Biology subjects

Ho, D. D.

Publications and source records attributed to Ho, D. D..

At least 19 recordsLinked to original sources

bioRxiv2026

A Bispecific Biologic That Robustly Reverses HIV-1 and SIV Latency

Antiretroviral therapy suppresses HIV-1 replication but cannot eliminate the latent viral reservoir persisting in memory CD4 T cells. Existing latency reversal candidates have yet to achieve robust viral reactivation at tolerable doses. We engineered T4IL15{triangleup}, a bispecific biologic that selectively delivers IL-15 signaling to memory CD4 T cells, with minimal off-target stimulation. T4IL15{triangleup} reactivated latent virus in 94% (48/51) of clinical samples ex vivo, 75% (15/20) of administrations in HIV-1-infected and ART-suppressed humanized mice, and 100% (6/6) of SIV-infected and ART-suppressed rhesus macaques at doses well tolerated. We also found that off-target stimulation of non-CD4 cells hindered HIV-1 reactivation ex vivo. T4IL15{triangleup} provides a robust reactivation platform that could complement other reservoir-elimination strategies toward an HIV-1 cure.

microbiology↗

bioRxiv2026

Antibody evasion and receptor binding of SARS-CoV-2 RW.1.1

The continued evolution of SARS-CoV-2 is shaped by changes in antibody evasion and receptor engagement that influence viral fitness. RW.1.1, an emerging descendant of XFJ carrying five additional spike substitutions, has recently increased in frequency in North America. Here, we characterized the serum antibody evasion, monoclonal antibody sensitivity, and ACE2 receptor engagement of RW.1.1. Pseudovirus neutralization assays using sera from adults showed that RW.1.1 was not more resistant to serum neutralization than currently circulating variants, with neutralizing titers comparable to XFG, BA.3.2.2, and NB.1.8.1 in the tested cohort. Neutralization of RW.1.1 also did not differ significantly among adults, children, and infants and toddlers. Despite the absence of increased overall serum antibody resistance, monoclonal antibody neutralization assays revealed substantial resistance to several RBD class 1 antibodies and increased resistance to a subset of class 1/4 antibodies. Moreover, RW.1.1 exhibited reduced ACE2 receptor engagement compared with XFG, which itself has reduced receptor engagement relative to earlier JN.1 subvariants. Thus, RW.1.1 has continued to expand despite a further reduction in receptor engagement and without a substantial increase in overall serum antibody evasion. These findings suggest that the fitness of emerging SARS-CoV-2 variants may depend not only on the magnitude of antibody evasion but also on the specific components of the polyclonal antibody response that are evaded, highlighting the increasingly complex interplay between population immunity and receptor engagement in shaping SARS-CoV-2 evolution.

microbiology↗

bioRxiv2026

SARS-CoV-2 BA.3.2.2 is more evasive of neutralization by sera from young children

Dominant SARS-CoV-2 variants have most prominently displayed greater evasion of serum neutralizing antibodies than predecessor strains. BA.3.2, a descendant of Omicron BA.3, carrying 43 additional spike mutations, emerged in 2024, and over the last several months its subvariant BA.3.2.2 has slowly increased in prevalence globally. BA.3.2.2 continues to circulate at lower frequency than the genetically and antigenically distant dominant JN.1 subvariants NB.1.8.1 and XFG. However, concerningly, epidemiologic analyses have suggested that a larger proportion of COVID-19 cases in children are caused by BA.3.2.2 compared to adults, raising the possibility that susceptibility to BA.3.2.2 differs across age groups. Since immune imprinting shapes variant-specific anti-SARS-CoV-2 antibody profiles and children born after 2021 primarily were first exposed to Omicron subvariants, we hypothesized that young children may have lower circulating neutralizing antibody titers against BA.3.2.2 than adults. Using pseudovirus neutralization assays, we measured titers against BA.3.2.2 and other SARS-CoV-2 variants in serum or plasma samples from a total of 36 adults ([≥]18 years old), school-age children (3-10 years old), and infants/toddlers (6-28 months old) in the US. We found that both cohorts of children had lower geometric mean titers against BA.3.2.2 than adults, even though all tested age groups had similar titers against dominant strains NB.1.8.1 and XFG. Together, these findings suggest that susceptibility to emerging SARS-CoV-2 variants may diverge across age groups, perhaps as a result of their different exposure histories. Furthermore, these results highlight the importance of SARS-CoV-2 surveillance and the monitoring of immunity against viral variants across age ranges.

