IP Library › Granted Patent US 12,691,172
Granted Patent B2
US 12,691,172 · App. 17/916,369 · Granted Jul 28, 2026

Coronavirus vaccines

Inventors: Jonathan Luke Heeney (Cambridge, GB); Sneha Vishwanath (Cambridge, GB); George William Carnell (Cambridge, GB); David Wells (Hertford, GB); Matteo Ferrari (Hertford, GB)
Assignees: DIOSynVax Ltd; Cambridge Enterprise Limited
A61K39/215A61P31/14C07K14/005C12N7/00A61K2039/5256C12N2770/20034
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Quick Facts
Patent No.
US 12,691,172
App. No.
17/916,369
Filed
Sep 30, 2022
Granted
Jul 28, 2026
Kind
B2
Art Unit
1651
USPC
424/221.1
Abstract

Designed coronavirus polypeptide sequences are described, and their use as vaccines against viruses of the coronavirus family. The designed sequences include designed coronavirus spike(S) proteins and fragments thereof, including designed S protein receptor binding domain (RBD) sequence SEQ ID NO:17, designed truncated S protein sequence SEQ ID NO:15, and designed full length S protein sequence SEQ ID NO:13. Designed coronavirus envelope (E), membrane (M), and nucleocapsid (N) protein sequences are also described, and their use as vaccines. Nucleic acid molecules encoding the polypeptides, vectors, fusion proteins, pharmaceutical compositions, cells, and their use as vaccines against viruses of the coronavirus family are also described.

Claims (77)

1 . An isolated polypeptide, which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31.

2 . A polypeptide according to claim 1 , which comprises at least one, or all of the amino acid residues, optionally at least five, at least ten, or at least fifteen of the amino acid residues, at the following positions: A at a position corresponding to residue position 3 of SEQ ID NO:11; K at a position corresponding to residue position 6 of SEQ ID NO:11; E at a position corresponding to residue position 7 of SEQ ID NO:11, V at a position corresponding to residue position 8 of SEQ ID NO:11; P at a position corresponding to residue position 30 of SEQ ID NO: 11; E at a position corresponding to residue position 36 of SEQ ID NO:11; T at a position corresponding to residue position 54 of SEQ ID NO: 11; T at a position corresponding to residue position 120 of SEQ ID NO: 11; T at a position corresponding to residue position 126 of SEQ ID NO: 11; T at a position corresponding to residue position 127 of SEQ ID NO:11; S at a position corresponding to residue position 152 of SEQ ID NO: 11; D at a position corresponding to residue position 153 of SEQ ID NO:11; S at a position corresponding to residue position 163 of SEQ ID NO:11; N at a position corresponding to residue position 201 of SEQ ID NO:11; L at a position corresponding to residue position 211 of SEQ ID NO:11; and D at a position corresponding to residue position 214 of SEQ ID NO:11.

3 . A polypeptide according to claim 1 , which comprises at least one, or all of the amino acid residues at the following positions: V at a position corresponding to residue position 99 of SEQ ID NO:11; S at a position corresponding to residue position 137 of SEQ ID NO: 11; L at a position corresponding to residue position 138 of SEQ ID NO:11; K at a position corresponding to residue position 142 of SEQ ID NO:11; S at a position corresponding to residue position 156 of SEQ ID NO: 11; P at a position corresponding to residue position 157 of SEQ ID NO: 11; G at a position corresponding to residue position 159 of SEQ ID NO:11; K at a position corresponding to residue position 160 of SEQ ID NO:11; Y at a position corresponding to residue position 172 of SEQ ID NO:11; R at a position corresponding to residue position 175 of SEQ ID NO: 11; and F at a position corresponding to residue position 180 of SEQ ID NO: 11.

4 . A polypeptide according to claim 1 , which comprises at least one, or all of the amino acid residues at the following positions: K at a position corresponding to residue position 28 of SEQ ID NO: 11; K at a position corresponding to residue position 39 of SEQ ID NO: 11; and I at a position corresponding to residue position 123 of SEQ ID NO:11.

5 . A polypeptide according to claim 1 , which comprises amino acid residue T at the position corresponding to the amino acid residue position 185 of SEQ ID NO:11.

