| Protocol No: | ECCT/18/12/01 | Date of Protocol: | 02-10-2018 |
| Study Title: | A Phase 1b, open-label, age de-escalation, dose-escalation study to evaluate the safety and immunogenicity of different doses of a candidate malaria vaccine; adjuvanted R21(R21/MM) in adults, young children and infants in Kilifi, Kenya. |
| Study Objectives: |
Primary objective
To evaluate the safety and tolerability of R21 with adjuvant Matrix-M in healthy adults then
children and finally infants.
Secondary objective(s)
To assess the cellular and humoral immunogenicity of R21 in humans with adjuvant Matrix-
M in healthy adults, children and infants. Immunology bloods will be collected prior to
enrolment and vaccination and during follow-up visits.
|
| Laymans Summary: |
Lay Title: A study to determine if a new malaria vaccine is safe and induces immunity among
Kenyan adults, young children and infants.
What is the problem/background?
RTS,S/AS01, is the only malaria vaccine in advance clinical development but could be better by
preventing malarial infection particularly in vaccinated infants and is being evaluated for use in the
infant vaccine schedule recommended by the World Health Organisation as well as determining the
significance of any safety concerns. There are several thoughts as to why RTS, S may not prevent
more clinical infections; Only a small proportion of the vaccine is made up of Malaria parasite
protein, in our candidate vaccine the particle is coated with malaria parasite protein. Another
hypothesis is that the majority of RTS, S/AS01 is composed of a Hepatitis B surface protein which
may interfere with the immune response in infants, R21/MM has very little of this protein on its
surface. R21/MM also induces a good immune response, is cheap and easy to make and as such
there is a good case for further clinical development of this vaccine. Malaria deaths have fallen with
the advent of new drug combinations and widespread use of insecticide treated bed nets but the hope
malaria eradication is threatened by emerging resistance to these drugs and insecticides. One of the
primary strategic goals outlined by WHO in the Malaria Vaccine Roadmap, is the development of
malaria vaccines which would protect against clinical malaria in 3 out of 4 vaccinated individuals,
and would be suitable for administration in malaria endemic areas and appropriate at-risk groups by
2030. R21/MM is a candidate malaria vaccine and biologically similar to RTS,S/AS01 and RTS,S
has been evaluated extensively in clinical trials. R21 has had 3 formulations to date; R21, R21c and
now R21/MM. R21 that was evaluated in animal studies then in an effort to progress to clinical trials,
purification of the vaccine was required and this was challenging hence components of a protein
were added to R21 making R21c which was manufactured in Oxford, UK. R21c has been evaluated
in animal and human trials but to move forward in clinical development a large-scale manufacturer
was required and the current vaccine (R21/MM) has been subjected to some minor changes. These
products (R21/R21c and R21MM) are all very similar but R21/MM has yet to be evaluated in human
subjects. The main difference being R21/MM does not have 4 components of a protein, the c-tag
which was present in R21c. Also, each vaccine has a different manufacturer, however we do not anticipate the immune response or safety profile to change given the removal of this protein
component or the new manufacturer. Matrix-M is a component of the vaccine that has been
demonstrated to improve vaccine response of R21c and to be safe in healthy adults.
What questions are we trying to answer?
We plan to evaluate if R21/MM, a candidate malaria vaccine, is safe and provides good vaccine
responses at different doses in healthy Kenyan adults (aged 18-45 years), young children (aged 1-5
years) and infants (5-<12 months) and investigate the immune responses following vaccination and
the persistence of these in the first 2 years following a 3- dose vaccination course, given 4 weeks
apart.
Where is the study taking place, how many people does it involve and how are they selected?
The study is taking place in Kilifi County (Pingilikani and Junju) dispensaries as well as KEMRIWellcome
Trust outpatient departments and we will recruit healthy participants. This study will
evaluate the safety and vaccine responses of R21/MM in 20 adults, 20 young children and 51 infants.
We will screen potential participants until we identify the required number of healthy participants
from the different age groups.
What does the study involve for those who are in it?
For individuals who are screened for potential participation, 5- 9mls of blood will be drawn at the
different time-points (maximum of 5mls for infants and young children, 9 mls for adults per visit).
