Cross-Reactive Fc-Fused Single-Domain Antibodies to Hemagglutinin Stem Region Protect Mice from Group 1 Influenza a Virus Infection

Viruses. 2022 Nov 10;14(11):2485. doi: 10.3390/v14112485.


The continued evolution of influenza viruses reduces the effectiveness of vaccination and antiviral drugs. The identification of novel and universal agents for influenza prophylaxis and treatment is an urgent need. We have previously described two potent single-domain antibodies (VHH), G2.3 and H1.2, which bind to the stem domain of hemagglutinin and efficiently neutralize H1N1 and H5N2 influenza viruses in vivo. In this study, we modified these VHHs with Fc-fragment to enhance their antiviral activity. Reformatting of G2.3 into bivalent Fc-fusion molecule increased its in vitro neutralizing activity against H1N1 and H2N3 viruses up to 80-fold and, moreover, resulted in obtaining the ability to neutralize H5N2 and H9N2 subtypes. We demonstrated that a dose as low as 0.6 mg/kg of G2.3-Fc or H1.2-Fc administered systemically or locally before infection could protect mice from lethal challenges with both H1N1 and H5N2 viruses. Furthermore, G2.3-Fc reduced the lung viral load to an undetectable level. Both VHH-Fc antibodies showed in vivo therapeutic efficacy when delivered via systemic or local route. The findings support G2.3-Fc as a potential therapeutic agent for both prophylaxis and therapy of Group 1 influenza A infection.

Keywords: Fc-fusion; VHH; influenza; single-domain antibody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antiviral Agents / therapeutic use
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Hemagglutinins
  • Humans
  • Influenza A Virus, H1N1 Subtype*
  • Influenza A Virus, H5N2 Subtype*
  • Influenza A Virus, H9N2 Subtype*
  • Influenza Vaccines*
  • Influenza, Human* / prevention & control
  • Mice
  • Single-Domain Antibodies*


  • Single-Domain Antibodies
  • Hemagglutinins
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antiviral Agents
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Influenza Vaccines

Grants and funding

This research was funded by the State Assignment of The Ministry of Health of the Russian Federation, number 121031800132-4.