Immunization Potpourri 2010

1. Immunization Potpourri 2010 Peter N. Wenger, MD Departments of Preventive Medicine and Community Health/Pediatrics UMDNJ-New Jersey Medical School Newark, NJ

2. Pandemic Influenza A Virus H1N1 2009

3. aka Swine Flu, Novel Influenza A H1N1, Swine-Origin Influenza A Virus H1N1, The Pandemic, End of Life as we Know It Flu

4. CDC Estimates of 2009 H1N1 Cases from April 2009 – March 13, 2010, By Age Group http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm #Table%20Cumulative

5. CDC Estimates of 2009 H1N1 Related Hospitalizations from April 2009 – March 13, 2010, By Age Group http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm #Table%20Cumulative

6. CDC Estimates of 2009 H1N1 Related Mortality from April 2009 – March 13, 2010, By Age Group http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm #Table%20Cumulative

7. Percentage of Visits for Influenza-like Illness (ILI) Reported by the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet) National Summary 2008-2009 and Previous Two SeasonsThrough the week Ending May 22, 2010 http://www.cdc.gov/h1n1flu/updates/us/

8. National H1N1 Flu Survey*Week of December 6-12, 2009 • ~46 million people (15.3%) vaccinated vs 2009 pandemic influenza A virus H1N1 • 28 million adults (13.0%) • 18 million children (24.0%) • Amount of vaccine distributed to providers • ~21% of US population • 3 of 4 shipped doses administered • 74% of vaccine went to people in initial target groups • 42% of all vaccine given to children • 23% of vaccine doses given were nasal spray *http://www.cdc.gov/h1n1flu/in_the_news/influenza_vaccination.htm

9. Pandemic Influenza A (H1N1) 2009 Monovalent Vaccination Coverage, New Jersey, October 2009 – January 2010* • Children aged 6 months to 17 years • 32.7% (95% CI, + 4.6) • Persons aged ≥18 years • 13.1% (95% CI, + 2.0) • Persons in initial target groups • 29.0% (95% CI, + 4.5) • Persons aged 25-64 years at high risk • 17% (95% CI, + 5.8) • Persons aged 25-64 years not included in the initial target groups • 9.5% (95% CI, + 2.4) • Persons aged ≥ 65 years • 12.2% (95% CI, + 3.7) *CDC. MMWR April 2, 2010. 59;12:363-68

10. Influenza Vaccine Development

11. http://www.ifpma.org/Influenza/index.aspx?000_The_Influenza_Virus/001a_Influenza_Virus.htmlhttp://www.ifpma.org/Influenza/index.aspx?000_The_Influenza_Virus/001a_Influenza_Virus.html

12. InfluenzaStrategy to Escape Immune Detection • Drift • Minor change in HA glycoprotein • Gradual accumulation of amino acid changes • Mutations in viral RNA • Occurs continuously • Shift • Major change in HA glycoprotein • Reassortment (Reassortant) • Exchange of gene segments • Direct transmission from a different species to humans without reassortment • 1918? • 1997 – 2005 Hong Kong; Netherlands; Canada; South Asia; New York • Occurs infrequently • ~ 33 years Cox NJ, Subbarao K. Lancet. 1999;354:1277–82.

13. PB1 PB1 PB2 PB2 PA PA HA HA NA NA NP NP M M NS NS PB1 PB2 PA HA NA NP M NS Genetic Reassortment To Generate Vaccine Strains Master strain - high-growth potential in eggs or cell culture Circulating wild-type strain Co-infect cells From wild-type strain From Master strain New high-growth reassortant vaccine strain

14. Currently Available Influenza Vaccines Ruben FL. Clin Infect Dis. 2004;38:689-91. cdc.gov/nip/publications/pink/flu.pdf.

15. Considerations • Include strain that closely match community circulating strains • May differ in different regions • Dose considerations • Induces protective immune response in individuals • Age-dependent • <6 months: inadequate response • Older individuals: less robust response • Hemagglutinin antigen (HA) • 15 µg in those ≥3 years of age • 7.5 µg in those 6 - 35 months of age • Vaccine-naïve children, 6 months through 8 years of age require a priming dose • Priming dose for pandemic (novel) strains? • Maximizing population coverage • Minimizing adverse reactions

16. Timeline for Vaccine Development • Reflect the need to produce and administer vaccine before and during each influenza season • Global surveillance • Year round in both hemispheres • Trends in viral antigenic changes • Collection, analysis, and assessment of circulating strains for selection of appropriate vaccine strains • Timing is everything! • Too early – significant antigenic changes may be missed • Too late – vaccine output may be affected

