	US 11,969,466 B2
	Stabilized influenza hemagglutinin stem region trimers and uses thereof
John R. Mascola, Rockville, MD (US); Jeffrey C. Boyington, Clarksburg, MD (US); Hadi M. Yassine, Doha (QA); Peter D. Kwong, Washington, DC (US); Barney S. Graham, Smyrna, GA (US); and Masaru Kanekiyo, North Bethesda, MD (US)
Assigned to The United States of America, as represented by the Secretary, Department of Health and Human Services, Bethesda, MD (US)
Filed by The United States of America, as represented by the Secretary, Department of Health and Human Services, Bethesda, MD (US)
Filed on May 8, 2023, as Appl. No. 18/314,052.
Application 18/314,052 is a division of application No. 17/504,002, filed on Oct. 18, 2021, granted, now 11,679,151.
Application 17/504,002 is a division of application No. 16/455,242, filed on Jun. 27, 2019, granted, now 11,147,867, issued on Oct. 19, 2021.
Application 16/455,242 is a division of application No. 15/313,265, granted, now 10,363,301, issued on Jul. 30, 2019, previously published as PCT/US2015/032695, filed on May 27, 2015.
Claims priority of provisional application 62/003,471, filed on May 27, 2014.
Prior Publication US 2023/0330210 A1, Oct. 19, 2023
Int. Cl. A61K 39/145 (2006.01); A61K 39/12 (2006.01); C07K 14/005 (2006.01); C07K 14/47 (2006.01); C12N 7/00 (2006.01); A61K 39/00 (2006.01)

CPC A61K 39/145 (2013.01) [A61K 39/12 (2013.01); C07K 14/005 (2013.01); C07K 14/47 (2013.01); C12N 7/00 (2013.01); A61K 2039/55555 (2013.01); A61K 2039/55566 (2013.01); A61K 2039/6031 (2013.01); C07K 2319/00 (2013.01); C12N 2760/16122 (2013.01); C12N 2760/16134 (2013.01)]

20 Claims

1. A method to vaccinate an individual against influenza virus, comprising administering to the individual a nanoparticle comprising a protein construct, the protein construct comprising:

an HA protein domain and a linker sequence, wherein the HA protein domain comprises the sequence of an influenza hemagglutinin (HA) protein that lacks at least 95% of the head region amino acid sequence, and in place of the missing sequence comprises a first linker sequence, wherein the first linker sequence is less than 10 amino acids in length; and wherein the HA protein domain comprises at least one alteration selected from the group consisting of:

a. deletion of the amino acid region corresponding to amino acids N403-W435 of the internal loop region of the influenza HA protein set forth as SEQ ID NO: 8, wherein the resulting ends of the HA protein are joined directly together;

b. replacement of the amino acid sequence corresponding to the internal loop region with a second linker sequence; and,

c. substitution of at least one amino acid residue in a pair of amino acid residues in the HA protein domain, wherein the pair of amino acid residues form a noncovalent bond in the folded HA protein; and, wherein the strength of the noncovalent bond between the amino acid pair in the folded protein construct is greater than the strength of the non-covalent bond between the amino acid pair in a folded wild-type HA protein.