Biology subjects

Korber, B.

Publications and source records attributed to Korber, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Impact of RNA modification and IL-12 boosts on mRNA-LNP vaccine-elicited CD8+ T cell responses

Development of effective HIV-1 vaccines requires strategies for inducing both CD8+ T cell and neutralizing antibody responses. Nucleoside-modified mRNA-lipid-nanoparticles (LNP) induce more potent antibody responses than unmodified mRNA-LNP vaccines, while unmodified mRNA is typically employed for CD8+ T cell-inducing vaccines. Here, we compared the abilities of differing ratios of unmodified versus modified mRNA expressing a SIV conserved-region CD8+ T cell immunogen co-administered with IL-12-encoding mRNA-LNP during boosting to induce CD8+ T cell and humoral responses in non-human primates, assessing responses in ChAdOx1-primed controls in parallel. Serial priming and boosting with fully-unmodified mRNA elicited higher-magnitude, more CD8-biased T cell responses than fully-modified mRNA, that were durably maintained after the IL-12-encoding mRNA boosts. Inclusion of 30% nucleoside-modified mRNA enhanced antibody titers, suggesting potential benefits to a mixed-composition vaccine.

immunology↗

bioRxiv2026

Shared Maturation Pathways of HIV-1 Envelope-reactive V3-glycan bnAb Lineages in Human and Rhesus Macaque

ABSTRACTUnderstanding broadly neutralizing antibody (bnAb) lineage development in rhesus macaques (RMs) infected with Simian-HIV (SHIV) may inform HIV-1 vaccine designs. We analyzed HIV-1 envelope-antibody coevolution in 18 RMs infected by SHIV.BG505 (subtype A) and found highly conserved patterns of antibody recognition and Env escape, including in three animals that developed V3-glycan bnAbs. From one RM with V3-glycan targeted plasma breadth, we isolated 203 members of a single clonal Ab lineage designated DH1030. DH1030 Abs demonstrated striking genetic, functional and structural similarities with the human V3-glycan bnAb lineage DH270, which was isolated from an individual with subtype C HIV-1 CH848 infection. Notably, human-DH270 and macaque-DH1030 bnAbs shared early improbable mutations in HCDR2 that were critical for bnAb development. Thus, key improbable mutations and convergent patterns of antibody evolution and epitope recognition were shared across primate species and distinct HIV-1 subtypes, findings that may be leveraged in new HIV-1 vaccine designs. ONE SENTENCE SUMMARYBroadly neutralizing antibodies targeting HIV-1 envelope surface protein develop via a common maturation pathway across primate phylogeny.

immunology↗

bioRxiv2025

Contemporary HIV-1 envelope pseudovirus panels for detecting and assessing B cell lineages with broadly neutralizing antibody potential

Although a protective HIV-1 vaccine has not yet been realized, significant progress has been made in vaccine designs that trigger B cell lineages with potential to produce broadly neutralizing antibodies (bnAbs). Advancing these strategies by optimizing vaccine boosting regimens requires early detection of maturing antibodies with neutralizing activity against native envelope glycoprotein (Env) trimers and streamlined strategies to identify antibodies as they begin to manifest desired levels of breadth and potency. Thus, we designed three types of pseudovirus screening panels based on Envs of contemporary HIV-1 isolates to facilitate detection of bnAb lineages that are on favorable trajectories during a vaccination course. The panels were selected from Tier 2 Transmitted Founder Lineage (TFL) HIV-1 Envs from placebo participants in the Antibody Mediated Prevention (AMP) efficacy trials. Using 15 bnAbs to evaluate the neutralization sensitivity of the viruses, we selected 8-member bnAb class-specific panels most sensitive to bAbs representing their class: V2-apex, V3-glycan, CD4-receptor binding site (CD4bs), Membrane-Proximal External Region (MPER), or fusion peptide (FP). Next, we combined the most sensitive viruses among the class-specific panels to create a 12-virus panel to enable optimal detection of low-titer bnAb activity across epitope specificities. Finally, as HIV-1 continues to evolve greater levels of antigenic diversity and as current global pseudoviruses bnAb panels rely on viruses collected more than twenty years ago, we showed the importance of using contemporary viral panels to assess bnAb breadth and potency and designed a 12-virus panel representative of the spectrum neutralization profiles among AMP placebo viruses. We characterized pseudoviruses bearing each selected Env using standardized human sera to confirm their Tier 2 status and biological relevance. These updated panels enable sensitive screening of neutralization activity in vaccine studies and can also provide a realistic assessment of the expected breadth and potency of maturing responses against contemporary HIV-1 Envs. AUTHOR SUMMARYA primary goal of HIV-1 vaccine research is to elicit neutralizing antibodies that can prevent infection, but HIV-1 is highly variable and so stimulating responses that can work effectively against the diverse array of HIV-1 variants remains an unsolved challenge. However, the HIV-1 vaccine field has made significant progress in terms of stimulating B cell lineages that produce antibodies known to have features able to ultimately generate potent broadly neutralizing antibodies. Inducing such precursor B cells is just the first step, as B cells need evolve in response to an antigenic stimulus through a process called affinity maturation to acquire potency and breadth against the natural diversity of circulating HIV-1 strains. The next step is to discover and optimize vaccine strategies that will selectively induce such maturation. To facilitate this work, we have designed panels of biologically relevant, contemporary HIV-1 Envelope pseudotyped viruses that will enable sensitive detection of neutralizing antibodies in human and animal vaccine studies. We also have defined a small screening panel intended to provide a quick but realistic assessment of the potential of a vaccine-stimulated antibody response or a monoclonal antibody being evaluated for clinical use to effectively counter and block currently circulating HIV-1 variants.

