Category: Corona Virus Vaccine

Varying binding affinities and neutralization efficacies of Spike by antibodies

We performed biophysical characterization of nine human monoclonal IgG antibodies (HuMAbs), namely LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016, LSI-CoVA-017 which were discovered in this study, along with 4A833, 5A634, CR302235, CoVA-0236, and CoVA-3936. These monoclonal antibodies were principally discovered from convalescent patients of COVID-19 with the exception of CR3022 that was derived from a SARS-CoV-1 patient35, and 5A6 which was derived from a nave human phage-FAB library. The binding activity of each antibody to SARS-CoV-2 Spike trimer (Spike) and isolated RBD (RBD) from the Wuhan-Hu-1 strain was determined using Quartz Crystal Microbalance (QCM) and enzyme-linked immunosorbent assay (ELISA). As indicated by the half-maximal effective concentration (EC50) values, seven of the nine antibodies bound strongly to both Spike trimer and RBD (Fig.1b). Antibody LSI-CoVA-017 binds strongly to Spike but not RBD, suggestive of an epitope outside RBD. Antibody 4A8 binds weakly to Spike and showed negligible binding to RBD, consistent with previous studies that show 4A8 binds NTD33. Next, we determined the binding kinetics of these HuMAbs against Spike and observed high affinity binding with slow off-rates (Supplementary Fig.1 and Supplementary Table1). The affinity constants (KD) were in the sub-nM range, with LSI-CoVA-017 being the lowest (0.088nM). The association-dissociation kinetics clearly indicate stable binding of the HuMAbs to the Spike trimer.

We next investigated their neutralization efficacies using a pseudotyped virus neutralization test (PVNT). A neutralization capacity of >50% was considered significant in accordance with WHO standards. Correspondingly, we observed differential levels of neutralization, wherein LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016, and CR3022 showed less than 50% efficacy. On the other hand, 4A8, LSI-CoVA-017, and CoVA2-04 showed significant neutralization capacities, while the highest neutralization was observed for CoVA2-39 and 5A6. On this basis, the antibodies were classified as (i) weak, (ii) moderate, and (iii) strong neutralizing HuMAbs (Fig.1ce).

The epitopes of the HuMAbs were mapped by comparative HDXMS analysis of complexes with Spike and RBD. We observed extensive protection against deuterium exchange across peptides spanning RBD of Spike and isolated RBD, in the presence of LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016. This indicates binding to eitherthereceptor-binding motif (RBM) or at a site distal to RBM (Fig.2af). Overlapping peptides covering residues 361395 showed large-scale protection against deuterium exchange in both Spike (Fig.2h, i) and RBD complexes with LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016, indicating that these three antibodies bind RBD at a site distal to the RBM site. In the trimeric Spike, the region spanning residues 361395 becomes accessible only when the RBD adopts an up-position. These changes indicate that the epitope sites identified for LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 are similar to the site observed for the CR3022 antibody (Supplementary Fig.2a), previously characterized as a cryptic site binder37. Alongside antibodies discovered in the current study, we mapped the binding interfaces of known RBD-binding IgGsCoVA2-04, CoVA2-39, and CR3022 (Supplementary Fig.2). The binding hotspots mapped using HDXMS agree with reported cryo-EM structures38. Consistent with our expectations, increased deuterium exchange was observed across the peptides spanning the RBM/ACE2 binding site upon binding of either of these three antibodies (Fig.2af and Supplementary Fig.2a). This correlates to increased conformational dynamics at the ACE2 binding site, suggesting that binding of LSI-CoVA-014, LSI-CoVA-015, or LSI-CoVA-016 locks the RBD in the up- position resulting in higher solvent exposure (Fig.2g). Also, binding of LSI-CoVA 014, 015, 016 may induce allosteric destabilization at RBM, which further needs to be probed (Fig.2g).

Difference plots showing changes in deuterium exchange (D) for a LSI-CoVA-014, b LSI-CoVA-015, and c LSI-CoVA-016 antibody complexes with isolated RBD compared to free RBD, at different labelling times as indicated. Pepsin-proteolyzed fragment peptides are represented by a dot and their residue numbers are indicated. Average values (n=3 independent experiments) and the standard deviations are plotted using Microsoft Excel. A significant value of 0.5D was considered as threshold and is indicated by red-dashed line. Epitope sites are highlighted in yellow. Differences in deuterium exchange values at 1min labeling time for d LSI-CoVA-014, e LSI-CoVA-015, and f LSI-CoVA-016 antibody complexes are mapped on to the structure of RBD shown in surface representation, as per key. g The effects of ACE2 binding to RBDWuhan are mapped and shown for reference, with the RBM-site highlighted in pink box. Comparative HDXMS analysis of Spike trimer (purified from insect cell culture) in the presence and absence of h LSI-CoVA-014 and i LSI-CoVA-015 and LSI-CoVA-016 highlighting S1 subunit (left), S2 subunit (centre), and Spike monomer (right, 11208 residues), with the other two monomers shown in grey. Peptides spanning key regions are highlighted by arrows. Epitopes on RBD (345361, 375390, 471495) are indicated in yellow. Inset highlights a close-up view of Spike trimer (cartoon representation) along the transverse axis. Differences are mapped onto all the three monomers of Spike. RBD-binding antibodies (LSI-CoVA-014, LSI-CoVA-015, and LSI-COVA-016) induce destabilizing effects at the inter-protomer contacts. Peptides spanning residues 304317, fusion peptide (FP), and heptad repeat 1 (HR1) constituting a part of intermonomer interaction interface are indicated. Source data is provided as Source data file.

Similar effects were observed across the other regions of Spike upon binding of LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 (Supplementary Fig.2bd). Notably, peptides spanning residues 516533 showed increased deuterium exchange (Fig.2h, i, left panels), confirming that antibody-binding stabilized RBD in an up-conformation. This is accompanied by the loss of inter- and intra-monomer contacts between RBD and NTD, with residues 166182 which interact with RBD, and 289305 that connect NTD to the central Spike core showing the most significant changes (Fig.2h, i, left panels). In the presence of LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016, an overall increased deuterium exchange was observed for peptides spanning the NTD regions of the Spike trimer. Further, multiple regions of the S2 subunit including the fusion peptide (FP), heptad repeats (HR1 and HR2) and residues 902916 also showed increased deuterium exchange in the presence of these three HuMAbs (Fig.2h, i, centre panels and Supplementary Fig.3ac), except the S1/S2 cleavage site which was associated with a decreased deuterium exchange. These sites are essential for intermonomer interactions (Fig.2h, i, right panels). Taken together, the conformational changes observed at the NTD and the S2 subunit suggest antibody-binding at RBD induces allosteric changes across the Spike trimer, resulting in its global destabilization that may lead to dissociation of adjacent monomers.

These observations were further supported by the HDX changes at the paratope sites of LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 (Supplementary Figs.3d, e and4). Peptides spanning CDRL1-3 and CDRH1-3 showed greater differences in deuterium exchange in the RBD-bound complex, as compared to Spike-bound antibody complexes (Supplementary Table2). The epitope sites are not hidden in the isolated RBD construct but are readily accessible to stably bind the paratope sites. On the other hand, in the Spike trimer, the RBDs must move from a down- to an up- position, and antibody binding is further hindered spatially by the NTD and the S2 subunit, leading to less stable antibody binding.

We next investigated the effects of LSI-CoVA-017, which shows moderate neutralization. In the LSI-CoVA-017-bound state, protection against deuterium exchange was observed across the Spike trimer, with only a few peptides showing deprotection (Fig.3a and Supplementary Fig.5a). Upon closer examination, peptides spanning residues 92110, 136143 (N3 loop), and 243265 (N5 loop) showed large-scale decreases in deuterium exchange in the LSI-CoVA-017-bound state (Fig.3a). These peptides are positioned towards the outer edge of NTD, and are likely the epitope sites bound by LSI-CoVA-017. This region also corresponds to the NTD antigenic supersite20,39. Reduction in deuterium exchange at short labeling times was observed across residues 3648, 166182, and 303318, while increased deuterium exchange was observed for residues 6083, 107117, 213228, and 266276. These differences, mapped onto the structure of NTD (Fig.3a, right panels), revealed that peptides encompassing the epitope site are clustered closely to form a structural epitope and facilitate complexation of Spike with LSI-CoVA-017. These peptides also showed a reduction in deuterium exchange in our comparative HDX analysis of free Spike and its complex with 4A8, which has been previously characterized as an NTD-binding antibody40 (Fig.3b and Supplementary Fig.5b). Thus, our binding assays and HDX data identify LSI-CoVA-017 as an NTD-binding antibody, with both LSI-CoVA-017 and 4A8 being moderate neutralizers.