For participants enrolled be the maximum blood samples taken per visit will be 5 mls for infants,
10mls for young children and 30 mls for adults. Recruited infants will have an average of 66mls
taken, young children 121mls and adults 351mls over 2 year and 5 months which will be within the
limits stipulated by the World Health Organisation. Repeat blood samples may be taken to verify
abnormal results. Medical history will also be obtained and a clinical assessment including a check of
the functioning of the heart. For children oxygen levels and listening to the heart will serve as an
assessment of heart function, for adults a test will be conducted to assess the baseline function of the
heart, and to exclude any significant heart problems. Those that pass screening, will be enrolled in
the trial. Blood will be taken at screening, a day prior to enrolment, prior to each vaccination, 2 days
and 7 days post each vaccination, 28 days post the 3rd vaccination and at 6, 12 and 24 months post
the 3rd vaccine dose. There will be a total of 31 visits, 15 of which will be conducted at home. The
study duration for each participant will be a minimum of 2 years and 5 months.
What are the benefits and risks/costs of the study for those involved?
Participants may benefit from receipt of the vaccine if we demonstrate that the immune response in a
Kenyan population is favourable and the vaccine is safe. Participants will also have close oversightand treatment support from the study team although this will primarily be for risk monitoring. There
will also be wider benefit in the field of malaria vaccine research in building on data available on
safety and immune responses to R21 which will help with WHO aim to identify a malaria vaccine
with high protection rates. R21c and Matrix-M(MM) have been given to 108 and >1400 healthy adult
human volunteers respectively in the US, Europe, Australia and Burkina Faso. R21c and MM have
both been found to be safe and R21c to provide good vaccine responses. The most common adverse
event seen with both is pain at the injection site which resolves in a few days. The current
formulation is termed R21/MM and has, technically, not been evaluated in human subjects before,
although there is no reason to believe the safety profile and immune responses should be changed by
the slight change in the vaccine, we plan for close and extended follow-up following vaccination.
Participants will be immunised then allowed to go home and followed up daily for 7 days postimmunisation.
Current data show R21c to be safe and immunogenic in 100 malaria-naïve British and
8 West African adults. We now need to determine if R21/MM is safe and immunogenic in Kenyans
of different ages.
How will the study benefit society?
This study will build on safety and immunogenicity data on R21 and Matrix M and will provide
safety and immunogenicity for R21/MM which will inform the design of a phase II study of this
candidate malaria vaccine. There is reason to believe this is a promising candidate vaccine given that
a smaller dose is required to illicit a similar vaccine response to RTS,S, manufacture is cheap, the
data thus far on the vaccine and adjuvant MM demonstrates they are safe, the vaccine has less
Hepatitis B protein which may mean a better immune response compared to RTS,S in infants and
pre-clinical vaccine studies followed by challenge with malaria infection have demonstrated that a
high proportion of vaccinated mice fail to develop malaria after deliberate infection.
When does the study start and finish?
The study will start upon receipt of ethical clearance; data collection, analysis and write up will take place over 3.5 years.
|
| 1 | LAY SUMMARY Formal Title: A Phase 1b, open-label, age de-escalation, dose-escalation study to evaluate the safety and immunogenicity of different doses of a candidate malaria vaccine; adjuvanted R21(R21/MM) in adults, young children and infants in Kilifi, Kenya.Lay Title: A study to determine if a new malaria vaccine is safe and induces immunity among Kenyan adults, young children and infants. What is the problem/background?RTS,S/AS01, is the only malaria vaccine in advance clinical development but could be better by preventing malarial infection particularly in vaccinated infants and is being evaluated for use in the infant vaccine schedule recommended by the World Health Organisation as well as determining the significance of any safety concerns. There are several thoughts as to why RTS, S may not prevent more clinical infections; Only a small proportion of the vaccine is made up of Malaria parasite protein, in our candidate vaccine the particle is coated with malaria parasite protein. Another hypothesis is that the majority of RTS, S/AS01 is composed of a Hepatitis B surface protein which may interfere with the immune response in infants, R21/MM has very little of this protein on its surface. R21/MM also induces a good immune response, is cheap and easy to make and as such there is a good case for further clinical development of this vaccine. Malaria deaths have fallen with the advent of new drug combinations and widespread use of insecticide treated bed nets but the hope malaria eradication is threatened by emerging resistance to these drugs and insecticides. One of the primary strategic goals outlined by WHO in the Malaria Vaccine Roadmap, is the development of malaria vaccines which would protect against