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  1. Article ; Online: Structure and antigenicity of divergent Henipavirus fusion glycoproteins.

    Isaacs, Ariel / Low, Yu Shang / Macauslane, Kyle L / Seitanidou, Joy / Pegg, Cassandra L / Cheung, Stacey T M / Liang, Benjamin / Scott, Connor A P / Landsberg, Michael J / Schulz, Benjamin L / Chappell, Keith J / Modhiran, Naphak / Watterson, Daniel

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 3577

    Abstract: In August 2022, a novel henipavirus (HNV) named Langya virus (LayV) was isolated from patients with severe pneumonic disease in China. This virus is closely related to Mòjiāng virus (MojV), and both are divergent from the bat-borne HNV members, Nipah ( ... ...

    Abstract In August 2022, a novel henipavirus (HNV) named Langya virus (LayV) was isolated from patients with severe pneumonic disease in China. This virus is closely related to Mòjiāng virus (MojV), and both are divergent from the bat-borne HNV members, Nipah (NiV) and Hendra (HeV) viruses. The spillover of LayV is the first instance of a HNV zoonosis to humans outside of NiV and HeV, highlighting the continuing threat this genus poses to human health. In this work, we determine the prefusion structures of MojV and LayV F proteins via cryogenic electron microscopy to 2.66 and 3.37 Å, respectively. We show that despite sequence divergence from NiV, the F proteins adopt an overall similar structure but are antigenically distinct as they do not react to known antibodies or sera. Glycoproteomic analysis revealed that while LayV F is less glycosylated than NiV F, it contains a glycan that shields a site of vulnerability previously identified for NiV. These findings explain the distinct antigenic profile of LayV and MojV F, despite the extent to which they are otherwise structurally similar to NiV. Our results carry implications for broad-spectrum HNV vaccines and therapeutics, and indicate an antigenic, yet not structural, divergence from prototypical HNVs.
    MeSH term(s) Humans ; Henipavirus ; Glycoproteins/metabolism ; Viral Proteins/metabolism ; Henipavirus Infections ; Nipah Virus/metabolism
    Chemical Substances Glycoproteins ; Viral Proteins
    Language English
    Publishing date 2023-06-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-39278-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates

    Isaacs, Ariel / Cheung, Stacey T. M. / Thakur, Nazia / Jaberolansar, Noushin / Young, Andrew / Modhiran, Naphak / Bailey, Dalan / Graham, Simon P. / Young, Paul R. / Chappell, Keith J. / Watterson, Daniel

    Viruses. 2021 Sept. 28, v. 13, no. 10

    2021  

    Abstract: Nipah virus (NiV) and respiratory syncytial virus (RSV) possess two surface glycoproteins involved in cellular attachment and membrane fusion, both of which are potential targets for vaccines. The majority of vaccine development is focused on the ... ...

    Abstract Nipah virus (NiV) and respiratory syncytial virus (RSV) possess two surface glycoproteins involved in cellular attachment and membrane fusion, both of which are potential targets for vaccines. The majority of vaccine development is focused on the attachment (G) protein of NiV, which is the immunodominant target. In contrast, the fusion (F) protein of RSV is the main target in vaccine development. Despite this, neutralising epitopes have been described in NiV F and RSV G, making them alternate targets for vaccine design. Through rational design, we have developed a vaccine strategy applicable to phylogenetically divergent NiV and RSV that comprises both the F and G proteins (FxG). In a mouse immunization model, we found that NiV FxG elicited an improved immune response capable of neutralising pseudotyped NiV and a NiV mutant that is able to escape neutralisation by two known F-specific antibodies. RSV FxG elicited an immune response against both F and G and was able to neutralise RSV; however, this was inferior to the immune response of F alone. Despite this, RSV FxG elicited a response against a known protective epitope within G that is conserved across RSV A and B subgroups, which may provide additional protection in vivo. We conclude that inclusion of F and G antigens within a single design provides a streamlined subunit vaccine strategy against both emerging and established pathogens, with the potential for broader protection against NiV.
    Keywords Nipah henipavirus ; Respiratory syncytial virus ; epitopes ; glycoproteins ; immune response ; immunization ; membrane fusion ; mice ; models ; mutants ; neutralization ; phylogeny ; subunit vaccines ; vaccine development
    Language English
    Dates of publication 2021-0928
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    ZDB-ID 2516098-9
    ISSN 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v13101942
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Adjuvant Selection for Influenza and RSV Prefusion Subunit Vaccines.

