Clinical trial NCT04661579
Conditions: Plasmodium Falciparum
Keywords: RTS,S/AS01E hypo-immuno-responsiveness open-label randomized study Phase 2b Kenyan adults anti-malarials fractional dose RTS,S/AS01E
Sponsor: PATH
Start date: 2020-11-06; Completion date: 2022-08-17
Enrollment: 620 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main goal of this study is to assess the efficacy of RTS,S/AS01E, a candidate vaccine against malaria caused by Plasmodium falciparum (P. falciparum), in adults positive for P. falciparum at the start of the study, but treated with anti-malarial medications to clear the parasite before receiving multiple doses of the vaccine. The goal is to overcome the reduced vaccine efficacy (hypo-responsiveness to the vaccine) reported in actively or chronically infected adults.

Detailed description:
PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the burden of malaria disease in children and contribute to malaria elimination. GSK has developed a candidate vaccine against malaria caused by P. falciparum called RTS,S/AS01E. The vaccine has been shown to be safe in multiple trials and efficacy data in pediatric populations has led to a pilot implementation program in three African countries including Kenya. The RTS,S/AS01E vaccine mechanism of action is presumed to work on the initial sporozoite and liver stages of P. falciparum infection through neutralization of the circumsporozoite (CS) antigen on parasites invading after a mosquito bite in individuals immunized with the RTS,S/AS01E vaccine. In order to inform whether a vaccine such as RTS,S/AS01E may have a future role in malaria elimination, it will be important to establish vaccine efficacy in adults in Sub-Saharan Africa who are reservoirs of parasites and who contribute to ongoing malaria transmission. However, in previous trials, the vaccine has been less effective in adults who have had malaria before. There are probably multiple reasons for this, but one possible reason that is probably very important is that prior infection with malaria or an infection with malaria for long periods, even without symptoms of the disease, can prevent the vaccine from working properly.

This study postulates that treatment of infection prior to immunization can reset the immune response leading to an improved vaccine efficacy. To evaluate this hypothesis, the study will recruit 5 groups. Groups 1 and 4 will have asymptomatic infection with P. falciparum as measured by a highly sensitive polymerase chain reaction (PCR) assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01E or the comparator rabies vaccine, respectively, with the primary objective of evaluating the vaccine efficacy of RTS,S/AS01E relative to the rabies vaccine in this context. Groups 2 and 5 will be negative for asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01E or the comparator rabies vaccine, respectively, with the secondary objective of evaluating the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. Group 3 will have asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay but will not be treated with antimalarial medications prior to immunization with the RTS,S/AS01E vaccine; the immunological profile of this group and groups 1 and 2 will be evaluated as part of secondary and exploratory objectives. Other secondary objectives include safety assessments.

The study will include an initial immunization period (vaccine given on 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations) followed by 6-12 months of follow-up (varying based on the number of events),

Arms: arm 1: Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of artemether/lumefantrine (A/L) plus LD PQ was administered.

Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations. arm 2: Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered.

Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations. arm 3: Participants with detectable P. falciparum parasitemia at baseline did not receive any anti-malarial medications to clear parasites.

Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.

This group is included only for immunological assessment and not for vaccine efficacy. arm 4: Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of artemether/lumefantrine (A/L) plus LD PQ was administered.

Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule. arm 5: Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered.

Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.
Interventions: intervention 1: Malaria Vaccine RTS,S/AS01E intervention 2: Abhayrab rabies vaccine intervention 3: Dihydroartemisinin-piperaquine (DHA/Pip) intervention 4: Artemether / Lumefantrine intervention 5: Primaquine
Intervention descriptions: intervention 1: RTS,S/AS01E vaccine 0.5 mL, containing 25 μg protein comprising circumsporozoite protein (CS) and hepatitis B surface antigen (RTS,S), 25 μg monophosphoryl lipid (AMPL), 25 μg Quillaja saponaria 21 (QS21) in a liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E vaccine was used for the third immunization. intervention 2: Abhayrab rabies vaccine, 0.5 mL, contains 2.5 IU rabies antigen. intervention 3: Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days.

DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites. intervention 4: Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days.

Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy. intervention 5: One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.

Protocol documents:
ICF_000.pdf: 
CVIA 078 – ADULT CONSENT FORM      Page 1 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
A Phase 2b randomized, open-label, controlled, single center study 
in Plasmodium falciparum-infected and uninfected adults age 18-55 
years old in Kenya to evaluate the efficacy of the delayed, fractional 
dose RTS,S/AS01E malaria vaccine in subjects treated with 
artemisinin combination therapy plus primaquine 
 
Research Team 
 
US Army Medical Research Directorate-Africa (USAMRD-A) & Kenya Medical 
Research Institute (KEMRI), Kombewa, Kenya 
 Nathanial Copeland MD, MTM&H 
0705 251782 
 Lucas Otieno Tina MBChB, MPH 
0705 251819 
 After hours Kombewa Clinical Research Centre contact: 
0715 458337 or 0733 333530
 
Sponsor: PATH 
 
Study Funder: PATH 
 
You are being asked to take part in a research study. The box below tells you important things 
you should think about before deciding to join the study. We will provide more detailed 
information below the box. Please ask questions about any of the information before you decide 
whether to participate. You may also wish to talk to others (for example, your family, friends, or 
your doctor) about this study, before agreeing to join.  
 
Please contact one of the research team (above) if you have any questions concerning the study 
or if you have any other questions or concerns.  
 
 


CVIA 078 – ADULT CONSENT FORM      Page 2 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
Key Information for You to Consider 
 Voluntary Consent. You are being asked to volunteer for a research study. It 
is up to you whether you choose to take part or not. There are no penalties and 
you will not lose anything if you decide not to join or if you join and drop out 
later. 
 Purpose. We are doing this research to test the RTS,S malaria vaccine here in 
western Kenya. We will test the safety of the vaccine, test how your body’s 
immune system works when given the vaccine, and see if the vaccine helps 
prevent malaria in adults when used with or without drugs that kill malaria.  
 Duration. You will take part in the study for about 14.5 to 20.5 months. This 
will include up to 35 visits at either the Kombewa Clinical Research Centre or 
your home. Visits will last from 30 minutes up to 4 hours. 
 Procedures and Activities. The study involves: 
 Having physical exams;  
 Answering questions about yourself and your medical history;  
 Giving blood samples throughout the study; 
 Receiving either the RTS,S malaria vaccine or the rabies vaccine; 
 Reporting any problems you have after vaccination; 
 Coming to the clinic for visits and sometimes having visits in your home.  
The study will include 619 adult men and women. Each person is put into 1 of 5 
study groups by chance. These groups will receive either the RTS,S or the rabies 
vaccine. Four of the groups will be treated with anti-malarial drugs prior to each 
vaccination. You will be screened with a test to see if there are any parasites in 
the blood and will be assigned to the different groups depending upon the results 
of this test.  
If you are a woman, you must avoid pregnancy until 2 months after all 
vaccinations are received. We will counsel you about the best way to avoid 
pregnancy. 
There are no costs to you to be in the study.  
We will keep your study information confidential. 
We will ask to keep your biological samples for future research. If you decline to 
permit us to keep your biological samples, you can still take part in the study. 
 Risks. Most studies have some possible harms that could happen to you if you 
join. In this study, we expect that the risks are few. This is because all drugs and 
vaccines being used in this study have already been studied a lot and found to be 
safe. With the malaria medicines, you may have mild side effects including 
stomach upset, and there is a risk of anemia (a drop in red blood cells). For the 
vaccinations, the most likely side effect is pain or irritation where the vaccine is 
injected. While very rare, you can have a life-threatening allergic reaction with 
all medicines and vaccines. 
 Benefits. You will receive free medical screening and medical care for acute 
medical problems during the study. You will also receive the rabies vaccine 
either during or after the study. The rabies vaccine helps protect you against 
rabies if you are bitten by a rabid animal. If you receive the RTS,S malaria 


CVIA 078 – ADULT CONSENT FORM      Page 3 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
vaccine, the vaccine may prevent you from getting malaria. This study may 
benefit others because it may help to make a malaria vaccine available.  
 Alternatives. Taking part is voluntary. The only alternative is to not take part.
 
1. We are asking you to be in a research study. 
A research study is a way to learn new things. It is not the same as treatment or medical care. 
This is a study about how the vaccine, RTS,S, prevents malaria infection in adults.  
Malaria comes from the bite of a mosquito that has been infected with malaria parasites. Malaria 
affects many people in tropical countries such as Kenya. It is a big cause of death in young 
children. It causes serious disease in adults in Kenya and throughout tropical countries. In areas 
such as Kenya, many adults have had malaria infections in childhood and into adulthood. Often 
adults with malaria parasites may not feel ill. Scientists are working together to understand how 
the RTS,S malaria vaccine provides protection in adults. Adults may have very low levels of the 
malaria parasite in their blood but have no other symptoms. We are trying to understand if giving 
anti-malarial drugs before RTS,S immunization makes the vaccine work better. In some persons, 
there may be no parasites in the blood and we think that the vaccine will work better in these 
persons.  
The RTS,S malaria vaccine is approved by Kenyan regulatory agencies for use in young children 
in a pilot vaccination program in Kenya, Malawi and Ghana. In a large study in young children, 
the RTS,S vaccine lowered the risk of getting malaria by about one-half and decreased the 
severity of disease by about one-third. We now want to understand how well the RTS,S vaccine 
prevents infection in adults.  
This form explains what will happen in this study. The entire study is expected to last between 
20.5 and 26.5 months, though your participation will be only 14.5 to 20.5 months. 
We will tell you the risks and benefits of being in the study. Take your time to decide if joining 
the study is right for you. If it helps, talk to people you trust. Ask questions about anything that is 
not clear. If you decide to join, you will sign or make your thumbprint on this form. We will give 
you a copy to keep. 
Researchers from PATH, the U.S. Army Medical Research Directorate-Africa (USAMRD-A; 
known locally as the Walter Reed Project), and the Kenya Medical Research Institute (KEMRI) 
are doing this study. PATH is an international public health organization. PATH, with support 
from The Bill and Melinda Gates Foundation, is providing funding to USAMRD-A and KEMRI 
to conduct this study. This study is also supported by the U.S. Department of Defense. 
2.  What do we want to learn in this study? 
We want to learn these things: 
 We will look at the safety of the vaccine,  
 We will test how the vaccine helps your body protect itself from malaria, and  
 We will see whether the vaccine helps prevent malaria infection when used with or 
without anti-malarial drugs.  


CVIA 078 – ADULT CONSENT FORM      Page 4 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
3. Will this study benefit you? 
Being in this research study may benefit you personally.  
 This study may help prevent malaria infection if you receive the RTS,S vaccine.  
 If you receive the rabies vaccine, you may be protected against rabies if you are bitten by 
a rabid animal.  Rabies is a health problem in Kombewa. If you do not receive the rabies 
vaccine during the study, you can get it at the end of the study for free.  
 The physical exams we do may help you better manage your health.  
 We will screen you for HIV infection. If the results show you have HIV, we will refer 
you to proper care and treatment options. You can still take part in the study if the study 
doctor thinks you are healthy enough to complete the study. 
 You will receive free medical care for new medical problems that arise from the day of 
the first blood draw up until the time it is determined you are not eligible for the study. If 
you are eligible for the study and receive the first anti-malarial drug treatment or 
vaccination, you will continue to receive free medical care until the completion of the 
study (approximately 14.5 to 20.5 months). This does not include care for chronic 
conditions which are not related to your taking part in the study; in these cases you will 
be referred to an appropriate health provider.  
 We will give you a free meal during your study visits at the Kombewa Clinical Research 
Centre. 
What we learn may help others in the future. What we learn may help improve our current or 
future malaria vaccines and help make a malaria vaccine available for adults. 
4. How will you find out if you can be in the study? 
Before you decide if you want to join the study, we will need to see if you meet the study 
requirements. You will need to agree to take part and sign this form before we see if you are able 
to be in the study. We will:  
 
Ask you questions about yourself.  
 
Take blood to test your overall health and for HIV infection. We will take blood from 
your arm using a needle. We will tell you the results of these tests. If the tests show you 
have a health concern, we will refer you for care. You can still take part in the study if 
the study doctor thinks you are healthy enough to complete the study. 
 
Take a small sample of blood from your finger (finger-stick) to see if you have malaria 
parasites and to place you into one of the 5 study groups. 
 
If you are a woman, we test your urine to see if you are pregnant. You cannot begin the 
study if you are pregnant or breastfeeding. If you become pregnant during the study the 
investigator will determine if you are able to continue. 
You may be allowed to take part in the study if: 
 
You sign and date or thumbprint this informed consent form. 
 
You are willing to comply with all study procedures and are available for the entire 
study. 
 
You are a male or female between 18 and 55 years of age. 


CVIA 078 – ADULT CONSENT FORM      Page 5 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 
You are in good general health as determined by the study doctor. 
 
You are able to take medicines by mouth and are willing to follow the treatment plan. 
 
If you are female, you must avoid pregnancy beginning 30 days before through 2 
months after the study vaccination period. This means either you are unable to have 
children or you are willing to prevent pregnancy by using a family planning method. If 
you are not on a family planning method, the study team will be willing to assist you to 
obtain a method from a health facility of your choice. We will test for pregnancy before 
starting the study and before each study treatment course and vaccine is given. 
You are not allowed to take part in this study if: 
 
You are planning on receiving or have received any vaccine from within 30 days before 
the first dose of the study vaccine until 30 days after the last dose of the study vaccine. 
 
You have ever received any rabies vaccine or an experimental malaria vaccine. 
 
You have or are suspected of having a condition that limits your immune system, 
including clinical stage 3 or 4 HIV. Clinical stage 3 or 4 HIV means that your immune 
system is limited, you have an increased risk of infections and that you are not likely to 
respond as well to the vaccination. 
 
Someone in your family has a disease of the immune system that can be passed down in 
families. 
 
You have a history of certain allergic diseases including a reaction to vaccination. 
 
You have been diagnosed with a disease of the nervous system. 
 
You are actively sick, including active malaria, at the time the study starts. If you are 
sick on the day you are to start, you can return after recovering from the illness to be 
screened again if you would still like to participate. 
 
You have a disease of the lungs, heart, liver, or kidneys. 
 
You have sickle cell disease. 
 
You have any abnormal labs that the investigator thinks will make it unsafe for you to 
take part in the study. 
 
Your spleen has been removed. 
 
You have received any human blood products (e.g. blood transfusions) within 3 months 
of the first vaccination, or you will receive any during the study. 
 
If you are female, you are pregnant or breastfeeding from the start of the study through 
completion of vaccinations. 
 
If you are female, you are planning on becoming pregnant or stopping one of the 
approved family planning methods. 
 
You currently or have previously abused alcohol or drugs. Alcohol abuse includes 
drinking an amount of alcohol that harms your health, relationships, or job, or that 
causes legal problems. This includes drinking more than 3 drinks in one sitting or 7 
drinks in a week for women or more than 4 drinks in one sitting or 14 drinks in a week 
for men. 
 
You are receiving medicines that impair your immune system. 
 
You were born with a major medical problem or have a chronic disease that the study 
doctor thinks will make it unsafe for you to take part in the study. 
 
You are part of any other clinical trial. 


CVIA 078 – ADULT CONSENT FORM      Page 6 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 
You have any other findings that the investigator feels would make it unsafe for you to 
take part in the study. 
We will review the results of the screening with you. If you meet the requirements, then you can 
decide if you want to join. If you do not meet the criteria, you will not be able to join the study. 
5. What will happen during the study? 
Being put in a study group: You will be assigned to one of 5 groups. The group to which you 
are assigned will be based on whether or not you have malaria parasites in your blood that are 
not causing you to be sick. You will be assigned to one of 5 groups by chance (like the rolling of 
dice). This means you that you could be assigned to any of the groups you qualify for.  
 Group 1 will include people infected with malaria who will be given anti-malarial drugs 
and the RTS,S malaria vaccine.  
 Group 2 will include people not infected with malaria who will be given anti-malarial 
drugs and the RTS,S malaria vaccine.  
 Group 3 will include people infected with malaria who will not be given anti-malarial 
drugs but will be given the RTS,S malaria vaccine.  
 Group 4 will include people infected with malaria who will be given anti-malarial drugs 
and the rabies vaccine.  
 Group 5 will include people not infected with malaria who will be given anti-malarial 
drugs and the rabies vaccine.  
The table below summarizes these groups. 
Group 
Number 
Malaria 
Infection? 
Given Anti-malarial 
Drugs? 
Vaccine Used 
1 
Yes
Yes
RTS,S malaria vaccine
2 
No
Yes
RTS,S malaria vaccine
3 
Yes
No
RTS,S malaria vaccine
4 
Yes
Yes
Rabies vaccine
5 
No
Yes
Rabies vaccine
 
Study visits: There will be up to 13 visits to the Kombewa Clinical Research Centre and up to 
22 home visits by a field/community health worker. The staff will tell you when to come to the 
Kombewa Clinical Research Centre or when the field/community health workers will visit you at 
your home. The time at the Kombewa Clinical Research Centre may be up to 4 hours. The home 
visits will last less than 30 minutes. 
Study procedures include: 
 A study briefing with information presented about the study and time for questions 
and answers; 
 Written informed consent form reviewed and signed or thumbprinted by you; 
 Photograph taken for a study identification card; 


CVIA 078 – ADULT CONSENT FORM      Page 7 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 Answering questions about your health and any side effects you may have during the 
study; 
 Physical examinations including measurements of temperature, heart rate, blood 
pressure, examination of vaccine injection site, and other examinations as needed; 
 Cheek swab for HLA-typing (optional). 
 Blood draws from veins and finger sticks: 
o We will not take more than 11 teaspoons (52.5 mL) at any single visit, 
o Most collections will be less than 1 teaspoon (5 mL), 
o The total blood collected will be about 57 teaspoons (281 mL);  
 Vaccination given 3 times over 7 months (either RTS,S malaria vaccine or rabies 
vaccine). 
Some people will: 
 If female, have urine collected for a pregnancy test at study start and before each 
study drug or vaccination; 
 Have anti-malarial drugs given before vaccination in 4 of the 5 groups; this will 
include primaquine and either dihydroartemisin-piperaquine or Coartem; 
 Some subjects receiving the RTS,S malaria vaccine will be given Memory Aid Cards 
to record side effects that will be reviewed with study staff. 
You will be given a schedule of your study visits after being assigned to a study group. 
The photograph we take of you for the study will be saved on a password-protected computer at 
our clinic. If you take part in the study, it will be used to make a study identification card, which 
you will keep for the entire study. If you are not eligible or choose not to take part in the study, 
your photograph will be deleted. If you take part in the study, your photograph will be deleted 
from our computer and you may destroy your identification card after the end of the study. 
6. What study procedures or products are experimental? 
All the anti-malaria drugs used in this study, dihydroartemisin-piperaquine, primaquine, and 
Coartem, have been approved for use in Kenya. The rabies vaccine, Abhayrab, is also approved 
for use in Kenya.  
The RTS,S malaria vaccine used in this study has been approved by Kenyan regulatory agencies 
for use in young children in Western Kenya under a pilot program to prevent malaria disease. 
For adults, the RTS,S vaccine is still being investigated. This means that the drug has not yet 
been approved by the Kenyan regulatory agencies for adults. Our use of this vaccine in  this 
study is experimental. The Kenyan regulatory authority has approved its use in this research 
study to learn more about its safety and how it works. This study will look at how the RTS,S 
malaria vaccine works to prevent infection when used in combination with anti-malarial drugs. 


CVIA 078 – ADULT CONSENT FORM      Page 8 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
The safety of this vaccine in humans has been tested in prior research studies. Some side effects 
may not yet be known. 
The test for malaria parasites from your finger stick blood sample is an experimental test. But 
this test detects malaria parasites better than other tests. 
7. Will you be told any of your test results?  
We will tell you the results of any standard health testing done, including the results of the HIV 
test at screening. If your results show that you may have a health concern, we will treat you or 
refer you to proper treatment. 
Other tests will be for research only and will not be used for your health care. We will not tell 
you the results of research only tests. 
8. Will you learn the results of the study? 
We will share the overall results of the study with your community by informing the village 
chiefs and elders upon the conclusion of the study. 
9. What are the risks of this study?  
All research studies have some risks. Here are the risks we know about with this study and how 
we will manage those risks.  
Risks from study medications or vaccines 
Volunteers in some of the groups will take the anti-malaria drugs dihydroartemisin-piperaquine, 
primaquine, and Coartem, at different times during the trial. The side effects are generally mild 
and the majority are non-serious. Reactions such as: cough; headache; loss of appetite; dizziness; 
nausea; diarrhea; and anemia are usually mild and rare. If they occur, these side effects should 
clear up within a few days of your last dose of the anti-malarial drug.  
Each time we give you a vaccine, you might have a reaction to it. If you receive the RTS,S 
malaria vaccine there may be mild pain or swelling where the injection was given. This should 
disappear after about 2 or 3 days. In addition, muscle soreness, slight fever, tiredness, or 
headache may occur. You may have other reactions to the malaria vaccine that at this time are 
not known. The same symptoms just described may occur if you receive the rabies vaccine. 
Other symptoms that have been reported with the rabies vaccine are: redness at the site of 
injection; itching; and dizziness. As may happen with any vaccine, there is a small chance that 
you could have an allergic reaction due to either the malaria or rabies vaccines. Allergic 
reactions to the anti-malaria medications are also possible. An allergic reaction may be mild, 
such as a rash, or may be severe and life-threatening. A life-threatening reaction to any of the 
anti-malaria drugs, malaria or rabies vaccine is extremely rare. Medicines and equipment needed 
to treat allergic reactions are available at the Clinic. 
It is not known whether the RTS,S malaria vaccine can cause birth defects or other problems in 
an unborn or breastfeeding child. This is why women must agree to use effective birth control 
during the study. If you become pregnant or think you might be pregnant, contact your personal 


CVIA 078 – ADULT CONSENT FORM      Page 9 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
physician and the principal investigator of this study listed in the “Who to contact if you have 
questions” section at the end of this document. 
Harm from taking blood 
 
Taking blood can cause pain and bruising. This should not last long. 
 
It is very rare, but sometimes taking blood can cause an infection. This is not likely to 
happen because we clean the skin and use trained people to take the blood. 
 
Sometimes people faint when blood is taken. We will make sure you are seated or lying 
down when we take the blood. We are trained to provide care if fainting occurs. 
 
Your body will make more blood to replace the blood that we take out. 
Loss of confidentiality 
We keep your personal information secure. However, there is always a small chance that 
someone who is not allowed could see your personal information by mistake.  This risk will be 
minimized by ensuring only authorized individuals have access to your personal information. 
Also, we will only use your study identification number on study documents whenever possible - 
to further decrease the risk that you can be identified. 
Other risks  
There may be other risks that we do not know about yet. If we learn new information during the 
study that might affect your decision to stay in the study, we will tell you about it. 
10. 
What will happen if you are hurt? 
If you are hurt as a direct result of taking part in this research project, PATH will pay for health 
care to treat the illness/injury. If you are injured by a vaccine, medicine or treatment that you 
would not have been given outside our study, you may be entitled to compensation. PATH has 
insurance to cover the costs of research-related injuries. This is provided that you followed all 
the instructions and advice of the study doctor and did nothing to cause or contribute to the 
research-related injury. By signing this form, you do not give up any legal right you may have. 
The Principal Investigator for this study, Dr Nathanial Copeland, can give you more information. 
Free medical care for research-related injuries will be provided at the Kombewa Clinical 
Research Centre. If you require medical care beyond the abilities of the Kombewa Clinical 
Research Centre, we will transport you to an appropriate medical facility and pay for your care 
there.  
11. 
What other choices do you have besides taking part in the study? 
You can choose not to join the study. You will not have any penalties or lose any benefits if you 
say “no”. 
12. 
How we use your samples during the study 
In this study, we will take blood from you at screening to assess your general level of health and 
the results of these tests will be provided to you.  


CVIA 078 – ADULT CONSENT FORM      Page 10 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
We will also take blood at various times during the study. We will test these samples to see how 
well the vaccine works.  We will not tell you the results of these study tests, which are for 
research only and will not be used for your health care. The total amount of blood to be collected 
is about 57 teaspoons (281 mL) spread out over 14.5 to 20.5 months. 
In addition to collecting samples of blood, we will also take a swab from inside your cheek. This 
is to collect cells to look at your genes involved in the immune response to the vaccine. This test 
is called “HLA-typing” and involves genetic testing of your samples (cells from your blood or 
cheek). This information about your DNA structure (genetic information) from your samples is 
unique to you. While genetic information can be used to look at your risk for developing certain 
diseases and possible changes in your future health status or life expectancy, or that of your 
children and other relatives, this study will not be looking at those things.  We will not be giving 
you information on results of this testing. This genetic testing (HLA-typing) is optional. You can 
choose not to have this testing done, and still be a part of the study.   
Your blood samples may be sent to: a PATH-designated central laboratory in the United States; 
and to other laboratories working with PATH, including those outside Kenya. 
If you are a woman, we test your urine before the anti-malarial drug treatments and before the 
vaccinations to check whether you are pregnant. 
13. 
How we use and protect your personal information 
In this study, we will record some personal information about you. We need some of this 
information to show that you agreed to take part in this study and that you meet the study 
requirements. We will also need your name, location where you live, and mobile phone number 
to reach you during the study. If you seek medical care during the study, we may need to look at 
your medical records.  
We will keep your personal information confidential. Here is how we protect it: 
 
Your name and contact information are kept in a locked cabinet. Only the study team 
can unlock it. 
 
On study forms, we will use an identification number in place of your name.  
 
The information using your identification number in place of your name is put into 
computers. These are password protected.  
 
The study team keeps a link between your name and your study number in case you 
need to be contacted in the future. After 15 years we will destroy the link and any 
documents that identify you. 
14. 
Who can see your personal information? 
Information about your taking part in this study will remain confidential. Only Kombewa 
Clinical Research Centre staff have access to your study records. They are not allowed to share 
any personal information. All files will be kept in locked cabinets when they are not in use. The 
information we collect may be reviewed by: 


CVIA 078 – ADULT CONSENT FORM      Page 11 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 Representatives of the KEMRI Scientific and Ethics Review Unit (SERU);  
 Representatives of PATH;  
 The U.S. Department of Defense (DoD);  
 U.S. Army Medical Research and Development Command (USAMRDC);  
 The Walter Reed Army Institute of Research Institutional Review Board (WRAIR IRB); 
and the Kenya Pharmacy and Poisons Board (PPB).  
They are not allowed to share any personal information about you.  
Complete confidentiality cannot be guaranteed. But every effort will be made to keep the records 
as confidential as possible within the limits of the law. All data and medical information obtained 
about you as an individual will be considered important and held in confidence. All the above 
representatives are bound by rules of confidentiality not to reveal your identity to others.  
15. 
What happens to your information when the study ends? 
We will keep your information in a secure locked cabinet or scanned onto secure, password 
protected computers. We will keep the data for up to 15 years. After that time, the data may be 
destroyed if it is no longer needed for further research. 
We will share what we learn in this study with others. We will share the study data with the Bill 
and Melinda Gates Foundation, which is providing support to PATH for the conduct of this 
study. We will remove your name and other identifying information when we share the study 
information with others. 
Here are the ways we may share your study information: 
 
We may write an article or share the study results at meetings or on websites. 
Publications or presentations of results will not reveal your identity. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
 
We will put the study results on a public website. 
 
We may put the research results in a public database. This lets other researchers see and 
use the results. No one can find out who are you are from this sharing. 
16. 
Using your information and samples for future research 
We want to store your samples and study information for future research to better understand 
malaria. You can say “no” and still take part in the study. If you agree to this storage and future 
use of your samples, your samples may be stored and used for up to 15 years. Research on your 
samples will be used to study malaria and other research areas. Future studies may involve 
genetic testing.  
If you say yes now and change your mind later, we will destroy any extra samples and 
information that are in our storage. We cannot destroy samples and information that are already 
used or that have your code number removed. 


CVIA 078 – ADULT CONSENT FORM      Page 12 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
If you say yes, we will store blood samples in a secure area at a PATH-designated central 
laboratory, in the United States, and at Kombewa Clinical Research Centre. Your study 
information will be stored on secure computers. The samples and information are labeled with a 
study identification number, not with your name. When we share your data or specimens for 
future research, we will do this in a way that other researchers will not be able to identify you.  
Someone using your samples or information may make a new discovery that makes money. 
There are no plans to share the money with you or others.  
Here is what you should know to make your decision: 
 
Samples are labeled only with a study identification number and will be stored securely 
at the PATH-designated central laboratory in the United States and at Kombewa 
Clinical Research Centre. 
 
Studies done on these samples would look further at the malaria parasite or your body’s 
response to malaria infection or vaccination. 
 
Allowing us or others to use your extra samples and study information will not help 
you. It may help other people in the future. 
17. 
Will you be paid for being in this study? 
We will give you a minimum of 500 KES per scheduled visit at Kombewa Clinical Research 
Centre. This is to compensate you for lost wages, time, and inconvenience at approximately a 
day’s work at minimum wage. For visits at Kombewa Clinical Research Centre, we will provide 
transport for you or reimburse you for transportation costs. If you are being reimbursed, you will 
be reimbursed between 500 and 1000 KES for scheduled visits and between 300 and 500 KES 
for unscheduled visits, as determined by the study team on a case-by-case basis based on the 
distance you traveled. Other than medical care that may be provided and any other payment 
specifically stated in this form, you will not receive any other compensation for your taking part 
in this study. 
18. 
Are there any costs to you if you join the study? 
There are no costs to you if you join the study.  
19. 
What to do you if you want to leave the study 
If you want to leave the study, please tell us.  
 
We may ask why you are leaving the study because it is helpful for us to know. You do 
not have to tell us.  
 
We may ask to complete any study procedures that are important for your diagnostic or 
treatment options. You do not have to agree. 
 
We may refer you for medical care elsewhere. You do not have to accept this referral. 
20. 
Can you be taken off the study? 
The researchers may remove you from the study if these things happen: 


CVIA 078 – ADULT CONSENT FORM      Page 13 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 
The study doctors think that staying in the study is not good for your health. 
 
You are not able to follow the directions of the study staff. 
 
The study ends early.  
21. 
Your rights 
You have rights in this study: 
 
You do not have to be in this study. You can say yes or no to joining. You can leave 
the study at any time. If you do not join or you leave early, you will not have any 
penalties. You should not feel pressure to join or stay in the study. 
 
By signing this consent form, you do not lose any rights you normally have. 
 
If we learn new information about the study, we will tell you. You can decide if you 
want to stay in the study after you learn this new information. 
22. 
Who has reviewed the study? 
All research is reviewed by an independent group of people, called a research ethics committee. 
This group protects your safety, rights, well-being and dignity. This study has been reviewed and 
approved by the Health Authorities and has been reviewed and given a favorable opinion by the 
KEMRI Scientific and Ethics Review Unit, the WRAIR Institutional Review Board (IRB), and 
the Expert Clinical Trials Committee of the Pharmacy and Poisons Board of Kenya.  
 
KEMRI Scientific Ethics Review Unit 
P.O. Box 54840-00200, Nairobi-Kenya 
Phone: (020)2722541 or 0722205901.  
E-mail: SERU@kemri.org 
 
The Director, Human Subject Protection Branch, Walter Reed Army Institute of Research 
(WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910. Telephone (301-319-
9940) or email (usarmy.detrick.medcom-wrair.mbx.hspb@mail.mil) 
The Registrar, 
Pharmacy and Poisons Board, 
P.O. Box: 27663-00506, 
Nairobi, Kenya 
Email: cta@pharmacyboardkenya.org 
23. 
Who to contact if you have questions 
 
If you have questions about this study or you believe you have been hurt as a result of 
the research study, please call: 
 
Dr Nathanial Copeland, Tel 0705251782 
 
Dr. Lucas Otieno Tina, Tel 0705251819 


CVIA 078 – ADULT CONSENT FORM      Page 14 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 
If you have questions about your rights in this research study, you may contact the 
Committee Chairperson, KEMRI Scientific and Ethics Review Unit, P.O. Box 54840-
00200, Nairobi. Telephone: (020)2722541 or 0717719477. Email address: 
seru@kemri.org. 
 
 


CVIA 078 – ADULT CONSENT FORM      Page 15 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
Confirmation of written consent 
Use of your stored samples and data for future research: 
Please initial or thumb print by the sentences that reflect your choices, and then sign or 
thumb print below: 
 
_____ I authorize the storage of data collected as a part of this study for use in future 
research studies. 
OR 
_____ I do not authorize the storage of data collected as a part of this study for use in future 
research studies. 
Please initial or thumb print by the sentences that reflect your choices, and then sign or 
thumb print below: 
 
_____ I authorize the storage of my biological specimens for use in future research studies. 
OR 
_____ I do not authorize the storage of my biological specimens for use in future research 
studies. 
Use of your samples for genetic testing for HLA-typing: 
Please initial or thumb print by the sentences that reflect your choices, and then sign or 
thumb print below: 
 
_____ I authorize the genetic testing of my blood or cheek sample for HLA-typing. 
OR 
_____ I do not authorize the genetic testing of my blood or cheek sample for HLA-typing. 
Study participant
Signing your name below means you voluntarily choose to be in this research study. It also 
means you:  
- have received an explanation of the research  
- have asked any questions you want to ask and you are satisfied with the answers 
- know who to contact for future questions


CVIA 078 – ADULT CONSENT FORM      Page 16 of 16          Version 1.4, WRAIR #2711, 3 March 2020 
 
 
- agree to receive HIV counseling and testing by a study HIV counselor 
- agree to having your photo taken for the study identification card 
- agree to having some of your samples shipped outside of Kenya.  
You will be given a copy of this signed consent form to keep. 
_________________________________________ 
Printed Name
____________________ 
Date
_________________________________________ 
Signature of Participant
   
 
 
 
Thumbprint of Participant
Member of research team 
Signing my name below means I have explained this research study to you and answered your 
questions to the best of my ability. I will give you a copy of this form to keep.
_________________________________________ 
Printed Name
_________________________________________ 
Signature of Person Obtaining Consent
____________________ 
Date
Witness (Include if enrolling participants who are illiterate and using written consent) 
Signing below means that the study participant whose thumbprint is above chose voluntarily to 
be in this research study. It also means I was present the whole time the study was being 
explained to them. I confirm that: 
- the information provided to the participant was complete and accurate  
- the participant had a chance to ask questions 
- and that the participant appeared to understand the information provided.  
The participant will get a copy of this form to keep. 
_________________________________________ 
Printed Name 
 
_________________________________________ 
Signature of Witness 
____________________ 
Date  

SAP_002.pdf: 
ClinicalTrials.gov NCT 
Number
NCT04661579




Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
 
Version: 4.0 
Confidential 
Page 3 of 120 
Date: Mar 5th, 2023 
 
Revision History 
 
Version 
Date 
Summary of Revision 
0.1 
March 22, 2021 
Initial version 
0.2 
April 02, 2021 
Added Shells
0.3 
April 16, 2021 
Clean version for ERC 
0.4 
May 3, 2021 
Updated shells 
1.0 
May 17, 2021 
Final version 
1.1 
May 18th 2021 
Small update to clarify the Total 
cohort for efficacy and ATP cohort 
for efficacy population definition 
2.0 
May 20th 2022 
Updated the protocol version, Co-
PI, and the values that define a 
positive result for Anti-CS results 
2.1 
Sep 27th 2022 
Added a new section on the 
Timing of Analysis 
3.0 
Nov 2nd 2022 
Finalized for signature 
3.1 
Jan 31st 2023 
Updated the start of at risk to 7 
days after dose 3 instead of 14 
days after dose 3.  
Updated the shells  
3.2 
Feb 28th 2023 
Added survival curves for 
exploratory analysis and updated 
the list of TLF shells  
4.0 
Mar 5th 2023 
Finalized for signature 
 
Apr 14th 2023 
Updated the model for 
immunogenicity group 
comparisons and associated TLF 
shells  
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
 
Version: 4.0 
Confidential 
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Date: Mar 5th, 2023 
 
Table of Contents 
1.
LIST OF ABBREVIATIONS ............................................................................................. 11
2.
INTRODUCTION ............................................................................................................... 13
2.1
Background and rationale............................................................................................... 13
2.2
Study Objectives ............................................................................................................ 13
2.2.1
Primary Objective ................................................................................................... 13
2.2.2
Secondary Objective ............................................................................................... 13
2.2.3
Exploratory Objective ............................................................................................. 14
2.3
Study Design and Study Endpoints................................................................................ 14
2.3.1
Study Design ........................................................................................................... 14
2.3.2
Study Endpoints ...................................................................................................... 15
2.4
Randomization and Treatment Assignment ................................................................... 17
2.5
Sample Size and Power Considerations ......................................................................... 18
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES .......................................... 20
3.1
Statistical Hypotheses .................................................................................................... 20
3.2
Definition of Populations to be Analyzed (Analysis Datasets)...................................... 20
3.2.1
Enrolled population ................................................................................................. 20
3.2.2
Total vaccinated cohort (TVC)............................................................................... 20
3.2.3
Safety analysis population ...................................................................................... 20
3.2.4
According to protocol (ATP) cohort for efficacy ................................................... 21
3.2.5
Total cohort for efficacy ......................................................................................... 21
3.2.6
ATP cohort for immunogenicity ............................................................................. 21
3.3
Time Window for Analysis ............................................................................................ 21
3.4
Missing Data and Outliers .............................................................................................. 23
3.4.1
Missing Data ........................................................................................................... 23
3.4.2
Outliers .................................................................................................................... 23
3.5
Data Handling Conventions and Transformations ......................................................... 23
3.6
Statistical Summaries, Confidence Intervals and P values ............................................ 23
3.7
Multiple Comparisons/Multiplicity ................................................................................ 24


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
 
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3.8
Interim Analysis and Final Analysis.............................................................................. 24
3.9
Statistical Software......................................................................................................... 24
4.
SUBJECT DISPOSITION.................................................................................................. 25
4.1
Subject Enrollment ......................................................................................................... 25
4.2
Disposition of Subjects................................................................................................... 25
4.3
Eligibility Criteria .......................................................................................................... 25
5.
SUBJECT CHARACTERISTICS AND ADHERENCE ................................................. 26
5.1
Baseline Demographics and Characteristics .................................................................. 26
5.2
Subject Characteristics at Each Visit ............................................................................. 26
5.3
Visit and Vaccination Adherence, Sample Availability ................................................. 26
5.4
Anti-Malarial Compliance.............................................................................................. 26
5.5
Protocol Deviations ........................................................................................................ 26
6.
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT ........................................... 27
7.
ANALYSIS OF THE SECONDARY ENDPOINT(S) ...................................................... 28
7.1
Secondary Efficacy ........................................................................................................ 28
7.2
Immunogenicity ............................................................................................................. 28
7.3
Safety Analyses .............................................................................................................. 29
7.3.1
Definition................................................................................................................ 29
7.3.2
Analysis of Safety Endpoints.................................................................................. 30
8.
EXPLORATORY ANALYSES.......................................................................................... 32
9.
LIST OF TABLES, LISTINGS AND FIGURES ............................................................. 33
10.
TLF SHELLS ................................................................................................................... 34
11.
TIMING OF ANALYSIS ................................................................................................ 34
DEMOGRAPHICS TABLES .................................................................................................... 37
Table 10.1.1: Enrollment Status by Group................................................................................ 37
Table 10.1.2: Summary of eligibility criteria ............................................................................ 38
Table 10.1.3: Summary of Demographics by Treatment (TVC, total efficacy cohort and Per 
Protocol Populations) ................................................................................................................ 39
Table 10.1.4: Summary of HLA Typing by Treatment (TVC Population) ............................... 41
Table 10.1.5: Protocol Deviations ............................................................................................. 42


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Table 10.1.6: Medical History................................................................................................... 43
Table 10.1.7: Vital Signs ........................................................................................................... 44
Table 10.1.8: Physical Examination.......................................................................................... 45
Table 10.1.9: Prior Medications ................................................................................................ 46
Table 10.1.10: Concomitant Medications ................................................................................. 47
Table 10.1.11: Vaccine Administration .................................................................................... 48
Table 10.1.12: Anti-Malarial Compliance ................................................................................ 49
TABLE 10.1.13.1: VISIT ATTENDANCE (EPOCH 1) .......................................................... 50
TABLE 10.1.13.2: VISIT ATTENDANCE (EPOCH 2) .......................................................... 51
TABLE 10.1.13.3: VISIT ATTENDANCE (EPOCH 3) .......................................................... 52
VACCINE EFFICACY TABLES ............................................................................................. 53
Table 10.2.1.1 and 2. Vaccine efficacy (Group 1 vs Group 4): First Infection Events (FIEs) of 
P. falciparum during the Active Detection of Infection period by HIV status and overall (ATP 
cohort for efficacy and Total cohort for efficacy) ..................................................................... 53
Table 10.2.2.1 and 2 Vaccine efficacy (Group 2 vs Group 5): First Infection Events (FIEs) of 
P. falciparum during the Active Detection of Infection period by HIV status and overall (ATP 
cohort for efficacy and Total cohort for efficacy) ..................................................................... 54
Table 10.2.3.1 and 2 Vaccine efficacy (Group 1 vs Group 2): First Infection Events (FIEs) of 
P. falciparum during the Active Detection of Infection period by HIV status and overall (ATP 
cohort for efficacy and Total cohort for efficacy) ..................................................................... 55
Table 10.2.4.1 and 2 Vaccine efficacy (Group 4 vs Group 5): First Infection Events (FIEs) of 
P. falciparum during the Active Detection of Infection period by HIV status and overall (ATP 
cohort for efficacy and Total cohort for efficacy) ..................................................................... 56
Table 10.2.5.1 and 2 Summary of subjects at risk, person-time, number of FIEs and incidence 
rate (ATP cohort for efficacy and Total cohort for efficacy) for Group 1 and 4 ...................... 57
Table 10.2.6.1 and 2 Summary of subjects at risk, person-time, number of FIEs and incidence 
rate (ATP cohort for efficacy and Total cohort for efficacy) for Group 2 and 5 ...................... 58
Table 10.2.7.1 and 2 Summary of median time to FIEs and hazards (ATP cohort for efficacy 
and Total cohort for efficacy).................................................................................................... 59
IMMUNOGENICITY TABLES ............................................................................................... 60
Table 10.3.1.1 and 2: Number and Percentage of Subjects with anti-CS NANP Antibody 
Titer/Avidity Equal to or above Cut-off (seropositive) and GMTs (ATP cohort for 
immunogenicity and Total vaccinated cohort) .......................................................................... 60