microbiology↗

bioRxiv2026

A Monoclonal Antibody Panel to Track Ongoing Antigenic Evolution of SARS-CoV-2 Variants

SARS-CoV-2 continues to evolve, generating successive variants with enhanced resistance to antibody-mediated neutralization. However, many existing monoclonal antibody (mAb) repertoires were derived from exposures to ancestral or early Omicron strains and thus incompletely capture the antigenic landscape of newly emerging strains. Here, we generated a mAb panel by immunizing naive, unimprinted VelocImmune humanized mice with spike from the KP.3.1.1 variant, and isolated and characterized 11 neutralizing antibodies targeting diverse epitopes of recently evolved antigenic variants. We then integrated these antibodies with previously characterized mAbs to establish an expanded toolbox for profiling antigenic evolution among emerging variants. Application of this panel to currently emerging SARS-CoV-2 variants provided mechanistic insight into recent antigenic evolution, highlighting the potential role of altered receptor-binding domain conformation. Our data also revealed clear differences in antibody-evasion profiles between JN.1-derived lineages and BA.3.2 lineages. Together, our findings establish an updated mAb panel for monitoring SARS-CoV-2 antigenic evolution.

microbiology↗

bioRxiv2026

A Panel of Human Monoclonal Antibodies for Tracking the Antigenic Evolution of Influenza H5N1 Clade 2.3.4.4b

The ongoing panzootic of clade 2.3.4.4b H5N1 influenza has resulted in widespread infection of birds, mammals, and livestock, underscoring the need for tools to interpret its real-time evolution. Here, we describe the isolation and characterization of a panel of 19 human monoclonal antibodies that potently neutralize current isolates. Competition immunoassays and cryo-electron microscopy analyses revealed their collective near-complete epitope coverage of the H5-hemagglutinin surface. Neutralization profiling across multiple historical and contemporary H5 viruses defined their epitope-specific patterns of virus neutralization. One cluster of antibodies potently neutralized only clade 2.3.4.4b viruses, while many others exhibited broadly neutralizing activity against diverse H5N1 clades. Application of this structurally calibrated antibody panel to recent North American human isolates revealed genotype-specific antigenic divergence between lineages that have spread among cattle (B3.13) and poultry (D1.1). Together, the findings of this study establish a structurally grounded antibody reference panel spanning major vulnerable sites of H5 hemagglutinin and provide a toolbox for interpreting emergent mutations, monitoring ongoing antigenic drift, and anticipating the evolutionary trajectory of circulating H5N1 influenza viruses.

microbiology↗

bioRxiv2026

VYD2311 is a promising candidate for passive immunization against COVID-19 in immunocompromised individuals

For millions of immunocompromised individuals, vaccines may not elicit adequate protection from infections, so alternative strategies for pre-exposure prophylaxis are essential. There is only one non-vaccine product authorized in the U.S. as pre-exposure prophylaxis against COVID-19: the monoclonal antibody pemivibart. We previously showed that pemivibart had lower neutralizing activity in vitro against many recent dominant SARS-CoV-2 variants, such as KP.3.1.1, NB.1.8.1, and LP.8.1.1, than it had against JN.1, which was dominant when the antibody was first authorized. The manufacturer of pemivibart (Invivyd) recently initated clinical testing of a new monoclonal antibody derived from pemivibart, VYD2311, but there are no available studies of the activity of VYD2311 against dominant and emerging SARS-CoV-2 variants. Here, using pseudovirus neutralization assays, we measured the neutralizing activity of laboratory-synthesized VYD2311 and pemivibart against dominant and emerging SARS-CoV-2 variants, including XFG, NB.1.8.1, and the genetically distant BA.3.2.2. We found that VYD2311 potently neutralized all tested variants in vitro, dramatically more so than pemivibart. Combined with interpretation of earlier clinical trials of a parental antibody product, we conclude that VYD2311 is a promising candidate for passive immunoprophylaxis against COVID-19, particularly for those who do not respond well to vaccination.