Difference plots for NTD showing changes in deuterium exchange for a LSI-CoVA-017 and b 4A8 antibody complexes with Spike (purified from insect cell culture) compared to apo Spike, at different labelling times as indicated. Pepsin-proteolyzed fragment peptides spanning NTD of the Spike are represented by a dot and their residue numbers are indicated on the x axis. Average values (n=3 independent experiments each for two biological replicates) and the standard deviations (error bars) are plotted using Microsoft Excel. A significant value of 0.5D was considered as threshold and is indicated by red-dashed line. Epitope sites are highlighted in yellow. Right panels: Differences at 1min labeling time mapped on to NTD of Spike is shown in cartoon representation. Comparative HDXMS analysis of Spike trimer in the presence and absence of c LSI-CoVA-017 and d 4A8 mapped onto the S1 subunit (left) and trimeric Spike protein (right), as indicated. Peptides spanning key regions are highlighted by arrows with epitopes on NTD (92110, 136143, 243265) indicated by yellow ellipse. Inset highlights a close-up view of Spike trimer along the transverse axis. Differences are mapped onto all the three monomers of Spike. NTD-binding LSI-CoVA-017 reduce overall conformational dynamics (shades of blue). Peptides spanning residues 304317, fusion peptide (FP), and heptad repeat 1 (HR1) constituting a part of intermonomer interaction interface are indicated. Source data is provided as Source data file.

Large-magnitude decreases in deuterium exchange were observed across all peptides (including residues 320-350, 516533) spanning the RBD of Spike bound to LSI-CoVA-017 (Supplementary Fig.5a and Supplementary Table2). This indicates significantly reduced conformational dynamics across RBD, suggesting restricted domain motions in the LSI-CoVA-017-bound state. HDXMS analysis of LSI-CoVA-017 and 4A8 with isolated RBD, revealed no significant changes in deuteration levels of RBD (Supplementary Fig.5a). Hence, it is clear that the antibodies binding at NTD induce distinct conformational changes across RBD and the S2 subunit compared to RBD-binding antibodies. Decreased deuterium exchange was observed for peptides spanning the S2 subunit of the Spike-LSI-CoVA-017 complex (Fig.3c, d and Supplementary Fig.5b). Upon LSI-CoVA-017 binding, notable changes in conformational dynamics were observed at the S1/S2 cleavage site, FP, central helix, and HR (Fig.3c, inset). While both LSI-CoVA-017 and 4A8 binding resulted in similar effects on the Spike trimer, the changes induced by 4A8 HuMAb were less prominent. Overall, these HDXMS results reveal that LSI-CoVA-017 binding at NTD induces global stabilization of the Spike trimer.

HDXMS analysis of the LSI-CoVA-017 antibody showed significant changes across both heavy and light chains in the presence of Spike (Supplementary Fig.5c and Supplementary Table2). Peptides overlapping CDRH2 (residues 4870), CDRH3 (96103), and CDRL2 (4871) showed protection against deuterium exchange, while CDRL3 (101129) showed increased deuterium exchange. Interestingly, similar changes were observed for 4A8 complexed to Spike. No significant changes were observed for the light chain of 4A8 with or without Spike, consistent with available high-resolution structures33.

The commonalities in effects of 4A8 and LSI-CoVA-017 upon Spike suggest similar modes of neutralization, as reflected in their neutralization capacities. However, our biophysical data showed LSI-CoVA-017 binds Spike trimer with an affinity much greater than 4A8 (Fig.1b). To rationalize this, we determined the stoichiometry of the Spike-LSI-CoVA-017 complex by size-exclusion chromatography (Supplementary Fig.6 and Supplementary Table3). Three chromatographic peaks were detected and analyzed by denaturing polyacrylamide electrophoresis. Densitometry analysis of different amounts of peak B suggested a binding stoichiometry of three LSI-CoVA-017 antibodies per Spike trimer. With a 1:3 Spike:IgG stoichiometry, two models are plausible where: (i) Fab arms from three LSI-CoVA-017 antibodies bind to three monomers of a single Spike trimer; or (ii) two Fab arms of the same LSI-CoVA-017 bind monomers of two different Spike trimers. This is similar to the model predicted for the Spike:4A8 complex33. We further probed this computationally, as discussed below.

Multiple studies have reported high-resolution structures of HuMAbs bound to RBM, including CoVA2-04, 5A6, and CoVA2-39, showing direct competition with ACE2 binding38. However, given that these HuMAbs display varying neutralization potencies in inhibiting viral entry while binding to overlapping epitopes, a mechanistic explanation for their contrasting behavior remains elusive, particularly for CoVA2-04, a moderate neutralizer, as opposed to 5A6 and CoVA2-39 that are strong neutralizers. We therefore monitored the binding of CoVA2-04, 5A6, and CoVA2-39 to the Spike trimer and observed a distinct impact on its conformational dynamics (Fig.4 and Supplementary Fig.7). A large-magnitude decrease in deuterium exchange was observed across RBD, particularly the peptide clusters spanning RBM (485-502) of Spike complexes with 5A6, CoVA2-04 and CoVA2-39 (Fig.4d, e and Supplementary Fig.7a). Interestingly, HDXMS analysis of CoVA2-04 and CoVA2-39 complexes with the isolated RBD construct showed lower deuterium exchange across RBM, and only minor changes at other regions (Fig.4a). These results indicate that binding of HuMAbs at RBM induces localized changes that lead to a significant reduction in the structural dynamics of RBD, including the peptides spanning the base and linker regions that connect RBD to the Spike trimer. Notably, the Spike variants contain mutations at different sites including E484K, N501Y- or K417N/E484K/N501 that are localized at RBM, and are reported to reduce the neutralization efficacy of antibodies1,26,41.

Difference plots showing changes in deuterium exchange for a CoVA2-39 and b CoVA2-04 antibody complexes with isolated RBD, and c 5A6 antibody with RBD of Spike compared to apo RBD, at 1- and 10-min labelling times. Pepsin-proteolyzed fragment peptides spanning NTD of the Spike are represented by a dot and their residue numbers are indicated. Average values (n=3 independent experiments each for two biological replicates) and their standard deviations (error bars) are plotted using Microsoft Excel. A significant value of 0.5D was considered as threshold and is indicated by red-dashed line. Epitope sites are highlighted in yellow. (right panels) Differences at 1min labeling time mapped on to NTD of Spike is shown. Comparative HDXMS analysis of Spike trimer (purified from insect cell culture) in the presence and absence of d CoVA2-39 and e 5A6 mapped onto the S1 subunit (left), and Spike monomer (right), as indicated. Peptides spanning RBM epitope site are highlighted in yellow. Inset highlights a close-up view of Spike trimer along the transverse axis. Differences are mapped onto all the three monomers of Spike. Peptides spanning residues 304317, fusion peptide (FP), and heptad repeat 1 (HR1) constituting a part of intermonomer interaction interface are indicated. Source data is provided as Source data file.

Binding of CoVA2-04, 5A6, and CoVA2-39 to Spike resulted in increased deuterium exchange across peptide clusters covering residues 3142, 92110, 177191, 265276 of NTD (Fig.4d, e and Supplementary Fig.7a). Some of these peptides span the interface interacting with the RBD and the C-terminal region of NTD. As binding of these HuMAbs leads to RBD domain movement, it induces NTD movement as well, disrupting their interaction. Significant protection against deuterium exchange was observed at the S1/S2 cleavage site (residues 672695), regions flanking the FP (residues 770782, 878898), HR1 (residues 927962), central helix (10031031), and 11031117 of the S2 subunit (Fig.4d, e, right panels, Supplementary Fig.7b). These sites are essential for the Spike trimer to transition from its pre-fusion state to post-fusion state. Decreased deuterium exchange across the S2 subunit suggests that binding of these strong neutralizing HuMAbs leads to global reduction in the conformational dynamics of the Spike trimer, which may prevent the transition to the fusogenic intermediate. Collectively, the HDXMS results provide detailed insights into the mechanism of action of CoVA2-04, 5A6, and CoVA2-39, wherein they compete with ACE2 binding and induce stabilization throughout the Spike trimer to restrict its mobility.

Next, we performed molecular docking to model the Fab domains of LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016, and LSI-CoVA-017 at their respective epitope sites of the Spike protein (RBD or NTD) using HDXMS footprints as restraints (Fig.5 and Supplementary Table4), followed by atomic-resolution MD simulations. Out of 100 Fab:RBD/NTD complexes generated, five top-scoring binding poses were selected for 200ns simulations (Fig.5ad). Among the simulated models of Fab:RBD/NTD complexes, multiple models were observed to either displace from the epitope site (Model 3, RBD-LSI-CoVA-014) or completely detach from RBD (Model 4, RBD-LSI-CoVA-014 and Model 3 of RBD-LSI-CoVA-016), and were not considered for further analysis(Supplemenary Fig. 8a). To select the best models from the stable complexes with each antibody, we next calculated the root mean square deviation (RMSD) of backbone atoms of the Fab domain (Supplementary Fig.8b) and the model with the lowest RMSD was selected for additional replicate simulations to improve the conformational sampling (Supplementary Table4 and Supplementary Fig.9). A stable Fab binding orientation from the most populated cluster was identified via cluster analysis, of each Fab:RBD/NTD complex (Supplementary Fig.9a) and the cluster analysis identified 34, 79, 52 and 65 clusters sampled for LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016 and LSI-CoVA-017, respectively (Fig.5eh and Supplementary Fig.9). Further, contact frequencies were calculated between the glycan moieties and Fab from RBD/NTD simulations of the top 5 docking poses and triplicate MD trajectories of selected poses, revealing that N-glycans interact with residues across Fab arms of LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016 and LSI-CoVA-017 (Fig.5il, Supplementary Fig.8b, and Supplementary Fig.9c). Interestingly, the glycan moieties at N343 of RBD and N74, N122 and N149 on NTD were observed to interact with the Fab (Fig.5c). For the residues interacting with the N-glycans at N331 and N343, contact frequency maps showed the highest number and magnitude of contact frequencies made by LSI-CoVA-014 Fab, as compared to those by LSI-CoVA-015 and LSI-CoVA-016 (Supplementary Fig.8b and Supplementary Fig.9c). Similarly, simulation trajectories of the NTD-LSI-CoVA-017 complex showed prominent interactions between the N74, N122 and N149 N-glycans and the Fab (Supplementary Fig.8b and Supplementary Fig.9c). The contact frequencies measured for the NTD-LSI-CoVA-017 Fab complex indicated stable interactions with a larger surface compared to any of the RBD-Fab complexes, suggesting a potential role for glycans in forming the antibody epitope.

