Biology subjects

Harvey, R.

Publications and source records attributed to Harvey, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Emergence and antigenic characterisation of influenza A(H3N2) viruses with hemagglutinin substitutions N158K and K189R during the 2024/25 influenza season

BackgroundSeasonal human influenza viruses can escape from antibody-mediated neutralization when amino acid changes occur in the hemagglutinin protein. Routine surveillance identified circulation of an A(H3N2) virus variant in the Netherlands with amino acid substitutions at hemagglutinin positions 158 and 189. These amino acid positions were previously responsible for antigenic change of influenza A(H3N2) viruses and potentially lead to escape of this variant from vaccine-mediated immunity. AimTo characterize the emergence and antigenic properties of N158K and K189R double substitution virus variants. MethodsWe analyzed the geographical and temporal dynamics of the double-substitution variant using a phylogeographic approach and used hemagglutination inhibition assays and antigenic cartography methods to map its antigenic properties. ResultsA(H3N2) viruses carrying K189R were first detected in Guatemala in June 2024, before subsequently gaining the N158K substitution, which was intially detected in Colombia in November 2024, followed by detection in the Netherlands in December 2024. However, detections within Europe remained almost entirely confined to the Netherlands. The proportion of viruses carrying the N158K and K189R substitutions increased to 16% - 24% per collection week of sequenced Dutch viruses during the peak of the epidemic of the 2024-2025 respiratory season. Antigenic characterization of viruses with N158K and K189R substitutions indicated that these are antigenically distinct from the A(H3N2) components of 2025-2026 Northern Hemisphere vaccines, showing 8-192-fold reduction in hemagglutination inhibition titers with antisera against the vaccine strain compared to antisera against the homologous virus. ConclusionsInfluenza A(H3N2) viruses with N158K and K189R escaped recognition by antibodies raised against the 2024-2025 and 2025/2026 Northern Hemipshere vaccine strains in hemagglutination inhibition assays. These variants circulated widely in the Netherlands during the 2024-2025 influenza season, raising concerns about reduced vaccine-mediated protection if such variants would spread more broadly during 2025-2026 Northern Hemipshere season.

microbiology↗

bioRxiv2025

Spillover of H5 influenza viruses to vampire bats at the marine-terrestrial interface

The highly pathogenic H5N1 avian influenza A virus (IAV) clade 2.3.4.4b has spread globally and spilled over into multiple mammalian species, raising concerns about its pandemic potential. In late 2022, clade 2.3.4.4b viruses devastated seabird and marine mammal populations along the Pacific coast of South America. Here, we report the first evidence of H5 IAV infections in wild bats globally, focusing on common vampire bats (Desmodus rotundus) in coastal areas of Peru. Longitudinal serological screening, stable isotope analysis and metabarcoding revealed repeated exposures to H5 IAVs in vampire bats which feed on coastal wildlife species heavily impacted by the 2.3.4.4b epizootic, but no evidence of infection in populations without access to marine prey. We further report bat gene flow between IAV-exposed and IAV-naive populations, and IAV infections in a vampire bat colony that fed on both marine and terrestrial livestock prey, providing insights into how future IAV epizootics might spread spatially within bats and between marine and terrestrial ecosystems if a bat reservoir were established. Immunohistochemistry demonstrated that the H5 haemagglutinin protein binds to the upper respiratory tract of vampire bats, suggesting bat tissue susceptibility to H5 IAVs. Finally, vampire bat-derived kidney, liver, and lung cells supported entry, replication, and egress of avian and mammalian 2.3.4.4b viruses, confirming cellular infectivity. These results illustrate how combining ecological inference and experimental virology can pinpoint the species origins and biological significance of viral spillover at species interfaces. Recurrent exposures from marine wildlife, tissue and cellular susceptibility to H5N1 IAVs, and connections to other IAV-susceptible terrestrial mammals establish the prerequisite conditions for vampire bats to spread IAVs between marine and terrestrial environments or to form a novel reservoir of highly pathogenic IAVs.

ecology↗

bioRxiv2025

Post-infection pig and ferret antisera show similar antigenic profiles for human influenza A(H1N1pdm09) viruses

