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Cited by 117Rabies epidemiology and controlRNA Interference and Gene DeliveryVirology and Viral Diseases

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A thermostable messenger RNA based vaccine against rabies

Open access
Stitz, Lothar, Vogel, Annette, Schnee, Margit, Voss, Daniel, Rauch, Susanne, Mutzke, Thorsten, Ketterer, Thomas, Kramps, Thomas, Petsch, Benjamin·2017·PLOS Neglected Tropical Diseases
DOI 10.1371/journal.pntd.0006108PMC PMC5737050
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Abstract

Although effective rabies virus vaccines have been existing for decades, each year, rabies virus infections still cause around 50.000 fatalities worldwide.Most of these cases occur in developing countries, where these vaccines are not available.The reasons for this are the prohibitive high costs of cell culture or egg grown rabies virus vaccines and the lack of a functional cold chain in many regions in which rabies virus is endemic.Here, we describe the excellent temperature resistance of a non-replicating mRNA based rabies virus vaccine encoding the rabies virus glycoprotein (RABV-G).Prolonged storage of the vaccine from -80˚C to up to +70˚C for several months did not impact the protective capacity of the mRNA vaccine.Efficacy after storage was demonstrated by the induction of rabies specific virus neutralizing antibodies and protection in mice against lethal rabies infection.Moreover, storing the vaccine at oscillating temperatures between +4˚and +56˚C for 20 cycles in order to simulate interruptions of the cold chain during vaccine transport, did not affect the vaccine's immunogenicity and protective characteristics, indicating that maintenance of a cold chain is not essential for this vaccine. Author summaryConventional prophylactic vaccines require transport and storage under controlled temperatures in an unbroken cold chain.Therefore, distribution of many vaccines is restricted to areas where the cold chain can be maintained which excludes especially rural areas in many countries from continues vaccine supply.Unfortunately, some diseases that can be prevented by vaccination, like the rabies virus infection, are still endemic in such areas.Therefore, logistic reasons often prevent delivery of life saving vaccines to areas in which they are most needed.Here, we describe an mRNA vaccine encoding the rabies virus glycoprotein (RABV-G) that remains protective in a mouse challenge model upon storage at highly variable temperatures.These results suggest that such a vaccine allows storage outside the cold chain and can therefore reach all areas of the world where rabies