Surface representation of central structures of the five most populated clusters from a RBD-LSI-CoVA-014, b RBD-LSI-CoVA-015, c RBD-LSI-CoVA-016, and d NTD-LSI-CoVA-017 complexes. RBD and NTD are in gray, with LSI-CoVA-014 (brown), LSI-CoVA-015 (green), LSI-CoVA-016 (orange), and LSI-CoVA-017 (yellow). Representative structures from the most populated cluster from MD simulation trajectories are depicted in two orientations for RBD (grey) complexes with Fab of e LSI-CoVA-014 (brown), f LSI-CoVA-015 (green), g LSI-CoVA-016 (orange); and NTD (grey) in complex with h LSI-CoVA-017 (yellow). Glycans are shown in ball-and-stick representation. il Maximum contact frequencies between glycan moieties and Fab from simulations of top five RBD/NTD:Fab docking poses are mapped onto the structure of each Fab. Plots showing the binding of varying concentrations of m LSI-CoVA-014, n LSI-CoVA-015, o LSI-CoVA-016, and p LSI-CoVA-017 antibodies with Spike (red circles) and deglycosylated Spike (blue squares) as determined by ELISA. Data is represented as mean SEM (n=3 independent experiments). Source data is provided as Source data file.

To verify this, we tested the binding of four novel HuMAbs (LSI-CoVA) with a deglycosylated Spike trimer. Binding of LSI-CoVA-017 was completely abolished with deglycosylated Spike, in contrast to the minor changes observed for LSI-CoVA-014, LSI-CoVA-015 and LSI-CoVA-016 (Fig.5mp and Supplementary Fig.10). Furthermore, significant reduction in binding kinetics of these four HuMAbs with deglycosylated Spike was observed, as compared to the glycosylated Spike trimer (Supplementary Fig.10b). To further validate the significance of glycosylation to RBD-binding HuMAbs, we tested 5A6 as a control, which showed a partial reduction. Collectively, these results demonstrate that the LSI-CoVA-017 epitope encompasses glycan moieties on the Spike protein surface. For other antibodies (LSI-CoVA-014/LSI-CoVA-015/LSI-CoVA-016/5A6) the primary binding sites were non-glycosylated epitopes, as identified by HDXMS, with only secondary interactions contributed by glycans. These results provide a view contrary to the prevailing notion that glycans only act as a shield for Spike protein to hide epitope sites from host immune recognition42,43 and suggest that non-specific interactions of glycans with the antibodies can play a substantial role in stabilizing Fab arm binding at the epitope site.

A competitive ELISA was performed to evaluate the extent of epitope site overlap among antibodies (Fig.6ad) and also to characterize the cooperative binding to Spike monomers in the trimeric Spike. This allowed us to distinguish the mechanisms of binding and neutralization of RBD-specific antibodies that share the same or highly overlapping epitopes, yet have different affinities and neutralization activities. Competitive binding ELISA results indicated similar OD450 values between LSI-CoVA-015 and LSI-CoVA-016 as detection or capture antibodies, suggesting a significant overlap in their binding orientation, which is in-line with our HDXMS-guided docking and MD simulations (Fig.6ej). On the other hand, LSI-CoVA-014 did not prevent binding of LSI-CoVA-015 or LSI-CoVA-016. Our simulation cluster analysisof trajectories showed that LSI-CoVA-014 bound to Spike in a different orientation than LSI-CoVA-015 or LSI-CoVA-016, and thus could, in principle, pair with either LSI-CoVA-015 or LSI-CoVA-016 (Fig.6eh). Competitive assays between RBD- and NTD- recognizing antibodies showed that the binding sites for these two antibody classes do not overlap with each other, as observed for LSI-CoVA-014 and LSI-CoVA-017 with LSI-CoVA-015/LSI-CoVA-016 antibodies (Fig.6ac).

Plots showing capture ELISA for pairs of selected antibodies. 0.1g SpikeWuhan (hexapro (purified from mammalian cell culture) was captured by a LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016 and CR3022, b LSI-CoVA-017 and 4A8, and c 5A6, CoVA2-04 and CoVA2-39, detected using peroxidase-labelled monoclonal antibodies. A low OD450 value is indicative of impaired binding of the peroxidase-labelled detection antibody, as listed. Data (n=3 independent experiments) and represented as meanSEM. d Neutralization of pseudo SARS-CoV-2 virus using antibody cocktail (described in methods). Pair-mAb cocktail in the ratio of 1:9 to a final total concentration of 10g/ml or the single huMAb at a concentration of 10g/ml were incubated with pseudovirus lentiviral construct expressing the SARS-CoV-2 Spike protein. The chemiluminescence readout from the luciferase-tagged reporter in the lentiviral construct, is plotted and represented as percentage neutralization. The plots and one-way ANOVA statistical analysis were done using GraphPad prism 9.0. P values determined were 0.0026 (LSI-CoVA-017 vs LSI-CoVA-017+CoVA2-04) and 0.0339 (CoVA2-04 vs LSI-CoVA-017+CoVA2-04) using 6 degrees of freedom, as indicated in the figure. Different antibodies are indicated by alternative colors. Data is reported as meanSEM (n=3 independent experiments). Lateral (upper panel) and top (lower panel) views of surface representations showing Fab arms of e LSI-CoVA-014 (brown), f LSI-CoVA-015 (green), g LSI-CoVA-016 (orange), and h LSI-CoVA-017 (yellow) aligned onto a Spike trimer (grey, PDB 7A98). Representative structures from most populated cluster of Fab:RBD and Fab:NTD cluster analysis were used respectively. Predicted models showing two Spike trimers (grey and blue) bound to both Fab arms of i LSI-CoVA-014 (brown) and j LSI-CoVA-017 (yellow). Source data is provided as Source data file.

To infer stoichiometry and plausible mechanisms of neutralization, we then modelled the binding of full-length IgGs to Spike using a representative structure of Fab:RBD/NTD from the cluster analysis described above (Fig.6eh). Modelled full-length antibodies showed that RBD-binding antibodies specifically bind to RBD in the up-position. Models of LSI-CoVA-015 and LSI-CoVA-016 complexes with the Spike trimer indicate that IgG binding to a single RBD of a Spike monomer sterically hinders the binding of a second IgG to the same Spike trimer. In the case of LSI-CoVA-014 and LSI-CoVA-017, the predicted orientation allows the respective full-length antibody to bind all three RBDs or NTDs of the same Spike protein trimer. These results are consistent with our competitive ELISA and neutralization assays. Additionally, the second Fab arm of LSI-CoVA-017 and LSI-CoVA-014 can bind to a second Spike protein trimer, cross-linking two Spike trimers (Fig.6i, j and Supplementary Fig.6). Taken together, the Spike-IgG complex models suggest that the novel antibodies characterized in this study indirectly interfere with ACE2 binding by either cross-linking Spike trimers on the viral surface (LSI-CoVA-014 and LSI-CoVA-017), or by blocking RBD-ACE2 interaction on a single Spike trimer (LSI-CoVA-015 and LSI-CoVA-016).

The four novel antibodies isolated here from convalescent patients showed suboptimal levels of neutralisation efficacy compared to RBM binding antibodies. However, considering the mutually exclusive epitope sites complemented by high affinity binding to Spike protein, it would be of interest to investigate their use in antibody cocktails. We explored the possibility to induce destabilisation in individual monomers or stabilization to reduce the hinge dynamics between the region connecting S1 and S2 subunits in order to effectively neutralise the SARS-CoV-2. Synergistic effects of selected HuMAbs used in this study were thus evaluated. The selected HuMAbs were used in a pairwise cocktail to study the potential synergistic enhancement of neutralization efficacy, amongst which the paired Mab cocktail of LSI-CoVA-017 and CoVA2-04 displayed a significantly higher percentage neutralization in comparison to the treatment of either of the single HuMAbs (Fig.6d). We did not observe any enhancement in the neutralization efficacies of the two potent HuMAbs (CoVA2-39, 5A6) with NTD-binding LSI-CoVA-017. This could possiblybe due to the limitation of the method and warrants alternative method for quantification purposes. Surprisingly, a combination of NTD- (LSI-CoVA-017) with RBD- (LSI-CoVA-014) antibodies resulted in lower neutralization, than when added alone.

