Polysaccharide 23 (Pneumovax) & Conjugate 13 Now Togather as a New Reccomendation… If I am the one putting it in to practice, please don’t change any guideline without asking me ! Signed by a Family Physician in the WORLD DAY OF FAMILY DOCTORS 19 th of MAY 2015 Mehmet UNGAN, MD, Professor of Family Medicine, Ankara University School of Medicine, Dept of Family Medicine

2015 ACIP- CDC Vaccination Guideline Changes in the Schedule Effective February 3, 2015 Figure 1, the recommended adult immunization schedule by vaccine and age group, has been revised to designate PCV13 for adults aged 65 years or older as "recommended" (from the previous "recommended if some other risk is present"). Figure 2, showing vaccines that might be indicated for adults on the basis of medical and other indications, is unchanged. The footnotes for pneumococcal vaccination have been revised to provide algorithmic, patient-based guidance for the health care provider to arrive at appropriate vaccination decisions for individual patient

Those were the GOOD Old Days ! Efforts to develop effective pneumococcal vaccines began as early as 1911. However, with the advent of penicillin in the 1940s, interest in pneumococcal vaccination declined, Until it was observed that many patients still died despite antibiotic treatment ( late 1960s).

Without immunization/vaccination? The major clinical syndromes of pneumococcal disease are serious hospital care conditions, what we call invasive pulmonary diseases (IPD): pneumonia, bacteremia, and meningitis. Less burden but uncomfortable in primary care: Otitis media ! (28%–55% of middle ear aspirates)

Most S. pneumoniae serotypes have been shown to cause serious disease, But, only a few serotypes produce the majority of pneumococcal infections. The 10 most common serotypes are estimated to account for about 62% of invasive disease worldwide. The ranking and serotype prevalence differ by patient age group and geographic area (important for primary care ! ).

Prevalence of IPD varies with Geographical region Risk Factors: Age Underlying diseases Ethnic Groups

Are we lucky? We have more than 2 options Competing or Complementing ? Polysaccharide Vaccine Purified pneumococcal polysaccharide (23 types) Not effective in children younger than 2 years 60%–70% against invasive disease Less effective in preventing pneumococcal pneumonia Conjugate Vaccine More than 90% effective against invasive disease caused by vaccine serotypes in children 45% effective against vaccine-type non-bacteremic pneumococcal pneumonia in adults older than 65 years 75% effective against vaccine- type invasive disease in adults older than 65 years

We must look at those topics below ! Coverage Immunogenicity Persistence Protection against CAP (Communty Acquired Pnumonia) Hypo-responsiveness Tolerance Cost What is the Evidence? References, any relation with the industry ?

PPV23 PCV 13 1 . Coverage Does PCV 13 cover more serotypes important for protection in the elderly (>64) ?

Emergence of serotypes not included in the vaccine Serotype Replacement, Vaccine recommendations for the 65+ must take into account those trends below in epidemiology. Emergence of serotypes not included in the vaccine Routine use of PCV caused serotype replacement in USA Serotypes causing IPD were different in elderly and children The IPD epidemiology in the 65+ is undergoing change due to indirect effects of childhood immunization. 1. Pilishvili T J Infect Dis 2010 Jan 1;201(1):32-41

Different epidemiology of serotypes in Eldery & Children age ≥65 years age <5 years Serotip replasmanı sonrasında 5 yaşından küçük çocuklarda ön plana çıkan serotiplerin neredeyse tamamı 19A iken (hem PPV23 hem de PCV13 de mevcut), yaşlılarda non-vaccine type serotipler sadece 19 A’dan mevcut değildir. Sadece PPV 23’ün içerdiği serotiplerden kaynaklanan IPD oranları artmaktadır . (rates of IPD caused by serotypes that were only in PPV23 increased) Changes in overall IPD incidence in US among children aged <5 years and adults aged ≥65 due to routine immunization in between 1998–2007 Rates of IPD caused by serotypes that were only in PPV23 increased Pilishvili T J Infect Dis 2010;201(1):32-41

