This document discusses influenza disease and vaccination, with a focus on India. It provides an overview of influenza viruses and infection, influenza outbreaks and pandemics throughout history, and an analysis of the 2009 H1N1 pandemic. It defines populations at high risk of influenza complications and analyzes influenza vaccine data from Chandigarh, India. Recommendations for influenza vaccines for the 2010-2011 and 2011-2012 seasons in India are also presented. Clinical studies on the effectiveness of influenza vaccines in reducing influenza-like illness among children in India are summarized.

1. Influenza Disease & Vaccination: Current Perspective with special reference to India Dr. Gaurav Gupta, Practising Pediatrician Member AAP, IAP Charak Clinics, Mohali, Punjab

2. Influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of pandemic H1N1 Defining at-risk populations Influenza Vaccine – Data from Chandigarh Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

3. Influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of pandemic H1N1 Defining at-risk populations Influenza Vaccine – Data from Chandigarh Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

5. Influenza A is divided into subtypes based on the HA and NA proteins

6. HA and NA genes can be reassorted (switched) between strains generating novel subtypesDifferent influenza A subtypes result from differentcombinations of the HA and NA proteins HA, hemagglutinin; NA, neuraminidase

7. Influenza infection has a variety of symptoms! Clinical symptoms Influenza infections are asymptomatic in30–50% of cases Common symptoms include abrupt onset of fever (38–40°C), sore throat, unproductive cough, runny or stuffy nose, headache, myalgia, chills, anorexia and extreme fatigue Uncommon symptoms include photophobia, abdominal pain and diarrhea Illness improves in under 7 days, cough and malaise may persist for weeks Children may experience high fevers that can lead to febrile seizures Fever may be absent in the elderly; presenting signs may include anorexia, lassitude or confusion Virus shedding Adults: from the day before symptoms appear until 5 days after illness onset Young children: several days before illness onset until >10 days afterwards Severely immunocompromised patients: weeks to months Influenza virus particles (brown) invade cilia (blue) in the airways Symptoms associated with seasonal influenza are well defined and can vary between individuals Zambon MC. J Antimicrob Chemother 1999; 44 (Suppl. B):3-9; CDC, Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 2007; 56:1-54.

8. Clinical Differentiation Between the Common Cold and the Flu The following symptoms are more commonly seen in influenza rather than the common cold: High fever lasting 3 to 4 days Headache Myalgia Fatigue and weakness Extreme exhaustion Severe chest discomfort and cough The following symptoms are more commonly seen in the common cold rather than influenza: Stuffy nose is common Sneezing is common Cough is generally mild to moderate Symptoms such as fever, headache, aches and pains and exhaustion are rare in those with colds.

9. Influenza viruses are spread by virus-laden aerosols! How influenza viruses are spread: From person to person primarily through large-particle respiratory droplet transmission Requires close contact betweensource and recipient as droplets only travel <1m By contact with surfaces contaminated with respiratory droplets By airborne transmission of evaporated droplets that may remain in the air for long periods of time (data are limited) Virus transmission may be slowed by social distancing CDC, Epidemiology and prevention of vaccine-preventable diseases. Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. 10th ed. Washington DC: Public Health Foundation; 2007:235-56; Rust MJ, et al.Nat Struct Mol Biol 2004; 11:567-573; CDC, Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 2007; 56:1-54.

10. Influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of pandemic H1N1 Defining at-risk populations Influenza Vaccine – Data from Chandigarh Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

11. Influenza virus changes due to antigenic drift or shift! Antigenic drift Antigenic shift NA HA NA HA A/H1N2 Geneticmutations A/H1N1 A/H1N1 Geneticressortment A/H3N2 A/H3N1 Antigenic drift occurs when there are small changes in the virus Antigenic drift produces new virus clades that may not be recognized by the immune system, meaning reinfection can occur Drifted strains may be mismatched with seasonal influenza vaccine Antigenic shift is a major change in the influenza A virus, altering the HA and/or NA proteins Antigenic shift leads to the emergence of a new influenza A subtype Most people have little or no protection against the new virus Antigenic drift can lead to epidemics; antigenic shift can lead to pandemic influenza Cox NJ, Subbarao K. Annu Rev Med 2000; 51:407-421; Zambon MC. J Antimicrob Chemother 1999; 44 (Suppl. B):3-9; Koelle K, et al. Science 2006; 314:1898-1903.

