Han Di

Centers for Disease Control and Prevention

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C. Todd Davis

Centers for Disease Control and Prevention

Margo A. Brinton

Georgia State University

David E. Wentworth

Centers for Disease Control and Prevention

John Barnes

Centers for Disease Control and Prevention

Joyce Jones

National Center for Immunization and Respiratory Diseases

Bin Zhou

Centers for Disease Control and Prevention

Yunho Jang

Centers for Disease Control and Prevention

Heather A. Vatter

Georgia State University

Li Wang

Vanderbilt University Medical Center

Elizabeth A. Pusch

National Center for Immunization and Respiratory Diseases

Cooperative Institutions

Centers for Disease Control and Prevention

146

National Center for Immunization and Respiratory Diseases

National Institutes of Health

Institut Pasteur du Cambodge

National Institute of Allergy and Infectious Diseases

Icahn School of Medicine at Mount Sinai

Emory University

National Center for Emerging and Zoonotic Infectious Diseases

Battelle

Johns Hopkins University

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Transmission of a human isolate of clade 2.3.4.4b A(H5N1) virus in ferrets

Nature (2024)

Joanna A. Pulit-Penaloza Jessica A. Belser Nicole Brock Troy J. Kieran Xiangjie Sun

Sars virus

10.1038/s41586-024-08246-7

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Citations (9)

An influenza mRNA vaccine protects ferrets from lethal infection with highly pathogenic avian influenza A(H5N1) virus

Science Translational Medicine (2024)

Masato Hatta Yasuko Hatta Angela Choi Jaber Hossain Chenchen Feng

The global spread of the highly pathogenic avian influenza (HPAI) A(H5N1) virus poses a serious pandemic threat, necessitating the swift development of effective vaccines. The success of messenger RNA (mRNA) vaccine technology in the COVID-19 pandemic, marked by its rapid development and scalability, demonstrates its potential for addressing other infectious threats, such as HPAI A(H5N1). We therefore evaluated mRNA vaccine candidates targeting panzootic influenza A(H5) clade 2.3.4.4b viruses, which have been shown to infect a range of mammalian species, including most recently being detected in dairy cattle. Ferrets were immunized with mRNA vaccines encoding either hemagglutinin alone or hemagglutinin and neuraminidase, derived from a 2.3.4.4b prototype vaccine virus recommended by the World Health Organization. Kinetics of the immune responses, as well as protection against a lethal challenge dose of A(H5N1) virus, were assessed. Two doses of mRNA vaccination elicited robust neutralizing antibody titers against a 2022 avian isolate and a 2024 human isolate. Further, mRNA vaccination conferred protection from lethal challenge, whereas all unvaccinated ferrets succumbed to infection. It also reduced viral titers in the upper and lower respiratory tracts of infected ferrets. These results underscore the effectiveness of mRNA vaccines against HPAI A(H5N1), showcasing their potential as a vaccine platform for future influenza pandemics.

Pandemic

Infectious dose

H5N1 genetic structure

10.1126/scitranslmed.ads1273

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Insertion position as well as the inserted TRS and gene sequences differentially affect the retention of foreign gene expression by simian hemorrhagic fever virus (SHFV)

Virology (2018)

Han Di Esther K. Morantz Heena Sadhwani Joseph C. Madden Margo A. Brinton

Subgenomic mRNA

Recombinant virus

10.1016/j.virol.2018.09.014

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Citations (3)

Functional Analyses of the Three Simian Hemorrhagic Fever Virus Nonstructural Protein 1 Papain-Like Proteases

Journal of Virology (2014)