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Table 10.3.2.1 and 2: Number and Percentage of Subjects with Anti-CS C-term Antibody 
Titer/Avidity Equal to or above Cut-off and GMTs (ATP cohort for immunogenicity and Total 
cohort for efficacy).................................................................................................................... 61
Table 10.3.3.1 and 2: Number and Percentage of Subjects with ŶƚŝͲ,Ɛď Titer Equal to or 
above Cut-off and GMTs (ATP cohort for immunogenicity and Total vaccinated cohort) ..... 61
Table 10.3.4.1 and 2 : Geometric Fold Rise in Anti-CS NANP Antibody Titer at Each Post-
Vaccination Timepoint Compared to Screening (ATP cohort for immunogenicity and Total 
vaccinated cohort) ..................................................................................................................... 62
Table 10.3.5.1 and 2: Geometric Fold Rise in Anti-CS C-term Antibody Titer at Each Post-
Vaccination Timepoint Compared to Screening (ATP cohort for immunogenicity and Total 
vaccinated cohort) ..................................................................................................................... 62
Table 10.3.6.1 and 2: Geometric Fold Rise in Anti-HBsAb Titer at Each Post-Vaccination 
Timepoint Compared to Screening (ATP cohort for immunogenicity and Total vaccinated 
cohort ) ...................................................................................................................................... 62
SAFETY TABLES ...................................................................................................................... 63
Table 10.4.1.1: Overall Safety Profile by Treatment (Safety Population) ................................ 63
Table 10.4.1.2: Frequency of Local Solicited Adverse Events by Treatment and Severity 
(Safety Population) .................................................................................................................... 64
Table 10.4.1.3: Frequency of Systemic Solicited Adverse Events by Treatment and Severity 
(Safety Population) .................................................................................................................... 65
Table 10.4.1.4: Summary of Unsolicited Adverse Events by Treatment (Safety Population) . 67
Table 10.4.1.5: Summary of Unsolicited Adverse Events by Treatment, Severity and 
Relationship to Study Treatment (Safety Population)............................................................... 68
Table 10.4.1.6: Summary of Serious Adverse Events by Treatment (Safety Population) ........ 70
Table 10.4.1.7: Frequency of Local Solicited Adverse Events by Treatment, Injection Period, 
and Severity (Safety Population)............................................................................................... 71
Table 10.4.1.8: Frequency of Systemic Solicited Adverse Events by Treatment, Injection 
Period, and Severity (Safety Population) .................................................................................. 72
Table 10.4.1.9: Summary of Adverse Events of Special Interest by Treatment (Safety 
Population) ................................................................................................................................ 74
Table 10.4.1.10: Summary of Adverse Events (Safety Population) ......................................... 75
Table 10.4.1.11: Summary of Recurrent Adverse Events (Safety Population)......................... 77
Table 10.4.1.12: Summary of Adverse Events that Persisted beyond 6 Days Post-IP 
Administration (Safety Population) .......................................................................................... 79


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Table 10.4.1.13: Exploration of Group Comparisons for Common Adverse Events (Safety 
Population) ................................................................................................................................ 80
Table 10.4.1.14: Safety Lab Data out of Range  (Safety Population)....................................... 81
Table 10.4.1.15: Summary of Safety Lab Results (Safety Population) .................................... 82
Table 10.4.1.16: Summary of Hemoglobinopathy Results (Safety Population) ....................... 83
Table 10.4.1.17: Summary of Urine Pregnancy Test Results (Safety Population)................... 84
Table 10.4.1.18: Summary of All Non-Serious Adverse Events by Treatment (Safety 
Population) ................................................................................................................................ 85
12.
DEMOGRAPHICS LISTINGS ...................................................................................... 86
Listing 10.1.1: Protocol Deviations........................................................................................... 86
Listing 10.1.2: Enrollment Status, Demographics and Subject Disposition ............................. 87
Listing 10.1.3: Eligibility Criteria Not Met .............................................................................. 88
Listing 10.1.4: Listing of All Eligibility Criteria ...................................................................... 89
Listing 10.1.5: Baseline Demographics .................................................................................... 90
Listing 10.1.6: HIV Status and HLA Typing ............................................................................ 91
Listing 10.1.7: Prior Medications .............................................................................................. 92
Listing 10.1.8: Concomitant Medication .................................................................................. 93
Listing 10.1.9: Medical History ................................................................................................ 94
Listing 10.1.10.1: Visit Attendance (Epoch 1).......................................................................... 95
Listing 10.1.10.2: Visit Attendance (Epoch 2).......................................................................... 96
Listing 10.1.10.3: Visit Attendance (Epoch 3).......................................................................... 97
Listing 10.1.11: Vaccine administration ................................................................................... 98
Listing 10.1.12: Anti-Malarials ................................................................................................. 99
Listing 10.1.13: Vital Signs .................................................................................................... 100
Listing 10.1.14: Physical Examinations .................................................................................. 101
13.
SAFETY LISTINGS ...................................................................................................... 102
Listing 10.2.1: Solicited Adverse Events (Safety Population) ................................................ 102
Listing 10.2.2: Unsolicited Adverse Events (Safety Population)............................................ 103
Listing 10.2.3: Serious Adverse Events (Safety Population).................................................. 104
Listing 10.2.4: Adverse Events of Special Interest (Safety Population) ................................. 105


Protocol No. CVIA-078; RTS,S/AS01 E  
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Listing 10.2.5: Safety Laboratory Results (Safety Population) .............................................. 106
Listing 10.2.6: Hemoglobinopathy Tests Results (Safety Population) ................................... 107
Listing 10.2.7: Urine Pregnancy Tests for Female Subjects (Safety Population)................... 108
14.
IMMUNOGENICITY LISTING.................................................................................. 109
Listing 10.3.1: Listing of Antibody Titers/Avidity................................................................. 109
15.
VACCINE EFFICACY LISTING................................................................................ 110
Listing 10.4.1 Listing of First Infection Events (FIEs) ........................................................... 110
Listing 10.4.2 Listing of Parasitemia Test Results (ADI) ....................................................... 111
16.
DEMOGRAPHICS FIGURES ..................................................................................... 112
Figure 10.1.1: CONSORT Diagram ........................................................................................ 112
17.
VACCINE EFFICACY FIGURES .............................................................................. 114
Figure 10.2.1: Kaplan-Meier survival curve for FIEs in Groups 1 and 4. .............................. 114
Figure 10.2.2: Kaplan-Meier survival curve for FIEs in Groups 1 and 4 stratified by HIV 
status. 115
Figure 10.2.3: Kaplan-Meier survival curve for FIEs in Groups 2 and 5. .............................. 116
Figure 10.2.4: Kaplan-Meier survival curve for FIEs in Groups 2 and 5 stratified by HIV 
status. 117
Figure 10.2.5: Kaplan-Meier survival curve for FIEs in Groups 1 and 2 ............................... 117
Figure 10.2.6: Kaplan-Meier survival curve for FIEs in Groups 4 and 5 ............................... 117
Figure 10.2.7: Scaled Schoenfeld residuals with 95% confidence interval versus time for 
Groups 1 and 4 FIEs during the entire study period (ATP cohort for efficacy) ..................... 118
Figure 10.2.8: Scaled Schoenfeld residuals with 95% confidence interval versus time for 
Groups 2 and 5 FIEs during the entire study period (ATP cohort for efficacy) ..................... 119
Figure 10.2.9: Scaled Schoenfeld residuals with 95% confidence interval versus time for 
Groups 1 and 2 FIEs during the entire study period (ATP cohort for efficacy) ..................... 119
Figure 10.2.10: Scaled Schoenfeld residuals with 95% confidence interval versus time for 
Groups 4 and 5 FIEs during the entire study period (ATP cohort for efficacy). .................... 119
18.
IMMUNOGENICITY FIGURES ................................................................................ 120
Figure 10.3.1: Reverse Cumulative Distribution Curves for Anti-CS NANP Antibody Titers in 
Each Group (ATP cohort for immunogenicity) ...................................................................... 120
Figure 10.3.2: Reverse Cumulative Distribution Curves for Anti-CS C-term Antibody Titers in 
Each Group (ATP cohort for immunogenicity) ...................................................................... 120


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Figure 10.3.3: Reverse Cumulative Distribution Curves for Anti-HBsAb Titers in Each Group 
(ATP cohort for immunogenicity)........................................................................................... 120
 
 
 
 


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ϭ͘ >/^dK&Zs/d/KE^
 
ADI
Active Detection of infection
AE
Adverse Event 
AESI 
Adverse event of special interest 
A/L 
Artemether/lumefantrine 
ALT 
Alanine aminotransferase
ATP 
According to protocol
anti-HBs 
Antibody to hepatitis B surface antigen 
AS01 
GSK s proprietary adjuvant system containing QS21, 
MPL, and liposomes 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CI
Confidence interval 
CMI 
Cell-mediated immunity 
CRF 
Case report form 
ELISA 
Enzyme-linked immunosorbent assay 
GCP 
Good Clinical Practice 
GMFRs 
Geometric Mean Fold Rises  
GMT 
Geometric Mean Titer 
CS 
Circumsporozoite protein 
DHA/Pip
Dihydroartemisinin-piperaquine 
ELISA 
Enzyme-linked immunosorbent assay 
GMT 
Geometric Mean Titer 
H0 
Null hypothesis 
H1 
Alternative hypothesis 
Hb 
Haemoglobin 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HIV
Human immunodeficiency virus
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IgG 
Immunoglobulin G 
IP 
Investigational Product 
LD PQ 
Low dose primaquine 
AESI 
Adverse Events of Special Interest 
MMRM 
Mixed Model for Repeated Measures 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIH 
National Institutes of Health 
P. falciparum 
Plasmodium falciparum 
PBMCs 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase chain reaction 


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PLT
Platelet
PT
Preferred Term 
RTS,S 
Protein comprising CS and hepatitis B surface antigen 
SAE 
Serious Adverse Event 
SAP
Statistical Analysis Plan
SOC 
System Organ Class 
TVC 
Total vaccine cohort 
VE
Vaccine efficacy 
WBC 
White blood count 
WHO 
World Health Organization


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Ϯ͘ /EdZKhd/KE
The main goal of this study is to assess the efficacy of RTS,S/AS01E, a candidate vaccine against 
malaria caused by Plasmodium falciparum, in adults positive for P. falciparum by PCR at 
baseline, but have been treated with anti-malarial medications to clear the parasite before 
receiving multiple doses of the vaccine. The goal is to overcome the reduced vaccine efficacy 
(hypo-responsiveness to the vaccine) reported in actively or chronically infected adults.     
Ϯ͘ϭ ĂĐŬŐƌŽƵŶĚĂŶĚƌĂƚŝŽŶĂůĞ
In previous clinical trials for the RTS,S/AS01E vaccine, it has been reported that the vaccine has 
been less effective in adults in endemic regions. Adults living in areas of moderate to high 
malaria transmission often have co-existing asymptomatic circulating blood stage P. falciparum 
parasites that results from multiple exposures to infective mosquito bites.  This has been 
recognized as inducing a level of immunologic hypo-responsiveness that may impede the 
development of a protective immune response following immunization. We hypothesize that 
treatment of malaria infection in individuals prior to immunization with the RTS,S/AS01 vaccine 
will reset the immune response to the vaccine and result in an increased vaccine efficacy.
The rationale of the trial is to compare the vaccine efficacy of RTS,S/AS01E in two groups of 
adults who differ with the presence/absence of baseline PCR-positive parasitemia. Both groups 
receive the same anti-malarial treatment to clear parasites or to prevent infection (prophylaxis) 
prior to immunization. A rabies comparator vaccine (Abhayrab) is administered to two parallel 
groups to assess the absolute vaccine efficacy (VE) against P. falciparum parasitemia and to 
investigate whether sub-optimal immune responses in previously infected or concurrently 
infected adults is a general phenomenon independent of the vaccine antigen.    
Ϯ͘Ϯ ^ƚƵĚǇKďũĞĐƚŝǀĞƐ
Ϯ͘Ϯ͘ϭ WƌŝŵĂƌǇKďũĞĐƚŝǀĞ
To evaluate the vaccine efficacy assessed by time to first P. falciparum infection in 
RTS,S/AS01E vaccinated adults who are positive for P. falciparum by PCR at baseline and 
treated to clear parasites compared to adults administered a comparator Rabies vaccine 
(Abhayrab) who are also positive for P. falciparum by PCR at baseline and treated to clear 
parasites. 
Ϯ͘Ϯ͘Ϯ ^ĞĐŽŶĚĂƌǇKďũĞĐƚŝǀĞ
Efficacy 
The secondary efficacy objective is to assess vaccine efficacy by time to first P. falciparum 
infection by PCR in RTS,S/AS01E vaccinated adults who are negative for P. falciparum at 
baseline and are provided anti-malarial chemo-prophylaxis versus the vaccine efficacy against P. 




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Table 2. The schedule of immunization and anti-malarial treatment (from protocol).  
Group
Month -
1 
Month 0 
(Vaccine 1) 
1-2 wks before 
Vx dose 2 
Month 1 
(Vaccine 2) 
1 wk before 
Vx dose 3
Month 7 
(Vaccine 3) 
Month 
8 to 14
Group 1 
DHA/Pip 
+ LD PQ 
RTS,S/AS01E 
DHA/Pip + LD 
PQ 
RTS,S/AS01E 
A/L + LD 
PQ 
1/5th dose 
RTS,S/AS01E
ADI 
Group 2 
DHA/Pip 
+ LD PQ 
RTS,S/AS01E 
DHA/Pip + LD 
PQ 
RTS,S/AS01E 
A/L + LD 
PQ 
1/5th dose 
RTS,S/AS01E
ADI 
Group 3 
- 
RTS,S/AS01E 
- 
RTS,S/AS01E 
- 
1/5th dose 
RTS,S/AS01E
- 
Group 4 
DHA/Pip 
+ LD PQ 
Rabies 
DHA/Pip + LD 
PQ 
Rabies 
A/L + LD 
PQ 
Rabies
ADI 
Group 5 
DHA/Pip 
+ LD PQ 
Rabies 
DHA/Pip + LD 
PQ 
Rabies 
A/L + LD 
PQ 
Rabies  
ADI 
 
Group 1. Subjects have detectable P. falciparum parasitemia at baseline measured by PCR. 
Anti-malarial treatment with DHA/Pip to clear asexual stage and young gametocyte parasites 
plus LD PQ to clear mature gametocytes will be given 4 weeks prior to immunization with 
RTS,S/AS01E. A 2nd course of DHA/Pip plus Primaquine will be given 2 weeks before second 
RTS,S/AS01E immunization. One week before 3rd RTS,S/AS01E immunization, a three-day 
course of A/L plus Primaquine will be administered to clear infection. 
Group 2. Subjects have no detectable P. falciparum parasitemia as measured by PCR at 
enrolment.  The same anti-malarial treatment regimen as for Group 1 will be administered before 
each dose of RTS,S/AS01E immunization as chemo-prophylaxis against P. falciparum.  
Group 3. Subjects have detectable P. falciparum parasitemia at baseline measured by PCR but 
will not receive any anti-malarial medications to clear PCR-positive parasites. This group 
includes 35 subjects and is included only for immunological assessment and not for vaccine 
efficacy.  
Group 4. Subjects have detectable P. falciparum parasitemia at baseline measured by PCR and 
will receive the same anti-malarial treatment on the same schedule as subjects in group 1. 
However, subjects in Group 4 will be administered the Abhayrab rabies vaccine instead of 
RTS,S/AS01 E.   
Group 5. Subjects have no detectable P. falciparum parasitemia as measured by PCR at 
enrolment and will receive the same anti-malarial treatment on the same schedule as subjects in 
group 2. Similarly, subjects in Group 5 will be administered the Abhayrab rabies vaccine instead 
of RTS,S/AS01 E.   
Ϯ͘ϯ͘Ϯ ^ƚƵĚǇŶĚƉŽŝŶƚƐ






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Figure 1. The schematic diagram of the randomization process for the study (from randomization plan). The 
HIV positive rate for each group are capped near 20%.  
Ϯ͘ϱ ^ĂŵƉůĞ^ŝǌĞĂŶĚWŽǁĞƌŽŶƐŝĚĞƌĂƚŝŽŶƐ
This is a Phase 2b study to assess the vaccine efficacy of RTS,S/AS01 E in adults in a malaria 
endemic region.  The statistical analysis will measure vaccine efficacy using Cox proportional 
hazards regression model (time to first PCR-positive infection). An attack rate of 40% over 6 
months has been assumed as a conservative estimate in an epidemiologic setting of perennial 
transmission in Western Kenya. A fixed vaccine efficacy of 50% is a conservative assumption 
according to the estimated vaccine efficacy. 
Using an event-based design and assuming 10% drop out of the enrolled population and a one-
table lists the power and required number of events to conduct the 
analysis. 


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Table 3. Sample Size Calculations (from protocol) 
Power 
N to enroll per 
group
Total events 
required to 
conduct 
analysis
Endpoint
90% 
164 
92 
Primary (Group 1 vs 4) 
80%
128
72
Secondary (Group 2 vs 5)
 
The impact of the event-driven design is that the study will continue to follow up until 92 first 
PCR-positive infection events, subsequently referred to as events, have been observed in 
aggregate between Groups 1 and 4, and 72 events have been observed in the aggregate of Groups 
2 and 5. If the aggregate numbers of events have been reached prior to 24 weeks of ADI, study 
actives will continue to occur through the end of the ADI. If the aggregate number of events 
during ADI does not reach the cutoff indicated in Table 3, then the ADI will be extended up to 
48 weeks or until the total number of events is reached, whichever occurs first. This will require 
the PCR lab to provide timely aggregated reports of event counts (across Group 1 plus 4; and 
Group 2 plus 5) and may result in more than the required events for either the primary or 
secondary endpoint. 
An additional cross-sectional PCR will be performed at the Study Termination Visit, but these 
PCR results will not count toward the study endpoints.  
Based on these assumptions we estimate a greater than 90% probability of observing the required 
number of events for the primary and secondary analyses by 6.9 months. However, larger 
dropout rates and/or a lower attack rate might extend the amount of follow-up time necessary to 
accumulate the required number of events. 
The sample size for the immunologic sub-cohort (CMI assays in all subjects in RTS,S/AS01 E 
groups 1, 2, and 3) is based on logistical considerations and the feasibility of the collection and 
processing of PBMCs. Analysis of these exploratory endpoints and inter-group differences will 
be descriptive in nature.


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ϯ͘ 'EZ>KE^/Zd/KE^&KZdE>z^^
ϯ͘ϭ ^ƚĂƚŝƐƚŝĐĂů,ǇƉŽƚŚĞƐĞƐ
The primary and secondary hypotheses will be assessed using Cox proportional hazards 
regression (time to first PCR-positive infection).  These hypotheses tests will be supplemented 
with two-sided confidence intervals for the hazard ratios as described below. 
The null (H0) and alternative (H1) hypotheses for the primary analysis of time to first malaria 
infection in Groups 1 and 4 is as follows: 
H0: Among adults positive for P. falciparum at baseline the hazard rate for first malaria 
infection for RTS,S/AS01E vaccinated adults (Group 1) is not different than that of adults 
administered the comparator rabies vaccine (Group 4) as measured by the hazard ratio. 
H1: Among adults positive for P. falciparum at baseline the hazard rate for malaria 
infection for RTS,S/AS01E vaccinated adults (Group 1) is different than that of adults 
administered the comparator rabies vaccine (Group 4) as measured by the hazard ratio. 
The null and alternative hypotheses for the secondary efficacy analysis of time to first malaria 
infection in Groups 2 and 5 is as follows: 
H0: Among adults negative for P. falciparum at baseline the hazard rate for malaria 
infection for RTS,S/AS01E vaccinated adults (Group 2) is not different than that of adults 
administered the comparator rabies vaccine (Group 5) as measured by the hazard ratio. 
H1: Among adults negative for P. falciparum at baseline the hazard rate for first malaria 
infection for RTS,S/AS01E vaccinated adults (Group 2) is different than that of adults 
administered the comparator rabies vaccine (Group 5) as measured by the hazard ratio. 
ϯ͘Ϯ ĞĨŝŶŝƚŝŽŶŽĨWŽƉƵůĂƚŝŽŶƐƚŽďĞŶĂůǇǌĞĚ;ŶĂůǇƐŝƐĂƚĂƐĞƚƐͿ
ϯ͘Ϯ͘ϭ ŶƌŽůůĞĚƉŽƉƵůĂƚŝŽŶ
All subjects who have provided writte
randomization, and vaccination status in the study. 
ϯ͘Ϯ͘Ϯ dŽƚĂůǀĂĐĐŝŶĂƚĞĚĐŽŚŽƌƚ;dsͿ
All subjects in the enrolled population who are randomized and received at least one vaccination. 
ϯ͘Ϯ͘ϯ ^ĂĨĞƚǇĂŶĂůǇƐŝƐƉŽƉƵůĂƚŝŽŶ
All subjects in the TVC for which any safety data is available. All safety analyses will be 
performed using this population. The denominators for different safety endpoints may vary 
according to the number of subjects with available data for the specific endpoint.   
 


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ϯ͘Ϯ͘ϰ ĐĐŽƌĚŝŶŐƚŽƉƌŽƚŽĐŽů;dWͿĐŽŚŽƌƚĨŽƌĞĨĨŝĐĂĐǇ
The ATP cohort for efficacy will include all subjects included in the TVC with no major protocol 
deviations that are determined to potentially interfere with the efficacy assessment of the study 
vaccine and contributed to the time at risk starting 7 days after the third dose. The membership in 
this study population will be determined in a blinded fashion at a data review meeting attended 
by the sponsor Medical Officer, the site PI/Co-PI, and the sponsor Statistician. The list of criteria 
used to exclude subjects from ATP, including anti-malarial administration and other relevant 
analysis protocol deviations, will be finalized before database freeze. The details can be found in 
the Note to File (NTF) from the meeting.
ϯ͘Ϯ͘ϱ dŽƚĂůĐŽŚŽƌƚĨŽƌĞĨĨŝĐĂĐǇ
Given the potential for some participants to receive COVID-19 vaccine during the study, an 
additional total efficacy cohort is defined to include all TVC subjects who receive all three doses 
of RTS,S/AS01E vaccine or comparator and contribute to time at risk starting 7 days after the 
third dose. 
ϯ͘Ϯ͘ϲ dWĐŽŚŽƌƚĨŽƌŝŵŵƵŶŽŐĞŶŝĐŝƚǇ
The ATP cohort for immunogenicity will include all subjects included in the TVC with no major 
protocol deviations that are determined to potentially interfere with the immunogenicity 
assessment of the study vaccine. This population will serve as the primary analysis population 
for the immunogenicity endpoints. The population will be adapted by time point to include all 
eligible 
 data up to the time of disqualifying protocol deviation. The criteria used to 
exclude subjects from this cohort will include but not limited to: performed blood samplings for 
immunogenicity according to protocol intervals; did not use any medication or blood products 
forbidden by the protocol; did not have any reported underlying medical condition influencing 
immune responses. Similarly, the membership in this study population will be determined in a 
blinded fashion at a data review meeting attended by the sponsor, investigator, and DFnet and 
finalized before database freeze. The details can be found in the Note to File (NTF) from the 
meeting.  
ϯ͘ϯ dŝŵĞtŝŶĚŽǁĨŽƌŶĂůǇƐŝƐ
Study day will be calculated as the actual date minus date of the first dose of vaccine (Day 1) + 1 
and will be used to show start/ stop day of assessments and events. If the event date is partial or 
missing, the corresponding study day and study duration will appear partial or missing in the 
listings. 
 
Study day is defined to account for potential deviation from the visit schedule and unscheduled 
visits, all by-visit summary tables, unless otherwise specified, will be based on analysis visits, 
which will be assigned based on time window around the scheduled visit days below. However, 
listings will include all scheduled, unscheduled, retest and early withdrawal data. In general: 


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 unscheduled measurements will not be included if they do not fall within the analysis 
window listed below, but will contribute to the baseline value, or best/worst case value 
where required (e.g. shift table).
 for retest measurements (with same visit number assigned or fall within the same time 
window as another measurement), the last available measurement for that visit will be used 
with the exception for ADI visits where the first result will be used.  
 early withdrawal data will be mapped to the next available visit number. 
 
The following general time windows will be used: 

Table 4. Time windows for Analysis 
Scheduled time point
Study Day Window
Visit 2 
Day -29 to -25 
Visit 5 
Day -3 to 4 
Visit 7 
Day 8 to 10 
Visit 11 
Day 26 to 32 
Visit 12 
Day 36 to 38 
Visit 13 
Day 54 to 60 
Visit 14 
Day 188 to 192 
Visit 17 
Day 194 to 200 
Visit 18 
Day 204 to 206 
Visit 19 
Day 208 to 214 
Visit 20 
Day 221 to 229 
Visit 21 
Day 242 to 250 
Visit 22 
Day 263 to 271 
Visit 23 
Day 284 to 292 
Visit 24 
Day 305 to 313 
Visit 25 
Day 326 to 334 
Visit 26 
Day 347 to 355 
Visit 27 
Day 368 to 376 
Visit 28 
Day 389 to 397 
Visit 29 
Day 410 to 418 
Visit 30 
Day 431 to 439 
Visit 31 
Day 452 to 460 
Visit 32 
Day 473 to 481 
Visit 33 
Day494 to 502 
Visit 34 
Day 514 to 523 
Visit 35 
Day 536 to 544 


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ϯ͘ϰ
DŝƐƐŝŶŐĂƚĂĂŶĚKƵƚůŝĞƌƐ
ϯ͘ϰ͘ϭ DŝƐƐŝŶŐĂƚĂ
Non-missing ELISA data are considered validated. Missing ELISA data are considered non-
retrievable. They will not be imputed and will be analyzed as if they were randomly missing. For 
subjects who discontinue from the study, their immunogenicity data collected before 
discontinuation will be analyzed under the analysis populations as applicable. 
If severity or relationship to the IP administration for a reported AE or serious adverse event 
(SAE) is missing, an 
 If a start or stop date 
associated with a reported concomitant medication, AE, or SAE is incomplete or missing, the 
following rules will be applied:  
 
If the day of the start date is missing and the month and year of the start date are known, compare the start 
month and year to the month and year of visits 1  3.  If the start month and year match exactly one of visits 
1  3, then use the day of the date of that matched visit; otherwise use the 15th day of the month. 
 
If either month or year is missing, no imputations will be done.   
If stop date for a concomitant medication/medical history (AE or SAE) is missing, the 
medication/medical history will be considered ongoing. 
If the study termination date is missing, it will not be imputed.
ϯ͘ϰ͘Ϯ KƵƚůŝĞƌƐ
Graphic inspection for outliers will be performed. No data will be excluded from the primary and 
secondary analyses, including any outliers. All transformations of the study data will be pre-
specified.  
ϯ͘ϱ ĂƚĂ,ĂŶĚůŝŶŐŽŶǀĞŶƚŝŽŶƐĂŶĚdƌĂŶƐĨŽƌŵĂƚŝŽŶƐ
The antibody titers will be transformed using log10 transformation for geometric mean analyses. 
Data will be back transformed to the original scale for presentation. 
ϯ͘ϲ ^ƚĂƚŝƐƚŝĐĂů^ƵŵŵĂƌŝĞƐ͕ŽŶĨŝĚĞŶĐĞ/ŶƚĞƌǀĂůƐĂŶĚWǀĂůƵĞƐ
Continuous data will be summarized by vaccination group with number of observations (n), 
mean, standard deviation (SD), median, Interquartile range, minimum, and maximum; 
Categorical results will be summarized by number of participants (n) and percentage (%) of 
subjects per vaccination group and visit. Unless otherwise specified, all statistical tests will be 
two-sided with a significance level of 0.05 and a 95% CI will be provided for estimates, as 
appropriate. 


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ϯ͘ϳ DƵůƚŝƉůĞŽŵƉĂƌŝƐŽŶƐͬDƵůƚŝƉůŝĐŝƚǇ
No multiplicity adjustments will be performed. 
ϯ͘ϴ /ŶƚĞƌŝŵŶĂůǇƐŝƐĂŶĚ&ŝŶĂůŶĂůǇƐŝƐ
There is no planned interim analysis for the study.  
A final analysis on all efficacy, safety and immunogenicity data will be performed after the study 
visit and the database is cleaned and locked. 
ϯ͘ϵ ^ƚĂƚŝƐƚŝĐĂů^ŽĨƚǁĂƌĞ
All statistical analyses will be performed using SAS® software version 9.4 or later. 
 
 


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ϰ͘ ^h:d/^WK^/d/KE
ϰ͘ϭ ^ƵďũĞĐƚŶƌŽůůŵĞŶƚ
Expected and actual subject enrollment will be tabulated by study group. The number and 
proportion of screened subjects meeting and not meeting entry criteria will also be tabulated. 
ϰ͘Ϯ ŝƐƉŽƐŝƚŝŽŶŽĨ^ƵďũĞĐƚƐ
Subject disposition will be summarized by study group. The following information will be 
tabulated. Summaries of subject disposition will be prepared for all subjects, including the 
number and percent enrolled, screened, randomized, and administered antimalarials and vaccines 
[T.10.1.1, L.10.1.2], as well as a CONSORT diagram [F.10.1.1] describing study participation 
and discontinuation. The reasons for screen failures, discontinuations, and population exclusions 
will be summarized and listed [T.10.1.5, L.10.1.1]. 
ϰ͘ϯ ůŝŐŝďŝůŝƚǇƌŝƚĞƌŝĂ
The inclusion and exclusion criteria used for screening in this study are listed in the protocol. 
The subjects excluded from the study for failing each inclusion/exclusion criteria and exclusion 
criteria will be listed and summarized [T.10. 1.2, L.10.1.3]


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ϱ͘ ^h:d,ZdZ/^d/^E,ZE
ϱ͘ϭ ĂƐĞůŝŶĞĞŵŽŐƌĂƉŚŝĐƐĂŶĚŚĂƌĂĐƚĞƌŝƐƚŝĐƐ
Baseline demographics and characteristics, including age, height, weight, BMI, sex, race, and 
HIV status will be summarized for the TVC, total efficacy cohort and per protocol populations 
by vaccination group using descriptive statistics (mean, standard deviation, median, interquartile 
range, minimum and maximum for continuous features and rates for categorical features). 
[T.10.1.3, L.10.1.4] 
Medical history will be tabulated by Medical Dictionary for Regulatory Activities (MedDRA 
v23) System Organ Class (SOC), Preferred Term (PT) and vaccination group. For the TVC 
population, medical history will be listed and summarized by category [T.10.1.6, L.10.1.9]. 
Using the World Health Organization (WHO, version: Mar2020) Drug Dictionary, prior and 
concomitant medications will be tabulated by anatomical therapeutic chemical (ATC) 
classification, preferred drug name and vaccination group [T.10.1.9, T.10.1.10, L.10.1.7, 
L.10.1.8]. 
ϱ͘Ϯ ^ƵďũĞĐƚŚĂƌĂĐƚĞƌŝƐƚŝĐƐĂƚĂĐŚsŝƐŝƚ
Vital signs [T.10.1.7] and physical exam results [T.10.1.8] collected at other visits will be 
summarized for the TVC, total cohort for efficacy and per protocol populations by vaccination 
group. 
Listings of vital signs [L.10.1.13] and physical exam results [L.10.1.14] at each applicable time 
point will be provided at participant-level. 
ϱ͘ϯ sŝƐŝƚĂŶĚsĂĐĐŝŶĂƚŝŽŶĚŚĞƌĞŶĐĞ͕^ĂŵƉůĞǀĂŝůĂďŝůŝƚǇ
A summary and listing of visit attendance [T.10.1.13.1-3, L.10.1.10.1-3] will be prepared, in 
addition to a summary and listing of vaccine administration and sample collection/availability for 
each sample [T.10.1.11, L.10.1.11]. 
ϱ͘ϰ
ŶƚŝͲDĂůĂƌŝĂůŽŵƉůŝĂŶĐĞ
The detailed information on the administration of three anti-malarials used in this study will be 
listed for the SAF population, including number of tablets dispensed, number of tablets returned, 
date, time, and compliance of dosing. Furthermore, since anti-malarial treatment does not allow 
for missed doses, their compliances will be listed by visits and summarized as the number and 
percentage of participants who have missed at least one dose of anti-malarials [T.10.1.12, 
L.10.1.12].   
ϱ͘ϱ WƌŽƚŽĐŽůĞǀŝĂƚŝŽŶƐ
A summary and listing of protocol deviations will be prepared [T.10.1.5, L.10.1.1]. 
 


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ϲ͘ E>z^/^K&d,WZ/DZz&&/zEWK/Ed
Vaccine efficacy against the first PCR-positive P. falciparum infection among adults who were 
P. falciparum positive at baseline will be assessed using Cox proportional hazards regression 
model with a covariate for group assignment to compare Groups 1 and 4. Specifically, the 
elapsed time starting 7 days after the third vaccination to the first PCR-positive P. falciparum 
detection or censoring will be analyzed. Time at risk will be presented as person years at risk 
(PYAR) dividing the days at risk by 365.25. As HIV status is a stratification factor in the 
randomization, it will be also included as covariate. An exploratory analysis, including Age, 
Gender and other baseline features might also be included as stratifications for the model if there 
is a randomization imbalance. Listing of FIEs and parasitemia testing results during ADI will be 
provided [L10.4.1 and L10.4.2].  
The vaccine efficacy estimates (1-hazard ratio), 95% CI, and p-values will be calculated from 
this model using the Wald test. Ties will be handled using the Efron method [T.10.2.1]. In 
addition, tests and graphs based on the scaled Schoenfeld residuals will be used to assess the 
proportional hazard assumption [F10.2.5]. The interaction between HIV status and group 
assignment will be evaluated using a Wald test. 
Descriptive statistics for each vaccination group and visit, the number of subjects at risk, person-
time, number of PCR-confirmed first P. falciparum events and incidence rate will be tabulated 
[T.10.2.5]. The censoring rules are summarized in table 5. Similar tables will describe the 
median time-to-event and accumulative hazard from the cox regression model [T.10.2.7]. 
Survival curves for each vaccine group will be calculated non-parametrically, tabulated and 
presented graphically overall and by HIV status using the Kaplan-Meier method [F10.1.1-2]. 
This analysis will be conducted using both the ATP cohort for efficacy and the total cohort for 
efficacy. 
 
 


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ϳ͘ E>z^/^K&d,^KEZzEWK/Ed;^Ϳ
ϳ͘ϭ ^ĞĐŽŶĚĂƌǇĨĨŝĐĂĐǇ
Vaccine efficacy against the first PCR-positive P. falciparum infection among adults who were 
P. falciparum negative at baseline will be assessed using Cox proportional hazards regression 
with a covariate for group assignment to compare Groups 2 and 5. Similarly, HIV status, age, 
gender and other features might also be included as stratifications for the model. The vaccine 
efficacy estimates (1-hazard ratio), 95% CI, and p-values will be calculated from this model 
using the Wald test. Ties will be handled using the Efron method [T.10.2.2].
Table 5. Censoring rules 
Situation 
Censoring Rules 
The FIEs for Groups 1&4 and 2&5 reached in Epoch 2 
The entire period of epoch 2 (1st ADI period) 
The FIEs for Groups 1&4 and 2&5 reached in Epoch 3 
The visit when the number of FIEs for both groups 
reached their targets during 2nd ADI period 
The FIEs for Groups 1&4 and 2&5 did not reach at the 
end of Epoch 3 
The entire period of epoch 2 and 3 (1st and 2nd ADI 
period) 
Early withdrawal 
The last visit available 
Subjects treated with non-protocol anti-malarial during 
either ADI period 
The last visit before anti-malarials were administration
 
Similar descriptive statistics table as in the primary efficacy endpoint will be provided, as well as 
a table for median time to event and accumulative hazard and the Kaplan-Meier survival curves 
for each vaccination group overall and stratified by HIV status [T.10.2.6, T.10.2.7, F.10.2.3-4]. 
And this analysis will be conducted using both the ATP cohort for efficacy and the total cohort 
for efficacy. 
ϳ͘Ϯ /ŵŵƵŶŽŐĞŶŝĐŝƚǇ
There are two antibodies, anti-CS, an antibody against both central repeat region (NANP) and C-
terminal region of circumsporozoite protein, and anti-HBs (against hepatitis B surface protein), 
will be included in antibody response analysis of secondary immunogenicity endpoints for 
Groups 1-3 (Table 6). The antibody titer and avidity against the NANP or C-terminal of CS 
protein will be analyzed for visits 2, 5, 11, 13, 17, 20, 27 and 35. Anti-HBs antibody titer will be 
analyzed for visits 2, 5, 11 and 20. The analysis will be based on the ATP for immunogenicity 
cohort unless a significant number of subjects have missing data (>10%), then a secondary 
analysis based on the TVC will be performed to complement the ATP analysis. For estimation of 
the geometric mean titer (GMT), geometric mean ratio (fold increases), and corresponding 
confidence limits, analyses will incorporate censoring where appropriate and log-scale 
coefficients will be back-transformed in order to compute the estimate and corresponding 
confidence limits for the relevant quantity.  
To calculate the fold increases in the antibody titer, an ELISA titer for a given sample being 
tested for anti-CS antibody levels will be considered seropositive if its value is greater than the 
following Lower Limit of Quantifications (LLOQs): anti-CS NANP (1XPBS) 54.1 1/DIL, anti-
CS NANP (4M UREA) 37.9 1/DIL, anti-CS C-Term (1XPBS) 89.4 1/DIL, anti-CS C-term (4M 
UREA) 37.5 1/DIL. ELISA titers for the anti-HBs antibody will be considered positive if its 
value is greater than 10 mIU/mL. Samples that do not generate above or equal to the cut-offs will 
be reported as LLOQ for analysis purposes. Geometric Mean Fold Rises (GMFRs) will be 
computed using standard two-sample methods for the log difference of the within-subject 
increase from baseline, with corresponding CIs computed via t-distribution, utilizing the antilog 
transformation to present the ratio. Analyses of binary variables will include 95% CIs computed 
via the Clopper-Pearson method, and antibody response rates between each other among Groups 
1-3 will be compared using eith
-square test.  Furthermore, at each 
visit, GMT will be compared among groups 1, 2 and 3 by a mixed model for repeated measures 
with the log-transformed  antibody titer as dependent variable, groups, HIV status and their 
interaction term as covariates and subject as a random effect. Compound symmetry will be 


Protocol No. CVIA-078; RTS,S/AS01 E  
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assumed for the covariance structure. The comparison of the ratios of GMT (estimated treatment 
differences between groups at all post baseline visits) will be estimated from a similar mixed 
model for repeated measures.  
 
Table 6. Sampling Visits for Immunogenicity Assessment (from Appendix F of protocol) 
SAMPLES 
COLLECTED FOR 
IMMUNOGENICITY 
Visit # 
2 
5 
6 
7
11
13
17
20
27
Termination 
Visit 
Study day 
-27 
1 
2 
8
29
57
197
225
372
TBD* 
Secondary endpoint -
Groups 1, 2, 3 
  
  
  
  
  
  
  
  
  
  
  
Serum 
anti-CS NANP 
levels 
 
 
  
  
 
 
 
 
anti-CS NANP 
avidity 
 
 
  
  
 
 
 
 
anti-CS C-term 
levels 
 
 
  
  
 
 
 
 
anti-CS C-term 
avidity 
 
 
  
  
 
 
 
 
anti-HbsAb 
antibodies 
 
 
  
  
 
  
 
  
  
 
The number and proportion of subjects exhibiting positive responses and their GMTs will be 
assessed for each antigen (anti-CS NANP or anti-CS C-term) and conditions (1XPBS or 4M 
Urea), including the number and proportion exhibiting a seroresponse (defined as a positive 
response among subjects negative at baseline) [T.10.3.1-3]. Individual fold increases will be 
listed and summarized as GMFRs by vaccination 
4-fold rises in their antibody titers will also be listed individually by visits and summarized by 
vaccination groups and visits [T.10.3.4-6]. Additionally, the distribution of antibody titers 
against three antigens will be summarized using reverse cumulative distribution curves [F.10.3.1-
3]. A listing of titer values will also be included [L.10.3.1]. 
ϳ͘ϯ ^ĂĨĞƚǇŶĂůǇƐĞƐ
ϳ͘ϯ͘ϭ ĞĨŝŶŝƚŝŽŶ
Solicited Adverse Event  
Solicited AEs are pre-specified local and systemic AEs that occur relatively more frequently or 
are known to be associated with immunization, which are monitored actively as potential 
indicators of vaccine reactogenicity. The following specific solicited local and systemic AEs and 
their intensity scales will be monitored for this study and listed in Table 7: 
Table 7. Intensity Scales for Solicited Symptoms in Adults 
Pain at injection site 
0 
Absent 
1 
Painful on touch
2 
Painful when limb is moved
3 
Pain that prevents normal activity 
Swelling at injection site 
0 
Absent 
1 
Present and is easily tolerated 
2 
Present and interferes with normal activity 
3 
Present and prevents normal activity 
Fever 
0 
<37.5oC (99.5oF) 
1 
37.5oC (99.5oF) to 38.0oC (100.4oF) 
2 
>38.0oC (>100.4oF) to 39.0oC (102.1oF) 
3 
>39.0oC (102.1oF) 
Headache 
0 
Normal 
1 
Headache feeling is easily tolerated 
2 
Headache feeling interferes with normal activity 
3 
Headache feeling prevents normal activity
0 
Gastrointestinal symptoms normal 
1 
Gastrointestinal symptoms that are easily tolerated 
2 
Gastrointestinal symptoms that interfere with normal activity


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Gastrointestinal symptoms 
3 
Gastrointestinal symptoms that prevent normal activity
Fatigue 
0 
Normal 
1 
Fatigue that is easily tolerated 
2 
Fatigue that interferes with normal activity
3 
Fatigue that prevents normal activity
Muscle ache 
 
0 
Absent 
1 
Muscle ache that is easily tolerated 
2 
Muscle ache that interferes with normal activity 
3 
Muscle ache that prevents normal activity
 
Unsolicited Adverse Events  
Unsolicited AEs are any AEs reported spontaneously by the subject, observed by the study staff 
during study visits or those identified during review of medical records or source documents. 
Solicited AEs with an onset after the seven-day solicitation period will be considered unsolicited 
AEs. In the absence of a diagnosis, abnormal physical examination findings or abnormal clinical 
safety laboratory test results that are assessed by the investigator to be clinically significant will 
be recorded as an AE. 
Adverse Events of Special Interest 
AESIs are unsolicited AEs of specific interest for safety monitoring include all seizures 
occurring within 30 days post-vaccination, meningitis and potential immune-mediated diseases 
(pIMDs). The full list of pIMDs can be found in the protocol.  
Serious Adverse Event  
An SAE is any AE that results in any of the following outcomes: 
 
Death 
 
Is life-threatening (i.e., the subject was, in the opinion of the investigator, at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more severe) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
 
Congenital anomaly or birth defect 
 
Important medical event that may not result in one of the above outcomes but may jeopardize the health of 
the study subject or may require medical or surgical intervention to prevent one of the outcomes listed 
above 
ϳ͘ϯ͘Ϯ ŶĂůǇƐŝƐŽĨ^ĂĨĞƚǇŶĚƉŽŝŶƚƐ
All safety assessments will take place using the safety analysis population, according to the 
vaccination groups. All subject-based percentages (solicited/unsolicited AEs, clinical safety 
laboratory abnormalities, etc.) will be supplemented with two-sided 95% CIs computed via the 
Clopper-Pearson method. Individual summaries (denominators for percentages) will be limited 
to the number of subjects within the appropriate analysis population with data available for 
analysis for the given endpoint. When an AE occurs more than once for a subject, the subject 
will be only counted once for the corresponding PT according to the maximum severity of the 
events. 
The overall safety profile for overall and each group will be summarized by the number of all 
solicited adverse events, the frequencies of local and systemic adverse events among them, the 
number of unsolicited events, the number and the percentages of subjects with any unsolicited 
adverse events, the number of adverse events of special interest, the number and the percentages 
of subjects with any adverse events of special interest, the number of adverse events, the number 
and the percentages of subjects with any adverse events [T.10.4.1.1].  
All solicited AEs will be summarized according to defined severity grading scales. Frequencies 
and percentages of subjects experiencing each solicited AE will be presented for each symptom 
severity [T.10.4.1.2-3, T.10.4.1.7-8]. Summary tables showing the occurrence of any local or 
systemic solicited AE overall and solicited AEs that persist up to 7 days post-administration of 
IP overall will also be presented [T.10.4.1.12]. Data listings of all solicited AEs will be provided 


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by subject [L.10.2.1]. For common AEs group comparisons, including each preferred terms, 
frequency of signs and symptoms and the occurrences of Grade 4 solicited and unsolicited 
T.10.4.1.13]. In addition 
to safety population, these analyses will be also performed using the TVC analysis population. 
All unsolicited AEs with onset occurring up to 28 days after each vaccine dose will be assessed 
as either related or not related to IP by the investigator and will be recorded. Additionally, all 
AESIs/SAEs throughout the study will be summarized [T.10.4.1.6, T10.4.1.9]. The original 
verbatim terms used by investigators to identify AEs in the eCRFs will be mapped to PTs using 
MedDRA. The AEs will then be grouped by MedDRA PTs into frequency tables according to 
SOC. All reported AEs, as well as AEs assessed by the investigator as related to IP, will be 
summarized according to SOC, PT within SOC, and severity [T.10.4.1.4-5]. Data listings sorted 
by subject will be provided [L.10.2.2]. 
A summary table [T.10.4.1.10] will be prepared for unsolicited AEs comprised of the following 
categories: 
 
Unsolicited AEs 
 
Related unsolicited AEs 
 
AESIs 
 
Related AESIs 
 
SAEs 
 
Related SAEs 
 
SAEs leading to death 
 
Unsolicited AEs leading to subject discontinuation 
An additional summary table will be provided including all AEs excluding SAEs, i.e., all 
solicited, unsolicited, and AESIs [T.10.3.1.18]. A descriptive summary of recurrent AEs 
[T.14.3.1.11] will also be generated. Listings of AESIs and SAEs sorted by subject will also be 
provided [L.10.2.3-4] 
For clinical safety laboratory data collected on the same day of the first dose of vaccination, 
individual hemoglobin, WBC count, platelet count, ALT, and creatinine values will be presented 
as number of subjects out of range (above and below normal range as appropriate) and tabulated 
by study group [T.10.4.1.14]. In addition, summary statistics of the lab result values will be 
presented, including mean, standard deviation (SD), 95% CIs, median, and interquartile range 
[T.10.4.1.15]. A listing of lab results will also be included [L.10.2.5]. 
Hemoglobinopathy test result at screening and urine pregnancy test results at screening, Visit 2, 
5, 8 and 17, will also be listed [L.10.2.6-7] and summarized by overall and each group 
[T.10.4.1.16-17].  
 