17. World Health Organization (WHO)Global Influenza Surveillance System ● Established in 1948 • 130 national influenza centers in 101 countries • Analyzed by 4 WHO Collaborating Centers for Reference and Research on Influenza • CDC; Atlanta, GA, US • National Institute on Medical Research; London, UK • Victoria Infectious Diseases Reference Laboratory; Melbourne, Australia • National Institute for Infectious Diseases; Tokyo, Japan • US Food and Drug Administration (FDA) determines viral components of US-licensed vaccines

18. Timeline for Vaccine Development • From selection to consumer release of trivalent influenza virus vaccine • Six to eight months • Preparation of each reassortant viral component • Development of high-growth reassortants • Capable of high growth in eggs/cell cultures • Purification • Solvents • Unnecessary viral antigens • Bacteria • Standardization and testing of HA components • Development of appropriate reagents • Safety and efficacy testing • Production of trivalent vaccine • Purification • Mass production • Regulatory Issues • Monovalent pandemic vaccine • Four to six months

19. Production of Influenza Vaccines for Pandemics or Pandemic Alerts1957 - 1998 Wood, JM. Developing vaccines against pandemic influenza. Phil. Trans. R. Soc. Lond. 2001;356:1953-60.

20. To Prime or Not To Prime Minimum Immunogenic Dose of H1N1, H2N2, and H5N3 Vaccines Data from many clinical trials from 1976 to 1999 Wood, JM. Developing vaccines against pandemic influenza. Phil. Trans. R. Soc. Lond. 2001;356:1953-60.

21. 2010 – 2011 Influenza Vaccine And the winners are…….. A/California/7/2009(H1N1)-like virus A/Perth/16/2009 (H3N2)-like virus B/Brisbane/60/2008-like virus

22. New Recommendation • February 24, 2010 • Advisory Committee on Immunization Practices (ACIP) • Universal immunization for all persons ≥6 months of age • Published in the MMWR • August 6, 2010 • Volume 59; RR-08

23. New Recommendation • June 24, 2010 • All children aged 6 months through 8 years of age who did not receive at least 1 dose of the monovalent 2009 Influenza A H1N1 vaccine: • Receive 2 doses of the 2010-11 seasonal influenza vaccine regardless of their previous vaccination history

24. High-Dose Inactivated Influenza Vaccine for Persons Aged ≥65 Years* • 12/23/2009 • FDA licensed an injectable inactivated trivalent influenza vaccine containing an increased amount of viral hemagglutinin antigen compared with other TIVs • Single dose for persons aged ≥65 years • Rationale • Greater risk of hospitalization and mortality from influenza • Less immunogenic response • 04/30/2010 • Advisory Committee on Immunization Practices (ACIP) • No preference for new vaccine over other TIVs *CDC. MMWR. Licensure of a high-dose inactivated influenza vaccine for persons aged ≥65 years and guidance for use-US 2010. 04/30/2010;59(16);485-86.

25. New Jersey • Attendance at pre-Kindergarten and daycare centers • Mandatory annual influenza immunization • For those 6 months through 8 years of age • Naïve • 2 doses • Administered at least 4 weeks apart

26. Estimates of Death Associated with Seasonal Influenza, United States, 1976-2007* • Annual estimates of influenza-associated deaths • Death certificate data • Respiratory and circulatory causes (includes pneumonia and influenza causes) • Estimated annual average: 23, 607 (range,3,349 [1986-87] to 48,614 [2003-04]) • Average: 9.0 per 100,000 persons (range,1.4 to 16.7) *CDC. Estimates of deaths associated with seasonal influenza, US. 1976-2007. MMWR August 27, 2010;59(33):1057-62.

27. Estimates of Death Associated with Seasonal Influenza, United States, 1976-2007* • Age-specfic estimates • <19 years of age • Estimated annual average: 124 (range, 57 [1981-82] to 197 [1977-78]) • Rate: 0.2 deaths per 100,000 (range, 0.1-0.3) • 19-64 years of age • Estimated annual average: 2,385 (range, 504 [1981-82] to 4,752 [2003-04]) • Rate: 1.5 per 100,000 persons (range, 0.4-3.1) • ≥65 years of age • Estimated annual average: 21,098 (range, 2,344 [1986-87] to 43,727 [2004-04] • Rate: 66.1 per 100,000 persons (range, 8.0 – 121.1) • 89.4% of influenza-associated mortality *CDC. Estimates of deaths associated with seasonal influenza, US. 1976-2007. MMWR August 27, 2010;59(33):1057-62.

