate will be washed to remove unbound primary antibodies. Bound IgG will 
be detected by the addition of a secondary anti-human antibody (total IgG 
specific), conjugated to HRP. Bound antibodies are quantified by the addition of 
the HRP substrate, tetramethylbenzidine (TMB) and hydrogen peroxide, whereby 
a colored product develops proportionally to the amount of anti-RSVPreF3 
protein total IgG antibodies present in the serum sample. The optical density of 
each sample dilution is then interpolated on the reference standard. The 
corresponding antibody concentration, corrected for the dilution factor, is 
expressed in arbitrary ELISA Laboratory Units per milliliter (ELU/mL).  
RSV A/B neutralization assay 
The serum neutralization assay is a functional assay that measures the ability of 
serum antibodies to neutralize RSV entry and replication in a host cell line. The 
method has been previously described in the study protocol published by Papi 
et. al. (2023) (19). Virus neutralization is performed by incubating a fixed amount 
of RSV A strain (Long, ATCC No. VR-26) with serial dilutions of the test serum. 
The serum-virus mixture is then transferred onto a layer of Vero cells (African 
Green Monkey, kidney, Cercopitheus aethiops, ATCC CCL 81) and incubated for 
2 days to allow infection of the Vero cells by non-neutralized virus and the 
formation of plaques in the cell layer. Following a fixation step, RSV-infected cells 
are detected using a primary antibody directed against RSV (polyclonal anti-RSV 
A IgG) and a secondary antibody conjugated to horse-radish peroxidase (HRP), 
allowing the visualization of plaques after coloration with TrueBlue peroxidase 
substrate. Viral plaques are counted using an automated microscope coupled to 
an image analyzer (Scanlab system with a Reading software). For each serum 
dilution, a ratio, expressed as a percentage, is calculated between the number of 
plaques at each serum dilution and the number of plaques in the virus control 
wells (no serum added). The serum neutralizing titre is expressed in ED60 
(Estimated Dilution 60) and corresponds to the inverse of the interpolated serum 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 61 of 72 
dilution that yields a 60% reduction in the number of plaques compared to the 
virus control wells, as described by others (20,21). Titres will also be expressed 
in International Units per millilitre (IU/mL). Secondary standard calibrated against 
the international reference (NIBSC 16/284) will be included in the runs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c
 
c

 
 
 
 
 
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Economic Burden of Respiratory Syncytial Virus in Adults in the United 
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5. Ruckwardt TJ. The road to approved vaccines for respiratory syncytial virus. 
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A Review of the Candidates and the Approved Vaccines. Pathogens. 2023 
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7. Mullard A. FDA approves mRNA-based RSV vaccine. Nature Reviews Drug 
Discovery. 2024 Jun 7;23(7):487–487.  
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19. Papi A, Ison MG, Langley JM, Lee DG, Leroux-Roels I, Martinon-Torres F, et 
al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. 
New England Journal of Medicine. 2023 Feb 15;388(7):595–608.  
20. Barbas CF, Crowe JE, Cababa D, Jones TM, Zebedee SL, Murphy BR, et al. 
Human monoclonal Fab fragments derived from a combinatorial library bind 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 66 of 72 
to respiratory syncytial virus F glycoprotein and neutralize infectivity. 
Proceedings of the National Academy of Sciences. 1992 Nov;89(21):10164–
8.  
21. Bates JT, Keefer CJ, Slaughter JC, Kulp DW, Schief WR, Crowe JE. Escape 
from neutralization by the respiratory syncytial virus-specific neutralizing 
monoclonal antibody palivizumab is driven by changes in on-rate of binding 
to the fusion protein. Virology. 2014 Apr 1;454–455:139–44.  
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 67 of 72 
18. 
Attachments 
18.1. 
List of pIMDs considered for the study 
 
