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Seasonal and Pandemic Influenza Vaccines : Vaccine Development and Production 1.

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Presentation on theme: "Seasonal and Pandemic Influenza Vaccines : Vaccine Development and Production 1."— Presentation transcript:

1 Seasonal and Pandemic Influenza Vaccines : Vaccine Development and Production 1

2 Learning Objectives Develop a basic understanding of how influenza vaccines are developed Be familiar with the major types of vaccines and methods of vaccine production Understand the importance of vaccine effectiveness and testing 2

3 Outline Overview of vaccine production Seasonal influenza vaccination Progress in developing vaccines for influenza viruses with pandemic potential 3

4 Overview of Vaccine Production 4

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7 Approaches to Influenza Vaccine Development Subtype/strain-specific vaccines: Induce immune response to hemagglutinin (HA) and neuraminidase (NA) viral proteins Examples: Inactivated influenza virus vaccines, Live- attenuated vaccines, virus-like particles Universal vaccines Current area of investigation Immunize with conserved proteins (for example: M2) Broad-based immunity Immune response against multiple subtypes 7

8 Composition of Vaccines against Seasonal Influenza Three strains selected to make a trivalent vaccine Based on global viral surveillance Selection decision precedes typical peak influenza season by months Northern Hemisphere strains selected in February Southern hemisphere strains selected in September New vaccine (one or more new strains) every year 8

9 Types of Influenza Vaccines Non-Replicating Vaccines Antigens are manufactured outside the host Inactivated Whole or split virus Recombinant protein Single protein, virus-like particles Peptide Replicating Vaccines Antigens are replicated in host Live attenuated vaccines Replication restricted to the cooler upper airways Microbial vector vaccines Bacterial vectors deliver DNA or RNA to host DNA vaccines 9

10 Egg-based Manufacturing of Inactivated Influenza Vaccines Must maintain flocks and viable eggs Bacteria inherent on surface of eggs Seed viruses must be adapted to eggs Not set-up for high-level bio- containment Cannot use wild type highly pathogenic viruses CDC/ Dr. Stan Foster 10

11 Cell-based Manufacturing of Inactivated Influenza Vaccines Storage in a working cell bank Fermenter for growth of tissue cultures Requirement for special supplements: Carrier beads (to maximize cell growth surface area) Protease or growth additives Variable replication efficiency: wild type and high growth reassortants Manufacturing with high biocontainment (BSL3) must be used for highly pathogenic strains 11

12 Production of Seasonal Influenza Vaccines (U.S. example) Jan-MarJul-SepOct-JanApr-Jun 12

13 Constraints with Current Seasonal Vaccines Selection of strains difficult and time consuming Annual, seasonal production Technical process, specialized facilities Lack of cross protection against antigenic variants Long term protection uncertain Relatively high cost Annual vaccine administration is required 13

14 Review Question 1 What type of manufacturing is most commonly used for influenza vaccines? a.Egg-based b.Cell-culture based c.Reverse genetics d.None of the above Answer: A. Currently available vaccines are manufactured using embryonated chicken eggs or egg- based manufacturing 14

15 Seasonal Influenza Vaccination: Safety and Effectiveness 15

16 Antibody Response to Influenza Vaccination Post-vaccination antibody correlates with protection Peak antibody response 2 weeks after vaccination in people needing only one dose Immunity wanes during the year Lasts through the influenza season Requires annual vaccination 16

17 Determinants of Antibody Response to Influenza Vaccines Age Elderly and young children can have lower antibody response Prior exposure to virus strains similar to those in vaccine (infection or vaccination) Immune competence of person being vaccinated Amount of antigen in vaccine Type of vaccine Presence of adjuvants 17

18 Measuring Effectiveness of Seasonal Influenza Vaccine Effectiveness varies by age group, risk group, and antigenic match Different study methods make comparisons difficult Observational studies: Easier to do but differences between vaccinated and unvaccinated persons can bias results Randomized controlled trials: Reduce bias, but costly Variety of outcomes can be measured that make comparisons between studies difficult Less specific: Influenza-like illness (ILI) More specific: Laboratory-confirmed influenza 18

