Post-fusion influenza vaccine adjuvanted with SA-2 confers heterologous protection via Th1-polarized, non-neutralizing antibody responses

Vaccine. 2023 Jul 12;41(31):4525-4533. doi: 10.1016/j.vaccine.2023.06.019. Epub 2023 Jun 15.


Development of a universal influenza vaccine that can provide robust and long-lasting protection against heterologous infections is a global public health priority. A variety of vaccine antigens are designed to increase the antigenicity of conserved epitopes to elicit cross-protective antibodies that often lack virus-neutralizing activity. Given the contribution of antibody effector functions to cross-protection, adjuvants need to be added to modulate antibody effector functions as well as to enhance antibody quantity. We previously showed that post-fusion influenza vaccine antigens elicit non-neutralizing but cross-protective antibodies against conserved epitopes. Here, using a murine model, we comparably assessed the adjuvanticity of the newly developed SA-2 adjuvant containing a synthetic TLR7 agonist DSP-0546 and squalene-based MF59 analog as representative Th1- or Th2-type adjuvants, respectively. Both types of adjuvants in the post-fusion vaccine comparably enhanced cross-reactive IgG titers against heterologous strains. However, only SA-2 skewed the IgG subclass into the IgG2c subclass in association to its Th1-polarizing nature. SA-2-enhanced IgG2c responses exhibited antibody-dependent cellular cytotoxicity against heterologous virus strains, without cross-neutralizing activity. Eventually, the SA-2-adjuvanted vaccination provided protection against lethal infection by heterologous H3N2 and H1N1 viruses. Together, we conclude that the combination with a SA-2 is advantageous for enhancing the cross-protective capability of post-fusion HA vaccines that elicit non-neutralizing IgG antibodies.

Keywords: Adjuvant; IgG2; Influenza; Toll-like receptor 7 agonist; Type 1 helper T cell; Vaccine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • Antibodies, Viral
  • Antibody Formation
  • Humans
  • Immunoglobulin G
  • Influenza A Virus, H1N1 Subtype*
  • Influenza A Virus, H3N2 Subtype
  • Influenza Vaccines*
  • Influenza, Human*
  • Mice
  • Orthomyxoviridae Infections*


  • Influenza Vaccines
  • Adjuvants, Immunologic
  • Immunoglobulin G
  • Antibodies, Viral