Immunogenicity of COVID-19 booster vaccination in IEI patients and their one year clinical follow-up after start of the COVID-19 vaccination program.

Purpose: Previous studies have demonstrated that the majority of patients with an inborn error of immunity (IEI) develop a spike (S)-specific IgG antibody and T-cell response after two doses of the mRNA-1273 COVID-19 vaccine, but little is known about the response to a booster vaccination. We studied the immune responses 8 weeks after booster vaccination with mRNA-based COVID-19 vaccines in 171 IEI patients. Moreover, we evaluated the clinical outcomes in these patients one year after the start of the Dutch COVID-19 vaccination campaign. Methods: This study was embedded in a large prospective multicenter study investigating the immunogenicity of COVID-19 mRNA-based vaccines in IEI (VACOPID study). Blood samples were taken from 244 participants 8 weeks after booster vaccination. These participants included 171 IEI patients (X-linked agammaglobulinemia (XLA;N=11), combined immunodeficiency (CID;N=4), common variable immunodeficiency (CVID;N=45), isolated or undefined antibody deficiencies (N=108) and phagocyte defects (N=3)) and 73 controls. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T-cell responses were evaluated. One year after the start of the COVID-19 vaccination program, 334 study participants (239 IEI patients and 95 controls) completed a questionnaire to supplement their clinical data focusing on SARS-CoV-2 infections. Results: After booster vaccination, S-specific IgG titers increased in all COVID-19 naive IEI cohorts and controls, when compared to titers at 6 months after the priming regimen. The fold-increases did not differ between controls and IEI cohorts. SARS-CoV-2-specific T-cell responses also increased equally in all cohorts after booster vaccination compared to 6 months after the priming regimen. Most SARS-CoV-2 infections during the study period occurred in the period when the Omicron variant had become dominant. The clinical course of these infections was mild, although IEI patients experienced more frequent fever and dyspnea compared to controls and their symptoms persisted longer. Conclusion: Our study demonstrates that mRNA-based booster vaccination induces robust recall of memory B-cell and T-cell responses in most IEI patients. One-year clinical follow-up demonstrated that SARS-CoV-2 infections in IEI patients were mild. Given our results, we support booster campaigns with newer variant-specific COVID-19 booster vaccines to IEI patients with milder phenotypes.

Immunogenicity and safety of a recombinant Omicron BA.4/5-Delta COVID-19 vaccine ZF2202-A in Chinese adults.

BACKGROUND: The Recombinant Omicron BA.4/5-Delta COVID-19 Vaccine (ZF2202-A) is primarily designed for the Delta and Omicron BA.4/5 variants. Our objective was to assess the safety and immunogenicity of ZF2202-A in Chinese adults. METHODS: A total of 450 participants aged ≥ 18 years, who had completed primary or booster vaccination with a COVID-19 vaccine more than 6 months prior, were enrolled in this randomized, double-blind, active-controlled trial. Participants in the study and control groups were administered one dose of ZF2202-A and ZF2001, respectively. Immunogenicity subgroups were established in each group. RESULTS: At 14 days after vaccination, the seroconversion rates of Omicron BA.4/5, BF.7, and XBB.1 in the ZF2022-A group were 67.7 %, 58.6 %, and 62.6 %, with geometric mean titers (GMTs) of neutralizing antibodies at 350.2, 491.8, and 49.5, respectively. The main adverse reactions (ARs) were vaccination site pain, pruritus, fatigue, and asthenia in both the ZF2022-A group and ZF2001 group. CONCLUSIONS: The novel bivalent vaccine ZF2202-A demonstrated satisfactory immunogenicity and safety against Omicron variants as booster dose in adults with prior vaccination of COVID-19 vaccines.

An integrated technology for quantitative wide mutational scanning of human antibody Fab libraries.

Antibodies are engineerable quantities in medicine. Learning antibody molecular recognition would enable the in silico design of high affinity binders against nearly any proteinaceous surface. Yet, publicly available experiment antibody sequence-binding datasets may not contain the mutagenic, antigenic, or antibody sequence diversity necessary for deep learning approaches to capture molecular recognition. In part, this is because limited experimental platforms exist for assessing quantitative and simultaneous sequence-function relationships for multiple antibodies. Here we present MAGMA-seq, an integrated technology that combines multiple antigens and multiple antibodies and determines quantitative biophysical parameters using deep sequencing. We demonstrate MAGMA-seq on two pooled libraries comprising mutants of nine different human antibodies spanning light chain gene usage, CDR H3 length, and antigenic targets. We demonstrate the comprehensive mapping of potential antibody development pathways, sequence-binding relationships for multiple antibodies simultaneously, and identification of paratope sequence determinants for binding recognition for broadly neutralizing antibodies (bnAbs). MAGMA-seq enables rapid and scalable antibody engineering of multiple lead candidates because it can measure binding for mutants of many given parental antibodies in a single experiment.

