Unmodified Rabies MRNA Vaccine Elicits High Cross-neutralizing Antibody Titers and Diverse B Cell Memory Responses

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jun 22

PMID 37349310

Authors

Fredrika Hellgren

Alberto Cagigi

Rodrigo Arcoverde Cerveira

Sebastian Ols

Theresa Kern

Ang Lin

Bengt Eriksson

Michael G Dodds

Edith Jasny

Kim Schwendt

Conrad Freuling

Thomas Muller

Martin Corcoran

Gunilla B Karlsson Hedestam

Benjamin Petsch

Karin Lore

Affiliations

Soon will be listed here.

Abstract

Licensed rabies virus vaccines based on whole inactivated virus are effective in humans. However, there is a lack of detailed investigations of the elicited immune response, and whether responses can be improved using novel vaccine platforms. Here we show that two doses of a lipid nanoparticle-formulated unmodified mRNA vaccine encoding the rabies virus glycoprotein (RABV-G) induces higher levels of RABV-G specific plasmablasts and T cells in blood, and plasma cells in the bone marrow compared to two doses of Rabipur in non-human primates. The mRNA vaccine also generates higher RABV-G binding and neutralizing antibody titers than Rabipur, while the degree of somatic hypermutation and clonal diversity of the response are similar for the two vaccines. The higher overall antibody titers induced by the mRNA vaccine translates into improved cross-neutralization of related lyssavirus strains, suggesting that this platform has potential for the development of a broadly protective vaccine against these viruses.

Citing Articles

Infection and Prevention of Rabies Viruses.

Chen S, Rai C, Wang S, Chen Y Microorganisms. 2025; 13(2).

PMID: 40005749 PMC: 11858514. DOI: 10.3390/microorganisms13020380.

Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations.

Aditham A, Radford C, Carr C, Jasti N, King N, Bloom J bioRxiv. 2025; .

PMID: 39763725 PMC: 11702696. DOI: 10.1101/2024.12.17.628970.

A nucleoside-modified rabies mRNA vaccine induces long-lasting and comprehensive immune responses in mice and non-human primates.

Wang Y, Wang S, Huang L, Haung L, Mao W, Li F Mol Ther. 2025; 33(2):548-559.

PMID: 39741409 PMC: 11853375. DOI: 10.1016/j.ymthe.2024.12.041.

IL-7 promotes mRNA vaccine-induced long-term immunity.

Wang L, Wan J, He W, Wang Z, Wu Q, Zhou M J Nanobiotechnology. 2024; 22(1):716.

PMID: 39550592 PMC: 11568559. DOI: 10.1186/s12951-024-02993-5.

Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications.

Shi Y, Shi M, Wang Y, You J Signal Transduct Target Ther. 2024; 9(1):322.

PMID: 39543114 PMC: 11564800. DOI: 10.1038/s41392-024-02002-z.

References

Fooks A, Cliquet F, Finke S, Freuling C, Hemachudha T, Mani R . Rabies. Nat Rev Dis Primers. 2017; 3:17091. DOI: 10.1038/nrdp.2017.91. View

Johnson N, Cunningham A, Fooks A . The immune response to rabies virus infection and vaccination. Vaccine. 2010; 28(23):3896-901. DOI: 10.1016/j.vaccine.2010.03.039. View

World Health Organization . Rabies vaccines: WHO position paper, April 2018 - Recommendations. Vaccine. 2018; 36(37):5500-5503. DOI: 10.1016/j.vaccine.2018.06.061. View

Ashwathnarayana D, Madhusudana S, Sampath G, Sathpathy D, Mankeshwar R, Ravish H . A comparative study on the safety and immunogenicity of Purified duck embryo vaccine [corrected] (PDEV, Vaxirab) with purified chick embryo cell vaccine (PCEC, Rabipur) and purifed vero cell rabies vaccine (PVRV, Verorab). Vaccine. 2009; 28(1):148-51. DOI: 10.1016/j.vaccine.2009.09.090. View

Warrell M . Current rabies vaccines and prophylaxis schedules: preventing rabies before and after exposure. Travel Med Infect Dis. 2012; 10(1):1-15. DOI: 10.1016/j.tmaid.2011.12.005. View

Tran C, Kligerman M, Andrecy L, Etheart M, Adrien P, Blanton J . Rabies vaccine initiation and adherence among animal-bite patients in Haiti, 2015. PLoS Negl Trop Dis. 2018; 12(11):e0006955. PMC: 6258545. DOI: 10.1371/journal.pntd.0006955. View