19 Effect of Co-circulation of Non-influenza Pathogens/Outcome Specificity on VE Estimate Assuming 100 vaccinated and 100 unvaccinated in each set: VE against influenza infection = 75% for both sets A and B, VE against respiratory illness = 30% in set A and 15% in set B. 19

20 Inactivated Seasonal Influenza Vaccine Effectiveness, by Age and Risk Group, when Vaccine Strains Match Circulating Strains Age/Risk groupOutcomeEffectiveness* 6 months-18 yearsInfluenza**50-90% yearsInfluenza**50-90% >65 years, communityInfluenza**50-70% Elderly, nursing homeInfluenza**30-40% Elderly, nursing homeHospitalization or death 40-80% *Effectiveness lower when vaccine and circulating strains antigenically different. No vaccine effectiveness is sometimes observed when the prevalence of antigenically different strains in the community is high. **Laboratory-confirmed influenza virus infection 20

21 Global Distribution of Influenza Vaccines, WHO Global Influenza Vaccine Distribution

22 Review Question 2 What are some of the individual or demographic attributes that affect vaccine effectiveness? Answers: Age Immunocompetence Amount of antigen present in vaccine Vaccine type Prior exposure to similar viral strains 22

23 Developing Vaccines for Influenza Viruses with Pandemic Potential 23

24 From Seasonal to Pandemic Influenza Vaccine Production Manufacturing facilities could shift production from seasonal vaccine to pandemic vaccines Pandemic vaccines will not available at beginning of pandemic Likely available within 4-6 months Once available, there will be limited quantities initially By this time there might be wide spread circulation of the pandemic strain 24

25 Challenges to Development of Vaccines against Influenza A (H5N1) Reduced immunogenicity compared to seasonal influenza vaccines, unless formulated with an adjuvant Expense Reduced yield in egg-based manufacturing processes High antigen content Proprietary adjuvants Unknown cross protection against other clades Predictive value of pre-clinical studies not established 25

26 Priorities in Development of Pandemic Influenza Vaccines 26 Evaluation of dose-sparing strategies including use of adjuvants Accelerated development of cell-culture based vaccines Novel approaches to vaccine development Including vaccines that provide broad cross protection

27 Potentially Pandemic Viral Strains under Study H5N1 Multiple clades H9N2 H7N7 H5N2 Swine-origin novel influenza A(H1N1) 27

28 Immunogenicity of a Candidate Influenza A (H5N1) Vaccine (Sanofi) (A/Vietnam/1203/H5N1; Clade 1) Vaccine dose (ug) GMT at baseline 28 days after 1 st dose of vaccine No. % with tested HI >1:40 28 days after 2 nd dose of vaccine No. % with tested HI >1:40 GMT after 2 nd dose %9957% %9341% %10024% %9513%14.9 Placebo % Treanor et al. N Eng J Med 2006;354:

29 Influenza A (H5N1) Clade 1 Vaccine with Adjuvant (GlaxoSmithKline) Inactivated influenza A (H5N1) clade 1 antigen and proprietary adjuvant Design: Placebo-controlled, ~400 healthy adults 2 doses vaccine +/- adjuvant in doses from 3.8 to 30 micrograms Results: Adjuvanted formulations more immunogenic Good antibody response (even at 3.8 micrograms) Induced cross-reactive antibody responses against clade 2 strain Met FDA requirements for licensure Leroux-Roels et al. Lancet. 2007;370(9587):

30 Candidate Influenza A (H5N1) Vaccines: Experience to Date Inactivated subvirion vaccines: Immunogenicity suboptimal High antigen content required (90 micrograms) Require 2 doses Few adverse events Adjuvanted inactivated subvirion vaccines Similar or better response compared to subvirion vaccines Without adjuvant at doses as low as 3.8 micgrgrams Need for 2 doses less certain Antigen sparing (reduced antigen content needed) Proprietary adjuvants have shown best antigen-sparing effects Increased reactogenicity with adjuvants 30

31 Target paradigm of an ideal H5N1 pandemic vaccine From: S Sambhara, CB Bridges, GA Poland. Lancet

32 Review Question 3 Which technology that might be used to reduce the dose of antigen that is needed in a vaccine? a.Cell-based technology b.Adjuvants c.Universal vaccine d.None of the above Answer: b. Adjuvants 32

