Global Evolution of the Pneumococcus and the Impact of Vaccination Keith P. Klugman Department of Global Health, Rollins School of Public Health and Division of Infectious Diseases, School of Medicine Emory University, Atlanta, USA
GMS - arlingtoncemetery.net; LP - en.wikipedia.org; CF - www.sammlungen.hu-berlin.de/.../content.128.jpg
The Pneumococcus 1880 - George M. Sternberg (1838-1915) isolates S. pneumoniae in New Orleans. Malkin HM. Sternberg GM. A fatal form of septicaemia in the rabbit, produced by the subcutaneous injection of human saliva. Natl Board Health Bull 1881;2:781-3. 1881 - Louis J. Pasteur (1822-1895) isolates S. pneumoniae in Paris. Pasteur L. Note sur la maladie nouvelle provoqué par la salive d'un enfant mort de la rage. Bull Acad Méd (Paris) 1881;10:94-103. 1882 - Carl Friedländer (1847-1887) recognizes bacterial causes of pneumonia in Berlin, including Streptococcus pneumoniae. Friedländer C. Über die Schizomyceten bei der acuten fibrösen Pneumonie. Virchow's Arch pathol Anat u Physiol 1882;87(Feb 4):319-24. Nomenclature: Diplococcus pneumoniae (1926) Streptococcus pneumoniae (1974) Pneumococcus
Earliest Pneumococcal Vaccine Trial 1911 - Almroth E. Wright (1861-1947) tested a whole-cell heat-killed pneumococcal vaccine (not serotype-specific) among 50,000 South African gold miners. Wright AE, Parry Morgan W, Colebrook L, Dodgson RW. Observations on prophylactic inoculation against pneumococcus infections, and on the results which have been achieved by it. Lancet 1914;i:1-10,87-95.
Development of Serotype Specific Vaccines 1914 F. Spencer Lister (1876-1939) uses typing system in South Africa to develop the first serotype-specific pneumococcal vaccine and conducts clinical trials of efficacy. Lister FS. An experimental study of prophylactic inoculation against pneumococcal infection in the rabbit and in man. Publ South Afr Institute Med Res 1916;8:231-87.
Discovery of Capsular Material as the Basis of Serotypes and the Principle of Conjugates Oswald T. Avery (1877-1955) and Michael Heidelberger (1888-1991) identify capsular antigens which are carbohydrates as the basis of serotypes of pneumococcal bacteria at Rockefeller Institute, NYC. Heidelberger M, Avery OT. The soluble specific substances of pneumococcus. J Exp Med 1923;38:73-9. 1929 - Avery couples polysaccharide to a protein in 1929 to improve immunogenicity. Avery OT, Goebel WF. Chemical-immunological studies on conjugated carbohydrate-proteins. II. Immunological specificity of synthetic sugar-protein antigens. J Exp Med 1929;50:533-42.
Robert Austrian Organizes Multivalent Vaccine Trials in Gold Miners in South Africa 1960s - Robert Austrian (1916-2007) conducts trials of 6 and 12-valent pneumococcal vaccines in South Africa. Austrian R, Douglas RM, Schiffman G, Coetzee AM, Koornhof HJ, Hayden- Smith S, Reid RD. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians. 1976;89:184-94. Austrian R. Of gold and pneumococci: A history of pneumococcal vaccines in South Africa. Trans Am Clin Climatol Assoc 1977;89:141-61.
Pneumococcal Conjugate Vaccine 1980 - John B. Robbins and Rachel Schneerson develop polysaccharide-protein conjugation technology, using Haemophilus influenzae type b as model, at US FDA, NIH. Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, characterization and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J Exp Med 1980;152:361-76. Schneerson R, Robbins JB et al. Serum antibody responses of juvenile and infant rhesus monkeys injected with Haemophilus influenzae type b and pneumococcus type 6A capsular polysaccharideprotein conjugates. Infect Immun 1984; 45: 582-91.