Emergence of new variants as a result of mutations of the Spike protein, have led to many antibody-mediated therapies faltering. Therefore, we assessed the impact of defined variant-linked mutations on binding and neutralization of the novel antibodies characterized in this study with isolated RBD and Spike proteins of the two former variants Delta () and Omicron (o1 for BA.1 and o2 for BA.2 lineages). LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 bind to Spike and isolated RBD of all strains tested, although the binding activities to Omicron variants were slightly lower (Fig.7), akin to CR3022 (Fig.7). Binding of these antibodies was preserved as the mutations among the variants are distant from the cryptic epitopes site. Interestingly, 4A8 bound to Spike of all strains tested, although the binding activity was drastically reduced among all variants compared to Wuhan-Hu-1 Spike. On the other hand, the other NTD-binding antibody LSI-CoVA-017 bound only to SpikeWuhan. This lack of binding of LSI-CoVA-017 and 4A8 to Spike or Spikeo is due to the deletions and mutations spanning the NTD antigenic supersite. Most importantly, 5A6, CoVA2-04, and CoVA2-39 which strongly bind and neutralize SpikeWuhan, bound only to Spike and RBD, but not the Omicron variants (Fig.7a, open symbol plots). We also observed that upon deglycosylation, the binding activity of LSI-CoVA-017 and 4A8 was lost for all Spike variants, while minimal reduction was detected for anti-RBD antibodies against the Spike variants (Supplementary Fig.10).

a Antibody binding activity to Delta and Omicron variants of Spike compared with Wuhan-Hu-1 strain (HexaPro, purified from mammalian cell culture). Antibodies at concentrations from 10pg/mL10g/mL were tested for binding to SARS-CoV-2 Spike and MBP-RBD by ELISA, shown with their EC50 values indicated. Data was collected (n=3 independent experiments) and represented as meanerror bars (SEM). Heat map of differences in deuterium exchange for bd LSI-CoVA-014 and eg LSI-CoVA-016 antibody complexes with isolated RBD variants (b, e) RBD (PDB: 7W98), c, f RBDo1 (PDB: 7WPA), and d, g RBDo2 (PDB: 7WPA) as compared to apo states. Cryptic epitope sites are highlighted in yellow. Source data is provided as Source data file.

Many studies have reported higher binding affinities of Spike variants with the ACE2 receptor44,45. We therefore set out to probe if any of the nine HuMAbs competed with ACE2 binding to Spike variants. We performed ACE2-binding inhibition assays and observed a lack of any inhibitory activity by the cryptic site binders or the NTD-binding antibodies (Fig.8a). Interestingly, LSI-CoVA-015 and LSI-CoVA-016 seemed to enhance ACE2 interaction with RBDo1, as indicated by the negative inhibition (Fig.8a, green arrows). These antibodies bind at the cryptic site, and maintain RBD in an up-position, making the RBM site accessible, which may lead to increased ACE2 binding. This is similar to the effects of antibodies (e.g., S309) recognizing epitopes outside the RBM locus, and show some efficacy against the Omicron variant46,47. Also, 5A6, CoVA2-04, and CoVA2-39 inhibited interactions between ACE2 and Spike Wuhan/Delta strains, but this was not the case for in Spikeo1 or RBDo1 (Fig.8a, bottom panels). For ACE2 inhibition assays, neutralizers that bind RBD often exhibit >40% inhibition. Therefore, the binding and ACE2-inhibition results suggest that only the cryptic-site binding antibodies retain binding to Spike and Spikeo2, and hence only their interactions were further explored.

a ACE2-binding inhibition assays for the nine antibodies at varying concentrations for Spike (purified from mammalian cell culture) and RBD constructs of Wuhan-Hu-1(HexaPro), Delta () and Omicron (o1, o2) variants. Negative values indicate enhanced ACE2 binding (green arrows), while positive values indicate inhibition of ACE2 binding by the antibody (Source data 8). Data was collected (n=3 independent experiments) and represented as meanerror bars (SEM). b Differences in HDX in the presence and absence of ACE2 for isolated RBD constructs of (left) Delta (PDB: 7W98), (centre) Omicron BA.1 (PDB: 7WPA), and (right) Omicron BA.2 (PDB: 7WPA) variants are mapped on to high-resolution structure of RBD, shown in cartoon. Shades of blue correspond to decreased deuterium exchange upon binding to ACE2. c Heat map of differences in deuterium exchange of (left) Spike Delta (PDB: 7W98) and (right) Spike Omicron BA.2 (PDB: 7WPA) in the presence and absence of ACE2 (yellow, cartoon) at 1min labeling time is shown. d, e Plots comparing differences in deuterium exchange (D) in the presence and absence of ACE2 for various peptides across the S1 subunit of Spike variants d Delta and e Omicron BA.2. Various labelling timepoints are indicated with peptide numbers are indicated in accompanying Source data. Data was collected (n=3 independent experiments) and represented as meanerror bars (standard deviation). Peptides covering NTD and RBD are grouped as per domain organization shown. ACE2-binding sites on RBM are highlighted in yellow. Source data is provided as Source data file.

We examined the effects of ACE2 binding on the conformational dynamics of the isolated RBD and trimeric Spike variants by HDXMS, and compared this with ACE2-binding footprints previously reported5,44,48. Binding of ACE2 elicited large-scale protection against deuterium uptake across all regions of isolated RBD, RBDo1 and RBDo2 (Fig.8b). This altered conformational dynamics of RBD variants upon ACE2 binding is reflective of their higher binding affinities44,48. Despite this, mutations of key residues of RBM disrupted specific contacts between the RBD and ACE2, as reflected by available cryo-electron microscopy structures45, and structural dynamics studies49. Upon closer examination of the HDX results, the ACE2 binding footprints were smaller for variants of RBD, as compared to RBDWuhan. Peptides spanning the mutation sites of the loop region (475-495) showed a lower degree of deuterium exchange, while residues 445-455 and 493-510 showed greater protection (Fig.8b and Supplementary Fig.11 ac). We further determined the effects of ACE2 bindingusing trimeric Spike and Spikeo2 (Fig.8c, d and Supplementary Fig.11d, e). Binding of ACE2 elicited conformational changes across RBD of Spike (Fig.8c, left, 8d) akin to those of isolated RBD (Fig.8b, left, 8d), as well as RBD of SpikeWuhan. Surprisingly, we observed marked differences between the ACE2-bound states of RBDo2 and Spikeo2 (Fig.8c, right, 8e). While domain-wide decreased deuterium exchange was observed for the RBDo2-ACE2 complex (Fig.8b, right and Supplementary Fig.11c), for RBD of the Spikeo2-ACE2 complex decreased deuterium exchange was observed only at residues 390417 and 450467 (Fig.8e), and at 1min labeling time for residues 488507, as observed in high-resolution structures. Peptides spanning residues 373384, 429446, and 468483 showed significantly increased deuterium exchange at all labeling time points, and residues 488507 showed increased deuterium exchange at longer labeling times. Peptides showing deprotection overlapped the RBD-specific mutation sites observed for the Omicron variant, while increased protection against HDX was observed for Wuhan-Hu-1and Delta variants (Fig.8c and Supplementary Fig.11d, e). These results describe the molecular mechanism of ACE2-binding by the Omicron variant, whereby the specific amino acid residues promote receptor-binding by maintaining the essential conformational dynamics, yet evade immune responses. Furthermore, these HDX findings also explain how ACE2 binding enhances the conformational sampling of variants, as observed by their high flexibility and fuzzy densities in cryo-EM maps44,45 as well as the comparative structural dynamics of Spike variants containing the D614G mutation.

Using HDXMS, we also mapped and characterized the interactions of LSI-CoVA-014, LSI-CoVA-015, LSI-CoVA-016 antibodies with Delta and Omicron variants. Firstly, we characterized the interactions of the cryptic site binding antibodies LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 with isolated RBD constructs of Delta (Supplementary Fig.12), Omicron BA.1 (Supplementary Fig.13), and Omicron BA.2 (Supplementary Fig.14) variants. Consistent with our expectations, the most notable differences in deuterium exchange were observed for peptides covering the cryptic site, with LSI-CoVA-014, showing lower deuterium exchange values, compared to the LSI-CoVA-015 and LSI-CoVA-016 antibodies. These varying deuterium exchange values are reflective of the differences in conformations of RBD induced by variant-specific mutations. Further, we observed enhanced conformational dynamics for peptides spanning the ACE2-binding sites of the Delta and Omicron variants.

Next, we monitored the effects of these three antibodies binding to Spike and Spikeo2 variants, which showed similar deuterium exchange profiles across the S1 (Fig.9) and the S2 (Supplementary Fig.15) subunits. Peptides flanking the mutated sites of NTD showed no significant change in deuteration as compared to SpikeWuhan, which exhibited lower deuterium exchange upon binding to these three antibodies (Fig.2). Importantly, the linker regions of NTD and RBD showed large-scale protection against deuterium exchange, due to reduced conformational flexibility, indicating that their domain motions were severely restricted. Specifically, peptides spanning residues 365390 of RBD showed protection from deuterium exchange in the antibody-bound states of Spike (Fig.9a, b) and Spikeo2 (Fig.9c, d), indicating that these three HuMabs bind at the same epitopes, akin to SpikeWuhan. Upon closer examination, the magnitude of HDX changes across SpikeWuhan, Spike and Spikeo2 were different, owing to the differences in their binding affinities (Fig.9ad and Supplementary Fig.15). Overall LSI-CoVA-015 and LSI-CoVA-016 (Fig.9e, f, right panels) showed similar deuterium exchange values for peptides spanning the S1 subunit of Omicron Spike and were different compared to changes observed upon binding of LSI-CoVA-014 to Omicron Spike (Fig.9e, f, left panels). Furthermore, HDX kinetics observed across the epitope sites of individual RBD variants (RBD, RBDo1, and RBDo2) in the presence of LSI-CoVA-015, LSI-CoVA-016, and LSI-CoVA-014, were stronger than their corresponding Spike trimers. This indicates that variant-specific mutations on Spike induce subtle changes in the conformational dynamics, which alter the binding strengths of antibodies even though the epitope sites are conserved. This is further supported by the varying HDX effects observed across peptides spanning RBM in antibody-bound Spike and Spikeo2 (Fig.9). This effect was more prominent for RBD, RBDo1 and RBDo2, where binding of LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 antibodies led to significant protection against deuterium exchange at the ACE2-binding sites (Fig.9d). Our results show destabilization of the RBD of Spike and Spikeo2upon antibody binding and explain why the up-position of RBD is favored in the variants50.