6 . A polypeptide according to claim 1 , which comprises the following discontinuous amino acid sequences:

a)

(i)

(SEQ ID NO: 57)

NITNLCPFGEVENATK;

(ii)

(SEQ ID NO: 58)

KKISN;

(iii)

(SEQ ID NO: 59)

NI;

b)

(i)

(SEQ ID NO: 71)

YNSTSFSTFKCYGVSPTKLNDLCFT;

(ii)

(SEQ ID NO: 72)

DDFT;

iii)

(SEQ ID NO: 62)

FELLN;

or

c)

(i)

(SEQ ID NO: 63)

RGDEVRQ;

(SEQ ID NO: 73

TGVIADY

iii)

(SEQ ID NO: 74)

YRSLRKSK;

(iv)

(SEQ ID NO: 75)

YSPGGK;

(v)

(SEQ ID NO: 77)

FNCYYPLRSYGFFPTNGTGY;

wherein the discontinuous amino acid sequences of (a) (i)-(iii) are present in the order recited, the discontinuous amino acid sequences of (b) (i)-(iii) are present in the order recited, and the discontinuous amino acid sequences of (c) (i)-(v) are present in the order recited.

7 . An isolated nucleic acid molecule encoding a polypeptide according to claim 1 , or the complement thereof.

8 . A vector comprising a nucleic acid molecule of claim 7 , optionally which further comprises a promoter operably linked to the nucleic acid.

9 . A vector according to claim 8 , wherein the promoter is for expression of a polypeptide encoded by the nucleic acid in mammalian cells.

10 . A vector according to claim 8 , which is a vaccine vector.

11 . An isolated cell comprising a vector of claim 8 .

12 . A fusion protein comprising a polypeptide according to claim 1 .

13 . A pharmaceutical composition comprising:

a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31;

a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof, or

a vector comprising a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof, optionally which further comprises a promoter operably linked to the nucleic acid;

and a pharmaceutically acceptable carrier, excipient, or diluent.

14 . A pharmaceutical composition according to claim 13 , which further comprises an adjuvant for enhancing an immune response in a subject to the polypeptide, or to a polypeptide encoded by the nucleic acid, of the composition.

15 . A pseudotyped virus comprising a polypeptide according to claim 1 .

16 . A method of inducing an immune response to a coronavirus in a subject, which comprises administering to the subject an effective amount of:

i) a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31;

ii) a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof;

iii) a vector comprising a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof; or

iv) a pharmaceutical composition comprising:

a) a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, and a pharmaceutically acceptable carrier, excipient, or diluent;

b) a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof, and a pharmaceutically acceptable carrier, excipient, or diluent; or

c) a vector comprising a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO: 31, or the complement thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

17 . A method of immunizing a subject against a coronavirus, which comprises administering to the subject an effective amount of:

i) a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31;

ii) a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof;

iii) a vector comprising a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof, optionally which further comprises a promoter operably linked to the nucleic acid; or

iv) a pharmaceutical composition comprising:

a) a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, and a pharmaceutically acceptable carrier, excipient, or diluent;

b) a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO:31, or the complement thereof, and a pharmaceutically acceptable carrier, excipient, or diluent; or

c) a vector comprising a nucleic acid molecule encoding a polypeptide which comprises an amino acid sequence of SEQ ID NO: 31 (COV_S_T2_17), or an amino acid sequence which has at least 95%, 96%, 97%, 98%, or 99% amino acid identity over its entire length with the amino acid sequence of SEQ ID NO: 31, or the complement thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

18 . A method according to claim 16 , wherein the coronavirus is a β-coronavirus.

19 . A method according to claim 18 , wherein the β-coronavirus is a lineage B β-coronavirus.

20 . A vector according to claim 10 , wherein the vaccine vector is a viral vaccine vector, a bacterial vaccine vector, an RNA vaccine vector, or a DNA vaccine vector.

21 . A method according to claim 18 , wherein the β-coronavirus is a lineage B or C β-coronavirus.