Cases Per 100,000 Population Deaths per 100,000 Population 45 40 35 30 25 20 15 10 5 0 S. pneumoniae ABCs US Data: 2009 Cases Deaths < 1 1 2-4 5-17 18-34 35-49 50-64 65 Age (years) CDC ABC Surveillance report. http://www.cdc.gov/abcs/reports-findings/survreports/spneu09.html. Accessed Nov 2011. 7 6 5 4 3 2 1 0
Efficacy of PCVs Against Pneumococcal Disease Disease Vaccine PCV Efficacy, % (95% CI), PP VT IPD Black S, et al. Pediatr Infect Dis J. 2000;19:187-195. O Brien KL, et al. Lancet. 2003;362:355-361. Klugman KP, et al. N Engl J Med. 2003;349:1341-1348. Cutts FT, et al. Lancet. 2005;365:1139-1146. Palmu AA, et al. Lancet. 2013 ;381:214-22 Palmu AA, et al. Lancet. 2013 ;381:214-22 Pneumonia (CXR+) (1 st episode) Hansen J, et al. Pediatr Infect Dis J. 2006;25:779-781. Klugman KP, et al. N Engl J Med. 2003;349:1341-1348. Cutts FT, et al. Lancet. 2005;365:1139-1146. Lucero MG, et al. Pediatr Infect Dis J. 2009;28:455-462. Tregnaghi M, et al Proc XIV SLIPE, Punta Cana, May 2011 PCV7 3 + 1 PCV7 3 + 1 PCV9 a 3 + 0 PCV9 a 3 + 0 PCV10 c 3 + 1 PCV10 c 2 + 1 PCV7 PCV9 a PCV9 a PCV11 b PCV10 c 97% (83-100) 77% (-9-95) 83% (39-97) (HIV-) 71% (76-86) 100% (83 100) 92% (58-100) 30% (11-46) 25% (4-40) 37% (27-45) 23% (-1-41) 26% (8-40) VT AOM (vaccine serotype episodes) Eskola J, et al. N Engl J Med. 2001;344:403-409. PCV7 57% (44-67) Prymula R, et al. Lancet. 2006;367:740-748. PCV11 c 53% (35-66) Kilpi T, et al. Clin Infect Dis. 2003;37:1155-1164. PCV7 d 56% (44-66) AOM (tympanostomy tube placement) Palmu AA, et al. Pediatr Infect Dis J. 2004;23:732-738. PCV7 39% (4-61) VT = Vaccine type; PP = Per-protocol analysis; CI = confidence interval. a PCV9, investigational CRM 197 -conjugated pneumococcal conjugate vaccine b PCV11, investigational tetanus-diphtheria toxoid-conjugated pneumococcal conjugate vaccine C 11 Pn-PD, investigational and PCV10 licensed nontypeable Haemophilus influenzae protein D-conjugated pneumococcal conjugate vaccine d PncOMPC, investigational pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine 10
Vaccine Impact on Colonization is More Important as VE Against Disease Reduces Goldblatt et al, Vaccine, 6 Aug 2013 epub ahead of print 11
PCV9 Reduced Carriage of Vaccine Types By 50% After Primary Immunization of Infants in 1 st Year of Life Carriage of vaccine serotypes Carriage of nonvaccine serotypes PCV9 n=242 (n [%]) Control n=239 (n [%]) P-value 43 (18) 86 (36) 6.5 x 10 6 87 (36) 59 (25) 0.0007 Overall carriage 130 (54) 145 (61) 0.123 Vaccination at 6, 10, and 14 weeks; carriage measured at 9 months of age. Mbelle et al. JID 1999; 180:1171 6 12
Reduction in PCV7 Types Carried by Children in MA, USA Post 2000 Wroe at el, Pediatr Infect Dis J. 2012 Mar;31(3):249-54
Cases/100,000 population Direct Effect of Vaccination: Invasive Pneumococcal Disease Among Children < 5 Years, 1998/99 2007 90 PCV7 introduced 80 70 60 50 40 30 20 10 Serotype group PCV7 type Non-PCV7 type 19A *100% reduction in PCV7 serotypes, 2007 vs baseline 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year Pilishvili T, et al. J Infect Dis. 2010;201:32-41. *
Cases/100,000 population Invasive Pneumococcal Disease Among Adults 65 Years, 1998/99 2007 40 PCV7 introduced 35 30 25 20 15 10 *92% reduction in PCV7 serotypes, 2007 vs baseline Serotype group PCV7 type Non-PCV7 type 19A 5 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year Pilishvili T, et al. J Infect Dis. 2010;201:32-41. *
Figure 2. Cumulative Proportions of Children With New Acquisition of Serotype 19A After Finishing Primary Series of 7-Valent Pneumococcal Conjugate Vaccine vs Unvaccinated Children van Gils, E. J. M. et al. JAMA 2010;304:1099-1106 Copyright restrictions may apply.
