A 25 Gauge View of Prevention: Adult Vaccinations

1. A 25 Gauge View of Prevention: Adult Vaccinations Shobhina Chheda, M.D., M.P.H Laurel Romer, M.D. Primary Care Conference September 14, 2005

2. Learning Objectives Understand epidemiology of vaccine preventable diseases. Review recommendations for common adult vaccinations. Offer vaccination to appropriate patients. Answer patient questions regarding upcoming vaccines.

3. Influenza Epidemiology Hospitalizations (From 1979/80 to 2000/01) 54,000 to 430,000 per epidemic 226,000 influenza-related hospitalizations/year 63% of these among patients > 65 years old Deaths 19,000 per season from 1976-1990 36,000 per season from 1990-1999 Deaths result from pneumonia, exacerbations of cardiopulmonary disease 0.4-0.6/100,000 age 0-49 7.5 age 50-64 98.3 age >65 Increasing because of the number of older persons increasing Deaths result from pneumonia, exacerbations of cardiopulmonary disease 0.4-0.6/100,000 age 0-49 7.5 age 50-64 98.3 age >65 Increasing because of the number of older persons increasing

4. Influenza Virus characteristics Influenza A Envelope glycoproteins/Hemagglutinins 1,2,3/ Neuraminidases 1,2 Antigenic shift (epidemics/pandemics) Antigenic drift (localized outbreaks) Influenza B Antigenic drift

5. Influenza Vaccine Characteristics Changes yearly to approximate currently circulating strains of Influenza A/B Trivalent inactivated influenza vaccine intramuscular Trivalent live-attenuated, cold-adapted influenza vaccine Intranasal Protection conferred by induction of antibodies (mainly against the hemagglutinin) Inactivated � 9 months to manufactureInactivated � 9 months to manufacture

6. Influenza Vaccine Efficacy Greater reduction in serologically confirmed cases than in clinical influenza Healthy adults ages 14-65 years: 68% reduction in serologically confirmed influenza 48% reduction with intranasal vaccine 24% reduction in clinical influenza 13% reduction with intranasal vaccine Review of literature through 1997 identified 20 trials in healthy adultsReview of literature through 1997 identified 20 trials in healthy adults

7. Influenza Vaccine efficacy Elderly > 90% of influenza-related deaths occur among those > age 60

8. Influenza Vaccine Recommendations for 2005-2006 Persons age > 65 with comorbid conditions Residents of long-term care facilities Persons aged 2-64 with comorbid conditions Persons age > 65 without comorbid conditions Children age 6-23 months Pregnant women Health-care personnel who provide direct patient care Household contacts and out-of-home caregivers of children < 6 months This group until 10-24-05 All persons thereafterThis group until 10-24-05 All persons thereafter

9. Pneumococcus Epidemiology Illness 150,000 - 570,000 cases per year 36% of community-acquired pneumonias in adults Deaths 6,000�12,000 per year Case-fatality rate 5%-7%, higher in elderly Risk highest in Older adults Any age with certain underlying chronic diseases More people die from pneumococcal infections than from any other vaccine preventable diseaseMore people die from pneumococcal infections than from any other vaccine preventable disease

10. Pneumococcus Vaccine characteristics First used in 1945 First vaccine developed from a capsular polysaccharide 23-valent formulation created in 1983 (PPV23) Intramuscular injection Not widely used then due to the coincident discovery of penicillin around that same time PPV23 pneumococcal polysaccaride vaccine PCV7 protein conjugate vaccine 2/2000; polysaccharides are not immunogenic in children under age 2Not widely used then due to the coincident discovery of penicillin around that same time PPV23 pneumococcal polysaccaride vaccine PCV7 protein conjugate vaccine 2/2000; polysaccharides are not immunogenic in children under age 2

11. Pneumococcus Efficacy: Cochrane database Review of all RCT from 1/66 to 6/03 Combined results fail to show PPV is effective in preventing pneumonia (OR 0.77) or death (OR 0.90) Review of all case-control studies for same interval Combined results show significant efficacy in preventing invasive pneumococcal disease (OR 0.47), corresponding to an efficacy of 53% CI 0.58 to 1.02 CI 0.76 to 1.07 CI 0.37 to 0.59 Earlier studies showed more encouraging results; from 1977 on suggests no effect ? Whether due to improvements in trial methodology and reporting, differences in trial setting or real loss in efficacy over time Early trials were conducted in high-risk healthy populations where the expected benefit is the greatestCI 0.58 to 1.02 CI 0.76 to 1.07 CI 0.37 to 0.59 Earlier studies showed more encouraging results; from 1977 on suggests no effect ? Whether due to improvements in trial methodology and reporting, differences in trial setting or real loss in efficacy over time Early trials were conducted in high-risk healthy populations where the expected benefit is the greatest

