Periodic Reporting for period 2 - Prevent-nCoV (Prevention of SARS-CoV-2 infection through development and clinical testing of a novel Virus Like Particle (VLP) vaccine)
Okres sprawozdawczy: 2021-04-01 do 2022-06-30
The Prevent-nCoV consortium has during the project period generated pre-clinical proof of concept as well as cGMP manufacture, toxicological studies for capsid virus like particle (cVLP) delivery of SARS-CoV-2 antigens, as well as concluded a first-in-human clinical trial. The Prevent-nCoV consortium set out to develop a potential highly effective (>80% protection), rapidly protective (within 2 weeks of vaccination) SARS-CoV-2 sub-unit vaccine, and within 11 months initiate a Phase I/IIa clinical study of a vaccine to help protect medical workers and the public from the coronavirus pandemic, thus the objectives have been completed with minimal delays.
The lead antigen selected for clinical development is the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, while we in parallel investigate other antigens, routes of administration and stability of the vaccine. The antigen is expressed using the proprietary S2 system of Expres2ion biotechnologies. The RBD antigens are displayed on AP205 cVLPs through a split-protein Tag/Catcher ensuring unidirectional and high-density display of RBD. The cVLPs are expressed at high yield in E. coli. Both soluble recombinant RBD, and RBD displayed on cVLPs bind the ACE2 receptor with nano-molar affinity. The consortium early on identified the ideal partners for pre-clinical toxicological testing, Charles River/Scantox as well as for the cGMP production, AGC biologics. In July 2020 consortium member AdaptVac out licensed their technology for corona virus vaccines to Bavarian Nordic.
The SARS-CoV-2 lead vaccine was named ABNCoV2 (AdaptVac/Bavarian Nordic Corona virus 2). The drug substance was shipped to filling site Q4 2020 under quarantine, and released mid Q1 2021. The clinical trial dossier was submitted in December 2020 and was approved in March 2021. The COUGH1 (https://clinicaltrials.gov/ct2/show/NCT04839146) trial started in early March 2021. The clinical Phase I/II trial was concluded in June 2022. All dose groups in the COUGH1 phase I/II study demonstrated an excellent safety and reactogenicity profile and high-level SARS-CoV-2 in vitro live virus neutralization levels (up to 12 fold vs. convalescent sera) compared to reported levels for leading mRNA COVID-19 vaccines (up to 4.1 fold convalescent sera). High in vitro efficacy was achieved in all groups receiving ABNCoV2, including non-adjuvanted formulations. Importantly, high levels of cross-variant live viral in vitro neutralization were shown for variants of concern.
The SARS-CoV-2 lead vaccine was named ABNCoV2 (AdaptVac/Bavarian Nordic Corona virus 2). The drug substance was shipped to filling site Q4 2020 under quarantine, and released mid Q1 2021. The clinical trial dossier was submitted in December 2020 and was approved in March 2021. The COUGH1 (https://clinicaltrials.gov/ct2/show/NCT04839146) trial started in early March 2021. The clinical Phase I/II trial was concluded in June 2022. All dose groups in the COUGH1 phase I/II study demonstrated an excellent safety and reactogenicity profile and high-level SARS-CoV-2 in vitro live virus neutralization levels (up to 12 fold vs. convalescent sera) compared to reported levels for leading mRNA COVID-19 vaccines (up to 4.1 fold convalescent sera). High in vitro efficacy was achieved in all groups receiving ABNCoV2, including non-adjuvanted formulations. Importantly, high levels of cross-variant live viral in vitro neutralization were shown for variants of concern.
The RBD-cVLP vaccines induce more than 500-fold higher levels of neutralizing anti-RBD antibodies, than the soluble RBD vaccines. Remarkably, one injection with our lead RBD-cVLP adjuvanted vaccine in mice and non-human primates elicits virus neutralization antibody titers equal to those found in patients recovered from severe Covid-19 with the highest neutralizing capacity. Following booster vaccinations generated in mice and NHP, the virus neutralization titers exceed those measured after natural infection more than fifty times.