13. Transmission dynamics are described using the reproductive number (R0) and case fatality ratio, which may vary depending on country and season The emergence of H1N1 has demonstrated the difficulty in predicting pandemics Nicholson KG, Wood JM, Zambon M. Lancet 2003; 362:1733-1745; WHO, Cumulative number of confirmed human cases of avian influenza A/(H5N1), available at: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_09_10/en/index.html(accessed 5 November 2008); CDC, Avian Influenza, available at: http://www.cdc.gov/flu/avian/outbreak.htm (accessed 5 November 2008).

14. Influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of pandemic H1N1 Defining at-risk populations Influenza Vaccine – Data from Chandigarh Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

15. Swine New Reassorted virus Emergence of Swine Flu Virus Avian virus Avian Reservoir Human virus Other mammals?

17. Phase 4 of pandemic alert was declared on 27 April, and Phase 5 on 29 April

18. By 30 April, 257 cases including eight deaths had been reported in 11 countriesWHO, H1N1 number of laboratory confirmed cases, available at http://gamapserver.who.int/h1n1/atlas.html (accessed 30 April 2009); WHO, H1N1 cases, situation update 6, available at http://www.who.int/csr/don/2009_04_30_a/en/index.html (accessed July 2009).

19. Pandemic H1N1 rapidly spread worldwide: May 2009 April 2009 May 2009 START March 2009 Cumulative cases 1-10 11-50 51–500 500-5,000 >5,000 29 May *, 15,510 cases including 99 deaths reported by 53 countries * Date of last report for May 2009. WHO, H1N1 number of laboratory confirmed cases, available at: http://gamapserver.who.int/h1n1/atlas.html (accessed 29 May 2009); WHO, H1N1 cases situation update 41, available at http://www.who.int/csr/don/2009_05_29/en/index.html (accessed July 2009).

20. Pandemic Influenza : Status in 2010 http://www.who.int/csr/don/2010_07_09/en/index.html

21. Influenza virological Surveillance (ILI) from 1st week Dec 2010 till now http://gamapserver.who.int/GlobalAtlas/sharedFunction/sharedFunctionInterface.asp?displayType=map

22. Influenza : % positive cases & virus subtypes http://www.who.int/csr/don/2010_07_09/en/index.html

23. Influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of current pandemic H1N1 Defining at-risk populations Influenza Vaccine – Data from Chandigarh Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

25. Complication rate higher for subjects with chronicheart disease (46.9%) vs. those without (22.8%)4In hospitalized children: Febrile seizures reported by 6-20%1 Intensive care required by 4-11%1 80% were <5 years of age; 27% were <6 months of age1 Cumulative hospitalization rates for laboratory-confirmed influenza among children 0-4 and 5-17 years of age, by season, US2 Annual rates of influenza-associated cardiorespiratory hospitalizations in those ≥50 years of age, US5 Age range (years) Season 1,000 5 2004-05 0-4 2005-06 0-4 2006-07 0-4 2007-08 0-4 800 4 600 3 Hospitalization rate per 10,000 person-years 2004-05 5-17 2005-06 5-17 2006-07 5-17 2007-08 5-17 Population-based rate 2 400 1 200 0 0 50-64 65-69 70-74 75-79 80-84 40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18 Age (years) Week 1. CDC, 2010 Yellow Book, available at http://wwwn.cdc.gov/travel/yellowbook/2010/chapter-2/influenza-seasonal-avian-pandemic.aspx (accessed August 2009). 2. CDC, Mortality and Morbidity Weekly Report 2009; 58:369-374. 3. Bridges CB, et al. Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia: Saunders; 2008. 4. Irwin DE, et al. BMC Health Serv Res 2001; 1:8. 4. Thompson WW, et al. JAMA 2004; 292:1333-1340.

26. The majority of pandemic H1N1 cases have occurred in subjects <20 years of age! Seasonal influenza attack rates and proportionof population at high risk of serious complications, by age (US)1 Age distribution and travel status of pandemic H1N1 2009 cases in EU and EEA countries2 Higher incidence of pandemic H1N1 than seasonal influenza in age group 10-19 years 2,500 60 Gross attack rate At high risk ofserious complications 50 2,000 Travel related Domestic The high level of domestic cases indicates community-level spread of the virus, meeting the WHO criteria for Phase 6 pandemic alert3 40 1,500 Proportion of population (%) Number of cases 30 1,000 20 500 10 0 0 0-4 5-17 18-49 50-64 65+ ≥60 50-59 40-49 30-39 20-29 10-19 0-9 Age group Age group N=7,681 cases reported by 28 EU/EEA countries as of 6 July 2009 H1N1 pandemic influenza is predominantly found in patients <20 years of age; in contrast, the very young and the elderly are most at risk from seasonal influenza 1. Molinari NA, et al. Vaccine 2007; 25:5086-5096. 2. ECDC Surveillance Report, Analysis of Influenza A(H1N1)v individual case reports in EU and EEA countries, Update 9 July 2009. 3. WHO, Current WHO phase of pandemic alert, available at http://www.who.int/csr/disease/avian_influenza/phase/en/ (accessed July 2009).