Functional and antigenic characterization of SARS-CoV-2 spike fusion peptide by deep mutational scanning.

The fusion peptide of SARS-CoV-2 spike protein is functionally important for membrane fusion during virus entry and is part of a broadly neutralizing epitope. However, sequence determinants at the fusion peptide and its adjacent regions for pathogenicity and antigenicity remain elusive. In this study, we perform a series of deep mutational scanning (DMS) experiments on an S2 region spanning the fusion peptide of authentic SARS-CoV-2 in different cell lines and in the presence of broadly neutralizing antibodies. We identify mutations at residue 813 of the spike protein that reduced TMPRSS2-mediated entry with decreased virulence. In addition, we show that an F823Y mutation, present in bat betacoronavirus HKU9 spike protein, confers resistance to broadly neutralizing antibodies. Our findings provide mechanistic insights into SARS-CoV-2 pathogenicity and also highlight a potential challenge in developing broadly protective S2-based coronavirus vaccines.

Original COVID-19 priming regimen impacts the immunogenicity of bivalent BA.1 and BA.5 boosters.

Waning antibody responses after COVID-19 vaccination combined with the emergence of the SARS-CoV-2 Omicron lineage led to reduced vaccine effectiveness. As a countermeasure, bivalent mRNA-based booster vaccines encoding the ancestral spike protein in combination with that of Omicron BA.1 or BA.5 were introduced. Since then, different BA.2-descendent lineages have become dominant, such as XBB.1.5, JN.1, or EG.5.1. Here, we report post-hoc analyses of data from the SWITCH-ON study, assessing how different COVID-19 priming regimens affect the immunogenicity of bivalent booster vaccinations and breakthrough infections (NCT05471440). BA.1 and BA.5 bivalent vaccines boosted neutralizing antibodies and T-cells up to 3 months after boost; however, cross-neutralization of XBB.1.5 was poor. Interestingly, different combinations of prime-boost regimens induced divergent responses: participants primed with Ad26.COV2.S developed lower binding antibody levels after bivalent boost while neutralization and T-cell responses were similar to mRNA-based primed participants. In contrast, the breadth of neutralization was higher in mRNA-primed and bivalent BA.5 boosted participants. Combined, our data further support the current use of monovalent vaccines based on circulating strains when vaccinating risk groups, as recently recommended by the WHO. We emphasize the importance of the continuous assessment of immune responses targeting circulating variants to guide future COVID-19 vaccination policies.

Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody.

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

A murine model of post-acute neurological sequelae following SARS-CoV-2 variant infection.

Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. Here, we studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies in surviving mice up to 4 months post-acute infection revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. In the brain, no detectable viral RNA and minimal residential immune cell activation was observed in the surviving mice post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and gene expression levels associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent systemic T helper 1 prone cellular immune responses and strong sera neutralizing antibodies against Delta and Omicron variants months post-acute infection. Overall, our findings suggest that infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long-COVID patients and provides new insights into the role of systemic and brain residential immune factors in PASC pathogenesis.

Long-term humoral and cellular immunity against vaccine strains and Omicron subvariants (BQ.1.1, BN.1, XBB.1, and EG.5) after bivalent COVID-19 vaccination.

Background: The assessment of long-term humoral and cellular immunity post-vaccination is crucial for establishing an optimal vaccination strategy. Methods: This prospective cohort study evaluated adults (≥18 years) who received a BA.4/5 bivalent vaccine. We measured the anti-receptor binding domain immunoglobulin G antibody and neutralizing antibodies (NAb) against wild-type and Omicron subvariants (BA.5, BQ.1.1, BN.1, XBB.1 and EG.5) up to 9 months post-vaccination. T-cell immune responses were measured before and 4 weeks after vaccination. Results: A total of 108 (28 SARS-CoV-2-naïve and 80 previously infected) participants were enrolled. Anti-receptor binding domain immunoglobulin G (U/mL) levels were higher at 9 months post-vaccination than baseline in SAR-CoV-2-naïve individuals (8,339 vs. 1,834, p<0.001). NAb titers against BQ.1.1, BN.1, and XBB.1 were significantly higher at 9 months post-vaccination than baseline in both groups, whereas NAb against EG.5 was negligible at all time points. The T-cell immune response (median spot forming unit/106 cells) was highly cross-reactive at both baseline (wild-type/BA.5/XBB.1.5, 38.3/52.5/45.0 in SARS-CoV-2-naïve individuals; 51.6/54.9/54.9 in SARS-CoV-2-infected individuals) and 4 weeks post-vaccination, with insignificant boosting post-vaccination. Conclusion: Remarkable cross-reactive neutralization was observed against BQ.1.1, BN.1, and XBB.1 up to 9 months after BA.4/5 bivalent vaccination, but not against EG.5. The T-cell immune response was highly cross-reactive.

