Influenza Today Joseph Mester, Ph.D. September 24, 2009

Control of Infectious Diseases

 Sanitation  Diagnosis  Antimicrobials  Vaccines  Still, an ongoing effort

Influenza Surveillance: CDC & WHO Monitor prevalence of circulating strains and detect new strains Rapidly detect outbreaks Assist disease control through rapid preventive action Estimate influenza-related morbidity, mortality and economic loss

On the Web ucm htm

Influenza Virus: Morbidity and Mortality Debilitating illness lasting 5-7 days  Most severe when there is underlying cardiac or pulmonary disease In the USA:  ~150,000 influenza-associated hospitalizations per year  ~7,000-70,000 average deaths per year  Up to 10x this number of deaths during pandemics  >500,000 (USA) and 20 Million deaths (world wide) in 1918 pandemic

PeriodYearsAvg. Deaths Per year Pandemic ,000 Interpandemic ,300 Interpandemic ,100 Pandemic ,000 Interpandemic ,300 Pandemic ,000 Interpandemic ,000 Interpandemic ,000 Influenza in the USA Glezen, Epidemiology Revs :64-76

Influenza Pathogenesis Respiratory & contact transmission Replication in respiratory epithelium with subsequent destruction of cells Viremia rarely documented Viral shedding in respiratory secretions for days

Virus Variables Virulence of Strain(s) e.g., H5N1 (pandemic) vs. H1N1 (seasonal) Influenza Immune suppression? Immune over-activation? Tissue invasiveness Speed of replication Amount of necrosis Dose Co-infection / multiple infection

Influenza Virus Strains Type A- moderate to severe illness - all age groups - humans and other animals Type B- milder epidemics - humans only - primarily affects children Type C- rarely reported in humans - no epidemics

Influenza Virus A/Moscow/21/99 (H3N2) Neuraminidase Hemagglutinin Type of nuclear material Virus type Geographic origin Strain number Year of isolation Virus subtype

Influenza Virus  Enveloped RNA Virus  Capsid with helical symmetry  Polymorphic shape  Segmented Genome  8 Negative sense RNAs

Influenza Virus Evolution Genetic Variability  Virus is prone to accrue nucleotide misincorporations  error-prone viral RNA-dependent RNA polymerase with no proof-reading function  Misincorporation rate for Influenza A virus:  1 x changes/ nucleotide position/ replication cycle

Antigenic Drift

Replication in Animals (Other Than Man) Agricultural Animals - Hogs - Horses - Cattle - Sheep - Goats - Chickens - Turkeys Aquatic/Wild Birds - Ducks - Geese - Quail - Pheasants Companion Animals - Dogs - Cats

Antigenic Shift: Reassortment

Shift Timeline

Triple-Reassortant Swine Influenza A (H1) 11 sporadic cases NEJM 2009

Pandemic Flu 40 million deaths world-wide 675,000 in US Mortality 2.5% Flu killed more than WWI (1918) Estimated that half of the US WWI casualties were due to Flu 1957 Asian Flu (H2N2) 1968 Hong Kong (H3N2) 1976 Swine Flu (H1N1) 2009 Swine Flu (H1N1) Avian Flu’s 1997 H5N1 Hong Kong 1999 H9N2 Hong Kong 2004 H5N (H1N1) Others San Francisco

Phases of the Immune Response to Influenza

Influenza Vaccines Inactivated subunit (TIV) Intramuscular Trivalent Live attenuated vaccine (LAIV) Intranasal Trivalent

Composition of the Seasonal Influenza Vaccine A/Brisbane/10/2007 (H3N2) A/Brisbane/59/2007 (H1N1) B/Brisbane/60/2008

Vaccine Attenuation

Influenza Antiviral Agents Amantadine and rimantadine effective against influenza A only approved for treatment and prophylaxis Zanamivir and oseltamivir neuraminidase inhibitors “generally” effective against influenza A and B Most currently circulating seasonal influenza A strains are resistant! oseltamivir approved for prophylaxis