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1 Conflict Disclosure Information Speaker: Ethan Rubinstein, M.D., L.Lb. Professor & Head Section of Infectious Diseases University of Manitoba, Faculty of Medicine Title of the event : The Changing Landscape of Adult Immunization FINANCIAL DISCLOSURE Grants/Research Support: CIHR, NIH, Trius Speaking Engagements/Honoraria: Pfizer, Astellas, Theravance, Merck Consulting Fees: Trius, Merck, Bayer, Pfizer, Astellas, Theravance, Optimer, BiondVax, Atox Bio, Canadian Copper Board, BiondVax, Other:

2 Disclosure I had full editorial control over the content of this presentation and wish to advise that it may contain content that is not consistent with the approved Canadian Product Monographs.

3 Adult Vaccinations What s new? What s needed? Zoster Vaccine Conjugated Pneumococcal Vaccine New Influenza Vaccines Pertusis Anti smoking vaccine Staphylococcal Vaccine Military Vaccines

4 Shingles: A Painful Vesicular Eruption in a Dermatomal Distribution

5 Annual Incidence of Herpes Zoster by Age Decile per 1000 Manitobans 2003/ Incidence per Age (years) By age 85 yrs, 25% will experience an episode of HZ

6 Studies demonstrating that exposure to chickenpox reduces risk of HZ Hope Simpson (1965); Solomon (1998), Terada (1998) Pediatricians exposed to CP have reduced rates of HZ Gershon (1996) Rate HZ lower in vaccinated children with household exposure to chickenpox Thomas (2002) Case control study demonstrated protection against HZ by exposure to children and to varicella (with dose response relationship) Brisson (2002) Exposure to varicella in adult cohort protected against HZ

7 Brisson et al Vaccine 2002;20:2500 Living with children: 0.75 (0.63, 0.89)

8 HZ Causes Three Problems Acute pain until the HZ rash heals, approximately 4 weeks In HZ ophthalmicus, ocular damage including vision impairment and facial scarring Post herpetic neuralgia (PHN) The most common problem A therapeutic challenge

9 Treatments for Established PHN are not Uniformly Efficacious Amitrytiline 1 Gabapentin 2 Topical Capsaicin 3 Lidocaine 4 Transcutaneous nerve stimulation 5 1. Watson et al. J Neurol 1982; 32: Rowbotham et al. JAMA 1998; 280: Watson et al. Pain 1988; 33: Rowbotham et al. Pain 1989; 9: Bates et al. Anaesthesia 1980; 35:817

10 Comparison of Pain Scores for Acute Pain Conditions Various Conditions More Pain Chronic Pain Conditions Abdominal hysterectomy Acute headache Zoster Labor pain Postsurgical pain Mucositis Angioplasty sheath removal Less Pain Fibromyalgia Postherpetic neuralgia Atypical facial pain Musculoskeletal pain Arthritis Osteoarthritis Rheumatoid arthritis Chronic cancer pain Adapted from Surgical Clinics of North America, Vol 79, Katz J, Melzack R, Measurement of pain, pp Copyright 1999, with permission from Elsevier.

11 Antiviral Drugs May Reduce the Probability of PHN But Their Efficacy is Limited Acyclovir, famciclovir & valacyclovir Must be initiated less than 72 H after rash onset Cochrane Systematic Review: Acyclovir not effective Efficacy of famciclovir & valacyclovir not yet established Li et al. Cochrane Systematic Review 2009

12 Research Question To determine whether vaccination with a live attenuated VZV vaccine would decrease the incidence, severity, or both of HZ and PHN, in adults 60 years of age or older. PHN = pain > grade 3/10 persisting > 90 days after the rash began Oxman M et al. N Engl J Med 2005; 352:2271

13 Study Design Randomized 1:1 Zoster Vaccine or placebo Double blind, placebo controlled, multicenter trial 22 U.S. sites Study Timeline: Nov 1998 to April 2004 Enrolled 38,546 subjects 60 years of age Age stratified (60 to 69 years, 70 years) Oxman M et al. N Engl J Med 2005; 352:2271