microbiology↗

bioRxiv2026

ACE-2-like Enzymatic Activity in Anti-SARS-CoV-2 Spike Protein Monoclonal Antibodies

Many people with acute COVID-19 have clinical disease not clearly attributable to viral replication and many COVID-19 convalescents are affected by post-acute sequelae of COVID-19 (PASC, or long COVID, LC). LC has severely affected public health and economies worldwide. Features of LC including blood pressure dysregulation, coagulopathies, high levels of inflammation, and neuropsychiatric complaints. The mechanisms responsible for the pathogenesis of some of COVID-19s clinical features and LC have not been well established. The host cell receptor for SARS-CoV-2 is human angiotensin converting enzyme 2 (ACE2), which binds the SARS-CoV-2 spike protein receptor-binding domain (RBD) to initiate infection. We hypothesized that some people may produce anti-RBD antibodies that sufficiently resemble ACE2 structure to have ACE2-like catalytic activity after infection. Those antibodies, ACE2-like abzymes, may contribute to the pathogenesis of LC. Our previous studies showed that ACE2-like activity was associated with immunoglobulin in some acute and convalescent COVID-19 patients. ACE2-like catalytic activity correlated with blood pressure changes following a moderate exercise challenge in people convalescing from COVID-19. To further establish that ACE2-like activity could be attributed to antibodies, we screened human monoclonal antibodies (mAbs) against SARS-CoV-2 spike protein from 3 different research centers and others purchased from a commercial source for ACE2-like catalytic activity. We identified 4 human monoclonal antibodies with ACE2-like catalytic activity. The ACE2-like catalytic activity of these mAbs was not inhibited by MLN-4760, a compound that inhibits native human ACE2 catalytic activity, nor by EDTA, unlike native ACE2, a Zinc metalloprotease, but was inhibited by an overlapping pool of spike peptides. Enzyme kinetic studies showed that the mAbs had substantially lower Vmax and Km values than native ACE2. The data therefore suggested that the antibodies cleave ACE2 substrate via a different mechanism than native ACE2. The identification of specific mAbs with ACE2-like catalytic activity supports the hypothesis that antibodies induced by SARS-CoV-2 infection could help mediate the pathogenesis of COVID-19 and LC, and more generally, the hypothesis that catalytic antibodies induced by infectious agents can contribute to disease pathogenesis.

microbiology↗

bioRxiv2026

Distinct allosteric remodeling of HIV-1 Env dynamics on virions by gp41-directed antibodies reveals two modes of neutralization

HIV-1 envelope glycoprotein (Env), a gp120-gp41 trimer, undergoes coordinated conformational changes that drive membrane fusion and allow immune evasion by transiently concealing neutralization-sensitive epitopes. Most broadly neutralizing antibodies (bNAbs) target gp120, whereas a distinct subset recognizes conserved gp41 regions, such as the fusion peptide and the membrane-proximal external region; however, their impact on Env dynamics and associated neutralization mechanisms remains unclear. Using bioorthogonal tagging for single-molecule FRET, we monitored real-time bNAb-induced conformational sampling of Env on intact virions. Most gp41-directed bNAbs allosterically stabilized the prefusion-closed (PC) state, whereas the bivalent 10E8.4/iMab favored both PC and CD4-bound open (predominant) states. Antibodies redistributed the conformational populations of Env with modest kinetic effects, preserving the sequential transition pathway. These findings reveal two modes of neutralization for gp41-directed antibodies: fixing the prefusion-closed conformation and opening it, in both cases via long-range allosteric control of Env dynamics.