    Isaacs, Ariel / Li, Zheyi / Cheung, Stacey T M / Wijesundara, Danushka K / McMillan, Christopher L D / Modhiran, Naphak / Young, Paul R / Ranasinghe, Charani / Watterson, Daniel / Chappell, Keith J

    Vaccines

    2021  Volume 9, Issue 2

    Abstract: Subunit vaccines exhibit favorable safety and immunogenicity profiles and can be designed to mimic native antigen structures. However, pairing with an appropriate adjuvant is imperative in order to elicit effective humoral and cellular immune responses. ... ...

    Abstract Subunit vaccines exhibit favorable safety and immunogenicity profiles and can be designed to mimic native antigen structures. However, pairing with an appropriate adjuvant is imperative in order to elicit effective humoral and cellular immune responses. In this study, we aimed to determine an optimal adjuvant pairing with the prefusion form of influenza haemagglutinin (HA) or respiratory syncytial virus (RSV) fusion (F) subunit vaccines in BALB/c mice in order to inform future subunit vaccine adjuvant selection. We tested a panel of adjuvants, including aluminum hydroxide (alhydrogel), QS21, Addavax, Addavax with QS21 (AdQS21), and Army Liposome Formulation 55 with monophosphoryl lipid A and QS21 (ALF55). We found that all adjuvants elicited robust humoral responses in comparison to placebo, with the induction of potent neutralizing antibodies observed in all adjuvanted groups against influenza and in AdQS21, alhydrogel, and ALF55 against RSV. Upon HA vaccination, we observed that none of the adjuvants were able to significantly increase the frequency of CD4
    Language English
    Publishing date 2021-01-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines9020071
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates.

    Isaacs, Ariel / Cheung, Stacey T M / Thakur, Nazia / Jaberolansar, Noushin / Young, Andrew / Modhiran, Naphak / Bailey, Dalan / Graham, Simon P / Young, Paul R / Chappell, Keith J / Watterson, Daniel

    Viruses

    2021  Volume 13, Issue 10

    Abstract: Nipah virus (NiV) and respiratory syncytial virus (RSV) possess two surface glycoproteins involved in cellular attachment and membrane fusion, both of which are potential targets for vaccines. The majority of vaccine development is focused on the ... ...

    Abstract Nipah virus (NiV) and respiratory syncytial virus (RSV) possess two surface glycoproteins involved in cellular attachment and membrane fusion, both of which are potential targets for vaccines. The majority of vaccine development is focused on the attachment (G) protein of NiV, which is the immunodominant target. In contrast, the fusion (F) protein of RSV is the main target in vaccine development. Despite this, neutralising epitopes have been described in NiV F and RSV G, making them alternate targets for vaccine design. Through rational design, we have developed a vaccine strategy applicable to phylogenetically divergent NiV and RSV that comprises both the F and G proteins (FxG). In a mouse immunization model, we found that NiV FxG elicited an improved immune response capable of neutralising pseudotyped NiV and a NiV mutant that is able to escape neutralisation by two known F-specific antibodies. RSV FxG elicited an immune response against both F and G and was able to neutralise RSV; however, this was inferior to the immune response of F alone. Despite this, RSV FxG elicited a response against a known protective epitope within G that is conserved across RSV A and B subgroups, which may provide additional protection in vivo. We conclude that inclusion of F and G antigens within a single design provides a streamlined subunit vaccine strategy against both emerging and established pathogens, with the potential for broader protection against NiV.
    MeSH term(s) Animals ; Antibodies, Viral/blood ; Antibodies, Viral/immunology ; Female ; Henipavirus Infections/prevention & control ; Humans ; Mice ; Mice, Inbred BALB C ; Nipah Virus/immunology ; Respiratory Syncytial Virus Infections/prevention & control ; Respiratory Syncytial Virus Vaccines/administration & dosage ; Respiratory Syncytial Virus Vaccines/immunology ; Respiratory Syncytial Virus, Human/immunology ; Vaccine Development/methods ; Vaccines, Subunit/administration & dosage ; Vaccines, Subunit/immunology ; Viral Envelope Proteins/administration & dosage ; Viral Envelope Proteins/genetics ; Viral Envelope Proteins/immunology ; Viral Fusion Proteins/immunology
    Chemical Substances Antibodies, Viral ; Respiratory Syncytial Virus Vaccines ; Vaccines, Subunit ; Viral Envelope Proteins ; Viral Fusion Proteins
    Language English
    Publishing date 2021-09-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v13101942
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: An Optimized High-Throughput Immuno-Plaque Assay for SARS-CoV-2.

    Amarilla, Alberto A / Modhiran, Naphak / Setoh, Yin Xiang / Peng, Nias Y G / Sng, Julian D J / Liang, Benjamin / McMillan, Christopher L D / Freney, Morgan E / Cheung, Stacey T M / Chappell, Keith J / Khromykh, Alexander A / Young, Paul R / Watterson, Daniel

    Frontiers in microbiology

    2021  Volume 12, Page(s) 625136

    Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been identified as the causative agent of coronavirus disease 2019 and is capable of human-to-human transmission and rapid global spread. The rapid emergence and global spread of SARS-CoV-2 ...

    Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been identified as the causative agent of coronavirus disease 2019 and is capable of human-to-human transmission and rapid global spread. The rapid emergence and global spread of SARS-CoV-2 has encouraged the establishment of a rapid, sensitive, and reliable viral detection and quantification methodology. Here, we present an alternative assay, termed immuno-plaque assay (iPA), which utilizes a combination of plaque assay and immunofluorescence techniques. We have extensively optimized the conditions for SARS-CoV-2 infection and demonstrated the great flexibility of iPA detection using several antibodies and dual-probing with two distinct epitope-specific antibodies. In addition, we showed that iPA could be utilized for ultra-high-throughput viral titration and neutralization assay within 24 h and is amenable to a 384-well format. These advantages will significantly accelerate SARS-CoV-2 research outcomes during this pandemic period.
    Language English
    Publishing date 2021-02-12
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2021.625136
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Author Correction: Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses.

    McMillan, Christopher L D / Cheung, Stacey T M / Modhiran, Naphak / Barnes, James / Amarilla, Alberto A / Bielefeldt-Ohmann, Helle / Lee, Leo Yi Yang / Guilfoyle, Kate / van Amerongen, Geert / Stittelaar, Koert / Jakob, Virginie / Lebas, Celia / Reading, Patrick / Short, Kirsty R / Young, Paul R / Watterson, Daniel / Chappell, Keith J

    NPJ vaccines

    2022  Volume 7, Issue 1, Page(s) 3

    Language English
    Publishing date 2022-01-05
    Publishing country England
    Document type Published Erratum
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-021-00428-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: A platform technology for generating subunit vaccines against diverse viral pathogens.

    Young, Andrew / Isaacs, Ariel / Scott, Connor A P / Modhiran, Naphak / McMillan, Christopher L D / Cheung, Stacey T M / Barr, Jennifer / Marsh, Glenn / Thakur, Nazia / Bailey, Dalan / Li, Kenneth S M / Luk, Hayes K H / Kok, Kin-Hang / Lau, Susanna K P / Woo, Patrick C Y / Furuyama, Wakako / Marzi, Andrea / Young, Paul R / Chappell, Keith J /
    Watterson, Daniel

    Frontiers in immunology

    2022  Volume 13, Page(s) 963023

    Abstract: The COVID-19 pandemic response has shown how vaccine platform technologies can be used to rapidly and effectively counteract a novel emerging infectious disease. The speed of development for mRNA and vector-based vaccines outpaced those of subunit ... ...

    Abstract The COVID-19 pandemic response has shown how vaccine platform technologies can be used to rapidly and effectively counteract a novel emerging infectious disease. The speed of development for mRNA and vector-based vaccines outpaced those of subunit vaccines, however, subunit vaccines can offer advantages in terms of safety and stability. Here we describe a subunit vaccine platform technology, the molecular clamp, in application to four viruses from divergent taxonomic families: Middle Eastern respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), Lassa virus (LASV) and Nipah virus (NiV). The clamp streamlines subunit antigen production by both stabilising the immunologically important prefusion epitopes of trimeric viral fusion proteins while enabling purification without target-specific reagents by acting as an affinity tag. Conformations for each viral antigen were confirmed by monoclonal antibody binding, size exclusion chromatography and electron microscopy. Notably, all four antigens tested remained stable over four weeks of incubation at 40°C. Of the four vaccines tested, a neutralising immune response was stimulated by clamp stabilised MERS-CoV spike, EBOV glycoprotein and NiV fusion protein. Only the clamp stabilised LASV glycoprotein precursor failed to elicit virus neutralising antibodies. MERS-CoV and EBOV vaccine candidates were both tested in animal models and found to provide protection against viral challenge.
    MeSH term(s) Animals ; Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 ; Humans ; Middle East Respiratory Syndrome Coronavirus ; Pandemics ; Spike Glycoprotein, Coronavirus ; Technology ; Vaccines, Subunit ; Viral Vaccines
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; Vaccines, Subunit ; Viral Vaccines ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2022-08-18
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.963023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Dermal Delivery of a SARS-CoV-2 Subunit Vaccine Induces Immunogenicity against Variants of Concern.

    McMillan, Christopher L D / Azuar, Armira / Choo, Jovin J Y / Modhiran, Naphak / Amarilla, Alberto A / Isaacs, Ariel / Honeyman, Kate E / Cheung, Stacey T M / Liang, Benjamin / Wurm, Maria J / Pino, Paco / Kint, Joeri / Fernando, Germain J P / Landsberg, Michael J / Khromykh, Alexander A / Hobson-Peters, Jody / Watterson, Daniel / Young, Paul R / Muller, David A

    Vaccines

    2022  Volume 10, Issue 4

    Abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic continues to disrupt essential health services in 90 percent of countries today. The spike (S) protein found on the surface of the causative agent, the SARS-CoV-2 virus, has been the prime target ... ...