22 . A method according to claim 19 , wherein lineage B β-coronavirus is SARS-COV or SARS-COV-2.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 24, 2026
From: WELLS, DAVID; FERRARI, MATTEO
To: DIOSYNVAX LTD
Reel/Frame 074955/0623 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 24, 2026
From: HEENEY, JONATHAN LUKE; VISHWANATH, SNEHA; CARNELL, GEORGE WILLIAM; THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
To: CAMBRIDGE ENTERPRISE LIMITED
Reel/Frame 073874/0808 →
Priority Claims (5)
GB 2004826 · Apr 1, 2020 · national
GB 2010672 · Jul 10, 2020 · national
GB 2015775 · Oct 5, 2020 · national
GB 2101824 · Feb 10, 2021 · national
GB 2103214 · Mar 8, 2021 · national
Continuity (1)
Related Publication 20240285751A1 · Aug 29, 2024
References Cited (166)
US 10702600B1 · Ciaramella et al. · 2020 [cited by applicant]
US 11918643B2 · Roth · 2024 [cited by examiner]
US 20060121580A1 · Crucell · 2006 [cited by applicant]
US 20080027006A1 · Tripet et al. · 2008 [cited by applicant]
US 20100150923A1 · Jiang et al. · 2010 [cited by applicant]
US 20170096455A1 · Baric et al. · 2017 [cited by applicant]
CN 102690336A · 2012 [cited by applicant]
CN 106928326A1 · 2017 [cited by applicant]
JP 2019169120A · 2019 [cited by applicant]
WO 2015143335A1 · 2015 [cited by applicant]
WO 2021156267A1 · 2021 [cited by applicant]
WO 2021160346A1 · 2021 [cited by applicant]
WO 2023275538A1 · 2023 [cited by applicant]
International Search Report and Written Opinion dated Sep. 27, 2021 issued in PCT/GB2021/050830. [cited by applicant]
Du Lanying et al., “A 219-mer CHO-Expressing Receptor-Binding Domain of SARS-CoV S Protein Induces Potent Immune Responses and Protective Immunity”, Viral Immunology (Apr. 1, 2010), vol. 23, No. 2, pp. 211-219, XP055784… [cited by applicant]
Yan R. et al., “Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human ACE2”, [cited by applicant]
Yang J. et al., “A Vaccine Targeting the RBD of the S Protein of SARS-CoV-2 Induces Protective Immunity”, [cited by applicant]
Yip M S et al., “Antibody-Dependent Infection of Human Macrophages by Severe Acute Respiratory Syndrome Coronavirus”, [cited by applicant]
Yu J. et al., “DNA Vaccine Protection Against SARS-CoV-2 in Rhesus Macaques”, [cited by applicant]
Yurkovetskiy L. et al., “Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant”, [cited by applicant]
Zahradnik J. et al., “SARS-CoV-2 RBD In Vitro Evolution Follows Contagious Mutation Spread, Yet Generates an Able Infection Inhibitor”, bioRxiv preprint doi: https://doi.org/10.1101/2021.01.06.425392 (Jan. 29, 2021). [cited by applicant]
Zahradnik J. et al., “SARS-CoV-2 Variant Prediction and Antiviral Drug Design are Enabled by RBD In Vitro Evolution”, [cited by applicant]
Zhang J. et al., “Progress and Prospects on Vaccine Development Against SARS-CoV-2”, [cited by applicant]
Zhang L. et al., “Antibody Responses Against SARS Coronavirus are Correlated With Disease Outcome of Infected Individuals”, [cited by applicant]
Zhao J. et al., “Antibody Responses to SARS-CoV-2 in Patients of Novel Coronavirus Disease 2019”, medRxiv prepint doi: https://doi.org/10.1101/2020.03.02.20030189 (Mar. 3, 2020). [cited by applicant]
Sarwar U.N. et al., “Safety and Immunogenicity of DNA Vaccines Encoding Ebolavirus and Marburgvirus Wild-Type Glycoproteins in a Phase I Clinical Trial”, [cited by applicant]
Self W.H. et al., “Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Amond A dults Without Immunocompromising Conditions”, [cited by applicant]
Seow J. et al., “Longitudinal Evaluation and Decline of Antibody Responses in SARS-CoV-2 Infection”, medRxiv preprint doi: https://doi.org/10.1101/2020.07_09_20148429 (Jul. 11, 2020). [cited by applicant]
Shaimardanova A.A. et al., “Production and Application of Multicistronic Constructs for Various Human Disease Therapies”, [cited by applicant]
Shen M-Y et al., “Statistical Potential for Assessment and Prediction of Protein Structures”, [cited by applicant]
Shin M.D. et al., “COVID-19 Vaccine Development and a Potential Nanomaterial Path Forward”, [cited by applicant]