PPV23 matches more S. pneumoniae serotypes circulating in the elderly population than PCV13 6B The principal disease-causing pneumococcal serotypes are shown in the grey bar. Serotypes indicated in red have shown increasing clinical relevance in adults as a result of post-PCV 7 serotype replacement. Boxes show serotypes that are covered by PPV23 but not PCV 13. Lexau JAMA 2005; 294:2043–51. Ardanuy Clin Infect Dis 2009; 48:57–64. Tsigrelis J Infect 2009;59:188–93. Hammitt J Infect Dis 2006;193:1487–94. Hicks J Infect Dis 2007;196(9):1346-54. Singleton JAMA 2007; 297:1784–92. Aguiar Clin Microbiol Infect 2008;14(9):835-43. Jacobs Clin Infect Dis 2008;47:1388–95. Mera Microb Drug Resist 2008;14:101–7. Hsu N Engl J Med 2009; 360:244–56. Kellner Clin Infect Dis 2009; 49:205–12. Guevara Clin Microbiol Infect 2009;15:1013–9

PPV23 matches more S. pneumoniae serotypes circulating in the elderly population than PCV13 In 2008, the serotypes covered in PCV13 caused 53%, 49%, and 44% of IPD cases among persons aged 18–49 years, 50–64 years, and ≥65 years, respectively; serotypes covered in PPSV23 caused 78%, 76%, and 66% of IPD cases among persons in these age groups (Figure). CDC. MMWR Recomm Rep. 2010;59(RR-11):1-18

PPV23 matches more S. pneumoniae serotypes that are associated with high case fatality rates in the adult and elderly population than does PCV13 Sjostrom Clin Infect Dis 2006 Feb 15;42(4):451-9, Jansen Clin Infect Dis 2009 Jul 15;49(2):e23-9, Harboe PLoS Med 2009 May 26;6(5):e1000081

2. Immunogenicity Is a single dose of PCV more immunogenic than PPV23 (Pneumovax) in adults and elderly?

immunogenicity of PPV23 and PCV 7 Goldblatt et al. [16] in a study conducted in 599 naive healthy adults (50-80 years stratified by age), studied antibody responses induced after a single dose of PCV 7 or PPV23. In contrast with the study by De Roux, no significant differences in serotype specific IgG antibody concentrations were reported. The dichotomy between the results of De Roux (sponsored by Wyeth) and those of Goldblatt, prompted Goldblatt to question why the results obtained in the De Roux trial showing differences between PPV and PCV 7 had not been reproduced elsewhere [16]. In a separate editorial, Katherine O’Brien also questioned the differences in the results of the Goldblatt vs. those of the De Roux studies [8]. Summary of head-to-head trials comparing the immunogenicity of PCV 7 to PPV23 in adults and elderly Similar immunogenic response de Roux Clin Infect Dis 2008;46(7):1015-23. Goldblatt Clin Infect Dis 2009;49(9):1318-25. Miernyk Clin Infect Dis 2009;49(2):241-8. Jackson Vaccine 2007;25(20):4029-37. Ridda Vaccine 2009;27(10):1628-36.

Recall responses booster IgG to Capsular Polysaccharide (CPS), after patients received PPV23 or PCV7 dashed line  PPV23, followed 6 months later by PCV7 solid line  PCV7, followed 6 months later by PPV23 adapted from reference Initial higher recall response becomes equal in six months P.S.: No indication of PCV booster 6 months after PPV23 in daily practice Musher DM, et al. Clinical Infectious Diseases 2011;52(5):633–640

3. Persistency Does PCV offer more persistent antibody responses in adults and elderly than PPV23?

Does PCV induce higher recall responses in the elderly than PPV23?