clinical malaria in 3 out of 4 vaccinated individuals, and would be suitable for administration in malaria endemic areas and appropriate at-risk groups by 2030. R21/MM is a candidate malaria vaccine and biologically similar to RTS,S/AS01 and RTS,S has been evaluated extensively in clinical trials. R21 has had 3 formulations to date; R21, R21c and now R21/MM. R21 that was evaluated in animal studies then in an effort to progress to clinical trials, purification of the vaccine was required and this was challenging hence components of a protein were added to R21 making R21c which was manufactured in Oxford, UK. R21c has been evaluated in animal and human trials but to move forward in clinical development a large-scale manufacturer was required and the current vaccine (R21/MM) has been subjected to some minor changes. These products (R21/R21c and R21MM) are all very similar but R21/MM has yet to be evaluated in human subjects. The main difference being R21/MM does not have 4 components of a protein, the c-tag which was present in R21c. Also, each vaccine has a different manufacturer, however we do not anticipate the immune response or safety profile to change given the removal of this protein component or the new manufacturer. Matrix-M is a component of the vaccine that has been demonstrated to improve vaccine response of R21c and to be safe in healthy adults. What questions are we trying to answer?We plan to evaluate if R21/MM, a candidate malaria vaccine, is safe and provides good vaccine responses at different doses in healthy Kenyan adults (aged 18-45 years), young children (aged 1-5 years) and infants (5-<12 months) and investigate the immune responses following vaccination and the persistence of these in the first 2 years following a 3- dose vaccination course, given 4 weeks apart. Where is the study taking place, how many people does it involve and how are they selected? The study is taking place in Kilifi County (Pingilikani and Junju) dispensaries as well as KEMRIWellcome Trust outpatient departments and we will recruit healthy participants. This study will evaluate the safety and vaccine responses of R21/MM in 20 adults, 20 young children and 51 infants. We will screen potential participants until we identify the required number of healthy participants from the different age groups. What does the study involve for those who are in it? For individuals who are screened for potential participation, 5- 9mls of blood will be drawn at the different time-points (maximum of 5mls for infants and young children, 9 mls for adults per visit). For participants enrolled be the maximum blood samples taken per visit will be 5 mls for infants, 10mls for young children and 30 mls for adults. Recruited infants will have an average of 66mls taken (81mls for those in the booster phase), young children 121mls (131mls in the booster phase) and adults 351mls (381mls for those in the booster phase) over 2 year and 5 months which will be within the limits stipulated by the World Health Organisation. Repeat blood samples may be taken to verify abnormal results. Medical history will also be obtained and a clinical assessment including a check of the functioning of the heart. For children oxygen levels and listening to the heart will serve as an assessment of heart function, for adults a test will be conducted to assess the baseline function of the heart, and to exclude any significant heart problems. Those that pass screening, will be enrolled in the trial. Blood will be taken at screening, a day prior to enrolment, prior to each vaccination, 2 days and 7 days post each vaccination, 28 days post the 3rd vaccination and at 6, 12 and 24 months post the 3rd vaccine dose. There will be a total of 38 visits, 22 of which will be conducted at home. We will invite participants to receive a booster dose of R21/MM 9-14 months after their 3rd vaccination and have a field worker visit daily at home with a clinic visit and bloods 28 days later. The study duration for each participant will be a minimum of 2 years and 5 months. What are the benefits and risks/costs of the study for those involved? Participants may benefit from receipt of the vaccine if we demonstrate that the immune response in a Kenyan population is favourable and the vaccine is safe. Participants will also have close oversight and treatment support from the study team although this will primarily be for risk monitoring. There will also be wider benefit in the field of malaria vaccine research in building on data available on safety and immune responses to R21 which will help with WHO aim to identify a malaria vaccine with high protection rates. R21c and Matrix-M(MM) have been given to 108 and >1400 healthy adult human volunteers respectively in the US, Europe, Australia and Burkina Faso. R21c and MM have both been found to be safe and R21c to provide good vaccine responses. The most common adverse event seen with both is pain at the injection site which resolves in a few days. The current formulation is termed R21/MM and has, technically, not been evaluated in human subjects before, although there is no reason to believe the safety profile and immune responses should be changed by the slight change in the vaccine, we plan for close and extended follow-up following vaccination. Participants will be immunised then allowed to go home and followed up daily for 7 days postimmunisation. Current data show R21c to