immunology↗

bioRxiv2025

Vaccine Elicitation of HIV-1 Neutralizing Antibodies Against Both V2 Apex and Fusion Peptide in Rhesus Macaques

Broadly neutralizing antibodies targeting multiple sites of HIV-1 Env vulnerability can be induced by infection, but simultaneous elicitation of neutralizing antibodies (NAbs) against multiple epitopes has not yet been achieved by vaccination. In this study, we designed a dual-epitope vaccine targeting both fusion peptide (FP) and V2 apex and evaluated its capacity to induce NAbs against both epitopes in rhesus macaques. This vaccine combined an FP conjugate with a cocktail of engineered Env trimers with enhanced V2 apex recognition and increased antigen retention in lymph nodes. Immunization of macaques with the dual-epitope vaccine elicited >1000-fold higher autologous tier 2-neutralization titers than the wildtype Env trimer and enhanced heterologous NAb breadth. Both FP and V2-apex monoclonal antibodies (mAb) were isolated from immunized macaques and showed heterologous neutralization with genetic and structural signatures that were similar to well-characterized FP and V2 apex bNAbs, although the V2 apex mAbs showed incomplete maturation. These results demonstrate proof-of-concept for simultaneous vaccine elicitation of NAbs against multiple sites of Env vulnerability, which will likely be critical for an effective HIV-1 vaccine. HIGHLIGHTSO_LIDesigned a dual-epitope vaccine targeting both fusion peptide (FP) and V2 apex C_LIO_LIV2-SET Env trimer conferred higher binding of V2 apex bNAbs, longer retention in draining lymph nodes, and >1000-fold higher induction of autologous neutralization titers compared with wildtype Env trimer C_LIO_LIDual-epitope vaccine enhanced serum tier 2 neutralization breadth C_LIO_LIDual-epitope vaccine elicited FP- and V2 apex-specific neutralizing mAbs with genetic signatures similar to well-characterized FP and V2 apex bNAbs C_LI

immunology↗

bioRxiv2025

A conserved region T-cell vaccine for Sarbecoviruses

The rapid development of vaccines was a critical part of the global response to the COVID-19 pandemic. SARS-CoV-2 (a Sarbecovirus and member of the Betacoronavirus genus responsible for the pandemic) virus was first detected in Wuhan, China in late 2019. Effective mRNA vaccines based on the viral Spike protein were designed from the earliest isolates and available by December of 2020. SARS-CoV-2 has continued to evolve in the human population, accruing neutralizing antibody resistance mutations that have necessitated updating the vaccine periodically to better match contemporary variants. Neutralizing antibody cross-reactivity is generally very limited among the diverse members of the betacoronavirus genus that are of clinical importance in people. Here, we present an alternative vaccine strategy based on eliciting T-cell responses targeting four highly conserved regions shared across the betacoronavirus proteomes. We hypothesized that cross-reactive responses to these regions could temper disease severity. Focusing immune responses on highly conserved epitopes could be beneficial as SARS-CoV-2 continues to evolve, or if a novel betacoronavirus should enter the human population. Vaccination with these highly conserved regions induced robust T-cell responses in mice and rhesus macaques. Vaccinated hamsters were significantly protected against weight loss and lung inflammation after challenge with the SARS-CoV-2 Omicron variant. After a SARS-CoV-2 Delta challenge in rhesus macaques, 3 out of 4 animals in the control group had infectious virus in their bronchoalveolar lavage samples, while the 4 animals in the vaccinated group did not.

