Cross-Species Tropism and Antigenic Landscapes of Circulating SARS-CoV-2 Variants

Mutations in the SARS-CoV-2 spike receptor-binding domain (RBD) may alter the viral host tropism and affect the activities of neutralizing antibodies (nAbs). Here, we investigated 153 RBD mutants and 10 globally circulating VOC/VOI variants for their cross-species infection potentials and sensitivities to nAbs. Several RBD mutations strengthened viral infectivity in cells-expressing ACE2 orthologs of non-human animals, particularly those less susceptible to the ancestral strain. Antigenic profiles revealed the mutations surrounding aa 439-448 and aa 484 were more likely to cause neutralization resistance. Strikingly, the enhanced cross-species infection potentials to the mouse and ferret, instead of the neutralization-escape scores of the mutations, accounted for the positive correlation with the current cumulative prevalence of mutations in humans. Our results provided prospective landscapes for the cross-species transmission potentials and antigenic drift of circulating spike mutants and highlighted the possible spillover of variants to originally-insusceptible animals in associating with their quick spread worldwide. Funding: This study was supported by the National Natural Science Foundation of China 81902057 (to Y.L.Z.), U1905205 (to Q.Y.), and 81871316 (to Q.Y.) and the CAMS Innovation Fund for Medical Sciences (No. 2019RU022 to N.X.). Declaration of Interests: None to declare. Ethics Approval Statement: The study was approved (number: SPHIRB-202101) by the institutional review board of the School of Public Health of Xiamen University following the Declaration of Helsinki, and written informed consent was obtained.Animal studies were carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals, and were conducted under the approval of the Institutional Animal Care and Use Committee of Xiamen University (mouse experiments) or JOINN Laboratories, Inc. (monkey experiments).