A novel "antibody-mimetic" molecule administered intranasally in animal model prevented coronavirus infection from older, current and emerging variants.
Intranasal administration of a novel, non-vaccine "antibody-mimetic" molecule has been shown to prevent coronavirus infection by blocking the receptor binding of SARS-CoV-2, including on recently emerging immunoevasive Omicron subvariants, in animal studies conducted by virologists at the University of Helsinki.
The investigators indicate that they embarked on developing the molecule TriSb92, a trimeric "sherpabody" (SH3 Recombinant Protein Affinity) to neutralize infecting SARS-CoV-2 virus, given the limitations of current approaches.
Vaccines, they point out, aren't able to be utilized by some immunocompromised individuals, and are less effective for emerging viral variants resistant to the induced neutralizing antibodies.They note that monoclonal antibodies against the spike envelope protein are increasingly being investigated in combinations to ascertain whether targeting different regions of the spike can avoid mutational escape.
"In addition to pharmaceuticals for treating COVID-19 disease, new approaches for preventing transmission and spreading of SARS-CoV-2 are therefore urgently needed," declared lead author Anna Mäkelä,PhD, and colleagues in the research group of Kalle Saksela, MD, PhD, Department of Virology, University of Helsinki, Helsinki, Finland.
Mäkelä and colleagues acknowledge that other laboratories have moved from monoclonal antibodies to investigate small antibody fragments, including single variable domain-based nanobodies.The Helsinki group's efforts, however, have focused on smaller antibody-mimetic scaffold proteins, which they describe as "even more robust, versatile to engineer, and cheaper to produce for diverse biological targeting purposes."
They initially screened a large antibody-mimetic phage library (displaying -1011 unique sherpabodies) using the receptor binding domain (RBD) of the glycoprotein of the original Wuhan-Hu-1 strain as the "affinity bait".The strongest binding candidates were then assessed against the RBD of SARS-CoV-1, assuming that strong binding here as well would indicate a very highly conserved target epitope across different variants.
The investigators further enhanced targeting specificity of the trimeric cell surface spike protein by constructing a multimerized derivative, the TriSb92.The broad efficacy was initially determined against different incubated viral isolates, including clinical SARS-CoV-2 isolates from the Beta and Delta variants, and Omicron subvariants BA.1 and BA.5.A pseudovirus model infecting ACE2 expressing cells followed to test TriSb92 against a wider panel of viruses.
Mäkelä and colleagues determined that TriSb92 effectively bound to a highly conserved site in the RBD of the spike protein, inducing a conformational change in the S2 subunit "in the older as well as the currently prevalent and emerging SARS-CoV-2 variants."
The effectiveness of TriSb92 in preventing infection was then tested in a mouse model of COVID-19 (BALB/c mice inoculated intranasally with a mouse-adapted SARS-CoV-2 virus).The infected mice and uninfected controls received intranasal TriSb92 in different doses and at different time periods prior to inoculation. The animals were euthanized 2 days post-infection; with the presence of SARS-CoV-2 nucleoprotein in the nasal mucosa, airways and left lungs ascertained by histology and immunohistology.
The investigators reported that the lungs of the untreated control mice exhibited abundant SARs-CoV-2, while none was present in the mice receiving a 5 or 50mcg prophylactic dose of TriSb92; whether administered 8 hours, or 4 hours before the SARS-CoV-2 challenge.
In addition to finding TriSb92 effective in this animal model, Mäkelä and colleagues anticipate that the TriSb92 solution will be well suited as a nasal spray—subject to clinical trials—as it is relatively inexpensive to produce and stable for at least 18 months at room temperature.
"The easily and inexpensively produced TriSb92 could be a very important first line of defense in curbing...a new pandemic, pending the development, production and distribution of vaccines," Mäkelä commented in a statement to the press.