immunology↗

bioRxiv2025

Env-antibody coevolution identifies B cell priming as the principal bottleneck to HIV-1 V2 apex broadly neutralizing antibody development

Broadly neutralizing antibodies (bNAbs) are rarely elicited during HIV-1 infection. To identify obstacles to bNAb development, we longitudinally studied 122 rhesus macaques infected by one of 16 different simian-human immunodeficiency viruses (SHIVs). We identified V2 apex as the most common bNAb target and a subset of Envs that preferentially elicited these antibodies. In 10 macaques, we delineated Env-antibody coevolution from B cell priming to bNAb development. Antibody phylogenies revealed permissive developmental pathways guided by evolving Envs that contained few mutations in or near the V2 apex C-strand, which were a sensitive indicator of apex-targeted responses. The absence of such mutations reflected a failure in bNAb priming. These results indicate that efficiency of B cell priming, and not complexities in Env-guided affinity maturation, is the primary obstacle to V2 apex bNAb elicitation in SHIV-infected macaques and identify specific HIV-1 Envs to advance as novel vaccine platforms. One sentence summaryB cell priming is the primary bottleneck to HIV-1 V2 apex bNAb elicitation.

immunology↗

bioRxiv2024

Transient glycan-shield reduction induces CD4-binding site broadly neutralizing antibodies in SHIV-infected macaques

Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 CD4-binding site (CD4bs) occur infrequently in macaques and humans and have not been reproducibly elicited in any outbred animal model. To address this challenge, we first isolated RHA10, an infection-induced rhesus bNAb with 51% breadth. The cryo-EM structure of RHA10 with HIV-1 envelope (Env) resembled prototypic human CD4bs bNAbs with CDR-H3-dominated binding. Env-antibody co-evolution revealed transient elimination of two Env CD4bs-proximal glycans near the time of RHA10-lineage initiation, and these glycan-deficient Envs bound preferentially to early RHA10 intermediates, suggesting glycan deletions in infecting SHIVs could consistently induce CD4bs bNAbs. To test this, we constructed SHIV.CH505.D3 with CD4bs-proximal glycan deletions. Infection of 10 macaques resulted in accelerated CD4bs bNAb responses in 8, compared with 1 of 115 control macaques. Glycan hole-based immunofocusing coupled to Env-Ab co-evolution can consistently induce broad CD4bs responses in macaques and thus serve as a model for HIV vaccine design. HighlightsO_LIOut of 115 wildtype HIV-1 Env bearing SHIV infected macaques, only one macaque (T681) developed CD4bs bNAbs C_LIO_LICD4bs bNAbs in macaque T681 recognized Env similarly to previously described CDR-H3 dominated human CD4bs bNAbs and exhibited comparable breadth and potency C_LIO_LITransient CD4bs-proximal glycan deletions in macaque T681 preceded bNAb induction C_LIO_LIA novel SHIV with CD4bs-proximal glycan holes and enhanced CD4bs antigenicity immunofocused B cell responses to the CD4bs and elicited cross-clade neutralizing responses in 80% of macaques C_LI

microbiology↗

bioRxiv2024

A Comprehensive Engineering Strategy Improves Potency and Manufacturability of a Near Pan-neutralizing Antibody Against HIV

Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing cGMP manufacturing capability. Here we report the engineering of an anti-CD4 binding-site (CD4bs) bnAb, N49P9.3, purified from the plasma of an HIV elite-neutralizer. Through a series of rational modifications we produced a variant that demonstrates: enhanced potency; superior antiviral activity in combination with other bnAbs; low polyreactivity; and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.

bioengineering↗

bioRxiv2024

SARS-CoV-2 Omicron lineage XBB spike structures, conformations, antigenicity, and receptor recognition