27. Age sex pattern of H1N1 cases in India http://mohfw-h1n1.nic.in/documents/PDF/EpidemiologicalTrendsInIndia.pdf

29. Win – Win Situation vaccinating Pregnant Women ACIP/ CDC/ ACOG recommend Flu vaccination during pregnancy Can be done at any gestational age, earlier the better. Benefits mothers by reducing serious respiratory infections during pregnancy Benefits fetus – Better weight gain & decreased incidence of SGA Benefits infant – the most effective way to prevent influenza in the first 6 months of life.

30. Influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of current pandemic H1N1 Defining at-risk populations Influenza Vaccine – Data from Chandigarh Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

31. Methodology-Clinical Effectiveness Study 25

32. Continued….. Methodology-Clinical Effectiveness Study 26

33. Continued….. Methodology-Clinical Effectiveness Study 27

34. Overall Results

35. Clinical Effectiveness of Influenza vaccine-1 Fully vaccinated cohort (n=154) vs. Unvaccinated cohort (n=330)* Conclusion: Influenza vaccine is effective in reducing the ILI and visits to physician for ARI in fully vaccinated Indian children as compared to unvaccinated children. *Renuka R, Gupta G, Tiwari P. Clinical effectiveness of the 2010-2011 seasonal influenza vaccine among healthy Indian children. WSPID-2011, Melbourne.

36. Clinical Effectiveness of Influenza vaccine-2 Partially vaccinated cohort (n=16) vs. Unvaccinated cohort (n=330)* Conclusion: Partially vaccinated children had no significant protection against ILI and visits to physician as compared to unvaccinated children. *Renuka R, Gupta G, Tiwari P. Clinical effectiveness of the 2010-2011 seasonal influenza vaccine among healthy Indian children. WSPID-2011, Melbourne.

37. Clinical Effectiveness of Influenza vaccine-3 Age-wise efficacy for prevent of ILI* Conclusion: Children aged 3-9 year had the best protection rates against ILI as compared to unvaccinated children. *Renuka R, Gupta G, Tiwari P. Clinical effectiveness of the 2010-2011 seasonal influenza vaccine among healthy Indian children. WSPID-2011, Melbourne.

38. Comparative Vaccine Effectiveness * Singh H, Gupta G, Tiwari P. Clinical effectiveness of the 2009-2010 seasonal influenza vaccine among healthy Indian children. ISPOR 4th Asia Pacific Conference, Phuket, Thailand.

39. Safety and Tolerability of Influenza vaccine-1 Singh H, Gupta G, Tiwari P. Safety and tolerability of trivalent inactivated influenza (TIV) vaccine in healthy Indian children. 62nd Indian Pharmaceutical Congress, 2010. Manipal, India. (Poster No. L-6).

40. Safety and Tolerability of Influenza vaccine-2 *Singh H, Gupta G, Tiwari P. Safety and tolerability of trivalent inactivated influenza (TIV) vaccine in healthy Indian children. 62nd Indian Pharmaceutical Congress, 2010. Manipal, India. (Poster No. L-6).

41. Pandemic influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of current pandemic H1N1 Defining at-risk populations Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

43. Currently, WHO have 128 institutions from 99 countries as recognized National Influenza centersObjectives: Surveillance enables to recommend twice the content of Influenza vaccine for the season Serves as a global alert mechanism for the emergence of Influenza virus with Pandemic potential 1 Laboratory New Delhi AIIMS ≥ 2 Laboratory Dibrugarh V P Chest RMRC No Laboratory Nagpur IGGMC Kolkata Mumbai NICED Haffkine Inst Pune NIV RegionalCenters Vellore Chennai CMC NewCenters KIPM ReferralCenter

44. Pandemic Flu protection added to Seasonal flu vaccine WHO Influenza strain for Northern Hemisphere 2010 – 2011 season: an A/California/7/09 (H1N1)-like virus; * an A/Perth /16/2009 (H3N2)-like virus; ** a B/Brisbane/60/2008-like virus.*** *A/California/7/09 (H1N1)-like virus is the pandemic (H1N1) 2009 influenza virus. A monovalent vaccine containing this strain was made available to the United States in the fall of 2009. **A/Perth/16/2009 (H3N2)-like virus is a change from the 2009-2010 influenza vaccine formulation. ***and B/Brisbane /60/2008-like virus is a current vaccine virus. http://www.who.int/csr/disease/influenza/recommendations201010north/en/