14 Study Population All eligible subjects had a history of varicella or had resided in the U.S. for at least 30 years. Immunocompromised persons were excluded All subjects provided written consent Oxman M et al. N Engl J Med 2005; 352:2271

15 Intervention Vaccine type: Live attenuated OKA/MERCK VZV vaccine (Zoster Vaccine) Administration: Subcutaneous injection The minimal potency of the Zoster Vaccine was at least 14 times greater than the Varicella live attenuated Oka/Merck VZV vaccine. Oxman M et al. N Engl J Med 2005; 352:2271

16 Cumulative Incidence of HZ (%) Results Vaccine Efficacy: HZ incidence 6 VE =51% Placebo (n=642) HZ 5 p< Zoster Vaccine (n=315) Years of follow-up Oxman M et al. N Engl J Med 2005; 352:2271

17 Results Vaccine Efficacy: PHN Incidence Cumulative Incidence of PHN (%) VE PHN =67% p<0.001 Placebo (n=80) 0.2 Zoster vaccine (n=27) Years of follow-up Oxman M et al. N Engl J Med 2005; 352:2271

18 The Shingles Prevention Study Results Vaccine Efficacy: PHN Incidence by Age Efficacy Incidence of PHN (95% CI) * 66.5% ( ) 79.2) 65.7% ( ) Vaccine Placebo 66.8% ( ) 0.0 All Subjects yr 70 yr *P <0.001 Adapted from Oxman M et al. N Engl J Med 2005; 352:2271

19 HZ Vaccine Local Side Effects Vaccine Placebo Pain or tenderness 35% 9% Redness 36% 7% Swelling 26% 5% Oxman et al. N Engl J Med 2005; 352:2271

20 Conclusions The HZ vaccine reduced the incidence of HZ by 51% The incidence of PHN was reduced by 67%

21 Effect was similar in those < 69 and those > 70 years old Well tolerated Recommended for prevention of HZ and its sequelae in U.S. adults > 60 years of age NACI guideline awaited

22 Herpes Zoster Vaccine in Older Adults and the Risk of Subsequent Herpes Zoster Disease Hung Fu Tseng, PhD, MPH, Ning Smith, PhD, Hung Fu Tseng, PhD, MPH, Ning Smith, PhD, Rafael Harpaz, MD, MPH, Stephanie R. Bialek, MD, MPH, Lina S. Rafael Harpaz, Sy, MPH, MD, MPH, Steven Stephanie J. Jacobsen, R. Bialek, MD, PhD MD, MPH, Lina S. Sy, MPH, Steven J. Jacobsen, MD, PhD JAMA 2011;305(2): JAMA 2011;305(2):

23 Results Kaplan Meier estimates of the cumulative risk of HZ by HZ vaccination status HZ vaccine was associated with a 55% reduction in incidence of HZ Tseng HF et al. JAMA 2011;305(2):

24 Results Hazard ratio of HZ in study cohorts according to age, sex, race and chronic conditions/diseases In contrast to the SPS, the lower HZ risk associated with the vaccine was retained across all age strata The lower HZ risk associated with the vaccine did not vary with the presence of chronic diseases Tseng HF et al. JAMA 2011;305(2):

25 Herpes Zoster Vaccine in Older Adults and the Risk of Subsequent Herpes Zoster Disease Conclusion: Conclusion: Among Among immunocompetent immunocompetent community dwelling community dwelling adults adults aged aged years years or or older, older, receipt receipt of of the the HZ HZ vaccine vaccine was was associated associated with with a a lower lower incidence incidence of of HZ HZ (reduction (reduction of of 55%). 55%). The The HZ HZ risk risk was was reduced reduced regardless regardless of of age, age, race, race, and and presence presence of of chronic chronic diseases. diseases. The The results results support support recommendations recommendations to to offer offer HZ HZ vaccine vaccine to to all all eligible eligible patients patients of of all all ages ages including including the the oldest oldest population. population. Tseng HF et al. JAMA 2011;305(2):