microbiology↗

bioRxiv2026

LP.8.1-directed COVID-19 mRNA vaccines boost neutralizing antibodies and mitigate ancestral immune imprinting

As SARS-CoV-2 evolves, it evades existing immunity elicited by exposure to earlier strains of the virus. In response, vaccine manufacturers have updated COVID-19 vaccines annually since 2022, though immune imprinting to the ancestral strain has blunted antibody responses to modern viral variants. In early 2025, the JN.1 subvariant LP.8.1 was dominant and manufacturers updated mRNA vaccine formulations to target LP.8.1 (LP.8.1 MV). However, by late 2025, other subvariants were dominant (XFG and NB.1.8.1) or emerging (e.g., PE.1.4, BA.3.2, PY.1.1.1) around the world. It is critical to understand the extent to which updated vaccine boosters elicit titers against both their target strain and recent variants. Further, it is important to quantify the extent to which immune imprinting continues to shape antiviral immune responses. Using pseudoviruses, we measured neutralizing antibody titers against a panel of 11 SARS-CoV-2 variants in serum samples from 36 adult participants in the United States before and approximately 1 month after LP.8.1 MV booster. We found that neutralizing antibody titers were substantially increased by the boost, with the greatest increases elicited against LP.8.1 and XFG. For the first time since 2022, post-boost titers were higher against the homologous vaccine target (LP.8.1) than against D614G (representing the ancestral strain). Combined, these results indicate that ancestral immune imprinting is mitigated to the greatest extent observed to date by LP.8.1 MV. Lastly, for a subset of participants, we measured neutralizing titers at approximately 4 months post-booster and found that LP.8.1-directed antibody titers were durable, with an estimated average half-life of approximately 66 days.

microbiology↗

bioRxiv2025

Antibody evasion and receptor binding of SARS-CoV-2 LP.8.1.1, NB.1.8.1, XFG, and related subvariants

SARS-CoV-2 continues to evolve, causing repeated waves of infections around the world. It is critical to understand the features of the virus that explain its growth advantages. Recently, the SARS-CoV-2 Omicron JN.1 subvariants KP.3.1.1 and XEC were outcompeted by later JN.1 progenies, most prominently LP.8.1 and LP.8.1.1. Other recent JN.1 subvariants, such as LF.7.2.1, which became prevalent in Asia, and MC.10.1, have also been under monitoring. Subsequently, NB.1.8.1 and XFG subvariants began increasing in prevalence, as well. We found that serum neutralizing antibody titers against LP.8.1, LP.8.1.1, LF.7, LF.7.2.1, MC.10.1 were similar to XEC in a cohort of 20 KP.2-based monovalent mRNA vaccine (KP.2 MV) recipients and in a cohort 20 adults who did not receive KP.2 MV. NB.1.8.1 and XFG were more evasive of serum neutralization than LP.8.1.1. We then characterized subvariant susceptibility to monoclonal antibody (mAb) neutralization using a panel of 12 mAbs spanning several epitopes on the SARS-CoV-2 spike, and found that LP.8.1 and XFG, MC.10.1 and NB.1.8.1, and LF.7.2.1 evade different classes of mAbs relative to earlier JN.1 subvariants, even if the tested polyclonal serum neutralizing antibody titers were not different overall. Next, we found that the receptor-binding affinity of LP.8.1 to ACE2 was the highest among the tested viruses, while that of LF.7.2.1 was lowest. Therefore, unlike most prior SARS-CoV-2 sublineage evolutionary trajectories, receptor-binding affinity, possibly reflecting enhanced transmissibility-and not increased antibody evasion-better explained the rise of LP.8.1, while the expansion of NB.1.8.1 and XFG again appear correlated with their enhanced antibody evasion.

microbiology↗

bioRxiv2025

Do Existing COVID-19 Vaccines Need to Be Updated in 2025?