Plots comparing differences in deuterium exchange across the S1 subunit of a, b Spikeo2 and c, d Spike complexed to a, c LSI-CoVA-014 and b, d LSI-CoVA-016 versus the apo states are shown at various labelling times. Residue numbers for the peptides are labeled on x axis of the bottom plots of a, b Spikeo2 and c, d Spike, with domain organization shown. Average (n=3 independent experiments) values with standard deviations (error bars) were used to generate the plots (Microsoft Excel). Yellow zones highlight the peptides spanning the cryptic epitope site, as observed for SpikeWuhan. LSI-CoVA-016 showed larger decreases in deuterium exchange to the two variants. Differences in HDX of Spike variantse Delta and f Omicron BA.2 in the presence and absence of (left) LSI-CoVA-014 and (right) LSI-CoVA-016 antibody are mapped onto a monomer of delta Spike (PDB: 7W98) and Omicron Spike (PDB: 7WPA), shown in surface representation. The insets show a transverse view of the conformational changes across the trimer. Source data is provided as Source data file.

Within the S2 subunit of Spike, the LSI-CoVA-014/015/016 deuterium exchange profiles (Fig.9e, Supplementary Fig.15b) were similar to that of SpikeWuhan, but were significantly different from Spikeo2 (Fig.9f and Supplementary Fig.15a). Peptides spanning the S1/S2 cleavage site showed minor differences in deuterium exchange and were lower than those observed for SpikeWuhan. The reduced deuterium exchange indicates that the S1/S2 cleavage site is more concealed in Spike and Spikeo2, and is further occluded by antibody binding. These results also help to explain the reduced propensity for cleavage of variants and the inaccessibility to host proteases observed for the Omicron variant29,51. The most notable changes in conformation upon antibody binding were observed across peptide clusters spanning FP1, FP2 and HR1 (Supplementary Fig.15). Large-magnitude increases in deuterium exchange were observed across these sites for Spike and Spikeo2, as compared to the effects observed for SpikeWuhan. Higher deuterium uptake correlates with increased dynamics and/or solvent accessibility across regions which span peptide clusters including residues 539565 (subdomain 1), 757779, and 936974 (Fig.9e, f right panels,). Increased deuterium exchange at these sites reflects greater solvent accessibility accompanied by the loss of intermonomer contacts. This translates to a long-range effect induced effect by LSI-CoVA-014, LSI-CoVA-015, and LSI-CoVA-016 across the Spike and Spikeo2 trimers. Overall, these antibodies likely cause destabilization of the Spike trimers into antibody-bound monomers. This destabilization ofthe trimer, likely into individual monomers also reflects the altered interaction of ACE2 with Spikeo2 by LSI-CoVA-015/016, accompanied by weak neutralization efficacy.

Our binding assays indicated that 5A6, CoVA2-39, and CoVA2-04 bound to the Delta variant, but not the Omicron variant (Fig.7a). We then compared the effects of binding of 5A6 and CoVA2-04 to Spike and RBD, using HDXMS. Upon binding of these HuMAbs, significant protection against deuterium exchange was observed across the RBDs, both in isolated constructs (Supplementary Fig.16a) and in Spike (Supplementary Fig.16b, c). While the HDX changes observed across the RBM-sites of SpikeWuhan were about ~4Da, the average changes observed for the Delta variant were lower in magnitude (~2.5Da) with a relatively smaller antibody-binding footprint. As the Delta variant has two key mutations at the RBM-site26, the antibody footprint at the epitope site is reduced, affecting the overall conformational dynamics of the RBDs of Spike. Although 5A6, CoVA2-39 and CoVA2-04 directly compete with ACE2 binding, various studies have reported that both CoVA2-39 and CoVA2-04 are unable to neutralize Delta or Omicron variants52,53.

We further determined the effects of 5A6 (Supplementary Fig.16b) and CoVA2-04 on the S2 subunit of Spike. No significant change was observed for peptides covering the S1/S2 cleavage site. Decreased deuterium exchange was observed for peptides spanning FP2, HR1, connector domain (CD) and HR2. Importantly, peptides spanning the central helix (residues 9901010), showed increased deuterium exchange in the presence of these two antibodies, suggesting higher localized conformational dynamics. This is in contrast to the effects observed for SpikeWuhan (Fig.4). While the sites essential for trimerization of Spike showed increased conformational rigidity induced by 5A6 and CoVA2-04 HuMAbs, increased conformational mobility was observed across the central helix. Collectively, the binding assays and HDX results indicate that the HuMAbs recognizing the RBM antigenic supersite cannot bind Omicron at all, and bind Spike variant with reduced affinity, by allosterically reducing the conformational dynamics of the S1 and the S2 subunit, thereby mediating overall stabilization.

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Defining neutralization and allostery by antibodies against COVID ... - Nature.com

Nearly four years since the COVID-19 pandemic first plunged Americas education system into turmoil, schools across the country are still fighting to recover from widespread disruptions to student learning and mental health. Many hope to focus their efforts not only on academic recovery and acceleration but also on comprehensive and transformative school redesign.

The term school redesign typically refers to restructuring at the system level meant to address longstanding inequities and facilitate stronger teaching and learning. Redesign is a community-based process that involves transforming not only the physical environment of schools but also the policies and procedures that drive classroom instruction and organize the school day.

School redesign is challengingand given constraints around time, finances, staff capacity, school schedules, credit systems, and a lack of data about what works, it is often also not easily scalable across districts and states. Consequently, a central question remains as state and federal governments look to reimagine education in the wake of the pandemic: How can policymakers promote and scale innovation in school design? The recommendations in this article outline actions that state and federal policymakers can take to foster thoughtful, transformative school redesign and pave the way for community-driven innovation.

Credit systems based solely on hours of instruction, such as the Carnegie unit, do little to address students individual needs. This traditional model holds seat time constant while making learning the variable. However, several states are leading the way in implementing innovative competency-based models that center content mastery as the basis for high school graduation. In Iowa, Kentucky, and Oregon, school districts have the option to offer proficiency-based credit to students who have successfully completed course requirements or otherwise demonstrated mastery of standards. Maine and New Hampshire require all their districts to base credit systems on mastery of course content or state standards. Research has shown that these systems are associated with increased intrinsic motivation and self-management skills among students, particularly in math courses.

Schools must recognize that learning can and does take place outside the classroom. Work-based learning opportunities, internships, apprenticeships, part-time jobs, after-school programs, service learning, at-home learning, and community-based projects all provide valuable opportunities for building knowledge and skills. Rhode Island and New Hampshire have embraced a credit for learning approach to personalize students individual graduation pathways and award credit for out-of-school experiences. Policies such as these improve student engagement and better prepare students for college and careers by recognizing and validating multiple forms of experience and community-based funds of knowledge.

The drawback of offering more flexibility in learning programs, however, is that some students, particularly those who are already marginalized, may fall through the cracks. Robust data collection and transparency are therefore essential to ensure that all students needs are being met in school. Statewide longitudinal data systems that collect students information from their entry into early childhood education to their entry into and participation in the workforceoften referred to as P-20W systemsare key for monitoring school redesign initiatives and making evidence-based decisions that meet student needs. Texas provides the Texas Public Education Information Resource website, which combines multiple sources of data on all the states public school students with reports on teacher certification and school district staffing. Similarly, California recently established its Cradle-to-Career Data System to gather a variety of data points, including students socioeconomic circumstances, in a centralized hub that families, educators, and policymakers can access in their pursuit of equitable educational outcomes. Strategies and systems such as these will help ensure that all students are seen and supported throughout their educational journeys.

To ensure that federal funding is available for states seeking to redesign their assessment systems, Congress should maintain and expand investments in the Competitive Grants for State Assessments (CGSA) program and the Innovative Assessment Demonstration Authority (IADA). Both can play a key role in promoting innovation in response to COVID-19. Funding should be prioritized toward states implementing personalized and competency-based learning approaches. Additionally, Congress should permanently eliminate the original seven-state cap on IADA participation to enable more states to take advantage of redesign opportunities in the future, as well as expand flexibility for states to establish their own timelines for innovative pilot programs. Most importantly, Congress should authorize the IADA to provide federal funding opportunities to support the startup costs associated with state pilot projects in order to incentivize equitable participation. These changes will help address the variety of challenges that participating states have experienced in implementing the authority.

