Influenza What have we learned from the 2009 pandemic

1. Influenza What have we learned from the 2009 pandemic? Allison McGeer, MSc, MD, FRCPC Mount Sinai Hospital University of Toronto

4. After receptor-mediated endocytosis, the viral ribonucleoprotein (vRNP) complexes are released into the cytoplasm and subsequently transported to the nucleus, where replication and transcription take place. Messenger RNAs are exported to the cytoplasm for translation. Early viral proteins, that is, those required for replication and transcription, are transported back to the nucleus. Late in the infection cycle, the M1 and NS2 proteins facilitate the nuclear export of newly synthesized vRNPs. PB1-F2 associates with mitochondria. The assembly and budding of progeny virions occurs at the plasma membrane. After receptor-mediated endocytosis, the viral ribonucleoprotein (vRNP) complexes are released into the cytoplasm and subsequently transported to the nucleus, where replication and transcription take place. Messenger RNAs are exported to the cytoplasm for translation. Early viral proteins, that is, those required for replication and transcription, are transported back to the nucleus. Late in the infection cycle, the M1 and NS2 proteins facilitate the nuclear export of newly synthesized vRNPs. PB1-F2 associates with mitochondria. The assembly and budding of progeny virions occurs at the plasma membrane.

6. Viral shedding

7. Annual Influenza in Canada (Pop 33M) 5 million (1 in 6) infected per year ~50,000 hospitalizations 1% of those >65yrs; 0.5% of those <1yr 4,000 - 8,000 deaths (10 in children) 7% of children get otitis media 1.5 million work-days lost

10. Since the H5 and H9 investigation we have learned that a reassortment event that could create a pandemic strain could directly occur in humans potentially increasing the likelihood of a pandemic With this in mind�Since the H5 and H9 investigation we have learned that a reassortment event that could create a pandemic strain could directly occur in humans potentially increasing the likelihood of a pandemic With this in mind�

16. Epidemic curve of pandemic (H1N1) 2009 hospitalized cases, ICU admissions and deaths in Canada by date of onset, as of December 19, 2009*

17. What�s next? - Pandemic There will be another pandemic ~3% risk per year Severity of next pandemic is unpredictable Goal is planning that is: Efficient (but recognizes that insurance is important) Fills the gaps we identified in 2009 pandemic Sustainable

18. What�s next? - 2010/11 season Activity around the world is mixed A(pH1N1) A(H3N2) B/Victoria So, 2010/11 season could be any strain Very few isolates so far, so no indication that season is starting

19. One means to improve diagnostic ability is to recognize that influenza activity is concentrated in a relatively short period each year. This slide shows viral activity from a Canadian surveillance system for the 2005-2006 winter season. The yellow bar marks the weeks from November to April. RSV infections (in blue) are seen through the entire winter season. However, influenza infections (red line) are concentrated within an 8- to 10-week period. Public Health Agency of Canada. FluWatch. August 13, 2006, to August 26 2006 (Week 33 & 34). One means to improve diagnostic ability is to recognize that influenza activity is concentrated in a relatively short period each year. This slide shows viral activity from a Canadian surveillance system for the 2005-2006 winter season. The yellow bar marks the weeks from November to April. RSV infections (in blue) are seen through the entire winter season. However, influenza infections (red line) are concentrated within an 8- to 10-week period. Public Health Agency of Canada. FluWatch. August 13, 2006, to August 26 2006 (Week 33 & 34).

20. What�s next? - 2010/11 season Patient messages about influenza vaccine Made exactly the way we have always made seasonal influenza vaccines More the 100M people around the world have been vaccinated with pH1N1 containing vaccines Influenza continues to kill more Canadians than any other infectious disease � vaccination is the best prevention

