Pneumococcal vaccines

1. Pneumococcal disease and Pneumococcal vaccines Dr.R.Jayaprada

2. Introduction The description by Sir William Osler, “Pneumonia remains now, as then, the most serious acute disease with which physicians have to deal; serious because it attacks the old, the feeble … persons who are not able to withstand the sudden sharp onset of the malady,” still stands the test of time. 1) Silverman ME, Murray TJ, Bryan CS. The Quotable Osler. Philadelphia: American College of Physicians; 1998:139.

3. Pneumococcal disease Streptococcus pneumoniae (pneumococcus) is a gram-positive bacterium with more than 90 known serotypes. Pneumococcus is spread by airborne droplets and is a leading cause of serious illness, including bacteremia, meningitis, and pneumonia among children and adults worldwide(2,3). Approximately, 1 million children under 5 years of age die of pneumococcal disease annually (3). In 2005, WHO estimated that 1.6 million people die of pneumococcal disease every year; this estimate includes the deaths of 0.7–1 million children 3 aged <5 years, most of whom live in developing countries. (2)Nuorti JP, Whitney CG. Prevention of pneumococcal disease among infants and children—use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010; 59(RR-11): 1–18. (3)Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States, 1998–2007. N Engl J Med. 2011; 364(21): 2016–25.

4. Review of S.pneumoniae and pneumococcal diseases (1/2) Invasive Pneumococcal Disease (IPD) carries high risk of mortality (4). S. pneumoniae is the leading cause of Community-acquired pneumonia (CAP) (5) >90 serotypes of S. pneumoniae (6) 8-10 cause two-thirds of serious infections in adults (7)

5. Review of S.pneumoniae and pneumococcal diseases (2/2) Pneumococcal diseases are serious and associated with significant mortality (6) 1 in every 20 adults who gets pneumococcal pneumonia die . 2 out of every 10 adults who get bacteremia die . 3 out of every 10 adults who get meningitis die . (4) World Health Organization. Weekly Epidemiological Record. Pneumococcal vaccines No. 14, 2003, 78, 97-120. (5) Jokinen C, Heiskanen L, Juvonen H et al. Microbial etiology of community-acquired pneumonia in the adult population of 4 municipalities in eastern Finland. Clin Infect Dis. 2001 Apr 15;32(8):1141-54. (6) Fedson DS, Musher D. Pneumococcal polysaccharide vaccine. In: Plotkin A, Orenstein WA editors. Vaccines. 4th ed. Philadelphia, USA: WB Saunders Company; 2004. p. 529-88. (4) Pneumococcal. In: The green book chapter 25. Immunization against infectious disease. London, United Kingdom Department of Health; 2006. (7) Musher DM. Streptococcus pneumoniae. In: Mandell G, Bennett JE, Dolin R editors. Principles and practice of infectious disease. 4th ed. New-York, USA: Churchill Livingstone, Inc.; 1995. p. 1811-26.

6. Invasive pneumococcal disease Invasive pneumococcal disease Pneumococcal pneumonia Meningitis, arthritis,pleuritis etc. Overlap between pneumococcal pneumonia and invasive pneumococcal disease (8) Adapted from Fedson DS. Pneumococcal vaccination for older adults—the first 20 years. Drugs Aging 15(suppl 1):21–30, 1999. Serotypes 1 and 5 (epidemic serotypes) account for 29% of IPD in India .

7. Invasive Pneumococcal Disease Incidence by Age Group Rate per 100,000 population. Active Bacterial Core Surveillance/EIP Network

8. Study in India In India, the Invasive Bacterial Infection Surveillance (IBIS) network and South Asian Pneumococcal Alliance (SAPNA) have been involved in collection of important data regarding serotype distribution and antimicrobial resistance of pneumococcal infections for more than 12 years. The program has been funded by INCLEN with financial assistance from United States Agency for International Development (USAID) and the Pneumococcal vaccines Accelerated Developmental and Introduction Plan (Pneumo ADIP) of the Global Alliance for Vaccine and Immunization (GAVI).