12. Pneumococcus Recommendations for use Adults age 65 or older Persons age >2 with chronic disease (similar to influenza) No spleen Compromised immunity (HIV, malignancy, chronic renal disease, organ transplant, chemotherapy) Second dose of vaccine if patient received vaccine > 5 years previously and was < 65 In immunocompromised group, single revaccination if >5 years have elapsed since first dose If patient <10, consider revaccination 3 years after previous doseIn immunocompromised group, single revaccination if >5 years have elapsed since first dose If patient <10, consider revaccination 3 years after previous dose

13. Hepatitis B Incidence In endemic areas, ~70% of adult population positive for prior infection 8-15% with chronic Hep B Globally 2 billion with evidence of prior Hep B infection 350 million chronic carriers 1 million deaths annually due to cirrhosis/hepatocellular carcinoma Africa, Eastern Europe, Mid East, Central Asia, China, Southeast Asia, Pacific Islands, Amazon basin of South AmericaAfrica, Eastern Europe, Mid East, Central Asia, China, Southeast Asia, Pacific Islands, Amazon basin of South America

14. Hepatitis B Viral source Blood or blood-derived body fluids Transmission Percutaneous, mucosal Sex, injection drug use, mother-child, health care 100x more infectious than HIV Nonsexual transmission among long-term household contacts has been reported (mechanism unclear) Not transmitted through breast milk Endemic areas, mainly mother-child transmission U.S. young adults at greatest risk for transmission � sex practices, drug useNonsexual transmission among long-term household contacts has been reported (mechanism unclear) Not transmitted through breast milk Endemic areas, mainly mother-child transmission U.S. young adults at greatest risk for transmission � sex practices, drug use

15. Hepatitis B Vaccine characteristics First generation HBV vaccine was plasma derived Current vaccines are recombinant HBV Schedule: 3 doses, intramuscular injection 0, 1-2 months, 4-6 months Combined form with Hepatitis A Safety Soreness at injection site (25%) Fever, malaise, headache, myalgia, joint pain (1-3%) MS association? No clear association, exacerbation/initiation of demyelinating disorders, no clear association Thimerosal � not an issue Several rare adverse events reported, strength of association is unclear Can be considered the first anticancer vaccineMS association? No clear association, exacerbation/initiation of demyelinating disorders, no clear association Thimerosal � not an issue Several rare adverse events reported, strength of association is unclear Can be considered the first anticancer vaccine

16. Hepatitis B Efficacy After completing the 3 dose course of vaccine 90% of adults have protective serum antibody concentrations 95% of infants, children and adolescents

17. Hepatitis B Vaccine recommendations All infants Catch-up vaccination Pregnant women Homosexual/bisexual men Multiple sexual partners (4 or more/lifetime) Household contacts of patients with Hep B Injection drug users Healthcare workers Patients on hemodialysis (recipients of frequent transfusion) Patients with chronic illness Immunocompromised patients Different dose of vaccine for HD patients In U.S., vaccine recommended for all persons up to age 18 reduction in annual incidence 8.5 cases/100,000 1990 2.8 cases/100,000 in 2002 a 67% decrease Increased risk of nonresponse to HBV vaccine age> 30Different dose of vaccine for HD patients In U.S., vaccine recommended for all persons up to age 18 reduction in annual incidence 8.5 cases/100,000 1990 2.8 cases/100,000 in 2002 a 67% decrease Increased risk of nonresponse to HBV vaccine age> 30

18. Hepatitis A Significant decrease in incidence with vaccine Most occurs in community wide epidemics Higher disease incidence in West and Southwest Highest incidence in children ages 5-14 Children � reservoir Handout onlyHandout only

19. Hepatitis A Transmission: Fecal-oral 70% children asymptomatic or nonspecific symptoms > 70% adults have jaundice Liver failure rare Chronic infection doesn�t occur

20. Hepatitis A and Hurricane Katrina No transmission from contaminated water in US since 1980�s No outbreak seen in other recent hurricane/floods < 10 cases of hepatitis A in New Orleans in past 3 months

21. Hepatitis A Inactivated vaccine 2 brands licensed for children>2 and adults Different pediatric and adult formulations

22. Hepatitis A 2 doses � 6 months apart 97% immunogenic with first dose 100% with second dose- long term immunity No severe/adverse reactions Side effects Soreness/tenderness �50% Headache-15% Malaise-7%

