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Prof Rick Malley @ Meningitis & Septicaemia in Children & Adults 2017

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What next for prevention of pneumococcal disease in light of serotype replacement? Is there a pathway to licensure for novel pneumococcal vaccines?
https://www.meningitis.org/mrf-conference-2017

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Prof Rick Malley @ Meningitis & Septicaemia in Children & Adults 2017

  1. 1. What next for prevention of pneumococcal disease in light of serotype replacement? Rick Malley, MD Boston Children’s Hospital Harvard Medical School Meningitis and Septicaemia in Children and Adults British Museum, London November 14-15 2017 I’m fed up with this guy – let’s become pathogenic
  2. 2. PotentialConflictofInterestDisclosure I disclose the following financial relationships with commercial entities that produce health care-related products or services relevant to the content I am planning, developing, or presenting: Company Relationship Content Area Merck Scientific Advisor Vaccines I also disclose membership on the Scientific Advisory Board of Arsanis Biosciences, and Advanced InhalationTherapies I am a Scientific Founder, consultant and member of the Board of Directors of Affinivax, Inc. Funding from: NIH, PATH, Bill and Melinda Gates Foundation, TRP andTIDO (Boston Children’s Hospital)
  3. 3. Importance of bacterial polysaccharides as vaccine targets Antibodies to polysaccharides are the basis of protection of many of our most successful bacterial vaccines
  4. 4. 4 Surface Polysaccharides are key virulence factors of pneumococcus • The surface Ps defines the serotype •90+ serotypes of pneumococcus • Protects organism from killing by complement or phagocytes • Antibody to Ps is protective: drives antigenic diversity Bar = 100 nm
  5. 5. Polysaccharide vaccines induce a T cell-independent response Polysaccharide- specific antibody * * B cell v Directly stimulate B cells v No memory, no boosting v Do not induce protective Ab response in children <2 years v Repeat doses in adults may induce tolerance
  6. 6. Conjugate vaccines induce a CD4+ T-cell-dependent response B * * CD4 Protein Polysaccharide- Specific Antibody Memory B Cells [Ab] Conjugate Ps 2mos 12mos
  7. 7. CD4+ Th17 responses help control mucosal colonization by encapsulated organisms, including pneumococcus
  8. 8. CD4+ Th17 responses help control mucosal colonization by encapsulated organisms, including pneumococcus
  9. 9. Manufacturing Process for Prevnar-7™ Large Scale Fermentation and Purification of Saccharide QC 7-V Conjugates Are Mixed to Formulate Vaccine QC Each Type of Saccharide is Separately Activated and Conjugated to CRM197 Protein Carrier QC 4 6B 9V 14 18C 19F 23F
  10. 10. QC Testing of pneumococcal conjugate vaccine Vaccines are not “well-defined biologicals” • Release testing does not fully guarantee potency and consistency of the product • Therefore “the Process is the Product” • Must assure and verify that all steps in the process are precisely controlled
  11. 11. QC Testing of pneumococcal conjugate vaccine Carrier Protein Bulk Conjugate Final Vaccine Polysaccharide Activated Saccharide1. Identity 2. Polysaccharide composition 3. Moisture content 4. Protein impurity 5. Nucleic acid impurity 6. Pyrogen content 7. Molecular size distribution 1. Extent of activation 2. Molecular size distribution 1. Identity 2. Purity 3. Toxicity 4. Extent of derivatisation (if appropriate) NR 1. Identity 2. Residual reagents 3. Saccharide:protein ratio & conjugation markers 4. Capping markers 5. Saccharide content NR 6. Conjugated v. free saccharide 7. Protein content 8. Molecular size distribution 9. Sterility 10. Specific toxicity of carrier 11. Endotoxin content 1. Identity 2. Sterility 3. Saccharide content (of each) 4. Residual moisture 5. Endotoxin content 6. Adjuvant content (if used) 7. Preservative content (if used) 8. General safety test 9. pH 10. Inspection Formulation 1. Extent of activation 2. Molecular size distribution Courtesy of Neil Ravenscroft ~500 QC tests
  12. 12. February 17th, 2000: US FDA approves the licensure of a seven-valent pneumococcal vaccine (PCV7,Wyeth/Pfizer) Since then: • PCV10 in Europe in 2009 • PCV13 in US in 2010 Impressive success of conjugate vaccines in US, with near-total eradication of the 7, now 13, serotypes included in the vaccine •Remarkable impact on herd protection, most notable in elderly •Efficacy against pneumonia
  13. 13. Some issues with current vaccine conjugates + serotype 3 story + 19A/F story
  14. 14. But this is not the case…