9. Pneumococcal sero type distribution- Indian scenario Invasive Pneumococcal Disease (IPD) serotypes 6, 1, 19, 14, 4, 5, 45, 12, 7, 23 are the most prevalent . Serotypes 1 and 5 accounting for 29% of invasive pneumococcal disease ( Invasive Bacterial Infection Surveillance (IBIS) study (1993-1997). The most prevalent serotypes in India are 6 (17%), 1 (12.5%), 5 (9.6%), 14 (9.6%), 19 (7.7%) and 23 (5.8%) -- common among children (South Asian Pneumococcal Alliance (SAPNA) ( 2006-2007)  

10. Serotype distribution in adults Serotype 1 and type 3 were common serotypes (Fig. 1) in all age groups (22–50, 51– 64, >64 years).

11. Risk factors Age (6) Chronic illnesses (8) Functional or anatomical asplenia (8) Immunodeficiency (8) Environmental factors (6) (7) Musher DM. In Mandell G, Bennett JE, Dolin R editors. Principles and practice of infectious disease. 4th ed. New York, USA: Churchill Livingstone, Inc.; 1995. p.1811-26. (9) CDC. Recommendations of the ACIP. Prevention of pneumococcal disease. MMWR 1997; 46 (N° RR-8): 1-2

12. Streptococcus pneumoniae Common inhabitant of the respiratory tract (nasopharynx of 5-70% healthy adults) Asymptomatic carriage: Vary with age, environment & + of URTI 5-10% of adults w/o children 27-58% of residents in schools/orphanages 50-60% of service personnel Duration of carriage varies & is generally longer in children than in adults

13. Figure 1. Diseases caused by Streptococcus pneumoniae. Pneumococci colonise the nasopharynx, evade host immunity and spread to the middle ear, sinus, lower respiratory tract, blood and meninges. Pneumococci cause otitis media in the middle ear, sinusitis in the sinus, pneumonia in the lower respiratory tract, bacteraemia in blood and meningitis in the meninges. The incidences of different types of pneumococcal infection are inversely related to the severity of disease: otitis media is the most common but the least severe. Redrawn and redesigned with permission from Ref. [2]. Bogaert, D. et al. (2004) Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4, 144–154

14. Pneumococcal disease Pneumococcal disease is the term used to describe infections caused by the bacterium Streptococcus pneumoniae (also called Pneumococcus). S. pneumoniae is an encapsulated gram-positive coccus . The capsule is the most important virulence factor of S. pneumoniae; pneumococci that lack the capsule are normally not virulent. Over 90 different capsular types have been characterized. About 66% of the serious infections in adults and about 80% of invasive infections in children are caused by eight to ten capsular types (Health Protection Agency, 2003).

15. Characteristics of S.pneumoniae S. pneumoniae has typical characteristics: 1. It has specific polysaccharide capsule which is demonstrated by quellung reaction. Capsular polysaccharides are the primary basis for pathogenicity; antigenic; basis for serotypes. 2. Bile solubility. 3. Optochin sensitivity. 4. Ferments inulin which is the differentiating feature from other streptococci. 5. Lancet-shaped, Gram positive diplococci, alpha-hemolytic 6.Catalase(-) : requires source of catalase to grow on agar plates e.g. blood, generate H2O2

16. Typing of pneumococcus Pneumococci are classified into types based on the antigenic nature of the capsular polysaccharide. Pneumococci isolated from lobar pneumonia were originally classified into three types I, II and III, and a heterogeneous group IV. Members of group IV were later classified into types, and now more than 90 different serotypes are recognized, named 1, 2, 3, and so on.

17. Typing of pneumococcus Typing may be carried out by (1)Agglutination of the cocci with the type specific antiserum by Co-agglutination (Co-A); test (2) Precipitation of the SSS with the specific serum by counter current immunoelectrophoresis(CIEP); or (3) By the capsule swelling reaction described by Neufeld (1902).

18. More than 90 capsule types and serotypes are known in S. pneumoniae (Hausdorff et al., 2002). Out of which 23 serotypes cause human infection. Type-specific Ab to capsular polysaccharide is protective. These Abs & complement interact to opsonize pneumococci. Antibodies to some pneumococcal capsular polysaccharides may cross-react with related types Hausdorff, W. P., Bryant, J., Paradiso , P. R. & Siber , G. R. (2000). Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I. Clin Infect Dis 30, 100–121.