A recombinant lineage of the SARS-CoV-2 Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryo-EM structures of XBB.1.5, XBB.1.16, EG.5 and EG.5.1 spike (S) ectodomains to reveal reinforced 3-RBD-down receptor inaccessible closed states mediated by interprotomer receptor binding domain (RBD) interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters including stability, receptor binding and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape.

biochemistry↗

bioRxiv2023

Engineering immunogens that select for specific mutations in HIV broadly neutralizing antibodies

Vaccine development targeting rapidly evolving pathogens such as HIV-1 requires induction of broadly neutralizing antibodies (bnAbs) with conserved paratopes and mutations, and, in some cases, the same Ig-heavy chains. The current trial-and-error search for immunogen modifications that improve selection for specific bnAb mutations is imprecise. To precisely engineer bnAb boosting immunogens, we used molecular dynamics simulations to examine encounter states that form when antibodies collide with the HIV-1 Envelope (Env). By mapping how bnAbs use encounter states to find their bound states, we identified Env mutations that were predicted to select for specific antibody mutations in two HIV-1 bnAb B cell lineages. The Env mutations encoded antibody affinity gains and selected for desired antibody mutations in vivo. These results demonstrate proof-of-concept that Env immunogens can be designed to directly select for specific antibody mutations at residue-level precision by vaccination, thus demonstrating the feasibility of sequential bnAb-inducing HIV-1 vaccine design.

immunology↗

bioRxiv2023

Neutralization Escape by SARS-CoV-2 Omicron Subvariant BA.2.86

The continued evolution of SARS-CoV-2 may lead to evasion of vaccine immunity and natural immunity. A highly mutated Omicron variant BA.2.86 has recently been identified with over 30 amino acid changes in Spike compared with BA.2 and XBB.1.5. As of September 4, 2023, BA.2.86 has been identified in 37 sequences from 10 countries, which is likely an underestimate due to limited surveillance. The ability of BA.2.86 to evade NAbs compared with other currently circulating Omicron variants remains unknown. Our data show that NAb responses to BA.2.86 were lower than to BA.2 but were comparable or slightly higher than to the current circulating recombinant variants XBB.1.5, XBB.1.16, EG.5, EG.5.1, and FL.1.5.1.

microbiology↗

bioRxiv2023

Mutational basis of serum cross-neutralization profiles elicited by infection or vaccination with SARS-CoV-2 variants

A series of SARS-CoV-2 variants emerged during the pandemic under selection for neutralization resistance. Convalescent and vaccinated sera show consistently different cross-neutralization profiles depending on infecting or vaccine variants. To understand the basis of this heterogeneity, we modeled serum cross-neutralization titers for 165 sera after infection or vaccination with historically prominent lineages tested against 18 variant pseudoviruses. Cross-neutralization profiles were well captured by models incorporating autologous neutralizing titers and combinations of specific shared and differing mutations between the infecting/vaccine variants and pseudoviruses. Infecting/vaccine variant-specific models identified mutations that significantly impacted cross-neutralization and quantified their relative contributions. Unified models that explained cross-neutralization profiles across all infecting and vaccine variants provided accurate predictions of holdout neutralization data comprising untested variants as infecting or vaccine variants, and as test pseudoviruses. Finally, comparative modeling of 2-dose versus 3-dose mRNA-1273 vaccine data revealed that the third dose overcame key resistance mutations to improve neutralization breadth. HIGHLIGHTSO_LIModeled SARS-CoV-2 cross-neutralization using mutations at key sites C_LIO_LIIdentified resistance mutations and quantified relative impact C_LIO_LIAccurately predicted holdout variant and convalescent/vaccine sera neutralization C_LIO_LIShowed that the third dose of mRNA-1273 vaccination overcomes resistance mutations C_LI