Table 5 List of pIMDs considered in this study (according to MedDRA version 28.0) 
Blood disorders and 
coagulopathies 
Cardio-pulmonary 
inflammatory disorders 
Endocrine disorders 
- Antiphospholipid syndrome 
- Autoimmune aplastic anemia 
- Autoimmune hemolytic anemia, 
including: 
- 
Warm antibody hemolytic 
anemia 
- 
Cold antibody hemolytic 
anemia 
- Autoimmune 
lymphoproliferative syndrome 
(ALPS) 
- Autoimmune neutropenia  
- Autoimmune pancytopenia 
- Autoimmune thrombocytopenia 
- 
Frequently used related 
terms include: 
“autoimmune 
thrombocytopenic purpura”, 
“idiopathic 
thrombocytopenic purpura 
(ITP)”, “idiopathic immune 
thrombocytopenia”, 
“primary immune 
thrombocytopenia”. 
- Evans syndrome 
- Pernicious anemia 
- Thrombosis with 
thrombocytopenia syndrome 
(TTS) 
- Thrombotic thrombocytopenic 
purpura 
- 
Also known as 
“Moschcowitz-syndrome” or 
“microangiopathic 
hemolytic anemia” 
- Idiopathic Myocarditis/Pericarditis, 
including: 
- 
Autoimmune / Immune-mediated 
myocarditis 
- 
Autoimmune / Immune-mediated 
pericarditis 
- 
Giant cell myocarditis 
- Idiopathic pulmonary fibrosis, 
including: 
- 
Idiopathic interstitial pneumonia 
(Interstitial lung disease, 
Pulmonary fibrosis, 
Immune-mediated pneumonitis) 
- 
Pleuroparenchymal fibroelastosis 
(PPFE) 
- Pulmonary alveolar proteinosis (PAP) 
- 
Frequently used related terms 
include: “pulmonary alveolar 
lipoproteinosis”, 
“phospholipidosis” 
- Addison’s disease 
- Autoimmune / Immune-
mediated thyroiditis, 
including: 
• Hashimoto thyroiditis 
(autoimmune 
hypothyroidism, 
lymphocytic thyroiditis) 
- 
Atrophic thyroiditis  
- 
Silent thyroiditis  
- 
Thyrotoxicosis 
- Autoimmune diseases of 
the testis and ovary, 
including: 
- 
Autoimmune oophoritis 
- 
Autoimmune ovarian 
failure 
- 
Autoimmune orchitis 
- Autoimmune hyperlipidemia 
- Autoimmune hypophysitis 
- Diabetes mellitus type I 
- Graves’ or Basedow’s 
disease, including: 
- 
Marine Lenhart 
syndrome 
- 
Graves' 
ophthalmopathy, also 
known as thyroid eye 
disease (TED) or 
endocrine 
ophthalmopathy 
- Insulin autoimmune 
syndrome 
- Polyglandular autoimmune 
syndrome, including: 
- 
Polyglandular 
autoimmune syndrome 
type I, II and III 
Eye disorders 
Gastrointestinal disorders 
Hepatobiliary disorders 
- Ocular Autoimmune / 
Immune-mediated disorders, 
including: 
- 
Acute macular 
neuroretinopathy (also 
- Autoimmune / Immune-mediated 
pancreatitis 
- Celiac disease 
- Inflammatory Bowel disease, 
including: 
- 
Crohn’s disease  
- Autoimmune cholangitis 
- Autoimmune hepatitis 
- Primary biliary cirrhosis 
- Primary sclerosing 
cholangitis 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 68 of 72 
known as acute macular 
outer retinopathy) 
- 
Autoimmune/Immune-medi
ated retinopathy  
- 
Autoimmune/Immune-medi
ated uveitis, including 
idiopathic uveitis and 
sympathetic ophthalmia  
- 
Cogan's syndrome: an 
oculo-audiovestibular 
disease 
- 
Ocular pemphigoid 
- 
Ulcerative keratitis 
- 
Vogt-Koyanagi-Harada 
disease 
- 
Microscopic colitis  
- 
Terminal ileitis 
- 
Ulcerative colitis  
- 
Ulcerative proctitis 
Musculoskeletal and 
connective tissue 
disorders 
Neuroinflammatory/neuromusc
ular disorders 
Renal disorders 
- Gout, including: 
- 
Gouty arthritis 
- Idiopathic inflammatory 
myopathies, including: 
- 