26 Pneumococcal Invasive Disease Conjugated pneumoccoal Vaccine

27 Efficacy, Immunogenicity, Safety and Tolerability of Zoster Vaccine in Subjects 50 to 59 Years of Age Schmader et al IDSA October, 2010

28 Disposition of Subjects All Randomized Subjects Subjects in Population (N=22,439) Subjects Vaccinated (N=22,396) Not Vaccinated (N=43) Zoster vaccine n (%) Randomized 11,186 (99.8) Completed 10,550 (94.1) Discontinued 661 (5.9) Adverse Event 19 (0.2) Lost to Follow-Up 353 (3.1) Subject Withdrawal 263 (2.3) Other Reasons 26 (0.2) Placebo n (%) Randomized 11,210 (99.8) Completed 10, ) Discontinued 673 (6.0) Adverse Event 29 (0.3) Lost to Follow-Up 375 (3.3) Subject Withdrawal 255 (2.3) Other Reasons 14 (0.1) Schmader et al, IDSA Octobre, 201

29 Statistical Analysis of Incidence of HZ ITT Population Vaccine Efficacy (95% CI) (0.541*, 0.806) Estimated Incidence Rate of HZ (Per 1000 Person-Years) n=30 n=99 ZOSTAVAX Placebo *A lower bound of >25% indicates that the success criterion was met Schmader et al, IDSA Octobre, 2010

30 VZV gpelisa Antibody Responses Week 6 Postvaccination Random Subcohort Population Estimated GMT Ratio 2.3; p<0.001 Estimated GMT n=1124 n=1125 ZOSTAVAX Placebo Schmader et al, IDSA Octobre, 201

31 Invasive Pneumococcal disease in Canada and Anti pneumococcal immunization

32 The burden of pneumococcal disease in the Canadian population 2001 estimates before the significant use of the conjugated vaccine cases of pneumococcal infections Meningitis : 226 cases Bacteremia : 3773 cases Pneumonia : Acute otitis media : Total cost : 193 million Morrow A et al. Can J Infect Dis Med Microbiol 2007; 18(2):

33 Pneumonia is the most common presentation of PD among adults aged 65 years IPD Clinical Presentation: Source of Pneumococcal Isolates in Calgary, by Age Groups, Kellner JD, Vanderkooi OG, MacDonald J, Church DL, Tyrrell GJ, Scheifele DW. Changing epidemiology of invasive pneumococcal disease in Canada, : update from the Calgary-area Streptococcus pneumoniae research (CASPER) study. Clin Infect Dis. 2009;49(2):

34 In adults aged 65 years, CAP is costly CAP patients (n=60; mean age 70 years) Total societal cost (medical cost plus private cost) within 30 days of hospital admission was $8,970 per patient Average hospital stay was 11 days Medical costs included emergency room visit, hospital stay, and physician fees Private costs (which are not commonly covered or sometimes not covered by health plans) included lost wages, travel and communications costs, child care expense, ambulance fees, prescriptions, and supplies Jacobs P, Marrie TJ, Calder P. Private costs of patients hospitalized with community-acquired pneumonia. Can Respir J. 2005;12(4):

35 Pneumonia causing change in employment status at time of study enrollment Percentage N=236 Marrie TJ, Beecroft MD, Herman-Gnjidic Z. Resolution of symptoms in patients with community-acquired pneumonia treated on an ambulatory bases. Journal of Infection 2004;49:

36 Factors Predicting Mortality in Invasive Pneumococcal Disease in Adults : Alberta Study Marrie T et al. Medicine (Baltimore) 2011 May;90(3): patients with IPD 14.1% (163) died within 30 days. 62.6% of the deaths occurred within 5 days of admission. Factors independently associated with increased 30 day mortality: cancer within 5 years Diabetes cirrhosis. treatment with a single antibiotic.