46. ! Have chronic pulmonary, cardiovascular, renal, hepatic, cognitive, neurologic/neuromuscular,

47. hematological or metabolic disorders (including diabetes mellitus)

48. ! Are immunosuppressed (Caused by medications or by HIV)

49. ! Are receiving long-term aspirin therapy and therefore might be at risk for experiencing Reye syndrome after influenza vaccination

50. ! Are residents of long-term care facilities; and

51. ! Will be pregnant during the influenza season.Source: CDC recommendation available at http://www.cdc.gov/flu

52. Pandemic influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of current pandemic H1N1 Defining at-risk populations Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

53. WHO Recommended strains 2011 -12 season It is recommended that vaccines for use in the 2011-2012 influenza season (northern hemisphere) contain the following: an A/California/7/2009 (H1N1)-like virus; an A/Perth/16/2009 (H3N2)-like virus; a B/Brisbane/60/2008-like virus. A/H3N2 B A/H1N1 California Brisbane Perth Brisbane Brisbane Brisbane 2009-10 2011- 12 2010-11 2011-12 season WHO recommended strain are similar to 2010-11 season northern hemisphere strains

54. WHO monitors strain drifts and recommends strains for vaccine inclusion Drift has led to 15 changes in recommended strains since 1997-19981,2 A/H3N2 B A/H1N1 Bayern Beijing NewCaledonia Brisbane SolomonIslands Brisbane Wuhan Sydney Moscow Fujian Wisconsin California Sichuan Beijing Malaysia Hong Kong Florida Shanghai 1997-98 2007-08 2005-06 2001-02 2002-03 2003-04 2006-07 1998-99 2004-05 1999-00 2000-01 2008-09 Influenza Season (year) For the Northern hemisphere, the recommended strains have changed 12 times since 1997-1998 1. www.who.int; 2. http://www.fda.gov/cber/flu/flu2008.htm.

55. Key Questions Question 1 Is annual vaccination reqd. if the strain remains the same for consecutive years?

57. International guidance

59. Northern hemisphere Tropics Southern hemisphere 45 1 29 41 25 37 5 9 13 17 21 33 49 Week Influenza spread occurs inseasonal patterns 10 Influenza activity peak: November-March2,3 8 6 ILI/1000 Population 4 2 0 E.g. India 1 3 5 7 9 11 13 15 40 42 44 46 48 50 52 Week 50 40 30 ILI/1000 Population Year-round activity3,4 20 10 0 J F M A M J J A S O N D Month 20 18 16 14 ILI Consultations/1000 Population 12 Influenza activity peak: April-September4,5 10 8 6 Globe image: www.phimap.com 4 2 0 ILI = influenza-like illness. 1. Bridges et al. 2008; 2. EISS 2004; 2. Cox and Subbarao 2000; 4. CHP 2008; 5. Yohannes et al. 2003.

61. Pandemic influenza: An overview! General introduction to influenza viruses and infection Influenza outbreaks and pandemics Analysis of current pandemic H1N1 Defining at-risk populations Influenza Vaccines Recommendations 2010-11 season Influenza Vaccines Recommendations 2011-12 season Influenza Vaccines

63. Currently, WHO have 128 institutions from 99 countries as recognized National Influenza centersObjectives: Surveillance enables to recommend twice the content of Influenza vaccine for the season Serves as a global alert mechanism for the emergence of Influenza virus with Pandemic potential 1 Laboratory ≥ 2 Laboratory No Laboratory Seasonal influenza vaccines are trivalent vaccines derived from the three viral types that are currently in global circulation http://www.who.int/csr/disease/influenza/surveillance/en/index.html

65. Inactivated Influenza Vaccine

66. Whole virus vaccines

67. Split-virion Vaccine

68. Subunit vaccine

69. Adjuvanted vaccines

70. Virosomal vaccines

71. Cell culture derived vaccinesA) whole-virus, B) split-virion, C) subunit, D) virosomal, E) adjuvanted. Amorij JP, Huckriede A, Wilschut J, Frijlink HW, Hinrichs WL. Development of stable influenza vaccine powder formulations: Challenges and possibilities. Pharm Res. 2008;25(6):1256-1273.

72. Comparison of Influenza Vaccines +Low; ++ Medium; +++ High.

73. Live vs Inactivated Influenza Vaccine http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5213a1.htm

74. Thank You