COVID-19 vaccines have been updated each year since 2022 to improve protection against evolving SARS-CoV-2 variants. However, it is unclear whether a reformulation will be necessary for 2025. KP.2-based monovalent COVID-19 mRNA vaccines (KP.2 MV) were authorized for use in 2024, and they conferred substantial protection against hospitalizations caused by viral variants that emerged and dominated later, such as KP.3.1.1 and XEC. Today, LP.8.1 and its subvariant LP.8.1.1 have become dominant worldwide, particularly so in North America. Other variants, such as the LF.7 subvariant LF.7.2.1, have emerged with a growth advantage in Asia. To characterize the antigenicity of LP.8.1, LP.8.1.1, LF.7, LF.7.2.1, and another variant under monitoring, MC.10.1, we tested serum samples from 20 individuals who recently received KP.2 MV in neutralization assays against JN.1, KP.2, KP.3, KP.3.1.1, XEC, LP.8.1, LP.8.1.1, LF.7, LF.7.2.1, or MC.10.1 pseudoviruses. Serum neutralizing antibody titers against LP.8.1, LP.8.1.1, LF.7, LF.7.2.1, and MC.10.1 were comparable to those against KP.3.1.1 and XEC, indicating that LP.8.1.1 and other recently dominant subvariants are antigenically similar to their predecessors. Therefore, the currently authorized KP.2 MV may not need to be updated for 2025, if the vaccine manufacturers could demonstrate comparable immunogenicity for KP.2 MV and LP.8.1-based mRNA vaccines and, of course, in the absence of an antigenically divergent SARS-CoV-2 variant emerging.

microbiology↗

bioRxiv2024

Structure of a zoonotic H5N1 hemagglutinin reveals a receptor-binding site occupied by an auto-glycan

Highly pathogenic avian influenza has spilled into many mammals, most notably U.S. dairy cows with several dozen human breakthrough infections. Zoonotic crossovers, with hemagglutinins mutated to enhance viral ability to use human 2-6-linked sialic acid receptors versus avian 2-3-linked ones, highlight the pandemic risk. To gain insight into these crossovers, we determined the cryo-EM structure of hemagglutinin from the zoonotic H5N1 A/Texas/37/2024 strain (clade 2.3.4.4b) in complex with a previously reported neutralizing antibody. Surprisingly, we found that the receptor-binding site of this H5N1 hemagglutinin was already occupied by an 2-3-linked sialic acid and that this glycan emanated from asparagine N169 of a neighboring protomer on hemagglutinin itself. This structure thus highlights recognition by influenza hemagglutinin of an "auto"-2-3-linked sialic acid from N169, an N-linked glycan conserved in 95% of H5 strains, and adds "auto-glycan recognition" to the complexities surrounding H5N1 zoonosis. HighlightsO_LIWe report the structure of hemagglutinin from the zoonotic H5N1 strain A/Texas/37/2024 from clade 2.3.4.4b responsible for the current H5N1 outbreak C_LIO_LIStructural analysis revealed that each receptor-binding site of H5N1 A/Texas/37/2024 HA is bound to an "auto" sialic acid originating from glycan N169 on an adjacent protomer C_LIO_LIThis structure provides new aspects of receptor binding for a highly pathogenic strain of avian influenza, and raises questions about the impact of auto-binding sialic acid, especially with respect to zoonosis C_LI

immunology↗

bioRxiv2024

Optimizing a Human Monoclonal Antibody for Better Neutralization of SARS-CoV-2

SARS-CoV-2 has largely evolved to resist antibody pressure, with each successive viral variant becoming more and more resistant to serum antibodies in the population. This evolution renders all previously authorized anti-spike therapeutic monoclonal antibodies inactive, and it threatens the remaining pipelines against COVID-19. We report herein the isolation of a human monoclonal antibody with a broad but incomplete SARS-CoV-2 neutralization profile, but structural analyses and mutational scanning lead to the engineering of variants that result in greater antibody flexibility while binding to the viral spike. Three such optimized monoclonal antibodies neutralize all SARS-CoV-2 strains tested with much improved potency and breadth, including against subvariants XEC and LP.8.1. The findings of this study not only present antibody candidates for clinical development against COVID-19, but also introduce a unique engineering approach to improve antibody activity via increasing conformational flexibility.