28. Estimates of Death Associated with Seasonal Influenza, United States, 1976-2007* • Wide variation in the estimated mortality from season to season associated with predominant influenza type and subtypes • ≥20% of all isolates tested during season • Influenza A(H3N2) • 2.7 times higher • 22 seasons *CDC. Estimates of deaths associated with seasonal influenza, US. 1976-2007. MMWR August 27, 2010;59(33):1057-62.

29. Estimates of Death Associated with Seasonal Influenza, United States, 1976-2007* • Substantial variability in influenza-associated mortality estimates • Year (season to season) • Age group • Influenza type/subtype • A single estimate cannot be used to summarize influenza-associated mortality • A range of estimates should be used • Age groups • Circulating types/subtypes *CDC. Estimates of deaths associated with seasonal influenza, US. 1976-2007. MMWR August 27, 2010;59(33):1057-62.

30. Intradermal Influenza Vaccine • Sanofi Aventis submitted FDA application for approval • Becton Dickinson • Short, thin needle • 1/10th size of regularly used needle • 1.5 mm vs 25 to 40 mm • 1/5th antigen dose • Stimulates the dendritic cells • Extends vaccine supply • Less discomfort • Less expensive? • Approval in early 2011?

31. 13-valent Pneumococcal Conjugate Vaccine (PCV13)

32. Transition from PCV7 to PCV 13 • Since introduction of PCV7 in 2000 • Dramatic overall decrease in invasive pneumococcal disease (IPD) • IPD due to serotypes not included in PCV7 have increased • February 24, 2010 • FDA approved a new 13-valent pneumococcal conjugate vaccine (PCV13) • ACIP recommended transition from PCV7 to PCV 13

33. Pneumococcal Serotypes in PCV7 and PCV 13

35. Invasive Pneumococcal Disease (IPD) in Newark Residents*December 1, 2007 – November 30, 2008 • 2/72 (2.8%) were serotypes included in the PCV7 • Reflected success of PCV7 in decreasing IPD due to vaccine serotypes • 32/72 (44.4%) were covered by PCV13 • Serotypes 3 (6), 6A (3), and 19A (19) • Serotype 19A was dominant • 19/72 (26.4%) • Serotype 19A was most closely associated with penicillin-resistance • Consistent with trends reported in US • A significantly higher proportion was found in children compared with adults and the elderly *Tasslimi A, et al. Clinical and Vaccine Immunology. August 2009. 16;8:1256

36. Pneumococcal Immunization with PCV13 Advisory Committee on Immunization Practices (ACIP) Recommendations • Infants and children under 2 years of age • 4-dose regimen • 2, 4, 6, and 12-15 months • Older children and adolescents • Healthy between 2nd and 5th birthdays • Not completed PCV7 or PCV13 series before age 2 • 1 dose • Children at high risk between 2nd and 6th birthday • Received 3 doses of PCV7/PCV13 before 2 years • 1 dose • Received ≤2 doses of PCV7/PCV13 before 2 years • 2 doses • Children and adolescents at high risk 6 through 18 years • 1 dose • Even if previous recipient of PCV7 or PPSV23 • Children who have completed the 4-dose series with PCV7 and are healthy and <5 years or at high risk and <6 years • 1 dose

37. Risk Factors for Invasive Pneumococcal Disease • Sickle cell disease • Functional or anatomical asplenia • Cochlear implants • CSF leaks • Diabetes • Chronic heart and lung disease • Immunocompromised conditions • HIV infection and congenital immunodeficiencies • Chronic renal failure and nephrotic syndrome • Diseases associated with treatment with immunosuppressive medications or radiation therapy • Solid organ transplantation • Lymphomas, leukemias, malignant neoplasms • Asthma if treated with prolonged, high-dose oral corticosteroids

38. Mumps Outbreak New York and New Jersey 2009-2010

39. Mumps • RNA virus • Systemic disease • Swelling of ≥1 salivary glands • Parotids • ~1/3 of patients do not demonstrate salivary gland swelling • Respiratory tract symptoms • >50% of patients have CSF pleocytosis • <10% have CNS symptomology

40. Mumps

41. Mumps • Systemic Disease (continued) • Orchitis • Post-pubertal complication • Sterility is rare • Rare complications • Arthritis, thyroiditis, mastitis, glomerularnephritis, myocarditis, endocardial fibroelastosis, pancreatitis, oophoritis, hearing impairment • Infections in adults more likely to be severe • Death, though rare, occurs most often in adults • Infection in first trimester associated with increased risk of spontaneous abortion

42. Mumps • Epidemiology • Transmission via infected respiratory tract secretions • Incubation period • 12–25 days (usually 16-18 days) • Period of maximum communicability • 1 to 2 days prior to parotid swelling • 5 days after onset of swelling • Virus has been isolated in salivia from 7 days prior to swelling onset to 9 days after onset of swelling • Reported incidence in US in 1967 • 186,000