Immunological studies have failed to demonstrate that PCV induces more persistent antibody responses in the elderly than PPV23 Pneumococcal immunoglobulin G (IgG) geometric mean concentrations (GMCs) 4–6 weeks after receipt of a single dose of 7-valent pneumococcal conjugate vaccine (n:428; checked bars) and 23-valent polysaccharide vaccine (n:155; white bars) and antibody persistence at 1 year (with 95% confidence interval) for 7-valent pneumococcal conjugate vaccine (gray bars) and 23-valent polysaccharide vaccine (striped bars). Pneumococcal IgG GMCs 4–6 weeks after receipt of a single dose of; PCV 7 (n:428; checked bars) and PPV 23 (n:155; white bars) and antibody persistence at 1 year PCV7 (gray bars) and PPV23 (striped bars). No differences in terms of persistance between PCV and PPV Goldblatt D et al. Clin Infect Dis. 2009;49:1318-1325

PPV23 induced antibodies persist for at least 5 years Five years persistance with PPV23 Manoff SB et al. The Journal of Infectious Diseases 2010; 201:525–33.

4. Protection against Community Acquired pneumonia (CAP) Has PCV been shown to provide better protection against community acquired pneumonia (CAP) than PPV23?

*CAPITA trial (85,000 adults ≥ 65 years who had not been previously immunized with pneumococcal vaccines) investigating the efficacy of PCV13 against community acquired pneumonia (CAP) is one of the based researches. However, this study will not answer the essential question of which vaccine is better in adults because, it compares PCV13 with placebo. (1) PPV23 prevents hospitalizations and deaths associated with CAP in nursing home residents. (2) Two recent case control studies report PPV23 to be effective against CAP in the community-dwelling elderly and in immunocompromised patients. (3-4) Musher Clinical Infectious Diseases 2011; 52(5): 633–40. Maruyama BMJ. 2010 Mar 8;340:c1004. Dominguez Eur Respir J. 2010 Jan 14. Vila-Corcoles Vaccine 2009 Mar 4;27(10):1504-10. * Pfizer Capita Trial Study

5. Hyporesponsiveness Does primary vaccination with PPV23 always result in significant hyporesponsiveness to revaccination ?

Serotype-specific functional antibody as measured by opsonophagocytic killing (OPK) before and 30 days after vaccination with PPV23 Repeat revaccination with 23-valent pneumococcal polysaccharide vaccineamong adults aged 55–74 years living in Alaska: No evidence of hyporesponsiveness. Serotype-specific functional antibody as measured by opsonophagocytic killing (OPK) before and 30 days after vaccination with PPV23. Group 1 = 1st dose of PPV23. Group 2 = 2nd dose of PPV23. Group 3 = 3rd or 4th dose of PPV23. Statistically significant differences are shown in bold Group 1 = 1st dose of PPV23. Group 2 = 2nd dose of PPV23. Group 3 = 3rd or 4th dose of PPV23 Hammitt LLVaccine 29 (2011) 2287–2295.

6. Tolerance How well tolerated is revaccination with PPV23?

Repeat revaccination with PPV23 is well tolerated Repeat revaccination with PPV23, was immunogenic and generally well tolerated (Previous study- even 3rd and 4th dose was used). (1) Younger age, healthier status, and revaccination at 1 year are associated with increased rate of local reactions. (2) if we consider recommendations on PPV 23 and conditions associated with increased rate of local reactions, one should expect the saftey profile of PPV23 be tolerable ≥ 65 years Revaccination at 5 years People with underlying chronic diseases Hammitt LLVaccine 29 (2011) 2287–2295. Musher Clinical Infectious Diseases 2011; 52(5): 633–40.

7. Cost What would be the budget impact of replacing PPV23 by PCV13 or using both as 2 doses in publicly funded programs?

Pharmacoeconomic evaluation Economic evaluation of routine Prevenar vaccination programs have been published from 11 countries: Australia, Canada, Finland, Germany, Italy, Netherlands, Norway, Spain, Switzerland, UK and US ALL ARE PCV 7, some supported by industry Routine immunization with Prevenar (PCV 7) has been shown to significantly reduce the overall cost associated with treatment of pneumococcal disease But no study by using both as 2 doses in older than 65, yet ! We dont know NNV values yet?