The U.S. Department of Education should assemble and support peer-to-peer interstate learning networks to examine the effectiveness of innovative assessment models in improving student learning outcomes, as well as scale best practices from pilot programs and ongoing redesign efforts. The National Equity Projects District Redesign Network provides an excellent example of a local-level learning network in which participants come together for the purpose of transforming schools. Congress should consider appropriating the funds necessary to revive the Department of Educations State Support Network, a four-year initiative that, before ceasing operations in 2020, brought states together and offered technical assistance for school improvement efforts. As public schools continue to grapple with transforming schools while addressing the effects of the pandemic, state collaboration and federal support are more important than ever to taking advantage of this pivotal moment for the national education system. Finally, Congress should continue to invest in targeted professional development for educators and school leaders in order to expand educators capacity to implement school redesign initiatives from the ground up.

Top-down mandates alone cannot drive the reimagining of public education. Equally necessary is locally driven transformation from the inside outtransformation based on the unique strengths and needs of individual communities. However, state governments still hold an important role in school transformation, including expanding flexibility in scheduling and graduation requirements while holding schools accountable for student outcomes. Further, both state and federal governments can and should fund equitable pilot and seed projects targeted toward schools that have the least capacity and greatest need to restructure their learning environments. This will empower schools to redesign teaching and learning for the generations to come.

Excerpt from:

5 Ways Government Can Reimagine K-12 School Design in the ... - Center For American Progress

A survey presented to the CDC shows vaccination rates for the latest COVID-19 booster are in the single digits. Health experts are urging people to get the shot.

Author: 13newsnow.com

Published: 11:09 PM EDT November 1, 2023

Updated: 11:09 PM EDT November 1, 2023

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As COVID-19 vaccination rates dwindle, health experts urge the ... - 13newsnow.com WVEC

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Changes in self-reported cannabis use during the COVID-19 ... - BMC Public Health

Authors: Shanti Narayanasamy, Mwaba Mulenga, Prudence Haimbe, Hilda Shakwelele, Lloyd Mulenga, Jessica Joseph, and Nellie Bristol on behalf of the COVID Treatment QuickStart Consortium

Although nirmatrelvir/ritonavir was strongly recommended more than a year ago by the World Health Organization for rapid treatment of COVID-19, the medication and the technical assistance needed to administer it are still only available in a handful of low- and middle-income countries (LMICs). As COVID-19 continues to circulate globally, ensuring equitable access to the drug and other oral antivirals has been a challenge.

The COVID Treatment QuickStart Consortium is in partnership with ten countries in Africa and Asia to address this inequity. Launched in September 2022, QuickStart brings together Duke University, Americares, the Clinton Health Access Initiative (CHAI), and the COVID Collaborative as implementing partners, with support from the Open Society Foundations, Pfizer, and the Conrad N. Hilton Foundation. QuickStart is supporting governments to introduce and scale up access to COVID-19 testing and treatment for high-risk populationsolder individuals and those with underlying health conditionsreducing their risk of hospitalization and death. In addition to protecting those most vulnerable to severe disease, QuickStart lowers the burden of COVID-19 management on health personnel and services while building capacity within primary care to respond to future emerging infections.

Zambia was the first country to receive a 1,000-course donation of nirmatrelvir/ritonavir in December 2022, coinciding with its 5th wave of COVID-19 infections. Over the next six weeks, health officials successfully integrated the drug into national treatment guidelines, trained healthcare personnel on appropriate use and side effects, and distributed nirmatrelvir/ritonavir across the country. The arrival of effective treatment spurred greater testing and 8,758 cases were reported in January and February compared to 693 recorded in the last quarter of 2022. The Zambia Ministry of Healths (MoH) swift launch of test-and-treat programs resulted in treatment initiation for 434 cases during that two-month period.

Zambias experience is a clear example of how health officials can quickly and effectively deploy new medical countermeasures if they have the necessary tools and partners in place to provide technical assistance. Several characteristics of the response provide key lessons for other LMICs as they launch their own test-and-treat programs.

1. Every program needs a champion

Prior to Zambias fifth COVID-19 wave in December 2022, cases had declined markedly and there was a growing perception globally that COVID was over. In this climate, and faced with other pressing health priorities, advocating for resources to integrate nirmatrelvir/ritonavir into standard-of-care treatment for high-risk patients with mild to moderate COVID-19 was daunting. Dr. Nyuma Mbewe, National COVID-19 Case Management Specialist in the Ministry of Health, drove awareness of the continued threat and its long-term impacts and emphasized the importance of test-and-treat as a fundamental tool in containing spread of the virus. Working closely with health care professionals, policymakers, and community leaders she led development of the program and integration into existing public health services. She also played a crucial role in communicating the significance of testing to the public, building trust in the new treatment, and encouraging widespread participation in the program. Dr. Mbewes actions epitomized the high-level political will and program ownership driven by MoH leadership and government officials. Having a well-placed, locally trusted champion willing to advocate for program implementation was crucial to creating a receptive climate and integral to the successful test-and-treat rollout.

2. Leveraging established organizational structures to integrate COVID-19 disease management into existing programs and management

The test-and-treat program in Zambia was launched through existing patient pathways and points of contact within the national public health system. COVID-19 testing was offered at all hospital clinical entry points for any patients showing symptoms. Patients testing positive had a specific record created and were referred to the COVID-19 center within the hospital. COVID-19 centers have been integrated into existing tuberculosis (TB) programs in Zambia, a crucial part of their success and sustainability. Recognizing the overlapping symptoms and transmission routes of the diseases, this allowed health systems to use well-established TB infrastructure, resources, and expertise to diagnose and manage both diseases simultaneously. The approach has also prevented siloing of COVID-19 testing and treatment and ensured the ongoing viability of the program.

3. A whole-of-team approach to programmatic training

Introducing nirmatrelvir/ritonavir in Zambia during a COVID-19 wave required rapid training of clinical providers. To expedite the process, different cadres of providers were all trained together rather than in individual groups, previously the norm. This was both a more efficient training model and facilitated conversation among providers on potential challenges during the roll-out of a new therapeutic product.

4. Taking a holistic approach to patient care

People at highest risk of severe COVID-19 disease are those with other medical comorbidities. Some high-risk factors, such as diabetes, cardiovascular disease, chronic respiratory diseases, and hypertensionconditions known as non-communicable diseases (NCDs)are not as well known or diagnosed in LMICs despite being a leading cause of death. In Zambia, screening for COVID-19 and NCDs has now become bi-directional, meaning that people testing positive for COVID-19 are now also being assessed for NCDs, while COVID-19 testing is also now occurring at NCD clinics. This new process has been a direct result of the QuickStart program.

COVID-19 is here to stay. Integrating effective test and treat programs into existing health services is critical to containing outbreaks, protecting health resources, and building capacities for primary care and future emergencies. The QuickStart Consortium is dedicated to addressing therapeutics inequities as well as collecting and disseminating implementation lessons to aid other countries in improving test-and-treat programs.

Photo credit: Training/information session with QuickStart data collectors at the TB Clinic at University Teaching Hospital in Lusaka.

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Lessons learned from the rapid rollout of nirmatrelvir/ritonavir for ... - PLOS

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It's no secret that the COVID-19 pandemic disrupted supply chains across the globe. In the United States, it often seemed like stores couldn't keep certain items in stock. Now, new research is diving more deeply into the resiliency and vulnerability of global supply chains during the COVID-19 pandemic.

The research team investigated the U.S.-China supply chain during each of its economic shutdowns in the COVID-19 pandemic and focused on measuring credit risk through one of its most liquid variables called credit default swaps, which essentially is insurance against default. The paper, "The impact of COVID-19 on supply chain credit risk," was published in the journal Production and Operations Management.

Researchers found that when China experienced its economic shutdown first and the rest of the world was not yet impacted, U.S. firms with Chinese suppliers and customers were vulnerable to the economic downturns happening in China.

Conversely, when China's economy reopened and the United States went into an economic shutdown, U.S. firms with Chinese suppliers and customers remained more resilient to the local shocks of the U.S. economy. Essentially, firms with global supply chains remain resilient to local shocks, but it exposes firms to global shocks.

Additionally, the researchers find that factors like firm size, investment grade rating, cash holdings, inventory, number of business segments, network centrality, and capital redeployability make a firm more resilient to global risks. On the other hands, factors like high financial leverage, operational leverage, and strong market competition make a firm more vulnerable to global economic shocks.

Senay Agca, study author and a professor of finance at the George Washington University, says this study demonstrates how markets adjust to global supply chain risks. She said it'll be important for companies moving forward to weigh these pros and cons as they re-evaluate their supply chain strategies.

More information: enay Aca et al, The impact of COVID19 on supply chain credit risk, Production and Operations Management (2023). DOI: 10.1111/poms.14079

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Investigating resiliency and vulnerability of global supply chains during the COVID-19 pandemic - Phys.org

ALBANY, NEW YORK Feast American Diners LLC and Dawood David Beshay, the corporate owner and managing member of multiple Dennys restaurants throughout Arizona and New York, including locations in Syracuse, Auburn, Camillus, Cicero, and Watertown, will pay $2 million to resolve allegations that Beshay falsely certified that Feast American Diners was eligible for a Restaurant Revitalization Fund (RRF) grant when he knew or should have known that his company owned and operated too many locations to qualify for the funding, announced United States Attorney Carla B. Freedman.

United States Attorney Freedman stated: The Restaurant Revitalization Fund was meant to provide a financial lifeline to restaurants and other eligible entities that were struggling to stay afloat during the COVID-19 pandemic. Feast American Diners and Dawood Beshay are paying a steep price for falsely certifying their eligibility for these funds.