23. Hepatitis A Not routine pediatric immunization Adult recommendations Certain international travelers Men who have sex with men Illicit drug users Chronic liver disease Persons receiving clotting factor concentrates Persons working with laboratory HAV Not routinely recommended for healthcare workers Slide could go� Only states with higher than average incidence 1987-97 International travelers Men who have sex with men Illicit drug users Persons with chronic liver disease Persons receiving clotting factor concentrates Persons working with laboratory HAV Slide could go� Only states with higher than average incidence 1987-97 International travelers Men who have sex with men Illicit drug users Persons with chronic liver disease Persons receiving clotting factor concentrates Persons working with laboratory HAV

24. Combined Hepatitis A and B vaccine FDA approved for > age 18 Immunogencity/safety similar to single antigen vaccines Schedule 0, 1, 6 months (same as Hep B) Total 3 injections instead of 5

25. Meningococcal disease 1,400-2,800 cases/yr Rate 0.5-1.1/100,000 College freshman* 1.9/100,000 Living in dorms 5.1/100,000 Leading cause of bacterial meningitis Dramatic reductions of Strep Pneumoniae and HIB meningitis from universal vaccination of children Handout onlyHandout only

26. Meningococcal disease Three clinical forms Meningitis (49%) Bacteremia (33%) Pneumonia (9%) High case- fatality ratio (10-14%) High morbidity 11-19% of survivors have sequelae Transmission: direct contact with large droplet respiratory secretions 5-10% carries bacteria Hand out onlyHand out only

27. Meningococcal disease Disease caused by 5 serogroups worldwide A, B, C, Y W-135 United States B, C, Y Serogroup B (no vaccine available) > 50% cases in age <1 < 25% cases age >11 Hand out onlyHand out only

28. Meningococcal vaccines MCPV4 � licensed 1981 Polysaccharide vaccine Mature B-lymphocyte response, no T-cell stimulation Not long lasting, no amnestic response MCV4 � licensed 2005 for ages 11-55 Polysaccharide protein conjugate vaccine T-cell dependent immune response Longer lasting and stronger amnestic response bothboth

29. Meningococcal disease:MCV4 use Universal vaccination Ages 11-12 Adolescents at age 15 if not previously vaccinated Groups at elevated risk College freshman in dorms Military recruits Certain microbiologists Certain travelers Asplenia/Terminal complement component deficiencies Single dose IM

30. Meningococcal disease:MCV4 use (continued) Adverse reactions Mild injection site pain and tenderness Brief fever 5% Severe allergic reaction (<0.1/100,000) Neurological reaction (<0.1/100,000)

31. Meningococcal disease:MPSV4 use Groups at elevated risk ages 2-10; >55 Groups at elevated risk if MSV4 not available No longer recommended for routine vaccination Single dose IM Adverse reactions similar to MCV4 Both Serogroup B polsacc poorly immunogenic in humans Focus on membrane proteins..ok for adoles and adults not infantsBoth Serogroup B polsacc poorly immunogenic in humans Focus on membrane proteins..ok for adoles and adults not infants

32. Pertussis: Secular Trends Incidence 1940 (Prior to vaccination): 150 cases /100,000 1960: 8 cases/100,000 1980-90: 1 cases/100,000 (2,900 cases/yr) 2003: 11,647 cases Only disease for which universal immunization is recommended that incidence is on the rise ! Hand out onlyHand out only

33. Pertussis: Why the increase? Increase in reporting vs. actual disease True burden is at least 10x > reported Waning immunity Less passive Ab transmitted to newborns Decreased herd immunity Aging cohort ? Under-vaccination in childhood bothboth

34. Pertussis: Important to internists? Number of cases high in adults Rate, morbidity and mortality higher in < age 1 Adults are source of infection for children 80% secondary attack rate Wisconsin with high number of cases Handout onlyHandout only

35. Pertussis Children Catarrhal stage 1-2 weeks Paroxysmal cough stage 1-6 weeks Convalescent stage weeks-months Handout onlyHandout only

36. Pertussis Adults Accounts for 7% of all cough illnesses per year Mild disease No phases Persistent cough >21d Often not diagnosed/treated until after maximum transmission Handout onlyHandout only

37. Pertussis Aerobic gram negative rod Attaches to cilia Local tissue damage Decreased ability to clear secretions Challenging to diagnose Gold standard-culture (Low sensitivity) PCR (Sensitivity highly age dependent) DFA (now rarely used) Serology (not practical) Handout onlyHandout only

38. Pertussis: Vaccine Acellular (DTaP) Licensed 1996 for primary series Replaced whole- cell vaccine for children More effective and fewer side effects Purified subunit vaccine Varies between 2 and 4 subunit components bothboth

39. Immunogenicity and Safety Study Prospective, randomized, double blinded trial comparing safety and efficacy of dT and DTaP 4480 participants enrolled Ages 11-64 Results: Elicited robust immune responses to all antigens No differences observed in side effects in 2 vaccines groups Handout onlyHandout only

