Periodic Reporting for period 5 - VSV-EBOPLUS (SYSTEMS ANALYSIS OF ADULT AND PEDIATRIC RESPONSES TO THE VSV-ZEBOVEBOLA VACCINE - Sofia ref.: 116068)
Período documentado: 2021-10-01 hasta 2023-03-31
Ebolavirus Disease (EVD) is a severe haemorrhagic fever that occurs in epidemic outbreaks, with a high fatality rate and no specific therapies available. rVSV-ZEBOV-GP (Ervebo®), a live-attenuated recombinant vesicular stomatitis virus vector expressing the glycoprotein G of Zaire Ebolavirus, is the first vaccine approved for prevention of EVD.
The overall objective of VSV-EBOPLUS was to comprehensively decipher, using systems biology approaches, the immune and molecular signatures of the human response elicited in adults and children by rVSV-ZEBOV-GP.
The VSV-EBOPLUS project characterized the immune responses from rVSV-ZEBOV-GP phase I/Ib/II clinical trials including (i) dose-ranging, (ii) a pediatric cohort, and (iii) long-term follow-up studies. VSV-EBOPLUS thus significantly accelerated the innovation to Ebola vaccine development combining clinical and cutting-edge systems biology approaches that together address the safety and immunogenicity of rVSV-ZEBOV-GP. VSV-EBOPLUS assessed immune responses beyond the demonstrated duration of protection and comparing responses in children to those identified in adults, having a significant impact on Ebola vaccine development.
The overall objectives of VSV-EBOPLUS were:
• Build and extend up to M60 the WHO and Wellcome-Trust sponsored VEBCON Phase I/II trial of the rVSV-ZEBOV-GP in healthy adults in Switzerland and Gabon
• Organize distribution of samples from subjects enrolled in the MSD-sponsored Phase 1 trial of the rVSVΔG-ZEBOV Ebola Vaccine in Healthy Adult Subjects
• Perform the Phase 1/2 study of the safety and immunogenicity of the rVSV-ZEBOV-GP in healthy children 1-12 years of age, collect and distribute clinical samples
• Characterize the innate and adaptive immune responses elicited by various doses of rVSV-ZEBOV-GP in adults and children and define how they correlate to vaccine reactogenicity and viral control
• Identify the contribution of specific cells to rVSV-ZEBOV-GP-induced innate responses and adverse reactions
• Determine the transcriptomic profiles of adult and pediatric responses to rVSV-ZEBOV-GP vaccination at multiple time points
• Generate/exploit the clinical safety/reactogenicity and the immunology databases for integrative analysis
In conclusion, the VSV-EBOPLUS project has contributed to the identification of signatures of the immune response and adverse events to the rVSV-ZEBOV-GP vaccine against Ebola. Detailed analyses of immune and molecular signatures of immune responses, elicited by rVSV-ZEBOV-GP in humans, have been conducted. The dynamic transcriptomic and metabolomic profiles of the human immune response to rVSV-ZEBOV-GP vaccination at multiple time points were analysed in samples collected in Europe, Africa and North America. These data provided relevant information to characterize rVSV-ZEBOV-GP Ebola vaccine immunogenicity and support its development.
The overall objective of VSV-EBOPLUS was to comprehensively decipher, using systems biology approaches, the immune and molecular signatures of the human response elicited in adults and children by rVSV-ZEBOV-GP.
The VSV-EBOPLUS project characterized the immune responses from rVSV-ZEBOV-GP phase I/Ib/II clinical trials including (i) dose-ranging, (ii) a pediatric cohort, and (iii) long-term follow-up studies. VSV-EBOPLUS thus significantly accelerated the innovation to Ebola vaccine development combining clinical and cutting-edge systems biology approaches that together address the safety and immunogenicity of rVSV-ZEBOV-GP. VSV-EBOPLUS assessed immune responses beyond the demonstrated duration of protection and comparing responses in children to those identified in adults, having a significant impact on Ebola vaccine development.
