Ignite Creation Date:
2024-05-06 @ 4:17 PM
Last Modification Date:
2024-10-26 @ 2:07 PM
Study NCT ID:
NCT04934111
Status:
UNKNOWN
Last Update Posted:
2022-04-22
First Post:
2021-06-10
Brief Title:
Safety and Immunogenicity of LNP-nCOV saRNA-02 Vaccine Against SARS-CoV-2 the Causative Agent of COVID-19
Sponsor:
MRCUVRI and LSHTM Uganda Research Unit
Organization:
MRCUVRI and LSHTM Uganda Research Unit
Study Overview
Official Title:
A Clinical Trial to Assess the Safety and Immunogenicity of LNP-nCOV saRNA-02 a Self-amplifying Ribonucleic Acid saRNA Vaccine in SARS-CoV-2 Seronegative and Seropositive Uganda Population
Status:
UNKNOWN
Status Verified Date:
2022-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
COVAC-Uganda
Brief Summary:
COVAC Uganda is a study that is looking at the use of an innovative self-amplifying RNA saRNA vaccine LNP-nCOV saRNA-02 against the virus SARS-CoV-2 that causes COVID-19 and assessing the immune response in SARS-CoV-2 antibody seronegative and seropositive individuals saRNA is designed to amplify the quantity of RNA upon injection to produce further antigen thereby enabling lower doses for administration In the trial COVAC1 Imperial College London is currently evaluating one COVID-19 saRNA vaccine candidate in doses from 01-10ug for individuals who are seronegative for SARS-CoV-2 antibodies at baseline Interim analyses of COVAC1 has shown a dose dependent response however up to 50 of seronegative participants receiving doses of 25-10ug do not seroconvert The investigators hypothesize that a lack of seroconversion is due to type I and III interferon IFN production which can inhibit translation and degrade cellular mRNA Another variable that can enhance antibody production is serological history recent studies have shown that seropositive individuals respond significantly better than naïve individuals who received the Pfizer or Moderna RNA-based COVID-19 vaccine Therefore designing the saRNA backbone to dampen IFN production and evaluating this in individuals seropositive at baseline will inform the optimised use of this innovative technology In COVAC Uganda the investigators aim to test an saRNA vaccine modified to dampen the activation of type I and III IFN to increase antibody production for individuals who are seronegative and seropositive for SARS-CoV-2 antibodies at baseline to evaluate whether people with pre-existing seropositivity have enhanced immune responses compared to those without This trial is NOT looking at whether or not the vaccine is effective in terms of protection It is just assessing whether and how well the immune system responds based on SARS-CoV-2 antibodies at baseline and its safety
Detailed Description:
Background The ongoing pandemic coronavirus severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 emerged in humans in China sometime between October to November 2019 and the disease coronavirus infectious disease 2019 COVID-19 was identified in China in December 2019
By the end of January 2021 SARS-CoV-2 had infected with confirmed diagnosis over 106 million people worldwide resulting in over 23 million deaths and over 59 million people recovered from infection This yields a nominal infection fatality rate IFR of 2 and around 10 of infected people have been left with health effects lasting for 6 months or more As of 8 March 2021 Uganda had reported 40452 coronavirus cases and 334 deaths Through COVAX Uganda started rolling out the AstraZeneca vaccine adenoviral based from 10 March 2021
The developing assessment is that the only way the world can exit from the COVID-19 pandemic is through the deployment of an effective vaccine A number of vaccines have been developed and received emergency use authorization by the United States Food and Drug Administration andor the World Health Organization Examples include Pfizer-BioNTech and Modernas messenger ribonucleic acid mRNA-based vaccines which have both shown efficacy at 95 Oxford-AstraZenecas ChAdOx1 nCoV-19 and Johnson and Johnsons adenovirus based vaccines which have demonstrated efficacies of 70 and 66 respectively The problem comes with the scale needed and the time frame in which vaccines need to be developed and deployed A self-amplifying RNA saRNA vaccine provides a novel feasible and time-sensitive solution to contribute to addressing the SARS-CoV-2 problem either during the current pandemic or for ongoing seasonal epidemics
