Live-attenuated H1N1 influenza vaccine candidate displays potent efficacy in mice and ferrets


Autoři: Charles B. Stauft aff001;  Chen Yang aff001;  J. Robert Coleman aff001;  David Boltz aff002;  Chiahsuan Chin aff001;  Anna Kushnir aff001;  Steffen Mueller aff001
Působiště autorů: Codagenix, Inc., Farmingdale, New York, United States of America aff001;  Life Sciences Group, IIT Research Institute, Chicago, Illinois, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223784

Souhrn

Currently, influenza vaccine manufacturers need to produce 1–5 x 107 PFU of each vaccine strain to fill one dose of the current live-attenuated-influenza-vaccine (LAIV). To make a single dose of inactivated vaccine (15 ug of each hemagglutinin), the equivalent of 1010 PFU of each vaccine strains need to be grown. This high dose requirement is a major drawback for manufacturing as well as rapidly sourcing sufficient doses during a pandemic. Using our computer-aided vaccine platform Synthetic Attenuated Virus Engineering (SAVE), we created a vaccine candidate against pandemic H1N1 A/CA/07/2009 (CodaVax-H1N1) with robust efficacy in mice and ferrets, and is protective at a much lower dose than the current LAIV. CodaVax-H1N1 is currently in Phase I/II clinical trials. The hemagglutinin (HA) and neuraminidase (NA) gene segments of A/California/07/2009 (H1N1) (CA07) were “de-optimized” and a LAIV was generated ex silico using DNA synthesis. In DBA/2 mice, vaccination at a very low dose (100 or approximately 1 PFU) with CodaVax-H1N1 prevented disease after lethal challenge with wild-type H1N1. In BALB/c mice, as little as 103 PFU was protective against lethal challenge with mouse-adapted H1N1. In ferrets, CodaVax-H1N1 was more potent compared to currently licensed LAIV and still effective at a low dose of 103 PFU at preventing replication of challenge virus.

Klíčová slova:

Antibodies – Antigens – H1N1 – Influenza – Vaccination and immunization – Vaccines – Viral vaccines – Ferrets


Zdroje

1. Weekly U.S. Influenza Surveillance Report | Seasonal Influenza (Flu) | CDC [Internet]. 23 Mar 2018 [cited 23 Mar 2018]. Available: https://www.cdc.gov/flu/weekly/index.htm

2. Erbelding EJ, Post DJ, Stemmy EJ, Roberts PC, Augustine AD, Ferguson S, et al. A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis. doi: 10.1093/infdis/jiy103 29506129

3. HOFSTAD E. This is a preliminary, unedited transcript. The statements within may be inaccurate, incomplete, or misattributed to the speaker. A link to the final, official transcript will be posted on the Committee’s website as soon as it is available.: 84.

4. Coleman JR, Papamichail D, Skiena S, Futcher B, Wimmer E, Mueller S. Virus attenuation by genome-scale changes in codon pair bias. Science. 2008;320: 1784–1787. doi: 10.1126/science.1155761 18583614

5. Mueller S, Coleman JR, Papamichail D, Ward CB, Nimnual A, Futcher B, et al. Live attenuated influenza virus vaccines by computer-aided rational design. Nat Biotechnol. 2010;28: 723–726. doi: 10.1038/nbt.1636 20543832

6. Coffin JM. Attenuation by a thousand cuts. N Engl J Med. 2008;359: 2283–2285. doi: 10.1056/NEJMcibr0805820 19020330

7. Broadbent AJ, Santos CP, Anafu A, Wimmer E, Mueller S, Subbarao K. Evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de-optimization of the 2009 pandemic H1N1 influenza virus, in ferrets. Vaccine. 2016;34: 563–570. doi: 10.1016/j.vaccine.2015.11.054 26655630

8. Yang C, Skiena S, Futcher B, Mueller S, Wimmer E. Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice. Proc Natl Acad Sci U S A. 2013;110: 9481–9486. doi: 10.1073/pnas.1307473110 23690603