Shi P-Y et al., “Neutralization of N501Y Mutant SARS-CoV-2 by BNT162b2 Vaccine-Elicited Sera”, DOI: https://doi.org/10.21203/rs_3.rs-143532.vl (Jan. 7, 2021). [cited by applicant]
Siddell S.G., “The [cited by applicant]
Singh J. et al., “Evolutionary Trajectory of SARS-CoV-2 and Emerging Variants”, [cited by applicant]
Smith T.F. et al., “Comparison of Biosequences”, [cited by applicant]
Kruskal J.B., “Time Warps, String Edits and Macromolecules: the Theory and Practice of Sequence Comparison”, Sankoff & Kruskal (eds), pp. 1-44, Addison Wesley; programs available from http://www.ebi.ac.uk/tools/emboss/a… [cited by applicant]
Kustin T. et al., “Evidence for Increased Breakthrough Rates of SARS-CoV-2 Variants of Concern in BNT162b2- mRNA-Vaccinated Individuals”, [cited by applicant]
Larkin M.A. et al., “Clustal W and Clustal X Version 2.0”, [cited by applicant]
Larsen M D et al., “Afucosylated Immunoglobulin G Responses are a Hallmark of Enveloped Virus Infections and Show an Exacerbated Phenotype in COVID-19”, bioRxiv preprint doi: https://doi.org/10.1101/2020.05.18.099507 (M… [cited by applicant]
Le Bert N. et al., “SARS-CoV-2-Specific T Cell Immunity in Cases of COVID-19 and SARS, and Uninfected Controls”, [cited by applicant]
Letko M. et al., “Functional Assessment of Cell Entry and Receptor Usage for SARS-CoV-2 and Other Lineage B Betacoronaviruses”, [cited by applicant]
Leung K. et al., “Early Transmissibility Assessment of the N501Y Mutant Strains of SARS-CoV-2 in the United Kingdom, Oct. to Nov. 2020”, [cited by applicant]
Li Q. et al., “The Impact of Mutations in SARS-Co V-2 Spike on Viral Infectivity and Antigenicity”, [cited by applicant]
Liu K. et al., “Cross-Species Recognition of SARS-CoV-2 to Bat ACE2”, [cited by applicant]
Loeb M. et al., “Randomized Controlled Trial of Influenza Vaccine in Patients With Heart Failure to Reduce Adverse Vascular Events (IVVE): Rationale and Design”, [cited by applicant]
Needleman S.B. et al., “A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins”, [cited by applicant]
Nieto-Torres J.L. et al., “Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis”, [cited by applicant]
Olival K.J. et al., “Possibility for Reverse Zoonotic Transmission of SARS-CoV-2 to Free-Ranging Wildlife: A Case Study of Bats”, [cited by applicant]
Pantaleo G. et al., “Safety and Immunogenicity of a Multivalent HIV Vaccine Comprising Envelope Protein With Either DNA or NYVAC Vectors (HVTN096): A Phase 1b, Double-Blind, Placebo0-Controlled Trial”, [cited by applicant]
Pardi N. et al., “mRNA Vaccines—A New Era in Vaccinology”, [cited by applicant]
Pearson W.R. et al., “Improved Tools for Biological Sequence Comparison”, [cited by applicant]
Pedregosa F. et al., “Scikit-Learn: Machine Learning in Python”, [cited by applicant]
Peeples L., “Avoiding Pitfalls in the Pursuit of a COVID-19 Vaccine”, [cited by applicant]
Peng Y. et al., “Broad and Strong Memory CD4+ and CD8+ T Cells Induced by SARS-CoV-2 in UK Convalescent COVID-19 Patients”, bioRxiv preprint doi: doi: 10.1038/s41599-020-0782-6 (Jun. 8, 2020). [cited by applicant]
Perez P. et al., “The Combined Vaccination Protocol of DNA/MVA Expressing Zika Virus Structural Proteins as Efficient Inducer of T and B Cell Immune Responses”, [cited by applicant]
Long Q-X et al., “Clinical and Immunological Assessment of Asymptomatic SARS-CoV-2 Infections”, [cited by applicant]
Lopez Bernal J. et al., “Effectiveness of the Pfizer-BoNTech and Oxford-AstraZeneca Vaccines on Covid-19 Related Symptoms, Hospital Admissions, and Mortality in Older Adults in England: Test Negative Case-Control Study”, [cited by applicant]
Lopez Bernal J. et al., “Effectiveness of Covid-19 Vaccines Against the B.1.617.2 (Delta) Variant”, [cited by applicant]
Madhi S.A. et al., “Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine Against the B.1.351 Variant”, [cited by applicant]
Martin J.E. et al., “A SARS DNA Vaccine Induces Neutralizing Antibody and Cellular Immune Responses in Healthy Adults in a Phase I Clinical Trial”, [cited by applicant]
Martin D.P. et al., “Selection Analysis Identifies Unusual Clustered Mutational Changes in Omicron Lieage BA.1 That Likely Impact Spike Function”, bioRxiv preprint doi: https://doi.org/10.1101/2022.01.14.476382 (Jan. 18… [cited by applicant]