Elderly (60% coverage)  45.4 million TL (17,7million USD ) Pneumococcal vaccination led to savings Elderly (60% coverage)  45.4 million TL (17,7million USD ) High-risk adults (40% coverage) 21.8 million TL (8,47 million USD) PPV23 alone is already a cost ( 10 USD) but more cost saving than PCV 13 (50 USD) +PPV23 ( 10 USD) =60 USD/person. Akin L. Human Vaccines 7:4, 441-450; April 2011

Money is never more important than healthy people Money is never more important than healthy people ! But if almost equal NNV? PPV23 30 TL PCV13 (150) + PPV23 = 180 TL 150 TL

What is NNV (Number Needed to Vaccinate) ? The NNV can be calculated as the inverse of the absolute risk reduction (ARR), which is, in turn, divided by the estimated length of vaccine protection (VP). ARR is calculated as the difference in disease incidence between unvaccinated and vaccinated subjects. The NNV and incidence in vaccinated subjects are derived as follows: NNV=1/VP length×(1/[incidence unvaccinated−incidence vaccinated]) Incidence in vaccinated=incidence in unvaccinated × (1−[VE × % serotype coverage ]) ----------------------------------------------------------------------- ****Read NNV as=> “How many I need to inject to prevent one IPD (invasive disease) related with mortality”

Current Canadian guidelines recommend only one dose of PPV-23 without a booster in individuals who have a chronic condition, but who are not otherwise considered immune-compromised. Based on our calculations, not taking into account herd immunity and previous vaccination with PCV, the NNV to prevent one case of IPD is low but is it enough low ?. In fact, the NNV to prevent one case of IPD with both PCV-13 and PPV-23 is lower than in the high-risk groups that are routinely vaccinated. For example, the NNV with PPV-23 in adults ≥65 years of age has been calculated at 3333 in one study (7) and 5206 in another (8).

Authors used the serotype-specific notification data from the Norwegian Surveillance System for Communicable Diseases (MSIS; Norwegian Institute of Public Health, 2011) for IPDcases with a testing date between 1 January 2004 and 30 June 2014and aged 65+. Data were extracted on 23 July 2014. All IPD cases, defined as a case in which S. pneumoniae was isolated from a nor-mally sterile site, are notifiable to MSIS. vaccinationDuring the study period, 4365 IPD cases aged 65+ were notified in Norway, corresponding to 49% (4365/8847) of all notified IPD cases.

Should PCV13 be used routinely in healthy adults ≥ 50 y of age to protect them against pneumococcal infection? The rate of pneumococcal infection as a cause of pneumonia is substantially lower than it was a few decades ago. Recent studies in the US suggest that no more than about 10–12% of CAP is caused by pneumococcus. Taking this observation together with the steady decline in disease caused by serotypes contained in PCV13, it might well be regarded as entirely superfluous to initiate a campaign to vaccinate adults 50–64 years old with PCV13. In summary, the CAPITA trial demonstrates that PCV13 effectively protects adults against infection by pneumococcal serotypes that are represented in the vaccine. This trial was performed in a country where PCV10 utilization in infants and toddlers was in its earliest stages and where PCV13 had not yet been used at The trial did not support the use of PCV13 in immunocompromised adults and addressed neither the question of immunological “priming” nor the comparative effectiveness of this vaccine vs. PPV23. Taken together with the importance of the herd effect and the generally low rate with which S. pneumoniaeis implicated in CAP, these facts suggest that widespread use of PCV13 in adults ages 50–64, or even in all immunocompromised adults ≥ 19 y of age will have limited protective effect as a public health measure.

SUMMARY-Early for such decision? PPV23 PCV13 coverage immunogenicity persistence protection against CAP hyporesponsiveness tolerance Cost Protective as a public health measure? ? ? √ = = √ √ NO NO √ √ √