Studies have demonstrated that nucleic acid-based vaccination can protect against viral infections in non-human primate NHP studies providing proof of concept that gene-based vaccination can induce protective antibodies However DNA vaccines require multiple immunizations with the use of electroporation to induce significant immune responses in humans Non-replicating mRNA-based therapeutics typically require high doses of RNA 100-600 µg The requirement for high doses and associated cost suggest non-replicating mRNA may struggle to produce the potential hundreds of millions of doses required to rapidly respond to a pandemic In contrast small animal and non-human primate NHP experiments suggest that saRNA induces significantly enhanced responses in comparison to either DNA vaccines delivered with electroporation or mRNA Indeed a single immunization with a saRNA vaccine has shown protection against Ebola virus in animal models Should a 10 µg dose of saRNA provide protection from COVID-19 this would provide critical advantages for manufacturing where 100000 doses can by synthesized in a one liter reaction volume In contrast to viral vectors lack of anti-vector immunity provides the opportunity for repeat immunizations with multiple RNA-encoded immunogens
The first generation saRNA vaccine LNP-nCoV-saRNA is already undergoing safety assessment in humans in the COVAC1 trial in the United Kingdom The safety of this first generation saRNA vaccine has been assessed initially in healthy young adults ie 15 participants aged 18-45 years given one of three different doses 01 03 and 1 µg by injection into the muscle going slowly from the lowest to the highest over a period of several weeks To date there have been no reported serious adverse events SAEs associated with this vaccine and a low frequency of Grade 2 events An additional 35 volunteers have been randomized across each dose To date 105 healthy subjects have received two immunizations across each dose with few Grade 2 events All participants have safely received both doses Initial assessment of the first 15 subjects indicates that although the vaccine shows a good safety profile the levels of seroconversion 75 for the 1ug dose and binding antibody are lower than anticipated from preclinical models Indeed data generated to date suggest responses are at the lower end of a dose response curve An additional expansion phase has been initiated to explore three higher doses 25 5 and 10ug The disconnect between human immune response to the vaccine and preclinical models suggests that the level of saRNA expression in humans is less effective than in small animal models Current data indicate that 5ug dose administered at 0 and 4 weeks induces an acceptable immune response to most 83 individuals 4-weeks post 2nd vaccination
The investigators have improved on this initial design COVAC1 with the modified vector LNP-nCOV saRNA-02 which is to be investigated within this clinical trial
This study COVAC Uganda will evaluate an innovative saRNA vaccine LNP-nCOV saRNA-02 designed to increase vaccine potency by shielding the saRNA from cellular proteins known to reduce saRNA expression The investigators anticipate the safety profile of the modified vaccine to be highly similar to the first generation vaccine already undergoing human trials COVAC Uganda will use the same assessment criteria as the COVAC1 study designed to see how well the immune system has been activated using different dose levels of the modified vaccine COVAC Uganda will also enrol SARS-CoV-2 seropositive individuals to evaluate the immune response based on serological history Seronegative and seropositive participants aged 18-45 will be given one dose of 50 ug at 0 weeks and 4 weeks Seronegative is defined as IgG 10 AU mL-1 or IgM 10 AU mL-1 and seropositive is defined as IgG 10 AU mL-1 or IgM 10 AU mL-1 The vaccine is given by injection into the muscle of the upper arm There are likely to be mild side-effects near to the injection site As observed in COVAC1 there may also be more general side-effects such as headache temperature and chills Participants will be asked to record any symptoms in a vaccine diary In order to see how well the immune system is responding participants will need to give blood samples several times during the first 6 weeks then monthly for a few months then at 6 months
The investigators predict that the modified vaccine will induce higher levels of neutralising antibodies than the first generation saRNA vaccine However if any of the doses do not induce an adequate immune response there is no known reason why participants who received those doses could not be offered a further booster immunisation with LNP-nCOV saRNA-02 at a dose that has been shown to be safe Also there is no known reason why participants in COVAC Uganda could not be immunised with other approved SARS-CoV-2 vaccines including vectored or adjuvanted vaccines should they be shown to be safe and effective
Study Rationale This SARS-CoV-2 pandemic has infected over 106 million people and killed over 23 million people As a novel zoonotic virus no herd immunity is present and the only widely available interventions to date are social distancing to reduce pressure on intensive care beds and health systems but this is not sustainable for economic reasons Clinical trials of antivirals and other drug therapies are ongoing but the intervention most likely to mitigate the long-term medical social and economic impact of the pandemic remains population-wide immunisation