  15. 15. Other issues with current vaccine conjugates: Price In US: price of Pneumococcal conjugate = $160 per dose (4 doses per child) Critical role of GAVI in reducing price and ensuring availability of vaccine to poorest countries (Pfizer pricing to GAVI: $3.10 per dose, 3 doses per child) 40% of GAVI’s budget is dedicated to providing pneumococcal conjugate vaccine to the developing world However, this effort is entirely dependent on governments and NGOs, is still relatively expensive, and does not cover non GAVI- eligible countries GAVI countries 2016
  16. 16. Given success and nature of conjugates, following premises have been adopted by most: 1. A vaccine that does not confer broad protection against invasive disease is a nonstarter 2. A vaccine that does not confer broad protection against colonization is also a nonstarter Assumptionforfuturepneumococcalvaccine development
  17. 17. Option 1: Expanded (and possibly lower cost) polysaccharide-protein conjugates Advantages: Technology known Correlates of protection known Path to licensure clear Disadvantages: Limitation on total number of ST that can be included Complexity and cost of manufacture Possible interference Serotype replacement
  18. 18. OPTION 2: Killed whole cell pneumococcal vaccine Courtesy of David Briles First pneumococcal vaccine: Killed whole cells (ca. 1911) Revisited in 1996 by Porter Anderson (+ student) Support from MRF
  19. 19. 1. Vaccine protects against colonization and invasive disease by multiple serotypes Preclinical findings
  20. 20. 1. Vaccine protects against colonization and invasive disease by multiple serotypes 2. Various routes of immunization effective • Intranasal • Oral • Sublingual • Transcutaneous • Subcutaneous/Intramuscular (selected) Preclinical findings
  21. 21. 1. Vaccine protects against colonization and invasive disease by multiple serotypes 2. Various routes of immunization effective • Intranasal • Oral • Sublingual • Transcutaneous • Subcutaneous/Intramuscular (selected) 3. Various adjuvants effective • Cholera toxin, cholera toxin B (mucosal) • LT and mutant derivatives (mucosal, transcutaneous) • Aluminum hydroxide (selected) Preclinical findings
  22. 22. 1. Vaccine protects against colonization and invasive disease by multiple serotypes 2. Various routes of immunization effective • Intranasal • Oral • Sublingual • Transcutaneous • Subcutaneous/Intramuscular (selected) 3. Various adjuvants effective • Cholera toxin, cholera toxin B (mucosal) • LT and mutant derivatives (mucosal, transcutaneous) • Aluminum hydroxide (selected) 4. Dual mechanism of protection • Antibody-mediated (vs. sepsis), transferable • CD4+ IL-17A-mediated (vs. colonization), transferable Preclinical findings
  23. 23. First WCV clinical trial initiated in February 2012 § Phase I trial in healthy adult (18-40) volunteers sponsored by PATH § Setting: CRO in Seattle, WA § SPWCV comprised of killed whole cell antigen adsorbed with aluminum hydroxide § Three dose cohorts, each individual to receive 3 vaccinations with same dose 28 days apart; placebo comparator (saline) in each cohort
  24. 24. VAC-002 Trial: Summary of Results 1. Safe, well tolerated: mild pain and tenderness at site, no hematologic or chemical signals 2. Rise in antipneumococcal antibodies (directed against whole cell as well as against individual proteins) 3. Enhancement ofT cell responses in peripheral blood 4. Protection by passive transfer
  25. 25. WCV current status and plans § Phase 2 clinical trials in Kenya (M. Alderson, PATH) • Dose-escalation in adults and toddlers almost completed • Preliminary look at impact on colonization in toddlers (all ST) § Biofarma (Bandung, Indonesia) has taken over manufacture of the vaccine, multiple lots evaluated for potency and stability § Further clinical studies planned by PATH with K. Mulholland’s group in Indonesia, under auspices of BMGF
  26. 26. OPTION 2: Killed whole cell pneumococcal vaccine (summary) Advantages: Simplicity of manufacture Exposes host to numerous antigens at same time Some historical suggestions of efficacy Proteins not modified Disadvantages: Very complex antigen Precise mechanisms of protection hard to define Acceptability? Licensure path unclear
  27. 27. OPTION 2: Killed whole cell pneumococcal vaccine: Licensure issues § In contrast to PCVs, there are no known correlates of protection for WCV § In theory, could envision one of the following approaches: • Demonstration of impact on carriage • Demonstration of impact on otitis media • Demonstration of impact on non-bacteremic pneumonia • Demonstration of impact on bacteremia in country that has not yet implemented PCV • Placebo-controlled vs. PCV as control?
