Headless hemagglutinin-containing influenza viral particles direct immune responses toward more conserved epitopes.

Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE

Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.

Influenza Vaccines*/immunology ; Hemagglutinin Glycoproteins, Influenza Virus*/immunology ; Hemagglutinin Glycoproteins, Influenza Virus*/genetics ; Antibodies, Viral*/immunology ; Epitopes*/immunology ; Orthomyxoviridae Infections*/immunology ; Orthomyxoviridae Infections*/prevention & control ; Orthomyxoviridae Infections*/virology; Animals ; Mice ; Humans ; Female ; Neuraminidase/immunology ; Neuraminidase/genetics ; Virion/immunology ; Influenza, Human/immunology ; Influenza, Human/prevention & control ; Influenza, Human/virology ; Mice, Inbred BALB C ; Dogs ; Antibodies, Neutralizing/immunology ; Madin Darby Canine Kidney Cells ; Influenza A Virus, H1N1 Subtype/immunology

Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epitopes, we generated an influenza virus particle where the full-length hemagglutinin protein was replaced with a membrane-anchored, "headless" variant while retaining the normal complement of other viral structural proteins such as the neuraminidase as well as viral RNAs. We found that a single administration of a headless virus particle-based vaccine elicited high titers of antibodies that recognized more conserved epitopes on the major viral glycoproteins. Furthermore, the vaccine could elicit these responses even in the presence of pre-existing, hemagglutinin (HA) head-focused influenza immunity. Importantly, these antibody responses mediated protective, but non-neutralizing functions such as neuraminidase inhibition and antibody-dependent cellular cytotoxicity. Additionally, we show the vaccine can provide protection from homologous and heterologous challenges in mouse models of severe influenza without any measurable HA head-directed antibody responses. Thus, headless hemagglutinin containing viral particles may represent a tool to drive the types of antibody responses predicted to increase influenza vaccine breadth and durability.IMPORTANCECurrent seasonal influenza vaccines provide incomplete protection from disease. This is partially the result of the antibody response being directed toward parts of the virus that are tolerant of mutations. Redirecting the immune response to more conserved regions of the virus has been a central strategy of next-generation vaccine designs and approaches. Here, we develop and test a vaccine based on a modified influenza virus particle that expresses a partially deleted hemagglutinin protein along with the other viral structural proteins. We demonstrate this vaccine elicits antibodies that recognize the more conserved viral epitopes of the hemagglutinin stalk and neuraminidase protein to facilitate protection against influenza viruses despite a lack of classical viral neutralization activity.
Competing Interests: Duke University has filed for intellectual property protection of the vaccine production approaches and antigen designs described in this work.