Heather A. Vatter Han Di Eric Donaldson Gertrud U. Radu Taronna R. Maines

ABSTRACT The N-terminal region of simian hemorrhagic fever virus (SHFV) nonstructural polyprotein 1a is predicted to encode three papain-like proteases (PLP1α, PLP1β, and PLP1γ). Catalytic residues and cleavage sites for each of the SHFV PLP1s were predicted by alignment of the SHFV PLP1 region sequences with each other as well as with those of other arteriviruses, and the predicted catalytic residues were shown to be proximal by homology modeling of the SHFV nsp1s on porcine respiratory and reproductive syndrome virus (PRRSV) nsp1 crystal structures. The functionality of the predicted catalytic Cys residues and cleavage sites was tested by analysis of the autoproteolytic products generated in in vitro transcription/translation reactions done with wild-type or mutant SHFV nsp1 constructs. Cleavage sites were also analyzed by mass spectroscopy analysis of selected immunoprecipitated cleavage products. The data showed that each of the three SHFV PLP1s is an active protease. Cys63 was identified as the catalytic Cys of SHFV PLP1α and is adjacent to an Ala instead of the canonical Tyr observed in other arterivirus PLP1s. SHFV PLP1γ is able to cleave at both downstream and upstream nsp1 junction sites. Although intermediate precursor polyproteins as well as alternative products generated by each of the SHFV PLP1s cleaving at sites within the N-terminal region of nsp1β were produced in the in vitro reactions, Western blotting of SHFV-infected, MA104 cell lysates with SHFV nsp1 protein-specific antibodies detected only the three mature nsp1 proteins. IMPORTANCE SHFV is unique among arteriviruses in having three N-terminal papain-like protease 1 (PLP1) domains. Other arteriviruses encode one or two active PLP1s. This is the first functional study of the SHFV PLP1s. Analysis of the products of in vitro autoprocessing of an N-terminal SHFV nonstructural 1a polypeptide fragment showed that each of the three SHFV PLP1s is active, and the predicted catalytic Cys residues and cleavage sites for each PLP1 were confirmed by testing mutant constructs. Several unique features of the SHFV PLP1s were discovered. The SHFV PLP1α catalytic Cys63 is unique among arterivirus PLP1s in being adjacent to an Ala instead of a Trp. Other arterivirus PLP1s cleave only in cis at a single downstream site, but SHFV PLP1γ can cleave at both the downstream nsp1γ-nsp2 and upstream nsp1β-nsp1γ junctions. The three mature nsp1 proteins were produced both in the in vitro reactions and in infected cells.

Polyproteins

Cleavage (geology)

Arterivirus

NS3

10.1128/jvi.01020-14

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Citations (12)

Antigenic Characterization of Circulating and Emerging SARS-CoV-2 Variants in the U.S. throughout the Delta to Omicron Waves

Vaccines (2024)

Han Di Elizabeth A. Pusch Joyce Jones Nicholas A. Kovacs Norman Hassell

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into numerous lineages with unique spike mutations and caused multiple epidemics domestically and globally. Although COVID-19 vaccines are available, new variants with the capacity for immune evasion continue to emerge. To understand and characterize the evolution of circulating SARS-CoV-2 variants in the U.S., the Centers for Disease Control and Prevention (CDC) initiated the National SARS-CoV-2 Strain Surveillance (NS3) program and has received thousands of SARS-CoV-2 clinical specimens from across the nation as part of a genotype to phenotype characterization process. Focus reduction neutralization with various antisera was used to antigenically characterize 143 SARS-CoV-2 Delta, Mu and Omicron subvariants from selected clinical specimens received between May 2021 and February 2023, representing a total of 59 unique spike protein sequences. BA.4/5 subvariants BU.1, BQ.1.1, CR.1.1, CQ.2 and BA.4/5 + D420N + K444T; BA.2.75 subvariants BM.4.1.1, BA.2.75.2, CV.1; and recombinant Omicron variants XBF, XBB.1, XBB.1.5 showed the greatest escape from neutralizing antibodies when analyzed against post third-dose original monovalent vaccinee sera. Post fourth-dose bivalent vaccinee sera provided better protection against those subvariants, but substantial reductions in neutralization titers were still observed, especially among BA.4/5 subvariants with both an N-terminal domain (NTD) deletion and receptor binding domain (RBD) substitutions K444M + N460K and recombinant Omicron variants. This analysis demonstrated a framework for long-term systematic genotype to antigenic characterization of circulating and emerging SARS-CoV-2 variants in the U.S., which is critical to assessing their potential impact on the effectiveness of current vaccines and antigen recommendations for future updates.

spike protein

10.3390/vaccines12050505

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Citations (3)

Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022

Antiviral Research (2023)

Ha Nguyen Anton Chesnokov Juan De La Cruz Philippe Noriel Q. Pascua Vasiliy P. Mishin

Clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A(H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1,015 sequences of HPAI A(H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4b A(H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors, baloxavir and the investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A(H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.