  28. 28. OPTION 3: Proteins alone § Selection of two or more genetically conserved proteins (ie. common to the greatest majority of clinical isolates of pneumococci) § Several candidates that confer protection against invasive disease in animal models have been identified, and several have been evaluated in Phase I trials (e.g. PspA, StkP+PcsB, PhtD, Ply) § How about antigens that confer protection against colonization?
  29. 29. Collaboration between Genocea Biosciences, Boston Children’s Hospital and PATH: Identification of Th17 antigens Intranasally immunized with pneumococcal whole cell antigen CD4+T cells isolated from splenocytes Incubate and assay IL-17A in supernatant Peritoneally derived macrophages pulsed with TIGR4 expression library Mofffit, Gierahn et al., Cell Host & Microbe, 2011
  30. 30. Genocea Biosciences clinical trials: Immunization with Th17 antigens 1. Phase I trial of three putativeTh17 antigens (SP_2108, SP_0148 and SP_1912) combined and adsorbed on aluminum hydroxide, and injected intramuscularly, successfully completed in US (GEN-004) 2. GEN-004 then underwent Phase II clinical trials in healthy adults in Liverpool (S. Gordon’s intentional pneumococcal exposure model) • About 25% reduction in carriage density compared to placebo • Had been powered for 50% reduction • Program de-prioritized
  31. 31. OPTION 3: Proteins alone (summary) Advantages: Relative simplicity of manufacture Likely would require several proteins for coverage against both disease and colonization, but feasible Proteins not modified Disadvantages: Vaccine against what? Licensure path unclear
  32. 32. OPTION 4: Combination PS and protein vaccine • An attractive option would be to include these proteins as carriers for polysaccharides, to generate • Antibodies to PS • Antibodies to proteins • CD4+ Th17 responses to proteins
  33. 33. Carriers in traditional conjugate technology Carrier protein e.g. CRM197, Tetanus toxoid, OMPC, protein D Capsular polysaccharide (target) Protein used in conventional conjugates is generally an irrelevant (nonprotective) protein (possible exception of protein D, although very controversial). One advantage of using the protein as a carrier is that licensure of the product would not depend on demonstration of efficacy of the proteins, since it is included primarily as a carrier
  34. 34. Can we improve on the concept? The Multiple Antigen Complex Presenting System (MAPS) MAPS complex Rhizavidin fusion Biotinylation PS antigen Protein antigens Ab response Poor Ab response EnhancedAb response Th1 response Th17 response T-dependent Ab response Zhang, Lu and Malley, PNAS 2013
  35. 35. Advantages over conventional conjugation 1. Enhanced efficiency of manufacture of MAPS complex (>90% at laboratory scale and now scale-up, compared to 30-40% for conventional conjugates 2. Efficiency of manufacture and purification of protein carriers, with associated reduced costs and ease of tech transfer 3. Little to no PS epitope modification or damage due to controlled biotinylation of the PS and attachment via affinity-interactions with protein rather than cross-linking 4. Modular process, allowing for rapid optimization
  36. 36. Pneumococcal MAPS: 13 PS and comparison with PCV13
  37. 37. Pneumococcal MAPS: Protection against carriage Protection against colonization
  38. 38. OPTION 4: Combination protein + polysaccharide Advantages: Same advantages as traditional conjugates Potential added benefit of conserved pneumococcal proteins Antibody to proteins Th17 responses to proteins Does not require demonstration of efficacy of proteins Disadvantages: New proteins New technology Minor: Indication for universal coverage will not be granted based on clinical trials, would require Phase IV trials
  39. 39. Conclusions/Discussion § Concern that current strategy may not result in sustained reduction in pneumococcal disease or may not be affordable § Recent experience with conjugate vaccines strongly supports concept that reduction in transmission (with PS conjugate, +/-protein or whole cell vaccines) is the key to a successful strategy § Good justification for consideration of alternative/adjunctive approaches, particularly for developing world settings § Several adaptations of current approaches or novel strategies can be considered, each with theoretical advantages and disadvantages
  40. 40. “Professor? May I be excused? My brain is full” Questions/Comments?

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