37 Invasive pneumococcal disease and cancer in Canada Adults 18 and over Lung Cancer Multiple myeloma Rate 11 / per year / per year / per year 69% of cases were caused by serotypes in the 23 valent pneumococcal polysaccharide vaccine. 53 % of cases were caused by serotypes in 13 valent pneumococcal (investigational at the time of the study). Wong A et al. Epidemiol Infect 2010;138(12):

38 Pneumococcal meningitis : the most dreaded complication. Rare but severe consequences. Not to be missed. In adults up to age 60 : S. pneumoniae was responsible for 60 percent of cases. In adults age 60 and above : 70 percent of cases were due to S. pneumoniae.. Meningitis represents 4% of IPD

39 Current vaccine environment There are currently three available pneumococcal vaccines for adults in Canada: Pneumococcal polysaccharide vaccines (PPV) Pneumo 23 and Pneumovax 23, containing 25 μg of capsular polysaccharide from each of 23 pneumococcal serotypes: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F Pneumococcal conjugate vaccine (PCV) Prevnar 13, composed of the purified polysaccharides of the capsular antigens of 13 pneumococcal serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F 50

40 NACI recommendations for high-risk adults Current recommendations are that PPV23 should be given to persons at high risk of IPD: 1 Individuals with a history of chronic lung disease (including smoking) Heart failure Chronic renal failure (including nephrotic syndrome) Chronic liver disease (including alcohol dependence and cirrhosis) Diabetes Asplenia/sickle cell disease Congenital or acquired immune deficiency Chronic cerebrospinal fluid leak Residents of long-term care facilities All those 65 years of age or older Recently, homelessness and injection drug abuse were added as indications National Advisory Committee on Immunization (NACI). Canadian Immunization Guide, 7 th ed. Ottawa: Public Health Agency of Canada, 2006: Public Health Agency of Canada. National Advisory Committee on Immunization: Statement on the Recommended Use of Pneumococcal 23-Valent Polysaccharide Vaccine in Homeless Persons and Injection Drug Users. CCDR 2008;34:

41 Polysaccharide pneumococcal vaccine Meta analysis of 22 clinical trials ( participants) Pneumococcal polysaccharide vaccine : Decrease the risk of Invasive pneumococcal disease (OR = 0.26, 95% CI : ) No effect on all cause pneumonia and no reduction in all cause mortality (OR =0.87, 95% CI : ) Moberley SA et al. Cochrane Database Syst Rev (1): CD000422

42 PPV23 re-vaccination NACI guidelines do not recommend routinely re-vaccinating all adults who receive the polysaccharide vaccine as the data supporting re-vaccination is sparse. 1 The duration of protection has been estimated between 3 and 5 years 2 Thus, re-vaccination should be considered for those of any age at highest risk of invasive infection 1 If re-vaccination is carried out, it should be performed 5 years after the first dose 1 1. National Advisory Committee on Immunization (NACI). Canadian Immunization Guide, 7 th ed. Ottawa: Public Health Agency of Canada, 2006: Shapiro ED, Berg AT, Austrian R, et al: The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991; 325:

43 The debate surrounding the efficacy of adult pneumococcal polysaccharide vaccination Meta-analysis #1 findings* PPV23 efficacy seen in randomized controlled trials (RCTs), however, vaccine efficacy amongst the subgroup of adults with chronic disease appears poor in comparison to that of otherwise healthy adults, in developed or low income countries Protective efficacy for IPD demonstrated in non-rcts Inconclusive efficacy against all cause pneumonia No evidence of protective efficacy against all-cause mortality Note: high level of statistical heterogeneity was present No protective efficacy against pneumonia related mortality Note: high level of statistical heterogeneity was present * Cochrane review published in 2009 assessed the effectiveness of PPV in preventing disease or death in adults. Twenty-two studies were included. Fifteen were RCTs involving 48,656 participants and seven were non-rcts involving 62,294 participants. Moberly S, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database of Systematic Reviews 2009, Issue 1. 54

44 Incidence of invasive pneumococcal disease in Calgary, by serotype grouping, for persons aged 65 years, For 2007 vs , there was a 29% change in the incidence for all serotypes (p=0.11 ), a 92% change for 7-valent pneumococcal conjugate vaccine (PCV7) serotypes (P <0.001), and a +64% change for non-pcv7 serotypes (P=0.04).