Congress enacted the American Rescue Plan Act, in March 2021, as a continuation of the federal governments efforts to provide relief to American individuals and businesses suffering the economic and public health effects of the pandemic. The Act allocated $28.6 billion toward an RRF, to be administered by the United States Small Business Administration (SBA), that could grant qualifying restaurants and other eligible entities monetary awards equal to revenue losses caused by the pandemic. Any restaurant that owned or operated more than 20 locations as of March 13, 2020 was not eligible for an RRF grant.

In April 2021, SBA released guidelines for completing RRF applications. The guidance reiterated that an entity was not an eligible entity if it owned or operated more than 20 locations as of March 13, 2020. At various points throughout the guidance, SBA explained that a restaurant was in operation if it was making sales.

In the settlement agreement, Feast American Diners and Beshay admit, acknowledge, and accept responsibility for the following facts: In May 2021, Beshay applied for an RRF grant on behalf of Feast American Diners, in the amount of $928,554. One of the questions on the application asked whether Feast American Diners owned or operated more than 20 locations as of March 13, 2020, to which Feast American Diners responded no. That same question indicated that an applicant who responded yes would not be eligible for the grant. Later in the application, Beshay affixed his initials next to the following statement: The Applicant, together with its affiliates, does not own or operate more than 20 locations. In fact, Feast American Diners owned 21 Dennys locations as of March 13, 2020 and each of those locations made sales that day, facts that Beshay acknowledges that he should have known.

Those who provide false information for the purpose of receiving and retaining SBA program funds meant for eligible small businesses will be held accountable, said SBA Office of Inspector General (OIG) Eastern Region Special Agent in Charge Amaleka McCall-Brathwaite. Todays settlement sends a strong message that those responsible will be brought to justice. I want to thank the U.S. Department of Justice and our law enforcement partners for their dedication and pursuit of justice.

The investigation began in December 2022, when a whistleblower filed a qui tam complaint under seal in the United States District Court for the Northern District of New York. When a whistleblower, or relator, files a qui tam complaint, the False Claims Act requires the United States to investigate the allegations and elect whether to intervene and take over the action or to decline to intervene and allow the relator to go forward with the litigation on behalf of the United States. The relator is generally able to then share in any recovery. Pursuant to the settlement agreement, the relator will receive $200,000 of the settlement.

The investigation and settlement were the result of a coordinated effort between the United States Attorneys Office for the Northern District of New York, SBA-OIG, and SBAs Office of General Counsel. The United States was represented by Assistant United States Attorney Adam J. Katz.

On May 17, 2021, the Attorney General established the COVID-19 Fraud Enforcement Task Force to marshal the resources of the Department of Justice in partnership with agencies across the federal government to enhance efforts to combat and prevent pandemic-related fraud. The Task Force bolsters efforts to investigate and prosecute the most culpable domestic and international criminal actors and assists agencies tasked with administering relief programs to prevent fraud by, among other methods, augmenting and incorporating existing coordination mechanisms, identifying resources and techniques to uncover fraudulent actors and their schemes, and sharing and harnessing information and insights gained from prior enforcement efforts. For more information on the Departments response to the pandemic, please visit https://www.justice.gov/coronavirus.

Anyone with information about allegations of attempted fraud involving COVID-19 can report it by calling the Department of Justices National Center for Disaster Fraud (NCDF) Hotline at 866-720-5721 or via the NCDF Web Complaint Form at: https://www.justice.gov/disaster-fraud/ncdf-disaster-complaint-form.

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United States Attorney Freedman Announces First-Ever Settlement ... - Department of Justice

A 1990s phone booth, part of the Boulder County Public Health sponsored Story Collective art installation, is seen on North Public Road near East Geneseo Street in Lafayette on Wednesday. Other locations are at the Firehouse Art Center in Longmont and at Barker Reservoir in Nederland. (Matthew Jonas/Staff Photographer)

Boulder County Public Health is working with community partners to create a series of interactive art installations across the county that reflect community members experiences of the COVID-19 pandemic.

According to a project website, the exhibits feature oral histories of hope and loss from the pandemic. They were developed with guidance from residents and leaders in each municipality in the county.

All of the installations together form the Story Collective project, which is intended to capture the communitys journey through this time by expressing the fears of the unknown woven with poignant memories, disconnects between the actions we take for ourselves and how they affect the community, and the not-so-subtle push and pull of constant, crucial, conflicting information leaving us feeling disjointed, pulled apart by violent ambivalence, the website stated.

The campaign centers around real voices from our communities and is the result of focus groups with residents from across Boulder County, Indira Gujral, deputy director of Boulder County Public Health, stated in a release. This led to the creation of a design team that included local government representatives and a diverse mix of residents consisting of, among others, a University of Colorado Boulder professor, a bluegrass musician, an opera singer and an immigration activist who worked collaboratively to shape the project.

There will be a total of six art installations, with several already installed at the Firehouse Art Center at 667 Fourth Ave. in Longmont, the Fairy Garden between the intersection of East Street and East Second Street and the western shore of Barker Reservoir in Nederland, and at 186-189 N. Public Road in Lafayette. Others are slated to be added in Lyons and Boulder in the coming months.

More information about the project is available at storycollective.co.

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Boulder County collaborates on interactive art pieces in response to COVID-19 pandemic - Boulder Daily Camera

With Halloween just days away, and the wider autumn and winter holiday season fast approaching, now is the time for most everyone to get their updated COVID-19 vaccine, officials say especially since initial supply shortages have eased.

There are some indications the winter respiratory virus season is just beginning, exacerbating the threat not only of another potential coronavirus wave, but a resurgence of flu and respiratory syncytial virus, or RSV. Last year, all three viruses surged roughly simultaneously, leaving hospitals straining under the weight of a so-called tripledemic.

We have a good supply of COVID-19 and flu vaccines in Los Angeles County and there are options for everyone 6 months and older, county Public Health Director Barbara Ferrer said in a statement. I hope that if many people take advantage of the updated vaccines, L.A. County can avoid a big surge in respiratory virus cases this winter that strains our healthcare system and leads to more deaths.

So far, though, uptake of the updated shots has not been up to snuff for public health officials.

Only 5% of Californians, or 1.8 million people, have received the updated COVID-19 vaccine since it became available last month. Among seniors, the rate is 14%.

Thats not good enough. We should really be seeing much higher rates, especially amongst the old, Dr. Toms Aragn, director of the California Department of Public Health, said at a briefing Thursday. Winter is coming.

Getting the updated shot now, health officials say, will help protect people against the expected wave of COVID-19 thats historically arrived in November and December.

Federal survey data suggest that 7% of U.S. adults got the new COVID-19 vaccine in the first month of the rollout. In a survey in August, 43% of U.S. adults said they planned to get the latest COVID-19 vaccine, according to findings shared by the U.S. Centers for Disease Control and Prevention.

Such uptake would be more in line with that of the annual flu shot. Survey results suggest 47% of U.S. adults got vaccinated during the 202223 flu season. By contrast, only 21% of adults nationwide received the previously updated COVID-19 shot after it was introduced a year ago.

Separately, a survey of more than 1,000 L.A. County adults by the USC Pandemic Research Center suggested that 64% planned on getting the updated COVID-19 vaccine. That would be significantly higher than the 20% of county residents 5 and older and 41% of seniors countywide who received last years reformulated COVID-19 vaccine.

While state officials are pushing for more residents to get vaccinated, the L.A. City Council on Wednesday introduced a motion to sunset that requirement for city employees. If enacted, it would align with similar outside policies, including in L.A. County and the federal government. The state of California ended coronavirus test requirements for unvaccinated state employees in 2022.

There remain demographic disparities among those who are getting vaccinated. Nearly 9% of those living in Californias wealthiest communities have received the new COVID vaccine, compared with fewer than 2% of those living in the lowest-income areas.

Roughly 7% of white Californians have gotten the vaccine, as have 6% of Asian Americans, 4% of Native Hawaiian/Pacific Islanders, 3% of Black, Native American and multiracial Californians and 1.5% of Latino residents.

If youre 6 months or older, you should be getting vaccinated against COVID-19, regardless of previous immunizations, Aragn said. Its no longer a booster. This is now just one shot. And if its been at least two months since the last time you may have received the old bivalent ... booster, or at least three months since youve recovered from an infection, all you need is one shot.

There are a couple of exceptions. The youngest children and those who are immunocompromised may need more than one dose. That is also the case for previously unvaccinated people choosing to get the Novavax vaccine for their first COVID inoculation.

Vaccine supply shortages have eased in recent weeks. But Kaiser Permanente members in Southern California in particular have reported major problems, including being unable for weeks to find appointments close to their homes.

In a statement Thursday, Kaiser said it has a stable supply of the Pfizer-BioNTech vaccine for all age groups.

All healthcare providers nationwide have experienced supply and shipment challenges during the initial launch of the updated COVID-19 vaccine. The majority of those issues have been resolved, the statement said.

Kaiser said some of its locations do not require appointments and that appointments are being added as needed.

The L.A. County Department of Public Health has said anyone including Kaiser members can get the COVID-19 vaccine at no cost at their vaccine sites, including Ted Watkins Memorial Park in Florence-Firestone and Eugene A. Obregon Park in East L.A., which are open from 11 a.m. to 6 p.m. Wednesday through Sunday.