Oseltamivir

Zanamivir

Neuraminidase inhibitor

Antiviral drug

10.1016/j.antiviral.2023.105679

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Citations (16)

Identification of Novel Host Cell Binding Partners of Oas1b, the Protein Conferring Resistance to Flavivirus-Induced Disease in Mice

Journal of Virology (2012)

Sean Courtney Han Di Bronislava M. Stockman Haifeng Liu Svetlana V. Scherbik

Oas1b was previously identified as the product of the Flv(r) allele that confers flavivirus-specific resistance to virus-induced disease in mice by an uncharacterized, RNase L-independent mechanism. To gain insights about the mechanism by which Oas1b specifically reduces the efficiency of flavivirus replication, cellular protein interaction partners were identified and their involvement in the Oas1b-mediated flavivirus resistance mechanism was analyzed. Initial difficulties in getting the two-hybrid assay to work with full-length Oas1b led to the discovery that this Oas protein uniquely has a C-terminal transmembrane domain that targets it to the endoplasmic reticulum (ER). Two peptides matching to oxysterol binding protein-related protein 1L (ORP1L) and ATP binding cassette protein 3, subfamily F (ABCF3), were identified as Oas1b interaction partners in yeast two-hybrid assays, and both in vitro-transcribed/translated peptides and full-length proteins in mammalian cell lysates coimmunoprecipitated with Oas1b. Knockdown of a partner involved in Oas1b-mediated antiflavivirus activity would be expected to increase flavivirus replication but not that of other types of viruses. However, RNA interference (RNAi) knockdown of ORP1L decreased the replication of the flavivirus West Nile virus (WNV) as well as that of other types of RNA viruses. This virus-nonspecific effect may be due to the recently reported dysregulation of late endosome movement by ORP1L knockdown. Knockdown of ABCF3 protein levels increased the replication of WNV but not that of other types of RNA viruses, and this effect on WNV replication was observed only in Oas1b-expressing cells. The results suggest that Oas1b is part of a complex located in the ER and that ABCF3 is a component of the Flv(r)-mediated resistance mechanism.

Flavivirus

Identification

Host resistance

10.1128/jvi.00333-12

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Citations (50)

Detection of highly pathogenic avian influenza A(H5N6) viruses in waterfowl in Bangladesh

Virology (2019)

Genyan Yang Sukanta Chowdury Erin Hodges Mohammed Ziaur Rahman Yunho Jang

Highly pathogenic

10.1016/j.virol.2019.05.011

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Citations (16)

Antiviral Susceptibility of Swine-Origin Influenza A Viruses Isolated from Humans, United States

Emerging infectious diseases (2024)

Rongyuan Gao Philippe Noriel Q. Pascua Anton Chesnokov Ha Nguyen Timothy M. Uyeki

Since 2013, a total of 167 human infections with swine-origin (variant) influenza A viruses of A(H1N1)v, A(H1N2)v, and A(H3N2)v subtypes have been reported in the United States. Analysis of 147 genome sequences revealed that nearly all had S31N substitution, an M2 channel blocker-resistance marker, whereas neuraminidase inhibitor-resistance markers were not found. Two viruses had a polymerase acidic substitution (I38M or E199G) associated with decreased susceptibility to baloxavir, an inhibitor of viral cap-dependent endonuclease (CEN). Using phenotypic assays, we established subtype-specific susceptibility baselines for neuraminidase and CEN inhibitors. When compared with either baseline or CEN-sequence-matched controls, only the I38M substitution decreased baloxavir susceptibility, by 27-fold. Human monoclonal antibodies FI6v3 and CR9114 targeting the hemagglutinin's stem showed variable (0.03 to >10 µg/mL) neutralizing activity toward variant viruses, even within the same clade. Methodology and interpretation of laboratory data described in this study provide information for risk assessment and decision-making on therapeutic control measures.

Neuraminidase inhibitor

Oseltamivir

10.3201/eid3011.240892

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Studies on the Stabilites of Yogurt Powder

Shipin yanjiu yu kaifa (2010)

Han Di

For determining the shelf life of yogurt powder,the viable counts of probiotics and effection on the yogurt in different storage envionment were measured.It is indicated that the viable probiotics counts declined 3 magnitudes in accelerated test and the yogurt couldn't ferment successfully.In room temperature test,the viable counts decreased 1 magnitudes and the quality of yogurt merely changed.In low temperature test,the viable counts decreased 1 magnitude in 18 months and It had little effection on the quality of yogurt.The shelf life of yogurt powder was determind 5 months-6 months at last.

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