Designing boosting immunogens for HIV-1 vaccine development.

Inducing HIV-1 broadly neutralizing antibodies (bnAbs) through vaccination poses exceptional challenges. In this issue of Cell Host & Microbe, Wiehe and colleagues report the elicitation of affinity-matured bnAbs in knock-in mice through boosting immunogen vaccination, which selects for key improbable mutations.

Rapid development and mass production of SARS-CoV-2 neutralizing chicken egg yolk antibodies with protective efficacy in hamsters.

Despite the record speed of developing vaccines and therapeutics against the SARS-CoV-2 virus, it is not a given that such success can be secured in future pandemics. In addition, COVID-19 vaccination and application of therapeutics remain low in developing countries. Rapid and low cost mass production of antiviral IgY antibodies could be an attractive alternative or complementary option for vaccine and therapeutic development. In this article, we rapidly produced SARS-CoV-2 antigens, immunized hens and purified IgY antibodies in 2 months after the SARS-CoV-2 gene sequence became public. We further demonstrated that the IgY antibodies competitively block RBD binding to ACE2, neutralize authentic SARS-CoV-2 virus and effectively protect hamsters from SARS-CoV-2 challenge by preventing weight loss and lung pathology, representing the first comprehensive study with IgY antibodies. The process of mass production can be easily implemented in most developing countries and hence could become a new vital option in our toolbox for combating viral pandemics. This study could stimulate further studies, optimization and potential applications of IgY antibodies as therapeutics and prophylactics for human and animals.

Quantitative assay to analyze neutralization and inhibition of authentic Middle East respiratory syndrome coronavirus.

To date, there is no licensed vaccine for Middle East respiratory syndrome coronavirus (MERS-CoV). Therefore, MERS-CoV is one of the diseases targeted by the Coalition for Epidemic Preparedness Innovations (CEPI) vaccine development programs and has been classified as a priority disease by the World Health Organization (WHO). An important measure of vaccine immunogenicity and antibody functionality is the detection of virus-neutralizing antibodies. We have developed and optimized a microneutralization assay (MNA) using authentic MERS-CoV and standardized automatic counting of virus foci. Compared to our standard virus neutralization assay, the MNA showed improved sensitivity when analyzing 30 human sera with good correlation of results (Spearman's correlation coefficient r = 0.8917, p value < 0.0001). It is important to use standardized materials, such as the WHO international standard (IS) for anti-MERS-CoV immunoglobulin G, to compare the results from clinical trials worldwide. Therefore, in addition to the neutralizing titers (NT50 = 1384, NT80 = 384), we determined the IC50 and IC80 of WHO IS in our MNA to be 0.67 IU/ml and 2.6 IU/ml, respectively. Overall, the established MNA is well suited to reliably quantify vaccine-induced neutralizing antibodies with high sensitivity.

Follow-Up and Comparative Assessment of SARS-CoV-2 IgA, IgG, Neutralizing, and Total Antibody Responses After BNT162b2 or mRNA-1273 Heterologous Booster Vaccination.