be safe and immunogenic in 100 malaria-naïve British and 8 West African adults. We now need to determine if R21/MM is safe and immunogenic in Kenyans of different ages. How will the study benefit society? This study will build on safety and immunogenicity data on R21 and Matrix M and will provide safety and immunogenicity for R21/MM which will inform the design of a phase II study of this candidate malaria vaccine. There is reason to believe this is a promising candidate vaccine given that a smaller dose is required to illicit a similar vaccine response to RTS,S, manufacture is cheap, the data thus far on the vaccine and adjuvant MM demonstrates they are safe, the vaccine has less Hepatitis B protein which may mean a better immune response compared to RTS,S in infants and pre-clinical vaccine studies followed by challenge with malaria infection have demonstrated that a high proportion of vaccinated mice fail to develop malaria after deliberate infection. When does the study start and finish? The study will start upon receipt of ethical clearance; data collection, analysis and write up will take place over 3.5 years. |
| Abstract of Study: | In the era of anti-malaria drug resistance and resistance to insecticide treated bed nets, there is an urgent need for a highly efficacious vaccine. We plan to evaluate a candidate malaria vaccine incorporating the antigen R21 (part of the P. falciparum circumsporozoite malaria antigen co-expressed with hepatitis B antigen) plus an adjuvant to boost the immune responses (Matrix-M). R21c/MM showed promising safety and immunogenicity data in preclinical and early phase trials in Oxford. We will conduct an open label, age de-escalation, dose escalation study in 20 healthy adults (18-45 years), 20 young children aged 1-5 years and 51 infants aged 5- <12 months. Each participant will be screened to ensure they are in good health based on clinical assessment and laboratory results. Participants will have a blood test to ensure suitability prior to vaccination. For each participant, there will be a total of 31 visits to the clinic and at home, 15 of which will be associated with blood sampling. Participants will receive 3 vaccinations 4 weeks apart. Blood tests and clinical assessments will be conducted to screen out participants with health conditions that may impact participation in the study. Bloods will be taken at screening and a day prior to enrolment. Blood will also be taken prior to each vaccination and on days 2 and 7 post vaccination at the clinic. Home visits will be made on days 1, 3, 4, 5, and 6 to identify solicited adverse events. Bloods for immunology will be taken prior to vaccination, and throughout the study to assess the immune response to R21/MM. Should the vaccine be safe and immunogenic this trial is part of a programme of work that aims to develop a multi-stage malaria vaccine (R21 would be one component) that could provide very high rates of protection in the most vulnerable age groups in an endemic setting. Participants will have extended follow-up for 2 years following final vaccination to determine the longevity of the immune response. |
| 1 |
In the era of anti-malaria drug resistance and resistance to insecticide treated bed nets, there is an
urgent need for a highly efficacious vaccine. We plan to evaluate a candidate malaria vaccine
incorporating the antigen R21 (part of the P. falciparum circumsporozoite malaria antigen coexpressed
with hepatitis B antigen) plus an adjuvant to boost the immune responses (Matrix-M).
R21c/MM showed promising safety and immunogenicity data in preclinical and early phase trials in
Oxford. We will conduct an open label, age de-escalation, dose escalation study in 20 healthy adults
(18-45 years), 20 young children aged 1-5 years and 51 infants aged 5- <12 months. Each participant
will be screened to ensure they are in good health based on clinical assessment and laboratory results.
Participants will have a blood test to ensure suitability prior to vaccination. For each participant,
there will be a total of 31 visits to the clinic and at home, 15 of which will be associated with blood
sampling (38 visits for those in the booster phase). Participants will receive 3 vaccinations 4 weeks
apart. Blood tests and clinical assessments will be conducted to screen out participants with health
conditions that may impact participation in the study. Bloods will be taken at screening and a day
prior to enrolment. Blood will also be taken prior to each vaccination and on days 2 and 7 post
vaccination at the clinic. Home visits will be made on days 1, 3, 4, 5, and 6 to identify solicited
adverse events. Bloods for immunology will be taken prior to vaccination, and throughout the study
to assess the immune response to R21/MM. In addition we will invite participants to receive a
booster vaccine at 9-14 months after receipt of the 3rd vaccine of R21/MM and take bloods in clinic
28 days after boosting with field workers visiting daily in the week following vaccination Should the
vaccine be safe and immunogenic this trial is part of a programme of work that aims to develop a multi-stage malaria vaccine (R21 would be one component) that could provide very high rates of
protection in the most vulnerable age groups in an endemic setting. Participants will have extended
follow-up for 2 years following final vaccination to determine the longevity of the immune response.
|