microbiology↗

bioRxiv2024

KP.2-based monovalent mRNA vaccines robustly boost antibody responses to SARS-CoV-2

In response to the ongoing evolution of SARS-CoV-2, COVID-19 mRNA vaccines were recently updated to encode the spike protein of the KP.2 subvariant of the JN.1 sublineage. However, the immunogenicity of KP.2-based monovalent mRNA vaccines (KP.2 MV) has yet to be fully evaluated and reported, particularly against dominant and growing viral variants KP.3.1.1 and XEC, which bear some distinct mutations from KP.2. Here we report that KP.2 MV boosters elicit robust neutralizing antibody titers in a cohort of 16 healthy adult participants against all tested variants in pseudovirus neutralization assays. The highest post-boost geometric mean titers were against older variants D614G (17,293) and BA.5 (14,358), suggestive of immune imprinting, but the post-boost titers against currently dominant or growing viruses KP.3.1.1 (1,698) and XEC (1,721) were still robust. Fold-changes in titers were highest against recent JN.1 subvariants, including JN.1, KP.2, KP.3, KP.3.1.1, and XEC, (5.8-to-7.8-fold), compared to older variants D614G and BA.5 (1.6- and 2.5-fold), which suggests that KP.2 MV boosters have at least partially mitigated immune imprinting. Overall, these results show that KP.2 MV boosters elicit robust neutralizing antibodies against dominant SARS-CoV-2 viruses.

microbiology↗

bioRxiv2024

Antibody evasiveness of SARS-CoV-2 subvariants KP.3.1.1 and XEC

SARS-CoV-2 continues to evolve and spread around the world, and it remains critical to understand the functional consequences of mutations that lead to dominant viral variants. KP.3.1.1 is currently the most prevalent subvariant worldwide, while the recombinant subvariant XEC is exhibiting the fastest growth rate. Here we measured the in vitro neutralization of KP.3.1.1 and XEC by human sera, monoclonal antibodies, and soluble hACE2 receptor relative to their parental subvariants KP.3 and JN.1. KP.3.1.1 and XEC were slightly more resistant (1.3-1.6-fold) than KP.3 to serum neutralization, and the resultant antigenic map showed that the new subvariants are antigenically similar. Both also demonstrated greater resistance to neutralization by select monoclonal antibodies and soluble hACE2, all of which target the top of the viral spike. Our findings suggested that upward motion of the receptor-binding domain in spike is partially hindered by the N-terminal-domain mutations found KP.3.1.1 and XEC, thereby allowing these subvariants to better evade serum antibodies that target the viral spike when it is in the up position and thus having a growth advantage in the population.