Menachery V.D. et al., “A SARS-Like Cluster of Circulating Bat Coronaviruses Shows Potential for Human Emergence”, [cited by applicant]
Meng B. et al., “Altered TMPRSS2 Usage by SARS-CoV-2 Omicron Impacts Infectivity and Fusogenicity”, [cited by applicant]
Mooij P. et al., “Needle-Free Delivery of DNA: Targeting of Hemagglutinin to MHC Class II Molecules Protects Rhesus Macaques Against H1N1 Influenza”, [cited by applicant]
Montagutelli X. et al., “The B1.351 and P.1 Variants Extend SARS-CoV-2 Host Range to Mice”, bioRxiv preprint doi: https://doi.org/10_1101/2021.03_18.436013 (Dec. 2021). [cited by applicant]
La Vie M. et al., “Glycan Shielding and Modulation of Hepatitis C Virus Neutralizing Antibodies”, [cited by applicant]
Li W. et al., “Animal Origins of the Severe Acute Respiratory Syndrome Coronvirus: Insight from ACE2-S-Protein Interactions”, [cited by applicant]
Nguyen L-T et al., “IQ-TREE: A Fast and Effective Stochastic Algorithm for Estimating Maximum-Likelihood Phylogenies”, [cited by applicant]
Pinto D. et al., “Cross-Neutralization of SARS-CoV-2 by a Human Monoclonal SARS-CoV Antibody”, [cited by applicant]
Eswar N. et al., “Comparative Protein Structure Modeling Using Modeller”, [cited by applicant]
GenScript “SARS-CoV-2 Surrogate Virus Neutralization Test Kit”, (14 pages) (Jul. 20, 2020). [cited by applicant]
“WHO Announces Simple, Easy-to-Say Labels for SARS-CoV-2 Variants of Interest and Concern”, https://www.who.int/news/item/31-05-2021-who-announces-simple-easy-to-say-labels-for-sars-cov-2-variants-of-interest-and-concer… [cited by applicant]
Craven J., Regulatory Focus, News Articles, 2020, 3, COVID-19 Vaccine Tracker: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker (2022). [cited by applicant]
Chinese Office Action & Search Report dated Mar. 13, 2024 received in Chinese Patent Application No. 202180039232.6, together with an English-language translation. [cited by applicant]
Japanese Office Action dated Jun. 28, 2025 received in Japanese Patent Application No. 2022-560285, together with an English-language translation. [cited by applicant]
Vilar S. et al., “One Year of SARS-CoV-2: How Much Has the Virus Changed?”, [cited by applicant]
Volz E. et al., “Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity”, [cited by applicant]
Voysey M. et al., “Safety and Efficacy of the ChAdOx1 nCoV-19 Vaccine (AZD1222) Against SARS-CoV-2: An Interim Analysis of Four Randomised Controlled Trials in Brazil South Africa and the UK”, [cited by applicant]
Walls A.C. et al., “Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein”, [cited by applicant]
Wan Y. et al., “Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry”, [cited by applicant]
Wang P. et al., “Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization”, [cited by applicant]
Wang Y. et al., “mRNA Vaccine: A Potential Therapeutic Strategy”, [cited by applicant]
Weisblum Y. et al., “Escape from Neutralizing Antibodies by SARS-CoV-2 Spike Protein Variants”, [cited by applicant]
Wu K. et al., mRNA-1273 Vaccine Induces Neutralizing Antibodies Against Spike Mutants from Global SARS-CoV-2 Variants, bioRxiv preprint doi: https://doi.org/10.1101/2021.01.25.427948 (Jan. 25, 2021). [cited by applicant]
Wu Y. et al., “A Noncompeting Pair of Human Neutralizing Antibodies Block DOVID-19 Virus Binding to its Receptor ACE2”, [cited by applicant]
Planas D. et al., “Sensitivity of Infectious SARS-CoV-2 B.1.1.7 and B.1.351 Variants to Neutralizing Antibodies”, [cited by applicant]
Polack F.P. et al., “Safety and Efficacy of the BNT162v2 mRNA Covid-19 Vaccine”, [cited by applicant]
Polack F.P. et al., “Safety and Efficacy of the BNT162 mRNA Covid-19 Vaccine”, [cited by applicant]
Pond S.L.K. et al., “HyPhy: Hypothesis Testing Using Phylogenies”, [cited by applicant]
Raab D. et al., “The GeneOptimizer Algorithm: Using a Sliding Window Approach to Cope With the Vast Sequence Space in Multiparameter DNA Sequence Optimization”, [cited by applicant]
Resende P C, “Spike E484K Mutation in the First SARS-CoV-2 Reinfection Case Confirmed in Brazil, 2020”, (Jan. 2021), [Posted on www.virological.org on Jan. 10, 2021]) Website printed pdf. [cited by applicant]