Sci Rep. 2018 Jul 11;8(1):10432. (PMID: 29992986)
Front Immunol. 2021 Sep 16;12:746447. (PMID: 34603333)
PLoS Med. 2007 Feb;4(2):e59. (PMID: 17298168)
Viruses. 2014 Jun 23;6(6):2465-94. (PMID: 24960271)
J Virol. 2015 Jul;89(14):7224-34. (PMID: 25948745)
J Immunol. 2013 Feb 15;190(4):1837-48. (PMID: 23319732)
J Virol. 2012 Jun;86(11):6179-88. (PMID: 22491456)
Nat Med. 2021 Jan;27(1):106-114. (PMID: 33288923)
Viral Immunol. 1989 Fall;2(3):163-73. (PMID: 2483503)
PLoS One. 2008;3(12):e3942. (PMID: 19079604)
NPJ Vaccines. 2019 Jul 19;4:31. (PMID: 31341648)
J Virol. 2018 Aug 16;92(17):. (PMID: 29925654)
J Infect Dis. 2011 Dec 15;204(12):1879-85. (PMID: 21998477)
NPJ Vaccines. 2017 Sep 14;2:26. (PMID: 29263881)
Science. 2012 Sep 14;337(6100):1343-8. (PMID: 22878502)
Science. 2009 Apr 10;324(5924):246-51. (PMID: 19251591)
J Virol. 2021 Aug 10;95(17):e0075921. (PMID: 34160258)
J Immunol. 1987 Sep 15;139(6):2010-4. (PMID: 3624874)
J Virol. 2021 Mar 3;95(10):. (PMID: 33658342)
Virology. 2019 Sep;535:179-188. (PMID: 31310875)
Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18979-84. (PMID: 20956293)
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):125-30. (PMID: 24344259)
Science. 2011 Aug 12;333(6044):843-50. (PMID: 21737702)
NPJ Vaccines. 2016;1:. (PMID: 29250436)
Nat Med. 2019 Jun;25(6):962-967. (PMID: 31160818)
Nat Med. 2014 Feb;20(2):143-51. (PMID: 24412922)
J Virol. 1993 Oct;67(10):5721-3. (PMID: 8371337)
N Engl J Med. 1972 Jun 22;286(25):1329-32. (PMID: 5027388)
mBio. 2018 Apr 3;9(2):. (PMID: 29615508)
J Virol. 2013 Oct;87(19):10435-46. (PMID: 23903831)
Viruses. 2022 Jul 30;14(8):. (PMID: 36016306)
Acta Virol. 2003;47(4):229-36. (PMID: 15068378)
Lancet Infect Dis. 2022 Jul;22(7):1062-1075. (PMID: 35461522)
mBio. 2010 May 18;1(1):. (PMID: 20689752)
J Clin Virol. 2019 Oct;119:44-52. (PMID: 31491709)
Viruses. 2010;2(8):1530-1563. (PMID: 21442033)
Science. 2011 Aug 12;333(6044):850-6. (PMID: 21798894)
mBio. 2021 Dec 21;12(6):e0224121. (PMID: 34809451)
J Infect Dis. 1974 Apr;129(4):411-20. (PMID: 4593871)
J Infect Dis. 2013 Mar 15;207(6):974-81. (PMID: 23307936)
J Immunol. 1988 Feb 15;140(4):1264-8. (PMID: 2449498)
PLoS One. 2012;7(8):e43603. (PMID: 22928001)
J Virol. 2017 Nov 14;91(23):. (PMID: 28931689)
J Hyg (Lond). 1972 Dec;70(4):767-77. (PMID: 4509641)
Immunohorizons. 2019 Apr 1;3(4):133-148. (PMID: 31032479)
Nat Med. 2015 Sep;21(9):1065-70. (PMID: 26301691)
Nat Rev Drug Discov. 2015 Mar;14(3):167-82. (PMID: 25722244)
NPJ Vaccines. 2018 Nov 29;3:55. (PMID: 30510776)
Viruses. 2022 Jun 14;14(6):. (PMID: 35746776)
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20248-53. (PMID: 24277853)
Vaccines (Basel). 2021 Aug 02;9(8):. (PMID: 34451971)
Virology. 1983 Apr 15;126(1):106-16. (PMID: 6189287)
Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20748-53. (PMID: 22143798)
Science. 2015 Sep 18;349(6254):1301-6. (PMID: 26303961)
Cell Rep Med. 2020 Nov 03;1(8):100130. (PMID: 33294855)
Nat Rev Immunol. 2019 Jun;19(6):383-397. (PMID: 30837674)
J Gen Virol. 2012 Sep;93(Pt 9):1996-2007. (PMID: 22718569)
J Mol Biol. 2017 Aug 18;429(17):2694-2709. (PMID: 28648617)
Proc Natl Acad Sci U S A. 1987 Oct;84(19):6869-73. (PMID: 2958849)
J Virol. 2012 Nov;86(21):11686-97. (PMID: 22896619)
J Virol. 2014 Jan;88(1):699-704. (PMID: 24155380)
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10685-90. (PMID: 20498070)
Virology. 2012 Oct 10;432(1):39-44. (PMID: 22727831)
Cell Rep. 2017 Aug 15;20(7):1503-1512. (PMID: 28813663)

75N93019C00050 United States AI NIAID NIH HHS; PATH Burroughs Wellcome Fund (BWF)

Keywords: HA stalk; influenza A virus; neuraminidase; vaccines

0 (Influenza Vaccines)
0 (Hemagglutinin Glycoproteins, Influenza Virus)
0 (Antibodies, Viral)
0 (Epitopes)
EC 3.2.1.18 (Neuraminidase)
0 (Antibodies, Neutralizing)

Date Created: 20240926 Date Completed: 20241022 Latest Revision: 20241024

20241024

PMC11495035

10.1128/jvi.01166-24

39324791