The vaccine ABNCoV2 identified and advanced in the Prevent-nCoV project is subject to further clinical development by Bavarian Nordic A/S. In the Phase 2 clinical trial of ABNCoV2, without adjuvant, it was found that subjects, previously vaccinated with approved and marketed mRNA or adenoviral vaccines, acquired a significant boost to the neutralizing antibodies against the Omicron variant in the majority of subjects with a fold increase in the same range as against original Wuhan SARS-CoV2 variant. While the neutralizing antibody titers against Omicron were the lowest when compared to all other variants previously reported (Wuhan, Alpha, Beta and Delta) they were boosted to levels associated with a high level of protection across both dose groups, 50μg and 100μg. In August 2021 it was announced that a funding agreement with the Danish Ministry of Health to further advance the development of ABNCoV2 had been entered. The agreement is valued at up to DKK 800 million and aims to support the completion of the development towards regulatory approval of ABNCoV2 as a booster vaccine, which could help strengthen the reliability and security of supply of COVID-19 vaccines and address the need for revaccination globally. The Phase III trial of ABNCoV2 was initiated in September 2022, with expected outcome in late 2022 potentially leading to regulatory approval of the vaccine in 2023.
The potential increased longevity of the antibody response, as in other capsid-based virus like vaccines, such as human papilloma virus vaccines, could reduce the need for frequent booster vaccinations. The vaccine may in later clinical development be combined with adjuvant to achieve even higher levels of protection and duration. In addition, ongoing pre-clinical investigations of mucosal administration to increase efficacy and reduce transmission, as well as administration of delta and omicron specific vaccines will demonstrate the versatility of the vaccine technology employed in the Prevent nCoV project.
We expect that after upscaling it will be possible to cost-efficiently produce in the order of billions of dosages a year. The short-term storage of the vaccine is compatible with ambient temperatures and the vaccine appears amenable to freeze dry storage. The preclinical, Phase I and Phase II immunological results look at least as good as the reported mRNA vaccines yielding 90-95% efficacy in Phase III trials. Thus, the RBD-cVLP vaccine is one of the most promising 2nd generation candidates for preventing COVID-19 disease and SARS-CoV-2 transmission. Moreover, the cVLP vaccine technology has now been added to the pandemic preparedness toolbox and will also be employed against endemic infectious diseases such as malaria, hepatitis and influenza.
The vaccine ABNCoV2 identified and advanced in the Prevent-nCoV project is subject to further clinical development by Bavarian Nordic A/S. In the Phase 2 clinical trial of ABNCoV2, without adjuvant, it was found that subjects, previously vaccinated with approved and marketed mRNA or adenoviral vaccines, acquired a significant boost to the neutralizing antibodies against the Omicron variant in the majority of subjects with a fold increase in the same range as against original Wuhan SARS-CoV2 variant. While the neutralizing antibody titers against Omicron were the lowest when compared to all other variants previously reported (Wuhan, Alpha, Beta and Delta) they were boosted to levels associated with a high level of protection across both dose groups, 50μg and 100μg. In August 2021 it was announced that a funding agreement with the Danish Ministry of Health to further advance the development of ABNCoV2 had been entered. The agreement is valued at up to DKK 800 million and aims to support the completion of the development towards regulatory approval of ABNCoV2 as a booster vaccine, which could help strengthen the reliability and security of supply of COVID-19 vaccines and address the need for revaccination globally. The Phase III trial of ABNCoV2 was initiated in September 2022, with expected outcome in late 2022 potentially leading to regulatory approval of the vaccine in 2023.
The potential increased longevity of the antibody response, as in other capsid-based virus like vaccines, such as human papilloma virus vaccines, could reduce the need for frequent booster vaccinations. The vaccine may in later clinical development be combined with adjuvant to achieve even higher levels of protection and duration. In addition, ongoing pre-clinical investigations of mucosal administration to increase efficacy and reduce transmission, as well as administration of delta and omicron specific vaccines will demonstrate the versatility of the vaccine technology employed in the Prevent nCoV project.
We expect that after upscaling it will be possible to cost-efficiently produce in the order of billions of dosages a year. The short-term storage of the vaccine is compatible with ambient temperatures and the vaccine appears amenable to freeze dry storage. The preclinical, Phase I and Phase II immunological results look at least as good as the reported mRNA vaccines yielding 90-95% efficacy in Phase III trials. Thus, the RBD-cVLP vaccine is one of the most promising 2nd generation candidates for preventing COVID-19 disease and SARS-CoV-2 transmission. Moreover, the cVLP vaccine technology has now been added to the pandemic preparedness toolbox and will also be employed against endemic infectious diseases such as malaria, hepatitis and influenza.