The county also offers vaccinations at eight public health centers in downtown L.A., Hollywood, Willowbrook, Monrovia, Pacoima, Pomona, Whittier and Lancaster.

The county Department of Public Health is considered in-network for all insurers, and can bill Kaiser for the vaccinations.

Uninsured children can get COVID vaccines for free through the Vaccines for Children program. Uninsured adults can get access to free vaccines through Bridge Access Program sites, which include federally qualified health centers and CVS and Walgreens.

No-cost COVID-19 vaccines are also available at the Orange County Health Care AgencysFamily Health Clinic in Santa Ana.

For now, coronavirus levels in wastewater continue to trend downward in Los Angeles County. For the week that ended Oct. 14, the most recent available, the coronavirus level in sewage was 12% of last winters peak, down from 14% the previous week.

This late-year respiratory virus season is the first since the official end of the COVID-19 emergency. And as many return to pre-pandemic norms such as large indoor family gatherings, Aragn urged residents to get vaccinated not only against COVID-19, but the flu and, for those who are recommended, RSV.

As with COVID, officials recommend everyone 6 months and older get vaccinated against the flu via either a shot or a nasal spray. October is an ideal time to get the flu vaccine, but getting it later in the season can still be helpful. Older people also are eligible for a high-potency version of the flu vaccine.

One new development for the flu vaccine this year is that people with a history of allergy to eggs no longer need to take additional safety precautions, according to the CDC.

Most flu vaccines contain a small amount of egg proteins, such as ovalbumin. However, studies that have examined the use of both the nasal spray vaccine and flu shots in egg-allergic and non-egg-allergic patients indicate that severe allergic reactions in people with egg allergies are unlikely, the CDC said.

People who have allergies to other ingredients in the flu vaccine should still avoid getting vaccinated, the CDC said.

Though flu and COVID-19 are not yet spreading widely, circulation of RSV is starting to pick up, Aragn said. RSV can be dangerous, especially for infants and older adults. Immunizations are available at least for certain people.

Those who are at least 60 should talk with their doctor about getting an RSV vaccine, officials say. There are two brands of RSV vaccines available for this age group, one made by GSK, known as Arexvy;and Abrysvo, made by Pfizer.

Those that have chronic medical conditions are the ones that are at highest risk, Aragn said. However, if youre otherwise a very, very healthy 60-year-old, 65-year-old, in consultation with your doctor, you may decide that youre not going to get the vaccine for RSV.

Those who are pregnant can also get a RSV vaccine. They should get it during September through January, only when they are weeks 32 and 36 of their term, to reduce the risk of severe disease in their infants, as the baby will receive protection that will last for months after birth.

Another option to protect newborns is to give them, after birth, an immunization that has preventive antibodies that helps fight RSV infections and protects them from getting very sick.

The immunization is suggested for infants 8 months and younger, as well as those age 8 to 19 months who are at higher risk of severe illness. These antibodies known by the generic name nirsevimab and the trademarked name Beyfortus, which was developed by AstraZeneca and Sanofi are recommended between September and January to help protect babies during RSV season.

There is a shortage of the nirsevimab immunization, the CDC said this week, particularly for prefilled syringe doses intended for babies weighing 11 or more pounds. The CDC recommended that for babies in that weight range, only those at highest risk for severe RSV disease get the immunization.

Masking up continues to be an important tool to help prevent the transmission of infectious diseases, Aragn added, as well as opening the windows, choosing to eat outdoors, being in spaces that are well ventilated, making sure that you wash your hands, and of course, staying home when youre sick, and making sure that you get tested.

Free coronavirus tests remain available at libraries run by the city and the county of Los Angeles, vaccination sites run by the county Department of Public Health, and many food banks and senior centers. Households are also eligible to order four free at-home tests through covid.gov/tests.

In California, most private insurance plans regulated by the state must reimburse their members for eight at-home COVID test kits a month through Nov. 11. After that date, free COVID tests must still be provided through most insurance plans, but covered people must go through an in-network provider to get them at no cost.

For a number of Medicare patients in California, free COVID-19 at-home tests ended on May 11, but COVID-19 testing remains free if ordered by a doctor. For people with a Medicare Advantage plan, the cost of at-home test kits varies and might remain free in some plans, according to the California Department of Public Health.

The L.A. County Department of Public Health suggested that people test for the coronavirus ahead of indoor Halloween and other holiday activities if the guest list includes people at higher risk, such as grandparents, infants and those who are pregnant.

People who get COVID-19 or flu should ask their healthcare provider about treatment options, such as Paxlovid for COVID or a number of anti-flu drugs.

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New COVID vaccines are here: Now's the time to get one, officials say - Los Angeles Times

A new experimental vaccine that could provide protection against multiple varieties of dangerous coronaviruses just passed a major hurdle in its development that may bring it closer to being tested in clinical trials, according to David Martinez, PhD, assistant professor of immunobiology at Yale School of Medicine and a member of the Yale Center for Infection and Immunity.

Coronaviruses are behind some of the deadliest outbreaks of the past few decades. These viruses tend to jump from animal hosts to humans. This has occurred at least three times with different coronaviruses during this century. These viruses then produce deadly respiratory illnesses.

For these reasons, developing vaccines that can provide broad coverage against lethal coronaviruses is essential. In a study published in Cell Reports, Martinez and colleagues at the Duke Human Vaccine Institutewhere Martinez worked before coming to Yale in May 2023tested a newly developed vaccine intended to protect against three deadly coronaviruses, including SARS-CoV-2, the virus that led to the COVID-19 pandemic. Martinez, the studys first and lead corresponding author, led the research team along with co-corresponding authors Ralph Baric, PhD, of the University of North Carolina; and Barton Haynes, MD, and Kevin Saunders, PhD, of Duke University.

The study found that vaccinated mice infected with lethal SARS-CoV 2003 and MERS-CoV survived their infections, while unvaccinated mice did not. The vaccine also provided protection against rising SARS-CoV-2 variants, like XBB1.5. This finding could help move the vaccine into phase-1 clinical trials, says Martinez, andeventuallyinto peoples arms.

While the year 2020 is inextricably linked with the coronavirus dubbed SARS-CoV-2, that virus is just one of many that can cause illness and death. This massive group of viruseswhich can be found in animals all over the worldhad shown itself to be a potential danger to people nearly two decades earlier.

In 2003, a coronavirus called SARS-CoV-1, commonly known as SARS (for severe acute respiratory syndrome), started infecting people in Asia. Presumed to have jumped to people from bats, it infected around 8,000 people, nearly 800 of whom diedmaking SARS-CoV-1 the first new, highly-infectious disease of the 21 st century, according to the World Health Organization. Ten years later, anothertotally distinctcoronavirus called Middle East Respiratory Syndrome (or MERS) also emerged, this time spilling over into people from camels.

Despite their being genetically distinct from one another, the viruses had a few commonalities: each one came from animal hosts, mortality rates were relatively high, and the diseases manifested as respiratory illnesses.

It became very clear that coronaviruses are a public threat to humanity, says Martinez. And then came a virus that needs no introductionSARS-CoV-2.

Martinez started working on a universal coronavirus vaccine during his postdoctoral training at the height of the COVID-19 pandemic. After first focusing his research on the development of a vaccine for SARS-CoV-2 he got caught up in the idea of developing a vaccine that could provide broader coverage for other animal-origin coronaviruses.

The concept has precedent. Other scientists have tried to develop universal vaccines for HIV and viruses that cause influenzawith mixed success. To do this, Martinez and his colleagues searched for an Achilles heelan element that the viruses needed to survive, and that the immune system could be reliably expected to spot. The team chose the RBD receptor, a binding domain found both on MERS and SARS that the viruses need to infect host cells.

To make their vaccine, the researchers engineered a scaffold to attach all three versions of the RBD receptor. They then mixed up the vaccine and injected it into their mice, before introducing their subjects to the three deadly viruses.

Vaccinated mice all survived. But some of the unvaccinated succumbed to their infectionshinting that the vaccine was key to helping mice fend off the worst of the illness.

Previous studiesincluding in labs where Martinez has workedhave tested universal vaccines before. But this study is the first to show that a SARS and MERS vaccine can provide protection against three lethal respiratory illnesses in animals, says Martinez.

The vaccine is a triple threat to the viruses, he says.

The vaccine may work because it reduces viral load in the respiratory and nasal passages. One of the reasons that SARS-CoV-2 and other coronaviruses are thought to be so deadly is that the virus accumulates in cells in the lungs.

The researchers found that vaccinated mice had lower viral load in their upper airway in the respiratory system than unvaccinated micehinting that the vaccine was helping to keep down the viral count and potentially reduce transmission.

And the vaccine wasnt just broadly protective of original variants of SARS-CoV-2. Vaccinated mice also had greater immunity to new COVID variants like XBB1.5, which are being included in the updated versions of the fall COVID booster shots.

The universal coronavirus vaccine wont be available anytime soon. And even if it were, it wouldnt entirely eliminate the need for boosters, says Martinez, who is continuing his work on universal vaccines at Yale. But if it passes clinical trials, it might lengthen the time needed between boosters, he says, as newer variants would have less of an edge than they do now.

The vaccine may be good news for more just than tackling coronaviruses. If a universal coronavirus vaccine is approved, it could open the door for developing other universal vaccines to tackle tricky or deadly illnesses, including influenza, Martinez says.

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Could a New Vaccine Head Off the Next Pandemic? - Yale School of Medicine