 




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ϵ͘ >/^dK&d>^͕>/^d/E'^E&/'hZ^
Table 10.1.1 
Enrollment Status by Group 
Table 10.1.2 
Summary of eligibility criteria  
Table 10.1.3 
Summary of Demographics by Treatment (TVC, total cohort for efficacy and Per 
Protocol Population)  
Table 10.1.4 
Summary of HIV Status and HLA Typing by Treatment (TVC, total cohort for efficacy 
and Per Protocol Population)  
Table 10.1.5 
Protocol Deviations  
Table 10.1.6 
Medical History  
Table 10.1.7 
Vital Signs  
Table 10.1.8 
Physical Examination  
Table 10.1.9 
Prior Medications 
Table 10.1.10 
Concomitant Medications  
Table 10.1.11 
Vaccine Administration 
 
Table 10.1.12 
Anti-Malarial Compliance  
Table 10.1.13.1 
Visit Attendance (Epoch 1) 
 
Table 10.1.13.2 
Visit Attendance (Epoch 2) 
 
Table 10.1.13.3 
Visit Attendance (Epoch 3) 
 
Table 10.2.1.1 and 2  
Vaccine efficacy (Group 1 vs Group 4): First Infection Events (FIEs) of P. falciparum 
during the Active Detection of Infection period by HIV status and overall (ATP cohort 
for efficacy and total cohort for efficacy) 
Table 10.2.2.1 and 2  
Vaccine efficacy (Group 2 vs Group 5): First Infection Events (FIEs) of P. falciparum 
during the Active Detection of Infection period by HIV status and overall (ATP cohort 
for efficacy and total cohort for efficacy) 
Table 10.2.3.1 and 2  
Vaccine efficacy (Group 1 vs Group 2): First Infection Events (FIEs) of P. falciparum 
during the Active Detection of Infection period by HIV status and overall (ATP cohort 
for efficacy and total cohort for efficacy) 
Table 10.2.4.1 and 2  
Vaccine efficacy (Group 4 vs Group 5): First Infection Events (FIEs) of P. falciparum 
during the Active Detection of Infection period by HIV status and overall (ATP cohort 
for efficacy and total cohort for efficacy) 
Table 10.2.5.1 and 2  
Summary of subjects at risk, person-time, number of FIEs and incidence rate (ATP 
cohort for efficacy and total cohort for efficacy) for Group 1 and 4   
Table 10.2.6.1 and 2  
Summary of subjects at risk, person-time, number of FIEs and incidence rate (ATP 
cohort for efficacy and total cohort for efficacy) for Group 2 and 5  
Table 10.2.7.1 and 2  
Summary of median time to FIEs and hazard rates (ATP cohort for efficacy and total 
cohort for efficacy) 
Table 10.3.1.1 and 2  
Number and Percentage of Subjects with anti-CS NANP Antibody Titer/Avidity Equal 
to or above Cut-off (seropositive) and GMTs (ATP cohort for immunogenicity and 
Total vaccinated cohort) 
Table 10.3.2.1 and 2  
Number and Percentage of Subjects with Anti-CS C-term Antibody Titer/Avidity Equal 
to or above Cut-off and GMTs (ATP cohort for immunogenicity and Total vaccinated 
cohort) 
Table 10.3.3.1 and 2  
Number and Percentage of Subjects with Anti-HBsAb Titer Equal to or above Cut-off 
and GMTs (ATP cohort for immunogenicity and Total vaccinated cohort) 
Table 10.3.4.1 and 2 
Geometric Fold Rise in Anti-CS NANP Antibody Titer at Each Post-Vaccination 
Timepoint Compared to Screening (ATP cohort for immunogenicity and Total 
vaccinated cohort) 
Table 10.3.5.1 and 2 
Geometric Fold Rise in Anti-CS C-term Antibody Titer at Each Post-Vaccination 
Timepoint Compared to Screening (ATP cohort for immunogenicity and Total 
vaccinated cohort) 
Table 10.3.6.1 and 2 
Geometric Fold Rise in Anti-HBsAb Titer at Each Post-Vaccination Timepoint 
Compared to Screening (ATP cohort for immunogenicity and Total vaccinated cohort) 
Table 10.4.1.1 
Overall Safety Profile by Treatment (Safety Population)  
Table 10.4.1.2 
Frequency of Local Solicited Adverse Events by Treatment and Severity (Safety 
Population)  
Table 10.4.1.3 
Frequency of Systemic Solicited Adverse Events by Treatment and Severity (Safety 
Population)  
Table 10.4.1.4 
Summary of Unsolicited Adverse Events by Treatment (Safety Population)  
Table 10.4.1.5 
Summary of Unsolicited Adverse Events by Treatment, Severity and Relationship to 
Study Treatment (Safety Population) 
 
Table 10.4.1.6 
Summary of Serious Adverse Events by Treatment (Safety Population)  
Table 10.4.1.7 
Frequency of Local Solicited Adverse Events by Treatment, Injection Period, and 
Severity (Safety Population) 
 
Table 10.4.1.8 
Frequency of Systemic Solicited Adverse Events by Treatment, Injection Period, and 
Severity (Safety Population) 
 
Table 10.4.1.9 
Summary of Adverse Events of Special Interest by Treatment (Safety Population) 
Table 10.4.1.10 
Summary of Adverse Events (Safety Population) 
Table 10.4.1.11 
Summary of Recurrent Adverse Events (Safety Population) 
 
Table 10.4.1.12 
Summary of Adverse Events that Persisted beyond 6 Days Post-IP Administration 
(Safety Population) 
47 


Protocol No. CVIA-078; RTS,S/AS01 E  
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Table 10.4.1.13 
Exploration of Group Comparisons for Common Adverse Events (Safety Population) 
Table 10.4.1.14 
Safety Lab Data out of Range (Safety Population) 
 
Table 10.4.1.15 
Summary of Safety Lab Results (Safety Population)  
Table 10.4.1.16 
Summary of Hemoglobinopathy Results (Safety Population)  
Table 10.4.1.17
Summary of Urine Pregnancy Test Results (Safety Population)
Table 10.4.1.18 
Summary of All Non-Serious Adverse Events by Treatment (Safety Population)  
Listing 10.1.1 
Protocol Deviations  
Listing 10.1.2 
Enrollment Status, Demographics and Subject Disposition 
Listing 10.1.3 
Eligibility Criteria Not Met 
 
Listing 10.1.4 
Listing of All Eligibility Criteria 
 
Listing 10.1.5 
Baseline Demographics 
 
Listing 10.1.6 
HIV Status and HLA Typing  
Listing 10.1.7 
Prior Medications 
Listing 10.1.8 
Concomitant Medication  
Listing 10.1.9 
Medical History  
Listing 10.1.10.1 
Visit Attendance (Epoch 1) 
 
Listing 10.1.10.2 
Visit Attendance (Epoch 2) 
 
Listing 10.1.10.3 
Visit Attendance (Epoch 3) 
 
Listing 10.1.11 
Vaccine administration 
 
Listing 10.1.12 
Anti-Malarials 
 
Listing 10.1.13 
Vital Signs  
Listing 10.1.14 
Physical Examinations 
 
Listing 10.2.1 
Solicited Adverse Events (Safety Population) 
 
Listing 10.2.2 
Unsolicited Adverse Events (Safety Population)  
Listing 10.2.3 
Serious Adverse Events (Safety Population)  
Listing 10.2.4 
Adverse Events of Special Interest (Safety Population) 
 
Listing 10.2.5 
Safety Laboratory Results (Safety Population) 
 
Listing 10.2.6 
Hemoglobinopathy Tests Results (Safety Population)  
Listing 10.2.7 
Urine Pregnancy Tests for Female Subjects (Safety Population) 
 
Listing 10.3.1 
Listing of Antibody Titers/Avidity  
Listing 10.4.1 
Listing of FIEs 
Listing 10.4.2 
Listing of Parasitemia Test Results  
Figure 10.1.1 
CONSORT Diagram  
Figure 10.2.1 
Kaplan-Meier survival curve for FIEs in Groups 1 and 4.  
Figure 10.2.2 
Kaplan-Meier survival curve for FIEs in Groups 1 and 4 stratified by HIV status. 
Figure 10.2.3 
Kaplan-Meier survival curve for FIEs in Groups 2 and 5.  
Figure 10.2.4 
Kaplan-Meier survival curve for FIEs in Groups 2 and 5 stratified by HIV status. 
Figure 10.2.5 
Kaplan-Meier survival curve for FIEs in Groups 1 and 2.  
Figure 10.2.6 
Kaplan-Meier survival curve for FIEs in Groups 4 and 5.  
Figure 10.2.7 
Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 1 and 
4 FIEs during the entire study period (ATP cohort for efficacy) 
 
Figure 10.2.8 
Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 2 and 
5 FIEs during the entire study period (ATP cohort for efficacy) 
 
Figure 10.2.10 
Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 1 and 
2 FIEs during the entire study period (ATP cohort for efficacy) 
 
Figure 10.2.11 
Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 4 and 
5 FIEs during the entire study period (ATP cohort for efficacy) 
 
Figure 10.3.1 
Reverse Cumulative Distribution Curves for Anti-CS NANP Antibody Titers in Each 
Group (ATP cohort for immunogenicity) 
 
Figure 10.3.2 
 Reverse Cumulative Distribution Curves for Anti-CS C-term Antibody Titers in Each 
Group (ATP cohort for immunogenicity) 
 
Figure 10.3.3 
 Reverse Cumulative Distribution Curves for Anti-HBsAb Titers in Each Group (ATP 
cohort for immunogenicity) 
ϭϬ͘ d>&^,>>^
The TLF shells are included in a separate document/attached in the end. 
ϭϭ͘ d/D/E'K&E>z^/^
Upon completion of last visit for the final participant and availability of immunogenicity results, a partial 
lock of the database will be realized, and a topline analysis will be initiated to include the results for 
safety, efficacy and immunogenicity. Immunogenicity results will include the data available before the 
partial lock. Upon collection of the remainder of the data for immunogenicity and final database lock, the 
final analysis on immunogenicity will be performed.  
 
 


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TFL Shells for Protocol CVIA 078; RTS,S/AS10E corresponding to 
SAP v3.1 
 
Protocol title: A Phase 2b randomized, open-label, controlled, single center study in 
Plasmodium falciparum-infected and uninfected adults age 18-55 years old in Kenya to evaluate 
the efficacy of the delayed, fractional dose RTS,S/AS01 E malaria vaccine in subjects treated 
with artemisinin combination therapy plus primaquine 
Date created: v0.1 April 06th, 2021 
Updated: v0.3 April 16th, 2021,  
Updated: v0.4, May 3rd, 2021,  
Updated: v1.0/v1.1 May 17-18th, 2021 added Total cohort for efficacy population for efficacy 
summary tables and Total vaccinated cohort for immunogenicity summary tables   
Updated: Jan 31st,2023, removed change from baseline and toxicity grades from safety lab 
summaries and listings; updated TLF headers and footers  
Updated: Feb 28th, 2023, added two efficacy tables (Groups 1 vs 2 and 4 vs 5), four survival 
curves (groups 1 vs 2 and groups 4 vs 5), two residual plots and two efficacy listings (FIEs and 
parasitemia test results) 
Updated: Mar 5th, 2023, finalized to v4.0 for signature and updated again on April 14th, updated 
the model for the pairwise comparisons of immunogenicity and the TLF shells associated with.  


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
 
Version: 4.0 
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Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
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Date: Mar 5th, 2023 
DEMOGRAPHICS TABLES 
Table 10.1.1: Enrollment Status by Group 
 
Group 1 
(N=)
Group 2 
(N=)
Group 3 
(N=)
Group 4 
(N=)
Group 5 
(N=)
Total 
(N=)
Informed Consent signed 
 
 
 
 
xxxx 
Eligible 
 
 
 
 
xxxx 
Randomized 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
xxxx 
Randomized but received no study product at D1 
xx 
xx 
xx 
xx 
xx 
xx 
Received study product at D1 
xx 
xx 
xx 
xx 
xx 
xx 
Subjects who completed study 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Received study product at D1 who discontinued early 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Adverse Event  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Death 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Lost to follow-up  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Physician decision  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Eligibility criteria not met 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Withdrawal by subject 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Study terminated by sponsor 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Protocol deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
     Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Total vaccinated cohort, 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Safety analysis population, 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
ATP for efficacy 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
ATP for immunogenicity 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Total cohort for efficacy 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Total cohort for immunogenicty 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
N: Number of subjects in each group.
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
Denominator of percentage is number of subjects randomized and received at least one dose of IP. 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
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Table 10.1.2: Summary of eligibility criteria  
 
Total  
n (%)  
Informed Consent Signed  
xxxx  
Subjects who met all eligibility criteria  
xx (xx.x%)  
Subjects who did not satisfy at least one eligibility criterion  
xx (xx.x%)  
Subjects who did not meet at least one Inclusion Criterion  
xx (xx.x%)  
Subject has provided signed or thumb printed and dated informed consent form 
xx (xx.x%)  
Subject has stated willingness to comply with all study procedures and availability for the duration of the study.  
xx (xx.x%)  
xxxxxxxxxxxxxxxx  
xx (xx.x%)  
  
  
Subjects who met at least one Exclusion Criterion  
xx (xx.x%)  
Subject has planned administration/administration of a vaccine not foreseen by the study protocol from within 30 days before the first dose of study vaccine 
until 30 days after the last dose of study vaccine. 
xx (xx.x%)
Subject has prior receipt of any rabies vaccine or experimental malaria vaccine. 
xx (xx.x%)  
xxxxxxxxxxxxxxxxxxxxxxxxxx  
xx (xx.x%)  
  
xx (xx.x%)  
  
xx (xx.x%)  
  
xx (xx.x%)  
  
xx (xx.x%)  
xx (xx.x%)
  
  
   Denominator of percentage is number of subjects screened.  
  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
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Table 10.1.3: Summary of Demographics by Treatment (TVC, total efficacy cohort and Per Protocol Populations)  
 
 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Overall 
 
Statistics 
(N=) 
(N=) 
(N=) 
(N=) 
(N=) 
(N=) 
Age 
n 
 
 
 
 
 
 
Mean (SD) 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Q1, Q3 
 
 
 
 
 
 
Min, Max 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
n (%) 
 
 
 
 
 
     Female 
xx(xx.x%) 
 
 
 
 
 
     Male 
xx(xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity 
n (%) 
 
 
 
 
 
     Luo 
xx(xx.x%) 
 
 
 
 
 
     Luhya 
xx(xx.x%) 
 
 
 
 
 
     Not reported 
xx(xx.x%) 
 
 
 
 
 
     Unknown 
xx(xx.x%) 
 
 
 
 
 
     Other 
xx(xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
n (%) 
 
 
 
 
 
     White 
xx(xx.x%) 
 
 
 
 
 
     Black 
xx(xx.x%) 
 
 
 
 
 
     Not reported 
xx(xx.x%) 
 
 
 
 
 
     Unknown 
xx(xx.x%) 
 
 
 
 
 
     Other 
xx(xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Status
n(%)
     Positive 
xx(xx.x%) 
 
 
 
 
 
     Negative 
xx(xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Own Bednet? 
n (%) 
 
 
 
 
 
     Yes 
xx(xx.x%) 
 
 
 
 
 
No
xx(xx.x%)
 
 
 
 
 
 
 
Sleep Under Net? 
n (%) 
 
 
 
 
 
   Yes 
xx(xx.x%) 
 
 
 
 
 
        Once a week 
xx(xx.x%) 
 
 
 
 
 
        2-3 times a week 
xx(xx.x%) 
 
 
 
 
 
4-6 times a week
xx(xx.x%)
        Daily 
xx(xx.x%) 
 
 
 
 
 
   No 
xx(xx.x%) 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
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Date: Mar 5th, 2023 
 
 
 
 
 
 
 
Indoor residual 
spray within the past 
year 
n (%) 
 
 
 
 
 
     Yes 
xx(xx.x%) 
 
 
 
 
 
     No 
xx(xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
n 
 
 
 
 
 
 
Mean (SD) 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Q1, Q3 
 
 
 
 
 
 
Min, Max 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
n 
 
 
 
 
 
 
Mean (SD) 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Q1, Q3 
 
 
 
 
 
 
Min, Max 
 
 
 
 
 
 
 
 
 
 
 
 
BMI 
n 
 
 
 
 
 
 
Mean (SD) 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Q1, Q3 
 
 
 
 
 
 
Min, Max 
 
 
 
 
 
 
 
 
 
 
 
 
N: total number of subjects in each group
n: total number of subjects in each category   
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


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Table 10.1.4: Summary of HLA Typing by Treatment (TVC Population)  
Group 1
(N=) 
Group 2
(N=) 
Group 3
(N=) 
Group 4
(N=)
Group 5
(N=) 
Overall
(N=) 
 
 
 
 
 
 
 
HLA subtype 1: xxxx 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
HLA subtype 2: xxxx  
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
HLA subtype 3: xxxx 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
xx(xx.x%) 
 
 
 
 
 
 
 
Repeat for other HLA Class 1 and 
2 subtypes 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
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Table 10.1.5: Protocol Deviations 
 
 
 
 
 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
Protocol Deviation Type/classification 
Group 1
(N=) 
Group 2
(N=) 
Group 3
(N=) 
Group 4
(N=) 
Group 5
(N=) 
Total
(N=) 
Deviation Types 
 
 
 
 
 
 
Eligibility 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Informed consent 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Randomization error 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Antimalarial drugs administered incorrectly 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
IP administered incorrectly 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
IP administration missed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Missed visit 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Out-of-window visit 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Specimen not collected  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Procedure done incorrectly 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Procedure not done 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Other
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
 
 
 
 
 
 
 
Deviation Classifications 
 
 
 
 
 
 
Major  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Minor 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
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Table 10.1.6: Medical History 
System Organ Class/ 
Preferred Term 
Group 1 
(N=) 
Group 2 
(N=) 
Group 3 
(N=) 
Group 4 
(N=)
Group 5 
(N=) 
Total 
(N=) 
System Organ Class #1 
 
 
 
 
 
 
  Preferred term  #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term  #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term  #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
 
 
System Organ Class #2 
 
 
 
 
 
 
  Preferred term  #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term  #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term  #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
..  
 
 
 
 
 
 
System Organ Class #3 
 
 
 
 
 
 
  Preferred term  #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term  #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term  #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
..  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
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Table 10.1.7: Vital Signs 
Parameter/ Visit 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Overall 
Pulse Rate (beats/ min) at 
Screening 
 
 
 
 
 
 
N 
xx 
xx 
xx 
xx 
xx 
xx 
Mean (SD) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx
xx.xx 
xx.xx 
xx.xx 
Q1, Q3 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
Min, Max 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
 
 
 
 
 
 
 
Pulse Rate (beats/ min) Visit 5 
 
 
 
 
 
 
N 
xx 
xx 
xx 
xx 
xx 
xx 
Mean (SD) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx
xx.xx 
xx.xx 
xx.xx 
Q1, Q3 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
Min, Max 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
 
 
 
 
 
 
 
Pulse Rate (beats/ min) Visit 8 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
xx 
Mean (SD) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
xx .xx (xx.xx) 
Median 
xx.xx 
xx.xx 
xx.xx
xx.xx 
xx.xx 
xx.xx 
Q1, Q3 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
Min, Max 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
xx .xx, xx.xx 
 
 
 
 
 
 
 
 
 
(Display rows for additional 
visits and the other categories of 
vital signs, including oral 
temperature, and blood pressures) 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


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STATISTICAL ANALYSIS PLAN 
 
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Table 10.1.8: Physical Examination 
Body System 
Group 1 
(N=) 
Group 2 
(N=) 
Group 3 
(N=) 
Group 4 
(N=) 
Group 5 
(N=) 
Total 
(N=) 
General appearance at Visit 5 
 
 
 
 
 
 
  Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Abnormal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Not done 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
 
General appearance Visit 11 
 
 
 
 
 
 
  Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Abnormal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Not done 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
 
General appearance at Visit 17 
 
 
 
 
 
 
  Normal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Abnormal 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Not done 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Display additional rows for the 
other categories of physical 
exam) 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
The physical examination includes the following body system or part: 1. General appearance; 2. Skin; 3. Lymph nodes; 4. HEENT; 5. Neck; 6. Respiratory/pulmonary; 7. Cardiovascular; 8. Abdomen; 
9. Musculoskeletal; 10. Neurological; 11. Extremities; 12. Other 
 
 


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Table 10.1.9: Prior Medications 
ATC Level/ Preferred Term 
Group 1
(N=) 
Group 2
(N=) 
Group 3
(N=) 
Group 4
(N=) 
Group 5
(N=) 
Total
(N=) 
ATC Classification #1 
 
 
 
 
 
  Preferred term #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
ATC Classification #2 
 
 
 
 
 
  Preferred term #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
ATC Classification #3 
 
 
 
 
 
Preferred term #1
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
xx (xx.x%)
  Preferred term #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


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Table 10.1.10: Concomitant Medications 
ATC Level/ Preferred Term 
Group 1 
(N=) 
Group 2 
(N=) 
Group 3 
(N=) 
Group 4 
(N=) 
Group 5 
(N=) 
Total 
(N=) 
ATC Classification #1 
 
 
 
 
 
 
  Preferred term #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
 
ATC Classification #2 
 
 
 
 
 
 
  Preferred term #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  
 
 
 
 
 
 
ATC Classification #3 
 
 
 
  Preferred term #1 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #2 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Preferred term #3 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


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Table 10.1.11: Vaccine Administration 
Group
Visit 5-Dose1 
Visit 11-Dose2 
Visit 17-Dose3 
# of subjects 
who received 
all three 
vaccine doses 
 
 
 
 
Group 1 (N=) 
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
Group 2 (N=)
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Group 3 (N=) 
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
Group 4 (N=) 
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
Group 5 (N=) 
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
Total  
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
xx (xx.x %)  
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 


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Table 10.1.12: Anti-Malarial Compliance 
Group 
Visit 2 
Visit 3 
Visit 4 
Visit 8 
Visit 9 
Visit 10 
Visit 14 
Visit 15 
Visit 16 
Full 
Compliance 
DHA/Pip 
LD PQ 
DHA/Pip 
DHA/Pip 
DHA/Pip 
LD PQ 
DHA/Pip 
DHA/Pip 
A/L 
LD PQ 
A/L 
A/L 
Group 1 
(N=) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x %) 
Group 2
(N=) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x
%) 
xx (xx.x %) 
Group 4 
(N=) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x %) 
Group 5 
(N=) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x %) 
Total 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x 
%) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx: represents the number of subjects who took the full dose of anti-malarials.  
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 4: Rabies with anti-malarials to clear parasites. Group 
5: Rabies with anti-malarials to prevent infection (prophylaxis) 
DHA/Pip: Dihydroartemisinin-piperaquine; LD PQ: Low dose primaquine; A/L: Artemether/lumefantrine (Coartem) 
 


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TABLE 10.1.13.1: VISIT ATTENDANCE (EPOCH 1) 
Group 
Treatment and immunoization (Epoch 1) 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
 
Repeat until 
Visit 18 
Group 1 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Group 2 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Group 3 (N=)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
Group 4 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Group 5 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Total 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 




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TABLE 10.1.13.2: VISIT ATTENDANCE (EPOCH 2) 
Group 
Active Detection of Infection (Epoch 2) 
Visit 19 
Visit 20 
Visit 21 
Visit 22 
Visit 23 
Visit 24 
Visit 25 
Visit 26 
Visit 27 
Group 1 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Group 2 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Group 3 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Group 4 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Group 5 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Total 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
N: total number of subjects in each group
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 




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TABLE 10.1.13.3: VISIT ATTENDANCE (EPOCH 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: total number of subjects in each group 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
Group 
Active Detection of Infection-Extension (Epoch 3) 
Visit 28
Visit 29
Visit 30
Visit 31
Visit 32
Visit 33
Visit 34
Visit 35
Group 1 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Group 2 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Group 3 (N=)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
Group 4 (N=) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Group 5 (N=)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
xx (xx.x %)
Total 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
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VACCINE EFFICACY TABLES  
Table 10.2.1.1 and 2. Vaccine efficacy (Group 1 vs Group 4): First Infection Events (FIEs) of P. falciparum during the Active Detection of Infection period by HIV status and 
overall (ATP cohort for efficacyand Total cohort for efficacy) 
 
 
First or only 
infection 

Group 1 (RTS,S) 
  
Group 4 (Rabies) 
  
Vaccine Efficacy 
Adjusting 
variable 
Interaction VE 
 
N 
Events 
PYAR 
Rate 
 
N 
Event 
PYAR 
Rate 
 
Efficacy 
LL 
UL 
P value 
P value 
P value 
Overall 
unadjusted 
ǆǆǆ
xxx 
xxxx.x 
x.xx 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
  
  
Adjusted by HIV
 
 
 
xx.xx
xx.xx
xx.xx
x.xxx
x.xxx
x.xxx
   HIV positive 
ǆǆǆ
xxx 
xxxx.x 
x.x 
 
ǆǆǆ
xxx 
xxx 
xxxx.x 
 
 
 
 
 
 
 
   HIV negative 
yǆǆ
xxx 
xxxx.x 
x.x 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
  
  
  
  
  
  
N = total number of subjects at risk in each group (without missing values) 
Events = number of subjects having at least one confirmed P. falciparum infection detected by PCR in each group  
PYAR = sum of follow-up period (censored at the first occurrence of a confirmed P. falciparum infection) expressed in years 
Events/PYAR = Incidence rate of subjects reporting one event 
LL, UL = 95% Lower and Upper confidence limits 
Efficacy (%) = Vaccine Efficacy adjusted by gender (Cox regression model, 1-adjusted HR (Hazard ratio)) 
p-values for vaccine efficacy and statistically significant covariates are from Cox regression model and interaction vaccine efficacy p-value is from HIV status and treatment Group term.  
For the multivariable analysis, HIV (positive vs negative) will be included, and the next variables will be considered: Age (tertile 1-3), Gender (male vs female), the more significant between Ethnicity 
and Race, the most significant between Own bednet, Sleep under bednet and Indoor residual spray (IRS) and the most significant between Height, Weight and BMI (tertile 1-3). Any potential 
confounding factor will be identified with p-value lower than 0.1. 
 
 


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Table 10.2.2.1 and 2 Vaccine efficacy (Group 2 vs Group 5): First Infection Events (FIEs) of P. falciparum during the Active Detection of Infection period by HIV status and 
overall (ATP cohort for efficacyand Total cohort for efficacy) 
First or only 
infection 

Group 2 (RTS,S)
  
Group 5 (Rabies)
  
Vaccine Efficacy 
Adjusting 
variable 
Interaction VE 
 
N 
Events 
PYAR 
Rate 
 
N 
Event 
PYAR 
Rate 
 
Efficacy 
LL 
UL 
P value 
P value 
P value 
Overall 
unadjusted 
yǆǆ
xxx 
xxxx.x 
x.xx 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
  
  
Adjusted by HIV 
 
  
  
  
 
 
  
  
  
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
x.xxx 
x.xxx 
   HIV positive 
yǆǆ
xxx 
xxxx.x 
x.x 
 
ǆǆǆ
xxx 
xxx 
xxxx.x 
 
 
 
 
 
 
 
HIV negative
yǆǆ
xxx
xxxx.x
x.x
ǆǆǆ
xxx
xxx
xxxx.x
N = total number of subjects at risk in each group (without missing values) 
Events = number of subjects having at least one confirmed P. falciparum infection detected by PCR in each group 
PYAR = sum of follow-up period (censored at the first occurrence of a confirmed P. falciparum infection) expressed in years 
Events/PYAR = Incidence rate of subjects reporting one event 
LL, UL = 95% Lower and Upper confidence limits 
Efficacy (%) = Vaccine Efficacy adjusted by gender (Cox regression model, 1-adjusted HR (Hazard ratio)) 
p-values for vaccine efficacy and statistically significant covariates are from Cox regression model and interaction vaccine efficacy p-value is from HIV status and treatment Group term.  
For the multivariable analysis, HIV (positive vs negative) will be included, and the next variables will be considered: Age (tertile 1-3), Gender (male vs female), the more significant between Ethnicity 
and Race, the most significant between Own bednet, Sleep under bednet and Indoor residual spray (IRS) and the most significant between Height, Weight and BMI (tertile 1-3). Any potential 
confounding factor will be identified with p-value lower than 0.1.
 
 


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Table 10.2.3.1 and 2 Vaccine efficacy (Group 1 vs Group 2): First Infection Events (FIEs) of P. falciparum during the Active Detection of Infection period by HIV status and overall 
(ATP cohort for efficacyand Total cohort for efficacy) 
 
First or only 
infection 

Group 1 (RTS,S) 
  
Group 2 (RTS,S) 
  
Vaccine Efficacy 
Adjusting 
variable 
Interaction VE 
 
N 
Events 
PYAR 
Rate 
 
N 
Event 
PYAR 
Rate 
 
Efficacy 
LL 
UL 
P value 
P value 
P value 
Overall 
unadjusted 
yǆǆ
xxx 
xxxx.x 
x.xx 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
  
  
Adjusted by HIV 
 
  
  
  
 
 
  
  
  
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
x.xxx 
x.xxx 
   HIV positive 
yǆǆ
xxx 
xxxx.x 
x.x 
 
ǆǆǆ
xxx 
xxx 
xxxx.x 
 
 
 
 
 
 
 
   HIV negative 
yǆǆ
xxx 
xxxx.x 
x.x 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
  
  
  
  
  
  
N = total number of subjects at risk in each group (without missing values) 
Events = number of subjects having at least one confirmed P. falciparum infection detected by PCR in each group 
PYAR = sum of follow-up period (censored at the first occurrence of a confirmed P. falciparum infection) expressed in years 
Events/PYAR = Incidence rate of subjects reporting one event 
LL, UL = 95% Lower and Upper confidence limits 
Efficacy (%) = Vaccine Efficacy adjusted by gender (Cox regression model, 1-adjusted HR (Hazard ratio)) 
p-value from Cox regression model 
For the multivariable analysis, HIV (positive vs negative) will be included, and the next variables will be considered: Age (tertile 1-3), Gender (male vs female), the more significant between Ethnicity 
and Race, the most significant between Own bednet, Sleep under bednet and Indoor residual spray (IRS) and the most significant between Height, Weight and BMI (tertile 1-3). Any potential 
confounding factor will be identified with p-value lower than 0.1. 
 
 


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Table 10.2.4.1 and 2 Vaccine efficacy (Group 4 vs Group 5): First Infection Events (FIEs) of P. falciparum during the Active Detection of Infection period by HIV status and overall 
(ATP cohort for efficacyand Total cohort for efficacy) 
 
First or only 
infection

Group 4 (Rabies) 
  
Group 5 (Rabies) 
  
Vaccine Efficacy 
Adjusting 
variable
Interaction VE 
N 
Events 
PYAR 
Rate 
N 
Event 
PYAR 
Rate 
Efficacy 
LL 
UL 
P value 
P value 
P value 
Overall 
unadjusted 
yǆǆ
xxx 
xxxx.x 
x.xx 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
  
  
Adjusted by HIV 
 
  
  
  
 
 
  
  
  
  
xx.xx 
xx.xx 
xx.xx 
x.xxx 
x.xxx 
x.xxx 
   HIV positive 
yǆǆ
xxx 
xxxx.x 
x.x 
ǆǆǆ
xxx 
xxx 
xxxx.x 
   HIV negative 
yǆǆ
xxx 
xxxx.x 
x.x 
  
ǆǆǆ
xxx 
xxx 
xxxx.x 
  
  
  
  
  
  
  
N = total number of subjects at risk in each group (without missing values) 
Events = number of subjects having at least one confirmed P. falciparum infection detected by PCR in each group 
PYAR = sum of follow-up period (censored at the first occurrence of a confirmed P. falciparum infection) expressed in years 
Events/PYAR = Incidence rate of subjects reporting one event 
LL, UL = 95% Lower and Upper confidence limits 
Efficacy (%) = Vaccine Efficacy adjusted by gender (Cox regression model, 1-adjusted HR (Hazard ratio)) 
p-value from Cox regression model 
For the multivariable analysis, HIV (positive vs negative) will be included, and the next variables will be considered: Age (tertile 1-3), Gender (male vs female), the more significant between Ethnicity 
and Race, the most significant between Own bednet, Sleep under bednet and Indoor residual spray (IRS) and the most significant between Height, Weight and BMI (tertile 1-3). Any potential
confounding factor will be identified with p-value lower than 0.1. 
 
 


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Table 10.2.5.1 and 2 Summary of subjects at risk, person-time, number of FIEs and incidence rate (ATP cohort for efficacyand Total cohort for efficacy) for Group 1 and 4 
 
Group 1 (RTS/S) 
Group 4 (Rabies) 
Overall  
 
N 
Events 
PYAR 
Rate 
N 
Events 
PYAR 
Rate 
N 
Events 
PYAR 
Rate 
Visit 19
Xxx
xx
xx.x
x.x
xxx
xx
xx.x
x.x
xxx
xx
xx.x
x.x
Visit 20 
Xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 21 
Xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 22 
Xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 23 
Xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 24 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 25 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 26 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 27 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the targets are not 
reach by the end of 
Epoch 2, then ADI 
period will 
extended to when 
the target is reached 
or the end of the 
extension ADI 
period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of subjects at risk in each group at each visit (without missing values) 
Events = number of subjects having at least one confirmed P. falciparum infection detected by PCR 
PYAR = sum of follow-up period (censored at the first occurrence of a confirmed P. falciparum infection) expressed in years
Events/PYAR = Incidence rate of subjects reporting one event 
No parasitemia testing has been recorded for unscheduled visits.  
 
 
Commented [JA1]: Why is this footnote removed? 
Commented [JJ2R1]: There were no parasitemia data for 
unscheduled visits during ADI 
Commented [JA3R1]: Could you please include in the footnote 
that no parasitemia data for unscheduled visits was registered.
 
Please note that there are several AEs that are malaria,  but I have 
not check if they were during the ADI epochs.  
Commented [JJ4R1]: Updated


Protocol No. CVIA-078; RTS,S/AS01 E  
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Date: Mar 5th, 2023 
Table 10.2.6.1 and 2 Summary of subjects at risk, person-time, number of FIEs and incidence rate (ATP cohort for efficacy and Total cohort for efficacy) for Group 2 and 5 
 
Group 2 (RTS/S) 
Group 5 (Rabies) 
Overall  
 
N 
Events 
PYAR 
Rate 
N 
Events 
PYAR 
Rate 
N 
Events 
PYAR 
Rate 
Visit 19
xxx
xxx
xxx
Visit 20 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 21 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 22 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 23 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 24 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 25 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 26 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
Visit 27 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
xxx 
xx 
xx.x 
x.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
If the targets are not 
reach by the end of 
Epoch 2, then ADI 
period will 
extended to when 
the target is reached 
or the end of the 
extension ADI 
period 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of subjects at risk in each group at each visit (without missing values) 
Events = number of subjects having at least one confirmed P. falciparum infection detected by PCR 
PYAR = sum of follow-up period (censored at the first occurrence of a confirmed P. falciparum infection) expressed in years
Events/PYAR = Incidence rate of subjects reporting one event 
No parasitemia testing has been recorded for unscheduled visits. 
 
 


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Version: 4.0 
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Table 10.2.7.1 and 2 Summary of median time to FIEs and hazards (ATP cohort for efficacy and Total cohort for efficacy) 
Group1 (N=)
Group2 (N=)
Group4 (N=)
Group5 (N=)
Overall (N=)
Median time to FIEs (IQR) 
xxx(xxx.x-xxx.x) 
xxx(xxx.x-xxx.x) 
xxx(xxx.x-xxx.x)
xxx(xxx.x-xxx.x) 
xxx(xxx.x-xxx.x) 
Hazard (95% CI) 
x.xx(x.xx-x.xx) 
x.xx(x.xx-x.xx) 
x.xx(x.xx-x.xx) 
x.xx(x.xx-x.xx) 
x.xx(x.xx-x.xx) 
 
 
 
 
 
 
N = number of subjects at risk in each group (without missing values) 
Median time to FIEs (expressed in years) and hazard are derived from KM and cox regression model respectively. 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
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Date: Mar 5th, 2023 
 
IMMUNOGENICITY TABLES 
Table 10.3.1.1 and 2: Number and Percentage of Subjects with anti-CS NANP Antibody Titer/Avidity Equal to or above Cut-off (seropositive) and GMTs (ATP cohort for immunogenicity
and Total vaccinated cohort) 
 
 
 
 
Group 1 
Group 2 
Group 3 
Anti-CS NANP
(1XPBS) 
seroresponse 
Visit 
Statistics 
 
 
 
 
      Visit 2 
N 
xx 
xx 
Xx 
 
 
N 
xx 
xx 
Xx 
 
 
% 
xx.x 
xx.x 
xx.x 
LL, UL 
xx.x 
xx.x 
xx.x 
 
Repeat for visits 
11, 13, 17, 10 and 
27 and the 
termination visit 
 
 
 
 
 
 
Repeat for 
Anti-CS NANP 
(4M Urea) 
 
 
 
 
 
 
 
 
 
 
 
Anti-CS NANP 
(1XPBS) GMT 
 
 
 
 
 
 
Visit 2
Titer
xxx.x
xxx.x
xxx.x
 
 
LL, UL 
xxx.xx-xx.x 
xxx.xx-
xx.x
xxx.xx-
xx.x
 
Min, Max 
xxx.x-xxx.x 
xxx.x-
xxx.x
xxx.x-
xxx.x
 
 
p-value 
1 vs 2 
(x.xxx) 
2 vs 3 
(x,xxx) 
1 vs 3 
(x.xxx) 
 
Repeat for visits 
11, 13, 17, 10 and 
27 and the 
termination visit 
 
 
 
 
 
 
 
Repeat for 
Anti-CS NANP 
(4M Urea) 
GMT and 
 
 
 
 
 


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Anti-CS NANP 
Avidity Index 
 
Abbreviations: GMT = Geometric Mean Titer; N = Total number of subjects; n = Number of seropositive subjects; % = Percentage; LL = Lower limit of 95% CI; UL = Upper limit of 95% CI; Min = 
Minimum; Max = Maximum; 
p-values for pairwise comparisons are computed from mixed model for repeated measures using avidity index or log transformed antibody titers (Anti-CS NANP (1XPBS) and Anti-CS NANP (4M 
Urea)) and their interaction term as dependent variables and groups and HIV status as covariates and subject as random effect; 
Seropositivity criteria: antibody titer > LLOQ, lower limit of quantification 
 
Table 10.3.2.1 and 2: Number and Percentage of Subjects with Anti-CS C-term Antibody Titer/Avidity Equal to or above Cut-off and GMTs (ATP cohort for immunogenicityand 
Total cohort for efficacy) 
Same shell as T.10.3.1
Table 10.3.3.1 and 2: Number and Percentage of Subjects with ŶƚŝͲ,Ɛď Titer Equal to or above Cut-off and GMTs (ATP cohort for immunogenicity and Total vaccinated 
cohort) 
Same shell as T.10.3.1 except only antibody titer is assayed and the visits are 2, 5, 11 and 20.