9. Le Nouën C, Brock LG, Luongo C, McCarty T, Yang L, Mehedi M, et al. Attenuation of human respiratory syncytial virus by genome-scale codon-pair deoptimization. Proc Natl Acad Sci U S A. 2014;111: 13169–13174. doi: 10.1073/pnas.1411290111 25157129

10. Nouën CL, McCarty T, Brown M, Smith ML, Lleras R, Dolan MA, et al. Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure. Proc Natl Acad Sci. 2017;114: E386–E395. doi: 10.1073/pnas.1619242114 28049853

11. Shen SH, Stauft CB, Gorbatsevych O, Song Y, Ward CB, Yurovsky A, et al. Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference. Proc Natl Acad Sci U S A. 2015;112: 4749–4754. doi: 10.1073/pnas.1502864112 25825721

12. Kaplan BS, Souza CK, Gauger PC, Stauft CB, Robert Coleman J, Mueller S, et al. Vaccination of pigs with a codon-pair bias de-optimized live attenuated influenza vaccine protects from homologous challenge. Vaccine. 2018;36: 1101–1107. doi: 10.1016/j.vaccine.2018.01.027 29366707

13. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12: 36–44. doi: 10.1016/S1473-3099(11)70295-X 22032844

14. Weisfuse IB, Berg D, Gasner R, Layton M, Misener M, Zucker JR. Pandemic Influenza Planning in New York City. J Urban Health. 2006;83: 351–354. doi: 10.1007/s11524-006-9043-8 16739036

15. Uscher-Pines L, Barnett DJ, Sapsin JW, Bishai DM, Balicer RD. A systematic analysis of influenza vaccine shortage policies. Public Health. 2008;122: 183–191. doi: 10.1016/j.puhe.2007.06.005 17825858

16. He X-S, Holmes TH, Zhang C, Mahmood K, Kemble GW, Lewis DB, et al. Cellular Immune Responses in Children and Adults Receiving Inactivated or Live Attenuated Influenza Vaccines. J Virol. 2006;80: 11756–11766. doi: 10.1128/JVI.01460-06 16971435

17. Mazurek JM, Syamlal G, King BA, Castellan RM. Smokeless Tobacco Use Among Working Adults—United States, 2005 and 2010. 2014;63: 28.

18. Jin H, Zhou H, Lu B, Kemble G. Imparting Temperature Sensitivity and Attenuation in Ferrets to A/Puerto Rico/8/34 Influenza Virus by Transferring the Genetic Signature for Temperature Sensitivity from Cold-Adapted A/Ann Arbor/6/60. J Virol. 2004;78: 995–998. doi: 10.1128/JVI.78.2.995-998.2004 14694130

19. Pica N, Iyer A, Ramos I, Bouvier NM, Fernandez-Sesma A, García-Sastre A, et al. The DBA.2 Mouse Is Susceptible to Disease following Infection with a Broad, but Limited, Range of Influenza A and B Viruses. J Virol. 2011;85: 12825–12829. doi: 10.1128/JVI.05930-11 21917963

20. Boon ACM, deBeauchamp J, Krauss S, Rubrum A, Webb AD, Webster RG, et al. Cross-Reactive Neutralizing Antibodies Directed against Pandemic H1N1 2009 Virus Are Protective in a Highly Sensitive DBA/2 Mouse Influenza Model. J Virol. 2010;84: 7662–7667. doi: 10.1128/JVI.02444-09 20484500

21. Ye J, Sorrell EM, Cai Y, Shao H, Xu K, Pena L, et al. Variations in the Hemagglutinin of the 2009 H1N1 Pandemic Virus: Potential for Strains with Altered Virulence Phenotype? PLOS Pathog. 2010;6: e1001145. doi: 10.1371/journal.ppat.1001145 20976194

22. World Health Organization. WHO Manual on Animal Influenza Diagnosis and Surveillance. Geneva, Switzerland: World Health Organization; 2002.

23. Team NS-OIA (H1N1) VI. Emergence of a Novel Swine-Origin Influenza A (H1N1) Virus in Humans. N Engl J Med. 2009;360: 2605–2615. doi: 10.1056/NEJMoa0903810 19423869


Článek vyšel v časopise

PLOS One


2019 Číslo 10