Magnitude and breadth of antibody cross-reactivity induced by recombinant influenza hemagglutinin trimer vaccine is enhanced by combination adjuvants

• Published in: Scientific reports Vol. 12; no. 1; pp. 9198 - 20
• Main Authors: Hernandez-Davies, Jenny E, Dollinger, Emmanuel P, Pone, Egest J, Felgner, Jiin, Liang, Li, Strohmeier, Shirin, Jan, Sharon, Albin, Tyler J, Jain, Aarti, Nakajima, Rie, Jasinskas, Algimantas, Krammer, Florian, Esser-Kahn, Aaron, Felgner, Philip L, Nie, Qing, Davies, D Huw
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 02.06.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adjuvants; Adjuvants, Immunologic - pharmacology; Adjuvants, Pharmaceutic; Animals; Antibodies; Antibodies, Viral; CD4 antigen; CD8 antigen; Cross-reactivity; Cytokines; DNA microarrays; Hemagglutinins; Humans; Immunization; Immunogenicity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin G - chemistry; Influenza; Influenza Vaccines - immunology; Influenza, Human; Lymphocytes B; Lymphocytes T; Mice; Mice, Inbred BALB C; Protein arrays; Squalene; Toll-like receptors; Transcriptomics; Trimers; Vaccines; Vaccines, Synthetic - immunology; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-12727-y

The effects of adjuvants for increasing the immunogenicity of influenza vaccines are well known. However, the effect of adjuvants on increasing the breadth of cross-reactivity is less well understood. In this study we have performed a systematic screen of different toll-like receptor (TLR) agonists, with and without a squalene-in-water emulsion on the immunogenicity of a recombinant trimerized hemagglutinin (HA) vaccine in mice after single-dose administration. Antibody (Ab) cross-reactivity for other variants within and outside the immunizing subtype (homosubtypic and heterosubtypic cross-reactivity, respectively) was assessed using a protein microarray approach. Most adjuvants induced broad IgG profiles, although the response to a combination of CpG, MPLA and AddaVax (termed 'IVAX-1') appeared more quickly and reached a greater magnitude than the other formulations tested. Antigen-specific plasma cell labeling experiments show the components of IVAX-1 are synergistic. This adjuvant preferentially stimulates CD4 T cells to produce Th1>Th2 type (IgG2c>IgG1) antibodies and cytokine responses. Moreover, IVAX-1 induces identical homo- and heterosubtypic IgG and IgA cross-reactivity profiles when administered intranasally. Consistent with these observations, a single-cell transcriptomics analysis demonstrated significant increases in expression of IgG1, IgG2b and IgG2c genes of B cells in H5/IVAX-1 immunized mice relative to naïve mice, as well as significant increases in expression of the IFNγ gene of both CD4 and CD8 T cells. These data support the use of adjuvants for enhancing the breath and durability of antibody responses of influenza virus vaccines.