BackgroundMonitoring antigenic drift in human influenza A viruses is essential for vaccine strain selection and ensuring protection against circulating strains. Antigenic drift is traditionally assessed using ferret antisera, which provide monospecific responses, and human vaccinee sera, which reflect exposure to multiple antigens. In this study we evaluated the pig as an alternative source of antisera to study antigenic drift compared to immune responses in ferrets and humans. We included seasonal influenza A(H1N1pdm09) human viruses that had shown different antigenic characteristics when using ferret or human antisera. MethodsPairs of pigs were inoculated with six human A(H1N1)pdm09 viruses circulating between 2019 and 2023, a period of marked antigenic drift. Pig and ferret antisera were analysed by hemagglutination inhibition (HI) and virus neutralization (VN) assays. ResultsPigs were successfully infected with all strains, shedding virus and producing antibody responses, confirming their susceptibility to human influenza A viruses. Antigenic reactivity of pig antisera was qualitatively comparable to ferret antisera in both HI and VN assays, although maximum homologous antibody titres were significantly higher in ferrets. The antisera raised against viruses in circulation in 2019 and before, exempified by A/Guangdong-Maonan/SWL1536/2019, clade 5a.1, were clearly differentiated by both ferret and pig antisera from those in clade 5a.2 and its derivatives that became predominant. ConclusionsFerrets and pigs showed comparable responses and both distinguished clade 5a.1 from clade 5a.2. However, neither model recognised antigenically drifted variants from 2019-2022, including subclades 5a.2-C, 5a.2a-C.1/C.1.9, and .5a.2a.1-C.1.1/D, which were distinguishable using human post-vaccination antisera.

immunology↗

bioRxiv2025

Near real-time data on the human neutralizing antibody landscape to influenza virus to inform vaccine-strain selection in September 2025

The hemagglutinin of human influenza virus evolves rapidly to erode neutralizing antibody immunity. Twice per year, new vaccine strains are selected with the goal of providing maximum protection against the viruses that will be circulating when the vaccine is administered [~]8-12 months in the future. To help inform this selection, here we quantify how the antibodies in recently collected human sera neutralize viruses with hemagglutinins from contemporary influenza strains. Specifically, we use a high-throughput sequencing-based neutralization assay to measure how 188 human sera collected from Oct 2024 to April 2025 neutralize 140 viruses representative of the H3N2 and H1N1 strains circulating in humans as of the summer of 2025. This data set, which encompasses 26,148 neutralization titer measurements, provides a detailed portrait of the current human neutralizing antibody landscape to influenza A virus. The full data set and accompanying visualizations are available for use in vaccine development and viral forecasting.

microbiology↗

bioRxiv2025

Integrative modeling of seasonal influenza evolution via AI-powered antigenic cartography

Seasonal influenza viruses evade host immunity through rapid antigenic evolution. Antigenicity is assessed by serological assays and typically visualized as antigenic maps, which represent antigenic differences among virus strains. However, conventional maps cannot directly infer the antigenicity of unexamined variants from their genotypes. Here, we present PLANT, a protein language model that projects influenza A/H3N2 viruses onto an antigenic map using HA protein sequences. Using PLANT-based cartography, we show that (i) H3N2 antigenic evolution accelerates during periods of disrupted global circulation, (ii) antigenic novelty accounts for a substantial portion of viral fitness advantage, and (iii) vaccine strains are often antigenically distant from circulating viruses. We further propose a PLANT-based framework for selecting vaccine strains with improved antigenic match than the WHO-recommended strains. This study provides a statistical foundation for integrated modeling of viral genotype, antigenicity, and fitness, offering quantitative insights into seasonal influenza virus evolution and supporting rational vaccine design.

microbiology↗

bioRxiv2025

SARS-CoV-2 envelope protein induces LC3 lipidation via the V-ATPase-ATG16L1 axis

Coronaviruses encode envelope (E), a structural component of the virion that is important for assembly and egress. E has proton channel activity that prevents premature rearrangement of the spike glycoprotein as virions encounter acidic compartments as they exit the cell. How infected cells respond to this pH disruption during coronavirus infection is unknown. Here we show that SARS-CoV-2 E ion channel activity triggers the proton pump V-ATPases to recruit the ATG16L1 complex during infection. This results in ATG8 molecules such as LC3B decorating perturbed compartments. This recruitment of autophagy machinery does not inhibit viral replication, rather SARS-CoV-2 exploits this response. Inhibition of the V-ATPase/ATG16L1 interaction using the Salmonella effector SopF inhibits SARS-CoV-2 replication. Careful distinction between use of the autophagic machinery from canonical macroautophagy is required in order to better understand coronavirus replication and for rational targeting of any potential host-directed therapies.

cell biology↗

bioRxiv2024

A systematic review of professional society-backed biology education DEI research: The groups, research methods, and levels of analyses comprising the field