Dermatomyositis 
- 
Inclusion body myositis 
- 
Immune-mediated 
necrotizing myopathy 
- 
Polymyositis 
- Mixed connective tissue 
disorder 
- Polymyalgia rheumatica (PMR) 
- Psoriatic arthritis (PsA) 
- Relapsing polychondritis 
- Rheumatoid arthritis, including: 
- 
Rheumatoid arthritis 
associated conditions 
- 
Juvenile idiopathic arthritis 
- 
Palindromic rheumatism 
- 
Still's disease 
- 
Felty’s syndrome 
- Sjogren’s syndrome 
- Spondyloarthritis, including: 
- 
Ankylosing spondylitis 
- 
Juvenile spondyloarthritis 
- 
Keratoderma blenorrhagica 
- 
Psoriatic spondylitis  
- 
Reactive Arthritis 
- 
Undifferentiated 
spondyloarthritis 
- Systemic Lupus 
Erythematosus, including: 
- 
Lupus associated 
conditions (e.g., Cutaneous 
lupus erythematosus, 
Lupus nephritis, etc.) 
- Acute disseminated 
encephalomyelitis (ADEM) and other 
inflammatory-demyelinating variants, 
including:  
- 
Acute necrotizing myelitis 
- 
Bickerstaff's brainstem 
encephalitis  
- 
Disseminated necrotizing 
leukoencephalopathy (also known 
as Weston-Hurst syndrome, acute 
hemorrhagic leuko-encephalitis, 
or acute necrotizing hemorrhagic 
encephalomyelitis)  
- 
Myelin oligodendrocyte 
glycoprotein antibody-associated 
disease 
- 
Neuromyelitis optica (also known 
as Devic’s disease) 
- 
Noninfective encephalitis/ 
encephalomyelitis / myelitis 
- 
Postimmunization 
encephalomyelitis 
- Guillain-Barré syndrome (GBS), 
including: 
- 
Variants such as Miller Fisher 
syndrome and the acute motor 
and sensory axonal neuropathy 
(AMSAN) 
- Idiopathic cranial nerve 
palsies/paresis and inflammations 
(neuritis), including: 
- 
Cranial nerve neuritis (e.g., Optic 
neuritis) 
- 
Idiopathic nerve palsies/paresis 
(e.g., Bell’s palsy) 
- 
Melkersson-Rosenthal syndrome 
- Autoimmune/Immune-medi
ated glomerulonephritis, 
including: 
- 
IgA nephropathy 
- 
IgM nephropathy 
- 
C1q nephropathy 
- 
Fibrillary 
glomerulonephritis 
- 
Glomerulonephritis 
rapidly progressive 
- 
Membranoproliferative 
glomerulonephritis 
- 
Membranous 
glomerulonephritis 
- 
Mesangioproliferative 
glomerulonephritis 
- 
Tubulointerstitial 
nephritis and uveitis 
syndrome 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 69 of 72 
- 
Complications such as 
shrinking lung syndrome 
(SLS) 
- Systemic Scleroderma 
(Systemic Sclerosis), including: 
- 
Raynaud’s syndrome 
- 
Systemic sclerosis with 
diffuse scleroderma 
- 
Systemic sclerosis with 
limited scleroderma (also 
known as CREST 
syndrome) 
- 
Multiple cranial nerve 
palsies/paresis 
- Multiple Sclerosis (MS), including: 
- 
Clinically isolated syndrome (CIS)  
- 
Malignant MS (the Marburg type 
of MS)  
- 
Primary-progressive MS (PPMS) 
- 
Radiologically isolated syndrome 
(RIS) 
- 
Relapsing-remitting MS (RRMS) 
- 
Secondary-progressive MS 
(SPMS) 
- 
Uhthoff's phenomenon 
- Myasthenia gravis, including: 
- 
Ocular myasthenia 
- 
Lambert-Eaton myasthenic 
syndrome 
- Narcolepsy (with or without presence 
of unambiguous cataplexy) 
- Peripheral inflammatory 
demyelinating neuropathies and 
plexopathies, including 
- 
Acute Brachial Radiculitis (also 
known as Parsonage-Turner 
Syndrome or neuralgic 
amyotrophy) 
- 
Antibody-mediated demyelinating 
neuropathy 
- 
Chronic idiopathic axonal 
polyneuropathy (CIAP) 
- 
Chronic Inflammatory 
Demyelinating 