19. American and Danish Nomenclature for Streptococcus pneumoniae Serotypes USA Denmark USA Denmark USA Denmark USA Denmark USA Denmark 1 1 21 21 41 34 61 35C 81 44 2 2 22 22F 42 33B 62 35A 82 48 3 3 23 23F 43 11A 63 22A 83 12A 4 4 24 24F 44 18A 64 23B 84 47A 5 5 25 25F 45 40 65 24A ? 10B 6 6A 26 6B 46 23A 66 35B ? 10C 7 7A 27 27 47 35A 67 32A ? 11D 8 8 28 28F 48 7B 68 9V ? 12B 9 9N 29 29 49 9L 69 39 ? 16A 10 10F 30 15A 50 7C 70 33F ? 25A 11 11F 31 31 51 7F 71 38 ? 33D 12 12F 32 32F 52 47F 72 45 6C 6C 13 13 33 9A 53 11C 73 46 14 14 34 10A 54 15B 74 41A 15 15F 35 35F 55 18B 75 43 16 16F 36 36 56 18C 76 11B 17 17F 37 37 57 19A 77 15C 18 18F 38 41F 58 19B 78 17A 19 19F 39 33C 59 19C 79 28A 20 20 40 33A 60 24B 80 42 Physicians’ Desk Reference (49 th Edition, 1995, page 1610), Laboratory Diagnosis of Pneumococcus Infections by E. Lund (Bull. Wld . Hlth . Org. 23:5-13, 1960), H. Russell, et al (J. Clin. Microbiol. 8:355-359, 1978), J. Henrichsen (J. Clin. Microbiol. 33:2759-2762, 1995), and I. Park (J. Clin. Microbiol. 45:1225-1233 , 2007)

20. Gram’s stained smear of sputum

21. Pathogenesis CAPSULE Surface capsular poysaccharide Basis for serotyping (90 diff serotypes) 6, 14, 18, 19, 23  60-80% of infections Major antiphagocytic surface element ADHERENCE Exports proteins which noncovalently link to human cell carbohydrate or rPAF

22. Pneumococcal adherence

23. Pathogenesis INVASION Invade cells poorly, up to 10 x less than other streptococci Promoted by cell wall, adhesins, & cytotoxin pneumolysin Inhibited by capsular polysaccharide CHOLINE – cell wall component; ligand for rPAF; “mimicry”; activation of host cells to upregulate rPAF* Endocytosis  Transcytosis *1 study showed adenovirus-infected cells in vitro showed increased binding & uptake of S. pneumoniae

24. Pathogenesis REGULATORY MECHANISMS Use many regulatory mechanisms for surface changes in response to new environment Secrete pneumolysin – pore formation; promotes intraalveolar replication, penetration & dissemination of pneumococci

25. Pathogenesis HOST INFLAMMATORY RESPONSE Cell wall – important virulence determinant (induce strong IL-1 response exceeding that of endotoxin by at least 10 fold) Teichoic acid & Lipoteichoic acid of cell wall contribute strongly to host defense response Activate complement (alternative pathway) Bind CRP Activate procoagulant activity on endothelial surface Induce production of cytokines, nitric oxide, and PAF Initiate the influx of neutrophils

26. Pneumococcal disease MAJOR & MINOR CLINICAL SYNDROMES: Pneumonia Bacteremia Meningitis Otitis media Sinusitis

27. Pneumococcal disease PNEUMONIA Among adults, most common Account for 36% of adult CAP & 50% HAP Abrupt onset, fever, chills, pleuritic chest pain, productive cough, SOB, tachypnea, hypoxia, tachycardia, malaise Common bacterial complication of influenza & measles CFR is 5-7%, higher in elderly

