IrsiCaixa, IRTA-CreSA, BSC and Grifols develop new COVID-19 vaccines that are effective in preclinical models and feature an optimized production

IrsiCaixa –a centre jointly supported by the "la Caixa" Foundation and the Department of Health of the Government of Catalonia–, the Centre for Research in Animal Health of the Institute of Agrifood Research and Technology (IRTA-CReSA), and the Barcelona Supercomputing Center - National Supercomputing Centre (BSC-CNS), with funding from Grifols, have pioneered the development of two promising vaccine candidates against COVID-19. These vaccines are built upon two mutated versions of the spike protein, also known as the S protein, derived from the SARS-CoV-2 virus, named S29 and V987H. These variants with innovative genetic modifications allow for up to a 5-fold increase in the production of the S protein compared to other marketed vaccines.  Now, the scientific journal Nature Communications publishes results that add to those previously published in the journal Frontiers in Immunology and NPJ Vaccines, demonstrating the effectiveness of both vaccines in generating a protective immune response in two different preclinical models. With all this data, the research team suggests the possibility of incorporating the mutations of the S29 and V987H variants into the new generations of vaccines based on the S protein.

Most of the vaccines currently on the market for COVID-19 are based on the S protein for two reasons: it's an essential component for the infection process and activates the immune system against the virus. Despite these advantages, the S protein also presents a challenge as it is not stable and undergoes conformational changes. This, on one hand, complicates its production and, on the other hand, implies that certain conformations conceal the region of the protein –called RBD– with the highest capacity to activate the immune system. Hence, most vaccines focused on this compound –such as those from Pfizer/BioNTech, Moderna, AstraZeneca, and Janssen– stabilize the S protein by incorporating two mutations, resulting in the variant called 2P. "Despite the efforts made so far, the protein continues to be produced at low levels, and it is necessary to find alternative mutations that increase its production," comments Jorge Carrillo, principal investigator at IrsiCaixa. This was one of the objectives of the CBIG consortium, formed in 2020 by IrsiCaixa, IRTA-CReSA, and BSC-CNS, and financed by Grifols.

Effective vaccines with production up to 5 times higher

Using supercomputing techniques, the team has identified various mutations that enhance the stability of the protein. "We have employed computational tools to predict which mutations reduce its mobility, and we have selected those that provide us with a more stable version of the S protein and a better exposure of the RBD domain," specifies Victor Guallar, a researcher at the BSC.

From these mutations, the team has generated two new variants of the S protein, S-29 and S-V987H. The first contains the mutations S758E, T912R, K947R, K986P, and V987P, and the second contains the V987H mutation. These variants have demonstrated an improvement in production compared to current vaccines based on the S protein. "We have multiplied the level of protein production in the laboratory by two to five times," indicates Carlos Ávila, researcher at IrsiCaixa. Evaluation using two different preclinical models has shown that these new vaccines protect against infection by the Omicron, Beta, and D614G variants of SARS-CoV-2. "We have observed that in the severe disease model, the vaccines protect against progression to acute infection. Additionally, it has been observed that the vaccines reduce the amount of virus present in tissues in the moderate disease model. Using two models that simulate different contexts allows us to robustly demonstrate the potential of these vaccines to protect against infection," highlights Júlia Vergara-Alert, principal investigator at IRTA-CReSA. "Studying their immune response to infection, we have identified that the vaccines induce the production of antibodies capable of neutralizing the original, Beta, Delta, and Omicron variants", adds Ávila. Part of the preclinical studies were performed at the biosafety facilities of the Center for Comparative Medicine and Bioimaging (CMCiB) that the Germans Trias i Pujol Institute (IGTP) has at the Can Ruti Campus.

New generations of optimized vaccines

Despite the significant impact of COVID-19 vaccines on pandemic control, SARS-CoV-2 remains present in our daily lives. As the virus continues to infect and spread, it also acquires new mutations that grant it advantageous abilities, such as increased transmissibility or evasion of the immune response. In response to this virus evolution, the scientific community continues to work on developing vaccines that can adapt to these new capabilities of SARS-CoV-2. "Conducting studies like the one presented today serves to establish a robust knowledge foundation for developing new generations of vaccines and identifying novel modifications to optimize their efficacy," notes Joaquim Segalés, principal investigator at IRTA-CReSA. Therefore, the findings highlight the potential of the S29 or V987H variants to enhance S protein production, improve presentation of the immune system's activating domain, and provide protection against infection.