Update 2010: Vaccines: HZ, HPV, Pneumococcus T. Mazzulli, MD, FRCPC, FACP Department of Microbiology Mount Sinai Hospital and University Health Network

Learning Objectives: Realize that immunization against adult infectious diseases is one of the most successful interventions to protect the health of Canadians Describe recent clinical updates and what’s new in routine adult immunizations: Zoster, HPV and Pneumococcus Develop procedures to enhance immunization rates based on the most recent clinical guidelines in adult immunizations Acknowledge burden of diseases worth preventing and recognize that immunization against adult infectious diseases is one of the most successful interventions to help protect the health of Canadians   Review (Understand) the recent clinical updates and what’s new in adult vaccines Adapt current medical practices and empower patients in order to improve vaccine coverage rates

Ten Great Public Health Achievements 1900 - 19991 Vaccination Motor vehicle safety Safer workplaces Control of infectious diseases Decline in deaths from coronary heart disease and stroke Safer and healthier foods Healthier mothers and babies Family planning Fluoridation of drinking water Recognition of tobacco use as a health hazard Immunization: Saved more lives in Canada in the last 50 years than any other health intervention2 Single most cost-effective health investment, making immunization a cornerstone of efforts to promote health2 Even if Vaccination is THE greatest achievement we can be proud of in the last milenium, are we where we should be yet? MMWR, December 24, 1999 2. Canadian Coalition for Immunization Awareness & Promotion. 2005

Comparison of Maximum and Current Reported Morbidity: Vaccine-Preventable Diseases in the US Prevaccine Era* Year 1999 % Decrease Diphtheria 206,939 1921 1 99.99 Measles 894,134 1941 100 Mumps 152,209 1968 391 99.75 Pertussis 265,269 1934 7,288 97.25 Polio (wild) 21,269 1952 100.00 Rubella 57,686 1969 267 99.53 Cong. Rubella synd. 20,000+ 1964-65 6 99.96 Tetanus 1,560+ 1948 42 97.31 Invasive Hib disease 1984 1,309 99.65 Total 1,639,066 9,404 99.43 These are US data, Canadian data was not available for the actual numbers of decrease in prevalence of the infections.

Canadian Cost-Benefit of Adult Vaccination Cost per Life Year Saved for Selected Vaccine Programs and Other Public Health Interventions Cost per life year saved Vaccines Influenza for adults aged ≥ 65 years of age < 0 ($45 saved per $ spent) Pneumococcal polysaccharide for adults aged ≥ 65 years < 0 ($8 saved per $ spent) Other interventions Low cholesterol diet for men > 20 yo and cholesterol over 4.65 mmol/L (180 mg/dL) $360,000 Smoking cessation counseling $1,000-10,000 Annual screening for cervical cancer $40,000 “Cost per life-year saved” is a number used in risk analysis to compare the cost-benefit ratios of different interventions in health and safety. Adapted from 2006 Canadian Immunization Guide

Burden of Vaccine Preventable Diseases There are 200-300 vaccine preventable deaths in Children in the U.S. each year vs 50,000 Adult vaccine preventable deaths/year in the U.S.3 Total economic burden of treating vaccine preventable diseases in adults in the US is greater than $10 billion/year1 1. Inf Disease Clinics of NA. 15(1):9-19, 2000 Mar 2. Poland 2005 Vaccine 23 p 2251-2255 3. Poland 2003 Am J Prev Med, 25(2): 144-50

Comparison of Pediatric & Adult Immunization Coverage Pediatric Uptake Rates1 2 years of age n=4,988 Adult Uptake Rates 2 18-64 y.o. Total n = 2,237 with CMC n=395 65 + (n=287) DTaP or IPV n( %) 85.5% n=4,265 Influenza* 37.3 % 38.2% 69.9% Hib n(%) 85.8% n=4,278 Hepatitis A 25.1% 22.7% 10.3% Meningococcoal Conjugate n(%) 94.2% n=4,701 Hepatitis B 30.2% 29.2% 10.5% Pneumococcal Conjugate n(%) 83.8% n=4,181 Pertussis 3.9% 2.4% 2.5% MMR n(%) 93.0% n=4,641 Tetanus 46.5% 49.1% 28.5% Varicella n(%) 86.8% n=4,328 Pneumococcal* 29.4% n=599 16.7% n=271 38.6% n=287 1. CCDR: 32 (10 2006 Immunization coverage by age 2 for the five recommended vaccines in the Capital Health Region (Edmonton) 2. Canadian Adult National Immunization Coverage Survey 2006