28. Pneumococcal disease 2. BACTEREMIA Occurs in 25-30% with pneumococcal pneumonia CFR ~20; up to 60% in elderly Rates higher in extremes of age Asplenia – fulminant course 3. MENINGITIS 13-19% of all bacterial meningitis. CFR ~30%, up to 80% among elderly Neurologic sequelae common among survivors 4. OTITIS MEDIA 28-55% of middle ear aspirates

29. Childhood pneumonia is most commonly caused by serotypes 6, 14, 18,19,23. Pneumonia in adults is caused by serotypes 1,3,4,7,8 & 12. Growing resistance of S. pneumoniae to commonly used antibiotics ( penicillins, cephalosporins, trimethoprim–sulfamethoxazole, macrolides and fluoroquinolones) underlines the urgent need for vaccines to be used to control pneumococcal disease

30. Pneumococcal vaccines

31. Policy decisions for use of pneumococcal vaccines The policy decisions for use of pneumococcal vaccines should be based on following key factors: (i) incidence of the pneumococcal disease in the country (ii) distribution of its serotypes in the country and (iii) the anti-microbial resistance pattern of the invasive isolates in that country

32. Pneumococcal vaccine There are two types of pneumococcal vaccine: ● Pneumococcal polysaccharide vaccine (PPV) contains purified capsular polysaccharide from each of 23 capsular types* of pneumococcus ● Pneumococcal conjugate vaccine (PCV) contains polysaccharide from thirteen common capsular types. These are conjugated to protein (CRM197) using similar manufacturing technology to that for Haemophilus influenzae type b (Hib) and meningococcal C conjugate vaccines.

33. History of pneumococcal vaccine PNEUMOCOCCUS - First identified in 1881 by Pasteur & Sternberg (10). The first preventive strategy was introduced by Sir Almroth E. Wright in 1911, who suggested that inoculation of killed, whole pneumococci might induce a protective effect against pneumococcal infections (11). In 1926, Felton and Bailey (12) for the first time isolated pneumococcal capsular polysaccharides which directly led to the first capsular PS vaccine. Its effectiveness was proved by successfully aborting an outbreak of pneumonia at a state hospital in Worcester, MA in 1931 (13). (10)Austrian R. The pneumococcus at the millennium: not down, not out. J Infect Dis 1999;179(Suppl 2):S338–41. (11)Watson DA, Musher DM. A brief history of the pneumococcus in biomedical research. Semin Respir Infect 1999;14(3):198–208. (12)Felton L, Baily G. Biologic significance of the soluble specific substance of pneumococci. J Infect Dis 1926;38:131–44. (13) Smillie W, Warnock G, White H. A study of a type I pneumococcus epidemicat the state hospital in Worcester, MA. Am J Public Health 1938;28:293–302.

34. History of pneumococcal vaccine Emergence of multidrug-resistant (resistant to penicillin & cephalosporins) clones with serotypes 6B, 9V, 14, 19A, 19F and 23F (14) have lead to renewed interest in vaccine strategies, resulting in the production of a 14-valent pneumococcal PS vaccine by Robert Austrian and coworkers in 1977 (15). This vaccine was expanded in 1983 to a 23-valent vaccine and had a theoretical coverage of ≥80% of the pneumococci causing infections in adults. This vaccine was less immunogenic in small children and immunocompromised patients (16). (14) Kroon FP, van Dissel JT, de Jong JC, Zwinderman K, van Furth R. Antibody response after influenza vaccination in HIV-infected individuals: a consecutive 3-year study. Vaccine 2000;18(26): 3040–9. (15)Austrian R, Gold J. Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964;60:759–76. (16)Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997, 46(RR-8), 1–24.

35. Pneumococcal vaccines 1977 - 14-valent polysaccharide vaccine was first licensed 1983 - 23-valent polysaccharide vaccine licensed (PPSV23) 2000 - 7-valent polysaccharide conjugate vaccine was first licensed (PCV7) 2002 - Pneumococcal conjugate vaccine became available and was recommended for immunisation of at-risk groups under the age of two years 2003 -Pneumococcal polysaccharide immunisation was recommended for all people aged 65 and over 2004 -Conjugate vaccine policy was extended to at-risk children under five years of age 2006 - Pneumococcal conjugate vaccine containing polysaccharide from seven common capsular types was added to the routine childhood immunisation programme (PCV7) 2010 -Pneumococcal conjugate vaccine containing polysaccharide from thirteen common capsular types (including the seven capsular types in the earlier vaccine) replaced the seven valent conjugate vaccine (PCV13).