21. Motivation to Get the Flu Shot Ontarians would be more likely to get the flu shot if� There was a large outbreak in Ontario (73%) They were convinced the flu was a serious disease (73%) Their doctor recommended it (69%) It was offered in a convenient location (64%) They knew more about it and what it does (60%) The survey conducted by the Ontario Ministry of Health and Long-Term Care also questioned Ontarians about the factors that would motivate them to get the flu shot. Respondents indicated that they would be motivated to get the shot if� There was a large outbreak in Ontario (73%) They were convinced the flu was a serious disease (73%) Their doctor recommended it (69%) It was offered in a convenient location (64%) They knew more about it and what it does (60%) The survey conducted by the Ontario Ministry of Health and Long-Term Care also questioned Ontarians about the factors that would motivate them to get the flu shot. Respondents indicated that they would be motivated to get the shot if� There was a large outbreak in Ontario (73%) They were convinced the flu was a serious disease (73%) Their doctor recommended it (69%) It was offered in a convenient location (64%) They knew more about it and what it does (60%)

22. Why should Ontarians get the flu vaccine? Every year, Ontario�s Universal Influenza Immunization Program saves� 300 deaths 1,000 hospitalizations 30,000 visits to hospital emergency departments 200,000 physicians� consultation for illness In a recent study by Kwong and colleagues, the universal influenza immunization program has been shown to save 300 deaths, 1,000 hospitalizations, 30,000 visits to hospital emergency departments, and 200,000 visits to doctors� offices. Reference: Kwong JC, Stukel TA, Lim J, et al. The effect of universal influenza immunization on mortality and health care use. PLoS Med 2008;5:e211.In a recent study by Kwong and colleagues, the universal influenza immunization program has been shown to save 300 deaths, 1,000 hospitalizations, 30,000 visits to hospital emergency departments, and 200,000 visits to doctors� offices. Reference: Kwong JC, Stukel TA, Lim J, et al. The effect of universal influenza immunization on mortality and health care use. PLoS Med 2008;5:e211.

23. What�s next? - 2010/11 season Patient messages about influenza vaccine Made exactly the way we have always made seasonal influenza vaccines More the 100M people around the world have been vaccinated with pH1N1 containing vaccines Influenza continues to kill more Canadians than any other infectious disease � vaccination is the best prevention Influenza vaccination does not make you sick

24. Adverse Effects after Influenza Vaccine This slide demonstrates the rates of local (sore arm) and systemic side effects in the week after injection in the largest randomized controlled trial of influenza vaccine in healthy working adults. Just over 1 in 20 people had a fever, nearly 1 in 5 were abnormally tired, and 6% complained of muscle aches. Before you make conclusions,however, you need to see the next slide - This slide demonstrates the rates of local (sore arm) and systemic side effects in the week after injection in the largest randomized controlled trial of influenza vaccine in healthy working adults. Just over 1 in 20 people had a fever, nearly 1 in 5 were abnormally tired, and 6% complained of muscle aches. Before you make conclusions,however, you need to see the next slide -

25. Adverse Effects after Influenza Vaccine Here you can see that the data you were looking at were the data from the placebo group � when you compare the adverse event rates in placebo and vaccine groups, you seen that vaccine is associated with sore arm in about 40% of people. Although fever occurs after vaccination, it is not CAUSED by vaccination � because we vaccinate people in October and November, when many viruses which cause viral respiratory tract infections are circulating, it is not uncommon to develop illness after vaccine is given. This is a temporal, but not a causal association.Here you can see that the data you were looking at were the data from the placebo group � when you compare the adverse event rates in placebo and vaccine groups, you seen that vaccine is associated with sore arm in about 40% of people. Although fever occurs after vaccination, it is not CAUSED by vaccination � because we vaccinate people in October and November, when many viruses which cause viral respiratory tract infections are circulating, it is not uncommon to develop illness after vaccine is given. This is a temporal, but not a causal association.

26. 2010/11 VaccinationNew for physicians More evidence on prevention of cardiac disease New evidence about GBS New evidence about influenza and vaccination in pregnancy

