Low-Cost Vaccine Pipeline - Worldwide Perspective

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1 Low-Cost Vaccine Pipeline - Worldwide Perspective James Wai Kuo Shih, Ph.D. School of Public Health Xiamen University Xiamen, China

2 Humans are living longer 2

3 Causes of death: 1900 vs 2010 New England Journal of Medicine 3

4 Prospective on Vaccine Worldwide Vaccine market is growing faster than other health product sector; 10-15% growth yearly WHO estimated 5 billion in 2000, 2013 $24B and by 2025, $100B True in Europe, North America but also in China, India and other Pacific regions Adult vaccine is gaining larger share; will be doubled by 2020; while expanding on ID; therapeutic and cancer vaccines are being introduced Nearly 300 new vaccines are in development; research is focused on prevention and treatment; 60 are of importance for developing countires. High lights: Influenza pandemic and seasonal; cell culture grown egg free flu vaccine was first approved in 2013 Malaria irradiated whole sporozoite as vaccine in Ph. III Cervical Cancer: attenuated Listeria monocytogenes target HPV E7 (Advaxis) LM- LLO immunotherapy; produced antigen/adjuvant fusion protein to stimulate patient immunity; Ph.II Pancreatic cancer treatment vaccine

5 Leading causes of death in the poor countries 5 Sources of data: WHO

6 Deaths due to vaccine-preventable diseases: 2012 data Hib: 199,000 Pertussis: 195,000 Measles: 118,000 Neonatal tetanus: 59,000 Tetanus (non-neonatal): 2,000 Pneumococcal disease: 476,000 Rotavirus: 453,000 Sources: World Health Organization. Global immunization data [fact sheet]. Geneva: WHO; Available at: Immunization coverage page. WHO website. Available at: Accessed December 3, 2013.

7 Why the gap existed Many developing countries did/do not produce vaccines. Immunization programs in these countries rely on donated funds or donated vaccines. There was/is little financial incentive for the large vaccine producers in the developed countries to engage the developing-country market. In 2012, the United Nations Children s Fund paid $1 billion for about 2 billion doses of vaccine.

8 Global vaccine market in 2010 In 2010, global vaccine market total sale is $28 billion USD. Compare with $26 billion in 2009, it increased 7.7% which occupied 20 % of biopharmaceutical market (28/140) and was lower than therapeutic monoclonal antibody pharmacological market (34.3%, 48/140). Scale of global vaccine market grew by 15.23% per year(average value) in the last four years $ billion 29.7% 8.3% (Year) % 28

9 Compose of Vaccine Product Market Pneumonia(13-valent) vaccine (Prevnar13 from Pfizer) continued to lead the global vaccine market in This one product with annual sales of $3.657 B USD is on the top of global vaccine market (17%). This is a growth of 51% compared to Fluzon/Vaxigrip(S anofi) Gardasil(Merck) % 6% PENTAct- HIB(Sanofi) 1.5 7% Prevnar13(Pfizer) % Pediarix(GSK) 1.1 5% Other vaccines % Sales($ billion)

10 Global Market of Vaccine Product Sales in 2011 Serial number Brand name Generic name Producers Prevnar 13 Pneumonia(13-valent) Pfizer PENTAct-HIB DTPw-Hib/polio Sanofi Pasteur Gardasil HPV(6/11/16/18) Merck S&D Fluzone/Vaxigrip Influenza Sanofi Pasteur Pediarix DTaP-HepB-IPV GSK Hepatitis Vaccine Hepatitis Franchise GSK Varivax Varicella Merck S&D Cervarix HPV(Type16/18) GSK Prevnar Pneumococcus(7-valent) Pfizer Rotateq Rotavirus(5-valent) Merck S&D Menactra MenACYW135(DT Conjugate) Sanofi Pasteur Synflorix Pneumococcus(10-valent) GSK Pneumovax Pulmonitis(23-valent) Merck S&D Rotarix round shape (single valent) GSK Adacel TdaP Sanofi Pasteur FluLaval Influenza ID Biomedical Fluvirin Influenza Novartis Zostavax Simple shingles M-M-R II MMR Merck S&D Boostrix TdaP GSK Afluria Influenza CSL Fluzone ID Influenza Sanofi Pasteur FluMist Influenza MedImmune Menveo MenACYW135(CRM197 Conjugate) Novartis Menomune MenACYW135(Polysaccharide) Sanofi Pasteur Menitorix Hib-MenC GSK ProQuad MMR-Varicella Merck S&D Optaflu Influenza Novartis Unit:0.1 $ billion

11 2010 Market share of world vaccine manufactures Astellas,Solva y,mitsubishitanabe,csl 1.5 5% CNBG,etc 2.5 9% Novartis % Merck % Crucell 0.7 3% Pfizer % Baxter 0.3 1% Sales: ($ billion) GSK % Sanofi Pasteur % 5 major manufactures account for more than 80% sales