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Table 10.3.4.1 and 2 : Geometric Fold Rise in Anti-CS NANP Antibody Titer at Each Post-Vaccination Timepoint Compared to Screening (ATP cohort for immunogenicity and 
Total vaccinated cohort) 
 
  
  
  
  
  
  
  
  
95% CI 
>= 2 
>= 3 
>= 4 
Antibody
Group
N
Visit
GMT
Baseline 
GMT  
Ratio 
Order 
Ratio 
Value 
LL
UL
n
%   
(95% CI) 
p-
value 
n
%  
(95% CI) 
p-
value 
n
%  (95% CI)
p-value 
Anti-CS 
NANP 
1 
 
V11 
xx.x 
xx.x 
V11/V5 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
(xx.x, xx.x) 
1 vs 2 
(x.xxx) 
xx 
xx.x 
(xx.x, xx.x) 
1 vs 2 
(x.xxx) 
xx 
xx.x(xx.x, xx.x) 
1 vs 2 
(x.xxx) 
 
2 
 
V11 
xx.x 
xx.x 
V11/V5 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
(xx.x, xx.x) 
2 vs 3 
(x.xxx) 
xx 
xx.x 
(xx.x, xx.x) 
2 vs 3 
(x.xxx)
xx 
xx.x(xx.x, xx.x) 
2 vs 3
(x.xxx) 
 
3 
 
V11 
xx.x 
xx.x 
V11/V5 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
(xx.x, xx.x) 
1 vs 3 
(x.xxx) 
xx 
xx.x 
(xx.x, xx.x) 
1 vs 3 
(x.xxx)
xx 
xx.x(xx.x, xx.x) 
1 vs 3
(x.xxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat for 
visits 13, 
17, 10 and 
27 and the 
termination 
visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: GMT = Geometric Mean Titer; N = Total number of subjects; n = Number of seropositive subjects; % = Percentage; LL = Lower limit of 95% CI; UL = Upper limit of 95% CI; Min = 
Minimum; Max = Maximum; 
p-values for pairwise comparisons are computed from mixed model for repeated measures using log transformed fold increase (Anti-CS NANP (1XPBS) and Anti-CS NANP (4M Urea)) and their 
interaction term as dependent variables and groups and HIV status as covariates and subject as random effect; 
 >=2, >=3 and >=4 responder rates and their 95% CIs are calculated through Clopper-Pearson method and p-
-Square test. 
Table 10.3.5.1 and 2: Geometric Fold Rise in Anti-CS C-term Antibody Titer at Each Post-Vaccination Timepoint Compared to Screening (ATP cohort for immunogenicity and 
Total vaccinated cohort) 
Same shell as T.10.3.4.1 and 2 
Table 10.3.6.1 and 2: Geometric Fold Rise in Anti-HBsAb Titer at Each Post-Vaccination Timepoint Compared to Screening (ATP cohort for immunogenicityand Total 
vaccinated cohort ) 
Same shell as T.10.3.4.1 and 2  
 
 


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Date: Mar 5th, 2023 
SAFETY TABLES 
Table 10.4.1.1: Overall Safety Profile by Treatment (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=) 
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
EƵŵďĞƌŽĨ>ŽĐĂů^ŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xxx
xxx
xxx
xxx
xxx
xxx
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇ>ŽĐĂů^ŽůŝĐŝƚĞĚ
ĚǀĞƌƐĞǀĞŶƚƐ 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
EƵŵďĞƌŽĨ^ǇƐƚĞŵŝĐ^ŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇ^ǇƐƚĞŵŝĐ
^ŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
EƵŵďĞƌŽĨhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇhŶƐŽůŝĐŝƚĞĚ
ĚǀĞƌƐĞǀĞŶƚƐ 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
EƵŵďĞƌŽĨĚǀĞƌƐĞǀĞŶƚƐŽĨ^ƉĞĐŝĂů/ŶƚĞƌĞƐƚ
;^/ƐͿ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇĚǀĞƌƐĞǀĞŶƚƐ
ŽĨ^ƉĞĐŝĂů/ŶƚĞƌĞƐƚ;^/ƐͿ 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
EƵŵďĞƌŽĨ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐ;^ƐͿ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇ^ĞƌŝŽƵƐĚǀĞƌƐĞ
ǀĞŶƚƐ;^ƐͿ 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
All confidence intervals are two-sided 95% via Clopper-Pearson method. 
Denominator for percentage is subjects in safety population. 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
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Page 64 of 120 
Date: Mar 5th, 2023 
 
Table 10.4.1.2: Frequency of Local Solicited Adverse Events by Treatment and Severity (Safety Population) 
 
 
Group 1 
(N=)
n (%) [CI] 
Group 2 
(N=)
n (%) [CI] 
Group 3 
(N=)
n (%) [CI] 
Group 4 
(N=)
n (%) [CI] 
Group 5 
(N=)
n (%) [CI] 
Total 
(N=)
n (%) [CI] 
Any Events 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Total
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 1 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
Grade 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 3
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
Pain at SOI 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Total 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
Grade 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 3 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
 
 
 
 
 
 
 
(Repeat for 
Swelling at SOI) 
 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
Denominator for percentage is subjects in safety population.
Subject counted once at highest severity grade. 
All confidence intervals are two-sided 95% via Clopper-Pearson method  
Local solicited Adverse Events include: Pain at site of injection (Pain at SOI); Swelling at injection site; Each event has intensity scores 0-3 with 0 for no adverse event and 3 for the adverse event that 
prevents normal activity (for details see protocol for detail) 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
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Page 65 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.3: Frequency of Systemic Solicited Adverse Events by Treatment and Severity (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI]
Group 2 
(N=) 
n (%) [CI]
Group 3 
(N=) 
n (%) [CI]
Group 4 
(N=) 
n (%) [CI]
Group 5 
(N=) 
n (%) [CI]
Total 
(N=) 
n (%) [CI]
 
 
 
 
 
 
 
Any Events 
 
 
 
 
 
 
Total 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
Grade 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 2
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 3 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
Total 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 1 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
Grade 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 3 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
(Repeat for Fatigue, 
Headache, Muscle 
ache, and 
Gastrointestinal 
Symptoms) 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis).
Denominator for percentage is subjects in safety population for whom memory aid data was available.  
Subject counted once at highest severity grade.  
All confidence intervals are two-sided 95% via Clopper-Pearson method  
Systemic Solicited Adverse Events include: Fever; Headache; Gastrointestinal symptoms (nausea, vomiting, diarrhea and/or abdominal pain); Fatigue; Muscle ache. Each event has intensity scores 0-3 
with 0 for no adverse event and 3 for the adverse event that prevents normal activity. For fever, 0: <37.5oC (99.5oF); 1: 37.5oC (99.5oF) to 38.0oC (100.4oF); 2: >38.0oC (>100.4oF) to 39.0oC (102.1oF); 3: 
>39.0oC (102.1oF) (for additional details see protocol)


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
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Date: Mar 5th, 2023 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 67 of 120 
Date: Mar 5th, 2023 
 
Table 10.4.1.4: Summary of Unsolicited Adverse Events by Treatment (Safety Population) 
 
 
Group 1 
(N=)
n (%) [CI] 
Group 2 
(N=)
n (%) [CI] 
Group 3 
(N=)
n (%) [CI] 
Group 4 
(N=)
n (%) [CI] 
Group 5 
(N=)
n (%) [CI] 
Total 
(N=)
n (%) [CI] 
 
 
 
 
 
 
 
All Systems 






 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
System Organ Class 
1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 1 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Preferred Term 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 
2
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Preferred Term 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Preferred Term 2
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 3 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
 
 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis).
xx= Number of Events 
Subject counted once per adverse event term. 
All confidence intervals are two-sided 95% via Clopper-Pearson method. 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 68 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.5: Summary of Unsolicited Adverse Events by Treatment, Severity and Relationship to Study Treatment (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI]
Group 2 
(N=) 
n (%) [CI]
Group 3 
(N=) 
n (%) [CI]
Group 4 
(N=) 
n (%) [CI]
Group 5 
(N=) 
n (%) [CI]
Total 
(N=) 
n (%) [CI]
All Systems  






Total  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Grade 1  
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Grade 2  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
      Grade 3  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Related  
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Grade 1  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Grade 2  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
      Grade 3  
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
Not Related  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 1
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Grade 2  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
      Grade 3  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
System Organ Class 1  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Total  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Grade 1
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Grade 2  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 69 of 120 
Date: Mar 5th, 2023 
      Grade 3  
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
(Repeat similarly for 
other SOCs and PTs)  
 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis).
xx= Number of Events  
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
Subjects who experience one or more episodes of the same adverse event are counted once at highest severity grade and relatedness


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 70 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.6: Summary of Serious Adverse Events by Treatment (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI]
Group 2 
(N=) 
n (%) [CI]
Group 3 
(N=) 
n (%) [CI]
Group 4 
(N=) 
n (%) [CI]
Group 5 
(N=) 
n (%) [CI]
Total 
(N=) 
n (%) [CI]
All Systems






 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
System Organ Class 
1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Preferred Term 1
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 2 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Preferred Term 3 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
System Organ Class 
2
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
     Preferred Term 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
Preferred Term 2
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 3 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
(Repeat similarly for 
other SOCs and PTs)  
 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval.
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
xx= Number of Events  
Subjects who experience one or more episodes of the same adverse event are counted once
All confidence intervals are two-sided 95% via Clopper-Pearson method.
.
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 71 of 120 
Date: Mar 5th, 2023 
 
Table 10.4.1.7: Frequency of Local Solicited Adverse Events by Treatment, Injection Period, and Severity (Safety Population) 
 
 
Group 1 
(N=)
Repeat for Groups 2-5 and 
Total
Injection 1 
Day 1-7 
n (%) [CI] 
Injection 2 
Day 29-35 
n (%) [CI] 
Injection 3 
Day 197-203 
n (%) [CI] 
Any Events 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Total 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 1
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
Grade 2 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
 
Grade 3 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Pain at SOI 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Total
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
Grade 1 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
 
Grade 2 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 3
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
(Repeat for Swelling at SOI) 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval.
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
Solicited AEs are collected on the day of vaccine administration and for six days following each injection (Day 1-7).  
Denominator for percentage is subjects in safety population. 
All confidence intervals are two-sided 95% via Clopper-Pearson method.
Local solicited Adverse Events include: Pain at site of injection (Pain at SOI); Swelling at injection site.


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 72 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.8: Frequency of Systemic Solicited Adverse Events by Treatment, Injection Period, and Severity (Safety Population) 
 
Group 1 
(N=) 
Repeat for 
Groups 2-5 
and Total 
 
Injection 1 
Day 1-7 
n (%) [CI] 
Injection 2 
Day 29-35 
n (%) [CI] 
Injection 3 
Day 197-203 
n (%) [CI] 
 
 
 
 
 
 
Any Events 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Total 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
 
Grade 1 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 2 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 3 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
xxx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
Fatigue 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Total 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 1 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 2 
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
Grade 3
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
xxx (xx.x%) 
[xx.x-xx.x]  
 
 
 
 
 
(Repeat for 
Fever, 
Headache, ect.) 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval.
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
Solicited AEs are collected on the day of vaccine administration and for six days following each injection (Day 1-7).  
Denominator for percentage is subjects in safety population 
All confidence intervals are two-sided 95% via Clopper-Pearson method.


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 73 of 120 
Date: Mar 5th, 2023 
Systemic Solicited Adverse Events include: Fever; Headache; Gastrointestinal symptoms (nausea, vomiting, diarrhea and/or abdominal pain); Fatigue; Muscle ache. Each event has intensity scores 0-3 
with 0 for no adverse event and 3 for the adverse event that prevents normal activity. For fever, Grade 0: <37.5oC (99.5oF); Grade 1: 37.5oC (99.5oF) to 38.0oC (100.4oF); Grade 2: >38.0oC (>100.4oF) to 
39.0oC (102.1oF); Grade 3: >39.0oC (102.1oF) (for additional details see protocol) 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 74 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.9: Summary of Adverse Events of Special Interest by Treatment (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
All Systems 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
System Organ Class 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 3 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
System Organ Class 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 1 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 2 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
     Preferred Term 3 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
 
 
 
 
 
 
 
(Repeat similarly for 
other SOCs and PTs)  
 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
Subjects who experience one or more episodes of the same adverse event are counted once
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 75 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.10: Summary of Adverse Events (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
EƵŵďĞƌŽĨhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
EƵŵďĞƌŽĨZĞůĂƚĞĚhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇZĞůĂƚĞĚhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞ
ǀĞŶƚƐ 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
EƵŵďĞƌŽĨĚǀĞƌƐĞǀĞŶƚƐŽĨ^ƉĞĐŝĂů/ŶƚĞƌĞƐƚ;^/ƐͿ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇĚǀĞƌƐĞǀĞŶƚƐŽĨ^ƉĞĐŝĂů
/ŶƚĞƌĞƐƚ;^/ƐͿ 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
EƵŵďĞƌŽĨZĞůĂƚĞĚĚǀĞƌƐĞǀĞŶƚƐŽĨ^ƉĞĐŝĂů/ŶƚĞƌĞƐƚ
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 

 
 
 
 
 
 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇZĞůĂƚĞĚĚǀĞƌƐĞǀĞŶƚƐŽĨ
^ƉĞĐŝĂů/ŶƚĞƌĞƐƚ
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 

 
 
 
 
 
 
EƵŵďĞƌŽĨ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐ;^ƐͿ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐ;^ƐͿ 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
xx (xx.x%) 
[xx.x-xx.x] 
EƵŵďĞƌŽĨZĞůĂƚĞĚ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 

 
 
 
 
 
 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇZĞůĂƚĞĚ^ĞƌŝŽƵƐĚǀĞƌƐĞ
ǀĞŶƚƐ 
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]

EƵŵďĞƌŽĨ^ĞƌŝŽƵƐĚǀĞƌƐĞǀĞŶƚƐůĞĂĚŝŶŐƚŽĚĞĂƚŚ͘ 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇ^ĞƌŝŽƵƐĚǀĞƌƐĞ
ǀĞŶƚƐ ůĞĂĚŝŶŐƚŽĚĞĂƚŚ͘
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]

EƵŵďĞƌŽĨhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐůĞĂĚŝŶŐƚŽƐƵďũĞĐƚ
ĚŝƐĐŽŶƚŝŶƵĂƚŝŽŶ
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 

 
 
 
 
 
 
EƵŵďĞƌŽĨ^ƵďũĞĐƚƐǁŝƚŚĂŶǇhŶƐŽůŝĐŝƚĞĚĚǀĞƌƐĞǀĞŶƚƐ
ůĞĂĚŝŶŐƚŽƐƵďũĞĐƚĚŝƐĐŽŶƚŝŶƵĂƚŝŽŶ͘
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
xx (xx.x%) 
[xx.x-xx.x]
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval.


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 76 of 120 
Date: Mar 5th, 2023 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
All confidence intervals are two-sided 95% via Clopper-Pearson method. 
Denominator for percentage is subjects in safety population for whom memory aid data was available. 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 77 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.11: Summary of Recurrent Adverse Events (Safety Population) 
 
Episodes of 
AEs of this 
Type per 
Subject 
Group 1 
(N=) 
n (%) 
[CI] 
Group 2 
(N=) 
n (%) 
[CI] 
Group 3 
(N=) 
n (%) 
[CI] 
Group 4 
(N=)  
n (%) 
[CI] 
Group 5 
(N=) 
n (%) 
[CI] 
Total 
(N=) 
n (%) 
[CI] 
Local Solicited 
 
 
 
 
 
 
 
Pain at SOI 
 
 
 
 
 
 
 
2 
3 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
(Repeat for Swelling at SOI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Systemic Solicited 
 
 
 
 
 
 
Fever 
2 
3
xx 
xx
xx 
xx
xx 
xx
xx 
xx
xx 
xx
xx 
xx
(Repeat for Fatigue, Headache, 
Muscle ache, Gatrointestinal 
Symptoms) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unsolicited Adverse Events
System Organ Class 1 
 
 
 
 
 
 
     Preferred Term 1 
2 
3 
4+ 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
     Preferred Term 2 
2 
3 
4+ 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
System Organ Class 2 
 
 
 
 
 
 
    Preferred Term 1 
2 
3 
4+
xx 
xx 
xx
xx 
xx 
xx
xx 
xx 
xx
xx 
xx 
xx
xx 
xx 
xx
xx 
xx 
xx
    Preferred Term 2 
2 
3 
4+ 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
Repeat for other SOCs and PTs
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
Subjects who experience one or more episodes of the same adverse event are counted once  
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
Only Adverse Events that have count of occurrences greater than or equal to 2 will be included. 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 78 of 120 
Date: Mar 5th, 2023 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 79 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.12: Summary of Adverse Events that Persisted beyond 6 Days Post-IP Administration (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
 
 
 
 
 
 
 
Any Events 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
 






Total 
 
 
 
 
 
 
Grade 1 
 
 
 
 
 
 
Grade 2 
 
 
 
 
 
 
Grade 3
 
 
 
 
 
 
 
Local 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain at SOI 
 
 
 
 
 
 
    Total 
 
 
 
 
 
 
Grade 1
   Grade 2 
 
 
 
 
 
 
   Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Repeat for Swelling at SOI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Systemic
 
 
 
 
 
 
 
Fever 
 
 
 
 
 
 
   Total 
 
 
 
 
 
 
   Grade 1 
 
 
 
 
 
 
   Grade 2 
 
 
 
 
 
 
   Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Repeat for Fatigue, Headache, 
Muscle ache and gastrointestinal 
symptoms) 
 
 
 
 
 
 
N: total number of subjects in each group; n = Number of subjects; % = Percentage; CI = Confidence interval 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis).
Subjects who experience one or more episodes of the same adverse event are counted once  
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
All solicited Adverse Events that persisted beyond 6 days post-IP administration. 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 80 of 120 
Date: Mar 5th, 2023 
 
Table 10.4.1.13: Exploration of Group Comparisons for Common Adverse Events (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
P-value 
Pain at SOI 
 
 
 
 
 
 
 
     Yes 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
0.xxx 
     No 
xx (xx.x%) [xx.x-
xx.x]
xx (xx.x%) [xx.x-
xx.x]
xx (xx.x%) [xx.x-
xx.x]
xx (xx.x%) [xx.x-
xx.x]
xx (xx.x%) [xx.x-
xx.x]
xx (xx.x%) [xx.x-
xx.x]
 
Swell at SOI 
 
 
 
 
 
 
 
     Yes 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
0.xxx 
No
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
xx (xx.x%) [xx.x-
xx.x] 
 
 
 
 
 
 
 
 
(Repeat for Fever, 
Headache, Gastrointestinal 
symptoms (nausea, 
vomiting, diarrhea and/or 
abdominal pain), Fatigue 
and Muscle ache) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects who experience one or more episodes of the same adverse event are counted once  
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
p-
 
This table can be expanded to cover other group comparisons, including each preferred terms, grade 4 solicited and unsolicited reactions ect. 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 81 of 120 
Date: Mar 5th, 2023 
 
Table 10.4.1.14: Safety Lab Data out of Range  (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
Hemoglobin  
 
 
 
 
 
     Screening  
 
 
 
 
 
          Low 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
          Normal 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
          High 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
    Visit 5 
 
 
 
 
 
          Low 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
          Normal 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
          High 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
(Repeat for WBC, Platelets, 
ALT, Creatinine) 
 
 
 
 
 
N = total number of subjects in each group; n = Number of subjects; %=Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
All confidence intervals are two-sided 95% via Clopper-Pearson method.  


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 82 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.15: Summary of Safety Lab Results (Safety Population) 
 
Group 1 
(N=) 
Group 2 
(N=) 
Group 3 
(N=) 
Group 4 
(N=) 
Group 5 
(N=) 
Total 
(N=) 
Hemoglobin at Screening 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
95% CI 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
Hemoglobin at Visit 5 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
xx 
Mean (SD) 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Q1, Q3 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
95% CI 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
[xx.x-xx.x] 
(Repeat for WBC, Platelet, ALT, Creatinine) 
 
 
 
 
 
 
N = total number of subjects in each group. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
All confidence intervals are two-sided 95% via t-distribution.  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 83 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.16: Summary of Hemoglobinopathy Results (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
 
 
 
 
 
 
 
Sickle cell screen 
 
 
 
 
 
 
Normal 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
Heterozygous 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
Homozygous
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
 
 
 
 
 
 
 
G6PD 
 
 
 
 
 
 
Normal 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
Deficient 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
 






Alpha-
thalassemia






Normal 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
Heterozygous 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
Homozygous
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁ 
N = total number of subjects in each group; n = Number of subjects; %=Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 84 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.17: Summary of Urine Pregnancy Test Results (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=) 
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
 
 
 
 
 
 
 
Screening 
 
 
 
 
 
 
Positve 
ǆ 
ǆ 
ǆ 
ǆ 
ǆ 
ǆ 
Negative 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
N/A 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
 
 
 
 
 
 
 
Visit 2 
 
 
 
 
 
 
Positve
ǆ 
ǆ 
ǆ 
ǆ 
ǆ 
ǆ 
Negative 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
N/A 
ǆǆ
ǆǆ
ǆǆ
ǆǆ
ǆǆ
ǆǆ
 






Visit 5 






Positve 
ǆ
ǆ
ǆ
ǆ
ǆ
ǆ
Negative 
ǆǆ
ǆǆ
ǆǆ
ǆǆ
ǆǆ
ǆǆ
N/A 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
ǆǆ 
 






Repeat for Visit 8 
and 17 






N = total number of subjects in each group; n = Number of subjects; %=Percentage; CI = Confidence interval. 
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 85 of 120 
Date: Mar 5th, 2023 
Table 10.4.1.18: Summary of All Non-Serious Adverse Events by Treatment (Safety Population) 
 
Group 1 
(N=) 
n (%) [CI] 
Group 2 
(N=) 
n (%) [CI] 
Group 3 
(N=)
n (%) [CI] 
Group 4 
(N=)  
n (%) [CI] 
Group 5 
(N=) 
n (%) [CI] 
Total 
(N=) 
n (%) [CI] 
All Non-Serious Adverse 
Events 
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
ǆǆ;ǆǆ͘ǆйͿ
΀ǆǆ͘ǆͲǆǆ͘ǆ΁
 
 
 
 
 
 
 
System Organ Class 1 
 
 
 
 
 
 
     Preferred Term 1 
 
 
 
 
 
 
     Preferred Term 2 
 
 
 
 
 
 
     Preferred Term 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
 
 
 
 
 
 
     Preferred Term 1 
 
 
 
 
 
 
     Preferred Term 2 
 
 
 
 
 
 
     Preferred Term 3 
 
 
 
 
 
 
N = total number of subjects in each group; n = Number of subjects; %=Percentage; CI = Confidence interval. 
Denominator for percentage is subjects in the safety population. 
Subjects who experience one or more episodes of the same adverse event are counted once. 
Solicited AEs are included in the table within categories of system organ class and preferred term.
All confidence intervals are two-sided 95% via Clopper-Pearson method.  
Group 1: RTS,S/AS01E with anti-malarials to clear parasites; Group 2: RTS,S/AS01E with anti-malarials to prevent infection (prophylaxis); Group 3: RTS,S/AS01E without anti-malarials treatment to 
clear parasites; Group 4: Rabies with anti-malarials to clear parasites; Group 5: Rabies with anti-malarials to prevent infection (prophylaxis). 
. 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 86 of 120 
Date: Mar 5th, 2023 
12. DEMOGRAPHICS LISTINGS 
Listing 10.1.1: Protocol Deviations 
Subject ID
Group
Date Occurred
Date Reported
Category
Brief Description
 xxxxx 
Groups 1-5 
ddMMMyyyy  
ddMMMyyyy  
xxxx
 xxxxxxxxxx 
  
 
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
The following deviation categories are included for the study:   
Eligibility 
Informed consent 
Randomization error 
Antimalarial drugs administered incorrectly 
IP administered incorrectly 
IP administration missed 
Missed visit 
Out-of-window visit 
Specimen not collected  
Procedure done incorrectly 
Procedure not done 
Other 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 87 of 120 
Date: Mar 5th, 2023 
Listing 10.1.2: Enrollment Status, Demographics and Subject Disposition  
Subject ID  
Informed 
Consent Signed/ 
Date of 
Informed 
Consent   
Eligible  Randomized  
Group 
Reactogenicity 
Cohorts? 
Sex/Age (Years)  
Race/Ethnicity  
Completed 
Study?  
Date of 
Completion/  
Early 
Termination  
Reason for Early 
Termination  
xxx  
Yes/xxxxxx  
No  
No  
xxx 
(Yes/No) 
Female/39  
xxx/xxxx  
No  
xxxx  
xxxxxxxxxxxxxxx  
xxx  
Yes/xxxxxx  
Yes  
Yes  
xxx 
 
xxx  
xxx/xxxx  
Yes  
xxxx  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 88 of 120 
Date: Mar 5th, 2023 
Listing 10.1.3: Eligibility Criteria Not Met 
  
Subject ID
Eligibility Criteria
Criteria Description
xxxxx  
Inclusion Criteria  Subject has provided signed or thumb printed and dated informed consent form. 
  
  
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  
  
  
  
  
Exclusion Criteria   Subject has planned administration/administration of a vaccine not foreseen by the study protocol from 
within 30 days before the first dose of study vaccine until 30 days after the last dose of study vaccine. 
  
  
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 89 of 120 
Date: Mar 5th, 2023 
Listing 10.1.4: Listing of All Eligibility Criteria 
 
Eligibility Criteria   
Criteria Description  
Inclusion Criteria  
Subject has provided signed or thumb printed and dated informed consent form. 
  
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  
  
  
Exclusion Criteria   
Subject has planned administration/administration of a vaccine not foreseen by  
the study protocol from within 30 days before the first dose of study vaccine  
until 30 days after the last dose of study vaccine.
  
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 90 of 120 
Date: Mar 5th, 2023 
Listing 10.1.5: Baseline Demographics 
Subject ID 
Group 
Age (years) 
Race 
Sex 
Ethnicity 
Weight 
(unit) 
Height (unit) 
BMI (unit) 
xxxxx  
xxx 
xx 
xxxxxx 
x 
xxxxxx 
xx.x 
xxx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 91 of 120 
Date: Mar 5th, 2023 
Listing 10.1.6: HIV Status and HLA Typing 
Subject ID 
Group 
HIV Test 
Date/Time 
HIV Status 
Buccal Swab 
Date/Time 
HLA Typing  
Date/Time 
xxxxx  
xxx 
ddMMMyyyy/hh:mm 
Negative/Positive 
ddMMMyyyy/hh:mm  
HLA-A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 92 of 120 
Date: Mar 5th, 2023 
Listing 10.1.7: Prior Medications 
Subject ID 
Group 
Start Date/ End 
Date 
ATC Level 4/ Preferred 
Term/ Medication Name 
Dose/ Unit 
Route/ Freq 
Xxx 
xxxx 
ddMMMyyyy/ 
(ddMMMyyyy) 
xxxx/xxx/xxx 
xxxx/xxx 
xxxx/xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 93 of 120 
Date: Mar 5th, 2023 
Listing 10.1.8: Concomitant Medication 
Subject ID 
Group 
Start Date/ End 
Date 
ATC Level 4/ Preferred 
Term/ Medication Name 
Dose/ Unit 
Route/ Freq 
Xxx 
xxxx 
ddmmmyyyy/ 
(ddmmmyyyy or 
ONGOING) 
xxxx/xxx/xxx 
xxxx/xxx 
xxxx/xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 94 of 120 
Date: Mar 5th, 2023 
Listing 10.1.9: Medical History 
Subject ID 
Group 
Start Date / End 
Date  
System Organ Class 
Preferred Term 
Xxxx 
xxxx 
ddMMMyyyy / 
ddMMMyyyy or 
ongoing 
xxxxxx 
xxxxxxx 
 
 
ddMMMyyyy / 
ddMMMyyyy or 
ongoing  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 95 of 120 
Date: Mar 5th, 2023 
Listing 10.1.10.1: Visit Attendance (Epoch 1) 
Subject ID 
Group 
Treatment and immunization (Epoch 1) 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Repeat until 
Visit 18 
xxxx 
xxxx 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 96 of 120 
Date: Mar 5th, 2023 
Listing 10.1.10.2: Visit Attendance (Epoch 2) 
Subject ID 
Group 
Active Detection of Infection (Epoch 2) 
Visit 19 
Visit 20 
Visit 21 
Visit 22 
Visit 23 
Visit 24 
Visit 25 
Visit 26 
Visit 27 
xxxx 
xxxx 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 97 of 120 
Date: Mar 5th, 2023 
Listing 10.1.10.3: Visit Attendance (Epoch 3) 
Subject ID 
Group 
Active Detection of Infection-Extension (Epoch 3) 
Visit 28 
Visit 29 
Visit 30 
Visit 31 
Visit 32 
Visit 33 
Visit34 
Visit 35 
 
xxxx 
xxxx 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
(Yes/ No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 98 of 120 
Date: Mar 5th, 2023 
Listing 10.1.11: Vaccine administration  
Subject ID 
Group 
Visit Number 
Vaccine Dose 
Vaccination Date 
xxxx 
xxxx 
Xxx 
xxx 
ddMMMyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 99 of 120 
Date: Mar 5th, 2023 
Listing 10.1.12: Anti-Malarials   
Subject ID 
Group 
Visit Number 
Anti-Malarials 
Taken 
 Date/Time 
Number of tablets 
dispensed 
Number of 
tablets returned 
Full dose? 
xxxx 
xxxx 
Xxx 
xxx  
ddMMMyyyy:hh:mm 
x 
x 
(Yes/No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 100 of 120 
Date: Mar 5th, 2023 
Listing 10.1.13: Vital Signs 
 
 
 
Subject 
ID 
Group 
Parameter 
Visit 
Date: Time 
Results (Units) 
xxx 
xxxx 
Pulse Rate 
Screening  
(Visit 1 or 2) 
ddmmmyyyy: hh:mm 
xx (beats/min)) 
 
 
 
Visit 5 
ddmmmyyyy: hh:mm 
xx (beats/min)) 
 
 
 
Visit 8 
ddmmmyyyy: hh:mm 
xx (beats/min)) 
 
 
 
Visit 11 
ddmmmyyyy: hh:mm 
xx (beats/min)) 
 
 
 
Visit 17 
ddmmmyyyy: hh:mm 
xx (beats/min)) 
 
 
 
 
 
 
 
 
Systolic 
Blood 
Pressure 
Screening  
(Visit 1 or 2) 
ddmmmyyyy: hh:mm 
xxx (mmHg)) 
 
 
 
Visit 5 
ddmmmyyyy: hh:mm 
xxx (mmHg)) 
 
 
 
Visit 8 
ddmmmyyyy: hh:mm 
xxx (mmHg)) 
 
 
 
Visit 11 
ddmmmyyyy: hh:mm 
xxx (mmHg)) 
 
Visit 17 
ddmmmyyyy: hh:mm 
xxx (mmHg)) 
 
 
 
 
 
 
 
 
 
Repeat for Oral Temperature 
and diastolic Blood Pressure 
 
 
 
 
 
 
 
 
Repeat for 
other 
subjects


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 101 of 120 
Date: Mar 5th, 2023 
Listing 10.1.14: Physical Examinations 
Subject ID 
Group 
Body System 
Visit 
Date/Time of Exam 
Results/ 
Description 
Clinically 
Significant? 
xxxxx 
x 
Abdomen 
Screening 
ddmmmyyyy:hh:mm 
Normal 
(Yes/No) 
 
Visit 5
ddmmmyyyy:hh:mm
Normal
(Yes/No)
  
 
 
Visit 11 
ddmmmyyyy:hh:mm 
Normal 
(Yes/No) 
  
 
 
Visit 17 
ddmmmyyyy:hh:mm 
Normal 
(Yes/No) 
Repeat other body systems
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat other subjects
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 102 of 120 
Date: Mar 5th, 2023 
  
13. SAFETY LISTINGS
Listing 10.2.1: Solicited Adverse Events (Safety Population)
Subject ID  Group 
Reported at 
Visit  
Type  
AE Term  
Maximum Severity  
Start Date  
Stop Date  
Duration  
 (in days) *   
Days from Most 
Recent 
Vaccination**  
xxxxx  
 
xxx  
Local  
Pain at SOI  
Grade 2  
xxx  
xxxx  
xxxx  
2  
  
 
  
  
Swelling at SOI  
Grade 1  
xxx  
xxxx  
xxxx  
3  
  
 
  
Systemic  
Headache  
Grade 1  
xxx  
xxxx  
xxxx  
1  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
* Duration= AE stop date  AE start date + 1  
** Difference between AE start date and most recent vaccination date + 1. 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 103 of 120 
Date: Mar 5th, 2023 
 
Listing 10.2.2: Unsolicited Adverse Events (Safety Population) 
 
Subject 
ID  
Group AE Term  
MedDRA 
Preferred Term/  
System Organ 
Class  
Start 
Date  
Outcome/  
Outcome Date  
  
Duration  
 (in days) *  
Days from Most Recent 
Vaccination**  
Severity/  
Relation to Study 
Treatment  
Action Taken with 
Study 
Treatment/Action 
Taken with 
Antimalarials  
AESI?  
SAE? 
xxxxx  
xxx 
xxx  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
* Duration= AE stop date  AE start date + 1  
** Difference between AE start date and most recent vaccination date + 1. 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 104 of 120 
Date: Mar 5th, 2023 
Listing 10.2.3: Serious Adverse Events (Safety Population) 
  
Subject 
ID  
Group 
AE 
Term  
MedDRA Preferred
Term/  
System Organ 
Class  
Start 
Date  
Outcome/  
Outcome Date  
Duration  
(in days) *  
Days from Most 
Recent Vaccination**  
Severity/  
Relation to Study 
Treatment  
Action Taken with 
Study Treatment?  
Serious Adverse 
Event Category  
xxxxx  
xxx 
xxx  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
* Duration= AE stop date  AE start date + 1  
** Difference between AE start date and most recent vaccination date + 1. 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 105 of 120 
Date: Mar 5th, 2023 
Listing 10.2.4: Adverse Events of Special Interest (Safety Population) 
Subject 
ID  
Group 
AE 
Term  
MedDRA Preferred 
Term/
System Organ 
Class  
Start 
Date  
Outcome/  
Outcome Date  
Duration  
(in days) *  
Days from Most 
Recent Vaccination**  
Severity/
Relation to Study 
Treatment  
Action Taken with 
Study Treatment?  
Serious Adverse 
Event? 
xxxxx  
xxx 
xxx  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 * Duration= AE stop date  AE start date + 1  
** Difference between AE start date and most recent vaccination date + 1.
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 106 of 120 
Date: Mar 5th, 2023 
Listing 10.2.5: Safety Laboratory Results (Safety Population) 
Subject ID  Group 
Sex 
Test Name  
Visit 
Date 
Results 
Normal / 
Abnormal 
xxxxx  
xxx 
xxx 
Hemoglobin  
1  
ddMMMyyyy  
xx  
 Normal 
xxxxx  
xxx 
xxx 
Hemoglobin  
5 
ddMMMyyyy  
xx  
 Normal 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 107 of 120 
Date: Mar 5th, 2023 
Listing 10.2.6: Hemoglobinopathy Tests Results (Safety Population) 
Subject ID  Group 
Sex 
Test Name  
Date 
Results 
xxxxx  
xxx 
xxx 
Sickle Cell Screen  
ddMMMyyyy  
xx  
 
xxx 
xxx 
G6P  
ddMMMyyyy 
xx  
  
xxx  
xxx  
Alpha-thalassemia 
ddMMMyyyy  
xx  
  
  
  
  
  
  
Repeat for 
other 
subjects  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 108 of 120 
Date: Mar 5th, 2023 
Listing 10.2.7: Urine Pregnancy Tests for Female Subjects (Safety Population) 
Subject 
ID  
Group 
Sex 
Visit 
Date 
Results 
xxxxx  
xxx 
F 
1 
ddMMMyyyy 
Negative 
xxxxx  
xxx 
F 
5 
ddMMMyyyy 
Negative  
xxxxx  
xxx 
F 
8 
ddMMMyyyy 
Negative 
xxxxx  
xxx 
F 
 11 
ddMMMyyyy 
Negative 
xxxxx  
xxx 
F 
 17 
ddMMMyyyy 
Negative  
  
  
  
  
  
  
Repeat for 
other 
subjects  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 109 of 120 
Date: Mar 5th, 2023 
14. IMMUNOGENICITY LISTING 
Listing 10.3.1: Listing of Antibody Titers/Avidity 
Subject 
ID 
Timepoint
Date-time of Sample 
Draw 
Anti- CS 
NANP 
Titer (unit) 
Anti- CS 
NANP 
Avidity 
(unit) 
Anti-
CS C-
term 
Titer 
(unit) 
Anti-
CS C-
term 
Avidity 
(unit) 
Anti- 
HBsAb 
Titer 
(unit) 
xxxxx 
V2 
ddMMMyyyy/hh:mm 
 
 
 
 
 
 
V5 
 
 
 
 
 
 
 
V11 
 
 
 
 
 
 
 
V13 
 
 
 
 
 
 
V17 
 
 
V20 
 
 
 
 
 
 
V27 
 
Repeat as 
other 
subjects
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 110 of 120 
Date: Mar 5th, 2023 
 
15. VACCINE EFFICACY LISTING 
Listing 10.4.1 Listing of&ŝƌƐƚ/ŶĨĞĐƚŝŽŶǀĞŶƚƐ;&/ƐͿ
 
 
 
 
 
 
Subject ID 
Group 
Per Protocol 
Population for 
Efficacy 
Start Date at Risk  
End Date at Risk 
At Risk Time 
(yrs) 
Event 
xxxxx 
Group 1 
Y 
ddMMMyyyy 
ddMMyyyy 
x.xx 
Yes/No 









Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 111 of 120 
Date: Mar 5th, 2023 
 
Listing 10.4.2 Listing of Parasitemia Test Results (ADI) 

Subject ID 
Group 
Visit 
Date of Sample 
Collection 
Parasitemia Test Results 
xxxxx 
Group 1 
Visit 19 
ddMMMyyyy 
Positive/Negative 




















Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 112 of 120 
Date: Mar 5th, 2023 
 


16. DEMOGRAPHICS FIGURES 
Figure 10.1.1: CONSORT Diagram 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 113 of 120 
Date: Mar 5th, 2023 
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 114 of 120 
Date: Mar 5th, 2023 
17. VACCINE EFFICACY FIGURES 
 
Figure 10.2.1: Kaplan-Meier survival curve for FIEs in Groups 1 and 4.   
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 115 of 120 
Date: Mar 5th, 2023 
Figure 10.2.2: Kaplan-Meier survival curve for FIEs in Groups 1 and 4 stratified by HIV status.   
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 116 of 120 
Date: Mar 5th, 2023 
Figure 10.2.3: Kaplan-Meier survival curve for FIEs in Groups 2 and 5.   
 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 117 of 120 
Date: Mar 5th, 2023 
Figure 10.2.4: Kaplan-Meier survival curve for FIEs in Groups 2 and 5 stratified by HIV status.   
 
Repeat the same survival curves for groups 1 and 2, groups 4 and 5 
Figure 10.2.5: Kaplan-Meier survival curve for FIEs in Groups 1 and 2
Figure 10.2.6: Kaplan-Meier survival curve for FIEs in Groups 4 and 5  
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 118 of 120 
Date: Mar 5th, 2023 
 
Figure 10.2.7: Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 1 and 4 FIEs during the entire study period (ATP cohort for efficacy) 
 
 
p-value=x.xxx 
 
 


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 119 of 120 
Date: Mar 5th, 2023 
 Figure 10.2.8: Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 2 and 5 FIEs during the entire study period (ATP cohort for efficacy)
 
p-value=x.xxx
 
 Repeat the same residual plots for groups 1 and 2, groups 4 and 5: 
 Figure 10.2.9: Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 1 and 2 FIEs during the entire study period (ATP cohort for efficacy)
Figure 10.2.10: Scaled Schoenfeld residuals with 95% confidence interval versus time for Groups 4 and 5 FIEs during the entire study period (ATP cohort for efficacy).  