36. Pneumococcal polysaccharide vaccine (23-valent) Pneumovax Dosing:0.5mL IM/SC Pneumococcal conjugate vaccine (7-valent) Prevnar Dosing: 0.5mL IM

37. Polysaccharide vaccine The polysaccharide vaccine consists of purified polysaccharides from 23 serotypes (1, 2, 3, 4, 5, 6b, 7F, 8,9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F and 33F) (17). 23 valent pneumococcal polysaccharide vaccine (PPV) was licensed in 1983, replacing the 14-valent vaccine introduced in 1977. Vaccine serotypes account for 86% of bacteremia, 83% of meningitis & 65% of AOM among <6 yrs Pneumovax 23 produced by Merck Research Laboratories, USA. Immunity is induced primarily through stimulation of B-cells which release IgM (17) without the assistance of T cells (18). (17)Pletz MW, Maus U, Krug N, Welte T, Lode H (September 2008). "Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species" . Int. J. Antimicrob. Agents 32 (3): 199–206. (18)Stein KE (June 1992). "Thymus-independent and thymus-dependent responses to polysaccharide antigens" . J. Infect. Dis. 165 (Suppl 1): S49–52.

38. Recommendations to receive pneumococcal polysaccharide vaccine (PPSV23) PPSV23 is recommended for anyone who meets any of the criteria below: Age 65 years and older Age 2 through 64 years with any of the following conditions cigarette smokers age 19 years and older alcoholism chronic liver disease, cirrhosis chronic cardiovascular disease, excluding hypertension (e.g., congestive heart failure, cardiomyopathies) chronic pulmonary disease (including COPD and emphysema, and for adults age 19 years and older, asthma) diabetes mellitus candidate for or recipient of cochlear implant cerebrospinal fluid (CSF) leak functional or anatomic asplenia (e.g., sickle cell disease, splenectomy) immunocompromising conditions (e.g., HIV infection, leukemia, congenital immunodeficiency, Hodgkin’s disease, lymphoma, multiple myeloma, generalized malignancy, immunosuppressive therapy) solid organ transplantation; for bone marrow transplantation, chronic renal failure or nephrotic syndrome

39. Recommendations of PPSV by ACIP Advisory Committee on Immunization Practices (ACIP) recommends PPS vaccine in (a) persons aged ≥65 years, (b) immunocompetent children ≥5 years who are at increased risk for illness and death associated with pneumococcal disease because of chronic illness, (c) persons aged ≥5 years with functional or anatomic asplenia, (d) immunocompromised patients aged ≥5 years who are at high risk for infection. They also recommend (e) vaccination for people living in high-risk environments with emphasis on American Indians and Alaska natives (19,20). (19)Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1997, 46(RR-8), 1–24. (20)Preventing pneumococcal disease among infants and young children.Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2000, 49(RR-9), 1–35.

40. Pneumococcal polysaccharide vaccine (PPSV 23) Not more than two life time doses are recommended, as repeated doses may cause immunologic Hypo-responsiveness. The IAP COI recommends offering both PCV and PPSV 23 to all high-risk children. The PCV vaccines provide robust immune response and immune memory while PPV 23 provides expanded serotype coverage.

41. Pneumococcal polysaccharide vaccine (PPSV 23) 23-valent adult vaccine covered more than 80% of the serotypes identified in Indian adults. Protection offered in different age groups was 77% in 22–50 years,87% in 51–64 years & 86% in > 64 years age group.

42. Problems with polysaccharide vaccine in children Not effective in children less than 2 years ( because of less mature immune system) No effect on nasal carriage No herd effect Absence of immunologic memory Antibody level to several serotypes decline to pre-vaccination values within 3-7 years corresponding to a decline of clinical protection ( Immunization is not lifelong, so individuals must be re-vaccinated every 5–6 years (21). (21)Pletz MW, Maus U, Krug N, Welte T, Lode H (September 2008). "Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species" . Int. J. Antimicrob. Agents 32 (3): 199–206.