12 World Geographic Distribution of Vaccine Market Strategically focusing on China, Other region India, Brazil and N.america 1.1 other new raising S.america 0.7 5% markets 1.4 3% 6% India 1.4 7% China 1.6 7% Japan 1.8 8% Europe % Sales: ($ billion) US % USA and Europe account for 65%

13 Domestic vaccine Market 2010 Domestic vaccine market in 2010: 13.3billion yuan (increased by 14% vs. 2009) billion % %

14 The Developmental Plan for Strategic New Industries The developmental plan for strategic new industries Publication Date :First half of 2012 The key point of biological industry future development is in the five aspects of biological medicine, biological agriculture, biological energy, biological environmental protection, biological service outsourcing. The key point of biological industry future development is in the five aspects of biological medicine, biological agriculture, biological energy, biological environmental protection, biological service outsourcing. About biological medicine development, the next five years will focus on innovative varieties medicine of biotech drugs, new vaccines, diagnostic reagents and chemical medicine, which can prophylaxis and treat critical illness.

15 Introduction of under used and new vaccines to the low-income countries through GAVI Vaccines introduction by Global Alliance for Vaccines and Immunisation (GAVI) in Pentavalent Pneumococcal conjugate vaccine Rotavirus vaccine Meningitis A vaccine Japanese encephalitis vaccine (from China) Yellow fever vaccine 15

16 A new rotavirus vaccine developed in India is about to be rolled out Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial About this vaccine: The Lancet, 12 March 2014 Vaccine is well-tolerated 54-56% efficacy in the first year Approved in India; WHO pre-qualification is next. $1.00 per dose 16

17 A malaria vaccine candidate in advanced development Phase 3 studies with RTS,S in Africa Vaccine candidate: RTS,S Partners: GSK, PATH, and BMGF Study design: Study sites: 11 sites in seven African countries Children: 15,460 children Duration: Preliminary findings Vaccine is well tolerated Efficacy: 5-17 month old: 56% against clinical disease 6-12 week old: 31% against clinical disease 17

18 Meningitis caused by Neisseria meningitidis Meningitis is a severe disease with a high fatality rate if not treated. Case rates. United States: 0.3 per 100,000. Sub-Saharan Africa: 1 in 1,000 to 1 in 100. Death rate: 10 percent. Children under 5 years of age to young adults are most susceptible. Sub-Saharan countries have recurring epidemics and form a meningitis belt.

19 Meningitis belt in sub-saharan Africa Meningitis belt: Extends from Ethiopia to Senegal: Sudan, Ethiopia, Chad, Niger, Northern Nigeria, Burkina Faso, and Mali are considered hyperendemic. Group A meningococcus accounts for an estimated 80 to 85 percent of all cases. Annual epidemics. Major epidemics occurring at intervals of 7 14 years.

20 MVP partners AARSH Recherche en Santé Humaine

21 Safety immunogenicity immune Completed Ongoing Safety immunogenicity memory immune persistence Safety immunogenicity immune persistence carriage Phase I India year olds Aug 05 Oct 06 Phase II Mali, The Gambia month olds Sep 06 Apr 09 persistenceescmid Online Phase II/III India 2 10 year olds Aug 07 Nov 08 Phase II/III Senegal, Mali, The Gambia 1 29 year olds Aug 07 Apr 09 Meningococcal A conjugate vaccine (PsA-TT) clinical development MenAfriVac vaccine developed by MVP and Serum Institute of India, Ltd. Phase III Mali 1 9 year olds Feb 10 Nov 10 Phase III India 5 10 year olds Jan 10 Jun 10 Phase II Dose selection Ghana infant indication infants Schedule evaluation Nov 08 Jul 13 infant indication Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Jan Jun Expanding safety database Confirming lot consistency Immune persistence infant indication Lecture Library Jan Jun Jan Jun

22 Summary of results MenA conjugate vaccine safety and immunogenicity Safety A total of 9,943 subjects in trials; 6,920 subjects received the PsA-TT vaccine. No safety concern in any of the age groups evaluated. The PsA-TT vaccine was safe and well tolerated. Immunogenicity after a single dose of MenAfriVac Superior immune response versus licensed polysaccharide vaccines in all age groups (1 to 29 years of age). With induction of immune memory. Induction of bactericidal antibodies persisting at sustained levels up to 2 years after a single dose.

23 Licensure and prequalification of MenAfriVac MenAfriVac licensed by Drugs Controller General of India in December WHO prequalification awarded in June One-tenth of the normal development cost. US$0.5 per dose.

