Influenza vaccines

Inactive Publication Date: 2008-12-04
STATENS SERUM INST
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0025]The data herein demonstrates that gene gun administrated codon optimised DNA vaccine in plasmid encoding HA and NA with or without M and NP based on the H1N1 pandemic virus from 1918 induced protection in ferrets against infection with a H1N1 (A/New Caledonia/20/99(H1N1)) present day virus. The circulating H1N1 strain in Europe in the 2006-2007 seasons is New Caledonia-like. The viruses are separated by a time interval of 89 years and differ by 21.2% in the HA1 protein. By comparison, a similar DNA vaccine encoding the HA and NA of (A/New Caledonia/20/99 (H1N1)) induced less protection. These results suggest not only a unique ability of the DNA vaccines but also a unique and unexpected feature of the 1918 HA and/or NA in inducing especially broad and efficient protective immunity against even extremely drifted strain variants.
[0026]The present invention discloses that an induced immune response with a DNA vaccine encoding HA and/or NA of the 1918 H1N1 influenza A gives a high level of cross protection against present day influenza infection. Tests were carried out in ferrets vaccinated with this DNA vaccine synthesised using human preferred codons of the 1918 H1N1 influenza and challenged with a contemporary H1

Problems solved by technology

Also, swine are susceptible to human and avian influenza virus, since they possess both receptors in their respiratory tract.
Because swine get infection and pneumonia from human influenza strains, they may serve as a dangerous mixing vessel for the generation of new recombinant influenza strains with pandemic potential.
Influenza rapidly spreads in seasonal epidemics affecting 5-15% of the population and the burden on health care costs and lost productivity are extensive (World Health Organization (WHO)).
Moreover, the traditional influenza protein vaccines only have a limited protective effect.
However, in temperate climates it is a winter disease, probably because people come together and stay in less ventilated rooms due to the cold weather.
However, there is consideration disagreement about the actual origin of the virus and many still believe that also this 1918 pandemic strain is a reassortant between a mammalian and avian virus most likely occurring from swine.
The reassortant might be catastrophic if the virus is capable of efficient replication in the new host.
In the worst case, such a reasserted strain might lead to a pandemic, world-spanning infection to which there is no pre-existing immunity in the human population.
Whole inactivated influenza vaccine is not currently used due to high levels of side effects.
The protective effect of the traditional protein split vaccine is very limited and because of the continuous evolution of influenza A virus strains

Method used

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Examples

Experimental program
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Effect test

example 1

ion of Expression Vectors

[0072]The 1918 pandemic H1N1 genes were designed from nucleotide sequences published in GenBank (HA: A / South Carolina / 1 / 18 AF117241, and NA, NP and M: A / Brevig Mission / 1 / 18 AF250356, AY744035 and AY130766, respectively). The genes were made synthetically and designed to include the appropriate restriction enzymes and Kozak sequence (GCCACC), −1 base upstream from the start codon, for efficient cloning and transcription in the WRG7079 expression vector (PowderJect, Madison, Wis.). The genes were synthesised using only codons from highly expressed human genes (5) (codon optimised). By this the nucleotide codons are altered (humanised), but the encoded amino acids are identical to those encoded by the viral RNA. The genes were further cloned individually into the WRG7079 expression vector. Key elements in the expression vector are a kanamycin resistance gene, cytomegalovirus immediate-early promoter, intron A, and polyadenylation signal. The tissue plasminogen ...

example 2

ions

[0075]A total of 24 ferrets (Mustela Putorius Furo), approximately seven months old, were divided in four groups by using a chip-tag identification for dogs (E-vet, pet-id, Haderslev, Denmark), six animals in each group. All animals were kept together and fed a standard diet with food and water ad libitum. The animals were housed according to the Danish Animal Experimentation Act and kept at level II biosecurity facilities at the Faculty of Life Sciences, Copenhagen. The acclimatisation period was nine days.

[0076]Four groups of six ferrets were vaccinated as follows; (1) HA (codon optimised gene) and NA (codon optimised gene) 1918 H1N1 plasmid DNA vaccinated, (2) HA, NA, NP and M (all codon optimised) 1918 H1N1 plasmid DNA vaccinated, (3) empty plasmid vaccinated (negative vaccine control) and (4) HA and NA (not codon optimised) A / New Caledonia / 20 / 99(H1N1) plasmid DNA vaccinated (positive vaccine control). All ferrets received four standard gene gun shots onto shaved abdomen. HA...

example 3

ive Real Time RT-PCR Assay for Influenza A

[0077]At the day of blood serum collection the nostrils of each ferret were flushed with 1 ml PBS and the flushing were frozen down immediately for real-time RT-PCR analysis. Two hundred micro litres of nasal wash were extracted on an automated MagNA Pure LC Instrument applying the MagNa Pure LC Total Nucleic Acid Isolation Kit (Roche diagnostics, Basel, Switzerland). The extracted material was eluated in 200 μl Milli-Q H2O. The RT-PCR reactions were performed with oligonucleotide sequences as described by Spackman et al.,(23). Extracted material (5 μl) was added to 20 μl of master mix consisting of 10 nM of each primer and 2 nM of the Taqman probe labelled with FAM in the 5′ end and black hole quencher 1 in the 3′ end together with reagents from the OneStep® RT-PCR Kit (QIAGEN, Hilden, Germany) according to the manufacturer. Target sequences were amplified on the MX3005 system from Stratagene with the following program: 20 min 50° C., 15 mi...

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Abstract

Described herein are vaccines and the use of naked DNA and/or RNA encoding hemagglutinin (HA) from pandemic influenza, e.g., the 1918 H1N1 and/or the 1957 H2N2 and/or the 1968 H3N2 influenza A virus, as a vaccine component against present day and coming H1, H2, H3, H5, N1, N2 containing influenza A infections in humans and swine optionally with the naked DNA and/or RNA encoding Neuraminidase (NA) and/or matrix protein (M) and/or the nucleoprotein (NP) from pandemic influenza virus included. If the vaccine components are used as DNA or RNA vaccines with or without the corresponding protein, the codons can optionally be “humanized” using preferred codons from highly expressed mammalian genes and the administration of this DNA vaccine can be by saline or buffered saline injection of naked DNA or RNA, or injection of DNA plasmid or linear gene expressing DNA fragments coupled to particles. Addition of the matrix protein (M) and/or the nucleoprotein (NP) from the 1918 influenza strain is also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims the benefit under 35 USC 119(e) of U.S. Patent Application No. 60 / 934,117, filed Jun. 11, 2007.BACKGROUND OF THE INVENTION[0002]The invention concerns therapeutic and prophylactic vaccines for humans and swine, for influenza A infections in humans and swine.[0003]Influenza is one of the oldest and most common diseases known to man, causing between three and five million cases of severe illness and between 250,000 and 500,000 deaths every year around the world. Also, swine are susceptible to human and avian influenza virus, since they possess both receptors in their respiratory tract. Because swine get infection and pneumonia from human influenza strains, they may serve as a dangerous mixing vessel for the generation of new recombinant influenza strains with pandemic potential.[0004]Influenza rapidly spreads in seasonal epidemics affecting 5-15% of the population and the burden on health care costs and lost productiv...

Claims

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Application Information

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IPC IPC(8): A61K39/145A61K31/7088A61P31/12
CPCA61K39/145A61K2039/53A61K2039/70A61K2039/54C12N2760/16134A61K39/12A61P31/12
Inventor FOMSGAARD, ANDERS
Owner STATENS SERUM INST
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