Improving Flu Vaccines With Novel Adjuvants
Increasing antibody production and virus cross-reactivity with small molecule integrin inhibitors
Integrins are transmembrane proteins that function in cell adhesion and signaling. Drugs are in development and on the market that target integrins to treat cancer, eye diseases, and fibrotic conditions. Dr. Mridu Acharya is identifying small, integrin-targeting compounds for a different application – as influenza vaccine adjuvants.
Dr. Acharya and collaborators identified novel functions for integrins in antibody-producing B cells. They found that integrins regulate toll-like receptor (TLR) mediation of B cells as they mature, expand, and differentiate into long-lived memory cells and plasma cells that generate pathogen-directed antibodies. These cells are the key to long-term vaccine protection.
The Acharya group found that deleting the av integrin from B cells in a mouse model prolongs TLR signaling to increase B cell activity. Activities stimulated by integrin deletion include and generation of memory and plasma B cells and antibody production.
In findings with major implications for influenza vaccines, Dr. Acharya showed that integrin-knockout mice have improved responses to immunization with an inactivated influenza virus. Compared to mice in which integrin was not deleted, knockout mice produced three times more antibody, with titers increasing after a booster injection. The integrin-knockout mice produced more long-lived B cells, indicating the potential for extended vaccination responses. Integrin-knockout mice generated more diverse antibodies than control mice. Mice lacking integrin made antibodies with greater cross-reactivity to an influenza virus that was not included in their vaccine. These responses had clinical effects: After infection with influenza virus, vaccinated integrin-knockout mice survived while most vaccinated control mice did not.
Current influenza vaccines target only a few of the dozens of influenza virus subtypes. Increasing the diversity of antibodies produced after immunization could lead to vaccines that protect against more viral subtypes. Dr. Acharya’s group is using in vitro and in vivo systems to identify integrin inhibitors that are specific to B cells and reproduce the vaccine-enhancing effects of integrin knockout. The compounds could be applied, possibly in combination with TLR ligands that are already used as vaccine adjuvants, to increase and broaden the response to influenza vaccines. In more recent work, the Acharya group identified a role for peptide inhibitors of integrins in enhancing expansion of human memory B cells. Current work in the lab is focused on investigating this feature and devising methods to use this aspect of integrin inhibition to specifically expand vaccine-induced human memory B cells.
Dr. Acharya’s research focuses on how B cells respond to pathogens while maintaining self-tolerance. She contributes her expertise to B cell-editing projects with Drs. Richard James and David Rawlings. She is interested in partnerships to develop integrin-targeting compounds as vaccine adjuvants or drugs that modulate B cells to treat autoimmunity.
Stage of Development
- Pre-clinical in vitro and in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Acharya M, Raso F, Sagadiev S, et al. B Cell αv integrins regulate TLR-driven autoimmunity. J Immunol. 2020;205(7):1810-1818.
- Raso F, Sagadiev S, Du S, Gage E, Arkatkar T, Metzler G, Stuart LM, Orr MT, Rawlings DJ, Jackson SW, Lacy-Hulbert A, Acharya M. αv Integrins regulate germinal center B cell responses through noncanonical autophagy. J Clin Invest. 2018;128(9):4163-4178. doi: 10.1172/JCI99597.
- Acharya M, Sokolovska A, Tam JM, Conway KL, Stefani C, Raso F, Mukhopadhyay S, Feliu M, Paul E, Savill J, Hynes RO, Xavier RJ, Vyas JM, Stuart LM, Lacy-Hulbert A. αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells. Nat Commun. 2016;7:10917. doi: 10.1038/ncomms10917.
- Edkins AL, Borland G, Acharya M, Cogdell RJ, Ozanne BW, Cushley W. Differential regulation of monocyte cytokine release by αV and β(2) integrins that bind CD23. Immunol. 2012;136(2):241-51. doi: 10.1111/j.1365-2567.2012.03576.x.
- Borland G, Edkins AL, Acharya M, Matheson J, White LJ, Allen JM, Bonnefoy JY, Ozanne BW, Cushley W. αVβ5 integrin sustains growth of human pre-B cells through an RGD-independent interaction with a basic domain of the CD23 protein. Journal of Biological Chemistry. 2007 Sep 14; 282(37):27315-26.