Protocol No. CVIA-078; RTS,S/AS01 E  
STATISTICAL ANALYSIS PLAN 
 
Version: 4.0 
Confidential 
Page 120 of 120 
Date: Mar 5th, 2023 
18. IMMUNOGENICITY FIGURES 
Figure 10.3.1: Reverse Cumulative Distribution Curves for Anti-CS NANP Antibody Titers in Each Group (ATP cohort for immunogenicity) 
 
 
Repeat the same plots for Anti-CS C-terminal and Anti-HBsAb titers in Figures 10.2.6 and 10.2.7  
Figure 10.3.2: Reverse Cumulative Distribution Curves for Anti-CS C-term Antibody Titers in Each Group (ATP cohort for immunogenicity)
Figure 10.3.3: Reverse Cumulative Distribution Curves for Anti-HBsAb Titers in Each Group (ATP cohort for immunogenicity) 
 
 

Prot_001.pdf: 
CVIA 078 Study Protocol, version 6.0; 06 April 2023 
  WRAIR #2711 
Page 1 of 86 
A Phase 2b randomized, open-label, controlled, single center study in 
Plasmodium falciparum-infected and uninfected adults age 18-55 
years old in Kenya to evaluate the efficacy of the delayed, fractional 
dose RTS,S/AS01E malaria vaccine in subjects treated with 
artemisinin combination therapy plus primaquine 
Protocol Identifying Number: CVIA 078 
Principal Investigator: 
Co-Principal Investigator: 
Sponsor: PATH 
Funded by: PATH 
Version Number: 6.0 
WRAIR Number: 2711 
Date: 06 April 2023 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential investigators, consultants, 
study staff, and applicable independent ethics committees or institutional review boards.  The contents of this document 
shall not be disclosed to others without written authorization from PATH (or others, as applicable), unless it is necessary to 
obtain informed consent from potential study participants.
ClinicalTrials.gov NCT Number: NCT04661579


CVIA 078 Study Protocol, version 6.0; 06 April 2023                                           WRAIR #2711 
Page 2 of 86 
 
TABLE OF CONTENTS 
Table of Contents .......................................................................................................................................... 2 
List of Abbreviations ..................................................................................................................................... 7 
Statement of Compliance ........................................................................................................................... 10 
Protocol Summary ...................................................................................................................................... 11 
Schematic of Study Design .......................................................................................................................... 15 
Abstract ....................................................................................................................................................... 15 
Lay Summary ............................................................................................................................................... 16 
Main Protocol.............................................................................................................................................. 17 
1. KEY ROLES ............................................................................................................................................. 17 
2. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................... 20 
2.1. 
Background Information ............................................................................................................. 20 
2.2. 
Rationale ..................................................................................................................................... 22 
2.2.1. 
Study design rationale ........................................................................................................ 22 
2.2.2. 
Rationale for RTS,S/AS01E and rabies vaccine .................................................................... 23 
2.2.3. 
Rationale for antimalarials for treatment and prophylaxis ................................................ 23 
2.2.4. 
Rationale for using PCR as endpoint for vaccine efficacy ................................................... 24 
2.2.5. 
Rationale for immunology assays and timepoints .............................................................. 24 
2.3. 
Potential Risks and Benefits ........................................................................................................ 25 
2.3.1. 
Known Potential Risks and Risk Management .................................................................... 26 
 Risks of receipt of RTS,S/AS01E or rabies vaccine ........................................................... 26 
 Risks of receipt of dihydroartemisin-piperaquine .......................................................... 26 
 Risks of receipt of Coartem® ........................................................................................... 26 
 Risks of receipt of Primaquine ........................................................................................ 26 
 Risks of accidental disclosure of private medical information ....................................... 27 
 Risks of participation in the study ................................................................................... 27 
 Risks of phlebotomy ........................................................................................................ 27 
2.3.2. 
Known Potential Benefits .................................................................................................... 28 
3. OBJECTIVES AND PURPOSE .................................................................................................................. 28 
4. STUDY DESIGN AND ENDPOINTS .......................................................................................................... 29 
4.1. 
Description of the Study Design .................................................................................................. 29 
4.2. 
Study Endpoints .......................................................................................................................... 30 


CVIA 078 Study Protocol, version 6.0; 06 April 2023                                           WRAIR #2711 
Page 3 of 86 
 
4.2.1. 
Primary Endpoint ................................................................................................................ 30 
4.2.2. 
Secondary Endpoints .......................................................................................................... 31 
4.2.3. 
Exploratory Endpoints ......................................................................................................... 31 
5. STUDY ENROLLMENT AND WITHDRAWAL ........................................................................................... 32 
5.1. 
Participant Inclusion Criteria ....................................................................................................... 32 
5.2. 
Participant Exclusion Criteria ...................................................................................................... 32 
5.3. 
Strategies for Recruitment and Retention .................................................................................. 33 
5.3.1. 
Community information...................................................................................................... 33 
5.3.2. 
Recruitment ........................................................................................................................ 34 
5.4. 
Participant Withdrawal or Termination ...................................................................................... 34 
5.4.1. 
Reasons for Withdrawal or Termination ............................................................................. 34 
5.4.2. 
Handling of Participant withdrawals or termination .......................................................... 35 
5.5. 
Premature Termination or Suspensions of Study ....................................................................... 35 
6. STUDY VACCINE .................................................................................................................................... 35 
6.1. 
Study Vaccine and Antimalarial Medications ............................................................................. 35 
6.1.1. 
Acquisition .......................................................................................................................... 36 
6.1.2. 
Formulation, Appearance, Packaging, and Labeling ........................................................... 36 
6.1.3. 
Product Storage and Handling ............................................................................................ 37 
6.1.4. 
Preparation ......................................................................................................................... 37 
6.1.5. 
Dosing and Administration ................................................................................................. 37 
6.1.6. 
Route of Administration ...................................................................................................... 38 
6.1.7. 
Vaccination Schedule .......................................................................................................... 38 
6.1.8. 
Tracking of Dose .................................................................................................................. 38 
6.2. 
Study Vaccine Accountability Procedures ................................................................................... 38 
7. STUDY PROCEDURES ............................................................................................................................ 38 
7.1. 
Study procedures and evaluations .............................................................................................. 38 
7.1.1. 
Study specific procedures ................................................................................................... 38 
7.1.2. 
Standard of Care Study Procedures .................................................................................... 44 
7.2. 
Laboratory Procedures and Evaluations ..................................................................................... 44 
7.2.1. 
Clinical Laboratory Evaluations ........................................................................................... 44 
7.2.2. 
Other Assays or Procedures ................................................................................................ 44 
7.2.3. 
Specimen Preparation, Handling, and Storage ................................................................... 45 
7.2.4. 
Specimen Shipment ............................................................................................................ 45 


CVIA 078 Study Protocol, version 6.0; 06 April 2023                                           WRAIR #2711 
Page 4 of 86 
 
7.3. 
Study Schedule ............................................................................................................................ 45 
7.3.1. 
Final Study Visit ................................................................................................................... 45 
7.3.2. 
Unscheduled Visit ............................................................................................................... 46 
7.3.3. 
Schedule of Events Table .................................................................................................... 46 
7.4. 
Concomitant Medications, Treatments, and Procedures ........................................................... 46 
8. ASSESSMENT OF SAFETY ...................................................................................................................... 46 
8.1. 
Specification of Safety Parameters ............................................................................................. 46 
8.1.1. 
Definition of Adverse Events (AE) ....................................................................................... 46 
8.1.2. 
Definition of Serious Adverse Event ................................................................................... 47 
8.1.3. 
Definition of Unanticipated Problems ................................................................................ 47 
8.1.4. 
Definition of Adverse Events of Special Interest ................................................................. 48 
8.2. 
Classification of An Adverse Event .............................................................................................. 49 
8.2.1. 
Severity of Event ................................................................................................................. 50 
8.2.2. 
Relationship to Study Vaccine or Study scheduled anti-malarial treatment ...................... 50 
8.3. 
Time Period and Frequency of Event Assessment and Follow-up .............................................. 50 
8.4. 
Reporting Procedures ................................................................................................................. 51 
8.4.1. 
Serious Adverse Event Reporting ........................................................................................ 51 
8.4.2. 
Reporting Events of Special Interest ................................................................................... 52 
8.4.3. 
Unanticipated Problem Reporting ...................................................................................... 53 
8.4.4. 
Reporting of Pregnancy ....................................................................................................... 53 
8.5. 
Safety Oversight .......................................................................................................................... 54 
8.5.1. 
DoD Research Monitor ........................................................................................................ 54 
8.6. 
Solicited adverse events ............................................................................................................. 55 
8.6.1. 
Assessment of intensity ...................................................................................................... 55 
8.6.2. 
Assessment of causality ...................................................................................................... 56 
8.6.3. 
Follow-up and management of adverse events ................................................................. 56 
9. CLINICAL MONITORING ........................................................................................................................ 56 
10. STATISTICAL CONSIDERATIONS ............................................................................................................ 57 
10.1. 
Statistical Analysis Plan ........................................................................................................... 57 
10.2. 
Statistical Hypotheses ............................................................................................................. 57 
10.3. 
Analysis Datasets .................................................................................................................... 58 
10.3.1. 
Enrolled population............................................................................................................. 58 
10.3.2. 
Total vaccinated cohort (TVC) ............................................................................................. 58 


CVIA 078 Study Protocol, version 6.0; 06 April 2023                                           WRAIR #2711 
Page 5 of 86 
 
10.3.3. 
Safety analysis population .................................................................................................. 58 
10.3.4. 
According to protocol (ATP) cohort for efficacy ................................................................. 58 
10.3.5. 
ATP cohort for immunogenicity .......................................................................................... 58 
10.3.6. 
Total cohort for efficacy ...................................................................................................... 58 
10.4. 
Description of Statistical Methods .......................................................................................... 58 
10.4.1. 
General Approach ............................................................................................................... 59 
10.4.2. 
Analysis of the Primary Efficacy Endpoint ........................................................................... 59 
10.4.3. 
Analysis of the Secondary Endpoint(s) ................................................................................ 59 
10.4.4. 
Safety Analyses ................................................................................................................... 59 
10.4.5. 
Adherence and Retention Analyses .................................................................................... 60 
10.4.6. 
Baseline Descriptive Statistics ............................................................................................. 60 
10.4.7. 
Planned Interim Analyses .................................................................................................... 61 
10.4.8. 
Multiple Comparison/Multiplicity ....................................................................................... 61 
10.4.9. 
Exploratory Analyses ........................................................................................................... 61 
10.5. 
Sample Size ............................................................................................................................. 61 
10.5.1. 
Randomization Procedures ................................................................................................. 62 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................................ 62 
12. QUALITY ASSURANCE AND QUALITY CONTROL ................................................................................... 62 
13. ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................................................................ 63 
13.1. 
Ethical Standard ...................................................................................................................... 63 
13.2. 
Institutional Review Board ...................................................................................................... 63 
13.2.1. 
Ethics Approval ................................................................................................................... 63 
13.2.2. 
Protocol Amendments ........................................................................................................ 64 
13.2.3. 
Reporting requirements ...................................................................................................... 64 
 Continuing Review Reporting ......................................................................................... 64 
 Protocol Deviation Reporting .......................................................................................... 64 
 Reporting of Inspections or Audits ................................................................................. 65 
13.3. 
Informed Consent Process ...................................................................................................... 65 
13.3.1. 
Consent and Other Informational Documents Provided to Participants ............................ 65 
13.3.2. 
Consent Procedures and Documentation ........................................................................... 65 
13.4. 
Participant and Data Confidentiality ....................................................................................... 66 
13.4.1. 
Future Use of Stored Specimens ......................................................................................... 66 
13.5. 
Compensation ......................................................................................................................... 67 


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13.5.1. 
Compensation for injury ..................................................................................................... 67 
13.5.2. 
Compensation for subject participation ............................................................................. 67 
14. DATA HANDLING AND RECORD KEEPING ............................................................................................. 67 
14.1. 
Data Collection and Management Responsibilities ................................................................ 67 
14.1.1. 
Source Data ......................................................................................................................... 67 
14.1.2. 
Source documents .............................................................................................................. 67 
14.1.3. 
Data Capture Methods (CRF Development and Completion) ............................................. 68 
14.1.4. 
Data Management .............................................................................................................. 69 
14.1.5. 
Data Storage ........................................................................................................................ 69 
14.2. 
Study Records Retention and Disposal ................................................................................... 69 
14.3. 
Protocol Deviations ................................................................................................................. 69 
14.4. 
Publication and Data Sharing Policy ....................................................................................... 70 
15. CONFLICT OF INTEREST POLICY ............................................................................................................ 70 
16. STUDY LIMITATIONS AND POTENTIAL BIASES ...................................................................................... 70 
17. MILITARY RELEVANCE ........................................................................................................................... 70 
18. LITERATURE REFERENCES ..................................................................................................................... 71 
19. Appendices ........................................................................................................................................... 73 
APPENDIX A. SCREENING VISIT PROCEDURES ............................................................................................ 73 
APPENDIX B. EPOCH 1: TREATMENT AND IMMUNIZATION PHASE ............................................................ 74 
APPENDIX C. EPOCH 2: ACTIVE DETECTION OF INFECTION PHASE ............................................................ 76 
APPENDIX D. EPOCH 3: EXTENSION DETECTION OF INFECTION PHASE (IF REQUIRED) ............................. 78 
APPENDIX E. STUDY TERMINATION VISIT ................................................................................................... 80 
APPENDIX F. BIOLOGICAL SAMPLES FOR IMMUNOGENICITY TESTING ...................................................... 81 
APPENDIX G. ADULT NORMAL REFERENCE VALUES – KEMRI & USAMRD-A KISUMU CLINICAL 
LABORATORIES ............................................................................................................................................ 82 
APPENDIX H. WHO CLINICAL STAGING OF HIV INFECTION IN KENYA ........................................................ 83 
APPENDIX I. DETAILED ROLES AND RESPONSIBILITIES................................................................................ 84 
APPENDIX J: BUDGET .................................................................................................................................. 86 
 
 
 


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LIST OF ABBREVIATIONS 
ACT 
Artemisinin combination therapy 
ADI 
Active detection of infection 
AE 
Adverse event 
AESI 
Adverse event of special interest 
A/L 
Artemether/lumefantrine 
ALT 
Alanine aminotransferase 
anti-CS 
Antibody to P. falciparum circumsporozoite protein repeat region 
anti-HBs 
Antibody to hepatitis B surface antigen 
AS01 
GSK’s proprietary adjuvant system containing QS21, MPL, and liposomes 
ATP 
According to protocol 
BMGF 
Bill and Melinda Gates Foundation 
BP 
Blood pressure 
CRF 
Case Report Form 
CBC 
Complete Blood Count 
CDMS 
Clinical Data Management System 
CHW 
Community Health Worker 
CI 
Confidence Interval 
CMI 
Cell-mediated Immunity 
CMP 
Clinical Monitoring Plan 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CS 
Circumsporozoite protein 
DBS 
Dried blood spot 
DHA/Pip 
Dihydroartemisinin-piperaquine 
dL 
Deciliter 
DMP 
Data Management Plan 
DNA 
Deoxyribonucleic acid 
DOD 
Department of Defense 
DOT 
Directly observed therapy 
ECCT 
Expert Committee on Clinical Trials (ECCT) 
EDC 
Electronic date capture 
ELISA 
Enzyme-linked immunosorbent assay 
FDA 
Food and Drug Administration 
FV 
Field visit 
G6PD 
Glucose-6-Phosphate Dehydrogenase 
GCP 
Good Clinical Practice 
GHVAP 
Global Health Vaccine Accelerator Platform 
GMT 
Geometric Mean Titer 
GSK 
GlaxoSmithKline 
H0 
Null hypothesis 
H1 
Alternative hypothesis 


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Hb 
Haemoglobin 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HDSS 
Health and Demographics Surveillance System 
HIV 
Human immunodeficiency virus 
HJFMRI 
Henry Jackson Foundation Medical Research International 
HSPB 
Human Subject Protection Branch  
IAVI-HIL 
International AIDS Vaccine Initiative Human Immunology Laboratory 
IB 
Investigator's Brochure 
IEC 
Institutional Ethics Committee 
IMP 
Investigational Medical Product 
IRB 
Institutional Review Board 
ICH 
International Council for Harmonisation  
IM 
Intramuscular 
ITN 
Insecticide-treated bed net 
IU 
International Unit 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
JOOTRH 
Jaramogi Oginga Odinga Teaching and Referral Hospital 
KEMRI 
Kenya Medical Research Institute 
KEMRI SERU 
KEMRI Scientific and Ethical Review Unit 
KC 
KCRC Clinic visit 
KCRC 
Kombewa Clinical Research Center 
L 
Liter 
LD PQ 
Low dose primaquine 
MBF 
Malaria Blood Film 
MedDRA 
Medical Dictionary for Regulatory Activities 
mIU 
Milli-international units 
mL 
Milliliter 
MOP 
Manual of Procedures 
MPL® 
Monophosphoryl lipid A 
mRNA 
Messenger ribonucleic acid 
P. falciparum 
Plasmodium falciparum 
PATH REC 
PATH’s Research Ethics Committee 
PBMCs 
Peripheral Blood Mononuclear Cells 
PCR 
Polymerase chain reaction 
PI 
Principal Investigator 
PII 
Personally identifying information 
pIMD 
Potential immune-mediated disease 
PLT 
Platelet 
PPB 
Pharmacy and Poisons Board 
PPB ECCT 
PPB Expert Committee on Clinical Trials 
QA 
Quality Assurance 


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QC 
Quality Control 
QTc 
Corrected QT interval 
QS21 
Quillaja saponaria 21 
RDT  
 
Rapid diagnostic test for malaria 
rRNA 
Ribosomal ribonucleic acid 
RTS,S 
Protein comprising CS and hepatitis B surface antigen 
Rx 
Treatment 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SERU 
Scientific and Ethics Review Unit 
SOP 
Standard Operating Procedure 
TVC 
Total vaccine cohort 
µg 
Microgram 
µL 
Microliter 
µmol 
Micromole 
USAMRD-A 
US Army Medical Research Directorate-Africa 
USAMRDC 
U.S. Army Medical Research and Development Command 
VE 
Vaccine efficacy 
Vx 
Vaccine 
WBC 
White blood count 
WHO 
World Health Organization 
WRAIR 
Walter Reed Army Institute of Research 
 
 


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STATEMENT OF COMPLIANCE 
The signature below constitutes the approval of this protocol and the attachments and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements and ICH-GCP (E6) guidelines. 
 
 
 
 
Signed:  
 
Date: 
 
 


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PROTOCOL SUMMARY 
Title 
A Phase 2b randomized, open-label, controlled, single center study in Plasmodium 
falciparum-infected and uninfected adults age 18-55 years old in Kenya to evaluate the 
efficacy of the delayed, fractional dose RTS,S/AS01E malaria vaccine in subjects treated 
with artemisinin combination therapy plus primaquine 
Design 
The proposed trial design has been developed to answer several questions related to the 
nature of RTS,S vaccine efficacy in African adults that may be influenced by concurrent 
and/or past P. falciparum infection leading to a state of immunologic hypo-responsiveness. 
The proposed study design encompasses five groups. Three groups (Groups 1, 2, and 3) will 
be administered RTS,S/AS01E on a 0, 1, 7 month schedule with Dose 3 delivered as a 1/5th 
fractional dose shown below. Two groups (Groups 4 and 5) will be administered a 
comparator vaccine on a 0, 1, 7 month schedule. 
 
Group # 1 
Vaccine 
 
Sample 
size 
Baseline 
Parasitemia 
Anti-
malarial 
Rx 
Anti-malarial 
Rx rationale 
Group 1* 
RTS,S/AS01E 
164 
+ 
+ 
Clear 
parasites 
Group 2* 
RTS,S/AS01E 
128 
- 
+ 
Prophylaxis 
Group 3* 
RTS,S/AS01E 
35 
+ 
- 
- 
Group 4 
Rabies  
164 
+ 
+ 
Clear 
parasites 
Group 5 
Rabies 
128 
- 
+ 
Prophylaxis 
 
total 
619 
 
 
 
 
Group # 1 
Month -1 
Month 0 
(Vaccine 1) 
1-2 wks 
before Vx 
dose 2 
Month 1 
(Vaccine 2) 
1 wk before 
Vx dose 3 
Month 7 
(Vaccine 3) 
Month 
8 to 14 
Group 1* 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
A/L + LD PQ 
1/5th dose 
RTS,S/AS01E 
ADI 
Group 2* 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
A/L + LD PQ 
1/5th dose 
RTS,S/AS01E 
ADI 
Group 3* 
- 
RTS,S/AS01E 
- 
RTS,S/AS01E 
- 
1/5th dose 
RTS,S/AS01E 
- 
Group 4 
DHA/Pip + 
LD PQ 
Rabies 
DHA/Pip + 
LD PQ 
Rabies 
A/L + LD PQ 
Rabies 
ADI 
Group 5 
DHA/Pip + 
LD PQ 
Rabies 
DHA/Pip + 
LD PQ 
Rabies 
A/L + LD PQ 
Rabies  
ADI 
1 
Unsolicited AEs will be captured from all subjects in groups 1 to 5 for 28 days post anti-malarial 
treatment (DHA/Pip + LD PQ or A/L + LD PQ), as applicable, and following each immunization 
* 
The first 50 subjects from Groups 1 and 2, and all subjects in Group 3 will have solicited local and 
systemic AEs captured for 7 days after each immunization 
 
Vaccine efficacy rationale  
Groups of adults that are to be administered RTS,S/AS01E include individuals that differ 
with the presence/absence of baseline PCR-positive parasitemia that also receive anti-
malarial treatment to clear parasites. A rabies comparator vaccine (Abhayrab) is included in 
order to assess absolute vaccine efficacy (VE) against P. falciparum parasitemia and to 
investigate whether sub-optimal immune responses in previously infected or concurrently 


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infected adults is a general phenomenon independent of the vaccine antigen (RTS,S/AS01E 
versus rabies vaccine). 
 
The primary endpoint aims to elicit vaccine efficacy against P. falciparum infection  in  
African adults with sub-clinical PCR-positive parasitemia and treated to clear parasites prior 
to RTS,S/AS01E administration (Group 1) compared to adults with sub-clinical PCR-positive 
parasitemia and treated to clear parasites prior to administration of a comparator rabies 
vaccine (Group 4). 
 
The vaccine efficacy secondary endpoint assesses whether African adults administered 
RTS,S, negative for P. falciparum infection at baseline and given anti-malaria 
chemoprophylaxis (Group 2) can elicit high VE compared to adults administered a 
comparator rabies vaccine that are without infection at baseline and given anti-malaria 
chemoprophylaxis (Group 5). 
 
A smaller group of RTS,S-vaccinated subjects (Group 3) will be enrolled and followed only 
for immunological endpoints.  This group serves as the ‘positive control’ for immune 
dysregulation as a result of infection with P. falciparum, it is not powered to assess VE 
against P. falciparum parasitemia and subjects will not be treated with anti-malarial 
chemoprophylaxis in conjunction with vaccinations.  
 
Adults living in areas of moderate to high malaria transmission often have co-existing 
asymptomatic circulating blood stage P. falciparum parasites that results from multiple 
exposures to infective mosquito bites.  This has been recognized as inducing a level of 
immunologic hypo-responsiveness that may impede the development of a protective 
immune response following immunization. We hypothesize that treatment of malaria 
infection in individuals prior to immunization with the RTS,S/AS01 vaccine will reset the 
immune response to the vaccine and result in an increased vaccine efficacy.  
 
Immune profiling rationale  
In-depth immunological monitoring of CS-specific and HBsAg-specific antibodies will be 
assayed in all subjects from Groups 1, 2, and 3 (secondary objective). Note that the RTS,S 
antigen consists of sequences of both the P. falciparum circumsporozoite protein and 
Hepatitis B surface antigen and thus the testing for antibodies to both these antigens is 
included. In-depth immunological monitoring of rabies-specific antibodies will be assayed 
in the first 50 subjects from both groups 4 and 5 (exploratory objective).  
 
Anti-CS assays will include evaluating both the levels and avidity of antibody responses at 
PATH's reference center at Walter Reed Army Institute of Research (WRAIR). Anti-Hepatitis 
B surface antigen antibodies will be assessed at the International AIDS Vaccine Initiative 
Human Immunology Laboratory (IAVI-HIL) at Imperial College, London, UK, using a 
commercially available ELISA kit. Anti-rabies antibodies will be assessed at the Kansas State 
Veterinary Diagnostic Laboratory, Manhattan, Kansas. 
 
Cell-mediated immune (CMI) responses will be assessed in subjects from Groups 1, 2, and 3 
only (RTS,S-vaccinated cohort) and will be assayed at Stanford University, a Global Health 
Vaccine Accelerator Platform (GHVAP) partner of the Bill and Melinda Gates Foundation 
(BMGF). Other exploratory immunological assays evaluating the CS and HBsAg immune 


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responses, including but not limited to antibody isotype titer and isotype avidity, might be 
performed at additional BMGF partner organizations.  HLA typing as an exploratory 
endpoint may be performed to associate CS-specific immune responses with protection 
from P. falciparum infection. 
 
The results will inform our understanding on immune dysregulation in the context of 
antecedent or active P. falciparum infection. 
 
Objectives 
Primary Objective: To assess vaccine efficacy assessed by time to first P. falciparum 
infection in RTS,S vaccinated adults (Group 1) positive for P. falciparum by PCR at baseline 
and treated to clear parasites compared to adults administered a comparator vaccine 
(Group 4) positive for P. falciparum by PCR at baseline and treated to clear parasites. 
 
Secondary Objectives: 
Efficacy:  
• To assess vaccine efficacy by time to first P. falciparum infection in RTS,S vaccinated 
adults (Group 2) negative for P. falciparum by PCR at baseline and provided anti-malarial 
chemo-prophylaxis versus comparator group (Group 5) negative for P. falciparum by PCR at 
baseline and provided anti-malarial chemo-prophylaxis. 
 
Safety:  
• To assess the safety of RTS,S in terms of serious adverse events (SAEs) during the whole 
study period (from Dose 1 to study conclusion) 
• To assess the safety of RTS,S in terms of solicited adverse events within 7 days after each 
vaccination 
• To assess the safety of RTS,S in terms of unsolicited adverse events within 28 days after 
each vaccination 
 
Immunogenicity: 
• To assess anti-circumsporozoite (CS) antibody levels & avidity, hepatitis B surface 
antibodies (HBsAb), from select groups as shown in Appendix F. 
 
Exploratory Objectives: 
• To assess in subjects immunized with RTS,S/AS01E the relationship between HLA Class 1 
and Class 2 alleles with protection against P. falciparum infection. 
• To assess anti-rabies antibodies in a subset of subjects at time points from groups 4 and 5 
as shown in Appendix F. 
• To assess cell-mediated immune responses and transcriptomes in subjects from Groups 1 
– 3. 
• To assess malaria cross-sectional prevalence in all study participants at the end of the 
study. 
Note: additional immunological assays evaluating the immune response to CS and HBsAg 
might be performed. 
Endpoints 
Primary Endpoint:  The time to first malaria infection by PCR after completing vaccination 
in Groups 1 and 4 
 
Secondary Endpoints: 
Efficacy:  
• The time to first malaria infection by PCR after completing vaccination in Groups 2 and 5. 


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Safety:  
• Frequency count and proportion of subjects reporting serious adverse events (SAEs) 
during the whole study period (from Dose 1 to study conclusion) 
• Frequency count and proportion of subjects reporting solicited local and systemic adverse 
events within 7 days after each vaccination 
• Frequency count and proportion of subjects reporting unsolicited adverse events within 
28 days after each vaccination 
 
Immunogenicity: 
• Anti-circumsporozoite (CS) antibody levels & avidity and hepatitis B surface antibody 
(HBsAb) antibodies from subjects in Groups 1, 2, and 3 at time points indicated in Appendix 
F as measured by ELISA assays. 
 
Exploratory Endpoints: 
• 
Anti-rabies antibodies at timepoints indicated in Appendix F in subset of subjects in 
Groups 4 and 5. 
• 
Cell-mediated immune responses in subjects administered RTS,S/AS01E (Groups 1, 2, 
and 3) will be descriptive in nature. 
• 
RNA transcriptional responses for all subjects in Groups 1 – 5. 
• 
HLA typing in subjects administered RTS,S/AS01E (Groups 1, 2, and 3). 
• 
Cross-sectional malaria PCR/DBS at Study Termination visit in Groups 1 – 5. 
Note: additional immunological assays evaluating the immune response to CS and HBsAg 
might be performed. 
Population 
Adults 18 to 55 years old at enrollment, inclusive. 
Phase 
Phase 2b 
Number of 
sites 
enrolling 
participants 
One site; Kombewa Clinical Research Center, Kenya 
Description 
of study 
agent 
• 
RTS,S/AS01E vaccine 0.5mL, containing 25 µg RTS,S, 25 µg MPLs, 25 µg QS21 in a  
liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E 
vaccine for third immunization.  
• 
Comparator Abhayrab rabies vaccine (one dose, 0.5 mL, contains 2.5 IU rabies antigen). 
• 
Dihydroartemisinin-piperaquine (DHA/Pip) is a long acting anti-malarial.  
• 
Coartem®(artemether/lumefantrine); Coartem is a short-acting ACT that is used in this 
study to provide clearance of blood stage parasites before assessment of vaccine 
efficacy. It is used in this study to remove any confounding anti-malarial effects when 
analyzing time to infection and vaccine efficacy. 
• 
Primaquine; Low dose Primaquine (LD PQ) is an 8-aminoquinoline that clears stage 5 
gametocytes of P. falciparum.  
Study 
duration 
Estimated 20.5 months from when the study opens to enrollment until completion of last 
subject last visit. If ADI is extended to 12 months, then study duration will be an estimated 
26.5 months.  
Participant 
Duration  
 
Estimated 20.5 months it will take for each individual participant to complete all participant 
visits over the full 12-month ADI. If the number of events satisfying the primary and 
secondary endpoints has been achieved after at least 6 months of ADI, the trial will be 
truncated thus shortening the duration of participant participation.  


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SCHEMATIC OF STUDY DESIGN 
Table 1. Group Description 
Group # 1 
Vaccine 
Sample 
size 
Baseline 
Parasitemia 
Anti-malarial Rx 
Anti-malarial Rx rationale 
Group 1* 
RTS,S/AS01E 
164 
+ 
+ 
Clear parasites 
Group 2* 
RTS,S/AS01E 
128 
- 
+ 
Prophylaxis 
Group 3* 
RTS,S/AS01E 
35 
+ 
- 
- 
Group 4 
Rabies  
164 
+ 
+ 
Clear parasites 
Group 5 
Rabies 
128 
- 
+ 
Prophylaxis 
 
total 
619 
 
 
 
 
Table 2. Group Anti-malarial and Vaccine Schedule  
Group 
#1 
Month -1 
Month 0 
(Vaccine 1) 
1-2 wks 
before Vx 
dose 2 
Month 1 
(Vaccine 2) 
1 wk before 
Vx dose 3 
Month 7 
(Vaccine 3) 
Month 8 
to 14 
Group 
1* 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
A/L + LD PQ 
1/5th dose 
RTS,S/AS01E 
ADI 
Group 
2* 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
DHA/Pip + 
LD PQ 
RTS,S/AS01E 
A/L + LD PQ 
1/5th dose 
RTS,S/AS01E 
ADI 
Group 
3* 
- 
RTS,S/AS01E 
- 
RTS,S/AS01E 
- 
1/5th dose 
RTS,S/AS01E 
- 
Group 4 
DHA/Pip + 
LD PQ 
Rabies 
DHA/Pip + 
LD PQ 
Rabies 
A/L + LD PQ 
Rabies 
ADI 
Group 5 
DHA/Pip + 
LD PQ 
Rabies 
DHA/Pip + 
LD PQ 
Rabies 
A/L + LD PQ 
Rabies  
ADI 
1 
Unsolicited AEs will be captured from all subjects in groups 1 to 5 for 28 days post anti-malarial treatment (DHA/Pip + LD PQ or A/L + LD 
PQ), as applicable, and following each immunization 
* 
The first 50 subjects from Groups 1 and 2, and all subjects in Group 3 will have solicited local and systemic AEs captured for 7 days after 
each immunization 
 
ABSTRACT 
PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the 
burden of malaria disease in children and contribute to malaria elimination. GSK has developed a 
candidate vaccine against malaria caused by Plasmodium falciparum, RTS,S/AS01. The vaccine has been 
shown to be safe in multiple trials and efficacy data in pediatric populations has led to a pilot 
implementation program in three African countries including Kenya. The RTS,S/AS01 vaccine mechanism 
of action is presumed to work on the initial sporozoite and liver stages of P. falciparum infection through 
neutralization of the circumsporozoite (CS) antigen on parasites invading after a mosquito bite in 
individuals immunized with the RTS,S/AS01 vaccine. In order to inform whether a vaccine such as 
RTS,S/AS01 may have a future role in malaria elimination, it will be important to establish vaccine 
efficacy in adults in Sub-Saharan Africa who are reservoirs of parasites and who contribute to ongoing 
malaria transmission. However, in previous trials, the vaccine has been less effective in adults in 
endemic regions compared to challenge studies. While the cause of this is likely multi-factorial, there is a 
degree of immunologic hypo-responsiveness that occurs in endemic regions that may impede the 
development of a protective immune response following immunization that is presumed to be related 


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to chronic infection. This study postulates that treatment of infection prior to immunization can reset 
the immune response leading to an improved vaccine efficacy. To evaluate this hypothesis, the study 
will recruit 5 groups. Groups 1 and 4 will have asymptomatic infection with P. falciparum as measured 
by a highly sensitive PCR assay (planned assay is an RNA-based PCR though the backup utilizes both RNA 
and DNA PCR, see protocol for details) and will be treated with antimalarial medications prior to 
immunization with RTS,S/AS01 or the comparator rabies vaccine, respectively, with the primary 
objective of evaluating the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. 
Groups 2 and 5 will be negative for asymptomatic infection with P. falciparum as measured by a highly 
sensitive PCR assay and will be treated with antimalarial medications prior to immunization with 
RTS,S/AS01 or the comparator rabies vaccine, respectively, with the secondary objective of evaluating 
the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. Group 3 will have 
asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay but will not be 
treated with antimalarial medications prior to immunization with the RTS,S/AS01 vaccine; the 
immunological profile (including anti-CS and cell-mediated immune responses) of this group and groups 
1 and 2 will be evaluated as part of secondary and exploratory objectives. Other secondary objectives 
include safety assessments and other exploratory objectives defined in this protocol. A total of 619 
subjects will be enrolled (164 in groups 1 and 4, 128 in groups 2 and 5, and 35 in group 3) over a period 
of 6 months and will participate in the study for an initial immunization period (vaccine given on 0, 1, 
and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations) followed 
by 6-12 months of follow-up (varying based on the number of events), with the primary and secondary 
efficacy endpoints of time to first malaria infection by PCR. Total duration expected to be 20.5-26.5 
months. Those groups receiving antimalarial medications (1, 2, 3, 4) will receive either 
dihydroartemisinin-piperaquine or artemether/lumefantrine and low-dose primaquine as described in 
the protocol. 
LAY SUMMARY 
PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the 
burden of malaria disease in children and contribute to malaria elimination. GSK has developed a 
candidate vaccine called RTS,S/AS01 which helps the immune system of people vaccinated with 
RTS,S/AS01 prevent infection with the parasite that causes malaria. The RTS,S/AS01 vaccine has been 
shown to be safe in multiple studies around the world and is currently beginning a pilot implementation 
program in children in sub-Saharan Africa. The vaccine has been shown to be effective in adults who 
have never had malaria when they are challenged with malaria infection in the United States, but has 
been less effective when given to adults in Africa who have had malaria before. There are probably 
multiple reasons for this, but one possible reason that is probably very important is that prior infection 
with malaria or an infection with malaria for long periods, even without symptoms of the disease, can 
prevent the vaccine from working properly. This study is testing the question that if we treat individuals 
with antimalarial medications before giving the vaccine, will that make it more effective in people who 
have a history of malaria infection. The RTS,S/AS01 malaria vaccine will be compared to a rabies vaccine 
to see if this will improve the effectiveness. We will also be looking at the safety of the vaccine and the 
response of the immune system to this vaccine. 
 
 




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Investigator, 
Kombewa Clinical Research Center, 
HJFMRI/USAMRD-A 
P.O. Box 54-40100, 
Kisumu, Kenya 
    
 
 
 
Investigator, 
Kombewa Clinical Research Center, 
KEMRI/USAMRD-A 
P.O. Box 54-40100, 
Kisumu, Kenya 
  
 
 
  
Study Coordinator 
 
KEMRI/USAMRD-A, 
P.O. Box 54-40100, 
Kisumu, Kenya 
  
DOD Research Monitor 
 
 
 
KEMRI/USAMRD-A, 
P.O. Box 54-40100, 
Kisumu, Kenya 
  
Sponsor  
PATH 
2201 Westlake Avenue, Suite 200 
Seattle, Washington, 98121, United States 
WRAIR IRB 
Walter Reed Army Institute of Research 
Office of Research Management 
503 Robert Grant Avenue 
Silver Spring, MD 20910-7500 
USA 
Phone: +001.301.319.9940 
Fax: +001.301.319.9961 
Email:  usarmy.detrick.medcom-wrair.mbx.hspb@health.mil    


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KEMRI Scientific and 
Ethical Review Unit 
Secretary 
KEMRI SERU, c/o Kenya Medical Research Institute 
PO Box 54840, Nairobi, Kenya.  
Phone: +254.20.272.25.41 
Email : kemriseru18@gmail.comseru@kemri.go.ke  
GSK Clinical Safety 
Physician 
GlaxoSmithKline Biologicals 
Rue de l’Institut 89, 1330 Rixensart, Belgium 
Phone: +32.2.656.87.98 
Fax: +32.2.656.80.09 
Email: rix.ct-safety-vac-@gskbio.com  
Funder 
PATH 
Immunology Laboratories  WRAIR Malaria Serology Reference Center 
Immunology Core 
US Military Malaria Research Program 
503 Robert Grant Ave, 3W53 
Silver Spring, MD 20910, United States 
Phone: 301-319-9278    
Email: elke.s.bergmannleitner.civ@mail.mil  
International AIDS Vaccine Initiative Human Immunology 
Laboratory (IAVI-HIL)  
Imperial College, London, UK 
Phone: 020 331 56307 
Email c.wenden@imperial.ac.uk  
Kansas State Veterinary Diagnostic Laboratory 
College of Veterinary Medicine 
Kansas State University 
2005 Research Park Circle, Room 1014 
Manhattan, Kansas 66502, United States 
Email: sgatrell@vet.k-state.edu  
The Human Immune Monitoring Center (HIMC) 
Stanford University 
Palo Alto, CA 
Phone: 650-723-1671 
Email: maecker@stanford.edu 
Pharmacy 
 
Pharmacist, 
Kombewa Clinical Research Center, 
HJFMRI/USAMRD-A 
P.O. Box 54-40100, 
Kisumu, Kenya 
  
CRO -1 
Triclinium Clinical Development (Pty) Ltd (TCD) 
Design House, 121 Amkor Road, Centurion 0157, Gauteng, 
South Africa  


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CRO -2 
DFnet Research, Inc. (DFnet) 
140 Lakeside Ave, Seattle, WA 98122, United States  
 
The Principal Investigator, will be responsible for the overall conduct of the trial at this study site, 
administrative actions between USAMRD-A, Institutional Review Boards, and the sponsor, oversight of 
field activities and patient care. Both the Principal Investigator and Co-Principal investigator contributed 
to the protocol development and will contribute to the statistical analysis and writing of the scientific 
report(s). 
All Clinical Investigators listed above will be responsible for the clinical conduct of the trial, the care 
provided to patients, oversight of field activities, and will contribute to the statistical analysis and writing 
of scientific report(s). Dr. Ben Andagalu also contributed to the protocol development. See Appendix I 
for detailed roles and responsibilities for this study. 
2. INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1. Background Information 
PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the 
burden of malaria disease in children and contribute to malaria elimination. The latter will ultimately 
require extension of the target group for the vaccine beyond children to adults who contribute to 
malaria parasite transmission in endemic countries. GSK has developed a candidate antigen against 
malaria caused by Plasmodium falciparum, RTS,S/AS01. The RTS,S antigen consists of sequences of the 
circumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) and is formulated with an 
adjuvant AS01 (liposome formulation with 3-O-desacyl-4’-monophosphoryl lipid A (MPL) and Quillaja 
saponaria Molina, fraction 21 (QS21) immunostimulants).  
Vaccines containing the RTS,S antigen are being developed by GSK primarily for the prevention of 
disease in children in malaria-endemic countries, and therefore most of the data referring to the safety, 
immunogenicity and reactogenicity has, to date, been collected in the pediatric population in Africa [1-
4]. The RTS,S/AS01 vaccine has progressed through sequential stages of evaluation in trials in both 
adults, young children, and infants in Africa to evaluate safety and proof-of-concept efficacy trials. The 
vaccine has been shown to be safe, with acceptable reactogenicity. Efficacy against malaria in both 
controlled human challenge trials [5,6] and in field trials have been demonstrated [1-4]. Refer to the 
Investigators Brochure for details on the safety, reactogenicity, and efficacy.  
The mechanism by which the RTS,S malaria vaccine works to reduce the frequency and severity of 
clinical disease episodes is presumed to be through its effect on the initial sporozoite and liver stage 
parasite burden, leading to a significant reduction of the infectious inoculum of liver stage merozoites 
released into the blood stream. This hypothesis is fully consistent with the data observed in clinical trials 
of RTS,S/AS01 to date. Biologically, this occurs through the neutralization of the CS antigen on the 
surface of sporozoites after the bite of an infected anopheline mosquito by antibodies elicited after 


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RTS,S immunization [7]. Sterile protection in a person, as defined by the absence of blood stage 
parasites, prevents onward sexual-stage gametocyte transmission to mosquitoes. 
RTS,S/AS01 has been found to be highly immunogenic and in human challenge studies performed in 
Europe and the United States the RTS,S/AS01 vaccine prevents or delays infection as measured by sterile 
protection against peripheral blood stage parasitemia [5,6].  Depending upon dose and schedule, 
vaccine efficacy (VE) varies widely.  While the Phase 3 evaluation of the RTS,S/AS01 candidate malaria 
vaccine was ongoing, PATH and GSK continued to investigate ways to further improve VE and duration 
of protection. Higher VE levels may lead to improved malaria control and contribute to the malaria 
elimination goal set as a long-term target by the global health community. An important milestone was 
achieved in 2014–2015, when an alternative regimen of RTS,S/AS01—in which the third dose is delayed 
by six months and fractionated to one-fifth (1/5th) of the standard dose (thus the term “FxRTS,S”) 
achieved 87% protection (95% CI: 67–95), compared to 63% (95% CI: 20–80) for the standard full-dose 
regimen, in a controlled human malaria infection (CHMI) study [6].  Based on these results, the 
GSK/PATH partnership decided to proceed to a Phase 2b field study (MAL094), in young African children 
(ages 5 to 17 months), to evaluate the potential of FxRTS,S to prevent naturally acquired P. falciparum 
infection.  
In order to inform whether a vaccine such as RTS,S/AS01 may have a future role in malaria elimination, it 
will be important to establish vaccine efficacy in adults in Sub-Saharan Africa who are reservoirs of 
parasites and who contribute to ongoing malaria transmission. When the RTS,S/AS01 vaccine was 
evaluated in adults in an area of Western Kenya with moderate P. falciparum malaria transmission, VE 
was modest compared to individuals receiving a comparator rabies vaccine (VE  4 months of follow-up; 
29.5% (95% CI: -15.4 to 56.9, p = 0.164 vs control) and parasite prevalence at 16 weeks after the third 
vaccine dose was similar in subjects administered RTS,S/AS01 8.6% (95% CI 3.2 to 17.7) or the rabies 
comparator vaccine 4.2% (95% CI 0.9 to 11.9) [8].  
The reason for the differences in VE between adults in USA following CHMI and adults in Kenya 
following natural infection are unknown but may be attributable to various factors, including host 
genetic differences, parasite differences between challenge strain and naturally occurring parasites, and 
the presence of concurrent malaria infection during the immunization period. Additionally, significant 
and pronounced differences in anti-CS repeat antibody titers were observed between adults in the US 
and Kenya where anti-CS NANP repeat titers in US adults administered RTS,S/AS01 were approximately 
3 times higher than antibody titers of African adults.  
Despite a general decline in malaria in Kenya over the past 10-15 years, the study area in the western 
part of Kisumu County, Kenya remains holoendemic for malaria with moderate to high malaria 
transmission throughout the year, peaking during the rainy seasons. Adults living in areas of moderate 
to high malaria transmission, such as the study site catchment area, often have co-existing 
asymptomatic circulating blood stage P. falciparum parasites that results from multiple exposures to 
infective mosquito bites. In 2017, Dr. Andagalu completed the malaria Transmission Dynamic Study that 
showed in our study catchment area we have a 36% point-prevalence of asymptomatic parasitemia (vs. 
0.6% point-prevalence of symptomatic malaria during the same time period, resulting in 98.5% of 
individuals with detectable Plasmodium being asymptomatic) in adults over the course of the 1-year 
study [data unpublished]. Chronic infection has been recognized as inducing a level of immunologic 
hypo-responsiveness that may impede the development of a protective immune response following 


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immunization [9-15]. It is recognized that immunologic hypo-responsiveness as measured by decreased 
immune response to malaria and other infectious pathogens is influenced by concurrent asymptomatic 
sub-microscopic parasitemia and/or by prior malaria infection inducing both T cell exhaustion and B cell 
memory dysfunction. Preclinical models reveal an impaired ability to generate anti-CS antibody levels 
compared to animals whose parasitemia was cleared with anti-malarials [10]. Since the RTS,S/AS01 
vaccine does not elicit immune responses that kill existing blood stage parasites, but rather acts by 
neutralizing the infectious sporozoites delivered after an Anopheline mosquito bite, it may be necessary 
to clear blood stage infections with anti-malarial medications either prior to, or at the time of 
immunization to optimize vaccine take and induce higher and more potent antibodies. We hypothesize 
that treatment of malaria infection in individuals prior to immunization with the RTS,S/AS01 vaccine will 
reset the immune response to the vaccine and result in an increased vaccine efficacy compared to a 
rabies comparator. 
2.2. Rationale 
A vaccine such as RTS,S/AS01, which may be considered in malaria elimination strategies, would 
presumably have limited use if vaccine efficacy is compromised by co-existing sub-clinical malaria 
infections. The minimal threshold of vaccine efficacy needed to demonstrate an effect on reducing 
transmission is not known. We hypothesize that anti-malarial pre-treatment of individuals with 
coexisting malaria infections or prophylactic treatment to prevent malaria infection during the 
immunization period would elicit favorable vaccine efficacy in RTS,S/AS01-vaccinated individuals 
compared to individuals administered a  comparator vaccine (i.e. rabies) thereby restoring the 
immunologic setpoint. We also hypothesize that RTS,S/AS01 vaccine efficacy against a comparator 
vaccine would elicit favorable efficacy in individuals negative for P. falciparum infection and under 
malaria chemoprophylaxis during the immunization period (secondary objective). 
2.2.1. Study design rationale 
The underlying premise is that vaccines that may be considered in novel malaria control and/or malaria 
elimination initiatives in Sub-Saharan Africa would include anti-malarial drug administration in 
conjunction with other tools (ITNs, vector control). This study addresses the hypothesis with a design 
that is cost-effective and efficient (single study center, appropriate sample size, study completion within 
26.5 months, and also provides actionable knowledge based on both vaccine efficacy and immunological 
readouts likely to contribute to our understanding of immune exhaustion and correlates of protection.  
The study design below is not intended to represent the optimal dosage and vaccine schedule for 
RTS,S/AS01 (indicated for malaria elimination) under investigation elsewhere. There are several 
operating assumptions: 
a) It is assumed that RTS,S/AS01E formulation is appropriate in adults based on unpublished data 
from MAL-092, see Table 3. 
b) It assumes that a 0, 1, 7 month immunization schedule will elicit protective levels of anti-CS 
antibody 
c) It assumes that fractional 1/5th dose of RTS,S/AS01E delivered as the 3rd dose enhances 
immunogenicity 


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d) It assumes that a one-month window following clearance of asexual stage parasites in groups 
with baseline positive P. falciparum parasitemia is sufficient to reset the immunological set-
point  
e) It assumes an incidence rate of 40% per 6 months of observation with 50% VE as determined 
from Cox proportional hazard model for time to 1st infection identified by PCR (planned to be 
RNA-based PCR throughout protocol, though see section 2.2.4 for details) for sample size 
estimates (assumption of incidence rate based on unpublished data from the Transmission 
Dynamic Study by Dr. Ben Andagalu performed in our study catchment area). 
The practical implications for understanding whether concurrent P. falciparum malaria infection affects 
vaccine-take may likely influence if and how to best deliver RTS,S/AS01 or 2nd generation CS-based 
vaccines through strategies that employ anti-malarial medications that clear infection thereby resetting 
the immunological set point for optimal vaccine take. 
2.2.2. Rationale for RTS,S/AS01E and rabies vaccine 
The rationale to immunize with RTS,S/AS01E in African adults was based on comparable vaccine efficacy 
in CHMI challenge models in the U.S. comparing RTS,S/AS01B (a vaccine formulation in which a 0.5mL 
dose contains twice the active ingredients as RTS,S AS01E; 50 µg RTS,S, 50 µg MPL, 50 µg QS21 in a 
liposomal formulation) to the efficacy observed with the pediatric formulation, RTS,S/AS01E on a 0, 1, 7 
month immunization schedule where the 3rd vaccine dose was delivered as a 1/5th dose (FxRTS,S) (Table 
3).  
Table 3.  Malaria-092 CHMI trial in US 
RTS,S/AS01 
formulation 
RTS,S 
µg/immunization* 
Schedule 
(months) 
# 
Enrolled 
# 
Challenged 
# Uninfected 
(% 
uninfected) 
VE (95%CI)  
RTS,S/AS01B 
50-50-10 
0,1,7 
26 
20 
11 (55%) 
51% (19,70) 
RTS,S/AS01E 
25-25-5 
0,1,7 
26 
22 
14 (64%) 
60% (30,77) 
Infectivity controls 
  
  
24 
24 
2 (8%) 
- 
GSK data on file, Malaria-092 Clinical Study Protocol 
Rabies vaccine has been selected as the comparator because the vaccine has been used in previous 
studies of RTS,S-based vaccines in Africa, there is a validated serological marker for protection, and the 
subjects may benefit from receiving rabies vaccine as rabid animals occur in the study area. 
2.2.3. Rationale for antimalarials for treatment and prophylaxis 
We selected dihydroartemisin-piperaquine (DHA/Pip) for its pK properties with extended half-life of 
approximately 22 days in adults.  We designed the study to optimize parasite clearance in subjects that 
are positive for baseline parasitemia (Groups 1 and 4) at enrollment and that would be predicted to be 
“parasite-free” for an extended period of time between immunizations due to the ACT’s extended half-
life.  For those subjects that are parasite-negative at enrollment (Groups 2 and 5), we chose DHA/Pip for 
its prophylaxis effects.  
We selected artemether/lumefantrine (A/L; Coartem®) to be given prior to 3rd vaccine dose for its short 
half-life and to clear any volunteer subjects of blood stage parasites in order to establish a clean baseline 
for determination of vaccine efficacy during the active detection of infection (ADI) period of observation.  