27. Flu Vaccine Associated with Reduced Rate of Acute MI UK: 16,012� pts >40 years with first acute MI vs. 62,694 matched controls1 Influenza vaccination associated with� 19% reduction in acute MI when given within the past year 20% reduction in acute MI when given within the flu season Greater reductions in MI seen with vaccination early (ie, Sept to mid�Nov) vs. later in the season (21% vs. 12% vs. no vaccination) Influenza vaccination should be encouraged wherever indicated, especially in people with existing CV disease, among whom there is often suboptimum vaccine uptake2 In a study of the United Kingdom General Practice Research Database. A total of 16,012� patients older than 40 years of age with a first acute MI were compared with 62,694 matched controls.1 Influenza vaccination was associated with a 19% reduction in acute MI when given within the past year and a 20% reduction in acute MI when given within the flu season. Greater reductions in MI seen with vaccination early (ie, September to mid�November) vs. later in the season (21% vs. 12% compared with no vaccination). Because of the substantial reductions in MI associated with influenza vaccine, vaccination should be encouraged wherever indicated, especially among people with existing cardiovascular disease, among whom there is often suboptimum vaccine uptake.2 Reference Siriwardena AN, Gwini SM, Coupland CA. Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study. CMAJ 2010 Sep 20. [Epub ahead of print] Warren-Gash C, Smeeth L, Hayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis 2009;9:601-10. In a study of the United Kingdom General Practice Research Database. A total of 16,012� patients older than 40 years of age with a first acute MI were compared with 62,694 matched controls.1 Influenza vaccination was associated with a 19% reduction in acute MI when given within the past year and a 20% reduction in acute MI when given within the flu season. Greater reductions in MI seen with vaccination early (ie, September to mid�November) vs. later in the season (21% vs. 12% compared with no vaccination). Because of the substantial reductions in MI associated with influenza vaccine, vaccination should be encouraged wherever indicated, especially among people with existing cardiovascular disease, among whom there is often suboptimum vaccine uptake.2 Reference Siriwardena AN, Gwini SM, Coupland CA. Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study. CMAJ 2010 Sep 20. [Epub ahead of print] Warren-Gash C, Smeeth L, Hayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis 2009;9:601-10.

28. Influenza Vaccine and GBS Guillain-Barr� Syndrome (GBS) occurs in ~2 of 100,000 people per year, usually due to food-borne infection1 GBS occurrs in association with the flu vaccine - rarely 1.2 cases per million doses1 Influenza infection itself can cause GBS2 Vaccination not associated with overall increase in the risk of GBS2,3 Risk of GBS after ILI: 17 (9.4, 25) Overall risk of GBS in vaccinated: 0.58 (0.18, 1.9) This slide addresses one of the common fears and myths that people may have about the flu vaccine � the risk of Guillain-Barr� Syndrome (GBS). GBS occurs in approximately 2 of 100,000 people per year, usually due to food-borne infection.1 On rare instances, GBS has occurred in association with the flu vaccine. However, the association is very weak, with 1.2 cases occurring per million doses distributed.1 In fact, influenza infection itself can cause GBS,2 and at least one study has found that influenza vaccination reduces the overall risk of GBS2,3 Reference Public Health Agency of Canada. Information on seniors and the flu virus. http://www.phac-aspc.gc.ca/alert-alerte/h1n1/pdf/Factsheet_Seniors.pdf Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Guillain-Barr� syndrome and influenza virus infection. Clin Infect Dis 2009;48:48-56. Tam CC, O'Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues LC. Guillain-Barr� syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database. PLoS One 2007;2:e344. This slide addresses one of the common fears and myths that people may have about the flu vaccine � the risk of Guillain-Barr� Syndrome (GBS). GBS occurs in approximately 2 of 100,000 people per year, usually due to food-borne infection.1 On rare instances, GBS has occurred in association with the flu vaccine. However, the association is very weak, with 1.2 cases occurring per million doses distributed.1 In fact, influenza infection itself can cause GBS,2 and at least one study has found that influenza vaccination reduces the overall risk of GBS2,3 Reference Public Health Agency of Canada. Information on seniors and the flu virus. http://www.phac-aspc.gc.ca/alert-alerte/h1n1/pdf/Factsheet_Seniors.pdf Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Guillain-Barr� syndrome and influenza virus infection. Clin Infect Dis 2009;48:48-56. Tam CC, O'Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues LC. Guillain-Barr� syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database. PLoS One 2007;2:e344.