33 Summary Production using traditional methods will not meet global demand for a pandemic vaccine H5N1 Vaccines produced using traditional seasonal influenza vaccine methods have relatively poor immunogenicity Improved with use of adjuvants Considerable progress with alternative vaccines 33

34 Glossary Antigen: Are proteins or polysaccharides that are parts of viral or bacterial structure and which prompt the immune system response Adjuvant: A pharmacological or immunological agent added to a vaccine to modify (improve) the immune response to the vaccine, while having few if any direct affect when given by itself. Biocontainment or Biosafety level (BSL): The isolation and containment of extremely infectious or hazardous materials in specialized and secure scientific facilities Genetic engineering: the manipulation of genetic material, generally to produce a therapeutic or agricultural product either more quickly, or in greater quantities, than is seen in nature. 34

35 Glossary Embryonated: Egg containing an embryo, used to incubate viruses for vaccine study or production Reassortant: Viruses that contain 2 or more pieces of genetic material from different viruses. Reassortant happens when two viruses mix within a cell (or lab environment). Inactivated vaccine: a vaccine made from an infectious agent that has been inactivated or killed in some way. Live, attenuated vaccine: Vaccine includes live pathogens that have lost their virulence but are still capable of inducing a protective immune response to the virulent forms of the pathogen. Immunogenicity: Measure or ability of a substance (virus, drug, etc) to produce an immune system response 35

36 Glossary Clades: A biological group (for example, a viral species) that is classified according to genetic similarity Subivirion: An incomplete virus or virus particle Chemoprophylaxis: The use pharmaceutical or medical treatment to prevent disease or spread of infection Virulence: The virulence of a microorganism (such as a bacterium or virus) is a measure of the severity of the disease it is capable of causing. Pathogenicity: is the ability of an organism, a pathogen, to produce an infectious disease in another organism. 36

37 Glossary Trivalent influenza vaccine: synthetic vaccine consisting of three inactivated influenza viruses, two different influenza type A strains and one influenza type B strain. Trivalent influenza vaccine is formulated annually, based on influenza strains projected to be prevalent in the upcoming flu season. This agent may be formulated for injection or intranasal administration. Candidate strains: strains of influenza that are used in vaccines that are still early in developmental stages Antibody response: The immune system responds to antigens by producing antibodies. Antibodies are protein molecules that attach themselves to invading microorganisms and mark them for destruction or prevent them from infecting cells. Antibodies are antigen specific. That is antibodies produced in response to antigen exposure are specific to that antigen. 37

38 Glossary (S13) Egg-based (vaccine) manufacturing: Method of making influenza vaccines by inoculating live flu virus into fertilized chicken eggs, then purifying and inactivating the resulting egg-adapted virus. Vaccines created using this technique represent the majority of the currently licensed and marketed influenza vaccines worldwide (S14) Cell-based (vaccine) manufacturing: Method of manufacturing influenza vaccine that is more rapid than egg-based manufacturing. The live flu virus is used to infect cells in culture. Once the viral infection has propagated through the cells, the live virus is harvested and inactivated for use in vaccines. 38

39 Seasonal and Pandemic Influenza Vaccines: Programmatic Issues and Pandemic Preparedness 39

40 Learning Objectives Recognize the differences and challenges of seasonal vs. pandemic influenza vaccine development, manufacturing, and distribution 40

41 Outline Vaccine capacity Vaccine access Planning WHO strategies 41

42 Pre-pandemic: Vaccine Planning Definition: Vaccines developed against influenza viruses that are currently circulating in animals and that have the potential to cause a pandemic in humans Rationale: might provide priming or limited protection against pandemic strain Goal: Reduce morbidity or mortality Might not reduce number of viral infections Problem: Which vaccine strains, and when should it be given? 42

43 Pandemic Preparedness: Access to Vaccine Global influenza vaccine production capacity is limited: 300 million doses trivalent vaccine (900 million doses) Monovalent vaccine (2 dose course) = 450 million courses 65% of capacity is located in Europe 85% of influenza production is by 3 companies Countries with manufacturing capacity represent 12% of global population 43