This integrative literature review analyzes the corpus of biology education research published in the main biology education journals of major professional societies. The goal of this analysis is to determine which approaches (including groups of focus, research methods, and settings/perspectives) from social science fields (i.e., psychology, sociology, and anthropology) are utilized in published peer-reviewed biology education research relating to diversity, equity and inclusion (DEI). Scoping how social science approaches are used in this area is important to understanding whether biology education research could benefit from complementary approaches that might advance praxis. This analysis found that research informing the biology education community draws heavily from psychological perspectives that are overwhelmingly not disaggregated (78% of articles identifying a group used a lumped together one), are by far more quantitative (58% used survey, 26% grades, 20% school data) than qualitative (17% used interview, 10% observation), and did not (72%) adopt structural approaches. The addition of missing contributions from social science is critical to advancing interventions to broaden STEM participation given that merging paradigms can offer more robust, multi-level explanations for observed phenomena. This has important implications for education, biology education, biology education research, social science, and research in related STEM fields.

scientific communication and education↗

bioRxiv2024

Accurate evaluation of live-virus microneutralisation for SARS-CoV-2 variant JN.1

Emerging SARS-CoV-2 variants require rapid assessments of pathogenicity and evasion of existing immunity to inform policy. A crucial component of these assessments is accurate estimation of serum neutralising antibody titres using cultured live virus isolates. Here, we report our updated culture methods for Omicron sub-variant JN.1 using Caco-2 cells and the subsequent evaluation of neutralising antibody titres (nAbTs) in recipients of BNT162b2-XBB.1.5 monovalent and the Ancestral/BA.5 containing bivalent vaccines. We compared culture of JN.1 in either Vero V1 cells or Caco-2 cells, finding culture in Vero V1 either resulted in low-titre stocks or induced crucial mutations at the Spike furin cleavage site. Using the sequence-clean culture stocks generated in Caco-2 cells, we assessed serum samples from 71 healthy adults eligible for a COVID-19 vaccination given as a 5th dose booster: all participants had detectable nAbs against JN.1 prior to vaccination, with baseline/pre-existing nAbTs between both vaccine groups comparable (p = 0.240). However, nAbTs against JN.1 post-vaccination were 2.6-fold higher for recipients of the monovalent XBB1.5 vaccine than the BA.4/5 bivalent vaccine (p<0.001). Regular re-appraisal of methods involved in the evaluation of new variants is required to ensure robust data are used to underpin crucial severity assessments as variants arise and vaccine strain selection decisions.

microbiology↗

bioRxiv2023

Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.

immunology↗

bioRxiv2022

Emergence of new subgenomic mRNAs in SARS-CoV-2

Two mutations occurred in SARS-CoV-2 early during the COVID-19 pandemic that have come to define circulating virus lineages1: first a change in the spike protein (D614G) that defines the B.1 lineage and second, a double substitution in the nucleocapsid protein (R203K, G204R) that defines the B.1.1 lineage, which has subsequently given rise to three Variants of Concern: Alpha, Gamma and Omicron. While the latter mutations appear unremarkable at the protein level, there are dramatic implications at the nucleotide level: the GGG[->]AAC substitution generates a new Transcription Regulatory Sequence (TRS) motif, driving SARS-CoV-2 to express a novel subgenomic mRNA (sgmRNA) encoding a truncated C-terminal portion of nucleocapsid (N.iORF3), which is an inhibitor of type I interferon production. We find that N.iORF3 also emerged independently within the Iota variant, and further show that additional TRS motifs have convergently evolved to express novel sgmRNAs; notably upstream of Spike within the nsp16 coding region of ORF1b, which is expressed during human infection. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level, reminiscent of eukaryotic evolution. Greater attention to this aspect in the assessment of emerging strains of SARS-CoV-2 is warranted.

microbiology↗

bioRxiv2022

HOPX governs a molecular and physiological switch between cardiomyocyte progenitor and maturation gene programs

This study establishes the homeodomain only protein, HOPX, as a determinant controlling the molecular switch between cardiomyocyte progenitor and maturation gene programs. Time-course single-cell gene expression with genome-wide footprinting reveal that HOPX interacts with and controls core cardiac networks by regulating the activity of mutually exclusive developmental gene programs. Upstream hypertrophy and proliferation pathways compete to regulate HOPX transcription. Mitogenic signals override hypertrophic growth signals to suppress HOPX and maintain cardiomyocyte progenitor gene programs. Physiological studies show HOPX directly governs genetic control of cardiomyocyte cell stress responses, electro-mechanical coupling, proliferation, and contractility. We use human genome-wide association studies (GWAS) to show that genetic variation in the HOPX-regulome is significantly associated with complex traits affecting cardiac structure and function. Collectively, this study provides a mechanistic link situating HOPX between competing upstream pathways where HOPX acts as a molecular switch controlling gene regulatory programs underpinning metabolic, signaling, and functional maturation of cardiomyocytes.

developmental biology↗

bioRxiv2022

SARS-CoV-2 ORF6 disrupts innate immune signalling by inhibiting cellular mRNA export