Richert L. et al., “T Cell Immunogenicity, Gene Expression Profile, and Safety of Four Heterologous Prime-Boost Combinations of HIV Vaccine Candidates in Healthy Volunteers: Results of the Randomized Multi-Arm Phase I/I… [cited by applicant]
Robbiani D.F. et al., “Convergent Antibody Responses to SARS-CoV-2 in Covalescent Individuals”, [cited by applicant]
Sadoff J. et al., “Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine Against Covid-19”, [cited by applicant]
Sali A. et al., “Comparative Protein Modelling by Satisfaction of Spatial Restraints”, [cited by applicant]
Alberer M. et al., “Safety and Immunogenicity of a mRNA Rabies Vaccine in Healthy Adults: An Open-Label, Non-Randomised, Prospective, First-in-Human Phase 1 Clinical Trial”, Lancet 390(10101):1511-1520 (Sep. 2017). [cited by applicant]
Altschul S.F. et al., “Issues in Searching Molecular Sequence Databases”, Nature Genetics 6:119-129 (Feb. 1994). [cited by applicant]
Altschul S.F. et al., “Basic Local Alignment Search Tool”, J. Mol. Biol. 215:403-410 (1990). [cited by applicant]
Amanat F. et al., “A Serological Assay to Detect SARS-CoV-2 Seroconversion in Humans”, Nature Medicine 26:1033-1036 (Jul. 2020). [cited by applicant]
Asbach B. et al., “Priming With a Potent HIV-1 DNA Vaccine Frames the Quality of Immune Responses Prior to a Poxvirus and Protein Boost”, Journal of Virology 93(3):e01529-18 (Feb. 2019). [cited by applicant]
Baden L.R. et al., “Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine”, The New England Journal of Medicine 384(5):403-416 (Feb. 4, 2021). [cited by applicant]
Barnes C.O. et al., “SARS-CoV-2 Neutralizing Antibody Structures Inform Therapeutic Strategies”, Nature 588:682-687 (Dec. 24/31, 2020). [cited by applicant]
Barouch D.H. et al., “A Human T-Cell Leukemia Virus Type 1 Regulatory Element Enhances the Immunogenicity of Human Immunodeficiency Virus Type 1 DNA Vaccines in Mice and Nonhuman Primates”, Journal of Virology 79(14):88… [cited by applicant]
Berman H.M. et al., “The Protein Data Bank”, Nucleic Acids Research 28(1):235-242 (2000). [cited by applicant]
Boussif O. et al., “A Versatile Vector for Gene and Oligonucleotide Transfer into Cells in Culture and In Vivo: Polyethylenimine”, Proc. Natl. Acad. Sci. USA 92:7297-7301 (Aug. 1995). [cited by applicant]
Callaway E., “Delta Coronavirus Variant: Scientists Brace for Impact”, Nature 595:17-18 (Jul. 1, 2021). [cited by applicant]
Campanella J.J. et al., “MatGAT: An Application that Generates Similarity/Identity Matrices Using Protein or DNA Sequences”, BMC Bioinformatics 4(296) (2003). [cited by applicant]
Campbell F. et al., “Increased Transmissibility and Global Spread of SARS-CoV-2 Variants of Concern as at Jun. 2021”, Euro Surveill 26(24):pii=2100509 (2021). [cited by applicant]
Carnell G.W. et al., “SARS-CoV-2 Spike Protein Arrested in the Closed State Induces Potent Neutralizing Responses”, bioRxiv preprint doi: https://doi.org/10.1101/2021.01.14.426695 (Jan. 14, 2021). [cited by applicant]
Carnell G.W. et al., “SARS-CoV-2 Spike Protein Stabilized in the Closed State Induces Potent Neutralizing Responses”, Journal of Virology 95(15):e00203-21 (Aug. 2021). [cited by applicant]
Carnell G. et al., “An Optimized Method for Production Using PEI, Titration and Neutralization of SARS-CoV Spike Luciferase Pseudotypes”, Bio Protoc. 7(16):e2514 (Aug. 20, 2017). [cited by applicant]
Chakraborty S. et al., “Symptomatic SARS-CoV-2 Infections Display Specific IgG Fc Structures”, medRxiv preprint doi: https://doi.org.10.1101/2020.05.15.20103341 (Nov. 2020). [cited by applicant]
Choi Y. et al., “Viral Vectors for Vaccine Applications”, Clin Exp Vaccine Res 2:97-105 (2013). [cited by applicant]
Clay C. et al., “Primary Severe Acute Respiratory Syndrome Coronavirus Infection Limits Replication But Not Lung Inflammation Upon Homologous Rechallenge”, Journal of Virology 86(8):4234-4244 (Apr. 2012). [cited by applicant]
Corbett K.S. et al., “SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness”, Nature 586(7830):567-571 (Oct. 2020). [cited by applicant]