Adult Immunization: Routinely for All & Specific Groups Adult immunization programs present new and different challenges relative to childhood programs Adult Immunization Schedule Classification: Routinely for All2 Specific Groups2 Age1 Occupation1 Health Status1 Behaviour (travel, sexual behaviour)1 Adult Immunization Considerations: Immunizing adults is a more complicated undertaking than is immunizing children. Vaccination recommendations for adults depend on a person's age, occupation, health status, and behavior (e.g., sexual activity and drug use). For example, for adults younger than 50 years of age, influenza and pneumococcal vaccines are targeted to persons at high risk for illness-related complications or death. This requires physicians and nurses to establish procedures to identify persons who are eligible, often from long lists of qualifying conditions, in contrast to childhood immunization, in which all are offered vaccine unless there are contraindications. Reference: Plotkins, S. et al, Immunization in the United States. Vaccines 2008:1479-1510. 1. Plotkins, S. et al, Immunization in the United States. Vaccines 2008:1479-1510 2. 2006 Canadian Immunization Guide

Adult Immunization: Key Issues Immunosenescence: Diminished immune response of both innate and adaptive immune systems Decline in vaccine efficacy with age Increasing morbidity & mortality from natural infection => Increased burden as we age Physicians often question whether it is worthwhile to vaccinate older adults if the desirable immune response cannot be achieved.1 It should be strongly emphasized that unlike childhood vaccines that frequently prevent clinical illness altogether, most adult vaccines do not prevent illness but lessen the severity of a given infection.2 And are therefore bringing significant value and translate in meaningful gains. Increasing morbidity & mortality from natural infection translate into an increased burden form individual disease as we age! Kumar, R, et al, Expert Rev. Vaccines 2008 7(4) 467-479.

What’s New in Immunization? Herpes Zoster Vaccine Human Papilloma Virus Vaccine Pneumococcal Vaccine Influenza Vaccine (2010/2011)

Posterior column spinal cord VZV: Reactivation Posterior column spinal cord Dorsal root ganglion Site of VZV replication Herpes Zoster: Reactivation In response to waning cell-mediated immunity (CMI) that often accompanies increasing age or to other conditions characterized by immunosuppression (eg, HIV, malignancies, and immunosuppressive therapy), VZV may reactivate and replicate within the ganglion. Spread of the virus within the ganglion causes inflammation and necrosis of the neurons, often accompanied by neuralgia.2 Virus is then transported down the sensory nerves, causing intense neuritis, and is released around the nerve endings in the skin.2 Because VZV reactivation usually involves a single sensory nerve, the consequent vesicular rash occurs in the characteristic unilateral dermatomal distribution of herpes zoster lesions.1 VZV can also spread proximally along the posterior nerve root to involve the motor neurons of the anterior spinal cord, which may produce local palsies.2 [Arvin p2741; Straus p2431] [Arvin p2741] [Straus p2431] Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Vol 2. New York, NY: Lippincott Williams & Wilkins; 2001:2731-67 Straus SE, Oxman MN. Varicella and herpes zoster. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill; 1999:2427-50 [Arvin p2742] [Straus p2431] References: 1. Arvin AM. Varicella-zoster virus. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Vol 2. New York, NY: Lippincott Williams & Wilkins; 2001:2731–2767. 2. Straus SE, Oxman MN. Varicella and herpes zoster. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. Vol 2. New York, NY: McGraw-Hill; 1999:2427–2450.

Incidence of Zoster by Age The incidence of shingles increases significantly with age, with 67% of cases occurring in persons over 50 years of age. Johnson R. et al. JID 2007 11(Suppl 2) S43-48

Herpes Zoster: Canadian Epidemiology Estimated ~30% lifetime risk of one VZV reactivation1; ~50% if live to 80 years of age Estimated 129,882 cases of Shingles per year1 ~90% of cases occur in immunocompetent people; 13% of zoster episodes will result in PHN (Defined as Pain >90 days after rash onset) 17,108 episodes/year ~2,000 hospital admissions and 20 deaths per yr Lifetime risk – comes from Manitoba database Brisson M. et al. Human Vaccine 2008

Percent of patients reporting pain Prevalence of PHN and Duration of Pain Associated with PHN Increase with Age 100 >1 yr 6 - 12 mo 80 1 - 6 mo <1 mo 60 Percent of patients reporting pain 40 20 0-19 20-29 30-39 40-49 50-59 60-69 ≥79 Age (years) Kost R et al. N Engl J Med. 1996;355:32-42.