Polyradiculoneuropathy (CIDP), 
including atypical CIDP variants 
(e.g., multifocal acquired 
demyelinating sensory and motor 
neuropathy also known as Lewis-
Sumner syndrome) 
- 
Multifocal motor neuropathy 
(MMN) 
- Transverse myelitis (TM), including: 
- 
Acute partial transverse myelitis 
(APTM) 
- 
Acute complete transverse 
myelitis (ACTM) 
Skin and subcutaneous tissue 
disorders 
Vasculitis 
Other (including 
multisystemic) 
- Alopecia areata 
- Autoimmune / Immune-
mediated blistering 
dermatoses, including: 
- 
Bullous Dermatitis 
- 
Bullous Pemphigoid  
- 
Dermatitis herpetiformis  
- Large vessels vasculitis, including: 
- 
Arteritic anterior ischemic optic 
neuropathy (AAION or arteritic 
AION) 
- 
Giant cell arteritis (also called 
temporal arteritis)  
- 
Takayasu's arteritis 
- Anti-synthetase syndrome 
- Capillary leak syndrome 
- 
Frequently used related 
terms include: “systemic 
capillary leak syndrome 
(SCLS)” or “Clarkson's 
Syndrome” 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 70 of 72 
- 
Epidermolysis bullosa 
acquisita (EBA)  
- 
Linear IgA-mediated 
bullous dermatosis (LABD), 
also known as Linear IgA 
disease 
- 
Pemphigus 
- Erythema multiforme 
- Erythema nodosum 
- Lichen planus, including: 
- 
Lichen planopilaris 
- Localised Scleroderma 
(Morphoea) 
- 
Eosinophilic fasciitis (also 
called Shulman syndrome) 
- Psoriasis 
- Pyoderma gangrenosum 
- Reactive granulomatous 
dermatitis, including: 
- 
Interstitial granulomatous 
dermatitis 
- 
Palisaded neutrophilic 
granulomatous dermatitis 
- Stevens-Johnson Syndrome 
(SJS), including: 
- 
Toxic Epidermal Necrolysis 
(TEN)  
- 
SJS-TEN overlap 
- Sweet’s syndrome, including: 
- 
Acute febrile neutrophilic 
dermatosis 
- Vitiligo 
- Medium sized and/or small vessels 
vasculitis, including: 
- 
Anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified)  
- 
Behcet's syndrome  
- 
Buerger’s disease 
(thromboangiitis obliterans) 
- 
Churg–Strauss syndrome (allergic 
granulomatous angiitis)  
- 
Erythema induratum (also known 
as nodular vasculitis) 
- 
Henoch-Schonlein purpura (also 
known as IgA vasculitis) 
- 
Microscopic polyangiitis 
- 
Necrotizing vasculitis 
- 
Polyarteritis nodosa 
- 
Single organ cutaneous vasculitis, 
including leukocytoclastic 
vasculitis, hypersensitivity 
vasculitis and acute hemorrhagic 
edema of infancy (AHEI) 
- 
Granulomatosis with polyangiitis  
- Goodpasture syndrome 
- 
Frequently used related 
terms include: 
“pulmonary renal 
syndrome” and 
“anti-Glomerular 
Basement Membrane 
disease (anti-GBM 
disease)” 
- Immune-mediated 
enhancement of disease, 
including: 
- 
Vaccine associated 
enhanced disease 
(VAED and VAERD). 
Frequently used related 
terms include “vaccine-
mediated enhanced 
disease (VMED)”, 
“enhanced respiratory 
disease (ERD)”, 
“vaccine-induced 
enhancement of 
infection”, “disease 
enhancement”, 
“immune 
enhancement”, and 
“antibody-dependent 
enhancement (ADE) 
- Immunoglobulin G4 related 
disease 
- Langerhans' cell 
histiocytosis 
- Multisystem inflammatory 
syndromes, including: 
- 
Kawasaki’s disease 
- 
Multisystem 
inflammatory syndrome 
in adults (MIS-A) 
- 
Multisystem 
inflammatory syndrome 
in children (MIS-C) 
- Overlap syndrome 
- Raynaud’s phenomenon 
- Sarcoidosis, including: 
- 
Loefgren syndrome 
- Susac's syndrome 
 