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We selected low dose Primaquine (LDPQ, 15 mg) so as to clear circulating mature sexual stage 
gametocytes. 
2.2.4. Rationale for using PCR as endpoint for vaccine efficacy  
As this is an experimental medicine trial, we sought to use a molecular-based PCR assay to detect the 
presence of malaria parasites after exposure to infectious Anopheline mosquito bites. Since the majority 
of adults residing in the study area (western Kisumu County, see 5.3.2 for full description) may be semi-
immune to malaria infection due to frequent prior infections, a highly sensitive PCR is critical to detect 
sub-clinical parasitemia in subjects who otherwise may be negative when tested using more traditional 
methods of diagnosis such as malaria blood film (MBF) or rapid diagnostic tests (RDTs). The PCR assay to 
be used in this trial is a qualified assay, Plasmodium falciparum/ Pan-Plasmodium 18S rRNA LDT, used 
routinely in the US Army Medical Research Directorate-Africa (USAMRD-A) Laboratories in Kisumu, 
Kenya where the SOP is maintained.   A positive PCR result from blood samples collected at any of the 
time points during the trial will be recorded as a positive event for the presence of P. falciparum blood 
stage infection, and the time to positive first event for each subject will determine the vaccine efficacy 
between the different groups. 
In the event that a subject at any time during the trial experiences symptoms such as fever, chills, 
headache, and myalgia consistent with clinical malaria (prompting an unscheduled visit), clinicians at the 
Kombewa Clinical Research Center (KCRC) will collect a blood sample for routine diagnosis for malaria 
(MBF and/or RDT) along with a sample for PCR and a dry blood spot (DBS). If the diagnostic test is 
positive for the detection of malaria, the subject will be treated with standard of care anti-malarial 
medication. A PCR will also be done on a sample of blood collected among those currently undergoing 
ADI (groups 1, 2, 4, and 5; during ADI phases: Epoch 2 and 3; see Appendices C & D), and the results 
(positive or negative for P. falciparum) will be recorded and used for endpoint definitions both in ADI 
and passive case detection.   
2.2.5. Rationale for immunology assays and timepoints 
For secondary and exploratory immunogenicity endpoints, we chose to collect serum samples from all 
subjects in Groups 1 - 5 before and after each immunization.  
CS-repeat and C-term antibody levels and avidity will be quantified in groups 1-3 using a qualified ELISA-
based assay at WRAIR. Anti-CS antibody levels and avidity have previously been associated with 
protection against infection in CHMI trials and against clinical malaria in field trials in Sub-Saharan 
African children. Anti-HBsAg will be measured from subjects in groups 1-3.  
A primary exploratory objective is to assess whether immune hypo-responsiveness in cellular-based 
assays using PBMCs can be reversed with anti-malarial treatment in subjects that have been 
administered the RTS,S malaria vaccine. As an exploratory endpoint, serologic assays that measure 
antibody responses to the comparator rabies vaccine will be measured in the first 50 subjects from 
Groups 4 and 5 at the timepoints shown in Appendix F.  
PBMC collection and the assays for evaluating the cellular immune response are exploratory in nature; 
they include multi-color flow cytometry in excess of 20 different cellular markers.  Such exploratory 
assays will evaluate vaccine antigen-specific immune responses elicited by the RTS,S vaccine in order to 
evaluate whether immune exhaustion is a prominent feature related to the presence or absence of 


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asymptomatic baseline parasitemia and how reversal of immune exhaustion affects the RTS,S-elicited 
immune response and protection against P. falciparum infection. As such, the requirement to draw 
additional blood for PBMC from the comparator vaccine groups is not justified.  
PBMC will be collected at four timepoints from subjects administered the RTS,S malaria vaccine (Groups 
1, 2, and 3).  The nature of the exploratory cellular assays is based on measuring cell surface and/or 
intracellular markers on peripheral blood mononuclear cells using either multi-color flow cytometric 
panels or CYTOF panels to be conducted at the GHVAP Laboratories in the U.S.   
Exploratory analysis using whole blood that analyzes mRNA transcripts from all subjects may be 
analyzed. Such analysis would measure transcriptomes that change as a result of anti-malarial 
chemotherapy or change the innate immune transcriptional responses immediately before and after 
vaccination. Such transcriptional analysis will be limited to understanding the immune responses related 
to immunization and will not be used to identify specific genetic traits or diseases. 
HLA typing as an additional exploratory endpoint from subjects administered RTS,S/AS01E may be 
performed in order to associate immune responses to CS with protection from P. falciparum infection. 
Because RTS,S/AS01E is a vaccine composed of the hepatitis B surface antigen in which the CS antigen is 
co-expressed, and the strong association of the immune response to Hepatitis B surface antigen that is 
influenced by a persons’ MHC background, it is reasonable to ask whether there is any linkage between 
protection after malaria challenge in African subjects administered RTS,S/AS01E as has been 
demonstrated previously in U.S. based RTS,S/AS01-vaccinated subjects undergoing CHMI [16]. HLA 
typing will be limited to understanding the immune responses related to immunization and will not be 
used to identify specific genetic traits or diseases. 
The timepoints for all immunological assays are indicated in Appendices B, C, D and E and are 
summarized in Appendix F. 
2.3. Potential Risks and Benefits 
Details of potential risks are provided in the Investigator’s Brochure for RTS,S/AS01. Potential risks for 
licensed products to include DHA/Pip, Coartem®, Primaquine, and Abhayrab® are included below and 
details may be found in the package insert for the product.  
As indicated in section 5.2, pregnant women are excluded from participating in the vaccination portion 
of this study. While pregnant women and their fetuses are particularly susceptible to the effects of P. 
falciparum malaria, this study will exclude women who are pregnant at the time of screening, or who 
become pregnant during the immunization phase of the study for two reasons. First and foremost, the 
safety of the RTS,S/AS01E vaccine (intended for immunization of young children 5-17 months of age 
only) has not been previously evaluated in nonclinical reproductive toxicology studies by GSK.  This 
requirement for nonclinical toxicology is recommended in the draft FDA guidance document on the 
inclusion of pregnant women in clinical trials (https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/pregnant-women-scientific-and-ethical-considerations-inclusion-clinical-trials). 
Secondly, the current study is an experimental medicine study to examine whether immune 
hyporesponsiveness to a model CS-based vaccine (in this case RTS,S/AS01E) is observed in adults who 
may or may not be infected with P. falciparum parasites at the time of immunization. The study is not 
intended to support a clinical development plan for regulatory approval in either adult men or women.   


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2.3.1. Known Potential Risks and Risk Management 
 Risks of receipt of RTS,S/AS01E or rabies vaccine  
Recipients of any of the investigational (RTS,S/AS01E) or licensed products in this study (Abhayrab rabies 
vaccine) may experience pain and/or swelling at the injection site, fever, headache, fatigue, nausea, 
vomiting and/or abdominal pain, joint pain and/or muscle aches. As with any vaccination, there is the 
potential for an anaphylactic reaction. Additionally, there may be other reactions that at this time are 
not known. To facilitate management of these potential problems, medical staff experienced in the 
management of anaphylactic reaction will observe patients for at least 30 minutes following each 
vaccination to ensure that should any anaphylactic reaction occur it is managed in a timely manner. 
Subjects will be provided a follow up by study staff 7 days after each immunization of investigational 
product in order to assess solicited and unsolicited adverse events that may have occurred on the day of 
vaccination plus 6 additional days. In the large Phase III study, MALARIA-055, an imbalance of meningitis 
cases of any etiology (i.e. including cases with confirmed etiology and cases with no etiology found), 
with no cluster in time-to-onset, has been observed in children 5-17 months of age at first dose 
[reference 1]. Meningitis has not been a safety concern in RTS,S studies in adults. Potential immune-
mediated disease (pIMD) is a theoretical concern with adjuvanted vaccines as no evidence of 
autoimmune disease caused by RTS,S/AS01 has been observed. Nonetheless, both meningitis and pIMDs 
will be monitored as AEs of specific interest for the duration of the study. 
 Risks of receipt of dihydroartemisin-piperaquine  
The ADRs noted for DHA/Pip were generally mild in severity, and the majority were non-serious. 
Reactions such as cough, pyrexia, headache, P. falciparum infection, anaemia, asthenia, anorexia and 
the observed changes in blood cell parameters are consistent with those expected in patients with acute 
malaria. The effect on prolongation of the QTc interval has been observed on Day 2, but had resolved by 
Day 7 (the next time point at which ECGs were performed). To ensure compliance, Dose 1 of DHA/Pip 
will be given under the supervision of a medical provider at KCRC.  Dose 2 and Dose 3 of DHA/Pip will be 
given under the supervision of a fieldworker. Any subjects who are unwell at these visits will be referred 
to a study clinician at KCRC for evaluation and treatment. 
 
 Risks of receipt of Coartem®  
Subjects who receive Coartem® may experience abdominal pain, anorexia, nausea, vomiting, diarrhea, 
headache and/or dizziness. To ensure compliance, subjects will receive the first dose of Coartem® under 
the supervision of a medical provider at KCRC. Dose 2 and Dose 3 of Coartem® will be given under the 
supervision of a fieldworker. Any subjects who are unwell at these visits will be referred to a study 
clinician for evaluation and treatment. 
 Risks of receipt of Primaquine  
Subjects who receive primaquine may experience abdominal pain, nausea, vomiting, diarrhea, dizziness, 
pruritis, and anemia. Standard dose primaquine is contraindicated in subjects with severe glucose-6 
phosphate dehydrogenase (G6PD) deficiency due to the risk of hemolytic anemia. However, a single low 
dose (15 mg primaquine base) is safe in individuals with G6PD deficiency and recommended by the 
WHO for the clearance of sexual stage gametocytes of P. falciparum without specific testing for G6PD in 


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adults (except in pregnant or breastfeeding women) 
[https://www.who.int/malaria/publications/atoz/who htm gmp 2015.1.pdf?ua=1]. 
Primaquine is contraindicated in pregnant women. A single low dose 15 mg base of primaquine will be 
given under the supervision of a medical provider at KCRC. Any subjects who are unwell at these visits 
will be referred to a study clinician for evaluation and treatment. G6PD status will not be considered in 
the context of low dose primaquine administration though testing will be performed in the context of 
assessing the role of hemoglobinopathies that may impact time to infection detection after an infective 
mosquito bite.  
 Risks of accidental disclosure of private medical information  
In order to ensure that all information collected on study volunteers is kept confidential, the following 
safeguards will be applied:  Access to study files and personal information will be limited to study 
personnel, ethics committees, regulatory authorities, and sponsor.  Study information will be kept in 
locked rooms when not in use. All information or samples that leave USAMRD-A will be labeled with a 
unique study identification number and have no personal identifying information (PII). Any link between 
individual study identification number and an individual’s PII (e.g., an individual’s study file and 
associated documents) will be maintained at KCRC in accordance with site SOPs to maintain each 
individual’s confidentiality. 
There may be additional risks associated with disclosure of subjects’ HIV status as well as disclosure of 
any abnormal lab tests found during screening. In the case of HIV, subjects who are tested will undergo 
pre- and post-test counseling in accordance with Kenyan Ministry of Health Guidelines.  There is risk of 
disclosure of the subjects’ HIV status, and careful measures will be taken to ensure confidentiality is 
maintained. Standard pre-testing and post-testing counseling and linking to care will be followed. To the 
greatest extent possible, abnormal tests will be communicated to participants and screen failures in 
simplified language and referrals made to their regular health care provider as appropriate. 
 Risks of participation in the study  
If a participant is hurt as a direct result of participating in this study, the medical care will be provided by 
the study team at the respective research centers and the study will pay for the expenses. If the injury 
requires hospital admission, the participants will be admitted at the Kombewa Sub-County Hospital or 
the Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH) as appropriate. If specialized 
treatment is required, they will be referred to relevant hospitals for management and the study will pay 
for medical expenses. 
 Risks of phlebotomy 
Venipuncture is a routine clinical procedure the medical community commonly uses to obtain blood 
samples.  Immediate complications may be slight pain during the entry of the needle into the skin, very 
rarely possible dizziness and syncope.  Additionally, a hematoma may result from the venipuncture, but 
this has minimal risk.  Infection of the skin/soft tissue at the puncture site, vein, or blood stream can all 
occur, though are very rare with both finger sticks and venous blood draws.  Late complications might 
include thrombosis of the vein due to trauma or infection.  These complications are extremely rare.  
Participant monitoring, aseptic technique, including sterile disposable blood collection apparatus and 
adherence to standard medical precautions reduce any risk to a minimum.  A credentialed phlebotomist 


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or member of the clinical team experienced in venipuncture techniques will perform all venipunctures. 
The amount of blood to be taken for sampling will not be harmful to the subject’s health.  
2.3.2. Known Potential Benefits 
All volunteers for this study will receive the following benefits for their participation: 
• 
All volunteers will undergo a medical examination at screening free of charge. All volunteers, 
whether accepted for enrolment into the trial or not will benefit from this free health check-up. 
The results of all tests will be communicated to all volunteers. Where illnesses are newly-
diagnosed, a referral to an appropriate health provider will be made for the volunteer. 
• 
For the duration of their participation in the trial, all randomized subjects will receive free health 
care for acute conditions. In case of chronic conditions, subjects will be referred to appropriate 
health providers.  
• 
All enrolled subjects in RTS,S groups will be offered free of charge a full three-dose course of 
vaccinations against rabies to occur following the completion of the study. The vaccine offered 
will be either the same Abhayrab rabies control vaccine received by participants randomized to 
groups 4 or 5, or another licensed rabies vaccine available in Kenya at the time of completion of 
the study. Subjects who are randomized to receive the rabies control vaccine will receive these 
vaccinations during the course of the trial. Rabies is present among animals in Kisumu County, 
Kenya, and vaccination will provide pre-exposure protection against rabies to participants. 
• 
The care that is provided is by KEMRI/USAMRD-A staff working in collaboration with staff at the 
Kombewa Sub-County Hospital, the JOOTRH or other hospitals depending on the condition of 
the patient.  This will include treatment for symptoms caused by the study products 
(drugs/vaccines) or participation in the study as well as treatment for any acute illnesses during 
the study period. Individuals with acute medical problems requiring specialist attention not 
available on site will be referred appropriately and this cost will be covered by the study.   The 
site does not provide routine medical care for non-study participants.  However, poor access to 
appropriate diagnostics and medications (and personnel) at Ministry of Health facilities is well 
documented.  The sites have clinicians involved in the study and the study participants will be 
followed closely throughout the duration of the study and will have access to medical personnel, 
basic diagnostic evaluation including laboratory and radiologic evaluation and medications in 
accordance with Kenyan MOH guidelines. Thus, study participants will be managed in 
accordance with the Kenyan standard of care. All home visits for this protocol will be conducted 
by designated KEMRI/USAMRD-A staff who will be known to the participants and who will 
identify themselves using an identification card if necessary. 
3. OBJECTIVES AND PURPOSE  
Primary Objective: 
To assess vaccine efficacy assessed by time to first P. falciparum infection in RTS,S/AS01E vaccinated 
adults (Group 1) positive for P. falciparum by PCR at baseline and treated to clear parasites compared to 
adults administered a comparator vaccine (Group 4) positive for P. falciparum by PCR at baseline and 
treated to clear parasites. 
Secondary Objectives: 


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Efficacy:  
To assess vaccine efficacy by time to first P. falciparum infection by PCR in RTS,S/AS01E vaccinated adults 
(Group 2) negative for P. falciparum at baseline and provided anti-malarial chemo-prophylaxis versus 
comparator group (Group 5) negative for P. falciparum at baseline and provided anti-malarial chemo-
prophylaxis. 
Safety:  
• 
To assess the safety of RTS,S/AS01E in terms of serious adverse events (SAEs) during the whole 
study period (from Dose 1 to study conclusion) 
• 
To assess the safety and reactogenicity of RTS,S/AS01E in terms solicited local and systemic 
adverse events within 7 days after each vaccination in the first 50 subjects in groups 1 and 2, 
and in all 35 subjects from Group 3. 
• 
To assess the safety of RTS,S/AS01E in terms of unsolicited adverse events within 28 days after 
each vaccination 
Immunogenicity: 
• 
To assess anti-circumsporozoite (CS) antibody levels & avidity, hepatitis B surface antibodies 
(HBsAb), from groups 1, 2 and 3 as detailed in Appendix F.  
Exploratory Objectives: 
• 
To assess in subjects immunized with RTS,S/AS01E the relationship between HLA Class 1 and 
Class 2 alleles with protection against P. falciparum infection. 
• 
To assess anti-rabies antibodies in subset of subjects at time points from groups 4 and 5 as 
shown in Appendix F. 
• 
To assess cell-mediated immune responses and transcriptomes in Groups 1 – 3. 
• 
Other immunological assays evaluating the immune response to CS and HBsAg might be 
performed. 
• 
To assess malaria cross-sectional prevalence in all study participants at the end of the study. 
  
4. STUDY DESIGN AND ENDPOINTS  
4.1. Description of the Study Design 
Tables 1 and 2 above show the groups, sample size, and descriptors.  
The study design includes five groups.  
Group 1. Group 1 subjects have detectable P. falciparum parasitemia at baseline measured by PCR (note 
any positive result from PCR, per our lab derived cutoff in accordance to the PCR SOP, will be 
considered positive for purposes of group selection and study endpoints). Anti-malarial treatment 
with DHA/Pip to clear asexual stage and young gametocyte parasites plus LD PQ to clear mature 
gametocytes will be given 4 weeks prior to immunization with RTS,S/AS01E. A 2nd course of DHA/Pip 
plus Primaquine will be given 2 weeks before second RTS,S/AS01E immunization. One week before 
3rd RTS,S/AS01E immunization, a three-day course of A/L plus Primaquine will be administered to 


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clear infection. Rationale for administration of A/L is its preferred shortened half-life allowing for 
evaluation of vaccine efficacy thereby excluding any confounder effect due to prolonged anti-
malarial effect of drug. 
Group 2. Group 2 subjects have no detectable P. falciparum parasitemia as measured by PCR at 
enrolment.  It is proposed to initiate anti-malarial chemoprevention to subjects (prophylaxis effect) 
with DHA/Pip plus LD PQ 4 weeks prior to immunization with RTS,S/AS01E. A 2nd course of DHA/Pip 
plus Primaquine will be given 2 weeks before second RTS,S/AS01E immunization. One week before 
3rd RTS,S/AS01E immunization, a three-day course of A/L plus Primaquine will be administered to 
clear infection.  
Group 3. Group 3 subjects have detectable P. falciparum parasitemia at baseline measured by PCR but 
will not receive any anti-malarial medications to clear PCR-positive parasites. This group includes 35 
subjects and is included only for immunological assessment and not for vaccine efficacy. Subjects in 
Group 3 will be administered RTS,S/AS01E three times on a 0, 1, 7 month schedule. 
Group 4. Group 4 subjects have detectable P. falciparum parasitemia at baseline measured by PCR (note 
any positive result from PCR will be considered positive for purposes of group selection and study 
endpoints as with Group 1) and will receive DHA/Pip , Primaquine, and A/L on the same schedule as 
subjects in group 1. Subjects in Group 4 will be administered Abhayrab rabies vaccine on a 0, 1, 7 
month schedule.   
Group 5. Group 5 subjects have no detectable P. falciparum parasitemia as measured by PCR at 
enrolment and will receive DHA/Pip, Primaquine, and A/L on the same schedule as subjects in group 
2. Subjects in Group 5 will be administered Abhayrab rabies vaccine on a 0, 1, 7 month schedule.   
4.2. Study Endpoints 
The impact of the event-driven design is that we will continue to follow up until 92 first infection events 
have been observed in aggregate between Groups 1 and 4, and 72 first infection events have been 
observed in the aggregate of Groups 2 and 5 up to a maximum of 12 months of ADI. This clinical study 
was designed to capture positive P. falciparum infection events by PCR for at least 6 months of ADI (see 
section 10.5 for sample size calculation and presumed attack rate) but no longer than 12 months. If the 
aggregate numbers of first infection events have been reached between 6 and 12 months of ADI, the 
study endpoints will have been reached. The study will then be concluded. A final cross-sectional PCR 
(along with DBS and serum sampling) will be performed at study end. This will require the PCR lab to 
provide timely aggregated reports of first infection event counts (across Group 1 plus 4 and Group 2 plus 
5) and may result in more than the required first infection events for either the primary or secondary 
endpoint. 
4.2.1. Primary Endpoint 
The primary endpoint is defined as the time to first PCR-detectable malaria infection in Groups 1 and 
4 during the ADI phase of the study.  
Vaccine efficacy in African adults (Group 1) administered RTS,S with sub-clinical PCR-positive 
parasitemia at baseline and treated to clear parasites before immunization will be compared to 


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volunteers in Group 4 with sub-clinical PCR-positive parasitemia at baseline and treated to clear 
parasites before immunization with a comparator rabies vaccine. 
4.2.2. Secondary Endpoints 
Secondary endpoint for vaccine efficacy:  
The secondary endpoint is defined as the time to first PCR-positive malaria infection in Groups 2 and 5 
during the ADI phase of the study. Vaccine efficacy in African adults administered RTS,S, and who are 
negative for P. falciparum infection at baseline and given anti-malaria chemoprophylaxis (Group 2) are 
compared to rabies vaccinated adult subjects who are negative for P. falciparum infection at baseline 
and given anti-malaria chemoprophylaxis (Group 5). 
Secondary endpoint for safety: 
• 
Frequency count and proportion of subjects reporting serious adverse events (SAEs) during the 
whole study period 
• 
Frequency count and proportion of subjects reporting solicited local and systemic adverse 
events within 7 days after each vaccination 
• 
Frequency count and proportion of subjects reporting unsolicited adverse events within 28 days 
after each vaccination 
Secondary endpoint for immunogenicity: 
• 
Anti-circumsporozoite (CS) antibody levels & avidity at time points shown in Appendix F.  
• 
Hepatitis B surface antibody (HBsAb) levels at time points shown in Appendix F.  
4.2.3. Exploratory Endpoints 
Immune profiling of cell-mediated immune (CMI) responses will be assessed only in subjects 
administered RTS,S (Groups 1, 2, 3). Subjects in Groups 4 and 5 that are administered the comparator 
rabies vaccine will not have PBMC collected. The flow cytometric assays will measure T cell, B cell and 
innate cell markers associated with immune exhaustion.  The specific flow cytometric assays to be 
measured may include but are not limited to T cell markers CD3, CD4, CD8, TCRgD, CD56, CD45RA, 
CD27, CD25, CD127, CTLA4, PD-1 associated with immune exhaustion.  Flow cytometric assays specific 
for B cells, Monocyte, NK subsets may include but are not limited to, CD27, HLA-DR, CD16, CD14, CD123, 
PD-1, CD56, CD21. 
Whole blood samples will be collected for future use to measure RNA transcriptional responses related 
to innate immune responses before and after immunization as shown in Appendix F. While PAXgene 
tube samples will be collected from all subjects in Groups 1 through 5, it is anticipated that a small cross-
sectional case-control subset of samples may be selected to measure transcriptional immune responses.  
No genetic testing related to risk of disease will be performed from these samples. 
Anti-rabies antibody levels in the first 50 subjects in Groups 4 and 5 will be assayed at timepoints 
indicated in Appendix F. 
HLA typing from buccal swabs or from PBMC will be collected for determination of an association of 
RTS,S elicited immune responses and protection from P. falciparum infection. 


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The results from the immunological and transcriptional analyses will inform whether the presence or 
absence of P. falciparum infection is associated with immune exhaustion and will serve as a knowledge 
base for the development of improved second-generation CS-based vaccines. 
Malaria parasitemia will be assessed in Groups 1 through 5 at the Study Termination Visit within a 6 
week period to get a cross-sectional malaria prevalence.  
5. STUDY ENROLLMENT AND WITHDRAWAL  
5.1. Participant Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria:  
• 
Provision of signed or thumb printed and dated informed consent form  
• 
Stated willingness to comply with all study procedures and availability for the duration of the 
study  
• 
Male or female between 18 and 55 years of age, inclusive  
• 
In good general health as evidenced by medical history and clinical examination before entering 
the study 
• 
Ability to take oral medication and be willing to adhere to the medication regimen  
• 
For females, she must be of non-childbearing potential or use appropriate measures to prevent 
pregnancy for 30 days prior to vaccination through 2 months after completion of the vaccine 
series. Non-childbearing potential means she is surgically sterilized or at least one year post-
menopausal.  Appropriate measures to prevent pregnancy include abstinence or adequate 
contraceptive precautions (e.g. intrauterine contraceptive device; oral contraceptives; 
diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant or 
Depo-Provera). Kombewa clinical staff will assist with provision of acceptable birth control for 
study entry and will discuss with volunteer at screening visit. 
5.2. Participant Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study:  
• 
Planned administration/administration of a vaccine not foreseen by the study protocol from 
within 30 days before the first dose of study vaccine until 30 days after the last dose of study 
vaccine.† 
† In the context of the COVID-19 pandemic, the administration of the COVID-19 vaccine will be 
allowed as an exception to this exclusion criteria as follows. The study team will work with the 
participant to attempt to have any COVID-19 vaccine administration occur 30 days or more 
before or after study vaccinations. When this is not possible, COVID-19 vaccination will be 
allowed 10 days or more before or after study vaccination. Intervals shorter than 10 days can be 
allowed on a case-by-case basis in discussion with the sponsor. 
• 
Any prior receipt of any rabies vaccine or experimental malaria vaccine. 
• 
Confirmed or suspected significant immunosuppressive or immunodeficient condition as 
determined by the investigator, including clinical stage 3 or 4 human immunodeficiency virus 
(HIV) infection (Appendix H). 
• 
A family history of congenital or hereditary immunodeficiency. 


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• 
History of allergic reactions, significant IgE-mediated events or anaphylaxis to previous 
immunizations. 
• 
History of any neurologic disorders. 
• 
Acute disease (defined as the presence of a moderate or severe illness with or without fever), 
including acute malaria, at the time of enrolment. All vaccines can be administered to persons 
with a minor illness, such as diarrhea or mild upper respiratory infection without fever, i.e.  
temperature < 37.5°C*. Individuals excluded with acute disease, including acute malaria, can 
become eligible again after complete recovery of the illness, including appropriate treatment as 
applicable, and can be rescreened at a later date. 
* Temperature readings may be taken by site staff either using either oral, axillary, or infrared 
thermal thermometers during clinic or field visits, while subjects enrolled in the reactogenicity 
cohort will be supplied with oral thermometers for the purposes of recording their own 
temperature measurements in the memory aid over 7 days after each vaccination.  
• 
Acute or chronic, clinically significant pulmonary, cardiovascular (including cardiac arrythmias), 
hepatic or renal functional abnormality, as determined by medical history, physical examination 
or laboratory screening tests. 
• 
History of homozygous sickle cell disease (Hgb SS). 
• 
Any clinically significant laboratory abnormalities as determined by the investigator on screening 
labs (site reference ranges, Appendix G).  
• 
History of splenectomy. 
• 
Administration of immunoglobulins, blood transfusions or other blood products within the three 
months preceding the first dose of study vaccine or planned administration during the study 
period. 
• 
Pregnant (i.e. a positive pregnancy test) or lactating female during immunization phase of the 
study (refer to section 2.3 for rationale). If a woman becomes pregnant after all vaccinations are 
complete, she will not be excluded from the remainder of the study. 
• 
Female planning to become pregnant or planning to discontinue contraceptive precautions 
during the vaccination phase. 
• 
History of chronic alcohol consumption and/or drug abuse. 
• 
Chronic administration (defined as more than 14 days) of immunosuppressants or other 
immune-modifying drugs within six months prior to the first vaccine dose (for corticosteroids, 
this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are 
allowed). 
• 
Major congenital defects or serious chronic illness. 
• 
Simultaneous participation in any other clinical trial (apart from participation in the HDSS 
network). 
• 
Any other findings that the investigator feels would increase the risk of having an adverse 
outcome from participation in the trial. 
5.3. Strategies for Recruitment and Retention 
5.3.1. Community information 
The community in which the study will take place will be informed about the nature and design of the 
study. Community leaders (chiefs, local village elders, and opinion leaders) and local health authorities 


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will be formally briefed in their own language on the nature and purpose of the study. They will have the 
opportunity to ask questions of the PI or his designees. 
5.3.2. Recruitment 
Adults age 18 to 55 years will be recruited from the villages in the Kombewa Health and Demographics 
Surveillance System (HDSS) consisting of half of Kisumu West and all of Seme Sub-Counties of Kisumu 
County, Kenya. Potential participants identified from within the HDSS will be approached in the 
community using a recruitment script by study staff delegated to carry out recruitment. Informed 
consent will be obtained in accordance with section 13.3. Language and illiteracy will not be 
impediments in the recruitment process, all briefings and explanations will be in the understandable 
language of the participant. It is expected that approximately 1240 adult volunteers will have to be 
screened to achieve the 619 subject enrolment number. HIV-infected participants will be allowed to 
participate in this trial, assuming they meet all eligibility criteria (less than stage 3 HIV and in the opinion 
of the PI they are healthy enough to participate). The study is not seeking to actively enroll HIV-positive 
individuals. However, given the fact that the study area has a high prevalence of HIV, it is expected that 
there will be HIV-positive individuals in the screening population. Therefore, the screening for HIV and 
staging will ensure that only healthy HIV-positive individuals are included in the study. The proportion of 
HIV-positive subjects enrolled in the trial is intended to reflect the same proportionate make-up of HIV-
positives in the recruitment catchment areas, estimated to be approximately 15%.  As such, we intend 
to cap HIV-positive enrollees at approximately 20-25% to avoid an over-representation by HIV-positive 
subjects. Final determination for enrolment of HIV-positive subjects will be determined by the Principal 
Investigator. 
5.4. Participant Withdrawal or Termination 
5.4.1. Reasons for Withdrawal or Termination 
Subjects can leave the study at any time for any reason if they wish to do so without any penalty or loss 
of benefits to which they are otherwise entitled. Subjects can also be withdrawn from the study 
procedures at the discretion of the clinical investigator. The following reasons may lead to withdrawal of 
individual subjects: 
• 
Withdrawal of informed consent by volunteer;  
• 
Any serious adverse event;  
• 
Any adverse event that, according to clinical judgment of the investigator, is considered as a 
definite contraindication to proceeding with the study procedures;  
• 
Completely lost to follow-up (unable to contact after at least 3 phone or physical attempts by 
the study staff to locate the participant and 1 in-person attempt by a field supervisor to contact 
the individual; additional attempts may be made at the discretion of the PI);  
• 
Pregnancy during immunization phase 
• 
Ineligibility (arising during the study or retrospectively, having been overlooked at screening);  
• 
If the investigator or DoD Research Monitor believes that continuation would be detrimental to 
the subject’s well-being;  
• 
Volunteer non-compliance with study requirements;  
• 
Any other protocol deviation that results in a significant risk to the subject’s safety. 


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5.4.2. Handling of Participant withdrawals or termination 
Investigators, or designee, will follow subjects who are withdrawn as result of a SAE/AE until resolution 
of the event and/or chronicity is established. Study staff will make an attempt to contact those subjects 
who do not return for scheduled visits or follow-up. Information relative to the withdrawal will be 
documented on the CRF. The investigator will document whether the decision to withdraw from the 
study was made by the subject or the investigator and which of the following possible reasons was 
responsible for withdrawal: 
• 
serious adverse event 
• 
non-serious adverse event 
• 
protocol violation (specify) 
• 
consent withdrawal, not due to an adverse event 
• 
moved from the study area 
• 
lost to follow-up 
If a subject withdraws or is terminated from the study after enrolment and receipt of investigational 
product (including anti-malarial medications), including lost to follow-up, they will not be replaced. If a 
subject withdraws or is terminated from the study after enrolment but prior to receipt of investigational 
product, including lost to follow-up, (e.g., participant in group 3 who withdraws or is terminated 
between study visits 2 and 5) that participant may be replaced. 
If the reason for withdrawal from the study is pregnancy during the immunization phase of the study, 
the participant will be withdrawn from any further immunizations, but will be followed for safety until 
delivery or termination of the pregnancy.  
5.5. Premature Termination or Suspensions of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause as determined by the sponsor, PATH. Written notification, documenting the reason for study 
suspension or termination, will be provided to the investigator, GSK, WRAIR IRB, and to Kenyan 
regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly inform 
the IRB and will provide the reason(s) for the termination or suspension.  
 
 
6. STUDY VACCINE 
6.1. Study Vaccine and Antimalarial Medications 
Refer to the IB for details of the description of RTS,S/AS01E. The IB for RTS,S and the package inserts for 
Abhayrab®, DHA/Pip, A/L, and Primaquine will be provided to the ethical and regulatory review 
committees. The candidate RTS,S/AS01 vaccine to be used has been developed and manufactured by 
GSK Biologicals. The vaccine is labelled and packed according to applicable regulatory requirements. 
The RTS,S/AS01E vaccine presentation is provided as a clipped two-vial combination in 3 mL vials, one 
vial of RTS,S antigen and a second vial of AS01E adjuvant. RTS,S antigen is a lyophilized pellet containing 


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50 μg of RTS,S per vial. The pellet is reconstituted with 1mL adjuvant in liquid form and 0.5 mL dose of 
reconstituted vaccine contains 25 µg RTS,S. The AS01E adjuvant contains 25 µg of MPL®, 25 μg QS21 
(QS21 is a triterpene glycoside purified from the bark of Quillaja saponaria) in a suspension of liposomes 
in phosphate buffered saline per 0.5 mL and is presented in 3 mL vials. A dose of 0.5 mL (first two 
immunizations) or 0.1 mL (third immunization) will be delivered as appropriate. The presentation of the 
reconstituted RTS,S/AS01E candidate malaria vaccine is an opalescent liquid.  
Table 4.  Vaccine Formulation and Presentation 
Treatment 
name 
Vaccine/p
roduct 
name 
Formulation 
Presentation 
Volume to be 
administered 
RTS,S/AS01E 
(Full dose) 
RTS,S 
RTS,S=25µg 
Lyophilized pellet in a glass 
vial 
0.5 mL 
AS01E 
MPL=25µg; 
QS21=25µg; 
Liposomes 
Liquid solution in a glass vial 
RTS,S/AS01E 
(1/5th dose) 
RTS,S 
RTS,S=5µg 
Lyophilized pellet in a glass 
vial 
0.1 mL 
AS01E 
MPL=5µg; 
QS21=5µg; 
Liposomes 
Liquid solution in a glass vial 
Rabies vaccine 
Abhayrab 
Rabies virus = 2.5 
IU 
Powder and solvent for 
solution for injection. After 
dissolution of the white 
lyophilizate (powder), a 
clear colorless solution is 
obtained. 
0.5 mL 
 
The Abhayrab vaccine is a sterile freeze-dried vaccine obtained by growing the fixed-virus strain Flury 
LEP in primary cultures of chicken fibroblasts. The potency of one dose (0.5 mL) Abhayrab is at least 2.5 
IU of rabies antigen. Abhayrab is a white, freeze-dried vaccine for reconstitution with the diluent prior to 
use; the reconstituted vaccine is a clear to slightly opaque, colorless suspension. A dose of 0.5 mL will be 
delivered. The presentation of the reconstituted vaccine is as a clear or slightly opaque suspension. 
6.1.1. Acquisition 
RTS,S/AS01E will be provided by GSK and sent directly to the study site in Kisumu, Kenya. Abhayrab, 
DHA/Pip, Coartem®, and Primaquine will be procured by USAMRD-A. 
6.1.2. Formulation, Appearance, Packaging, and Labeling 
See IB and package inserts for details. 
 




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PRIMAQUINE*** 
primaquine phosphate tablets 
26.3 mg primaquine phosphate 
(equivalent to 15 mg primaquine 
base) 
> 35 kg 
1 tab 
- 
- 
- 
- 
- 
*Dihydroartemisin-piperaquine should be taken at approximately the same time each day – refer to the Manual of Operating 
Procedures for further details. Dihydroartemisin-piperaquine should be taken orally with water. No food should be taken within 
3 hours before and after each dose. 
** Coartem should be taken with food 
***Primaquine may be taken with food 
 
6.1.6. Route of Administration 
Route of administration for vaccines RTS,S/AS01E and Abhayrab will be by the intramuscular route to the 
deltoid of the arm.  
DHA/Pip, A/L, and Primaquine will be administered orally according to the dosages above by directly 
observed therapy (DOT) by study staff or field workers and documented in the CRF. 
6.1.7. Vaccination Schedule 
Refer to Appendix B for vaccination schedule. 
6.1.8. Tracking of Dose 
Adherence to and tracking doses of vaccines and anti-malarial study agents will be documented in the 
CRF for each participant.  
6.2. Study Vaccine Accountability Procedures 
The study vaccines will be distributed to and maintained by the KCRC pharmacy and will include amount 
of product shipped, documentation of adequate and safe handling and use, temperature log for vaccine 
product and plans for returning or destroying of unused product.  
7. STUDY PROCEDURES 
7.1. Study procedures and evaluations 
7.1.1. Study specific procedures 
This is a Phase 2b, single-center, open label, randomized controlled trial with five groups in one study 
site. 619 adults will be enrolled. It is assumed that 90% will complete study procedures and be 
evaluable. Prior to study start, a community information program will inform the local population of the 
study and study information will be presented at community centers. Screening procedure timelines for 
any single subject will include a 12-day window period before randomization. Data collection will be by 
CRF. Following the Screening Phase, trial-specific procedures are sub-divided into 3 separate Epochs. 
Epoch 1 describes the procedures during the Treatment and Immunization Phase (Appendix B). Epoch 2 
describes the procedures during the Active Detection of Infection Phase (Appendix C). If insufficient 
number of PCR-positive events to meet both the primary and secondary endpoints occur during Epoch 
2, it will be necessary to extend the ADI for an additional 24 weeks (Epoch 3, Extension Phase, Appendix 
D) (refer to Statistical Section 10). 
A. Study-specific Screening Procedures (Appendix A) 


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Screening procedures are to be completed as shown in Appendix A. Screening (day -39 to day -28) may 
be done on a separate visit from recruiting. Only adults aged 18 to 55 years with a signed/thumb printed 
and dated Informed Consent document will be eligible to be screened for the trial. At the screening visit 
each subject will be given a Subject Screening Number (only to be used for screening) and each will have 
a clinic record prepared. 
Volunteers will provide a medical history through a one-on-one interview with a clinical officer. 
Volunteers will also undergo physical examination and standard laboratory screening tests, which 
include complete blood count (CBC), creatinine, and ALT, and HIV infection. An additional sample of 
blood (350 µL to 500 µL) will be collected from each subject for determination of P. falciparum infection 
by PCR and to make a DBS card for a back-up sample. This finger-stick blood sampling is in addition to 
venous blood collected for safety laboratories and HIV screening. A urine pregnancy test will be 
performed on all female subjects. Volunteers may be screened one additional time if re- screening is 
determined to be necessary. Volunteers will be excluded from participation if they meet any of the 
exclusion criteria. Volunteers excluded from this study because of significant abnormalities will be 
referred to an appropriate health provider for evaluation and treatment. All screening tests will be 
completed within 12 days prior to entry into the study. Information gathered during screening (medical 
history, physical examination, and laboratory analysis) will be recorded in the Source Documents and 
the CRFs. Laboratory references values for the KCRC are shown in Appendix G.  
A photograph will be taken of each volunteer who is screened and stored securely in a computer at 
KCRC.  
Note: HIV screening will be obtained to identify subjects positive for HIV. Subjects found to be HIV 
positive will have a confirmatory laboratory test as per local standard of care procedures. A positive HIV 
test does NOT exclude the subject from participation in the trial by itself, though a cap on enrolment of 
HIV positive participants will be implemented as needed by the Principal Investigator, as discussed 
above. Subjects found to be HIV positive (stage 1 and 2) will be equally randomized among all study 
groups to the extent possible and within the limits of the cap. Subjects will be verbally consented for HIV 
testing according to the local standard of care. If a participant has been previously screened for this 
study and is being rescreened outside of the window, HIV-testing will only be repeated if it is >90 days 
from their initial negative screening HIV testing at the clinic. In this same scenario but where they 
initially screened HIV-positive at the clinic while screening for this study, they will not require any repeat 
HIV screening. In the cases where HIV screening will not be repeated, the prior HIV test result from their 
initial screening attempt will be transcribed to the CRF for their new screening ID. 
 