Aging & Zoster Risk Varicella Exposure Silent reactivation? Zoster vaccination VZV T-cells Zoster Threshold Varicella Herpes Zoster Varicella is the primary infection caused by VZV, and its resolution is associated with the induction of VZV-specific memory T cells (black line). Memory immunity to VZV may be boosted periodically by exposure to varicella or silent reactivation from latency (red peaks). VZV-specific memory T cells decline with age. The decline below a threshold (dashed orange line) correlates with an increased risk of zoster. The occurrence of zoster, in turn, is associated with an increase in VZV-specific T cells. The administration of zoster vaccine to older persons may prevent VZV-specific T cells from dropping below the threshold for zoster occurrence (dashed green line). Age Arvin A. Aging, Immunity, and the varicella-zoster virus. N Engl J Med 2005;352(22):2266-7. Arvin A, NEJM 352:2266, 2005

The Shingles Prevention Study Design Randomized Double-blind, placebo-controlled, multicenter trial 1:1 Zoster Vaccine or placebo (Study Timeline: Nov-1998 to April 2004) Enrolled 38,546 subjects  60 years of age Age-stratified (60 to 69 years, 70 years) Median of 3.12 years of surveillance for Herpes Zoster Randomized 1:1 Zoster Vaccine or placebo Most doses administrated near proposed expiry potency Double-blind, placebo-controlled multicenter trial Study Timeline: Nov-1998 to April 2004 Dept. Of Veteran Affairs Cooperative Studies Program (VA CSP) collaboration with the National Institutes of Health (NIH) and Merck & Co. inc Enrolled 38,546 subjects 60 years of age Age-stratified (60 to 69 years, 70 years) 90% had one or more underlying medical conditions Reference: Oxman M et al. N Engl J Med. 2005;352:2271-2284. Oxman M et al. N Engl J Med. 2005;352:2271-2284.

Shingles Prevention Study Vaccine Efficacy: HZ Incidence by age Efficacy (95% CI) 51.3% (44.2-57.6) 63.9% 37.6% 14 Vaccine 12 Placebo 10 Incidence of HZ 8 * 6 Randomized Double-blind, placebo-controlled, multicenter trial 1:1 Zoster Vaccine or placebo (Study Timeline: Nov-1998 to April 2004) Enrolled 38,546 subjects  60 years of age Age-stratified (60 to 69 years, 70 years) Median of 3.12 years of surveillance for Herpes Zoster VEHZ 51.3% (95% CI [44.2%, 57.6%]) Criterion for success: VEHZ 95% CI lower bound >25% Evaluable cases: n=957 Vaccine 315 Placebo 642 4 2 All 60-69 yr 70 yr *P <0.001 N=38,546 subjects  60 years of age Adapted from Oxman M et al. N Engl J Med. 2005;352:2271-2284.

Shingles Prevention Study Vaccine Efficacy: PHN Incidence by age Efficacy (95% CI) 66.5% (47.5-79.2) 65.7% (20.4-86.7) 66.8% (43.3-81.3) 0.0 0.5 1.0 1.5 2.0 2.5 All Subjects 60-69 yr 70 yr Incidence of PHN Vaccine Placebo Protocol definition of PHN PHN is defined as the presence of pain (score 3 on a 0 to 10 scale) beyond 90 days after HZ rash onset The threshold of 3 has been shown to correlate with interference of daily activities and other quality of life measures Vaccine efficacy is measured as the relative reduction in PHN incidence in vaccine recipients compared with placebo recipients VEPHN 66.5% (95% CI [47.5%, 79.2%]) PHN cases: n=107 Vaccine = 27 Placebo = 80 * *P <0.001 N=38,546 subjects  60 years of age Adapted from Oxman M et al. N Engl J Med. 2005;352:2271-2284.