Despite successfully approved COVID-19 vaccines being rolled out substantially more candidates are needed to supply 4265 billion doses for the worlds healthcare workers adults 65 age and people at higher risk with co-morbidities such as diabetes cardiovascular disease cancer obesity or chronic respiratory disease let alone doses for younger or healthier cohorts
Recent evidence suggests that immune responses to messenger RNA vaccines is enhanced for individuals previously infected by SARS-CoV-2 This trial investigates the role of seroconversion on the impact of a self-amplifying RNA vaccine candidate and it will inform on the possible application of LNP-nCOV saRNA-02 as a COVID-19 booster candidate for previously infected individuals
Pre-clinical data suggest that the LNP-nCOV saRNA-02 vaccine encoding a prefusion stabilised version of the S-glycoprotein will elicit neutralising antibodies in a higher proportion of individuals than natural infection 50 and that the LNP-nCOV saRNA-02 vaccine may provide increased immunogenicity andor dose reduction over the first generation construct as well as for seropositive individuals
Study Design This is a phase I clinical study which will build on clinical experience using the LNP nCoV saRNA vaccine currently under evaluation in COVAC1 in the UK The trial will be conducted in 18-45 year olds in a single centre supervised by the Chiefprincipal Investigator by allocating 42 participants into two groups based on seroconversion status
Subject Population The study will be conducted in healthy young adults as these individuals generate the most robust responses 18-45 years Both male and female participants will be included and the trial site will attempt to keep an equal proportion although the priority will be to ensure timely accrual to the trial
Dosage and Admiration
Participants will each receive one IM dose of 5 ug of LNP-nCOV saRNA-02 into the deltoid muscle at Week 0 and Week 4 as indicated in the table below
Study component Serological Status Route Dose Vaccination 1 Vaccination 2 Serological Group SARS-CoV-2 negative antibodies IM 50 ug LNP-CoV mod-saRNA-02 Week 0
Visit 2 Week 4
Visit 5 SARS-CoV-2 positive antibodies IM 50 ug LNP-CoV mod-saRNA-02 Week 0
Visit 2 Week 4
Visit 5
Safety Evaluations Vaccines are associated with a number of well-characterized local systemic and laboratory reactions referred to as solicited adverse events These adverse events will be purposively collected
Local and systemic assessments will take place on the day of each injection before the injection and 60 minutes after the injection Participants should remain at the clinic for at least one hour after each injection
Participants will be provided with Vaccine diary cards to assist collection and grading of adverse events that start within 7 days of the injection Study staff will go through the list of solicited adverse events in a structured interview and record these together with grade on the appropriate eCRF in the REDCap database If any of the events reported at one of the phone visits are moderately severe grade 2 or worse participants will be invited to the clinic for review
Blood 10 mL for routine safety parameters will be collected at all study visits If the total bilirubin is elevated study staff will request a result for conjugated bilirubin in order to grade the abnormality and determine any action to be taken with respect to further investigation and interruption to the vaccine schedule
Vital signs BP HR oxygen saturation and oral temperature will be measured at every study visit
Physical examinations of the injection site and other body systems if indicated will be performed on the day of each vaccination and 1 week after Symptom-directed physical examinations will be performed at all other follow-up visits
By the end of January 2021 SARS-CoV-2 had infected with confirmed diagnosis over 106 million people worldwide resulting in over 23 million deaths and over 59 million people recovered from infection This yields a nominal infection fatality rate IFR of 2 and around 10 of infected people have been left with health effects lasting for 6 months or more As of 8 March 2021 Uganda had reported 40452 coronavirus cases and 334 deaths Through COVAX Uganda started rolling out the AstraZeneca vaccine adenoviral based from 10 March 2021
The developing assessment is that the only way the world can exit from the COVID-19 pandemic is through the deployment of an effective vaccine A number of vaccines have been developed and received emergency use authorization by the United States Food and Drug Administration andor the World Health Organization Examples include Pfizer-BioNTech and Modernas messenger ribonucleic acid mRNA-based vaccines which have both shown efficacy at 95 Oxford-AstraZenecas ChAdOx1 nCoV-19 and Johnson and Johnsons adenovirus based vaccines which have demonstrated efficacies of 70 and 66 respectively The problem comes with the scale needed and the time frame in which vaccines need to be developed and deployed A self-amplifying RNA saRNA vaccine provides a novel feasible and time-sensitive solution to contribute to addressing the SARS-CoV-2 problem either during the current pandemic or for ongoing seasonal epidemics