B. Epoch 1 - The Treatment and Immunization Phase (Appendix B) 
Appendix B shows the visit number, study day, window periods, and blood sampling volumes for all 
study procedures for Visits 2 to 18.  When screening and review of inclusion/exclusion criteria are 
complete, a picture ID card of each eligible volunteer will be created using the stored photo. In addition 
to the subject’s photo, subject ID number and the study number and name, the card will contain contact 
information for KCRC. Subjects will be assigned a subject ID number sequentially upon randomization; 
example: CVIA078-001. This will ensure that the subject can contact an investigator, and the clinic can 
be contacted if medical care is received outside the study health facilities. Copies of these pictures will 


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be kept in the subjects’ records to aid the study staff in confirmation of the volunteers’ identification for 
future visits. The photos of subjects who are determined ineligible to participate during screening will be 
deleted from the computer. 
The subject is randomized to one of the 5 groups as determined by block randomization (section 10.5.1). 
A study subject ID number will be assigned. This number will be used throughout the study to identify 
every document and blood sample associated with the volunteer. The clinic records will contain the 
Subject ID Number, the subject’s date of birth, medical history, findings of the physical examination, the 
date of screening visit, whether the subject was enrolled, and (where applicable) reasons for exclusion 
from the study. The name of the study will be written on both the ID card and clinic records of enrolled 
volunteers. 
A subject is considered enrolled once they have been randomized and any Visit 2 laboratory test, 
excluding pregnancy test, is performed or any investigational product is administered. 
At enrollment, visit 2, subjects will have a blood sample for hemoglobinopathy panel (G6PD, alpha 
thalassemia, and sickle cell) collected. A urine pregnancy test will be performed on all female subjects. 
Subjects from Groups 1, 2, 4, and 5 that receive anti-malarial medications, will receive DHA/Pip plus LD 
PQ before the first 2 vaccinations. They will have the first dose of a 3-day regimen administered by DOT 
at the KCRC. The 2nd and 3rd doses will be administered by field workers by DOT. Prior to the 3rd 
vaccination, subjects in groups 1, 2, 4, and 5 will be treated with A/L plus LD PQ for presumptive 
clearance of malaria parasitemia and to ensure a clean baseline for determination of vaccine efficacy. 
They will receive the first dose of A/L and LD PQ by DOT at the KCRC and be sent home with their second 
dose to be taken 8 hours later. A field worker will visit the next morning and verify the second dose was 
taken and administer the 3rd dose by DOT and leave the 4th dose to be taken in the evening. The same 
will happen again the next day for the 5th dose by DOT and give the final dose to be taken in the evening. 
Compliance with this final dose will be verified at the next visit (vaccination visit) before vaccine 
administration. Any failure to follow the exact schedule for either antimalarial treatment will be 
reported as a deviation, but allowance can be made for completion of missed doses to complete the full 
treatment regimen outside this schedule prior to vaccination at the discretion of the PI and documented 
in a progress note.  
All subjects that are administered RTS,S or rabies vaccine will be observed for at least 30 minutes after 
vaccination to evaluate and treat any acute adverse events.  
The first 50 subjects in groups 1 and 2 and all subjects in group 3 will constitute the Reactogenicity 
Cohort, which will be evaluated for solicited local and general adverse effects seven days after each 
immunization. Following each injection, the Reactogenicity Cohort will be provided a memory aid, 
instructed on its use, and encouraged to fill it out as directed. When field workers visit subjects on day 7 
after each immunization, the field worker will review the memory aid document with the subject. The 
memory aid and/or the interview with the subject will be used to complete the CRF entries for solicited 
local and general AEs that have occurred on days 1 through day 7 post immunization. If the memory aid 
is not completed or not brought to a study visit by Day 28 following each dose, this will be documented 
in the CRF. Specifically, the Reactogenicity Cohort will be asked to: 


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• 
Record any local or general symptoms that they experience on a daily basis during the 7-day 
period after each injection in the memory aid. 
• 
Record their temperatures daily in the memory aid for the first 7 days after each injection to 
help assess for possible fevers. To more accurately account for possible fevers, subjects will be 
given an oral thermometer and instructed on its use.  
• 
Record local reactions at the injection sites in the memory aid for 7 days after each injection. 
Subjects in Groups 4 and 5 will not have solicited AEs captured.  
There will be a 28-day follow-up period after each dose of vaccine for reporting unsolicited symptoms in 
all subjects from all Groups and, where applicable, following each course of per protocol scheduled anti-
malarial treatment (i.e. Groups 1, 2, 4 and 5). 
Blood sampling for immunologic assays in selected groups of subjects at pre-defined timepoints will be 
collected as shown in Appendix F. For the determination of anti-rabies antibody levels, only the first 50 
subjects each in Groups 4 and 5 will have blood samples collected for rabies antibody determination. 
A urine pregnancy test will be performed prior to administering any vaccine or before each course of 
anti-malarial drug begins according to Appendix B. 
Any subjects presenting to KCRC with medical complaints (either during unscheduled or scheduled visits) 
will be evaluated thoroughly by a study provider and care or referral will be provided as needed. If a 
subject has medical complaints during a scheduled visit with study product administration, the 
investigator will determine if it is safe to proceed with the scheduled intervention. If there is clinical 
concern for malaria during either a scheduled or unscheduled visit during Epoch 1, appropriate testing 
and treatment according to local standard of care will be completed regardless of the group allocation 
(including testing with MBF or RDT as clinically indicated), with the malaria results recorded in the CRF. If 
the subject is within the window to receive scheduled anti-malarial medication at this same visit, then 
the subject may receive the study anti-malarial treatment unless deemed inappropriate by the 
investigator and an alternative anti-malarial drug is required. In addition to the diagnosis and 
management of suspect malaria described above, if there is concern for malaria during Epoch 1 that 
occurs during an unscheduled visit or a visit where a sample for parasitemia assessment is not scheduled 
according to the schedule in Appendix B, a sample of whole blood for DBS will be collected (by finger 
stick or venous blood). If this occurs on a visit where a parasitemia assessment is scheduled according to 
the schedule in Appendix B, then a sample of whole blood for PCR and DBS will be collected (optimally 
by finger stick) as scheduled. Malaria positivity on any testing during Epoch 1 will not be considered a 
study endpoint. 
 
C. Epoch 2 – The Active Detection of Infection Phase (Appendix C) 
Appendix C presents the visit number, study day, and blood sampling for detection of infection by PCR 
for Visits 19 to 27. Surveillance for Active Detection of Infection (ADI) will begin 2 weeks after Dose 3 of 
vaccine. The total period of surveillance for ADI will be 24 to 48 weeks, with Epoch 2 covering the initial 
24 weeks. All subjects will complete the entirety of Epoch 2 according to the description in this section, 
but whether individual subjects continue into Epoch 3 is determined by the aggregate number of events 
that have occurred among all subjects upon that individual’s completion of Epoch 2. An event is 


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designated as the first positive PCR for P. falciparum malaria during an ADI phase (either Epoch 2 or 3). If 
all events are achieved while all subjects are in Epoch 2, then visit 27 will be the final study visit and 
subjects will not continue into Epoch 3.  
Subjects will be seen at KCRC or visited by field workers or community health workers (CHW) every 21 
days during the ADI period per the schedule in Appendix C. At each contact for ADI a sample of whole 
blood will be collected by finger stick into EDTA-coated tubes (at KCRC a venous blood sample can be 
collected in cases where a finger prick sample cannot be collected). In the case of field visits, samples 
are then transported back to KCRC for processing. Approximately 350 to 500 µL of whole blood will be 
collected at each ADI visit. For all subjects an aliquot (approximately 250 µL) will be placed on DBS cards. 
If the subject has not yet had a positive PCR sample obtained during the ADI phase, then approximately 
100 to 250 µL blood will be sent for PCR testing. Subjects with a positive PCR during the ADI phase will 
have their results recorded in the CRF. Subjects with a prior positive P. falciparum PCR will continue to 
have finger prick blood samples for DBS collected every three weeks until the end of Epoch 2. Such 
samples may be used in a future exploratory study under a separate protocol in order to genotype 
parasites that are identical to or dissimilar from the P. falciparum parasite 3D7 strain used in the RTS,S 
vaccine.  All subjects will return for visit 27 where groups 1 – 3 will have serology assessment and all 
subjects will have a whole blood sample collected (optimally by finger stick) for parasitemia assessment 
(both DBS and PCR regardless of if they have had prior positive PCR during ADI). Note: only a 
participant’s first positive PCR during ADI will be counted as an endpoint. 
At each contact for ADI, history of fever will be queried, and temperature taken. At any ADI contact in 
the field, if a subject has a history of subjective fever within the previous 24 hours, temperature ≥37.5°C, 
or reports concern for having clinical malaria, arrangements will be made for that subject to present to 
KCRC for an unscheduled clinic visit (in addition to their scheduled field visit that day). Attempts should 
be made by the field team to collect the finger stick sample for PCR and DBS during the field visit 
according to protocol, but if not feasible for safety reasons, this will be reported to the clinic so the 
sample can be collected during the unscheduled visit. 
All subjects who present to KCRC for a scheduled or unscheduled visit during Epoch 2 and who have 
symptoms that are consistent with malaria in the clinical judgement of a study provider (including but 
not limited to: history of fever within previous 24 hours or temperature ≥37.5°C) will have blood 
collected for a MBF and/or RDT. Subjects with confirmed malaria by lab testing will be treated with 
appropriate anti-malarial chemotherapy within the same day. Subjects with negative testing or if there 
is a problem that prevents prompt testing, and for whom the clinical suspicion for malaria remains/is 
high may be treated with appropriate anti-malarial chemotherapy, at the discretion of the investigator, 
for the wellbeing of the participant. For all subjects who are seen for confirmed or suspected malaria 
during an unscheduled visit, a sample of whole blood for DBS and PCR (the latter if appropriate per 
previous discussion regarding PCR testing during ADI) will be collected (optimally by finger stick) during 
the unscheduled visit (unless already collected during a field ADI visit that same day). The results from 
the PCR, if collected, will be the only official determination of P. falciparum positivity for the study 
endpoint and will be entered into the CRF. 
Subjects in group 3 will not participate in ADI, but will continue to participate in immunological testing 
during Epoch 2. The blood sampling for immunologic assays in selected groups of subjects at pre-defined 


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timepoints will be collected as shown in Appendix F. For assessment of rabies antibodies, only the first 
50 subjects each in Groups 4 and 5 will have blood samples collected for rabies antibody determination. 
D. 
Epoch 3 Extension Phase (Appendix D) – if required 
Appendix D presents the visit number, study day, and blood sampling for detection of infection by PCR 
for Visits 28 to 35. 
Due to rolling enrollment at the site (planned enrollment of ~103 subjects per month over 6 months), 
some subjects recruited early will reach the end of Epoch 2 at the same time as other subjects recruited 
later on in the study are just entering Epoch 2. As such, the target number of events required to meet 
study endpoints may not have been achieved by the time the first subjects enrolled complete Epoch 2. If 
the total number of events (see section 10.5/Table 9) has not been reached for the primary and 
secondary endpoints by the time an individual in an ADI group (groups 1, 2, 4, and 5) reaches the end of 
Epoch 2, and that individual has yet to have an event (positive malaria PCR during an ADI phase), that 
individual will begin Epoch 3. Prior to the total number of required events being achieved among all 
subjects, any individual progressing into Epoch 3 will perform each visit per to the schedule in Appendix 
D and according to the guidance in the protocol. Once the total number of events required for the 
primary and secondary endpoints is reached among the ADI groups, then the study will move into 
completion as discussed in the next section regarding the Study Termination Visit. As such, it is not 
required for any individual to complete any or all study visits in Epoch 3 once the primary and secondary 
endpoints have been reached (though all visits in Epoch 2 must be completed). Once all required 
primary and secondary endpoints have been reached, all Epoch 3 visits, if applicable, will cease (this will 
have no impact on anyone still in Epoch 2 as they will be required to complete that Epoch through visit 
27 regardless).  
Subjects entering the extension phase will continue with ADI every 3 weeks as described for Epoch 2 
until study completion as described above. However, in Epoch 3, if an individual has had an event 
(positive malaria PCR during the ADI phase) then that individual will no longer have field visits to collect 
blood draws for PCR and DBS every 3 weeks, and will only complete the Study Termination Visit, as 
below. 
Concern for clinical malaria will be assessed and managed the same in Epoch 3 as was outlined in Epoch 
2. 
Subjects in group 3 will not participate in the extension of ADI.  
Blood sampling for immunologic assays in selected groups of subjects at pre-defined timepoints will be 
collected as shown in Appendix F. Immunological testing will only be performed in Epoch 3 at visit 35, if 
required. 
E. Study Termination Visit 
All participants who have not been withdrawn from the study will complete a Study Termination Visit. 
The Study Termination Visit will be scheduled once the following criteria have been met: 
1. The primary and secondary endpoints have been met; AND 
2. All participants have completed Epoch 2. 


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OR 
3. All participants have completed all scheduled visits in Epochs 2 and 3, as applicable (through 
Visit 35 for Groups 1, 2, 4, and 5; through Visit 27 for Group 3). 
The Study Termination Visit will occur within 6 weeks of the above criteria being met. During the Study 
Termination visit, a whole blood sample for a final cross-sectional parasitemia assessment for PCR and 
DBS will be collected. This assessment will not contribute to the primary or secondary endpoints.  
If the primary and secondary endpoints are not met during the first 6 months ADI and the study has 
continued into Epoch 3,  an additional serology timepoint will be collected at the Study Termination Visit 
for those subjects in Groups 1, 2, and 3 only. This will be an exploratory endpoint to evaluate the 
immune response to CS. 
The Study Termination Visit may occur at KCRC or as a field visit - see Appendices E and F. 
7.1.2. Standard of Care Study Procedures 
For the duration of their participation in the trial, all randomized subjects will receive free health care 
from study medical personnel in accordance with Kenya Ministry of Health guidelines for acute illnesses. 
The capabilities of the KCRC have been developed to ensure any acute illness or outpatient medical 
need of anyone involved in a study can be addressed. The KCRC is staffed during the study with at least a 
clinical officer, community nurse and a driver with an evacuation vehicle. All outpatient services for 
study participants will be provided by the staff at KCRC or an appropriate provider in the community.  
7.2. Laboratory Procedures and Evaluations 
All laboratory samples will be collected either in the field or at KCRC as per the study procedures 
outlined in Appendices A - E. The clinical laboratory at KCRC will perform initial processing of all samples 
according to local SOPs as appropriate for each specimen type. All biological materials collected will be 
handled according to established SOPs for the protection of participants and study staff. 
7.2.1. Clinical Laboratory Evaluations 
The clinical laboratories of USAMRD-A will conduct the following testing: CBC (Hb, WBC, PLT), creatinine, 
ALT, HIV, hemoglobinopathy panel (sickle cell, G6PD, alpha thalassemia), and urine pregnancy testing. 
These labs will be primarily performed at KCRC clinical labs or the USAMRD-A Basic Science Lab in 
Kisumu, but other USAMRD-A labs (e.g., Kericho Field Station) or commercial laboratories (e.g., 
Pathologists Lancet Kenya or PathCare Kenya) are available for back-up testing if the primary 
laboratories are not available. 
A urine pregnancy test must be done in all females of child-bearing potential no more than 24 hours 
prior to study intervention as indicated in Appendices A & B and the results must be available prior to 
administration of study products (DHA/Pip, Coartem, Primaquine, RTS,S, Abhayrab). 
7.2.2. Other Assays or Procedures 
Ultrasensitive quantitative PCR will be performed under the supervision of USAMRD-A personnel at the 
Kisian KEMRI Campus. The PCR assay SOP is maintained at USAMRD-A. 


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Serological, cell-mediated immunity, and other special testing will be performed at non-USAMRD-A 
laboratories in the United Kingdom and United States. The primary labs are: 
• 
Anti-CS antibody levels and avidity testing as described in reference 6: WRAIR, Silver Spring, MD, 
United States 
• 
Anti-HBs antibody levels: IAVI-HIL, Imperial College, London, United Kingdom  
• 
Rabies serology: Kansas State Veterinary Diagnostic Laboratory, Manhattan, KA, United States 
• 
Cell mediated immune testing: BMGF GHVAP partner, Stanford University, Palo Alto, CA, United 
States 
• 
Transcriptomics: BMGF GHVAP partner, Stanford University, Palo Alto, CA, United States. Future 
use to be determined if transcriptomics are performed at another Sponsor-designated 
laboratory. 
• 
HLA typing: C.W. Bill Young DoD Bone Marrow Program at Georgetown University 
Other commercial or academic labs may be utilized for exploratory assays. 
7.2.3. Specimen Preparation, Handling, and Storage 
Samples will be prepared, handled, and stored according to USAMRD-A SOPs at Kombewa CRC prior to 
assay performance or shipment, as applicable. All samples will be labeled with the subject ID number, 
date/time of collection, study designator, and bar code; no PII will be included on sample labels. 
Samples being shipped locally to another USAMRD-A or commercial lab for performance of an assay will 
be sent from the KCRC clinical lab to the performing lab maintaining appropriate temperatures 
according to local SOPs. A chain of custody will be maintained both at the sending lab and the receiving 
lab. All specimens being shipped internationally, except buccal swabs for HLA typing, will be sent to a 
PATH-designated central laboratory which will arrange for further aliquoting and shipping, as needed. 
The PATH-designated central laboratory will be the long-term storage facility for these specimens. 
Buccal swabs for HLA typing will be shipped to the C.W. Bill Young DoD Bone Marrow Program at 
Georgetown University directly (11333 Woodglen Drive, Rockville, MD 20852) with no long-term storage 
planned after testing is complete. Local storage of specimens (e.g., local back-up serological or PBMC 
samples, DBS) will be at appropriate temperatures and according to local SOP and will be maintained 
until at least study close-out. 
7.2.4. Specimen Shipment 
Serum and PBMC samples will be shipped to a PATH-designated central laboratory which will further 
distribute samples to the testing laboratories, according to the discussion in 7.2.2. 
 
7.3. Study Schedule 
Refer to Appendices A, B, C, D for details on study schedule. All visits completed according to this 
schedule are considered scheduled visits. If a scheduled visit occurs outside the permissible window, it 
will be reported as a protocol deviation. 
7.3.1. Final Study Visit 


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The final study visit for a subject is defined as the visit at the conclusion of the ADI phase of the trial as 
discussed in 7.1.1 (either visit 27 or 35).  
7.3.2. Unscheduled Visit 
Any subject visit to KCRC or evaluation by study staff at a health facility that takes place outside of the 
schedule in Appendices A – D will be considered an unscheduled visit. Any medical issues discovered at 
an unscheduled visit will be evaluated, treated, and/or referred as appropriate and their encounter 
documented on source documents and entered into the CRF as an unscheduled visit. Additionally, 
unsolicited AEs/SAEs will be collected at all unscheduled visits. Any suspected malaria cases will be 
handled as per procedures in 7.1.1 according to the Epoch.  
7.3.3. Schedule of Events Table  
Refer to the following Appendices for details: 
Appendix A. Screening Visit Procedures 
Appendix B. Epoch 1 
Appendix C. Epoch 2 
Appendix D. Epoch 3 
Appendix E. Study Termination Visit 
Appendix F. Biological sampling schedule  
7.4. Concomitant Medications, Treatments, and Procedures  
Concomitant medications, treatments and procedures will be recorded on the CRF. 
8. ASSESSMENT OF SAFETY 
8.1. Specification of Safety Parameters 
The investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an adverse event (AE) or serious adverse event (SAE) as provided in this protocol. During 
the study, when there is a safety evaluation, the investigator or site staff will be responsible for 
detecting AEs and SAEs. Each subject will be instructed to contact the investigator immediately should 
they manifest any signs or symptoms they perceive as serious. 
 
 
8.1.1. Definition of Adverse Events (AE) 
An AE is any untoward medical occurrence in a study participant, temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product, or temporally 
associated with a study procedure. 


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An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. 
For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of 
efficacy), abuse or misuse.  
8.1.2. Definition of Serious Adverse Event 
A Serious Adverse Event (SAE) is any adverse event that: 
• 
Results in death. 
• 
Is life-threatening. 
Note: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
study participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, had it been more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization. 
Note: In general, hospitalization signifies that the study participant has been admitted at the 
hospital or emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or outpatient setting.  
Complications that occur during hospitalization are also considered AEs. If a complication 
prolongs hospitalization or fulfils any other serious criteria, the event will also be considered 
serious. When in doubt as to whether ‘hospitalization’ occurred or was necessary, the adverse 
event should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition (known/diagnosed prior to 
informed consent signature) that did not worsen from baseline is NOT considered an SAE. 
• 
Results in disability/incapacity, 
Note: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions 
but do not constitute a substantial disruption. 
• 
Results in a congenital anomaly and / or birth defect. 
Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the study participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition. These should 
also be considered serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization. 
 
8.1.3. Definition of Unanticipated Problems 
Unanticipated problems are those problems that are not specifically described in the protocol. For 
example, misplacing a subject’s study records containing identifiable private information results in the 
risk of breach of confidentiality. Another example would be administering the wrong agent to a subject 


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at one time point in a series of vaccinations. Risks to others must also be reported. Appropriate 
supporting documents should be submitted with the unanticipated problem report.  
8.1.4. Definition of Adverse Events of Special Interest 
AEs of specific interest for safety monitoring include all seizures occurring within 30 days post-
vaccination, meningitis and pIMDs and will be recorded in the CRF. 
For the further evaluation of the safety signal of meningitis in the investigational vaccine groups all cases 
of meningitis occurring during the study will be reported as a SAE. 
pIMDs are a subset of AEs 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 6. 
Table 6. List of Potential Immune-mediated Diseases: 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including paralyses/paresis (e.g. 
Bell’s palsy)  
• 
Optic neuritis 
• 
Multiple sclerosis 
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, 
including Miller Fisher syndrome 
and other variants 
• 
Acute disseminated 
encephalomyelitis, including site 
specific variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis 
• 
Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome  
• 
Immune-mediated peripheral 
neuropathies and plexopathies, 
(including chronic inflammatory 
demyelinating polyneuropathy, 
multifocal motor neuropathy 
and polyneuropathies associated 
with monoclonal gammopathy). 
• 
Systemic lupus 
erythematosus and 
associated conditions 
• 
Systemic scleroderma 
(Systemic sclerosis), 
including diffuse systemic 
form and CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including 
dermatomyositis  
• 
Polymyositis  
• 
Antisynthetase syndrome 
• 
Rheumatoid arthritis, and 
associated conditions 
including juvenile chronic 
arthritis and Still’s disease 
• 
Polymyalgia rheumatica 
• 
Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis  
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous 
skin diseases (including 
pemphigus, 
pemphigoid and 
dermatitis 
herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localised Scleroderma 
(Morphoea) 


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• 
Narcolepsy 
• 
Mixed connective tissue 
disorder 
Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis 
including: giant cell arteritis 
such as Takayasu's arteritis 
and temporal arteritis.  
• 
Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, 
Kawasaki's disease, 
microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and anti-
neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis. 
• 
Autoimmune 
hemolytic anemia 
• 
Autoimmune 
thrombocytopenia 
• 
Antiphospholipid 
syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic 
anaemia 
• 
Autoimmune 
neutropenia  
• 
Autoimmune 
pancytopenia 
• 
Autoimmune glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune diseases 
(including autoimmune uveitis 
and autoimmune retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathySarc
oidosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis 
• 
Primary biliary 
cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune 
cholangitis 
• 
Inflammatory Bowel 
disease, including Crohn’s 
disease, ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis  
• 
Celiac disease 
• 
Autoimmune pancreatitis 
• 
Autoimmune thyroiditis (including 
Hashimoto thyroiditis) 
• 
Grave's or Basedow’s disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
• 
Polyglandular autoimmune 
syndrome 
• 
Autoimmune hypophysitis 
 
8.2. Classification of An Adverse Event 
All AE/SAEs either observed by the investigator or one of his clinical collaborators or reported by the 
subject spontaneously or in response to a direct question will be evaluated by the investigator. The 


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nature of each event, date and time (where appropriate) of onset, outcome, intensity and relationship 
to vaccination should be established. Details of any corrective treatment should be recorded on the 
appropriate page of the CRF.  
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation relative 
to the event. The investigator will then record all relevant information regarding an AE/SAE on the CRF 
or SAE Report Form as applicable.  
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the 
individual signs/symptoms. 
8.2.1. Severity of Event 
For AEs, the following guidelines will be used to describe severity.  
• 
Grade 1; Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Grade 2; Moderate – Events result in a low level of inconvenience or concern with therapeutic 
measures. Moderate events may cause some interference with functioning.  
• 
Grade 3; Severe – Events prevents a participant’s usual daily activity. 
8.2.2. Relationship to Study Vaccine or Study scheduled anti-malarial treatment 
All AEs must have their relationship to study agent assessed. In a clinical trial, the study product must 
always be suspect. To help assess, the following guidelines are used. 
• 
Related –The AE is considered related when there is a reasonable possibility that the study 
agent caused the AE  
• 
Not Related – There is not a reasonable possibility that the administration of the study agent 
caused the event and/or an alternate etiology has been established.  
8.3. Time Period and Frequency of Event Assessment and Follow-up 
All solicited local and systemic AEs occurring within 7 days following administration of each dose of 
vaccine must be recorded on the CRF for the first 50 subjects in groups 1 and 2 and from all subjects in 
group 3 (Reactogenicity Cohort). All subjects being followed for solicited AEs will be offered a memory 
aid to assist in recall of AEs. All unsolicited AEs occurring within 28 days following administration of each 
dose of vaccine and, where applicable, course of per protocol scheduled anti-malarial treatment, must 
be recorded on the CRF for all subjects.  All SAEs that occur will be collected and recorded from the time 
the subject consents to participate in the study until she/he is discharged. The occurrence of an AE or 
SAE may come to the attention of study personnel during study visits and field worker visits. Information 
to be collected includes event description, date of onset, clinician’s assessment of severity, relationship 
to study product, and date of resolution/stabilization of the event. All AEs occurring while on study must 
be documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  


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After the initial AE/SAE report, the investigator is required to proactively follow each subject and 
provide further information per study reporting procedures (section 8.4). All AEs and SAEs documented 
at a previous visit/contact and designated as not recovered/not resolved or recovering/resolving will be 
followed-up.  
Investigators will follow-up subjects: 
• 
with SAEs or who are withdrawn from the study as a result of an AE, until the event has 
resolved, subsided, stabilized, disappeared, the event is otherwise explained, or the subject is 
lost to follow-up; 
• 
or, in the case of other non-serious AEs, until the AE resolves, they complete the study, or they 
are lost to follow-up. 
PATH or the KEMRI Scientific and Ethics Review Unit may request that the investigator perform or 
arrange for the conduct of supplemental measurements and/or evaluations to elucidate as fully as 
possible the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a subject 
dies during participation in the study or during a recognized follow-up period, study contacts for 
reporting of a serious adverse event will be provided with a copy of post-mortem finding, including 
histopathology, if available. 
New or updated information for SAEs will be recorded on the originally completed SAE Report Form, 
with all changes signed and dated by the investigator. 
Outcome of any non-serious local or general solicited AE occurring within 7 days post-vaccination or 
unsolicited AE occurring within 28 days post-vaccination or 28 days of a scheduled course of anti-
malarials as per the protocol (i.e. unsolicited AE), or any SAE reported during the entire study will be 
assessed as: 
• 
Recovered/resolved 
• 
Not recovered/not resolved 
• 
Recovering/resolving 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
8.4. Reporting Procedures 
8.4.1. Serious Adverse Event Reporting 
All serious adverse events (SAEs) will be promptly (within 48 hours) reported to the KEMRI SERU and to 
the WRAIR IRB. Prompt (within 48 hours) reports will be submitted to the KEMRI SERU by email 
(kemriseru18@gmail.com; seru@kemri.go.ke) and to the WRAIR IRB by phone (301) 319-9940, or by 
email (usarmy.detrick.medcom-wrair.mbx.hspb@health.mil), or by facsimile (301) 319-9961. The 
Principal Investigator will then submit written reports within 10 working days to the WRAIR IRB at the 
following address: Walter Reed Army Institute of Research, ATTN: Human Subject Protection Branch 
(HSPB), 503 Robert Grant Ave, Silver Spring, MD 20910.  
In addition, all SAEs and Suspected Unexpected Serious Adverse Reactions will be reported to the Kenya 
Pharmacy and Poisons Board as soon as possible but within 7 calendar days of the notification of the 


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event and with follow-up reporting provided within 8 calendar days of the initial report. These reports 
can be submitted to the Board through the online system at www.pv.pharmacyboardkenya.org.  
Any SAEs or other events that meet PATH Research Ethics Committee’s (REC) expedited reporting 
requirements will be promptly (within 24 hours) reported to the PATH Study Representative by email. 
The PATH Study Representative will then promptly (within 48 hours) submit the report to PATH REC 
using their online submission and reporting website (www.irbnet.org). 
Follow up reports will be submitted as additional information becomes available. A summary of the non-
serious adverse events and the SAEs (both related and unrelated) that occurred during the reporting 
period should also be included in the continuing review report to the KEMRI SERU, and the WRAIR IRB. 
The WRAIR HSPB will report SAEs to the USAMRMC ORP HRPO as per WRAIR SOP UWZ-C-636. 
SAEs will be reported promptly to GSK within the timeframes described in Table 7, once the investigator 
determines that the event meets the protocol definition of a SAE. 
Table 7. Timeframes for submitting serious adverse event and other events reports to GSK 
Biologicals 
Type of Event 
Initial Reports 
Follow-up of Relevant Information on a 
Previous Report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours*‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
AEs of specific 
interest** 
24 hours*‡ 
electronic Expedited 
Adverse Events Report 
24 hours* 
electronic Expedited Adverse 
Events Report 
* Timeframe allowed after receipt or awareness of the information. 
** AEs of specific interest include meningitis and pIMDs. 
‡ The investigator will be required to confirm review of the SAE/AEs of specific interest causality by ticking the ‘reviewed’ box 
in the GSK electronic Expedited Adverse Events Report within 72 hours of submission of the SAE/AEs of specific interest. 
 
8.4.2. Reporting Events of Special Interest 
AEs of specific interest (all seizures occurring within 30 days post-vaccination, pIMDs, and meningitis) 
will be reported promptly to GSK within the timeframes described in Table 7, once the investigator 
determines that the event meets the protocol definition of an AEs of specific interest (all seizures 
occurring within 30 days post-vaccination, pIMDs and meningitis). 
Contact information for reporting serious adverse events and AEs of specific interest: 


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Study Contact for Reporting SAEs and AEs of specific interest* 
Refer to the local study contact information document. 
Back-up Study Contact for Reporting SAEs and AEs of specific interest* 
24/24 hour and 7/7 day availability: 
 
GSK Biologicals Clinical Safety & Pharmacovigilance 
Outside US & Canada sites: 
Fax: +32 2 656 51 16 or +32 2 656 80 09 
Email address: Rix.CT-safety-vac@gsk.com 
 
8.4.3. Unanticipated Problem Reporting 
All non-serious unanticipated problems (events not involving risk to participants or others) will be 
reported in the continuing review report to the KEMRI Scientific and Ethics Review Unit (SERU), and the 
WRAIR IRB. 
All serious unanticipated problems involving risk to participants or others should promptly (within 48 
hours) reported by telephone, by email, or by facsimile to the KEMRI SERU (kemriseru@gmail.com; 
seru@kemri.go.ke) and by phone (301) 319-9940, or by email (Usarmy.detrick.medcom-
wrair.mbx.hspb@health.mil), or by facsimile (301) 319-9961 to the WRAIR IRB. The Principal Investigator 
will then submit written reports within 10 working days to the WRAIR IRB at the following address: 
Walter Reed Army Institute of Research, ATTN: Human Subject Protection Branch, 503 Robert Grant 
Ave, Silver Spring, MD 20910. The WRAIR HSPB will report to USAMRMC ORP HRPO as per UWZ-C-636.  
In addition, all serious unanticipated problems will be reported to the Kenya PPB within 7 days. These 
reports can be submitted to the Board through the online system at www.pv.pharmacyboardkenya.org. 
Any adverse drug reactions considered as possibly related to DHA-Pip anti-malarial treatment will also 
be reported to the Pharmacovigilance department of Tridem Pharma SAS, who supplied the DHA-Pip to 
the Sponsor (PATH) for the purposes of this clinical study, within 24 hours.  
Any unanticipated problems that meet PATH Research Ethics Committee’s (REC) expedited reporting 
requirements will be promptly (within 24 hours) reported to the PATH Study Representative by email. 
The PATH Study Representative will then promptly (within 48 hours) submit the report to PATH REC 
using their online submission and reporting website (www.irbnet.org). 
Follow up reports should be submitted as soon as additional information becomes available. A summary 
of the serious unanticipated problems should also be included in the continuing review report submitted 
to the KEMRI SERU, and the WRAIR IRB. 
8.4.4. Reporting of Pregnancy 
Subjects who become pregnant during the study must not receive additional doses of investigational 
study vaccines but may continue other study procedures at the discretion of the investigator. The 
investigator, or his designee, will collect pregnancy information on any subject who becomes pregnant 
while participating in this study. The investigator, or his designee, will record pregnancy information on 
the Pregnancy Report Form and submit it to the WRAIR IRB, KEMRI SERU, Kenya PPB, PATH, and GSK. In 


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the event a woman becomes pregnant after completing all three vaccinations she will be eligible to 
continue in the ADI phase. If a pregnant female develops asymptomatic malaria infection discovered by 
a positive malaria PCR during ADI, she will be treated with standard of care malaria therapy. 
The subject will be followed to determine the outcome of the pregnancy. At the end of the pregnancy, 
whether that be full-term or premature, information on the status of the mother and child will be 
forwarded to the above ethical committees, regulatory authorities and sponsor for reporting. 
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or a SAE.  A spontaneous 
abortion is always considered to be a SAE and will be reported.   
8.5. Safety Oversight 
8.5.1. DoD Research Monitor 
The DoD Research Monitor or their approved alternate are required to review all unanticipated 
problems involving risks to participants or others, serious adverse event (SAE) reports, and all 
participant deaths. The DoD Research Monitor will provide an unbiased written report of all 
unanticipated problems involving risks to subjects or others, and related SAEs, and all deaths, promptly 
within 10 working days to the WRAIR IRB by phone (301) 319-9940 or by email 
(usarmy.detrick.medcom-wrair.mbx.hspb@health.mil), by facsimile (301) 319-9961 or at the following 
address: Walter Reed Army Institute of Research, ATTN: Human Subjects Protection Branch, 503 Robert 
Grant Ave, Silver Spring, MD 20910. In addition to submission of the DoD Research Monitor reports to 
the WRAIR IRB, a copy of the same report will be sent to the Sponsor team. All DoD Research Monitor 
reports for unrelated SAEs should be kept with the corresponding SAE reports at the study site. 
The WRAIR HSPB will submit copies of these reports to the USAMRMC ORP HRPO as per WRAIR SOP 
UWZ-C-636. The DoD Research Monitor or their approved alternate at a minimum must comment on 
the outcomes of the event or problem and in case of a serious adverse event or death, comment on the 
relationship to participation in the study. They must also indicate whether he/she concurs with the 
details of the report provided by the principal investigator.  
The DoD Research Monitor or their approved alternate should review all initial, follow up, and final 
reports for SAEs, unanticipated problems involving risks to participants or others, and all participant 
deaths in a timely manner, and provide their own independent report. 
The DoD Research Monitor will also: 
1. Discuss research progress with the PI, interview participants, consult on individual cases, or evaluate 
suspected adverse reaction reports on behalf of the IRB. 
2. Perform, at the direction of the IRB, oversight functions (e.g., observe recruitment, enrolment 
procedures, and the consent process for individuals, groups or units; oversee study interventions and 
interactions; review monitoring plans and (Unanticipated Problem Involving Risk to Subjects or Others) 
UPIRTSO reports; and oversee data matching, data collection, and analysis)   
3.  Promptly report discrepancies or problems to the IRB. 


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4.  Have the authority to stop a research study in progress, remove individual participants from a study, 
and take whatever steps are necessary to protect the safety and well-being of research participants until 
the IRB can assess the DoD Research Monitor's report 
8.6. Solicited adverse events 
Solicited local and general AEs will be collected among RTS,S vaccinated groups in the first 50 subjects 
enrolled in Groups 1 and 2 and all subjects enrolled in group 3 (Reactogenicity Cohort) for seven days 
(day of vaccination and six subsequent days) after each dose of vaccine. On the day of vaccination for 
each vaccine dose, the evaluation will be carried out by the study clinician at the KCRC. Seven days after 
each vaccination a field worker will visit each subject and review the memory aid for solicited local and 
systemic AEs and unsolicited AEs that have occurred since vaccination and per protocol scheduled anti-
malarial treatment, if applicable. 
Local (injection site) adverse events 
• 
Pain at injection site 
• 
Swelling at injection site 
Systemic adverse events 
• 
Fever (temperature ≥37.5oC) 
• 
Headache 
• 
Gastrointestinal problems 
• 
Fatigue 
• 
Muscle ache 
The visiting field worker will record these adverse events during the field worker visits. 
8.6.1. Assessment of intensity 
Table 8. Intensity Scales for Solicited Symptoms in Adults 
Pain at injection site 
0 
Absent 
1 
Painful on touch 
2 
Painful when limb is moved 
3 
Pain that prevents normal activity 
Swelling at injection site 
0 
Absent 
1 
Present and is easily tolerated 
2 
Present and interferes with normal activity 
3 
Present and prevents normal activity 
Fever 
0 
<37.5oC (99.5oF) 
1 
37.5oC (99.5oF) to 38.0oC (100.4oF) 
2 
>38.0oC (>100.4oF) to 39.0oC (102.1oF) 
3 
>39.0oC (102.1oF)  
Headache 
0 
Normal 
1 
Headache feeling is easily tolerated 
2 
Headache feeling interferes with normal activity 
3 
Headache feeling prevents normal activity 
0 
Gastrointestinal symptoms normal 
1 
Gastrointestinal symptoms that are easily tolerated 


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Gastrointestinal symptoms 
(nausea, vomiting, diarrhea 
2 
Gastrointestinal symptoms that interfere with normal activity 
3 
Gastrointestinal symptoms that prevent normal activity 
Fatigue 
0 
Normal 
1 
Fatigue that is easily tolerated 
2 
Fatigue that interferes with normal activity 
3 
Fatigue that prevents normal activity 
Muscle ache 
0 
Absent 
1 
Muscle ache that is easily tolerated 
2 
Muscle ache that interferes with normal activity 
3 
Muscle ache that prevents normal activity 
 
8.6.2. Assessment of causality 
The investigator is obligated to assess the relationship between investigational product and the 
occurrence of each solicited AE/SAE. The investigator will use clinical judgment to determine the 
relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors and the temporal relationship of the event to the investigational product will be 
considered and investigated. The investigator may also consult the Investigator Brochure and/or Product 
Information, for marketed products, in the determination of his/her assessment. The investigator may 
change his/her opinion of causality in light of follow-up information.  
All solicited local (injection site) reactions will be considered causally related to vaccination.  
Relatedness to the study product of all other solicited AE/SAEs will be classified by the same criteria 
established in 8.2.2.  
8.6.3. Follow-up and management of adverse events 
Follow-up of Solicited AEs/SAEs will be in accordance with section 8.3. AE/SAEs will be managed by the 
clinical team at KCRC, if possible, until resolution or study completion with nursing and clinical staff 
providing care under the supervision of the PI. Anything that requires treatment beyond what the KCRC 
can manage will be referred to an appropriate medical facility, but the staff will continue to follow-up as 
per section 8.3. At the end of the study, the KCRC staff will refer all subjects with unresolved/chronic 
AE/SAEs to an appropriate provider for continued management, but will continue to follow-up and 
document the AE/SAEs as appropriate per section 8.3.    
9. CLINICAL MONITORING 
Site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, 
that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s).  
A separate clinical monitoring plan (CMP) prepared by the CRO will describe: 
• 
Person who will conduct the monitoring, 
• 
Frequency monitoring will be done, 
• 
Level of detail monitoring will be performed, and  
• 
Distribution of monitoring reports.  