Safety of Herpes Zoster Vaccine: Serious Adverse Events Among All Subjects Vaccine Group Placebo Group No. Subjects 19,270 19,276 Day of Vaccination. To End of Study Death 218 (2.1%) 246 (2.4%) Vaccine-related SAE 2 (<0.1%) 3 (<0.1%) Day of Vaccination. To Day 42 14 (0.1%) 16 (0.1%) ≥1 SAEs 255 (1.4%) 254 (1.4%) Simberkoff MS, et al. Ann Intern Med 2010May;152(9); Oxman, M, et al, Shingles Prevention Study. NEJM 2005

Safety of Herpes Zoster Vaccine: Adverse events at the inoculation site Placebo N=3249 >1 Inoculation-site adverse event 48.2% 16.6% Erythema 35.8% 6.9% Pain or Tenderness 34.4% 8.5% Swelling 26.2% 4.5% Pruritus 7.1% 1.0% Temperature 38.3o C or higher 0.8% Rash 0.3% 0.1% *p<0.001 In the adverse-events sub-study, a significantly greater number of subjects in the vaccine group had one or more adverse events than in the placebo group, reflecting a greater frequency of adverse events at the injection site among subjects in the vaccine group. In the vaccine group, the most frequent adverse events at the injection site were: erythema (in 35.8 percent of the vaccine group), pain or tenderness (in 34.5 percent), swelling (in 26.2 percent), pruritus (in 7.1 percent). No other adverse event at the injection site was observed in more than 2 percent of the vaccine recipients. Overall, the proportion of subjects with one or more systemic adverse events was similar in the two groups. Simberkoff MS, et al. Ann Intern Med 2010May;152(9); Oxman, M, et al, Shingles Prevention Study. NEJM 2005 20

Zoster Vaccine in Patients 50 to 59 yrs 22,439 pts aged 50 to 59 yrs 2.2 yrs follow-up Efficacy for prevention of HZ was 69.8% (95% CI: 54.1 to 80.6) Adverse events (AE): 72.8% vs 41.5% (injection site AE & headache) 0.6% vs 0.5% for serious AE at 42 days Schmader K et al. Abstract 1380. IDSA. Vancouver, BC, October 2010

Zoster Vaccine (Oka/Merck) Live, attenuated, Oka/Merck strain of Varicella-zoster Virus Single-dose of entire vial (approx. 0.65ml) S.Q. administration only Contains at least 14-fold more PFU of VZV Oka/Merck/ dose than the Varicella Vaccine Health Canada Approval Zoster Vaccine for the prevention of shingles (herpes zoster) in individuals 60 years of age or older Vaccine is now available through Canadian physicians and pharmacists. STORE FROZEN - Average temperature of –15°C or colder until it is reconstituted for injection DISCARD RECONSTITUTED VACCINE IF NOT USED WITHIN 30 MINS 22

National Advisory Committee on Immunization (NACI) Members: Dr. J. Langley (Chairperson), Dr. B.Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Ms. A. Hanrahan, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan. Liaison Representatives: Dr. B. Bell (CDC), Dr P. Orr (AMMI Canada), Ms. S. Pelletier (CHICA), Ms. K. Pielak (CNCI), Dr. P. Plourde (CATMAT), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. D. Scheifele (CAIRE), Dr. N. Sicard (CPHA), Dr. V. Senikas (SOGC).

Zoster Vaccine in Canada Recommendations: For prevention of HZ and its complications in persons >60 yrs without contraindications May be used in patients aged 50 and older No recommendation for those with a past episode of zoster Should be given to patients irrespective of a prior history of chickenpox or documented prior varicella infection Booster doses are not recommended for healthy pts Individuals who indavertently receive systemic anti-viral therapy active against VZV within 2 days before and 14 days after vaccine may benefit from a second dose 42 days or later May be given with influenza vaccine; Pneumovax and zoster vaccine should be given at least 4 weeks apart National Advisory Committee on Immunization (NACI). CCDR January 2010; vol. 36

Zoster Vaccine in Canada Contraindications: History of hypersensitivity to any component of the vaccine, including gelatin History of anaphylactic/anaphylactoid reaction to neomycin (traces) History of dermatitis due to neomycin is not a contraindication to receiving live virus vaccines Primary and acquired immunodeficiency states Immunosuppressive therapy including high-dose corticosteroids Active untreated tuberculosis Pregnancy National Advisory Committee on Immunization (NACI). CCDR January 2010; vol. 36 25

