Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA

Bowen Li; Allen Yujie Jiang; Idris Raji; Caroline Atyeo; Theresa M Raimondo; Akiva G R Gordon; Luke H Rhym; Tahoura Samad; Corina MacIsaac; Jacob Witten; Haseeb Mughal; Taras M Chicz; Yue Xu; Ryan P McNamara; Sangeeta Bhatia; Galit Alter; Robert Langer; Daniel G Anderson

doi:10.1038/s41551-023-01082-6

Enhancing the immunogenicity of lipid-nanoparticle mRNA vaccines by adjuvanting the ionizable lipid and the mRNA

Nat Biomed Eng. 2023 Sep 7. doi: 10.1038/s41551-023-01082-6. Online ahead of print.

Authors

Bowen Li^#^{1

2

3

4

5}, Allen Yujie Jiang^#^{1

2}, Idris Raji^#^{1

2}, Caroline Atyeo^{6

7}, Theresa M Raimondo^{1

2}, Akiva G R Gordon^{1

2}, Luke H Rhym^{1

2}, Tahoura Samad^{1

8}, Corina MacIsaac^{1

9}, Jacob Witten^{1

2}, Haseeb Mughal^{1

10}, Taras M Chicz⁶, Yue Xu³, Ryan P McNamara⁶, Sangeeta Bhatia^{1

8

9

10

11

12

13

14

15}, Galit Alter⁶, Robert Langer^{1

2

8

9}, Daniel G Anderson^{16

17

18

19

20}

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
⁴ Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁷ Division of Medical Sciences, Harvard University, Boston, MA, USA.
⁸ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
¹⁴ Wyss Institute at Harvard, Cambridge, MA, USA.
¹⁵ Howard Hughes Medical Institute, Cambridge, MA, USA.
¹⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
¹⁷ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
¹⁸ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. dgander@mit.edu.
¹⁹ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.
²⁰ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

^# Contributed equally.

PMID: 37679571
DOI: 10.1038/s41551-023-01082-6

Abstract

To elicit optimal immune responses, messenger RNA vaccines require intracellular delivery of the mRNA and the careful use of adjuvants. Here we report a multiply adjuvanted mRNA vaccine consisting of lipid nanoparticles encapsulating an mRNA-encoded antigen, optimized for efficient mRNA delivery and for the enhanced activation of innate and adaptive responses. We optimized the vaccine by screening a library of 480 biodegradable ionizable lipids with headgroups adjuvanted with cyclic amines and by adjuvanting the mRNA-encoded antigen by fusing it with a natural adjuvant derived from the C3 complement protein. In mice, intramuscular or intranasal administration of nanoparticles with the lead ionizable lipid and with mRNA encoding for the fusion protein (either the spike protein or the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) increased the titres of antibodies against SARS-CoV-2 tenfold with respect to the vaccine encoding for the unadjuvanted antigen. Multiply adjuvanted mRNA vaccines may improve the efficacy, safety and ease of administration of mRNA-based immunization.