Corpet F., “Multiple Sequence Alignment With Hierarchical Clustering”, Nucleic Acids Research 16(22):10881-10890 (1988). [cited by applicant]
Dai L. et al., “A Universal Design of Betacoronavirus Vaccines Against COVID-19, MERS, and SARS”, Cell 182:722-733 (Aug. 6, 2020). [cited by applicant]
Daly C. et al., “Needle-Free Injectors for Mass Administration of Fractional Dose Inactivated Poliovirus Vaccine in Karachi, Pakistan: A Survey of Caregiver and Vaccinator Acceptability”, Vaccine 38:1893-1898 (2020). [cited by applicant]
Dong N. et al., “Genomic and Protein Structure Modelling Analysis Depicts the Origin and Infectivity of 2019-nCoV, a New Coronavirus Which Caused a Pneumonia Outbreak in Wuhan, China”, bioRxiv preprint doi: https://doi.… [cited by applicant]
Du L. et al., “Neutralizing Antibodies for the Prevention and Treatment of COVID-19”, Cellular & Molecular Immunology 18:2293-2306 (2021). [cited by applicant]
Du L. et al., “Introduction of Neutralizing Immunogenicity Index to the Rational Design of MERS Coronavirus Subunit Vaccines”, Nature Communications 7:13473 (2016). [cited by applicant]
Fehr A.R. et al., “Coronaviruses: An Overview of Their Replication and Pathogenesis”, Coronaviruses: Methods and Protocols, Methods in Molecular Biology 1282:1-23 (2015). [cited by applicant]
Garcia-Beltran W.F. et al., “Multiple SARS-CoV-2 Variants Escape Neutralization by Vaccine-Induced Humoral Immunity”, Cell 184:2372-2383 (Apr. 29, 2021). [cited by applicant]
Greaney A.J. et al., “Comprehensive Mapping of Mutations to the SARS-CoV-2 Receptor-Binding Domain that Affect Recognition by Polyclonal Human Serum Antibodies”, bioRxiv. [Preprint posted online Jan. 4, 2021]. [cited by applicant]
Grifoni A. et al., “Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans With COVID-19 Disease and Unexposed Individuals”, Cell 181:1489-1501 (Jun. 25, 2020). [cited by applicant]
Higgins D.G. et al., Fast and Sensitive Multiple Sequence Alignments on a Microcomputer, Comput Appl Biosci. 5(2):151-153 (Apr. 1989). [cited by applicant]
Higgins D.G. et al., “Clustal: A Package for Performing Multiple Sequence Alignment on a Microcomputer”, Gene 73:237-244 (1988). [cited by applicant]
Hoepel W. et al., “Anti-SARS-CoV-2 IgG from Severely III COVID-19 Patients Promotes Macrophage Hyper-Inflammatory Responses”, bioRxiv preprint doi: https://doi.org/10.1101/2020.07.13.190140 (Jul. 13, 2020). [cited by applicant]
Hoffmann M. et al., “SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and is Blocked by a Clinically Proven Protease Inhibitor”, Cell 181:271-280 (Apr. 16, 2020). [cited by applicant]
Horby P. et al., Nervtag Note on B.1.1.7 Severity. SAGE Meeting Report (Jan. 21, 2021). [cited by applicant]
Horspool A.M. et al., “SARS-CoV-2 B. 1.1.7 and B.1.351 Variants of Concern Induce Lethal Disease in K18-hACE2 Transgenic Mice Despite Convalescent Plasma Therapy”, bioRxiv preprint doi: https://doi.org/10.1101/2021.05.0… [cited by applicant]
Hou X. et al., “Lipid Nanoparticles for mRNA Delivery”, Nature 6:1078-1094 (Dec. 2021). [cited by applicant]
Hu B. et al., “Discovery of a Rich Gene Pool of Bat SARS-Related Coronaviruses Provides New Insights into the Origin of SARS Coronavirus”, PLoS Pathog 13(11):e1006698 (2017). [cited by applicant]
Huang A. T. et al., A Systematic Review of Antibody Mediated Immunity to Coronaviruses: Antibody Kinetics, Correlates of Protection, and Association of Antibody Responses With Severity of Disease, medRxiv preprint doi: … [cited by applicant]
Hubert B. et al., “The CureVac Vaccine, and a Brief Tour Through Some of the Wonders of Nature”, URL https://berthub.eu/articles/posts/curevac-vaccine-and-wonders-of-biology/.(accessed Sep. 15, 2021). [cited by applicant]
Hunter J.D., “Matplotlib: A 2D Graphics Environment”, Computing in Science & Engineering 9(3):90-95(May/Jun. 2007). [cited by applicant]
Jaume M. et al., “Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH- and Cystein Protease-Independent FcγR Pathway”, Journal of Virology 85(20):10582-10… [cited by applicant]
Jeong D-E et al., “Assemblies of Putative SARS-CoV2-Spike-Encoding mRNA Sequences for Vaccines BNT-162b2 and mRNA-1273”, https://virological.org/t/assemblies-of-putative-sars-cov2-spike-encoding-mrna-sequences-for-vacci… [cited by applicant]