HPV Vaccines

Estimated HPV Contribution in Cancer Cervix > 99% Anus 84.2% Vagina 69.9% Penis 47.0% Vulva 40.4% Oropharynx 35.6% The slide shows the cancer sites for which HPV has been identified as a risk factor, with estimates of the proportion of cancer attributable to HPV at each site. Note that, for some of the estimates (i.e., oro-pharyngeal cancer) the attributable fractions continue to be updated (from 30% to 72%) as technology and sampling methods are being developed. Reference: WHO Information Centre on HPV and Cervical Cancer. Available at: www.who.int.hpvcentre/statistics/en/. Oral cavity 23.5% 20 40 60 80 100 Percentage WHO Information Centre on HPV and Cervical Cancer. Available at: www.who.int/hpvcentre/statistics/en/.

National Advisory Committee on Immunization (NACI) Members: Dr. M. Naus (Chairperson), Dr. S. Deeks (Executive Secretary), Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. M.-N. Primeau, Dr. B. Tan, Dr. B.Warshawsky. Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), E. Holmes (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. D. Money (SOGC), Dr. P. Orr (AMMI Canada), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. J. Smith (CDC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE).

Recommended Use Group Recommendation Comments Females Age 9–13 years Efficacy is greatest prior to first sexual intercourse Although efficacy not demonstrated, immunogenicity data imply high efficacy Females Age 14–26 years Recommended, even after onset of sexual activity May not have been infected Very unlikely to have been infected with all 4 vaccine HPV types Need to be aware that they may already have been infected with HPV-related cervical or genital disease or current infection May not have been infected with vaccine HPV types Need to be aware that vaccine probably has no therapeutic effect scrapped 15 February 2007Statement on human papillomavirus vaccine. Canada Communicable Disease Report. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-2):1-32. 29

Canadian HPV Vaccine Public Programs No Public Announcement Multiple Age Groups (Uptake %) Quebec: Grade 4, Grade 9, and Girls < age 18 (84-87%) British Columbia: Grade 6 and Grade 9. (66%) Alberta: Grade 5 and Grade 9 (starting in 2009). Saskatchewan: Grade 6 with a one year Grade 7 catch-up. New Brunswick: Grade 7 with a one year Grade 8 catch-up. Nova Scotia: Grade 7 with a one year Grade 10 catch-up (80%) Newfoundland and Labrador: Grade 6 and Grade 9 (83%) Yukon: Grade 5 with a catch-up in Grade 6 and 7 One Age Group Manitoba: Grade 6 Ontario: Grade 8 (55%) Prince Edward Island: Grade 6 (80%) One Age Group Yuk NWT Multiple Age Groups Nun No Public Announcement To give you a snapshot of where we are at with our public performance. NACI recommendation In January 2007 the National Advisory Committee on Immunization (NACI), a group of Canada’s leading experts in the fields infectious diseases, vaccines and public health that reports to the Chief Public Health Officer of Canada, made a strong and inclusive recommendation. GARDASIL® is recommended for ALL females 9-26 even if they are sexually active with or without history of disease and / or infection (warts, Pap abnormality cervical cancer) and a discretional recommendation in females >26 years of age. NIS funding In March 2007 the federal government, as part of the National Immunization Strategy, renewed funding for vaccines and put aside $300M for HPV vaccination programs over a three year period. This funding will allow the provinces to vaccinate up to 5 cohorts (or approx. 1.1M adolescent girls) over the next three years. Public Programs To date we have had several programs announced, some of which will be started this fall and others in 2008. Ontario will implement a program in the coming weeks for 1 cohort in Gr. 8, NS – Gr. 7, NF – Gr. 7, PEI – Gr. 6. BC and Quebec have made public announcements that they will initiate multi-cohort programs in Q3, 2008. Specifics of these programs will be announced in the next few months. BC AB SK MB QC NF ON PEI NB NS February 2009