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Fig 1 RABV-G mRNA vaccine stored at temperatures up to +40°C retains immunogenicity and protective for up to twelve months. (A-B: storage for six months). Vaccine or control injections were done on day 0 and 21. Induction of rabies virus neutralizing antibodies was measured on day 35 in mice vaccinated with RABV-G mRNA stored from -80°C to +40°C or HDC stored at the recommended temperature of 4°C for six months (dashed line in A and C indicates the WHO recommended titer of 0.5 international units per ml [IU/ml]). (C, D: storage for twelve months) Mice were challenged with 40fold MLD50 of rabies virus CVS-11, 71 (A, B) or 63 (C, D) days after the first immunization. Body weight was recorded after immunization using material stored for six (B) or (D) twelve months. For antibody titers, the mean is indicated, for body weight kinetics the mean and standard deviation is given (n = 5). Significance ** p < .001 to buffer control group was calculated using the Mann Whitney test.
Fig 1 RABV-G mRNA vaccine stored at temperatures up to +40°C retains immunogenicity and protective for up to twelve months. (A-B: storage for six months). Vaccine or control injections were done on day 0 and 21. Induction of rabies virus neutralizing antibodies was measured on day 35 in mice vaccinated with RABV-G mRNA stored from -80°C to +40°C or HDC stored at the recommended temperature of 4°C for six months (dashed line in A and C indicates the WHO recommended titer of 0.5 international units per ml [IU/ml]). (C, D: storage for twelve months) Mice were challenged with 40fold MLD50 of rabies virus CVS-11, 71 (A, B) or 63 (C, D) days after the first immunization. Body weight was recorded after immunization using material stored for six (B) or (D) twelve months. For antibody titers, the mean is indicated, for body weight kinetics the mean and standard deviation is given (n = 5). Significance ** p < .001 to buffer control group was calculated using the Mann Whitney test.CC BY · PubMed Central
Fig 2 RABV-G mRNA vaccine stored at temperatures up to 70°C retains immunogenicity and protection for up to three months. mRNA vaccine or licensed vaccines were stored for one month (A-F) or three months (G-I). Storage temperature was 60°C (A-C), 70°C (D-F), or as indicated in the figure (G-I). Vaccine or control injections were done on day 0 and 21. Induction of rabies virus neutralizing antibodies was measured 35 days after first immunization (A, D, G; dashed line indicates the WHO standard titer of 0.5 IU/ml). Mice were challenged with a 40fold MLD50 of rabies virus CVS-11 on day 47 (B, C, E, F) and day 51 (H-I), respectively. Survival (B, E, H) and body weight (C, F, I) was recorded. For antibody titers, the mean is indicated, for body weight kinetics the mean and standard deviation is given (n = 6 to 8). Significance *p<0.1, **p<0.01, ***p < .001 to HDC or buffer control group in A and D/G, respectively, was calculated using the Mann Whitney test. Groups included in A-F were performed simultaneously; therefore buffer control displayed in D-F is valid for all groups.
Fig 2 RABV-G mRNA vaccine stored at temperatures up to 70°C retains immunogenicity and protection for up to three months. mRNA vaccine or licensed vaccines were stored for one month (A-F) or three months (G-I). Storage temperature was 60°C (A-C), 70°C (D-F), or as indicated in the figure (G-I). Vaccine or control injections were done on day 0 and 21. Induction of rabies virus neutralizing antibodies was measured 35 days after first immunization (A, D, G; dashed line indicates the WHO standard titer of 0.5 IU/ml). Mice were challenged with a 40fold MLD50 of rabies virus CVS-11 on day 47 (B, C, E, F) and day 51 (H-I), respectively. Survival (B, E, H) and body weight (C, F, I) was recorded. For antibody titers, the mean is indicated, for body weight kinetics the mean and standard deviation is given (n = 6 to 8). Significance *p<0.1, **p<0.01, ***p < .001 to HDC or buffer control group in A and D/G, respectively, was calculated using the Mann Whitney test. Groups included in A-F were performed simultaneously; therefore buffer control displayed in D-F is valid for all groups.CC BY · PubMed Central
Fig 3 Oscillating temperatures and potential handling and storage errors tested do not compromise mRNA vaccine efficacy. mRNA vaccine, Rabipur and HDC were reconstituted in buffer and subsequently stored at +40°C for one week (A-C). In a second experiment, RABV-G mRNA was stored as a lyophilisate at 56°C for 8–9 hours per day and then at 4°C for 15–16 hours with a total of 20 cycles of oscillating temperatures (D-F). Vaccine or control injections were done on day 0 and 21. Induction of rabies virus neutralization titer was measured on day 35 after first immunization (A, D: dashed line indicates the WHO standard titer of 0.5 IU/ml). Mice were challenged with a 40fold MLD50 of rabies virus CVS-11 on day 47 (B-C) or day 51 (E-F) and survival (B, E) and body weight (C, F) was recorded. As groups in A-F were treated in parallel, the buffer control group in Fig 3D–3F is valid also for Fig 3A–3C. For antibody titers, the mean is indicated, for body weight kinetics the mean and standard deviation is shown (n = 6 to 8). Significance: ns = non-significant, **p<0.01, ***p < .001 to HDC or buffer control group in A and D, respectively, was calculated using the Mann Whitney test.
Fig 3 Oscillating temperatures and potential handling and storage errors tested do not compromise mRNA vaccine efficacy. mRNA vaccine, Rabipur and HDC were reconstituted in buffer and subsequently stored at +40°C for one week (A-C). In a second experiment, RABV-G mRNA was stored as a lyophilisate at 56°C for 8–9 hours per day and then at 4°C for 15–16 hours with a total of 20 cycles of oscillating temperatures (D-F). Vaccine or control injections were done on day 0 and 21. Induction of rabies virus neutralization titer was measured on day 35 after first immunization (A, D: dashed line indicates the WHO standard titer of 0.5 IU/ml). Mice were challenged with a 40fold MLD50 of rabies virus CVS-11 on day 47 (B-C) or day 51 (E-F) and survival (B, E) and body weight (C, F) was recorded. As groups in A-F were treated in parallel, the buffer control group in Fig 3D–3F is valid also for Fig 3A–3C. For antibody titers, the mean is indicated, for body weight kinetics the mean and standard deviation is shown (n = 6 to 8). Significance: ns = non-significant, **p<0.01, ***p < .001 to HDC or buffer control group in A and D, respectively, was calculated using the Mann Whitney test.CC BY · PubMed Central

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  1. Montagnon B, Fanget B (1996) Purified Vero cell vaccine for humans, WHO Laboratory techniques in rabies 4th edition, chapter 26. 4.

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Metadata

Authors
Stitz, L., Vogel, A., Schnee, M., Voss, D., Rauch, S., Mutzke, T., Ketterer, T., Kramps, T., & Petsch, B.
Affiliations
  • Friedrich-Loeffler-Institut (DE)
  • CureVac (Germany) (DE)
Corresponding author
Petsch, Benjamin
ORCID
Venue
PLOS Neglected Tropical Diseases
Publisher
Public Library of Science (PLoS)
Published
2017-12-07
Volume
11
Issue
12
Pages
e0006108
ISSN
  • 1935-2727 (ISSN-L)
  • 1935-2735
DOI
10.1371/journal.pntd.0006108
PMC
PMC5737050
OpenAlex
W2772901255
Cited by
117
References
18
Citations by year
2026: 5 · 2025: 9 · 2024: 12 · 2023: 19 · 2022: 26 · 2021: 22 · 2020: 14 · 2019: 5 · 2018: 4
FWCI
3.42
Type
journal article
Language
en
Update notices
new_version (2017-12-19)
Open access
Licence
Locations
  • PLoS neglected tropical diseases (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OpenAgrar (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Bundesministerium für Bildung und Forschung (02PK2178)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › Rabies epidemiology and control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
Keywords
rabies virus, mRNA vaccines, rabies virus glycoprotein, thermostable vaccine, cold chain, vaccine storage, vaccine transport, virus-neutralizing antibodies, non-replicating vaccine, rabies prevention
MeSH terms
Immunogenicity, Vaccine, Animals, Antibodies, Viral, Antigens, Viral, Glycoproteins, Rabies, Rabies Vaccines, Rabies virus, RNA, Messenger, Temperature, Vaccines, Synthetic, Viral Envelope Proteins, Mice, Antibodies, Neutralizing, Vaccine Potency

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