immunology↗

bioRxiv2023

Waning Immunity Against XBB.1.5 Following Bivalent mRNA Boosters

The SARS-CoV-2 Omicron variant has continued to evolve. XBB is a recombinant between two BA.2 sublineages, XBB.1 includes the G252V mutation, and XBB.1.5 includes the G252V and F486P mutations. XBB.1.5 has rapidly increased in frequency and has become the dominant virus in New England. The bivalent mRNA vaccine boosters have been shown to increase neutralizing antibody (NAb) titers to multiple variants, but the durability of these responses remains to be determined. We assessed humoral and cellular immune responses in 30 participants who received the bivalent mRNA boosters and performed assays at baseline prior to boosting, at week 3 after boosting, and at month 3 after boosting. Our data demonstrate that XBB.1.5 substantially escapes NAb responses but not T cell responses after bivalent mRNA boosting. NAb titers to XBB.1 and XBB.1.5 were similar, suggesting that the F486P mutation confers greater transmissibility but not increased immune escape. By month 3, NAb titers to XBB.1 and XBB.1.5 declined essentially to baseline levels prior to boosting, while NAb titers to other variants declined less strikingly.

immunology↗

bioRxiv2022

SARS-CoV-2 variant transition dynamics are associated with vaccination rates, number of co-circulating variants, and natural immunity

BackgroundThroughout the COVID-19 pandemic, the SARS-CoV-2 virus has continued to evolve, with new variants outcompeting existing variants and often leading to different dynamics of disease spread. MethodsIn this paper, we performed a retrospective analysis using longitudinal sequencing data to characterize differences in the speed, calendar timing, and magnitude of 13 SARS-CoV-2 variant waves/transitions for 215 countries and sub-country regions, between October 2020 and October 2022. We then clustered geographic locations in terms of their variant behavior across all Omicron variants, allowing us to identify groups of locations exhibiting similar variant transitions. Finally, we explored relationships between heterogeneity in these variant waves and time-varying factors, including vaccination status of the population, governmental policy, and the number of variants in simultaneous competition. FindingsThis work demonstrates associations between the behavior of an emerging variant and the number of co-circulating variants as well as the demographic context of the population. We also observed an association between high vaccination rates and variant transition dynamics prior to the Mu and Delta variant transitions. InterpretationThese results suggest the behavior of an emergent variant may be sensitive to the immunologic and demographic context of its location. Additionally, this work represents the most comprehensive characterization of variant transitions globally to date. FundingLaboratory Directed Research and Development (LDRD), Los Alamos National Laboratory Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 variants with a selective advantage are continuing to emerge, resulting in variant transitions that can give rise to new waves in global COVID-19 cases and changing dynamics of disease spread. While variant transitions have been well studied individually, more work is needed to better understand how variant transitions have occurred in the past and how properties of these transitions may relate to vaccination rates, natural immunity, and population demographics. Added value of this studyOur retrospective study integrates metadata based on 12.8 million SARS-CoV-2 sequences available through the Global Initiative on Sharing All Influenza Data (GISAID) with clinical and demographic data to characterize heterogeneity in variant waves/transitions across the globe throughout the COVID-19 pandemic. We demonstrate that properties of the variant transitions (e.g., speed, timing, and magnitude of the transition) are associated with vaccination rates, prior COVID-19 cases, and the number of co-circulating variants in competition. Implications of all the available evidenceOur results indicate that there is substantial heterogeneity in how an emerging variant may compete with other viral variants across locations, and suggest that each locations contemporaneous immunologic landscape may play a role in these interactions.

bioinformatics↗

bioRxiv2022

Substantial Neutralization Escape by the SARS-CoV-2 Omicron Variant BQ.1.1

Omicron BA.5 has been the globally dominant SARS-CoV-2 variant and has demonstrated substantial neutralization escape compared with prior variants. Additional Omicron variants have recently emerged, including BA.4.6, BF.7, BA.2.75.2, and BQ.1.1, all of which have the Spike R346T mutation. In particular, BQ.1.1 has rapidly increased in frequency, and BA.5 has recently declined to less than half of viruses in the United States. Our data demonstrate that BA.2.75.2 and BQ.1.1 escape NAbs induced by infection and vaccination more effectively than BA.5. BQ.1.1 NAb titers were lower than BA.5 NAb titers by a factor of 7 in two cohorts of individuals who received the monovalent or bivalent mRNA vaccine boosters. These findings provide the immunologic context for the rapid increase in BQ.1.1 prevalence in regions where BA.5 is dominant and have implications for both vaccine immunity and natural immunity.