Capsular Size And Complexity Predicts Survival And Carriage Prevalence Weinberger et al, PLoS Pathogens, 2009,5,e1000476 17
Serotype 19A Moore et al, JID, 2008, 197(7):1016 1027 18
Serotype 19A Moore et al, JID, 2008, 197(7):1016 1027 19
Emergence of Antibiotic Resistant Serotype 15A - USA Gertz R E et al. J Infect Dis. 2010;201:770-775 20
Diversity of MA Carriage Serotypes Increased in 2004 1998/9 2001 2004 2007 Hanage et al, Epidemics 2010, 2, 80-84 21
Evolution of PMEN 1 Using WGS Crowther et al, Science, 2011, 331, 430-4 22
Maximum likelihood phylogeny of 626 carried strains in MA Multiple examples of capsular switches but selection of preexisting lineages SC = sequence cluster Croucher et al Nature Genetics 2013, June, epub ahead of print
PCV Impact on Selection of Serotypes Within Clusters Croucher et al Nature Genetics 2013, June, epub ahead of print
Evolution Within Cluster 9 Heatmap of Recombination Red = 2001 Orange = 2004 Blue = 2007 Croucher et al Nature Genetics 2013, June, epub ahead of print
Clusters of Authologous Genes Little significant change in population structure beside capsular genes Croucher et al Nature Genetics 2013, June, epub ahead of print
Changing Spectrum of IPD in the Post PCV7 Era in US 1998-1999 (n=5,699) 2009 (n=3,338) Median age (range), years 56 (18-101) 58 (18-104) Race White 62% 70% Black 35% 24% Other 2% 5% Gender Male 54% 51% Case Fatality Ratio 13% 11% Meningitis 5% 5% Bacteremia without focus 25% 15% Bacteremic Pneumonia 68% 75% ACIP Indication for PPV23 p-value <0.05 Excludes cases with unknown outcome; 60 in 1998-1999 and 25 in 2009. Includes all ACIP indications except age >65 years. 51% 61% Muhammad et al, Clin Infect Dis. 2013;56:e59-67.
Pneumococcal Vaccine Indications in Adults with IPD in USA, 2009 Any PPV indication 61% Diabetes 20% (10% in 1998/9) Chronic Lung Disease 19% Cardiac Disease 18% Cancer 13% Alcoholism 10% HIV AIDS 8% Muhammad et al, Clin Infect Dis. 2013;56:e59-67.
Conclusions PCV has induced serotype specific immunity in children which has reduced disease but also transmission of vaccine serotypes to adults Reduced transmission has altered the serotype distribution in all ages Replacement strains are less invasive and cause disease more often in patients with underlying comorbidities Population structure of lineages remains similar but selection of capsular switched strains is evident The gene content of the population has changed little except for specific capsular genes 29