43. Limitations of PPSV23 vaccine Antibody titers and efficacy appear to wane after 5 years (Shapiro, et al, NEJM, 1991) Effectiveness is very low in immunocompromised patients PPSV23 induces hyporesponsiveness to either another dose of PPSV23(Torling, et al Vaccine, 2003) or to a dose of conjugate (deRoux, et al IDSA, 2005). Re-vaccinations cause more severe adverse events (Jackson, et al JAMA, 1999, Vaccine, 2005) Therefore, PPSV23 is generally given only once, which provides only a narrow window of protection during a prolonged period of risk (ACIP recommendation: MMWR, 1997)

44. IMMUNOGENICITY & VACCINE EFFICACY OF PPSV >80% healthy adults develop Abs vs. vaccine-related serotypes Within 2-3 weeks after vaccination Poor Ab response in elderly, with chronic illness & <2yrs. Elevated Ab levels persist for at least 5 yrs in healthy adults & decline more quickly in persons with chronic disease. Antibody levels are likely to decline rapidly in individuals with no spleen,splenic dysfunction or chronic renal disease (Giebink et al., 1981; Rytel et al., 1986) and therefore re-immunisation with 23-valent PPV is recommended every five years in these groups. Revaccination is well tolerated (Jackson et al., 1999). 60-70% effective in preventing invasive disease. No protection against pneumococcal pneumonia.

45. Pneumococcal conjugate vaccine Conjugated vaccine: consists of capsular polysaccharides covalently bound to a nontoxic mutant of diphtheria toxin and the protein CRM197 or protein D of noncapsulated Hib or DT and TT and finally Men OMP which is highly immunogenic but non-toxic (23). This combination provokes a significantly more robust immune response by recruiting CRM197-specific type 2 helper T cells, which allow for immunoglobulin type switching (to produce non-IgM immunoglobulin) and production of memory B cells(23). (23) Pletz MW, Maus U, Krug N, Welte T, Lode H (September 2008). "Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species" . Int. J. Antimicrob. Agents 32 (3): 199–206.

46. Contd Conjugate vaccine results in mucosal immunity and eventual establishment of lifelong immunity after several exposures(23). Conjugate vaccine does not induce hypo responsiveness to subsequent PPSV23 or a 2 nd dose of conjugate

47. Pneumococcal conjugate vaccine (PCV 7, Prevenar® ) 7-valent pneumococcal conjugate vaccine Prevnar (Wyeth, USA) or Prevenar (Wyeth, Europe), containing polysaccharides of serotype 4, 6B, 9V, 14, 18C, 19F and 23F. Approved by the Food and Drug Administration (USA), and the Committee on Proprietary Medicinal Products (Europe) for the prevention of invasive diseases in children. These vaccines have a potential coverage of over 85% of the pneumococcal isolates for the USA, 60–70% for Europe and around 55% for Asia.

48. PCV7 PCV7 was licensed in the USA in 2000, in Europe in 2001 & India August 2006. Remarkable results in USA & UK. A limited increase in IPD caused by non-PCV7 serotypes, particularly 19A serotype has been registered to date However it covered only 55% of the serotypes prevalent in India. Dose is 0.5 ml IM.

49. PCV7 PCV7 was initially categorized in cat-3 meaning to be given after one to one discussion with parents in healthy children aged less than 2 years. It induces a T-cell dependent immune response characterized by immune memory as well as a booster antibody response on subsequent challenge with the pneumococcal polysaccharides included in the vaccine

50. Pneumococcal conjugate vaccine ( Prevenar13® PCV13) In February 24 th, 2010, a new 13-valent pneumococcal conjugate vaccine (PCV13) was licensed by the Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices (ACIP) for prevention of invasive pneumococcal disease in children. PCV13 contains the serotypes found in PCV7, plus an additional six serotypes: 1, 3, 5, 6A, 7F, and 19A individually conjugated to a nontoxic diphtheria cross-reactive material (CRM) carrier protein (CRM197) (25). PCV13 succeeds the 7-valent vaccine (PCV7) used in the routine childhood immunization schedule since 2000. Presently Indian Market has two options from Wyeth-Pfizer-- PCV-7, PCV-13 (24) MMWR 2010;(RR- 59):253-61. (25) Prevnar 13 (pneumococcal 13-valent conjugate vaccine [diphtheria CRM197 protein]). Philadelphia, PA: Wyeth Pharmaceuticals; 2011.