HPV Vaccines – Available in Canada Quadrivalent vaccine: Contains HPV Types 6, 18 (20 ug each), 11, 16 (40 ug each) Adjuvant: 225 ug Aluminum hydroxyphosphate sulfate Approved in Canada – May 2006 (initially for females 9 to 26 yrs of age; now expanded indications) 3 i.m. Doses: 0, 2 (± 1 m), and 6 (± 2 m) m Bivalent Vaccine: Contains HPV Types 16 and 18 (20 ug each) Adjuvant: 500 ug Aluminum hydroxide, 50ug 3-deacylated monophosphoryl Lipid A Approved in Canada – February 2010 for females from 10 to 25 yrs of age 3 i.m. Doses: 0, 1 (up to 2.5 m) and 6 (between 5 and 9 m after 1st dose) m

HPV2 and HPV4 – Efficacy L. Markowitz. CDC. Presented at ACIP Oct 2009

HPV Vaccine: Expanding Indications “Older” women >26 years of age Males http://www.cdc.gov/vaccines/recs/acip/slides-oct09.htm

Quadrivalent HPV Vaccine: Efficacy in Women Aged 24-45 Years: Future III Population Vaccine (n=1911) Placebo (n=1908) Vaccine Efficacy 95% CI All subjects 4 41 91% 74, 98 24-34 yr 2 24 92% 67, 99 35-45 yr 17 89% 52, 99 HPV 16 & 18 23 83% 51, 96 HPV 6 & 11 19 100% 79, 100 Attention: Please note that comments were made by the CCCEP reviewers that this graph is complex and could be confusing. It will therefore require a detailed explanation and a clear take home message Muñoz N, et al. Lancet 2009; 373:1949-57. 34

HPV Vaccine in Men The incidence of anogenital HPV infection in men is at least as high as in women.1 32% of all HPV-related cancers in the USA occur in men.2 Quadrivalent HPV vaccine is immunogenic in males.3 Preliminary data demonstrate efficacy of quadrivalent HPV vaccine versus infection and disease in both heterosexual4 and homosexual men.5 1. Partridge JM, et al. J Infect Dis 2007;196:1128-36. 2. Saraiya M, et al. Cancer 2008;113 (10 Suppl):2837-40. 3. Guris D. 25th International Papillomavirus Conference, Malmo. May 2009. Abstract P-27.16 4. Giuliano A, Palefsky J. 25th International Papillomavirus Conference, Malmo. May 2009. Abstract O-01.07 5. Palefsky J, Giuliano A. 25th International Papillomavirus Conference, Malmo. May 2009. Abstract O-27.01

Quadrivalent HPV Vaccine (n = 1,397) Efficacy Against HPV 6/11/16/18 Related External Genital Lesions (EGL) in Men 16-26 yr Per-protocol population Severity Quadrivalent HPV Vaccine (n = 1,397) Placebo (n = 1,408) % Efficacy 95% CI Cases Inc. per 100 PY Condyloma 3* 0.1 28 1.0 89.4 65.5, 97.9 PIN 1 0.0 2 -- PIN 2/3 1 Penile/perineal/ perianal cancer Randomized (1:1), double-blind, placebo-controlled in male 3 doses of Quadrivalent HPV Vaccine or placebo at 0, 2, and 6 months Planned 36 month follow-up (mean 30.1 months in current analysis) Enrolled subjects: Heterosexual men (HM) 16-23 year old 3463 Men having sex with men (MSM) 16-26 year old 602 Objectives: Safety Efficacy: Combined incidence of HPV 6/11/16/18‑related lesions Main study: HM + MSM External genital warts Penile/perianal/perineal intraepithelial neoplasia (PIN) Penile, perianal, or perineal cancer Sub-study: MSM Anal intraepithelial neoplasia (AIN) Anal Cancer Immunogenicity Geometric mean titers, seroconversion Secondary Objective: Incidence of persistent HPV 6/11/16/18 infection* Incidence of HPV 6/11/16/18 DNA detection at one or more visits *Two cases related to HPV 6 alone, and one case related to HPV 6/11/35 n = number of subjects randomized who received at least one injection and have follow-up after month 7 PY = person years; PIN = penile/perianal/perineal intraepithelial neoplasia; case counting began after month 7. A. Giulano & J Palefsky. IPVC 2009; O-01.07