Jo W.K. et al., “The Evolutionary Dynamics of Endemic Human Coronaviruses”, Virus Evolution 7(1):veab020 (2021). [cited by applicant]
Jordan I. et al., “A Deleted Deletion Site in a New Vector Strain and Exceptional Gemomic Stability of Plaque-Purified Modified Vaccina Ankara (MVA)”, Virologica Sinica 35:212-226 (2020). [cited by applicant]
Jordan I. et al., “A Genotype of Modified Vaccinia Ankara (MVA) that Facilitations Replication in Suspension Cultures in Chemically Defined Medium”, Viruses 5:321-339 (2013). [cited by applicant]
Jordan I. et al., “A Chemically Defined Production Process for Highly Attenuated Poxviruses”, Biologicals 39:50-58 (2011). [cited by applicant]
Joseph S. et al., “A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes”, Frontiers in Immunology 8(149):1-14 (Feb. 2017). [cited by applicant]
Korber B. et al., “Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus”, Cell 182:812-827 (Aug. 20, 2020). [cited by applicant]
Krivov G.G. et al., “Improved Prediction of Protein Side-Chain Conformations With SCWRL4”, Proteins 77(4):778-795 (Dec. 2009). [cited by applicant]
Tai W. et al., “Characterization of the Receptor-Binding Domain (RBD) of 2019 Novel Coronavirus: Implication for Development of RBD Protein as a Viral Attachment Inhibitor and Vaccine”, [cited by applicant]
Tay M Z et al., “The Trinity of COVID-19: Immunity, Inflammation and Intervention”, [cited by applicant]
Teixeira L. et al., “A First-in-Human Phase I Study of INVAC-1, an Optimized Human Telomerase DNA Vaccine in Patients With Advanced Solid Tumors”, [cited by applicant]
Tian F. et al., “Mutation N501Y in RBD of Spike Protein Strengthens the Inter-Action Between COVID-19 and its Receptor ACE2”, bioRxiv preprint doi: https://doi.org/10.1101/2021.02.14.431117 (Feb. 15, 2021). [cited by applicant]
Traggiai E. et al., “An Efficient Method to Make Human Monoclonal Antibodies from Memory B Cells: Potent Neutralization of SARS Coronavirus”, [cited by applicant]
Tse L. V. et al., “The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses”, [cited by applicant]
Tseng C-T et al., “Immunization With SARS Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge With the SARS Virus”, [cited by applicant]
Ura T. et al., “Developments in Viral Vector-Based Vaccines”, [cited by applicant]
Van Derr Spoel D. et al., “Gromacs: Fast, Flexible, and Free”, [cited by applicant]
Viana R. et al., “Rapid Epidemic Expansion of the SARS-CoV-2 Omicron Variant in Southern Africa”, [cited by applicant]
Zhou B. et al., “SARS-CoV-2 Spike D614G Variant Confers Enhanced Replication and Transmissibility”, bioRxiv preprint doi: https://doi.org/10.1101/2020.10.27_357558 (Oct. 27, 2020). [cited by applicant]
Xiao K. et al., “Isolation and Characterization of 2019-nCoV-Like Coronavirus from Malayan Pangolins”, bioRxiv preprint doi: https://doi.org/10.1101/2020.02.17.951335 (Feb. 20, 2020). [cited by applicant]
Xiong X. et al., “A Thermostable, Closed SARS-CoV-2 Spike Protein Trimer”, [cited by applicant]
Xue T. et al., “Single Point Mutations Can Potentially Enhance Infectivity of SARS-CoV-2 Revealed by In Silico Affinity Maturation and SPR Assay”, [cited by applicant]
Yuan M. et al., “A Highly Conserved Cryptic Epitope in the Receptor Binding Domains of SARS-CoV-2 and SARS-CoV”, [cited by applicant]
Watanabe Y. et al., “Structure of the Lassa Virus Glycan Shield Provides a Model for Immunological Resistance”, [cited by applicant]
Schymkowitz J. et al., “The FoldX Web Server: An Online Force Field”, [cited by applicant]
Edgar R.C., “Muscle: A Multiple Sequence Alignment Method With Reduced Time and Space Complexity”, [cited by applicant]
Hatcher E.L. et al., “Virus Variation Resource—Improved Response to Emergent Viral Outbreaks”, [cited by applicant]
Hwang W.C. et al., “Structural Basis of Neutralization by a Human Anti-Severe Acute Respiratory Syndrome Spike Protein Antibody, 80R”, [cited by applicant]
International Search Report and Written Opinion dated Jan. 25, 2023 received in International Application No. PCT/GB2022/052537. [cited by applicant]