45 Incidence of invasive pneumococcal disease in Calgary, (before the introduction of 7 valent pneumococcal conjugate vaccine [PCV7]) versus (after the introduction of PCV7), Kellner et al. C I D 2009;49: No Incidence per , PCV7 serotypes Non-PCV7 serotypes Difference between and years years >85 years * PCV7 serotypes change (%) Non- PCV7 serotypes change (%) +183*

46 Effect of PCV vaccination of children on IPD in adults Active Bacterial Core Surveillance=Active population and laboratory based system Conducted in 8 centres in 8 states (CA,GA,MD,MIN,NY,OR,TN, CT) Population surveillance ~19 months Period pre PCV , post PCV Pilishvili T et al. CID 2010;201:32

47 Changes in incidence of pneumococcal disease pre and post vaccine Incidence Rate Diff Per 10 5 Change % (95%CI) y All types (-25 to-9) Vaccine types (-90 to-83) 19A (202 to 551 Non-Vaccine types (25 to 84) >65 y All types (-42 to-32) Vaccine types (-94 to-89) 19A (84 to 223 non-vaccine types (9 to 38)

48 Change in IPD rates pre vs post PCV 7 vaccination in children adults ages y All sero-types Vaccine types Other -types n % * * * 1 0 Bacter * * Bacter.pneu * * * Meningitis * * Mortality * * *

49 Change in IPD rates pre vs post PCV 7 vaccination in children adults>65 y All sero-types Vaccine types Other -types n % * * * Primary Bacteremia Bacteremic.pneumonia * * * * * Meningitis * Mortality * * Pilishvili T et al. C I D 2010;201:32

50 Cases per

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53 Percentage of Penicillin* Non Susceptible S. pneumoniae in Canada: % intermediate resistance % high-level resistance *Non-meningitis, IV breakpoints used Canadian Bacterial Surveillance Network, Jun 2010

54 Polysaccharide vaccines activate B cells but do not induce immunological memory in infants 1,2 Polysaccharide B cell Cross linking Surface antibody Activated B cell T-cell independent pathway Weak and short-lasting IgM immune response No affinity maturation and antibody class switching to IgG Lack of booster effect on revaccination Limited impact on pneumococcal nasopharyngeal carriage IgM 1. Pollard AJ, et al. Nature Reviews Immunology. 2009;9(3): Overturf GD, et al. Pediatrics. 2000;106;

55 Conjugate vaccines induce a strong immune response and immunological memory in infants by activating B and T cells 1,2 The combination of polysaccharide protein antigen-conjugate is captured by B cells and other antigenpresenting cells (APC) APC present these antigens to T-helper 2 (Th2) cells Activation of Th2 cells helps B cells to differentiate into memory B cells and plasma cells Antibody class switching Polysaccharide-protein antigen conjugate (covalently linked) Peptide processing Dendritic cell polysaccharide protein T cell Memory B cells T cell B cell Differentiation Plasma cells 1. Ada G. N Engl J Med. 2001;345: Pollard AJ, et al. Nature Reviews Immunology. 2009;9(3): IgG antibodies

56 PCV13 vs PPSV23 in Subjects Year Old Who Are Naive to PPSV23 13vPnC (n=417) PPSV23 (n=414) vPnC (n=403) } Blood draw- 1 month after the dose

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59 Sequential Dosing With PCV13 in Subjects 70 years Old Pre-immunized with PPSV23 Subjects were immunized with 1 dose of PPSV23 5 yrs prior to study inclusion 13vPnC (n=463) PPSV23 (n=473) } 1 year interval between sequential doses 13vPnC (n=391) 13vPnC (n=404) } Blood draw- 1 month after the dose

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