 
 
 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 71 of 72 
 
 
18.2. 
Grading of solicited AEs 
Table 6 Grading of solicited AEs as applied in this study 
Event 
Intensity grade 
Parameter 
Pain at the injection site 
0 
None 
1 
Mild: Any pain neither interfering with nor preventing 
normal everyday activities 
2 
Moderate: Painful when limb is moved and interferes with 
every day activities 
3 
Severe: Significant pain at rest. Prevents normal 
everyday activities 
Headache 
0 
None 
1 
Mild: Headache that is easily tolerable 
2 
Moderate: Headache that interferes with normal activity 
3 
Severe: Headache that prevents normal activity 
Fatigue 
0 
None 
1 
Mild: Fatigue that is easily tolerated 
2 
Moderate: Fatigue that interferes with normal activity 
3 
Severe: Fatigue that prevents normal activity 
Myalgia 
0 
None 
1 
Mild: Myalgia that is easily tolerated 
2 
Moderate: Myalgia that interferes with normal activity 
3 
Severe: Myalgia 
Arthralgia 
0 
None 
1 
Mild: Arthralgia that is easily tolerated 
2 
Moderate: Arthralgia that interferes with normal activity 
3 
Severe: Arthralgia that prevents normal activity 
Erythema the injection 
site 
 
Record greatest surface diameter in mm 
Swelling at the injection 
site 
 
Record greatest surface diameter in mm 
Temperature* 
 
Record temperature in °C/°F 
* Fever is defined as a temperature ≥ 38.0°C/100.4°F by any route. The route for measuring temperature can be oral, 
axillary or tympanic. 
The investigator will assess the maximum intensity that occurred over the 
duration of the event for all unsolicited AEs (including SAEs) recorded during the 
study. The assessment will be based on the investigator’s clinical judgment. The 
maximum intensity of local injection site erythema/swelling and fever will be 
scored as follows: 
Table 7 Grading of Erythema/Swelling and Fever 
Intensity grade 
Erythema/Swelling 
Fever 

 
 
 
 
 
RISE_Study protocol_V2.0_12-June-2025_FINAL_CLEAN                                    Page 72 of 72 
0 
≤ 20 mm 
<38.0°C (100.4°F) 
1 
>20 - ≤50 mm 
≥ 38.0°C (100.4°F) - ≤38.5°C (101.3°F) 
2 
>50 - ≤100 mm 
> 38.5°C (101.3°F) - ≤39.0°C (102.2°F) 
3 
>100 mm 
> 39.0°C (102.2°F)