    Abstract The ongoing coronavirus disease 2019 (COVID-19) pandemic continues to disrupt essential health services in 90 percent of countries today. The spike (S) protein found on the surface of the causative agent, the SARS-CoV-2 virus, has been the prime target for current vaccine research since antibodies directed against the S protein were found to neutralize the virus. However, as new variants emerge, mutations within the spike protein have given rise to potential immune evasion of the response generated by the current generation of SARS-CoV-2 vaccines. In this study, a modified, HexaPro S protein subunit vaccine, delivered using a needle-free high-density microarray patch (HD-MAP), was investigated for its immunogenicity and virus-neutralizing abilities. Mice given two doses of the vaccine candidate generated potent antibody responses capable of neutralizing the parental SARS-CoV-2 virus as well as the variants of concern, Alpha and Delta. These results demonstrate that this alternative vaccination strategy has the potential to mitigate the effect of emerging viral variants.
    Language English
    Publishing date 2022-04-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines10040578
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Efficient Delivery of Dengue Virus Subunit Vaccines to the Skin by Microprojection Arrays.

    Muller, David A / Depelsenaire, Alexandra C I / Shannon, Ashleigh E / Watterson, Daniel / Corrie, Simon R / Owens, Nick S / Agyei-Yeboah, Christiana / Cheung, Stacey T M / Zhang, Jin / Fernando, Germain J P / Kendall, Mark A F / Young, Paul R

    Vaccines

    2019  Volume 7, Issue 4

    Abstract: Dengue virus is the most important arbovirus impacting global human health, with an estimated 390 million infections annually, and over half the world's population at risk of infection. While significant efforts have been made to develop effective ... ...

    Abstract Dengue virus is the most important arbovirus impacting global human health, with an estimated 390 million infections annually, and over half the world's population at risk of infection. While significant efforts have been made to develop effective vaccines to mitigate this threat, the task has proven extremely challenging, with new approaches continually being sought. The majority of protective, neutralizing antibodies induced during infection are targeted by the envelope (E) protein, making it an ideal candidate for a subunit vaccine approach. Using truncated, recombinant, secreted E proteins (sE) of all 4 dengue virus serotypes, we have assessed their immunogenicity and protective efficacy in mice, with or without Quil-A as an adjuvant, and delivered via micropatch array (MPA) to the skin in comparison with more traditional routes of immunization. The micropatch contains an ultra-high density array (21,000/cm
    Language English
    Publishing date 2019-11-20
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2703319-3
    ISSN 2076-393X
    ISSN 2076-393X
    DOI 10.3390/vaccines7040189
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Development of molecular clamp stabilized hemagglutinin vaccines for Influenza A viruses.

    McMillan, Christopher L D / Cheung, Stacey T M / Modhiran, Naphak / Barnes, James / Amarilla, Alberto A / Bielefeldt-Ohmann, Helle / Lee, Leo Yi Yang / Guilfoyle, Kate / van Amerongen, Geert / Stittelaar, Koert / Jakob, Virginie / Lebas, Celia / Reading, Patrick / Short, Kirsty R / Young, Paul R / Watterson, Daniel / Chappell, Keith J

    NPJ vaccines

    2021  Volume 6, Issue 1, Page(s) 135

    Abstract: Influenza viruses cause a significant number of infections and deaths annually. In addition to seasonal infections, the risk of an influenza virus pandemic emerging is extremely high owing to the large reservoir of diverse influenza viruses found in ... ...

    Abstract Influenza viruses cause a significant number of infections and deaths annually. In addition to seasonal infections, the risk of an influenza virus pandemic emerging is extremely high owing to the large reservoir of diverse influenza viruses found in animals and the co-circulation of many influenza subtypes which can reassort into novel strains. Development of a universal influenza vaccine has proven extremely challenging. In the absence of such a vaccine, rapid response technologies provide the best potential to counter a novel influenza outbreak. Here, we demonstrate that a modular trimerization domain known as the molecular clamp allows the efficient production and purification of conformationally stabilised prefusion hemagglutinin (HA) from a diverse range of influenza A subtypes. These clamp-stabilised HA proteins provided robust protection from homologous virus challenge in mouse and ferret models and some cross protection against heterologous virus challenge. This work provides a proof-of-concept for clamp-stabilised HA vaccines as a tool for rapid response vaccine development against future influenza A virus pandemics.
    Language English
    Publishing date 2021-11-08
    Publishing country England
    Document type Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-021-00395-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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