24 Impact in Chad Incidence of reported cases of meningitis in Chad, Vaccination with PsA TT was undertaken in patients aged 1 29 years at the end of Source: Daugla D, Gami J, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet. 2013;(13): Available at:

25 151 million Our approach: protected: Vaccines zero cases of meningitis A By 2020, the vaccine will prevent: 1 million cases 150,000 deaths Legend 250,000 cases of severe disability Countries that have rolled out MenAfriVac Other meningitis belt countries

26 Developing Countries Vaccine Manufacturers Network International Improving vaccination for all people 26

27 DCVMN: 43 manufacturers from 16 countries/territories are well placed to supply vaccines where needed : Members as of January 2014 Latin America Middle East Africa Members with WHO PQ vaccines Asia Pacific 2 New members

28 VACCINES BCG Rabies Typhoid Pertusis a OPV 3 OPV 1 OPV 1/3 OPV tri IPV Tetanus Toxoid DT or Td DTPacelular DTPwhole cell DTPwHepB PENTAVALENT Haemophilus i. b DTPhib Hepatitis A Hepatitis B Hepatitis E Yellow Fever Meninge A MeningeA/C MeningeB/C Measles (M) Rubella (R) MR MMR Japan. Encephal. Rotavirus Pneumo 10 Pneumo 23 Flu seasonal Flu H1N1 Cholera Hemoragic fever Leptospirosis Varicella Anthrax Tick encephalitis Brucella =PQ BHARAT Matrix of vaccines portfolio by DCVMN BIOFARMA BIOLOGICAL E BIOMANGUI NHOS BIONET BIRMEX BUTANTAN CADILA CIGB CNBG CDBIO FINLAY GPO HAFFKINE INDIAN IMMUNOL INNOVAX IVAC LGLS PANACEA PASTEUR INST. IRAN QSMI RAZI SERUM INST.INDIA SINOVAC MINHAI VABIOTECH VACSERA WALVAX 8

29 New vaccines under development for developing countries Diseases HIV Tuberculosis Malaria Shigella, ETEC, and rotavirus diarrhea Pneumococcal disease Vaccine programs International AIDS Vaccine Initiative Aeras Global Tb Vaccine Foundation PATH PATH PATH N. meningitides PATH Influenza RSV polio PATH PATH PATH

30 DCVMs preventing regional infectious diseases New conjugate vaccines to Typhoid Fever Jevax TM, Japanese encephalitis MenAfriVac TM Hepatitis E vaccine, Hecolin TM Yellow Fever Vaccines

31 Hepatitis E virology and vaccine/diag R&D Immunodominant epitope Structural basis of key epitopes Vaccine 2005b PLoS Pathogen 2009; PNAS 2011 Rev Med Virol 2012 Semin Liver Dis 2013; J Gastroenterol 2013 Cell Res 2015 Mechanism of host-virus interaction ESCMID Capsid assembly J Med Virol 2001 Vaccine 2005a Self assembly mechanism J Bio Chem 2005 FEMS. Immonol Med Micro biol 2007 Intervirol 2008 J Gen Virol 2008 J Gen Virol 2010 J Mol Model, HEV diagnostics J Med Virol 2003a Biomed Environ Sci 2007 PLoS One 个新药证书, 2 个欧盟认证 2010 年国家发明二等奖 HEV vaccine Vaccine 2001 Vaccine 2005b 2005b Mol Immunol 2007 Vaccine 2009 Lancet 2010 Hepatology 2011 Lancet 2012 Human Vaccine 2012, 2013 NEJM 2015 国家一类新药证书, 中国专利金奖 Hep E epi data and risk factors J Med Virol 2003b Vox Sang 2004 J Infect Dis 2006 Emerg Infect Dis 2006 J Clin Microbiol 2010 Online Lecture Library

32 PART 2 2 Hecolin Process of Production Page 30 Hecolin contains HEV Capsid Proteins Expressed in Escherichia coli (HEV239) Clone Gene for the Capsid Protein for HEV Intracellular expression in E. coli Purification Reassembl y HEV Virion non-infectious vaccine High safety and immunogenicity HEV Virus Like Particle

33 Highly immunogenic VLPs as vaccine antigen First and only licensed HEV vaccine(2012) 33 Lancet 2010; Hepatology 2012; HumanVac 2013

34 Positive feedback and comments from scientists from US CDC, etc

35 Durability of HEV vaccine efficacy

36 N Engl J Med 2015, 372:914

37 Pipeline of E.coli-derived HPV vaccines preclinical HPV 16/18 bivalent HPV 6/11 bivalent HEV-HPV quadrivalent HPV 9-valent HPV 11-valent HPV 17-valent Phase 1 Phase 2 Phase 3 HPV6/11/16/18 combined with Hecolin Pilot scale, Equivalent to Gardasil 9 Lab scale with 2 additional genotypes, 35 and 59 proof of concept by structural vaccinology

38 EM of 11 genotypes of HPV VLPs Viron-sized Φ50-60nm

39 Pseudoviron-based neutralization assay 11 genotypes Reporter genes: GFP, luciferase Cell model Animal model

40 Summary on Low-Cost Vaccine The need: filling the gap by DC The supply: developing countries The shift: Big Pharm & MNC The organization: NGOs The future: PQ