SARS-CoV-2 is a betacoronavirus and the etiological agent of COVID-19, a devastating infectious disease. Due to its far-reaching effect on human health, there is an urgent and growing need to understand the viral molecular biology of SARS-CoV-2 and its interaction with the host cell. SARS-CoV-2 encodes 9 predicted accessory proteins, which are presumed to be dispensable for in vitro replication, most likely having a role in modulating the host cell environment to aid viral replication. Here we show that the ORF6 accessory protein interacts with cellular Rae1 to inhibit cellular protein production by blocking mRNA export. We utilised cell fractionation coupled with mRNAseq to explore which cellular mRNA species are affected by ORF6 expression and show that ORF6 can inhibit the export of many mRNA including those encoding antiviral factors such as IRF1 and RIG-I. We also show that export of these mRNA is blocked in the context of SARS-CoV-2 infection. Together, our studies identify a novel mechanism by which SARS-CoV-2 can manipulate the host cell environment to supress antiviral responses, providing further understanding to the replication strategies of a virus that has caused an unprecedented global health crisis. Author SummarySARS-CoV-2 is the virus responsible for the current COVID-19 pandemic. Coronaviruses, like SARS-CoV-2, replicate their genome in the cytoplasm of the host cell by hijacking the cellular machinery. In addition to structural proteins and viral enzymes, SARS-CoV-2 encodes 9 accessory proteins. Although these are not required for in vitro replication, they are thought to modulate the host cell environment to favour viral replication. In this work, we show that the ORF6 accessory protein can supress cellular protein production by blocking mRNA nuclear export through interacting with the cellular protein Rae1, a known mRNA export factor. We also investigated which cellular mRNAs were retained in the nucleus when ORF6 was overexpressed. Interestingly, we found that ORF6 inhibited the export of many different mRNAs, including those encoding antiviral factors, like IRF1 and RIG-I, even in the absence of stimulation by interferon. Importantly, we found that the export of these mRNAs was similarly affected in the context of SARS-CoV-2 infection. Therefore, we believe we have identified a novel mechanism that SARS-CoV-2 uses to suppress antiviral responses in order to make the cell more permissive to infection.

microbiology↗

bioRxiv2021

Broad human and animal coronavirus neutralisation by SARS-CoV-2 S2-targeted vaccination

Several common-cold coronaviruses (HCoVs) are endemic in humans and several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current Coronavirus disease 2019 (COVID-19) pandemic. Whilst antibody cross-reactivity with the Spike glycoproteins (S) of diverse coronaviruses has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to or mediate protection, when induced naturally or through vaccination. Using a mouse model, we show that prior HCoV-OC43 S immunity primes neutralising antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, mouse vaccination with SARS-CoV-2 S2 elicits antibodies that neutralise diverse animal and human alphacoronaviruses and betacoronaviruses in vitro, and protects against SARS-CoV-2 challenge in vivo. Lastly, in mice with a history of SARS-CoV-2 Wuhan-based S vaccination, further S2 vaccination induces stronger and broader neutralising antibody response than booster Wuhan S vaccination, suggesting it may prevent repertoire focusing caused by repeated homologous vaccination. The data presented here establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern (VOCs), as well as to unpredictable, yet inevitable future coronavirus zoonoses.

immunology↗

bioRxiv2021

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterised pharmaceuticals for nsp13 inhibitors using a FRET-based high-throughput screening (HTS) approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.

biochemistry↗

bioRxiv2021

Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains

We examined the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.7 that arose in the United Kingdom and spread globally. Antibodies elicited by B.1.1.7 infection exhibited significantly reduced recognition and neutralisation of parental strains or of the South Africa B.1.351 variant, than of the infecting variant. The drop in cross-reactivity was more pronounced following B.1.1.7 than parental strain infection, indicating asymmetric heterotypic immunity induced by SARS-CoV-2 variants.

immunology↗

bioRxiv2021

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

immunology↗

bioRxiv2020

A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses

There is dire need for an effective and affordable vaccine against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a modular virus-like particle vaccine candidate displaying the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) using SpyTag/SpyCatcher technology (RBD-SpyVLP). Low doses of RBD-SpyVLP in a prime-boost regimen induced a strong neutralising antibody response in mice and pigs that was superior to convalescent human sera. We evaluated antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we showed that RBD-SpyVLP induced a polyclonal antibody response that recognised all key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. The induction of potent and polyclonal antibody responses by RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic. Moreover, RBD-SpyVLP is highly resilient, thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence.

immunology↗

bioRxiv2020

Plasmablast-derived antibody response to acute SARS-CoV-2 infection in humans

Serological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-RBD, three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.

microbiology↗