Studies have demonstrated that nucleic acid-based vaccination can protect against viral infections in non-human primate NHP studies providing proof of concept that gene-based vaccination can induce protective antibodies However DNA vaccines require multiple immunizations with the use of electroporation to induce significant immune responses in humans Non-replicating mRNA-based therapeutics typically require high doses of RNA 100-600 µg The requirement for high doses and associated cost suggest non-replicating mRNA may struggle to produce the potential hundreds of millions of doses required to rapidly respond to a pandemic In contrast small animal and non-human primate NHP experiments suggest that saRNA induces significantly enhanced responses in comparison to either DNA vaccines delivered with electroporation or mRNA Indeed a single immunization with a saRNA vaccine has shown protection against Ebola virus in animal models Should a 10 µg dose of saRNA provide protection from COVID-19 this would provide critical advantages for manufacturing where 100000 doses can by synthesized in a one liter reaction volume In contrast to viral vectors lack of anti-vector immunity provides the opportunity for repeat immunizations with multiple RNA-encoded immunogens
The first generation saRNA vaccine LNP-nCoV-saRNA is already undergoing safety assessment in humans in the COVAC1 trial in the United Kingdom The safety of this first generation saRNA vaccine has been assessed initially in healthy young adults ie 15 participants aged 18-45 years given one of three different doses 01 03 and 1 µg by injection into the muscle going slowly from the lowest to the highest over a period of several weeks To date there have been no reported serious adverse events SAEs associated with this vaccine and a low frequency of Grade 2 events An additional 35 volunteers have been randomized across each dose To date 105 healthy subjects have received two immunizations across each dose with few Grade 2 events All participants have safely received both doses Initial assessment of the first 15 subjects indicates that although the vaccine shows a good safety profile the levels of seroconversion 75 for the 1ug dose and binding antibody are lower than anticipated from preclinical models Indeed data generated to date suggest responses are at the lower end of a dose response curve An additional expansion phase has been initiated to explore three higher doses 25 5 and 10ug The disconnect between human immune response to the vaccine and preclinical models suggests that the level of saRNA expression in humans is less effective than in small animal models Current data indicate that 5ug dose administered at 0 and 4 weeks induces an acceptable immune response to most 83 individuals 4-weeks post 2nd vaccination
The investigators have improved on this initial design COVAC1 with the modified vector LNP-nCOV saRNA-02 which is to be investigated within this clinical trial
This study COVAC Uganda will evaluate an innovative saRNA vaccine LNP-nCOV saRNA-02 designed to increase vaccine potency by shielding the saRNA from cellular proteins known to reduce saRNA expression The investigators anticipate the safety profile of the modified vaccine to be highly similar to the first generation vaccine already undergoing human trials COVAC Uganda will use the same assessment criteria as the COVAC1 study designed to see how well the immune system has been activated using different dose levels of the modified vaccine COVAC Uganda will also enrol SARS-CoV-2 seropositive individuals to evaluate the immune response based on serological history Seronegative and seropositive participants aged 18-45 will be given one dose of 50 ug at 0 weeks and 4 weeks Seronegative is defined as IgG 10 AU mL-1 or IgM 10 AU mL-1 and seropositive is defined as IgG 10 AU mL-1 or IgM 10 AU mL-1 The vaccine is given by injection into the muscle of the upper arm There are likely to be mild side-effects near to the injection site As observed in COVAC1 there may also be more general side-effects such as headache temperature and chills Participants will be asked to record any symptoms in a vaccine diary In order to see how well the immune system is responding participants will need to give blood samples several times during the first 6 weeks then monthly for a few months then at 6 months