immunology↗

bioRxiv2022

Structural basis for breadth development in a HIV-1 neutralizing antibody

Antibody affinity maturation enables adaptive immune responses to a wide range of pathogens. In some individuals broadly neutralizing antibodies develop to recognize rapidly mutating pathogens with extensive sequence diversity. Vaccine design for pathogens such as HIV-1 and influenza have therefore focused on recapitulating the natural affinity maturation process. Here, we determined structures of antibodies in complex with HIV-1 Envelope for all observed members and ancestral states of a broadly neutralizing HIV-1 antibody clonal B cell lineage. These structures track the development of neutralization breadth from the unmutated common ancestor and define affinity maturation at high spatial resolution. By elucidating contacts mediated by key mutations at different stages of antibody development we have identified sites on the epitope-paratope interface that are the focus of affinity optimization. Thus, our results identify bottlenecks on the path to natural affinity maturation and reveal solutions for these that will inform immunogen design aimed at eliciting a broadly neutralizing immune response by vaccination. SummarySomatic hypermutation drives affinity maturation of germline-encoded antibodies leading to the development of their pathogen neutralization function1. Rational vaccine design efforts that aim to recapitulate affinity maturation rely on information from antibodies elicited and matured during natural infection. High-throughput next generation sequencing and methods for tracing antibody development have allowed close monitoring of the antibody maturation process. Since maturation involves both affinity-enhancing and affinity-independent diversification, the precise effect of each observed mutation, their role in enhancing affinity to antigens, and the order in which the mutations accumulated are often unclear. These gaps in knowledge most acutely hinder efforts directed at difficult targets such as pan-HIV, pan-Influenza, and pan-Coronavirus vaccines. In HIV-1 infection, antibody maturation over several years is required to achieve neutralization breadth. Here, we determined structures of antibodies in complex with HIV-1 Envelope trimers for all observed members and ancestral states of a broadly neutralizing HIV-1 antibody clone to examine affinity maturation as neutralization breadth developed from the unmutated common ancestor. Structural determination of epitope-paratope interfaces revealed details of the contacts evolving over a timescale of several years. Structures along different branches of the clonal lineage elucidated differences in the branch that led to broad neutralization versus off-track paths that culminated in sub-optimal neutralization breadth. We further determined structures of the evolving Envelope revealing details of the virus-antibody co-evolution through visualization of how the virus constructs barriers to evade antibody-mediated neutralization and the mechanisms by which the developing antibody clone circumvents these barriers. Together, our structures provide a detailed time-resolved imagery of the affinity maturation process through atomic level descriptions of virus-antibody co-evolution leading to broad HIV neutralization. While the findings from our studies have direct relevance to HIV-1, the principles of affinity optimization and breadth development elucidated in our study should have broad relevance to other pathogens.

immunology↗

bioRxiv2022

Characterization of SARS-CoV-2 Omicron BA.2.75 clinical isolates

The prevalence of the Omicron subvariant BA.2.75 is rapidly increasing in India and Nepal. In addition, BA.2.75 has been detected in at least 34 other countries and is spreading globally. However, the virological features of BA.2.75 are largely unknown. Here, we evaluated the replicative ability and pathogenicity of BA.2.75 clinical isolates in Syrian hamsters. Although we found no substantial differences in weight change among hamsters infected with BA.2, BA.5, or BA.2.75, the replicative ability of BA.2.75 in the lungs was higher than that of BA.2 and BA.5. Of note, BA.2.75 caused focal viral pneumonia in hamsters, characterized by patchy inflammation interspersed in alveolar regions, which was not observed in BA.5-infected hamsters. Moreover, in competition assays, BA.2.75 replicated better than BA.5 in the lungs of hamsters. These results suggest that BA.2.75 can cause more severe respiratory disease than BA.5 and BA.2 and should be closely monitored.

microbiology↗

bioRxiv2022

Multiple lineages of Monkeypox virus detected in the United States, 2021-2022

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of Monkeypox virus (MPXV) among nine 2021 and 2022 U.S. monkeypox cases. A 2021 case was highly similar to the 2022 MPXV outbreak variant, suggesting a common ancestor. Analysis of mutations among these two lineages revealed an extreme preference for GA-to-AA mutations indicative of APOBEC3 cytosine deaminase activity that was shared among West African MPXV since 2017 but absent from Congo Basin lineages. Poxviruses are not thought to be subject to APOBEC3 editing; however, these findings suggest APOBEC3 activity has been recurrent and dominant in recent West African MPXV evolution.

genomics↗