Abstract: Article
https://doi.org/10.1038/s41467-023-37290-6
Intranasal trimeric sherpabody inhibits
SARS-CoV-2 including recent immunoevasive
Omicron subvariants
Received: 22 December 2022
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Accepted: 10 March 2023
Anna R. Mäkelä1, Hasan Uğurlu 1, Liina Hannula2, Ravi Kant 1,3, Petja Salminen1,
Riku Fagerlund1, Sanna Mäki1, Anu Haveri 4, Tomas Strandin1, Lauri Kareinen1,3,
Jussi Hepojoki 1, Suvi Kuivanen1, Lev Levanov1, Arja Pasternack 5,
Rauno A. Naves5, Olli Ritvos5, Pamela Österlund 4, Tarja Sironen 1,3,
Olli Vapalahti 1,3,6, Anja Kipar 3,7, Juha T. Huiskonen 2, Ilona Rissanen 2 &
Kalle Saksela 1,6
The emergence of increasingly immunoevasive SARS-CoV-2 variants
emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Intranasal administration of neutralizing antibodies has shown encouraging protective potential but there
remains a need for SARS-CoV-2 blocking agents that are less vulnerable to
mutational viral variation and more economical to produce in large scale.
Here we describe TriSb92, a highly manufacturable and stable trimeric
antibody-mimetic sherpabody targeted against a conserved region of the
viral spike glycoprotein. TriSb92 potently neutralizes SARS-CoV-2, including the latest Omicron variants like BF.7, XBB, and BQ.1.1. In female Balb/c
mice intranasal administration of just 5 or 50 micrograms of TriSb92 as
early as 8 h before but also 4 h after SARS-CoV-2 challenge can protect from
infection. Cryo-EM and biochemical studies reveal triggering of a conformational shift in the spike trimer as the inhibitory mechanism of
TriSb92. The potency and robust biochemical properties of TriSb92 together with its resistance against viral sequence evolution suggest that
TriSb92 could be useful as a nasal spray for protecting susceptible individuals from SARS-CoV-2 infection.
The success of the current vaccines in the fight against the SARS-CoV-2
pandemic is challenged by the emergence of viral variants of concern
(VOCs) that show strong resistance to neutralizing antibodies induced
by vaccinations or prior infection. Moreover, immune disorders or
other health conditions can preclude appropriate vaccine responses in
many individuals. In addition to pharmaceuticals for treating COVID-19
disease, new approaches for preventing transmission and spreading of
SARS-CoV-2 are therefore urgently needed.
Since the nasal epithelium of the respiratory tract is the first
dominant replication site of SARS-CoV-2 preceding virus transport into
the lung1, intranasal administration of SARS-CoV-2 neutralizing agents
poses an attractive prophylactic concept. In animal models,
1
Department of Virology, University of Helsinki, Helsinki, Finland. 2Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, University of Helsinki,
Helsinki, Finland. 3Department of Basic Veterinary Sciences, University of Helsinki, Helsinki, Finland. 4Finnish Institute for Health and Welfare, Helsinki, Finland.
5
Department of Physiology, University of Helsinki, Helsinki, Finland. 6HUS Diagnostic Centre, HUSLAB, Clinical Microbiology, Helsinki University Hospital,
Helsinki, Finland. 7Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
e-mail: kalle.saksela@helsinki.fi
Nature Communications | (2023)14:1637
1
Article
https://doi.org/10.1038/s41467-023-37290-6
monoclonal antibodies..
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'SARS-CoV-2 variants emphasizes the need for prophylactic strategies to complement vaccination '
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'shown encouraging protective potential but there remains a need for SARS-CoV-2 blocking '
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