The investigators predict that the modified vaccine will induce higher levels of neutralising antibodies than the first generation saRNA vaccine However if any of the doses do not induce an adequate immune response there is no known reason why participants who received those doses could not be offered a further booster immunisation with LNP-nCOV saRNA-02 at a dose that has been shown to be safe Also there is no known reason why participants in COVAC Uganda could not be immunised with other approved SARS-CoV-2 vaccines including vectored or adjuvanted vaccines should they be shown to be safe and effective
Study Rationale This SARS-CoV-2 pandemic has infected over 106 million people and killed over 23 million people As a novel zoonotic virus no herd immunity is present and the only widely available interventions to date are social distancing to reduce pressure on intensive care beds and health systems but this is not sustainable for economic reasons Clinical trials of antivirals and other drug therapies are ongoing but the intervention most likely to mitigate the long-term medical social and economic impact of the pandemic remains population-wide immunisation
Despite successfully approved COVID-19 vaccines being rolled out substantially more candidates are needed to supply 4265 billion doses for the worlds healthcare workers adults 65 age and people at higher risk with co-morbidities such as diabetes cardiovascular disease cancer obesity or chronic respiratory disease let alone doses for younger or healthier cohorts
Recent evidence suggests that immune responses to messenger RNA vaccines is enhanced for individuals previously infected by SARS-CoV-2 This trial investigates the role of seroconversion on the impact of a self-amplifying RNA vaccine candidate and it will inform on the possible application of LNP-nCOV saRNA-02 as a COVID-19 booster candidate for previously infected individuals
Pre-clinical data suggest that the LNP-nCOV saRNA-02 vaccine encoding a prefusion stabilised version of the S-glycoprotein will elicit neutralising antibodies in a higher proportion of individuals than natural infection 50 and that the LNP-nCOV saRNA-02 vaccine may provide increased immunogenicity andor dose reduction over the first generation construct as well as for seropositive individuals
Study Design This is a phase I clinical study which will build on clinical experience using the LNP nCoV saRNA vaccine currently under evaluation in COVAC1 in the UK The trial will be conducted in 18-45 year olds in a single centre supervised by the Chiefprincipal Investigator by allocating 42 participants into two groups based on seroconversion status
Subject Population The study will be conducted in healthy young adults as these individuals generate the most robust responses 18-45 years Both male and female participants will be included and the trial site will attempt to keep an equal proportion although the priority will be to ensure timely accrual to the trial
Dosage and Admiration
Participants will each receive one IM dose of 5 ug of LNP-nCOV saRNA-02 into the deltoid muscle at Week 0 and Week 4 as indicated in the table below
Study component Serological Status Route Dose Vaccination 1 Vaccination 2 Serological Group SARS-CoV-2 negative antibodies IM 50 ug LNP-CoV mod-saRNA-02 Week 0
Visit 2 Week 4
Visit 5 SARS-CoV-2 positive antibodies IM 50 ug LNP-CoV mod-saRNA-02 Week 0
Visit 2 Week 4
Visit 5
Safety Evaluations Vaccines are associated with a number of well-characterized local systemic and laboratory reactions referred to as solicited adverse events These adverse events will be purposively collected
Local and systemic assessments will take place on the day of each injection before the injection and 60 minutes after the injection Participants should remain at the clinic for at least one hour after each injection
Participants will be provided with Vaccine diary cards to assist collection and grading of adverse events that start within 7 days of the injection Study staff will go through the list of solicited adverse events in a structured interview and record these together with grade on the appropriate eCRF in the REDCap database If any of the events reported at one of the phone visits are moderately severe grade 2 or worse participants will be invited to the clinic for review
Blood 10 mL for routine safety parameters will be collected at all study visits If the total bilirubin is elevated study staff will request a result for conjugated bilirubin in order to grade the abnormality and determine any action to be taken with respect to further investigation and interruption to the vaccine schedule
Vital signs BP HR oxygen saturation and oral temperature will be measured at every study visit
Physical examinations of the injection site and other body systems if indicated will be performed on the day of each vaccination and 1 week after Symptom-directed physical examinations will be performed at all other follow-up visits
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None