Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice
Open accessAbstract
A long-held dogma posits that strong presentation to the immune system of the dominant influenza virus glycoprotein antigens neuraminidase (NA) and hemagglutinin (HA) is paramount for inducing protective immunity against influenza virus infection. We have deliberately violated this dogma by constructing a recombinant influenza virus strain of A/PR8/34 (H1N1) in which expression of NA and HA genes was suppressed. We down-regulated NA and HA expression by recoding the respective genes with suboptimal codon pair bias, thereby introducing hundreds of nucleotide changes while preserving their codon use and protein sequence. The variants PR8-NA(Min), PR8-HA(Min), and PR8-(NA+HA)(Min) (Min, minimal expression) were used to assess the contribution of reduced glycoprotein expression to growth in tissue culture and pathogenesis in BALB/c mice. All three variants proliferated in Madin-Darby canine kidney cells to nearly the degree as WT PR8. In mice, however, they expressed explicit attenuation phenotypes, as revealed by their LD50 values: PR8, 32 plaque-forming units (PFU); HA(Min), 1.7 × 10(3) PFU; NA(Min), 2.4 × 10(5) PFU; (NA+HA)(Min), ≥3.16 × 10(6) PFU. Remarkably, (NA+HA)(Min) was attenuated >100,000-fold, with NA(Min) the major contributor to attenuation. In vaccinated mice (NA+HA)(Min) was highly effective in providing long-lasting protective immunity against lethal WT challenge at a median protective dose (PD50) of 2.4 PFU. Moreover, at a PD50 of only 147 or 237, (NA+HA)(Min) c…
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CPD can reduce stability of recoded mRNA and induce temperature-sensitivity in mutant viruses.
“In addition, it was shown that CPD can reduce stability of recoded mRNA (Broadbent et al., 2016;Yang et al., 2013) and induce temperature-sensitivity in mutant viruses (Le Noue ¨n et al., 2014;Yang et al., 2013).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Yang et al., 2013
The level of attenuation achieved by the elevation of CpG/UpA dinucleotide frequencies appears to be much weaker than that by CPD.
“Although these studies are not directly comparable, the level of attenuation achieved by the elevation of CpG/UpA dinucleotide frequencies (Gaunt et al., 2016) appears to be much weaker than that by CPD (Yang et al., 2013).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Yang et al., 2013
IAV double mutants with codon pair deoptimized NA and hemagglutinin genes were completely attenuated in BALB/c mice and ferrets.
“In a similar study, IAV double mutants with codon pair deoptimized NA and hemagglutinin genes were completely attenuated in BALB/c mice (Yang et al., 2013) and ferrets (Broadbent et al., 2016).”
From Mechanism of Virus Attenuation by Codon Pair Deoptimization (2020) · cites this paper as Yang et al., 2013
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- Authors
- Yang, C., Skiena, S., Futcher, B., Mueller, S., & Wimmer, E.
- Affiliations
- Stony Brook University (US)
- Departments of aMolecular Genetics and Microbiology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-05-20
- Volume
- 110
- Issue
- 23
- Pages
- 9481-9486
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3677463
- OpenAlex
- W2025342581
- Cited by
- 103
- References
- 30
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 12 · 2020: 11 · 2019: 9 · 2018: 10 · 2017: 4 · 2016: 7 · 2015: 16 · 2014: 10 · 2013: 2
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- other-oa
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM098400)
- National Institute of Allergy and Infectious Diseases (R01AI075219, R01AI07521901A1)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- influenza virus, live attenuated vaccine, hemagglutinin, neuraminidase, codon pair bias, recombinant influenza virus, vaccine attenuation, heterologous challenge protection, H3N2, protective immunity
- MeSH terms
- Animals, Dogs, Lethal Dose 50, Male, Mice, Inbred BALB C, Neuraminidase, Orthomyxoviridae Infections, Viral Vaccines, Blotting, Northern, Blotting, Western, Down-Regulation, Hemagglutinin Glycoproteins, Influenza Virus, Mice, Influenza A Virus, H1N1 Subtype, Cross Protection, Madin Darby Canine Kidney Cells
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