40. Immunogenicity and Safety Study Prospective, randomized, double blinded trial comparing safety and efficacy of dT and DTaP 4480 participants enrolled Ages 11-64 39 US centers Results Elicited robust immune responses to all antigens Slide show onlySlide show only

41. Pertussis: Bottom line DTaP � 2 vaccines licensed 2005 by FDA Adcel* ages 11 to 65 Boostrix ages 11-19 ACIP recommendations/most cost effective Ages 11-12 give DTaP instead of dT Ages 11-18 give DTaP even if dT given 5 year interval recommended BothBoth

42. Pertussis: Bottom line (cont.) Watch for ACIP recommendations for older adults Universal (using DTaP instead of dT for all) vs. �High risk-groups� (health care workers, those in contact with infants) Economic issue bothboth

43. Hurricane Katrina: Evacuees in crowded settings Influenza -all > 6 months < 8 years old need 2 doses Hepatitis A -all > 6 months Varicella, MMR, dT (DTaP) , meningococcal, pneumococcus Usual recommendations

44. Hurricane Katrina Evacuees not in crowded settings Usual recommendations Responders dT and Hepatitis B

45. Varicella Vaccine recommendations Who: Age >18 lacking history of chicken pox or documentation of prior vaccination Schedule: 2 doses 0, 4-8 weeks Characteristics: Oka/Merck VZV vaccine � 1350 plaque-forming units IM injection

46. Varicella Zoster Epidemiology Prevalence 15% of the population Incidence 74 per 100,000 age < 10 300 per 100,000 age 35-44 1200 per 100,000 age >75

47. Varicella Zoster Epidemiology Incidence and severity increase with advancing age Half of those who develop zoster are > 60 years old 36.6% of those > 60 have persistent pain > 1 year 47.5% of those > 70 have persistent pain > 1 year

48. Varicella Zoster Clinical Features Unilateral radicular pain and vesicular rash usually limited to a single dermatome Results from reactivation of latent VZV within the sensory ganglia Hand out onlyHand out only

49. Varicella Zoster Vaccine administration: Live attenuated VZV vaccine 18,700 to 60,000 plaque-forming units of virus (1350 p-f units in VZV vaccine for children) Higher dosage necessary to elicit a significant increase in cell-mediated immunity to VZV among older adults One subcutaneous injection

50. Varicella Zoster Efficacy Recent Randomized Controlled Trial in NEJM: 38,546 adults age 60 or older Administered adult VZV vaccine Primary endpoint: burden of illness due to herpes zoster (incidence, severity and duration of pain) Secondary endpoint: incidence of postherpetic neuralgia

52. Varicella Zoster Safety Adverse events equal between placebo and vaccine groups Greater chance of adverse events at injection site with vaccine (48% vaccine, 17% placebo) Erythema � 35.8% Pain � 34.5% Swelling � 26.2% Pruritis � 7.1%

53. Varicella Zoster Vaccine recommendations Pending FDA approval Submitted in April 2005 No current recommendations to use existing Varivax for prevention of Zoster Unclear whether the higher dosage vaccine is necessary for zoster prevention

54. Human PapillomavirusCervical cancer United states 10,000+ cases 3700 deaths In women worldwide� Third most common cancer Most common cause of cancer death

55. Age �adjusted SEER Cervical Cancer 1996-2000

56. On the horizon: HPV vaccine Two vaccines in phase 3 trials Cervarix- bivalent HPV 16 and 18 (cervical and anogenital cancer) women ages 15-25 Gardasil- quadrivalent HPV 16 and 18 HPV 6 and 11 (anogenital warts) Men and women ages 15-25 Possibly submit FDA request October 2005 Phase 3 safety immunogenicity and efficacyPhase 3 safety immunogenicity and efficacy

57. HPV vaccines Phase 2 trial bivalent HPV vaccine (16/18) 1,113 women for 18 months Results Efficacy persistent infection type 16: 93.9% Decreased cytological changes 95.2% Efficacy persistent infection type 18: 100% Decreased cytological changes 91.2%

58. HPV vaccines Phase 2 trial quadrivalent HPV vaccine (16/18/6/11) 552 women Results Persistent infection, cervical atypia or external genital lesions was decreased by 90% compared to control group

59. HPV vaccine Likely primary preventive efforts will target pre-adolescent (age 11) Age 15- median age of sexual activity in US Both vaccines require 3 doses in 6 months

60. On the horizon: HIV vaccine February 2003 failed Phase 3 trial Currently two phase 2 trials are underway Not primary prevention Prevent/limit viral replication and delay disease progression

61. How long it takes�..