Periodic Reporting for period 3 - OPENCORONA (Rapid therapy development through Open nCoronavirus Vaccine Platform)
Período documentado: 2022-10-01 hasta 2024-03-31
The OPENCORONA project aims at developing a universal SARS-CoV vaccine that is able to induce immune responses that can protect against viruses still present in animals. Although there has been a tremendous success in vaccine development globally to curb the current COVID-19 pandemic, there is almost a complete lack of vaccines that induce broadly reactive neutralizing antibodies and T cells that can help protect against future SARS-CoV outbreaks. This is the target for the OPENCORONA project, a universal SARS-CoV vaccine. Thus, the OPENCORONA project fills a gap in the COVID-19 vaccine development. To become a universal SARS-CoV vaccine, our vaccine not only contains parts of the so-called spike protein, but also proteins like the membrane and nucleocapsid that has sequences that are highly similar to the same proteins found in animal SARS-CoVs. Thus, our vaccine perfectly complements existing vaccines by inducing broadly cross-reactive neutralizing antibodies (NAbs) and T cells that can recognize animal SARS-CoVs. These responses should be able to curb new SARS-CoV infections by complementing the responses induced by the current vaccines. Our approach is to induce broadly cross-reactive NAbs, combined with T cell responses that can prevent hospitalization and death from future SARS-CoV outbreaks. This concept is strengthened by the observation that T cells from patients infected by SARS-CoV in 2003 recognized SARS-CoV-2 that appeared in 2019. Thus, maintained immunity for 17 years post a SARS-CoV infection that cross-reacted with proteins from SARS-CoV-2. This suggested that those experiencing a SARS-CoV infection in 2003, albeit very few, most likely have some level of protection toward SARS-CoV-2. This strongly support the concept of a universal SARS-CoV vaccine to be used as a booster vaccine to broaden the protective immunity, to also cover future SARS-CoVs most likely emanating from animals. This type of complementary vaccine has important implications for the society as a whole.
The overall objective of the project is to design universal SARS-CoV vaccine, evaluate immunogenicity in animal models and to select a candidate for clinical development to be evaluated in a phase 1 clinical trial. During the first year of the project a total of 24 different vaccine candidates has been designed by KI, produced and evaluated both in vitro and in vivo. The studies leading up to the final vaccine showed that although T cells alone can help to control the SARS-CoV-2 replication, the simultaneous presence of neutralizing antibodies (NAbs) are vital for an optimal protection. The final vaccine gene consists of a highly modified version of the receptor binding domain (RBD) of the Spike protein, the Nucleoprotein (N) and the Membrane (M) protein. This final vaccine construct (OC-2.4) was evaluated in vivo and to induce very high levels of neutralizing antibodies against both Wuhan, Alpha, and the Beta variants of SARS-CoV-2. The vaccine has been produced according to HQ and GMP standards by NorthX Biologics.
The phase I clinical trial show that the DNA vaccine delivered i.m. by in vivo electroporation using the EPSgun and the Cliniporator was safe and tolerable. No severe adverse event was recorded related to the vaccinations. All side effects were mild or moderate and all resolved, supporting the safety of the vaccine and the delivery technology. The immunogenicity of the OC-007 DNA vaccine as a single booster dose suggested the boosting of mean antibody levels the Spike protein Beta variant by 2-5 fold, and an increase in anti-N antibody levels by 5-10 fold. In addition, the neutralizing antibody levels to the SARS-CoV-2 Beta variant increased by 2-fold. This was supported by increases, and de-novo, T cell responses to the spike and N peptide pools and recombinant N protein as detected by ELISpot. However, it is important to note that the study is very small and that changes in both antibody and T cell responses may be influenced by SARS-CoV-2 infections during the clinical trial.
The overall objective of the project is to design universal SARS-CoV vaccine, evaluate immunogenicity in animal models and to select a candidate for clinical development to be evaluated in a phase 1 clinical trial. During the first year of the project a total of 24 different vaccine candidates has been designed by KI, produced and evaluated both in vitro and in vivo. The studies leading up to the final vaccine showed that although T cells alone can help to control the SARS-CoV-2 replication, the simultaneous presence of neutralizing antibodies (NAbs) are vital for an optimal protection. The final vaccine gene consists of a highly modified version of the receptor binding domain (RBD) of the Spike protein, the Nucleoprotein (N) and the Membrane (M) protein. This final vaccine construct (OC-2.4) was evaluated in vivo and to induce very high levels of neutralizing antibodies against both Wuhan, Alpha, and the Beta variants of SARS-CoV-2. The vaccine has been produced according to HQ and GMP standards by NorthX Biologics.
The phase I clinical trial show that the DNA vaccine delivered i.m. by in vivo electroporation using the EPSgun and the Cliniporator was safe and tolerable. No severe adverse event was recorded related to the vaccinations. All side effects were mild or moderate and all resolved, supporting the safety of the vaccine and the delivery technology. The immunogenicity of the OC-007 DNA vaccine as a single booster dose suggested the boosting of mean antibody levels the Spike protein Beta variant by 2-5 fold, and an increase in anti-N antibody levels by 5-10 fold. In addition, the neutralizing antibody levels to the SARS-CoV-2 Beta variant increased by 2-fold. This was supported by increases, and de-novo, T cell responses to the spike and N peptide pools and recombinant N protein as detected by ELISpot. However, it is important to note that the study is very small and that changes in both antibody and T cell responses may be influenced by SARS-CoV-2 infections during the clinical trial.
The project has identified a vaccine candidate that induce antibodies that neutralize different SARS- CoV-2 strains, and T cells that recognize T cells that even recognize proteins from Bat and Pangolin viruses. The original vaccine candidate induced T cells that alone can reduce SARS-CoV-2 replication in ferrets and eliminate virus in the lungs. Moreover, the same vaccine induces NAb and T cell responses in NHPs that mediate clearance of SARS-CoV-2 in the lungs. The final version of the vaccine contains RBD loops from the Wuhan, Alpha, and Beta variants of SARS-CoV-2, and the M and N proteins from the Wuhan strain. This version effectively induce NAbs and neutralize both the Wuhan and Beta variants. This vaccine was produced according to GMP in quantities sufficient for both phase 1 and 2 clinical trials containing more than 500 subjects. The DNA vaccine is delivered by the EPSgun, a new CE marked single step injection and in vivo electroporation device developed within the OPENCORONA project.
The work has resulted in five publications and manuscripts under preparation. The project has resulted in patent applications that cover the vaccine genes. The project has been highly exposed in media and many partners have been frequent guests in all types of national and international media such as TV, radio, Podcasts, webcasts, newspapers, and other media. Thus, the dissemination has been extremely effective.
The work has resulted in five publications and manuscripts under preparation. The project has resulted in patent applications that cover the vaccine genes. The project has been highly exposed in media and many partners have been frequent guests in all types of national and international media such as TV, radio, Podcasts, webcasts, newspapers, and other media. Thus, the dissemination has been extremely effective.
The OPENCORONA vaccines is clearly beyond the current state of the art. The OPENCORONA developed universal SARS-CoV vaccine is intended to be used as a booster vaccine to broaden the protective immunity to also cover future SARS-CoVs most likely emanating from animals. Thus, existing vaccines that induce NAbs and T cells to the SARS-CoV-2 Spike protein needs to be complemented by future safe vaccines that induce NAbs and T cells to diverse and possible future SARS-CoVs. This type of complementary vaccine has important implications for the society as a whole and is essential for pandemic preparedness.