The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution.

The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains of the virus. This immune evasion is largely a consequence of mutations in the BA.1 receptor binding domain (RBD), the major antigenic target of SARS-CoV-2. Previous studies have identified several key RBD mutations leading to escape from most antibodies. However, little is known about how these escape mutations interact with each other and with other mutations in the RBD. Here, we systematically map these interactions by measuring the binding affinity of all possible combinations of these 15 RBD mutations (215=32,768 genotypes) to 4 monoclonal antibodies (LY-CoV016, LY-CoV555, REGN10987, and S309) with distinct epitopes. We find that BA.1 can lose affinity to diverse antibodies by acquiring a few large-effect mutations and can reduce affinity to others through several small-effect mutations. However, our results also reveal alternative pathways to antibody escape that does not include every large-effect mutation. Moreover, epistatic interactions are shown to constrain affinity decline in S309 but only modestly shape the affinity landscapes of other antibodies. Together with previous work on the ACE2 affinity landscape, our results suggest that the escape of each antibody is mediated by distinct groups of mutations, whose deleterious effects on ACE2 affinity are compensated by another distinct group of mutations (most notably Q498R and N501Y).

An epitope-enriched immunogen expands responses to a conserved viral site.

Pathogens evade host humoral responses by accumulating mutations in surface antigens. While variable, there are conserved regions that cannot mutate without compromising fitness. Antibodies targeting these conserved epitopes are often broadly protective but remain minor components of the repertoire. Rational immunogen design leverages a structural understanding of viral antigens to modulate humoral responses to favor these responses. Here, we report an epitope-enriched immunogen presenting a higher copy number of the influenza hemagglutinin (HA) receptor-binding site (RBS) epitope relative to other B cell epitopes. Immunization in a partially humanized murine model imprinted with an H1 influenza shows H1-specific serum and >99% H1-specific B cells being RBS-directed. Single B cell analyses show a genetically restricted response that structural analysis defines as RBS-directed antibodies engaging the RBS with germline-encoded contacts. These data show how epitope enrichment expands B cell responses toward conserved epitopes and advances immunogen design approaches for next-generation viral vaccines.

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1.

The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the earlier SARS-CoV-2 variants, BA.1 has many mutations, some of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (215 = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.

Adult sports-related traumatic spinal injuries: do different activities predispose to certain injuries?

OBJECTIVE: Sports injuries are known to present a high risk of spinal trauma. The authors hypothesized that different sports predispose participants to different injuries and injury severities. METHODS: The authors conducted a retrospective cohort analysis of adult patients who experienced a sports-related traumatic spinal injury (TSI), including spinal fractures and spinal cord injuries (SCIs), encoded within the National Trauma Data Bank from 2011 through 2014. Multiple imputation was used for missing data, and multivariable linear and logistic regression models were estimated. RESULTS: The authors included 12,031 cases of TSI, which represented 15% of all sports-related trauma. The majority of patients with TSI were male (82%), and the median age was 48 years (interquartile range 32-57 years). The most frequent mechanisms of injury in this database were cycling injuries (81%), skiing and snowboarding accidents (12%), aquatic sports injuries (3%), and contact sports (3%). Spinal surgery was required during initial hospitalization for 9.1% of patients with TSI. Compared to non-TSI sports-related trauma, TSIs were associated with an average 2.3-day increase in length of stay (95% CI 2.1-2.4; p < 0.001) and discharge to or with rehabilitative services (adjusted OR 2.6, 95% CI 2.4-2.7; p < 0.001). Among sports injuries, TSIs were the cause of discharge to or with rehabilitative services in 32% of cases. SCI was present in 15% of cases with TSI. Within sports-related TSIs, the rate of SCI was 13% for cycling injuries compared to 41% and 49% for contact sports and aquatic sports injuries, respectively. Patients experiencing SCI had a longer length of stay (7.0 days longer; 95% CI 6.7-7.3) and a higher likelihood of adverse discharge disposition (adjusted OR 9.69, 95% CI 8.72-10.77) compared to patients with TSI but without SCI. CONCLUSIONS: Of patients with sports-related trauma discharged to rehabilitation, one-third had TSIs. Cycling injuries were the most common cause, suggesting that policies to make cycling safer may reduce TSI.