Use of Quadrivalent HPV Vaccine in Males Health Canada: Feb. 23rd, 2010 – Approved for use in males between 9 to 26 yrs for prevention of infection caused by HPV types 6, 11, 16 and 18 and genital warts caused by HPV types 6 and 11 http://www.cdc.gov/vaccines/recs/acip/slides-oct09.htm

Adverse Events to the HPV Vaccines Comparative Trial (Bivalent & Quadrivalent Vaccines) (N=1106): Local symptoms (pain, redness, swelling) & general symptoms (fatigue, myalgia): Bivalent > Quadrivalent SAEs similar between both (~7% vs 6.2%) http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm183835.htm; Einstein et al. Human Vaccines 2009

Duration of Protective Efficacy Both vaccines induce antibody titers substantially higher than after natural infection Minimum protective antibody threshold not known Different antibody assays used in clinical trials – can’t compare antibody titers between trials WHO: Protective efficacy of the 2 vaccines has been maintained throughout their respective observation periods: 6.4 years (bivalent) and 5 years (quadrivalent) http://www.who.int/wer/2009/wer8415.pdf

Seropositivity and Efficacy of quadrivalent vaccine against HPV 18 related CIN2/3 or AIS in Women 16–26 years 99% 71% 61% 100% 68% Seropositivity to HPV 18 neutralising antibodies as measured by cLIA Efficacy against HPV 18-related CIN 2/3 or AIS *Seropositivity to HPV 18 neutralizing antibodies to a single neutralizing epitope measured by cLIA Joura E, et al. Vaccine 2008; 26(52) 40

Immune memory demonstrated after immune challenge Demonstration of Immune Memory* with an Antigen Challenge at Month 60 Among Women 16-23 Years of Age (HPV 18) Anti-HPV GMT levels [log10 scale]) 60+1 week Immune memory demonstrated after immune challenge 10,000 1000 100 10 2 3 7 12 18 24 30 36 54 60 61 GARDASIL™ (n=82) Placebo (Sero and PCR neg) (n=70) Months 6 Similar results seen with HPV 16, 6, and 11 *In participants naïve to the relevant HPV type from day 1 through month 60. 41 Adapted from Olsson S-E et al. Vaccine (2007), doi:10.1016/j.vaccine.2007.03.049.4 41

Pneumococcal Vaccine

Estimated number of deaths (WHO 2002) Pneumococcal Disease Is the Leading Cause of Vaccine-preventable Deaths (WHO) Estimated number of deaths (WHO 2002) Key Points As shown on the slide, pneumococcal disease is the leading vaccine-preventable cause of death for all ages as well as children aged younger than 5 years. (p1 para2-4) This extraordinary disease burden supports the need for universal vaccination. Reference World Health Organization (WHO 2004 Global Immunization Data. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. Accessed June 7, 2009. aPolio, diphtheria, yellow fever. WHO 2004 Global Immunization Data. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. Accessed June 7, 2009. 43

Age-Specific Incidence of Invasive Pneumococcal Disease, Toronto, 1995

Pneumococcal Vaccines Conjugate vaccine (PCV-7): Jan. 2005 provincial program in Ontario started No catch-up; start with birth cohort Covers >80% of serotypes from blood and CSF of children in the pre-vaccine era 75% decrease in IPD in children 23-valent Polysaccharide vaccine: Oct. 1996 provincial program for routine vaccination of all persons 65 yrs All persons  5 yrs who are at high risk for IPD including those 19 – 65 yrs with asthma3 Routine booster not recommended; consider once in high risk group after 5 years Covers 90% of serotypes from bacteremia and meningitis in adults Has not been shown to reduce the incidence of CAP but may be associated with a decrease risk of bacteremia and death as well as severity High Risk Groups include: Immunosuppress. Malignancy Renal disease Asplenia Smokers Diabetes mellitus CHF COPD Sickle cell disease Nephrotic syndrome Steroids Cirrhosis Alcoholism 1. 2006 Canadian Immunisation Guide 2. Canadian Adult National Immunization Coverage Survey 2006 3. Ann Intern Med. March 2009

