Computationally designed antigen targets range of coronaviruses


In a recent study published in Nature Biomedical EngineeringThe researchers used an interdisciplinary approach incorporating phylogenetics, 3D protein modeling, and plasmid design to identify and computationally design antigens that represent the core of most of the currently known sarbecoviruses.

Study: A computationally designed antigen that elicits broad humoral responses against SARS-CoV-2 and related sarbecoviruses.  Image credit: Andrey Vodolazhsky/Shutterstock.com
Study: A computationally designed antigen that elicits broad humoral responses against SARS-CoV-2 and related sarbecoviruses. Image credit: Andrey Vodolazhsky/Shutterstock.com

This single antigen was used to develop a new class of vaccines with efficacy against a wide range of these pathogens, including severe acute respiratory syndrome coronavirus (SARS-CoV)-1, SARS-CoV-2, WIV16 and RaTG13 Was, which has been confirmed. in vitro Immunological tests on mice, guinea pigs and rabbits. This research could form the basis for next generation vaccines that are able to treat sarbecovirus outbreaks early in their course without suffering loss of efficacy due to the rapid evolution of these diseases.

about the study

In the current study, researchers used state-of-the-art digital immune-optimized synthetic vaccine (DIOSynVax) technology to computationally develop immune-optimized engineered antigens capable of binding to core regions of the sarbecovirus spike protein. This binding pattern makes these new antigens resistant to mutations in the RBD, allowing vaccines to trigger immune responses to the full range of SARS-CoV-2-related pathogens.

Researchers began obtaining and compiling phylogenetic sequences from all known humans and animals. sarbecovirus Sequences from the National Center for Biotechnology Information (NCBI) virus database. Based on ACE-2 receptor interactions, their analysis identified two main clades – clade 1 viruses that do not interact with the receptor, and clade 2 that do interact with the receptor. They focus on the hCoV-19/Wuhan/IVDC-HB-01/2019 strain of SARS-CoV-2 (clade 2) for future antigen development.

The researchers used phylogenetic analysis to computationally design an optimized core sequence (T2_13) representative of all clade 2 virus genomes.

Borrowing from previous research that characterized early virus variants, the researchers modified the T2_13 model to represent the S309, CR3022 and B38 epitopes (T2_14, T2_15 and T2_16, respectively). Since B38 is highly divergent, the researchers further modified the epitope through glycosylation to produce T2_17 and T2_18. The build model of the FoldX algorithm was used to evaluate the structural stability of these designed antigens in silico.

For antigen selection and immunogenicity confirmation, researchers performed in vivo screening of BALBino laboratory (BALB/c) mice infected with SARS-CoV-2 RBD (hCoV-19/Wuhan/IVDC-HB-01/2019) as a DNA immunogen. Used in. Flow cytometry was used to confirm the cross-reactivity of the designed antigen against the spike protein representative of SAR-CoV-1, SARS-CoV-2, SARS-like coronavirus WIV16, and bat coronavirus RaTG13. Sera from all antigen-immunized mice showed significantly higher binding than those from control mice, confirming the cross-reactivity of the designed antigens.

T2_17 consistently showed the highest or second-highest binding among pathogens and was therefore selected as the lead candidate in vaccine development. These results were confirmed via enzyme-linked immunosorbent assay (ELISA), in which T2_17 elicited antibodies in mice showed significant binding to both the SARS-CoV RBD and the SARS-CoV-2 RBD.

To minimize bias and confirm that binding was not a byproduct of the physiology of BALB/c mice, these analyzes were performed using pseudoviruses expressing the full-length spike proteins of SARS-CoV and SARS-CoV-2. was replicated in outbred guinea pigs. The results of T2_17 binding were consistent with those observed in murine models, thereby confirming T2_17 as a candidate capable of binding regardless of viral strain or mammalian host.

Finally, the researchers conducted challenge studies on homozygous K18-hACE-2 transgenic mice. Since most of the human population has been exposed to the SARS virus through direct environmental contact or vaccination campaigns against coronavirus disease 2019 (COVID-19), researchers tested the potential of T2_17 as a booster vaccine rather than a prime vaccine. Homozygous K18-hACE-2 transgenic mice were first primed with AZD1222 (ChAdOx1 nCoV-19), the most commonly used licensed vaccine in COVID-19 vaccination globally.

The T2_17 MVA boosted group demonstrated neutralizing antibodies against SARS-CoV, SARS-CoV-2, and Delta VOC, confirming its use as a booster. To verify the long-term efficacy of the antigen, a follow-up longitudinal serology study was conducted. A separate group of K18-hACE-2 mice were primed with the AZD1222 vaccine and boosted with T2_17 20 weeks later, compared with controls that did not receive a booster. Significantly higher antibody titers were observed for the T2_17(MVA) primed group compared to controls up to four weeks after booster administration, with antibodies persisting up to 44 weeks.

Immunogenicity experiments in mice (BALB/c), guinea pigs, and rabbits showed that animals that received the T2_17 vaccine were able to produce antibodies that blocked SARS-CoV-2 VOCs, namely alpha, beta, gamma, Neutralized a wide panel of Delta. , and Omicron BA.1.

conclusion

In the present study, researchers have developed a synthetic antigen ‘T2_17’ that is capable of binding to the core RBD of a broad spectrum of coronaviruses such as SARS. The results show that the computationally generated antigen showed good efficacy as a booster virus against the Alpha, Beta, Gamma, Delta and Omicron BA.1 variants of SARS-CoV-2, while SARS-CoV-2, Was also effective in neutralizing. Like corona virus WIV16, and bat corona virus RaTG13.

These results were confirmed both in vitro And in vivo Using rats, guinea pigs and rabbit model systems. The antibodies produced in these animal models showed significantly better binding than conventional vaccines, with neutralizing antibodies persisting at high titers up to 44 weeks after vaccination.

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