Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants.

Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

Weisblum Y ，Schmidt F ，Zhang F ，DaSilva J ，Poston D ，Lorenzi JC ，Muecksch F ，Rutkowska M ，Hoffmann HH ，Michailidis E ，Gaebler C ，Agudelo M ，Cho A ，Wang Z ，Gazumyan A ，Cipolla M ，Luchsinger L ，Hillyer CD ，Caskey M ，Robbiani DF ，Rice CM ，Nussenzweig MC ，Hatziioannou T ，Bieniasz PD ... -  《eLife》

Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein finds additional vaccine-induced epitopes beyond those for mild infection.

Control of the COVID-19 pandemic will rely on SARS-CoV-2 vaccine-elicited antibodies to protect against emerging and future variants; an understanding of the unique features of the humoral responses to infection and vaccination, including different vaccine platforms, is needed to achieve this goal. The epitopes and pathways of escape for Spike-specific antibodies in individuals with diverse infection and vaccination history were profiled using Phage-DMS. Principal component analysis was performed to identify regions of antibody binding along the Spike protein that differentiate the samples from one another. Within these epitope regions, we determined potential sites of escape by comparing antibody binding of peptides containing wild-type residues versus peptides containing a mutant residue. Individuals with mild infection had antibodies that bound to epitopes in the S2 subunit within the fusion peptide and heptad-repeat regions, whereas vaccinated individuals had antibodies that additionally bound to epitopes in the N- and C-terminal domains of the S1 subunit, a pattern that was also observed in individuals with severe disease due to infection. Epitope binding appeared to change over time after vaccination, but other covariates such as mRNA vaccine dose, mRNA vaccine type, and age did not affect antibody binding to these epitopes. Vaccination induced a relatively uniform escape profile across individuals for some epitopes, whereas there was much more variation in escape pathways in mildly infected individuals. In the case of antibodies targeting the fusion peptide region, which was a common response to both infection and vaccination, the escape profile after infection was not altered by subsequent vaccination. The finding that SARS-CoV-2 mRNA vaccination resulted in binding to additional epitopes beyond what was seen after infection suggests that protection could vary depending on the route of exposure to Spike antigen. The relatively conserved escape pathways to vaccine-induced antibodies relative to infection-induced antibodies suggests that if escape variants emerge they may be readily selected for across vaccinated individuals. Given that the majority of people will be first exposed to Spike via vaccination and not infection, this work has implications for predicting the selection of immune escape variants at a population level. This work was supported by NIH grants AI138709 (PI JMO) and AI146028 (PI FAM). JMO received support as the Endowed Chair for Graduate Education (FHCRC). The research of FAM was supported in part by a Faculty Scholar grant from the Howard Hughes Medical Institute and the Simons Foundation. Scientific Computing Infrastructure at Fred Hutch was funded by ORIP grant S10OD028685.

Garrett ME ，Galloway JG ，Wolf C ，Logue JK ，Franko N ，Chu HY ，Matsen FA 4th ，Overbaugh JM ... -  《eLife》

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.

Wang P ，Nair MS ，Liu L ，Iketani S ，Luo Y ，Guo Y ，Wang M ，Yu J ，Zhang B ，Kwong PD ，Graham BS ，Mascola JR ，Chang JY ，Yin MT ，Sobieszczyk M ，Kyratsous CA ，Shapiro L ，Sheng Z ，Huang Y ，Ho DD ... -  《-》

Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies.

Collier DA ，De Marco A ，Ferreira IATM ，Meng B ，Datir RP ，Walls AC ，Kemp SA ，Bassi J ，Pinto D ，Silacci-Fregni C ，Bianchi S ，Tortorici MA ，Bowen J ，Culap K ，Jaconi S ，Cameroni E ，Snell G ，Pizzuto MS ，Pellanda AF ，Garzoni C ，Riva A ，CITIID-NIHR BioResource COVID-19 Collaboration ，Elmer A ，Kingston N ，Graves B ，McCoy LE ，Smith KGC ，Bradley JR ，Temperton N ，Ceron-Gutierrez L ，Barcenas-Morales G ，COVID-19 Genomics UK (COG-UK) Consortium ，Harvey W ，Virgin HW ，Lanzavecchia A ，Piccoli L ，Doffinger R ，Wills M ，Veesler D ，Corti D ，Gupta RK ... -  《-》

Structural Basis of a Human Neutralizing Antibody Specific to the SARS-CoV-2 Spike Protein Receptor-Binding Domain.

Yang M ，Li J ，Huang Z ，Li H ，Wang Y ，Wang X ，Kang S ，Huang X ，Wu C ，Liu T ，Jia Z ，Liang J ，Yuan X ，He S ，Chen X ，Zhou Z ，Chen Q ，Liu S ，Li J ，Zheng H ，Liu X ，Li K ，Yao X ，Lang B ，Liu L ，Liao HX ，Chen S ... -  《Microbiology Spectrum》