51. Pneumococcal Conjugate Vaccine Recommendations All children 2-23 months Children >2-59months with cochlear implants Children 24-59months with Sickle Cell disease, Asplenia, HIV, immunocompromising/chronic illnesses (26) CDC. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR 2010;59:258–61.

52. Prevenar®PCV7 as per ACIP Infants 2-6 months: 4 doses at 2, 4, 6 & 12-15mos. Previously Unvaccinated: 7-11months – 3 doses, 2 doses 4 wks apart then 3 rd dose at 12-15mos. 12-23 months – 2 doses, 2 months apart 24-59 months – HEALTHY : 1 dose; CHRONIC/IMMUNOCOMPROMISED: 2 doses, 2 months apart Previously Vaccinated: 7-11 months – (received 1-2 doses) 2 doses at 7-11months then 12-15 months, at least 2 months apart 12-23 months – 1 dose, 2 months after last dose 24-59 months – HEALTHY: 1 dose; CHRONIC/IMMUNOCOMPROMISED: 2 doses, 2 mos. apart

53. PCV13 Dose : 0.5 ml IM Available as latex free, single -dose, prefilled syringes. Side effects: mainly local According to most recent estimates, PCV-13 covers around 73% of the prevalent serotypes in India. Present IAPCOI recommendation do not have similar categorization for this as there was for PCV – 7. Cost benefit ratio can be discussed with parents and let them take decision on named child basis.

54. Prevenar®PCV13 as per ACIP Un-vaccinated infants and children : PCV13 is recommended for all children aged 2 through 59 months  "3 plus 1" dosing schedule, with doses at 2, 4, and 6 months and a booster dose at 12 to 15 months.  Children incompletely vaccinated with PCV7 : Children aged 24 to 59 months who received 1 or more doses of PCV7 should complete their vaccine series with PCV13.  Children completely vaccinated with PCV7 : Children aged 14 to 59 months who have received all 4 doses of PCV7 should receive a single supplemental dose of PCV13.  {Age may be extended to 71 months for high-risk children (e.g., sickle cell disease, HIV infection or other immunocompromising conditions, cochlear implant, or cerebrospinal fluid leaks}.

55. Prevenar®PCV13 as per ACIP High-risk children aged 6 years and older: This permissive recommendation for an off-label use states: "[v] accination with a single dose of PCV13 may be appropriate for children 6 through 18 years of age who are at increased risk for pneumococcal disease".  Healthy older children should not receive the vaccine. Additional vaccine for children with underlying medical conditions : Children aged 2 years and older who are at increased risk for invasive pneumococcal disease should receive a 23-valent pneumococcal polysaccharide vaccine after vaccination with PCV13.

56. Difference between PCV13 and PPV23 PCV13 PPV23 Valency 13 valent 23 valent Target population Healthy Children At risk population Minimum age of vaccination > 6 weeks > 2 years (High Risk) Immune response ---- at 6 weeks of age Strong ---- at 2 years of age, Absent to weak Moderate to Strong Duration of immunity Long term Short term Vaccine efficacy- children < 2 years Yes None Important reductions in nasopharyngeal carriage Yes No effect Indirect protection Reported Unlikely Important reductions in the prevalence of antibiotic resistant isolates Reported Not established (21) PCV for childhood immunization – WHO position paper Weekly Epidemiological Record. 2007, 12 (82): 93–104. Prevenar13 Prescribing Information Wyeth Limited* 2010 (*A subsidiary of Pfizer Inc.). (22)23-valent pneumococcal polysaccharide vaccine - WHO position paper. WHO Weekly Epidemiological Record . 2008; 83(42): 373–384

57. Storage & Administration Storage Vaccines should be stored in the original packaging at +2°C to +8°C and protected from light. Both PCV and PPV are supplied as single doses of 0.5ml. Administration Vaccines are routinely given into the upper arm in children and adults or the anterolateral thigh in infants under one year of age. This is to reduce the risk of localised reactions, which are more common when vaccines are given subcutaneously (27). (27) Mark et al., 1999; Diggle and Deeks , 2000; Zuckerman, 2000).