44 Pandemic Preparedness: Global Response Increasing pressure from developing countries for access to influenza vaccine When pandemic declared, potential for: Rationing of vaccine No exportation of vaccine until manufacturing countrys needs are met 44 CDC/ Judy Schmidt

45 Pandemic Preparedness: Vaccine Development Strategy Strategies guided by the public health community WHO is expected to coordinate these efforts Manufacturers are being encouraged to develop vaccines that will meet global demand Countries/regions are being encouraged to articulate their needs/plans for Demonstrating burden of seasonal influenza Seasonal influenza vaccine Pandemic influenza vaccine 45

46 WHO Strategy to Increase Pandemic Influenza Vaccine Capacity 1.Development of immunization policy to reduce seasonal influenza burden Will increase demand for seasonal influenza vaccines 2.Increase influenza vaccine production capacity 3.Research and development for more effective influenza vaccines 46

47 1. Develop Seasonal Immunization Policies Objectives 1. Reduce disease burden from seasonal influenza infections 2. Increase manufacturing capacity for influenza vaccines Strategy 1: WHO Regional Offices develop plans with input from member states for seasonal influenza vaccination programs. These plans should form the basis for the Global Pandemic Influenza vaccine action plan Strategy 2: Mobilize resources to assist in the implementation of a global action plan to increase demand of seasonal influenza vaccine 47

48 2. Increase Influenza Vaccine Production Capacity Objectives 1.Produce enough vaccine to immunize two billion people within 6 months after transfer of vaccine prototype strain to industry. 2.Produce enough vaccine to immunize the world's population (6.7 billion people) Strategy 1: Increase production capacity for inactivated vaccines Strategy 2: Explore development of other types of influenza vaccines Strategy 3: Assess alternative ways to deliver vaccine 48

49 3. Research and Development for More Effective Influenza Vaccines Objectives 1.Development of influenza vaccines using new technologies 2.Recommend a research agenda 3.Improve collaboration between academia, industry, regulatory authorities, donors and international organizations Strategy 1: Enhance protective efficacy and immunogenicity of existing vaccines Strategy 2: Develop novel vaccines that induce broad spectrum and long lasting immune responses Strategy 3: Improve evaluation of vaccine performance 49

50 Other Pandemic Preparedness Activities Explore use of currently available H5N1 vaccines to prime immunity (prepandemic vaccines) Stockpile of H5N1 antigen in bulk Stockpile of vaccine supplies Increase egg supply Develop capacity for large scale influenza immunization programs 50

51 Preparedness Management and Coordination Technology transfer of cell culture technique to developing countries Mechanism for funding investments to increase vaccine production capacity Develop a management/coordination strategy (responsibilities, leadership, WHO role) Define a mechanism for the flow of donor funds 51

52 Review Question 4 What are the three WHO strategies for increasing pandemic vaccine capacity? Answer: 1. Development of immunization policy to reduce seasonal influenza burden 2. Increase in influenza vaccine production capacity 3. Research and development for more effective influenza vaccines 52

53 Summary Increasing (but still limited) use of seasonal flu vaccines in developed countries Linking increased use of seasonal flu vaccine to a strategy for pandemic preparedness Need consensus: Strategies for use of prepandemic vaccine Development and management of stockpile Evolving role of WHO to manage pandemic vaccine stockpile 53

54 Glossary Immunogenicity: Capability of inducing an immune response Antigen: A substance that stimulates the production of an antibody when introduced into the body. Antigens include toxins, bacteria, viruses, and other foreign substances. Antibody: A Y-shaped protein on the surface of B cells that is secreted into the blood or lymph in response to an antigenic stimulus, such as a bacterium, virus, parasite, or transplanted organ. Antibodies bind antigens and mark them for destruction or prevent cells from being infected. Antibodies are antigen specific. Antibody Response: The immune system responds to antigens by producing antibodies. Antibodies produced in response to an antigen work best on that antigen, but might have some activity against similar antigens. 54

55 Glossary Clade: A group of organisms, such as influenza viruses, whose members share homologous features derived from a common ancestor. Reactogenic: the capacity of a vaccine to produce adverse reactions Subvirion: An incomplete viral particle (e.g. like the HA antigen). 55

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