BACKGROUND: Priming with ChAdOx1 followed by heterologous boosting is considered in several countries. Nevertheless, analyses comparing the immunogenicity of heterologous booster to homologous primary vaccination regimens and natural infection are lacking. In this study, we aimed to conduct a comparative assessment of the immunogenicity between homologous primary vaccination regimens and heterologous prime-boost vaccination using BNT162b2 or mRNA-1273. METHODS: We matched vaccinated naïve (VN) individuals (n = 673) with partial vaccination (n = 64), primary vaccination (n = 590), and primary series plus mRNA vaccine heterologous booster (n = 19) with unvaccinated naturally infected (NI) individuals with a documented primary SARS-CoV-2 infection (n = 206). We measured the levels of neutralizing total antibodies (NTAbs), total antibodies (TAbs), anti-S-RBD IgG, and anti-S1 IgA titers. RESULTS: Homologous primary vaccination with ChAdOx1 not only showed less potent NTAb, TAb, anti-S-RBD IgG, and anti-S1 IgA immune responses compared to primary BNT162b2 or mRNA-1273 vaccination regimens (p < 0.05) but also showed ~3-fold less anti-S1 IgA response compared to infection-induced immunity (p < 0.001). Nevertheless, a heterologous booster led to an increase of ~12 times in the immune response when compared to two consecutive homologous ChAdOx1 immunizations. Furthermore, correlation analyses revealed that both anti-S-RBD IgG and anti-S1 IgA significantly contributed to virus neutralization among NI individuals, particularly in symptomatic and pauci-symptomatic individuals, whereas among VN individuals, anti-S-RBD IgG was the main contributor to virus neutralization. CONCLUSION: The results emphasize the potential benefit of using heterologous mRNA boosters to increase antibody levels and neutralizing capacity particularly in patients who received primary vaccination with ChAdOx1.

Epidemiological characteristics and antibody kinetics of elderly population with booster vaccination following both Omicron BA.5 and XBB waves in China.

After the termination of zero-COVID-19 policy, the populace in China has experienced both Omicron BA.5 and XBB waves. Considering the poor antibody responses and severe outcomes observed among the elderly following infection, we conducted a longitudinal investigation to examine the epidemiological characteristics and antibody kinetics among 107 boosted elderly participants following the Omicron BA.5 and XBB waves. We observed that 96 participants (89.7%) were infected with Omicron BA.5, while 59 (55.1%) participants were infected with Omicron XBB. Notably, 52 participants (48.6%) experienced dual infections of both Omicron BA.5 and XBB. The proportion of symptomatic cases appeared to decrease following the XBB wave (18.6%) compared to that after the BA.5 wave (59.3%). Omicron BA.5 breakthrough infection induced lower neutralizing antibody titers against XBB.1.5, BA.2.86, and JN.1, while reinfection with Omicron XBB broadened the antibody responses against all measured Omicron subvariants and may alleviate the wild type-vaccination induced immune imprinting. Boosted vaccination type and comorbidities were the significant factors associated with antibody responses. Updated vaccines based on emerging severe acute respiratory syndrome coronavirus 2 variants are needed to control the Coronavirus Disease 2019 pandemic in the elderly.

Evaluation of the immunogenicity of an mRNA vectored Nipah virus vaccine candidate in pigs.

Nipah virus (NiV) poses a significant threat to human and livestock populations across South and Southeast Asia. Vaccines are required to reduce the risk and impact of spillover infection events. Pigs can act as an intermediate amplifying host for NiV and, separately, provide a preclinical model for evaluating human vaccine candidate immunogenicity. The aim of this study was therefore to evaluate the immunogenicity of an mRNA vectored NiV vaccine candidate in pigs. Pigs were immunized twice with 100 µg nucleoside-modified mRNA vaccine encoding soluble G glycoprotein from the Malaysia strain of NiV, formulated in lipid nanoparticles. Potent antigen-binding and virus neutralizing antibodies were detected in serum following the booster immunization. Antibody responses effectively neutralized both the Malaysia and Bangladesh strains of NiV but showed limited neutralization of the related (about 80% amino acid sequence identity for G) Hendra virus. Antibodies were also capable of neutralizing NiV glycoprotein mediated cell-cell fusion. NiV G-specific T cell cytokine responses were also measurable following the booster immunization with evidence for induction of both CD4 and CD8 T cell responses. These data support the further evaluation of mRNA vectored NiV G as a vaccine for both pigs and humans.

Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.

An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against highly diverse Envelope glycoproteins (Env). Since Env with the longest hypervariable (HV) loops is more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated Env consensus sequences of subtypes B and C and CRF01_AE. Using modeling with AlphaFold2, we reduced the length of V1, V2, and V5 HV loops while maintaining the integrity of the Env structure and glycan shield, and modified the V4 HV loop. Spacers are designed to limit strain-specific targeting. All updated Env are infectious as pseudoviruses. Preliminary structural characterization suggests that the modified HV loops have a limited impact on Env's conformation. Binding assays show improved binding to modified subtype B and CRF01_AE Env but not to subtype C Env. Neutralization assays show increases in sensitivity to bnAbs, although not always consistently across clades. Strikingly, the HV loop modification renders the resistant CRF01_AE Env sensitive to 10-1074 despite the absence of a glycan at N332.

