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Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice
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Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice
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Journal Article
Deliberate reduction of hemagglutinin and neuraminidase expression of influenza virus leads to an ultraprotective live vaccine in mice
2013
Overview
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 × 10³ PFU; NA Min , 2.4 × 10⁵ PFU; (NA+HA) Min , ≥3.16 × 10⁶ 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 conferred protection against heterologous lethal challenges with two mouse-adapted H3N2 viruses. We conclude that the suppression of HA and NA is a unique strategy in live vaccine development.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ antigens
/ Codons
/ Dogs
/ Dosage
/ genes
/ H3N2 subtype influenza A virus
/ Hemagglutinin Glycoproteins, Influenza Virus - metabolism
/ immunity
/ Influenza A Virus, H1N1 Subtype
/ Lungs
/ Madin Darby Canine Kidney Cells
/ Male
/ Mice
/ Orthomyxoviridae Infections - immunology
/ Orthomyxoviridae Infections - prevention & control
/ Proteins
/ Rodents
/ Tissues
/ Transcriptional regulatory elements
/ Vaccines
/ Viruses