Newer Pneumococcal Conjugate Vaccine Pneumococcal 10 Conjugate Vaccine (Synflorix): Licensed in Canada in December 2008 for children 6 weeks up to 2 years of age Primary series: 4 i.m. doses (2, 4, 6, 12-15 months) Conjugated to Non-typeable H. influenzae (NTHi) protein D, Diphteria or tetanus toxid Pneumococcal 13 Conjugate Vaccine (Prevnar 13): Licensed in Canada in February 2010 for children 6 weeks through 5 yrs of age Previous PCV-7: 1 dose in 2nd year of life Conjugated to Diphtheria CRM197 protein Will be licensed for use in adults >55 yrs

Pneumococcal Vaccines PCV7 PCV10 PCV13 PPV23 4 2 6B 8 9V 9N 14 10A 18C 11A 19F 12F 23F 15B 1 17F 5 22F 7F 33F 3 19A 6A

Primary Objective: To evaluate the association between pneumococcal vaccination and the risk of myocardial infarction Pneumococcal vaccination associated with a decrease of more than 50% in the rate of myocardial infarction 2 years after exposure to vaccine

Influenza Vaccine

Pandemic H1N1 2009: Multiple Waves of Morbidity and Mortality in Canada

National Advisory Committee on Immunization (NACI) Members: Dr. J. Langley (Chairperson), Dr. B. Warshawsky (Vice-Chair), Dr. S. Ismail (Executive Secretary), Dr.N. Crowcroft, Ms. A. Hanrahan, Dr. B. Henry, Dr. D. Kumar, Dr. S. McNeil, Dr. C. Quach-Thanh, Dr. B. Seifert, Dr. D. Skowronski, Dr. C. Cooper.

Trivalent Influenza Vaccine 2010/2011 Five vaccines (4 i.m. & 1 intradermal) licensed in Canada containing 3 influenza strains: 2009 pandemic influenza A California (H1N1) - like 2009 Influenza A Perth (H3N2) - like 2008 Influenza B Brisbane – like None contains an adjuvant Publicly funded programs will use Fluviral (contains thimerosal but no antibiotics) and Vaxigrip (contains thimerosal and neomycin) vaccines Can be used in adults and children >6 months of age National Advisory Committee on Immunization (NACI). CCDR August 2010; vol. 36

Trivalent Influenza Vaccine 2010/2011 Recommended Recipients: Adults (including pregnant women) and children with chronic health conditions Residents of nursing homes People >65 yrs of age Healthy children 6 to 23 mos Healthy pregnant women (risk of influenza-related hospitalization increases with length of gestation) People capable of transmitting influenza to those at high risk (e.g. Healthcare workers, Household contacts, child care workers, etc.) National Advisory Committee on Immunization (NACI). CCDR August 2010; vol. 36

Trivalent Influenza Vaccine 2010/2011 Recommended Recipients (New for 2010/2011): Persons who are morbidly obese (BMI >40) Aboriginal peoples Healthy children 2 to 4 years of age The first time children <9 yrs receive TIV, a two-dose schedule is required REGARDLESS of whether or not the child received monovalent pH1N1 vaccine in 2009-2010 National Advisory Committee on Immunization (NACI). CCDR August 2010; vol. 36

What Can Be Done to Improve Adult Immunization Rates? 56

Adult Immunization: Strategies to Improve Vaccine Uptake Communication Explaining the need for immunization Clearly conveying the risks1 Strong physician/provider recommendation1 Recommendation is critical2 1Burns IT, Zimmerman RK. 2005:54:S58-62 2PHAC 2006 Canadian Adult Immunization Coverage Survey

Adult Immunization: Strategies to Improve Vaccine Uptake Patient Visit Strategy Assess vaccination at all visits: stamped chart reminders Improve tracking system CCIAP Adult Immunization Wallet Card Empower patient to become more involved Adult Immunization Questionnaire Assess vaccination at all visits: stamped chart reminders Improve tracking system CCIAP Adult Immunization Wallet Card Empower patient to become more involved Adult Immunization Questionnaire (completed by patient at scheduled appointment) Szilagyi, PG, et al. 2005:40:152-161.

Summary Immunization does not stop at childhood Prevention of infection by immunization is a lifelong process Health Care Practitioners need to Empower, Educate, Advocate and Recommend

Thank you for your attention!

Important Web-sites Public Health Agency of Canada www.phac-aspc.gc.ca Canadian Coalition for Immunization Awareness and Promotion (CCIAP) www.immunize.cpha.ca Centers for Disease Control and Prevention www.cdc.gov World Health Organization www.who.int