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10. STATISTICAL CONSIDERATIONS  
10.1. Statistical Analysis Plan 
The statistical analysis will be conducted following the principles as specified in the International 
Conference on Harmonization (ICH) Topic E9 (ICH, 1998). The final statistical analyses will be performed 
after database lock. 
All data will be collected and verified prior to analysis. Detailed statistical procedures, listings, table 
shells, and figures will be provided in a statistical analysis plan (SAP) prior to analysis. The SAP will be 
finalized before study close-out and database lock. The following key statistical components and a 
detailed description will be documented in the SAP: 
• 
Primary and secondary endpoints and how they will be measured 
• 
Statistical methods and tests that will be used to analyze the endpoints 
• 
Strategy that will be used if the statistical test assumptions are not satisfied  
• 
Indication of whether the comparisons will be using one-tailed or two-tailed tests (with 
justification of the choice) and the level of significance to be used  
• 
Identification of whether any adjustments to the significance level or the overall p value will be 
made to account for any planned or unplanned subgroup analyses or multiple testing  
• 
Specification of potential adjusted analyses and a statement with which covariates or factors 
will be included  
• 
Planned exploratory analyses and justification of their importance 
The number of subjects enrolled, vaccinated, completed, or withdrawn will be summarized. Reasons for 
withdrawal, when known, will be provided. Demographic data will be summarized by descriptive 
statistics and will include total number of observations (n), mean, standard deviation (SD) and range for 
continuous variables, and number and percentages for dichotomous variables.  
10.2. Statistical Hypotheses 
The primary and secondary hypotheses will be assessed using Cox proportional hazards regression (time 
to first PCR-positive infection).  These hypotheses tests will be supplemented with two-sided confidence 
intervals for the hazard ratios as described below. 
The null (H0) and alternative (H1) hypotheses for the primary analysis of time to first malaria infection in 
Groups 1 and 4 is as follows: 
H0:  
Among adults positive for P. falciparum at baseline the hazard rate for first malaria 
infection for RTS,S/AS01E vaccinated adults (Group 1) is not different than that of adults 
administered the comparator rabies vaccine (Group 4) as measured by the hazard ratio. 
H1:  
Among adults positive for P. falciparum at baseline the hazard rate for malaria infection 
for RTS,S/AS01E vaccinated adults (Group 1) is different than that of adults administered the 
comparator rabies vaccine (Group 4) as measured by the hazard ratio. 
The null and alternative hypotheses for the secondary efficacy analysis of time to first malaria infection 
in Groups 2 and 5 is as follows: 


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H0:  
Among adults negative for P. falciparum at baseline the hazard rate for malaria infection 
for RTS,S/AS01E vaccinated adults (Group 2) is not different than that of adults administered the 
comparator rabies vaccine (Group 5) as measured by the hazard ratio. 
H1:  
Among adults negative for P. falciparum at baseline the hazard rate for first malaria 
infection for RTS,S/AS01E vaccinated adults (Group 2) is different than that of adults administered 
the comparator rabies vaccine (Group 5) as measured by the hazard ratio. 
10.3. Analysis Datasets 
10.3.1. Enrolled population 
All subjects who provide written informed consent, regardless of the subject’s screening, randomization 
and vaccination status in the study. 
10.3.2. Total vaccinated cohort (TVC) 
All subjects in the enrolled population who were randomized and received at least one vaccination. 
10.3.3. Safety analysis population 
All subjects in the TVC for which any safety data is available. All safety analyses will be performed using 
this population.  The denominators for different safety endpoints may vary according to the number of 
subjects with available data for the specific endpoint.   
10.3.4. According to protocol (ATP) cohort for efficacy 
The ATP cohort for efficacy will include all subjects included in the TVC with no major protocol 
deviations that are determined to potentially interfere with the efficacy assessment of the study vaccine 
and contributed to the time at risk starting 14 days after the third dose. The membership in this study 
population will be determined in a blinded fashion at a data review meeting attended by the sponsor 
Medical Officer, the site PI/Co-PI, and the sponsor Statistician, and the list of criteria used to exclude 
subjects from the ATP cohort for efficacy, including vaccine or anti-malarial administration and other 
relevant analysis protocol deviations, will be finalized before database freeze.  
10.3.5. ATP cohort for immunogenicity 
The ATP cohort for immunogenicity will include all subjects included in the TVC who received all 
vaccinations according to protocol procedures and within the protocol specified intervals, performed 
blood samplings for immunogenicity according to protocol intervals, and did not use any medication or 
blood products forbidden by the protocol and did not have any reported underlying medical condition 
influencing immune responses. 
10.3.6. Total cohort for efficacy 
The total cohort for efficacy includes all TVC subjects who receive all three doses of RTS,S/AS01E vaccine 
or comparator and contributed to the time at risk starting 14 days after the third dose. 
 
10.4. Description of Statistical Methods 


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10.4.1. General Approach 
A positive PCR for the presence of P. falciparum parasites meets the definition of an event if the result is 
obtained from a blood sample collected at any time during the ADI phase of the trial (Epoch 2 or 3).  
10.4.2. Analysis of the Primary Efficacy Endpoint  
Vaccine efficacy against the first PCR-positive P. falciparum infection among adults who were P. 
falciparum positive at baseline will be assessed using Cox proportional hazards regression with a 
covariate for group assignment to compare Groups 1 and 4.  The vaccine efficacy estimates (1-hazard 
ratio), 95% CI, and p-values will be calculated from this model.  Cumulative incidence graphs will also be 
provided.  This analysis will be conducted in the ATP for efficacy cohort. 
10.4.3. Analysis of the Secondary Endpoint(s) 
Efficacy:   
Vaccine efficacy against the first PCR-positive P. falciparum infection among adults who were P. 
falciparum negative at baseline will be assessed using Cox proportional hazards regression with a 
covariate for group assignment to compare Groups 2 and 5.  The vaccine efficacy estimates (1-hazard 
ratio), 95% CI, and p-values will be calculated from this model.  Cumulative incidence graphs will also be 
provided.  This analysis will be conducted in the ATP for efficacy cohort. 
Immunogenicity: 
The primary analysis will be based on the ATP for immunogenicity cohort for analysis of 
immunogenicity. A secondary analysis based on the TVC will be performed to complement the ATP 
analysis. 
Anti-CS antibodies: 
The percentage of subjects with sero-positive levels of anti-CS (proportion of subjects with anti-CS 
antibody levels with 95% CI will be determined as shown in Appendix F. Antibody levels after the third 
dose will also be investigated using reverse cumulative curves. 
Anti-HBs antibodies: 
The percentage of subjects with sero-positive levels of anti-HBs (proportion of subjects with anti-HBs 
antibody levels greater than the lower limit of detection/assay dependent will be determined prior to 
vaccination, and 14 days post Dose 3. Antibody levels after the third dose will also be investigated using 
reverse cumulative curves. 
Anti-rabies antibodies: 
The percentage of subjects in Groups 4 and 5 with sero-positive levels of anti-rabies antibodies will be 
determined prior to vaccination, and 28 days post Dose 3. Antibody levels after the third dose will also 
be investigated using reverse cumulative curves. 
10.4.4. Safety Analyses 
For the safety analysis, data from all subjects from the safety analysis population will be included. All 
analyses will be descriptive. Data will be presented by dose, overall/dose and overall/subject. Results 


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will be summarized by study group. The percentage of subjects with at least one AE during the follow-up 
period will be tabulated with exact 95% CI (two-sided). No multiplicity adjustment will be implemented 
in analysis.  The reports of solicited and unsolicited AEs will be reviewed by a physician and will be 
categorized by the MedDRA dictionary. The percentage of subjects with at least one report of 
unsolicited AE and reported up to 28 days after each anti-malarial course will be tabulated with exact 
95% CI. The percentage of subjects with at least one report of unsolicited AE and reported up to 28 days 
after each vaccine dose will be tabulated with exact 95% CI.  
The occurrence of SAEs will be determined on the safety analysis population. The proportion of subjects 
with an SAE, classified by the MedDRA preferred term level, reported from study start until study 
conclusion will be tabulated with exact 95% CI. Comparisons between groups will be done using Fisher’s 
Exact Test for each preferred term. Serious adverse events (SAEs) occurring at any point during the trial 
will be summarized and relatedness to vaccine will be assessed. 
Withdrawals due to AEs/SAEs will also be summarized. Vital signs which are outside of the normal range 
and clinically significant will also be listed in tables. The frequency of signs and symptoms will be 
compared between groups with the chi-square test or Fisher’s exact test.  
The occurrence of Grade 3 solicited and unsolicited general reactions will be determined on the Total 
Vaccinated Cohort. The proportion of subjects with a Grade 3 solicited and unsolicited reaction, 
reported from study start until study conclusion will be tabulated with exact 95% CI. Comparisons 
between groups will be done using Fisher’s Exact Test. 
The occurrence of adverse events will be determined on the Total Vaccinated Cohort. The proportion of 
subjects with an AE, classified by the MedDRA preferred term level, reported from study start until study 
conclusion will be tabulated with exact 95% CI. Comparisons between groups will be done using Fisher’s 
Exact Test.  
10.4.5. Adherence and Retention Analyses 
Participants who prematurely discontinue from the study will not be included in analyses/summary 
statistics beyond the time of discontinuation. 
Rates of discontinuation and reason for discontinuation will be summarized in data listings or summary 
tables. 
10.4.6. Baseline Descriptive Statistics 
Baseline demographics and characteristics, including age, height, weight, sex, race and HIV status will be 
summarized for both the TVC and ATP populations by vaccine group using descriptive statistics (mean, 
standard deviation, median, minimum and maximum for continuous and rates for categorical).  
For the exposed population, medical history will be listed and summarized by category. Using the WHO 
Drug Dictionary, concomitant medications will be tabulated by anatomical therapeutic chemical (ATC) 
classification, preferred drug name and treatment group. Medical history will be tabulated by MedDRA 
System Organ Class (SOC), Preferred Term (PT) and vaccine group.  
Summaries of subject disposition will be prepared for all subjects, including the number and percent 
enrolled, screened, randomized, and administered vaccine, as well as a CONSORT diagram describing 


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study participation and discontinuation. The reasons for screen failures and discontinuations will be 
summarized and listed. 
A summary and listing of visit attendance will be prepared, in addition to a summary and listing of 
vaccine administration and sample collection/availability for each sample. 
10.4.7. Planned Interim Analyses 
There are no planned interim analyses. 
10.4.8. Multiple Comparison/Multiplicity 
No adjustment for multiplicity will be performed. 
10.4.9. Exploratory Analyses 
Exploratory analyses will be described in a separate Exploratory Statistical and Analysis Plan when the 
exploratory assays have been finalized. 
10.5. Sample Size 
This is a Phase 2b study to assess the vaccine efficacy of RTS,S in adults in a malaria endemic region.  The 
statistical analysis will measure vaccine efficacy using Cox proportional hazards regression (time to first 
PCR-positive infection).  An attack rate of 40% over 6 months has been assumed as a conservative 
estimate in an epidemiologic setting of perennial transmission in Western Kenya.  A fixed vaccine 
efficacy of 50% is a conservative assumption according to the estimated vaccine efficacy. 
Using an event-based design and assuming 10% drop out of the enrolled population and a one-sided 
α=0.025, the following are power and required number of events to conduct the analysis: 
Table 9. Sample Size Calculations 
Power 
N to enroll per 
group 
Total events 
required to 
conduct 
analysis 
Endpoint 
90% 
164 
92 
Primary (Group 1 vs 4) 
80% 
128 
72 
Secondary (Group 2 vs 5) 
 
The impact of the event-driven design is that we will continue to follow up until 92 events have been 
observed in aggregate between Groups 1 and 4 of the ATP cohort for efficacy, and 72 events have been 
observed in the aggregate of Groups 2 and 5 of the ATP cohort for efficacy. If the aggregate numbers of 
events have been reached prior to 24 weeks of ADI, study actives will continue to occur through the end 
of Epoch 2 only (though some subjects may have begun Epoch 3 as discussed in 7.1.1). If the aggregate 
number of events during Epoch 2 does not reach the cutoff indicated in Table 9, then the ADI will be 
extended up to 48 weeks or until the total number of events is reached, whichever occurs first. This will 
require the PCR lab to provide timely aggregated reports of event counts (across Group 1 plus 4; and 
Group 2 plus 5) and may result in more than the required events for either the primary or secondary 
endpoint. 


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An additional cross-sectional PCR will be performed at the Study Termination Visit as described in 
section 7.1.1, but these PCR results will not count toward the study endpoints.  
Based on these assumptions we estimate a greater than 90% probability of observing the required 
number of events for the primary and secondary analyses by 6.9 months.  However, larger dropout rates 
and/or a lower attack rate will extend the amount of follow-up time necessary to accumulate the 
required number of events.   
The immunologic sub-cohort for CMI assays in all subjects in RTS,S groups (groups 1, 2, and 3).  This 
sample size has been chosen based on logistical considerations and the feasibility of the collection and 
processing of PBMCs.  Analysis of these exploratory endpoints and inter-group differences will be 
descriptive in nature. 
 
10.5.1. Randomization Procedures 
Eligible subjects will be randomized to their assigned group with secure IWRS (or in the absence of web 
connectivity, IVRS), which will be developed and managed by the PATH designated CRO.  The IWRS/IVRS 
allows authorized staff from the study site to perform subject randomization and treatment assignment 
24 hours a day, 7 days a week. 
Subjects will be stratified by baseline parasitemia status and then block randomized.  Among those 
positive for parasitemia at baseline a total of 363 will be randomized. The first 105 will be randomized in 
a 1:1:1 ratio with 35 subjects assigned to each of Groups 1, 3 and 4. The next 258 subjects with baseline 
parasitemia will be randomized in a 1:1 ratio to Groups 1 and 4 with a total of 129 additional subjects 
per group. Two hundred fifty-six subjects that are negative for parasitemia at baseline will be 
randomized with a 1:1 ratio to Groups 2 and 5. This randomization schedule will result in a total of 164, 
128, 35, 164, and 128 for Groups 1 through 5, respectively. Additional details of the randomization 
procedure, such as block size, will be described in the Randomization Plan.  HIV infection status will be 
noted prior to randomization, and individuals will be stratified across the groups to the extent possible.  
The proportion of subjects per group that are HIV positive will be capped near 20-25% for each group. 
11. SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS  
The KCRC site will maintain appropriate medical and research records for this trial. Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
12. QUALITY ASSURANCE AND QUALITY CONTROL 
PATH has a Quality Assurance Standard for Document Management in Essential Medicines. SOPs for 
quality management to ensure compliance with the protocol, ethical standards, and regulatory 
requirements for the study are on file at PATH. Having the highest quality data and studies are essential 
aspects of vaccine development. For the purpose of compliance with Good Clinical Practice it may be 
necessary for PATH to conduct a site audit. This may occur at any time from start to after conclusion of 
the study. When an investigator signs the protocol, he agrees to permit PATH audits, providing direct 
access to source data/ documents to include: 


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• 
IRB/IEC approval 
• 
Vaccine accountability 
• 
Approved study protocol and amendments 
• 
Informed consent of the subjects (written consent [or witnessed oral if applicable] )  
• 
Medical records and other source documents supportive of CRF data 
• 
Reports to the IRB/IEC the sponsor, PATH, GSK and WRAIR 
• 
Record retention 
The KCRC site has SOPs for quality management that include staff training methods, product 
accountability records, specimen tracking logs, questionnaires, audio or video recordings.  
The Quality Control Standards and Requirements for the candidate RTS,S vaccine are described in 
separate release documents maintained by GSK.  
QC procedures will be implemented beginning with the data entry system and data QC checks that will 
be run on the database will be generated by the CRO selected by PATH. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. Following written SOPs, the 
monitors will verify that the clinical trial is conducted, data are generated, documented, and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirements.  
13. ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1. Ethical Standard 
This study will be conducted in accordance with the latest revision of the Declaration of Helsinki (2013), 
the Medical research Involving Human Subjects act (WMO), the ICH Good Clinical Practice, Department 
of Defense (DoD) requirements as outlined in 32 CFR 219, local rules of KEMRI SERU, and regulations of 
the Kenya Pharmacy and Poisons Board. The investigators are responsible for obtaining all relevant 
ethical approvals of the protocol and any subsequent amendments in compliance with local law before 
the start of the study.  
13.2. Institutional Review Board 
13.2.1. Ethics Approval 
Submission of the protocol and supporting documents will occur in accordance with local regulatory 
requirements. KEMRI SERU is the IRB of record for the Kenyan Site, Kombewa in Kisumu. This protocol 
will be submitted to KEMRI Center Scientific Committee for review and approval. It will also be 
submitted to the KEMRI SERU where ethical aspects of the protocol will be reviewed before the protocol 
can be approved. 
The Walter Reed Army Institute of Research IRB will also be involved in the approval process for this 
protocol. WRAIR IRB is the IRB of record for US Army Medical Research Directorate-Africa (USAMRD-A). 
For this reason, approval from the WRAIR IRB will be sought alongside the KEMRI SERU approval prior to 
implementation of the protocol or protocol amendments for this study. 
Headquarters-level oversight of the WRAIR Human Research Protection Program (HRPP) is provided by 
the USAMRDC ORP HRPO for studies involving outside collaborators.  HRPO will review all protocol life 
cycle actions as outlined in UWZ-C-636. 


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Regulatory Approval will also be obtained from the Kenya Pharmacy and Poisons Board (PPB) Expert 
Committee on Clinical Trials (ECCT) for the initial protocol and any subsequent protocol amendments, as 
well, as any amendments that increase the risks to subjects or others. 
PATH will delegate ethical review and oversight to KEMRI SERU. 
13.2.2. Protocol Amendments 
All amendments and modifications will be submitted to the WRAIR IRB, KEMRI SERU and PPB ECCT for 
review and approval.  No changes in protocol conduct will be implemented until approval is obtained 
from the WRAIR IRB, KEMRI SERU as well as USAMRMC ORP HRPO, and PPB, as applicable, unless 
required to eliminate apparent immediate hazards to the study subjects. Amendments and 
modifications cannot be implemented until the WRAIR Commander’s Memorandum has been issued. 
The WRAIR HSPB will submit amendments to USAMRMC ORP HRPO as per WRAIR SOP UWZ-C-636.  
Non-significant amendments from the sponsor that are defined as amendments that do not affect the 
safety and wellbeing of the subjects at the site, and that are more administrative will also require both 
WRAIR IRB and KEMRI SERU approval prior to implementation. 
13.2.3. Reporting requirements 
 Continuing Review Reporting 
The PI or designee will be responsible for submitting the required continuing review report and 
supporting documentation to the WRAIR IRB, KEMRI SERU and PPB ECCT, allowing sufficient time for 
review and continuation determination prior to the established continuing review date. A closeout 
report will be submitted at the end of the study upon completion of all the study activities or 5 years, 
whichever comes first.  The HSPB will submit the continuing review and closeout reports to the 
USAMRMC ORP HRPO as per SOP UWZ-C-636. 
PATH will submit a safety report to the PPB annually through the clinical trial or on request. The report 
will take into account all new available safety information received during the reporting period. The aim 
is to describe concisely all new safety information relevant for the trial and assess the safety conditions 
of subjects included in the trial 
 Protocol Deviation Reporting 
Major deviations will be promptly (within 48 hours) reported by email to the KEMRI SERU 
(kemriseru18@gmail.com; seru@kemri.go.ke) and by phone (301) 319-9940, or by email 
(usarmy.detrick.medcom-usamrmc.other.hrpo@health.mil), or by facsimile (301) 319-9961, to the 
WRAIR IRB. The Principal Investigator will then submit written reports within 10 working days to the 
WRAIR IRB at the following address: Walter Reed Army Institute of Research, ATTN: Human Subjects 
Protection Branch, 503 Robert Grant Avenue, RM 1W30, Silver Spring, Maryland, 20910-7500. All 
deviations will be summarized in the continuing review reports that are submitted to the WRAIR IRB and 
KEMRI SERU. The Principal Investigator is responsible for reporting the major and minor deviations to 
the WRAIR IRB and the KEMRI SERU appropriately.  
In addition, all major deviations will be reported to the Kenya PPB within 7 days. These reports can be 
submitted to the Board through the online system at www.pv.pharmacyboardkenya.org. 


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Any deviations that meet PATH Research Ethics Committee’s (REC) expedited reporting requirements 
will be promptly (within 24 hours) reported to the PATH Study Representative by email. The PATH Study 
Representative will then promptly (within 48 hours) submit the report to PATH REC using their online 
submission and reporting website (www.irbnet.org). 
Any suspensions (to include continuing review lapses), clinical holds (voluntary or involuntary), or 
terminations of this research by an IRB, the institution, the Sponsor, or regulatory agencies will be 
promptly reported to the WRAIR IRB, KEMRI SERU, PPB, and PATH REC.  
The WRAIR HSPB will submit deviations, suspensions, and terminations to USAMRMC ORP HRPO as per 
WRAIR SOP UWZ-C-636. 
In addition to the requirements listed above, minor deviations will be reported to WRAIR IRB and KEMRI 
SERU with the continuing review reports. 
 Reporting of Inspections or Audits 
Knowledge of any pending compliance inspections/visits by Office for Human Research Protections 
(OHRP) or other government agency concerning clinical investigation or research, the issuance of 
Inspection Reports, warning letters or actions taken by any Regulatory Agencies including legal or 
medical actions and any instances of serious or continuing noncompliance with the regulations or 
requirements will be reported immediately to the KEMRI SERU (kemriseru18@gmail.com; 
seru@kemri.go.ke) and WRAIR IRB by phone (301) 319-9940, or by email (Usarmy.detrick.medcom-
wrair.mbx.hspb@health.mil), or by facsimile (301) 319-9961.  The WRAIR HSPB will report to USAMRMC 
ORP HRPO as per WRAIR SOP UWZ-C-636. 
13.3. Informed Consent Process 
13.3.1. Consent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks and benefits are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study products.  
13.3.2. Consent Procedures and Documentation 
At the beginning of the study, potential participants selected from within the HDSS will be approached 
in the community using a recruitment script by study staff delegated to carry out recruitment. Prior to 
any volunteer joining the study or undergoing any screening procedures, an informed consent process 
will be carried out. The study staff will brief the participant about the study using the informed consent 
document. This briefing may be done individually or in groups with the aid of Study Briefing Slides 
(which will be submitted to ethical review along with this protocol) either done live or as recorded audio 
with the slides by the principle investigator or delegate. At the end of the briefing, there will be a 
question and answer session (when a group briefing is completed, this will be both as a group and as 
individual participants). This will enable participant to understand the purposes of the study as well as 
the study procedures. They will be given adequate time to think about participating, ask any questions 
and decide whether they want to participate or not. Subjects may take time to talk with their family 
and/or friends prior to deciding to consent for participation. Thereafter, signature of the written 
informed consent will be obtained from each participant who wants to participate in the study. The 


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participant and the study staff conducting informed consent explanation will sign and date the consent 
form. The participant signature confirms that (s)he has understood the information. For illiterate 
individuals, the informed consent process will be conducted in the presence of a literate impartial 
witness selected by the participant but not a member of the KCRC staff. The participant will thumb print 
the consent form and the witness will write the participant’s name, sign and date the consent form. 
Each volunteer’s consent form will be kept in their study folder and a copy will be given to the 
participant to take home on the same day. In case of any amendments to the protocol resulting in 
changes in study procedures, the participant will be informed and additional informed consent will be 
obtained if necessary. In accordance with Good Clinical Practice, the volunteer may terminate 
participation in the study at any time for any reason without penalty. Additionally, if the participant is 
unable or unwilling to adhere to the protocol design, the investigator may terminate volunteer’s 
participation. The study team will use the participant’s preferred language usually English, Kiswahili or 
Luo for informed consent. 
13.4. Participant and Data Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s). This confidentiality is extended to cover testing of biological samples in addition to the 
clinical information relating to participants. Therefore, the study protocol, documentation, data, and all 
other information generated will be held in strict confidence. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of PATH.  The 
study monitor, other authorized representatives of the sponsor, may inspect all documents and records 
required to be maintained by the investigator.  
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location. 
13.4.1. Future Use of Stored Specimens 
After the study is complete, sera, PBMC, and whole blood mRNA specimens will be maintained in a 
biorepository managed by PATH and will be stored for a period of up to 15 years. Dried blood spots of 
whole blood collected during the study will be maintained at the study site and/or shipped to a 
repository in the United States selected by PATH with the concurrence and approval by the Kenya 
Medical Research Institute (KEMRI)/US Army Medical Research Directorate-Africa (USAMRD-A) for a 
period of up to 15 years. Participants will be asked to consent for the future use of these specimens 
beyond the scope of the testing outlined in this protocol, but consent for future use will not be required 
for participation in this study and an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage will not be possible after the study is completed. The future use of biosamples 
obtained during this study includes further PCR or genetic characterization of malaria parasites or 
further characterization of participants’ serum, PBMC or mRNA samples (to potentially include further 
serological testing, additional cell-mediated immune response assays, HLA typing or further evaluation 
of transcriptomics profile). HLA typing will be limited to understanding the immune responses related to 
immunization and will not be used to identify specific genetic traits or diseases. The potential 
transcriptomics assays will assess the mRNA transcription profiles in response to vaccination and do not 
evaluate for hereditary genetic conditions in the subjects’ DNA. 


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13.5. Compensation 
13.5.1. Compensation for injury 
Participants will be insured against injury caused by the study according to legal requirements and 
compensation for research related injury (to include costs of long term and future medical care needs) is 
available, should it occur.  If a participant suffers injury or death directly attributable to participation in 
this study, the participant is asked to contact the PI using the emergency contacts that will be provided 
on the consent forms and emergency number in the participant ID card. They will also be provided the 
contacts of KEMRI SERU secretariat in the event that they would like to speak to someone independent 
of the trial. Appropriate treatment during the trial will be provided by the site personnel and paid by 
PATH.  
 
13.5.2. Compensation for subject participation 
The Kisumu Site will compensate participants for time, inconvenience and lost wages at the rate of 500 
KES per scheduled visit.  Kisumu (specifically Kombewa) does not have commercial agriculture and jobs 
are quite limited; most people practice subsistence farming or fishing and minimum wage for unskilled 
labor ranges from 300-500 KES per day.  To be equitable, therefore, Kisumu will compensate for lost 
wages, time and inconvenience at approximately a day’s work at minimum wage (500 KES).   
Participants taking part in this study will receive transport reimbursement (if they are not utilizing the 
site’s transport) in accordance with local SOPs, taking into consideration average cost of travel to the 
clinic between 500 and 1,000 Kenya shillings (US $ 5 and $ 10) for scheduled visits, and 300 and 500 
Kenya Shillings (US $ 3 to $ 5) for unscheduled visits as determined by the study team on a case by case 
basis. Unit transport may also be used as necessary. 
14. DATA HANDLING AND RECORD KEEPING  
Data collection is the responsibility of the clinical study staff at the site under the supervision of the site 
Principal Investigator (PI). The PI is responsible for assuring that the data collected is complete, legible, 
attributable, accurate, and recorded in a timely manner. Data recorded in the CRF should be consistent 
with the data recorded on the source documents. All source documents and laboratory reports must be 
reviewed by the site team, who will ensure that they are accurate and complete. The PATH designated 
CRO is responsible for data management activities, including quality and accuracy review, analysis, and 
reporting of the study data according to Standard Operation Procedures (SOPs). 
14.1. Data Collection and Management Responsibilities 
14.1.1. Source Data 
All information in original records and certified copies of original records or clinical findings, 
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). [ICH E6 
section 1.51]. 
14.1.2. Source documents 


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Original documents, data and records (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects' diaries of evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial are considered Source Documents. [ICH E6 section 1.52]  
This study is using a barcoded paper Case Report Form (CRF) which is also considered as Source 
Documents with a few exceptions where the CRF are not source and other documents are considered 
source. These include the following CRF pages:  
- 
The Informed Consent CRF, where the signed Informed Consent Form is considered source  
- 
The results sections of the Local Laboratory Results CRF, HIV Test Results CRF, Parasitemia 
Assessment CRFs and Hemoglobinopathy CRF, where the lab reports are considered source. 
(The urine pregnancy test results CRF is considered source.)  
- 
The PCR results section of the Parasitemia Assessment CRFs, where reports from the MDR 
laboratory are considered source. 
- 
The IP Administration CRF, where pharmacy IP dispensing and accountability records are 
considered. 
- 
The SAE CRF, where in case of hospitalizations the hospital records are considered as source. 
Printed copies of the barcoded CRF are completed by site staff and field staff during subject visits and 
then scanned and sent to the PATH designated data management CRO, DFnet. 
 
14.1.3. Data Capture Methods (CRF Development and Completion) 
Clinical data recorded in source documents, including the barcoded CRF pages, should be completed in a 
neat, legible manner to ensure accurate interpretation of data. Source documentation supporting the 
CRF data should document the dates and details of study procedures, AEs and subject status. The PI will 
ensure that all information in the CRFs and all other source documents that support the data collected 
from each subject are maintained in a secure area and treated as confidential material. 
Data reported in the CRF that is derived from other source documents should be consistent. It is the PI’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s 
CRF and any supporting documentation. 
Clinical data entered in the barcoded CRFs and other source documents (as listed above) are uploaded 
to a 21 CFR Part 11 compliant EDC system using intelligent character recognition software. The scanned 
pages are then verified against data captured in the database by the data management staff at DFnet. 
For randomization, data confirming eligibility of the subject, P.falciparum infection status and HIV status 
at screening (based on source data as listed above), is entered directly into the same EDC system by site 
staff at Visit 2.   
The database includes password protection and internal quality checks, such as automatic range checks, 
to identify data that appear inconsistent, incomplete, or inaccurate.  


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Additionally, a description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. The clinicaltrials.gov registry will not identify any individual participants and will 
include a summary of the results. 
14.1.4. Data Management 
The PATH designated Data Management CRO, DFnet, will develop a Data Management Plan (DMP) for 
review and approval by PATH.  The DMP will describe the roles of the stakeholders and specific 
procedures to ensure appropriate handling of data at all steps of the data management process, to 
assure a valid and high-quality database at the end of the study, ready for analysis. 
14.1.5. Data Storage 
All study documentation containing personal information relating to study subjects like consent forms 
and other documents that might link subject ID with other subject personal details will be kept in a 
secure locked area with limited access at the KCRC. Such documentation will only be made available to 
authorized personnel. These study documents will be made available to the investigators, clinical 
personnel who require this information to treat the subjects and the above-mentioned personnel for 
inspection or auditing reasons. In addition, access to subjects’ medical records will be granted to 
representatives of the Sponsor, regulatory agencies, ethics committees, and the USAMRDC for the 
purpose of validating data. 
14.2. Study Records Retention and Disposal 
Study documents should be retained for the duration required by PATH, applicable local regulations, and 
in according to U.S. DoD requirements, in a safe and secure facility. No records will be destroyed 
without the written consent of PATH. Upon study completion, all records will be stored safely at one of 
USAMRD-A’s archiving facilities or at a secure contracted storage facility for at least 15 years. If storage 
at an alternative facility is considered, this will be documented, and the documentation will be filed in 
the study’s regulatory file. Should longer storage be recommended by the sponsor or relevant 
authorities, the site will contact the reviewing IRBs for consideration and approval. Study files can be 
stored either as paper or digitally. Digitization, if done, will consist of the scanning of all paper records 
according to site SOPs to ensure accurate and complete representation of the same. This may be done 
by the site staff of a contracted third-party. All digitized records will be maintained on a secure, 
password protected computer system with access limited to those with access to study as previously 
listed in this protocol as well as USAMRD-A’s archivist(s) and IT personnel who will maintain the 
database. Upon completion of digitization of study records, and receipt of a sponsor’s approval, paper 
copies may be destroyed by incineration according to site SOPs. 
Paper or digitized records may be disposed of after storage duration has been met (15 years or as 
otherwise specified as above) and with the sponsor’s approval. Any remaining paper records will be 
incinerated and/or digitized records will be securely deleted. The final disposal of any remaining paper 
or digitized records will be witnessed by a representative of USAMRD-A’s regulatory affairs department 
and will be documented. The documentation of records disposal will be provided to the sponsor and a 
copy will be stored at the Regulatory Affairs department. 
14.3. Protocol Deviations 


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A protocol deviation is any noncompliance with the clinical trial protocol, or GCP requirements.  
The noncompliance may be either on the part of the participant, the investigator, or the study site staff.  
As a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations.   
14.4. Publication and Data Sharing Policy 
This study will comply with PATH and U.S. DoD policies. PATH policy ensures that the public has open 
access to the published results of Gates Foundation funded research. The International Committee of 
Medical Journal Editors (ICMJE) member journals have adopted a clinical trials registration policy as a 
condition for publication.  
The first publication or disclosure of study results shall be a complete publication or disclosure 
coordinated by PATH.  
15. CONFLICT OF INTEREST POLICY  
The independence of this study from any actual or perceived influence is critical. The sponsor, PATH has 
no conflict of interest to disclose. 
16. STUDY LIMITATIONS AND POTENTIAL BIASES 
Limitations of this study include that the ideal correlate of protection for a malaria vaccine is unknown 
given that antibody responses do not always correlate with protection. This study is exploring additional 
immunological responses to have a better understanding of the correlate of protection. Additionally, 
while the PCR assay used here tests for the presence of a blood stage infection, incubating liver stage 
parasites may be missed during screening resulting in misallocation of a subject to a group other than 
originally intended. We believe that such an occurrence would be rare and there is no way to mitigate 
should such an event would occur. The selection methods and randomization were designed to limit 
bias, but we may potentially have other confounding factors that were not considered and will fail to be 
randomly distributed despite our best efforts.  
17. MILITARY RELEVANCE 
US Service Members conduct operations in regions of the world where they are at risk of malaria 
acquisition. Acquiring malaria is significantly detrimental to individual Service Members and their units 
resulting in lost duty hours, increased utilization of medical resources in the field (often in austere 
settings), potential requirement for medical evacuation, risk of death to individual Service Members, 
and risk to a unit's mission if a significant proportion or key individuals become ill. As such medical 
countermeasures to malaria are essential in malaria endemic regions and include effective treatment, 
effective prophylaxis, and immunoprophylaxis (such as a vaccine). Malaria vaccines have the advantage 
of potentially eliminating the need for other prophylaxis (if high enough efficacy) and/or decreasing the 
severity of disease if an individual does become ill. To date, the RTS,S malaria vaccine is the most 
advanced in development and has shown reasonable efficacy in adults in challenge studies, but less so in 
field settings. This study attempts to optimize the RTS,S vaccines protective efficacy in endemic areas 


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and also further understand the immunology of a protective response. What is learned will help in 
advancing the understanding and application of this vaccine, and in the future development of malaria 
immunoprophylaxis. Additionally, an effective malaria vaccine may contribute to disease reduction in 
the long-term goals of malaria elimination. In the short term, reduced disease burden can improve the 
health of individuals in endemic regions which can improve regional stability. Also, any declines in 
malaria burden as we work toward elimination decreases the risk to service members deployed in 
endemic areas. 
 
 
 
18. LITERATURE REFERENCES  
1. The RTS,S Clinical Trials Partnership. First results of Phase 3 trial of RTS,S/AS01 malaria vaccine in 
African children. New England Journal of Medicine. 2011;365:1863–75. 
2. The RTS,S Clinical Trials Partnership. A Phase 3 trial of RTS,S/AS01 malaria vaccine in African 
infants. New England Journal of Medicine. 2012;367:2284–95. 
3. The RTS,S Clinical Trial Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 
18 months after vaccination: a Phase 3 randomized, controlled trial in children and young 
infants at 11 African sites. PLOS Medicine. 2014;11(7):e1001685. 
4. The RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or 
without a booster dose in infants and children in Africa: final results of a Phase 3, individually 
randomized, controlled trial. The Lancet. 2015;386(9988):31–45. 
5. Kester KE, Cummings JF, Ofori-Anyinam O, et al. Randomized, double-blind, phase 2a trial of 
falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults:  safety, 
efficacy, and immunologic associates of protection. J Infect Dis. 2009 Aug 1;200(3):337-46.  
6. Regules JA, Cicatelli SB, Bennett JW, et al. Fractional third and fourth dose of RTS,S/AS01 malaria 
candidate vaccine: A phase 2a controlled human malaria parasite Infection and immunogenicity 
study. J Infect Dis. 2016 Sep 1;214(5):762-71.  
7. Moorthy V, Ballou WR. Immunological mechanisms underlying protection mediated by RTS,S: a 
review of the available data. Malaria Journal. 2009;8:312. 
8. Polhemus ME, Remich SA, Ogutu BR, et al.  Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults 
in a high malaria transmission area. PLoS One. 2009 Jul 31;4(7):e6465. doi: 
10.1371/journal.pone.0006465.  
9. Wykes MN, Horne-Debets JM, Leow CY, Karunarathne DS. Malaria drives T cells to exhaustion. 
Front Microbiol. 2014 May 27;5:249. doi: 10.3389/fmicb.2014.00249.  
10. Keitany GJ, Kim KS, Krishnamurty AT, et al. Blood stage malaria disrupts humoral immunity to 
the pre-erythrocytic stage circumsporozoite protein. Cell Rep. 2016 Dec 20;17(12):3193-3205. 


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11. Illingworth J, Butler NS, Roetynck S, et al. Chronic exposure to Plasmodium falciparum is 
associated with phenotypic evidence of B and T cell exhaustion. J Immunol. 2013 Feb 
1;190(3):1038-47.  
12. Freeman GJ, Sharpe AH. A new therapeutic strategy for malaria: targeting T cell exhaustion. Nat 
Immunol. 2012 Jan 19;13(2):113-5. doi: 10.1038/ni.2211. 
13. Weiss GE, Crompton PD, Li S, et al. Atypical memory B cells are greatly expanded in individuals 
living in a malaria-endemic area. J Immunol. 2009 Aug 1;183(3):2176-82.  
14. Weiss GE, Traore B, Kayentao K, et al. The Plasmodium falciparum-specific human memory B cell 
compartment expands gradually with repeated malaria infections. PLoS Pathog. 2010 May 
20;6(5):e1000912.  
15. Butler NS, Moebius J, Pewe LL, et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears 
established blood-stage Plasmodium infection. Nat Immunol. 2011 Dec 11;13(2):188-95. 
16. Nielsen CM, Vekemans J, Lievens M, Kester KE, Regules JA, Ockenhouse CF. RTS,S malaria 
vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with 
HLA genotype. Vaccine. 2018 Mar 14;36(12):1637-1642. 
 
 


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19. APPENDICES 
APPENDIX A. SCREENING VISIT PROCEDURES 
Screening Visit  
1 
Type of Visit (KC = KCRC Clinic Visit or FV = Field visit) 
KC 
Study day 
-39 to -28 
Informed consent 
● 
Photo for ID card 
● 
Demographics 
● 
Medical History 
● 
Physical Examination 
● 
Concomitant medications 
● 
Check inclusion/exclusion criteria 
● 
Vital Signs (BP, pulse, temperature) 
● 
Urine Pregnancy test 
● 
Complete blood count (Hb, WBC, PLT; (4 mL) 
● 
Creatinine, ALT (4 mL) 
● 
HIV (4 mL) 
● 
Blood sampling for assessment of parasitemia (PCR and DBS) 
(0.35 to 0.5 mL) by finger stick 
● 
Record any SAEs  
● 
CUMULATIVE BLOOD VOLUME 
13 mL 
 
















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APPENDIX F. BIOLOGICAL SAMPLES FOR IMMUNOGENICITY TESTING 
SAMPLES COLLECTED 
Visit # 
2 
5 
6 
7 
11 
13 
17 
20 
27 
Study 
Termination 
Visit 
Study day 
-
27 1 
2 
8 
29 
57 
197 225 372 
TBD* 
Secondary endpoint -Groups 1, 2, 3 
  
  
  
  
  
  
  
  
  
  
  
Serum 
anti-CS NANP 
levels 
● 
● 
  
  
● 
● 
● 
● 
● 
● 
anti-CS NANP 
avidity 
● 
● 
  
  
● 
● 
● 
● 
● 
● 
anti-CS C-term 
levels 
● 
● 
  
  
● 
● 
● 
● 
● 
● 
anti-CS C-term 
avidity 
● 
● 
  
  
● 
● 
● 
● 
● 
● 
anti-HbsAb 
antibodies 
● 
● 
  
  
● 
  
  
● 
  
  
 
Exploratory  
  
  
  
  
  
  
  
  
  
  
  
Serum 
Anti-rabies 
antibodies -(first 
50 subjects in 
Group 4 and 
Group 5) 
  
● 
  
  
  
  
  
● 
  
  
  
  
  
  
  
  
  
  
  
  
  
PBMC 
Flow cytometry 
from all RTS,S 
vaccinated 
subjects (Gps 
1,2,3)  
● 
● 
  
● 
  
  
  
● 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Transcriptomics 
Transcriptomics 
Groups 1, 2, 3, 
4, 5 
● 
● 
● 
 ● 
  
  
  
● 
  
  
* Study Day for the Study Termination Visit will be the day according to the criteria as specified in section 7.1.1, part E of the protocol being met.


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APPENDIX G. ADULT NORMAL REFERENCE VALUES – KEMRI & 
USAMRD-A KISUMU CLINICAL LABORATORIES 
  
  
  
  
Critical Values 
Analyte 
Adult 
Male 
Adult 
Female 
Unit 
Low 
High 
Creatinine 
54.2 - 
137.8 
52.4 - 96.8 
µmol/L 
N/A 
Male:>248; 
Female:>174.2 
ALT 
12.0 - 80.6 
10.7 - 61.3 
U/L 
N/A 
Male:>201.5; 
Female:>153.3 
WBC  
3.3 - 9.6 
3.7 - 9.1 
x103/µL 
< 2.0 
> 40.0 
HGB 
12.6 - 17.2 
9.0 - 14.9 
g/dL 
Male: <8.0; 
Female: <7.0 
>20.0 
Platelets 
126 - 356 
147 - 454 
x103/µL 
<80 
>1000 
 
 


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APPENDIX H. WHO CLINICAL STAGING OF HIV INFECTION IN KENYA 
 
 
 


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APPENDIX I. DETAILED ROLES AND RESPONSIBILITIES 
The Principal Investigator (PI) will be responsible for ensuring the protocol is executed as written, 
obtaining consent, conducting physical examinations and medical histories, determining eligibility of an 
individual to participate in the study, collecting data, data analysis, protocol design, administrative 
support, adverse event reporting, observation of participants, progress/continuing review reporting, 
briefing volunteers, clinical care of participants, review of source documents, randomization, 
investigational product accountability, overseeing all other research activities, documenting protocol 
deviations, training and supervising study staff, and delegating responsibilities as appropriate. The Co-
Principle Investigator (Co-PI) will have the same responsibilities as the PI and can serve as an alternate 
in decision making if the PI is unavailable. However, if there are any disagreement between the Co-PI 
and the PI, the ultimate authority for a decision will rest with the PI. 
The Associate Clinical Investigators, as delegated by the PI, may be responsible for executing the 
protocol as written, obtaining consent, conducting physical examinations and medical histories, 
determining eligibility of an individual to participate in the study, collecting data, data analysis, protocol 
design, assist in supervising study staff, administrative support, adverse event reporting, observation of 
participants, progress/continuing review reporting, briefing volunteers, clinical care of participants, 
review of source documents, overseeing research activities, and any other study activities as delegated 
by the PI. 
The Clinical Research Coordinator, as delegated by the PI, may be responsible for executing the protocol 
as written, collecting data, data analysis, protocol design, administrative support, coordinating all 
protocol activities, maintaining essential trial documents, adverse event reporting, scheduling 
participant appointments, reviewing source documents, drug accountability,  randomization (though will 
not have access to manual randomization envelops), quality assurance/control, overseeing research 
activities, and any other study activities as delegated by the PI. 
The Clinicians, as delegated by the PI, may be responsible for obtaining consent, conducting physical 
examinations and medical histories, executing the protocol as written, adverse event reporting, 
observation of participants, progress reporting, recruiting study participants, briefing volunteers, 
appointing follow-up visits, clinical care of participants, reviewing source documents, and any other 
study activities as delegated by the PI. 
The Study Nurses, as delegated by the PI, may be responsible for obtaining consent, recording 
demographics, obtaining vital sign measurements, specimen collection, administering study 
vaccinations, observation of participants, briefing volunteers, appointing follow-up visits, clinical care of 
participants, dispensing of medications, and any other study activities as delegated by the PI. 
The Pharmacist, as delegated by the PI, may be responsible for drug accountability, vaccine preparation, 
randomization, dispensing of medications, and any other study activities as delegated by the PI. 
The Laboratory Staff, as delegated by the PI, may be responsible for specimen collection, specimen 
processing, transportation/shipping of samples, sample management, protocol design, quality 
assurance/control, malaria slide coordination, and any other study activities as delegated by the PI. 


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The Records Staff and Data Management Team, as delegated by the PI, may be responsible for photo 
taking and ID preparation, data entry, quality assurance/control, and any other study activities as 
delegated by the PI. 
The Community Relations and Field Team, as delegated by the PI, may be responsible for recruitment of 
participants, appointing follow-up visits, community education and outreach, and any other study 
activities as delegated by the PI.