29. Benefit of vaccinating pregnant women

30. Adjusted odds ratios of prematurity and small for gestational age by maternal influenza vaccine status (OR <1 imply a protective vaccine effect of )

31. Influenza in pregnancy and birthweightRCT, Bangladesh, 2004/5 Difference in birth weights (vaccine vs. placebo) during intervals with no influenza neonates of vaccinated moms babies were 0.25 gms heavier (P=.70) Difference in birth weights during intervals with influenza activity neonates of vaccinated moms were 215 gms heavier (P=.004)

32. Influenza vaccine in pregnancySafety data No pregnancy associated adverse events with ANY inactivated vaccine, EVER Vaccine is recommended in pregnancy by NACI, CDC, SOGC, ACOG1,2 Numerous safety studies, no evidence of teratogenicity No evidence to suggest that thimerosal given to mothers has any impact on fetus Since 1998, US has recommended vaccination of pregnant women - 500,000 to 2 million/yr x 11 years

34. Dosing of Influenza Vaccine for Children <9 Years of Age* Because they are less likely to have had prior priming exposure to an influenza virus and will receive a lower per-injection dose of TIV, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children 6 to 23 months of age. Whether or not a child has had 2009 pandemic influenza vaccine has no impact on recommendations for seasonal influenza vaccine. Reference National Advisory Committee on Immunization (NACI). Statement on Seasonal Trivalent Inactivated Influenza Vaccine (TIV) for 2010-2011. Can Commun Dis Rep 2010;36(ACS�6):1-49. Because they are less likely to have had prior priming exposure to an influenza virus and will receive a lower per-injection dose of TIV, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children 6 to 23 months of age. Whether or not a child has had 2009 pandemic influenza vaccine has no impact on recommendations for seasonal influenza vaccine. Reference National Advisory Committee on Immunization (NACI). Statement on Seasonal Trivalent Inactivated Influenza Vaccine (TIV) for 2010-2011. Can Commun Dis Rep 2010;36(ACS�6):1-49.

35. Key Messages About Influenza Prevention Get the flu shot Wash hands with soap and water at least 5 times per day Keep an alcohol-based hand sanitizer handy at work, home and in your car (minimum 60% alcohol) Cover the mouth and nose with a tissue to cough or sneeze and throw the tissue out. Cough into the upper sleeve if a tissue isn�t available Stay home when sick. Avoid crowds where viruses can spread easily Keep common surfaces and items clean The following key messages about flu prevention should be communicated to all Ontarians: Get the flu shot Wash hands with soap and water thoroughly and often Keep an alcohol-based hand sanitizer handy at work, home and in your car (minimum 60% alcohol) Cover the mouth and nose with a tissue to cough or sneeze and throw the tissue out. Cough into the upper sleeve if a tissue isn�t available Stay home when sick . Avoid crowds where viruses can spread easily Keep common surfaces and items clean and disinfected The following key messages about flu prevention should be communicated to all Ontarians: Get the flu shot Wash hands with soap and water thoroughly and often Keep an alcohol-based hand sanitizer handy at work, home and in your car (minimum 60% alcohol) Cover the mouth and nose with a tissue to cough or sneeze and throw the tissue out. Cough into the upper sleeve if a tissue isn�t available Stay home when sick . Avoid crowds where viruses can spread easily Keep common surfaces and items clean and disinfected

36. New in Testing and Treatment Many cohorts from pH1N1 that find an association between treatment, especially early treatment, with antivirals, and increase survival

37. Cohorts pH1N1 - IAntiviral efficacy

38. Cohorts pH1N1 - IIAntiviral efficacy

39. Testing recommendations Test when it will make a difference to management Kids in ED, if an influenza diagnosis means you don�t need antibiotics or admission Adults being admitted to hospital with pneumonia/COPD exacerbation/sepsis NYD

40. Treatment recommendations Use antivirals: During influenza season <48 hours after symptom onset, or not improving/getting worse WITH fever, sudden onset, early cough WITH risk factor for severe disease Choice of antivirals Oseltamivir 75 mg bid x 5 days Zanamivir 10mg (2 puffs) bid x 5 days

41. In sum Influenza remains the most common infectious disease cause of death in Canada Vaccination is our most important preventive strategy Biggest gap is those who don�t get vaccinated Pandemic confusion will impact vaccination rates this year Physician recommendation is critically important Antivirals are an useful adjunct to

42. Questions?