43. Mumps • Vaccine • Licensed in US in 1967 • Recommended for routine childhood immunization in 1977 • One-dose schedule • Disease incidence fell to very low levels • Outbreaks occurred between 1986-1991 • Two-dose schedule recommended in 1989 • 2000-2005: <300 reported cases/year • 2006: Mumps outbreak: 6584 cases • 18-24 years of age • Many received 2 doses MMR • Mumps least effective component of MMR • 73%-91% after 1 dose • 79%-95% after 2 doses

44. Mumps Immunization Advisory Committee on Immunization Practices (ACIP) Recommendations • Two doses of mumps-containing vaccine (in US – MMR) • All school-aged children (K-12) • 1st dose: 12-15 months • 2nd dose: 4-6 years • Adults at high-risk for infection • i.e., person who work in healthcare facilities, international travelers, students at post-high school educational institutions, etc.) • For healthcare workers born before 1957 without laboratory evidence of immunity • Consider receiving 1 dose • During outbreaks • Children aged 1-4 years • Offer 2nd dose • Confirm 2-doses in others

45. Mumps Outbreak New York and New Jersey2009-2010* • June 17, 2009: 11-year old boy returns from United Kingdom • ~7,400 reports of laboratory confirmed mumps in 2009 • Symptomatic by June 28 • At camp for tradition-observant Jewish boys • Subsequent transmission to other camp attendees and staff member • 25 cases reported from June 28th–September 8th • Transmission occurred in multiple locations when campers returned home • As of January 29, 2010: 1,521 cases reported *CDC. MMWR. Update: mumps outbreak-New York and New Jersey, June 2009-January 2010. February 12, 2010;59(5):125-29.

46. Mumps Outbreak New York and New Jersey2009-2010* • Confined primarily to the tradition-observant Jewish community • New York City {Brooklyn} (44%); Orange County, NY (24%); Rockland County, NY (20%); Four counties in New Jersey (10%) • Camp-associated cases in Sullivan County, NY (2%) • <3% of cases occurring outside the community • Reported regular contact with members of the affected community *CDC. MMWR. Update: mumps outbreak-New York and New Jersey, June 2009-January 2010. February 12, 2010;59(5):125-29.

47. Mumps Outbreak New York and New Jersey2009-2010* • 61% of cases occurred in persons aged 7-18 years of age • 4.9% in children aged 1-4 years • Range, 3 months-90 years • 76% were male • Among patients in which vaccination status was known (n=1,115) • 88% received at least 1 dose of mumps-containing vaccine (MCV) • 75% received 2 doses of MCV *CDC. MMWR. Update: mumps outbreak-New York and New Jersey, June 2009-January 2010. February 12, 2010;59(5):125-29.

48. Mumps Outbreak New York and New Jersey2009-2010* • Complications • 65 reports • Orchitis: 55 cases (85%) • Pancreatitis: 5 cases (8%) • Aseptic meningitis: 2 cases (3%) • Transient deafness: 1 case (1.5%) • Bell’s palsy: 1 case (1.5%) • Oophoritis: 1 case (1.5%) • 19 reported hospitalizations • No deaths *CDC. MMWR. Update: mumps outbreak-New York and New Jersey, June 2009-January 2010. February 12, 2010;59(5):125-29.

49. Mumps Outbreak New York and New Jersey2009-2010* • Mumps outbreak in a highly vaccinated population • Most cases occur in vaccinated people • Why????? • Specific close-knit, closed community • No sustained transmission outside the specific community • Congregate setting • Prolonged close contact • Large household size • Mean household size in the affected community was 5.7 versus mean US household size of 2.6 • Effectiveness of mumps component of MMR *CDC. MMWR. Update: mumps outbreak-New York and New Jersey, June 2009-January 2010. February 12, 2010;59(5):125-29.

50. Mumps Outbreak New York and New Jersey2009-2010* • Public Health Response • Health-care providers notified • Verify children are completely vaccinated • Offer 2nd dose in children aged 1-4 years • Offer vaccine to adults • Unknown immunity or vaccine status • State and local health departments • Affected schools • Enhance vaccination policies • Exclude unvaccinated children from school during outbreak • Home isolation for 5 days after onset of parotitis • Orange County, New York beginning 01/19/2010 • 3rd dose of MMR in 3 schools • Continued transmission of infection despite high level of 2-dose coverage • Institutional Review Board-approval protocol that includes evaluation of intervention *CDC. MMWR. Update: mumps outbreak-New York and New Jersey, June 2009-January 2010. February 12, 2010;59(5):125-29.