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  2. 2. Characteristics • Influenza virus belongs to the orthomyxoviridae family. • Influenza virus have segmented negative-sense single stranded RNA molecules, which are eight in number. • It’s an enveloped virus which is made up of proteins, glycoproteins, and lipid bilayer. • Helical in symmetry.
  3. 3. Orthomyxoviruses HA - hemagglutinin NA - neuraminidase helical nucleocapsid (RNA plus NP protein) lipid bilayer membrane polymerase complex M1 protein type A, B, C : NP, M1 protein sub-types: HA or NA protein 3
  4. 4. Types of Influenza virus Type A Type B Type C Severity of illness ++++ ++ + Animal reservoir Yes No No Human pandemics Yes No No Human epidemics Yes Yes No(sporadic) Antigenic changes Shift, drift Drift Drift Segmented genome Yes Yes Yes Amantadine, rimantidine Sensitive No effect No effect Zanamivir Sensitive Sensitive Surface glycoproteins 2 2
  5. 5. Influenza Biology HA attaches to the membrane of epithelial cells via sialic acid-galactose H+ ion passes through the viral M2 matrix ion protein channels After attachment endocytosis occurs Fusion of endosome membrane and viral membrane; release of RNA and NP M2 HA Acidification of the core leads to conformation changes in HA making it a fusogen Inside the endosome pH gets lowered
  6. 6. Influenza Biology
  7. 7. Mode of action of H1 N1 Virus infects upper respiratory system Hydrolyzing the mucus membrane by neuraminidase Virus adheres to epithelial cells (receptor mediated endocytosis) Action of lysosome on endosome When endosome pH decreases, haemagglutine molecule undergoes conformational change. The hydrophobic end of haemagglutine spring outward & extends towards the membrane of endosome.
  8. 8. Mode of action of H1 N1 Nucleocapsid is released into the cytoplasm Virus replication in epithelium cell nucleus Assembly of viron particles Released through budding Undigested virus particles engulf by macrophages Ag presentation by class 1 MHC molecule on macrophage Tc cells get activated Apoptosis As a result, there is reduced clearance of infectious agents from the respiratory tract. Gaps in the protective epithelium provide other pathogens with access to other cells.
  9. 9. Influenza Antigenic Changes
  10. 10. Antigenic Drift
  11. 11. Antigenic Shift Source:
  12. 12. Treatment Treatment Vaccine Antiviral Drugs Ex. Baxter vaccine (inactivated virus vaccine) Inhibitors of the viral M2 matrix protein ion channels Ex. Amantadine Rimantadine Neuraminidase inhibitors Ex. Oseltamivir :TAMIFLU Zanamivir :RELENAZA
  13. 13. Influenza Vaccines
  14. 14. Influenza Vaccines • Inactivated vaccine (TIV) • • • • • • flu shot (injection) Purified virus chemically inactivated by formalin or propiolactone trivalent (three strains; usually A/H1N1, A/H3N2, and B) non-replicating virus contain much more antigen than live vaccines works by putting into the bloodstream those parts of three strains of flu virus that the body uses to create antibodies • Live attenuated vaccine (LAIV) • • • • nasal spray (FluMist®) Live virus, completely devoid of pathogenicity provide continuous antigenic stimulation works by inoculating against those same three strains that have been genetically modified to minimize symptoms of illness. • Each of the three strains is a reassortant of internal proteins of a master donor virus (MDV) that contains the CA and TS phenotypes • surface proteins (HA, NA) are from wild-type influenza virus.
  15. 15. Flu vaccine production (Overview) • • • • • • Strain selection Preparation of seed virus Seed passaging and selection Large scale production Purification and testing Packaging and shipping
  16. 16. Strain selection and Preparation of seed virus 2 gene segments representing the HA and NA antigens are selected from the target strain. 6 gene segments come from a lab virus strain that confer high growth capacity in eggs. SEED VIRUS: a hybrid is formed which contains the inner components of the laboratory strain, and the outer components of the pandemic strain
  17. 17. Seed passaging and Selection • • • Accredited laboratories distribute seed viruses to manufacturers to begin the production process. Once the seed virus has been received, the working seed virus can be prepared by passaging the seed virus in eggs. These passages are necessary to determine the optimum growth conditions to improve virus yield in the industrial environment. Large – scale production • • Millions of specially - prepared chicken eggs are used to produce the vaccine. Throughout the year, fertilized eggs are delivered to the manufacturer. Each egg is injected with the working seed. The eggs are incubated for several days to allow the virus to multiply. After incubation, the virus – loaded fluid is harvested. Purification and Testing • Manufacturers test the vaccine concentrate using specially prepared reagents provided by WHO Collaboratoring Centers to measure the quantity of virus produced and guarantee the optimal dosage of ready to use vaccines.
  18. 18. Limitations • A limitation of current vaccines is that the antigenic regions of HA are highly susceptible to continuous mutation in circulating epidemic virus strains. •Thus, the currently available influenza vaccines need to be updated every year to match the antigenicity of the virus strains that are predicted to circulate in the next season. •However, current vaccines would not be effective in preventing the spread of a new pandemic strain containing a substantially different HA protein. Therefore, new approaches are being investigated to develop broadly crossprotective vaccines, focused primarily on type A influenza viruses
  19. 19. Universal influenza vaccine 1. The extracellular domain of M2 (M2e) is highly conserved among multiple influenza A viruses, indicating that M2 is an attractive antigenic target for developing a universal influenza vaccine. Also, an inactivated influenza vaccine supplemented with M2 VLP(virus like particles) prevents disease symptoms. 2. HA is a homotrimeric molecule consisting of a disulfide-linked globular head of HA1 and a stem domain composed of part of HA1 and all of HA2. It possesses conserved structural features in the HA2 segment involved in anchoring to the viral membrane. It has recently been recognized that this segment, termed the stalk, is a potential target for inducing broadly cross-reactive immunity.
  20. 20. Challenges • Non – egg – based production •Targeting generation of virus specific CTLs •Increasing immunogenicity and adjuvants •Rapid production •Dosage
  21. 21. References • Novel vaccines against influenza viruses: Virus Research, Volume 162, Issues 1–2, December 2011, Pages 31-38. S.M. Kang, J.M. Song, R.W. Compans • The Influenza Virus Enigma: Cell, Volume 136, Issue 3, 6 February 2009, Pages 402-410 Rachelle Salomon, Robert G. Webster • The 2009 A (H1N1) influenza virus pandemic: A review: Vaccine, Volume 28, Issue 31, 12 July 2010, Pages 4895-4902 Marc P. Girard, John S. Tam, Olga M. Assossou, Marie Paule Kieny
  22. 22. Thank you for your attention