The overall objectives of VSV-EBOPLUS were:
• Build and extend up to M60 the WHO and Wellcome-Trust sponsored VEBCON Phase I/II trial of the rVSV-ZEBOV-GP in healthy adults in Switzerland and Gabon
• Organize distribution of samples from subjects enrolled in the MSD-sponsored Phase 1 trial of the rVSVΔG-ZEBOV Ebola Vaccine in Healthy Adult Subjects
• Perform the Phase 1/2 study of the safety and immunogenicity of the rVSV-ZEBOV-GP in healthy children 1-12 years of age, collect and distribute clinical samples
• Characterize the innate and adaptive immune responses elicited by various doses of rVSV-ZEBOV-GP in adults and children and define how they correlate to vaccine reactogenicity and viral control
• Identify the contribution of specific cells to rVSV-ZEBOV-GP-induced innate responses and adverse reactions
• Determine the transcriptomic profiles of adult and pediatric responses to rVSV-ZEBOV-GP vaccination at multiple time points
• Generate/exploit the clinical safety/reactogenicity and the immunology databases for integrative analysis
In conclusion, the VSV-EBOPLUS project has contributed to the identification of signatures of the immune response and adverse events to the rVSV-ZEBOV-GP vaccine against Ebola. Detailed analyses of immune and molecular signatures of immune responses, elicited by rVSV-ZEBOV-GP in humans, have been conducted. The dynamic transcriptomic and metabolomic profiles of the human immune response to rVSV-ZEBOV-GP vaccination at multiple time points were analysed in samples collected in Europe, Africa and North America. These data provided relevant information to characterize rVSV-ZEBOV-GP Ebola vaccine immunogenicity and support its development.
VSV-EBOPLUS has successfully acquired important information on the safety and immunogenicity signatures of the rVSV-ZEBOV-GP vaccine.
Two clinical studies with rVSV-ZEBOV-GP in Healthy Adults conducted in Switzerland (NCT02287480) and Gabon (PACTR201411000919191) were successfully extended to include 60 months visit to evaluate the persistence of the vaccine-induced immune response and its comparison between subjects in Europe and Africa.
The distribution of samples, collected from healthy adult subjects enrolled in the MSD-sponsored trial to evaluate the safety and immunogenicity of the rVSVΔG-ZEBOV Ebola Vaccine (NCT02314923), was successfully organized.
The clinical trial to evaluate the safety and immunogenicity of the rVSVΔG-ZEBOV-GP Ebola Virus vaccine candidate in healthy children aged 1 to 12 years and in their relatives living in Lambaréné, Gabon (PACTR202005733552021) was conducted, enrolling 120 children and 163 relatives.
The one year antibody persistence to single-dose rVSV-ZEBOV-GP vaccination was demonstrated across dose ranges and settings, a key criterion in countries where booster vaccination would be impractical (Huttner A. et al. Lancet Infect Dis. 2018), and the long-term persistence of antibody responses after a single dose of rVSV-ZEBOV was characterized.
The natural Killer (NK) cell modulation and cytokine responses following human rVSV-ZEBOV-GP Ebolavirus vaccination was analysed, demonstrating that NK cells may contribute to the early protective efficacy in humans (Pejosky D. et al. NPJ Vaccines 2020).
Sera samples collected in paediatric study in Gabon and in the follow-up clinical trial in Geneva (from years 1 to 5) were analysed by Pseudovirion assay and the Serum-Neutralization Test (SNT).
It was Identified and cross-validated the transcriptomic signatures of immune response in 4 cohorts from different geographic and genetic backgrounds as well as identified signatures associated with immunogenicity and arthritis (Vianello E. et al The Lancet Microbe 2021).
Transcriptomic analysis allowed to identify an rVSVΔG-ZEBOV-GP-induced signature and it was demonstrated a direct correlation of blood transcriptomic changes with ZEBOV glycoprotein-specific antibody titres (Santoro F. et al. Vaccines (Basel). 2021), providing an important contribution to the identification of immune signatures.
The metabolomic profiles of the human immune response to rVSV-ZEBOV-GP vaccination at multiple time points were investigated, analyzing the changes in the amino acid metabolome induced by vaccination.
It was profiled the intracellular and circulating miRNome modulations at early timepoints after the administration of the rVSVΔG-ZEBOV-GP vaccine and miRNA signatures associated with the antibody response were identified.
A powerful computational tool “BioFeatS” specifically designed for integrative analyses, and an Internal Database and External Dashboard were developed, demonstrating their valuable use for people working on vaccine development, immunology, and public health, facilitating secure data exchange and easy visualization of complex biological information.
Sexual Dimorphism in Vaccine-Induced Immunity was investigated, integrating demographic information with omics data and immune responses.
Two clinical studies with rVSV-ZEBOV-GP in Healthy Adults conducted in Switzerland (NCT02287480) and Gabon (PACTR201411000919191) were successfully extended to include 60 months visit to evaluate the persistence of the vaccine-induced immune response and its comparison between subjects in Europe and Africa.
The distribution of samples, collected from healthy adult subjects enrolled in the MSD-sponsored trial to evaluate the safety and immunogenicity of the rVSVΔG-ZEBOV Ebola Vaccine (NCT02314923), was successfully organized.