Ngugi J, Maza A, Omolo O, Obonyo M . Epidemiology and surveillance of human animal-bite injuries and rabies post-exposure prophylaxis, in selected counties in Kenya, 2011-2016. BMC Public Health. 2018; 18(1):996. PMC: 6085719. DOI: 10.1186/s12889-018-5888-5. View

Lafon M, WIKTOR T, MacFarlan R . Antigenic sites on the CVS rabies virus glycoprotein: analysis with monoclonal antibodies. J Gen Virol. 1983; 64 (Pt 4):843-51. DOI: 10.1099/0022-1317-64-4-843. View

Seif I, Coulon P, Rollin P, Flamand A . Rabies virulence: effect on pathogenicity and sequence characterization of rabies virus mutations affecting antigenic site III of the glycoprotein. J Virol. 1985; 53(3):926-34. PMC: 254728. DOI: 10.1128/JVI.53.3.926-934.1985. View

10.

Benmansour A, Leblois H, Coulon P, Tuffereau C, Gaudin Y, Flamand A . Antigenicity of rabies virus glycoprotein. J Virol. 1991; 65(8):4198-203. PMC: 248855. DOI: 10.1128/JVI.65.8.4198-4203.1991. View

11.

Dietzschold B, Gore M, Casali P, Ueki Y, Rupprecht C, Notkins A . Biological characterization of human monoclonal antibodies to rabies virus. J Virol. 1990; 64(6):3087-90. PMC: 249498. DOI: 10.1128/JVI.64.6.3087-3090.1990. View

12.

Bakker A, Marissen W, Kramer R, Rice A, Weldon W, Niezgoda M . Novel human monoclonal antibody combination effectively neutralizing natural rabies virus variants and individual in vitro escape mutants. J Virol. 2005; 79(14):9062-8. PMC: 1168753. DOI: 10.1128/JVI.79.14.9062-9068.2005. View

13.

Goudsmit J, Marissen W, Weldon W, Niezgoda M, Hanlon C, Rice A . Comparison of an anti-rabies human monoclonal antibody combination with human polyclonal anti-rabies immune globulin. J Infect Dis. 2006; 193(6):796-801. DOI: 10.1086/500470. View

14.

Sloan S, Hanlon C, Weldon W, Niezgoda M, Blanton J, Self J . Identification and characterization of a human monoclonal antibody that potently neutralizes a broad panel of rabies virus isolates. Vaccine. 2007; 25(15):2800-10. DOI: 10.1016/j.vaccine.2006.12.031. View

15.

De Benedictis P, Minola A, Rota Nodari E, Aiello R, Zecchin B, Salomoni A . Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis. EMBO Mol Med. 2016; 8(4):407-21. PMC: 4818751. DOI: 10.15252/emmm.201505986. View

16.

Lafage M, Weber P, Badrane H, Tordo N, Lafon M . Protective activity of a murine monoclonal antibody against European bat lyssavirus 1 (EBL1) infection in mice. Vaccine. 1993; 11(12):1259-66. DOI: 10.1016/0264-410x(93)90052-y. View

17.

de Melo G, Sonthonnax F, Lepousez G, Jouvion G, Minola A, Zatta F . A combination of two human monoclonal antibodies cures symptomatic rabies. EMBO Mol Med. 2020; 12(11):e12628. PMC: 7645379. DOI: 10.15252/emmm.202012628. View

18.

Muller T, Dietzschold B, Ertl H, Fooks A, Freuling C, Fehlner-Gardiner C . Development of a mouse monoclonal antibody cocktail for post-exposure rabies prophylaxis in humans. PLoS Negl Trop Dis. 2009; 3(11):e542. PMC: 2765635. DOI: 10.1371/journal.pntd.0000542. View

19.

Schnee M, Vogel A, Voss D, Petsch B, Baumhof P, Kramps T . An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs. PLoS Negl Trop Dis. 2016; 10(6):e0004746. PMC: 4918980. DOI: 10.1371/journal.pntd.0004746. View

20.

Alberer M, Gnad-Vogt U, Hong H, Mehr K, Backert L, Finak G . Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet. 2017; 390(10101):1511-1520. DOI: 10.1016/S0140-6736(17)31665-3. View