Nucleic acid vaccine candidates encapsulated with mesoporous silica nanoparticles against MERS-CoV.

Middle East respiratory coronavirus (MERS-CoV) is a newly emergent, highly pathogenic coronavirus that is associated with 34% mortality rate. MERS-CoV remains listed as priority pathogen by the WHO. Since its discovery in 2012 and despite the efforts to develop coronaviruses vaccines to fight against SARS-CoV-2, there are currently no MERS-CoV vaccine that has been approved. Therefore, there is high demand to continue on the development of prophylactic vaccines against MERS-CoV. Current advancements in vaccine developments can be adapted for the development of improved MERS-CoV vaccines candidates. Nucleic acid-based vaccines, including pDNA and mRNA, are relatively new class of vaccine platforms. In this work, we developed pDNA and mRNA vaccine candidates expressing S.FL gene of MERS-CoV. Further, we synthesized a silane functionalized hierarchical aluminosilicate to encapsulate each vaccine candidates. We tested the nucleic acid vaccine candidates in mice and evaluated humoral antibodies response. Interestingly, we determined that the non-encapsulated, codon optimized S.FL pDNA vaccine candidate elicited the highest level of antibody responses against S.FL and S1 of MERS-CoV. Encapsulation of mRNA with nanoporous aluminosilicate increased the humoral antibody responses, whereas encapsulation of pDNA did not. These findings suggests that MERS-CoV S.FL pDNA vaccine candidate induced the highest level of humoral responses. This study will enhance further optimization of nanosilica as potential carrier for mRNA vaccines. In conclusion, this study suggests MERS-CoV pDNA vaccine candidate as a suitable vaccine platform for further pivotal preclinical testings.

Dynamics of SARS-CoV-2 antibodies after natural infection: insights from a study on Pasteur Institute of Tunis employees.

This study aimed to assess the kinetics of antibodies against the SARS-CoV-2, following natural infection in a cohort of employees of the Institut Pasteur de Tunis (IPT) and to assess the risk of reinfection over a 12-months follow-up period. A prospective study was conducted among an open cohort of IPT employees with confirmed SARS-CoV-2 infection that were recruited between September 2020 and March 2021. Sera samples were taken at 1, 3, 6, 9 and 12 months after confirmation of COVID-19 infection and tested for SARS-CoV-2-specific immunoglobulin G (IgG) antibodies to the spike (S-RBD) protein (IgG anti-S-RBD) and for neutralizing antibodies. Participants who had an initial decline of IgG anti-S-RBD and neutralizing antibodies followed by a subsequent rise in antibody titers as well as those who tested positive for SARS-CoV-2 by RT-PCR after at least 60 days of follow up were considered as reinfected. In total, 137 individuals were included with a mean age of 44.7 ± 12.3 years and a sex-ratio (Male/Female) of 0.33. Nearly all participants (92.7%) were symptomatic, and 2.2% required hospitalization. Among the 70 participants with three or more prospective blood samples, 32.8% were reinfected among whom 11 (47.8%) reported COVID-19 like symptoms. Up to 12 months of follow up, 100% and 42.9% of participants had detectable IgG anti-S-RBD and neutralizing antibodies, respectively. This study showed that humoral immune response following COVID-19 infection may persist up to 12 months after infection despite the potential risk for reinfection that is mainly explained by the emergence of new variants.

Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells.

While sclerostin-neutralizing antibodies (Scl-Abs) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Abs control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells in vitro and PDGFR signaling in these cells induces bone resorption through M-CSF secretion, we hypothesized that the prolonged anticatabolic effect of Scl-Abs could result from PDGFR inhibition. We show here that inhibition of PDGFR signaling in osteoblast lineage cells is sufficient and necessary to mediate prolonged Scl-Ab effects on M-CSF secretion and osteoclast activity in mice. Indeed, sclerostin coactivates PDGFRs independently of Wnt/ß-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs in preosteoblasts. In turn, Scl-Ab prevents sclerostin-mediated coactivation of PDGFR signaling and consequent M-CSF upregulation in preosteoblast cultures, thereby inhibiting osteoclast activity in preosteoblast/osteoclast coculture assays. These results provide a potential mechanism explaining the dissociation between anabolic and antiresorptive effects of long-term Scl-Ab.

A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity.

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.