58. Pneumococcal Vaccines Adverse Reactions Local reactions polysaccharide 30%-50% conjugate 10%-20% Fever, myalgia Polysaccharide <1% conjugate 15%-24% Severe adverse rare reactions

59. Serotypes included in the three pneumococcal vaccine formulations* available in the United States, 2010 Pneumococcal serotype Vaccine PPSV23 PCV13 PCV7 4 X X X 6B X X X 9V X X X 14 X X X 18C X X X 19F X X X 23F X X X 1 X X 3 X X 5 X X 6A X 7F X X 19A X X 2 X 8 X 9N X 10A X 11A X 12F X 15B X 17F X 20 X 22F X 33F X * The 13-valent pneumococcal conjugate vaccine (PCV13) includes the seven serotypes in the 7-valent vaccine (PCV7) and six additional serotypes. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) includes 12 of the serotypes included in PCV13 (it does not include serotype 6A) and 11 additional serotypes.

60. Immunogenic proteins Proteins including pneumolysin, pneumococcal surface protein A, pneumococcal surface adhesin A, choline binding protein A (CbpA), neuraminidase, and autolysin have been suggested as potential candidates. Proteins PspA, PsaA and pneumolysin are currently the leading vaccine candidates (28,29). ( 28) Briles DE, Hollingshead SK, Nabors GS, Paton JC, Brooks-Walter A. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumoniae. Vaccine 2000;19(Suppl 1):S87–95. (29) Ogunniyi , A.D. et al. (2007) Development of a vaccine against invasive pneumococcal disease based on combinations of virulence proteins of Streptococcus pneumoniae. Infect. Immun. 75, 350–357

61. Immunogenic proteins An ideal mucosal vaccine would include several pneumococcal proteins such as pneumolysin, PspA, PsaA or PspC. Thorough investigation of these proteins still is necessary before large-scale immunization studies in humans will become within reach. Thorough investigation of the efficacy and safety of these vaccine candidates and monitoring of side effects have to be performed before human use is optimized.

62. Antigen or vaccine Route Immunogenicity Protection against: PspA Intranasal Mucosal and systemic Colonisation, pneumonia, sepsis PspA/attenuated oral Mucosal and systemic Pneumonia, bacteraemia Salmonella PsaA oral Mucosal and systemic Pneumonia, bacteraemia PsaA/lactic acid bacteria Intranasal Mucosal and systemic Colonisation, Pneumonia, bacteraemia PotD Intranasal Mucosal and systemic Colonisation PsaA and PspA Intranasal Mucosal and systemic Pneumonia, bacteraemia PspA and PspC Intranasal Mucosal and systemic Colonisation, pneumonia PCV Intranasal Mucosal and systemic Colonisation, otitis media Mouse models of mucosal immunisation with pneumococcal protein antigens Abbreviations: PspA, pneumococcal surface protein A; PsaA, ‘pneumococcal surface adhesion A’ protein; PotD, PspC, pneumococcal surface protein C; PCV, pneumococcal conjugate vaccine

63. Recommendation from the Strategic Advisory Group of Experts (SAGE) on Immunization “…… WHO considers that is should be a priority to include pneumococcal conjugate vaccine in national immunization programmes, …… Countries with mortality among children aged <5 years of >50 deaths/1000 births or with more than 50 000 children’s deaths annually should make the introduction of PCV-13 a high priority for their immunization programmes. (30)WHO Weekly Epidemiological Record, 23 Mar 2007 Pneumococcal Conjugate Vaccine for childhood immunization – WHO position paper. 23 March 2011, 82 nd year. No. 12, 2011, 82, 93-104.

64. Thank you