microbiology↗

bioRxiv2024

Pemivibart is less active against recent SARS-CoV-2 JN.1 sublineages

Protection from COVID-19 vaccination is suboptimal in many immunocompromised individuals. In March 2024, the Food and Drug Administration issued an Emergency Use Authorization for pemivibart (Permagard/VYD222), an engineered human monoclonal antibody, for pre-exposure prophylaxis in this vulnerable population. However, SARS-CoV-2 has since evolved extensively, resulting in multiple Omicron JN.1 sublineages. We therefore evaluated the in vitro neutralizing activity of pemivibart against the prevalent forms of JN.1, including KP.2, KP.3, KP.2.3, LB.1, and, importantly, KP.3.1.1, which is now expanding most rapidly. A panel of VSV-based pseudoviruses representing major JN.1 sublineages was generated to assess their susceptibility to pemivibart neutralization in vitro. Structural analyses were then conducted to understand the impact of specific spike mutations on the virus-neutralization results. Pemivibart neutralized both JN.1 and KP.2 in vitro with comparable activity, whereas its potency was decreased slightly against LB.1, KP.2.3, and KP.3 but substantially against KP.3.1.1. Critically, the 50% inhibitory concentration of pemivibart against KP.3.1.1 was [~]6 {micro}g/mL, or [~]32.7 fold higher than that of JN.1 in our study. Structural analyses suggest that Q493E and the S31-deletion mutations in viral spike contribute to the antibody evasion, with the latter having a more pronounced effect. Our findings show that pemivibart has lost substantial neutralizing activity in vitro against KP.3.1.1, the most rapidly expanding lineage of SARS-CoV-2 today. Close monitoring of its clinical efficacy is therefore warranted. These results also highlight the imperative to expand our arsenal of preventive agents to protect millions of immunocompromised individuals who could not respond robustly to COVID-19 vaccines.

immunology↗

bioRxiv2024

Recurrent SARS-CoV-2 spike mutations confer growth advantages to select JN.1 sublineages

The recently dominant SARS-CoV-2 Omicron JN.1 has evolved into multiple sublineages, with recurrent spike mutations R346T, F456L, and T572I, some of which exhibit growth advantages, such as KP.2. We investigated these mutations in JN.1, examining their individual and combined effects on immune evasion, ACE2 receptor affinity, and in vitro infectivity. F456L increased resistance to neutralization by human sera, including those after JN.1 breakthrough infections, and by RBD class-1 monoclonal antibodies, significantly altering JN.1 antigenicity. R346T enhanced ACE2-binding affinity, without a discernible effect on serum neutralization. Individually, R346T and T572I modestly enhanced infectivity of each pseudovirus. Importantly, expanding sublineages such as KP.2 containing R346T, F456L, and V1104L, showed similar neutralization resistance as JN.1 with R346T and F456L, suggesting V1104L does not appreciably affect antibody evasion. Our findings illustrate how certain JN.1 mutations confer growth advantages in the population and could inform the design of the next COVID-19 vaccine booster.

microbiology↗

bioRxiv2024

Potent neutralization by a receptor binding domain monoclonal antibody with broad specificity for SARS-CoV-2 JN.1 and other variants

SARS-CoV-2 continues to be a public health burden, driven in-part by its continued antigenic diversification and resulting emergence of new variants. While increasing herd immunity, current vaccines, and therapeutics have improved outcomes for some; prophylactic and treatment interventions that are not compromised by viral evolution of the Spike protein are still needed. Using a rationally designed SARS-CoV-2 Receptor Binding Domain (RBD) - ACE2 fusion protein and differential selection process with native Omicron RBD protein, we developed a recombinant human monoclonal antibody (hmAb) from a convalescent individual following SARS-CoV-2 Omicron infection. The resulting hmAb, 1301B7 potently neutralized a wide range of SARS-CoV-2 variants including the original Wuhan and more recent Omicron JN.1 strain, as well as SARS-CoV. Structure determination of the SARS-CoV-2 EG5.1 Spike/1301B7 Fab complex by cryo-electron microscopy at 3.1[A] resolution demonstrates 1301B7 contacts the ACE2 binding site of RBD exclusively through its VH1-69 heavy chain, making contacts using CDRs1-3, as well as framework region 3 (FR3). Broad specificity is achieved through 1301B7 binding to many conserved residues of Omicron variants including Y501 and H505. Consistent with its extensive binding epitope, 1301B7 is able to potently diminish viral burden in the upper and lower respiratory tract and protect mice from challenge with Omicron XBB1.5 and Omicron JN.1 viruses. These results suggest 1301B7 has broad potential to prevent or treat clinical SARS-CoV-2 infections and to guide development of RBD-based universal SARS-CoV-2 prophylactic vaccines and therapeutic approaches.

immunology↗