The clinical trial to evaluate the safety and immunogenicity of the rVSVΔG-ZEBOV-GP Ebola Virus vaccine candidate in healthy children aged 1 to 12 years and in their relatives living in Lambaréné, Gabon (PACTR202005733552021) was conducted, enrolling 120 children and 163 relatives.
The one year antibody persistence to single-dose rVSV-ZEBOV-GP vaccination was demonstrated across dose ranges and settings, a key criterion in countries where booster vaccination would be impractical (Huttner A. et al. Lancet Infect Dis. 2018), and the long-term persistence of antibody responses after a single dose of rVSV-ZEBOV was characterized.
The natural Killer (NK) cell modulation and cytokine responses following human rVSV-ZEBOV-GP Ebolavirus vaccination was analysed, demonstrating that NK cells may contribute to the early protective efficacy in humans (Pejosky D. et al. NPJ Vaccines 2020).
Sera samples collected in paediatric study in Gabon and in the follow-up clinical trial in Geneva (from years 1 to 5) were analysed by Pseudovirion assay and the Serum-Neutralization Test (SNT).
It was Identified and cross-validated the transcriptomic signatures of immune response in 4 cohorts from different geographic and genetic backgrounds as well as identified signatures associated with immunogenicity and arthritis (Vianello E. et al The Lancet Microbe 2021).
Transcriptomic analysis allowed to identify an rVSVΔG-ZEBOV-GP-induced signature and it was demonstrated a direct correlation of blood transcriptomic changes with ZEBOV glycoprotein-specific antibody titres (Santoro F. et al. Vaccines (Basel). 2021), providing an important contribution to the identification of immune signatures.
The metabolomic profiles of the human immune response to rVSV-ZEBOV-GP vaccination at multiple time points were investigated, analyzing the changes in the amino acid metabolome induced by vaccination.
It was profiled the intracellular and circulating miRNome modulations at early timepoints after the administration of the rVSVΔG-ZEBOV-GP vaccine and miRNA signatures associated with the antibody response were identified.
A powerful computational tool “BioFeatS” specifically designed for integrative analyses, and an Internal Database and External Dashboard were developed, demonstrating their valuable use for people working on vaccine development, immunology, and public health, facilitating secure data exchange and easy visualization of complex biological information.
Sexual Dimorphism in Vaccine-Induced Immunity was investigated, integrating demographic information with omics data and immune responses.
VSV-EBOPLUS significantly contributed to accelerate and innovate the Ebola vaccine development through an ambitious programme combining clinical and high-tech cutting-edge technologies to address safety and immunogenicity of the rVSV-ZEBOV-GP Ebola vaccine. VSV-EBOPLUS conducted immune monitoring beyond the demonstrated duration of protection and comparing responses and signatures from children to those identified in adults, having a significant impact on Ebola vaccine.
The development of a protective vaccine against Ebola has a major impact on preventing and controlling Ebola epidemics, particularly in areas most affected by this often fatal disease.
The main achievements of the project have been published in the following manuscripts:
• Vianello E. et al The Lancet Microbe 2021; 3(2):e113
• Santoro F. et al. Vaccines (Basel). 2021;20;9(2):67
• Pejoski D. et al. npj Vaccines, 2020; 5/1
• Gonzalez-Dias P. et al. Human vaccines & immunotherapeutics vol. 16,2 (2020): 269-276
• Bache EB et al. Future Microbiol. 2020 Jan;15:85-106
• Huttner A. et al. Lancet Infect Dis. 2018;7:738-748
• Medaglini D. et al. Semin Immunol. 2018;39:65-72
• Huttner A. Siegrist CA. Expert Rev Vaccines. 2018;17:1105-1110
Several other manuscripts, redescribing the project results, are currently under submission.
The development of a protective vaccine against Ebola has a major impact on preventing and controlling Ebola epidemics, particularly in areas most affected by this often fatal disease.
The main achievements of the project have been published in the following manuscripts:
• Vianello E. et al The Lancet Microbe 2021; 3(2):e113
• Santoro F. et al. Vaccines (Basel). 2021;20;9(2):67
• Pejoski D. et al. npj Vaccines, 2020; 5/1
• Gonzalez-Dias P. et al. Human vaccines & immunotherapeutics vol. 16,2 (2020): 269-276
• Bache EB et al. Future Microbiol. 2020 Jan;15:85-106
• Huttner A. et al. Lancet Infect Dis. 2018;7:738-748
• Medaglini D. et al. Semin Immunol. 2018;39:65-72
• Huttner A. Siegrist CA. Expert Rev Vaccines. 2018;17:1105-1110
Several other manuscripts, redescribing the project results, are currently under submission.