Vaccines: Past, Present, and Future. Tapani Ronni, PhD

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1 Vaccines: Past, Present, and Future Tapani Ronni, PhD 1

2 About the Speaker PhD in Gene<cs, University of Helsinki, Finland Postdoctoral fellow, University of California, Los Angeles Scien<fic interests: gene therapy, microbial pathogenesis, immunology A full <me medical translator since 2007 (English-Finnish) 2

3 3

4 Contents of This Talk History of vaccina<on Immunological memory Classifica<on of vaccines Case studies in vaccine development Regulatory affairs and vaccine safety Vaccine safety and herd immunity Future challenges 4

5 History of Vaccina<on A Greek historian Thucydides noted that those who survived the plague epidemic in ancient Athens (430 BC) did not fall ill twice. Indeed, the recovered individuals were considered exempt from the disease -- they became immune. La<n: immunis exempt, free 5

6 History of Vaccina<on (cont d) In medieval <mes, Chinese used variola<on to protect against smallpox Skin material from pa<ent given to healthy recipient Dangerous but popular The real cause of smallpox not understood 6

7 History of Vaccina<on (cont d) Un<l 19 th century, Europeans believed that miasma (bad air) caused epidemics of plague etc. Variola<on adopted by Turks, and from them by English Edward Jenner developed the cowpox vaccine based on his observa<ons of milkmaids and their immunity from smallpox La<n: vaccinus ( from cows ) 7

Edward Jenner (1749-1823) Public Domain image.

8 Edward Jenner ( ) Public Domain image. Pain8ng by James Northcote. Na8onal Portrait Gallery, London. 8

9 History of Vaccina<on (cont d) Founda<on of Germ Theory: microscope invented by a Dutch scien<st Antonie van Leeuwenhoek ( ) Magnifica<on of up to 250x First person to see single-celled organisms (micro-organisms) 9

10 History of Vaccina<on (cont d) Germ Theory of Disease was firmly established in the 19 th century by Louis Pasteur and Robert Koch Pathogenic microbes were now isolated and studied systema<cally 10

Louis Pasteur (1822-1895) Public Domain image.

11 Louis Pasteur ( ) Public Domain image. Pain8ng by Albert Edelfelt. Musee D Orsay, Paris. 11

Robert Koch (1843 1910) Public Domain image.

12 Robert Koch ( ) Public Domain image. hlps://en.wikipedia.org/wiki/robert_koch 12

13 The First Golden Age of Vaccines Acenuated and inac<vated pathogens, inac<vated toxins Cell cultures study of viruses in vitro Vaccines against polio, mumps, rubella, measles, and others 13

14 Eradica<on of Smallpox Old scourge of mankind Infec<ous disease caused by Variola virus Mortality rate 20-60% (and over 80% of infected children) Systema<c vaccina<on campaigns led to global eradica<on of smallpox in 1979 No animal host for Variola 14

15 Eradica<on of Rinderpest Infec<ous viral disease of cacle High mortality (up to 100%) Widespread eradica<on efforts since the early 1900s Global Rinderpest Eradica<on Programme 1994->, last confirmed case in Kenya in 2001 Declared eradicated in

16 Immunological Memory Rapid, innate response (macrophages and other innate immune cells) Slower, acquired response (B and T cells) B cells make an<bodies T cells kill infected host cells Acquired response has a memory 16

17 Immunological Memory (cont d) Response Time 17

18 Efficacy and Safety Vaccina<on is based on immunological memory Sufficient immunogenicity -> efficacy Adjuvants as needed An<gen selec<on Both innate and adap<ve immunity ac<vated Purity, formula<on -> safety 18

19 Key Concepts An<gen: any molecular structure capable of genera<ng an immune response An<body: soluble protein from B cells, able to bind to an<gen Adjuvant: substance in vaccine that enhances its ability to induce protec<on against infec<on Alum only or Alum combined with lipid 19

20 Key Concepts (cont d) Prime: immune system is primed to a target an<gen using vaccine 1 Boost: immune response is enhanced by a second vaccina<on with vaccine 2 Vaccine 2 may be the same as vaccine 1 or different 20

21 An<body with An<gens Public Domain image. hlps://en.wikipedia.org/wiki/an8body 21

22 Classifica<on of Vaccines Live, acenuated vaccines Inac<vated vaccines Toxoid vaccines Subunit vaccines Nucleic acid vaccines Recombinant vector vaccines 22

23 Live, Acenuated Vaccines Viruses or bacteria that have been weakened by repeated growth cycles (in case of viruses) or by chemical methods (in case of bacteria) Example: Bacillus Calmece-Guerin (BCG) Easier to acenuate viruses Robust immunity Reversion may some<mes be an issue Example: Sabin polio vaccine 23

24 Inac<vated Vaccines Microbes rendered noninfec<ous by chemical or thermal treatment, or by radia<on No reversion More stable in storage May be less immunogenic Example: Salk polio vaccine 24

25 Toxoid Vaccines Contain bacterial toxins rendered harmless by formalin treatment S<ll an<genic and can generate an immune response Example: vaccines against diphteria and tetanus 25

26 Subunit Vaccines Contain only a subunit / subunits of the pathogenic micro-organism Safe and effec<ve (if subunits immunogenic) Fewer adverse effects (vaccine reac4ons) Usually protein subunits, some<mes carbohydrates Example: vaccine against Haemophilus influenzae type b (Hib) 26

27 Nucleic Acid Vaccines S<ll experimental but show great promise Instead of heat labile, complex formula<ons, DNA or RNA given to recipient s muscle Cheap to make and deliver Suitable adjuvants necessary DNA an<bodies? Inser<on mutagenesis? 27

28 Nucleic Acid Vaccines (cont d) RNA vaccines are in development RNA into cells -> translated to protein Self replica<ng RNA constructs RNA ac<ve in cytoplasm (no nuclear safety concerns) RNA itself highly immunogenic -> innate immunity ac<va<on No concerns with DNA an<bodies 28

29 Nucleic Acid Vaccines (cont d) Courtesy: Na8onal Ins8tute of Allergy and Infec8ous Diseases 29

30 Recombinant Vector Vaccines Hybrid viruses (or bacteria) Harmless microbe (vector) combined with an<gen of interest For example: VSV vector Vectors well understood and safe As living microbes, they give long challenge to the immune system 30

31 Recombinant Vector Vaccines (cont d) Courtesy: Na8onal Ins8tute of Allergy and Infec8ous Diseases 31

32 Case Studies in Vaccine Development Good protec<ve vaccina<on urgently needed for some important diseases, such as HIV/ AIDS, tuberculosis, malaria, and hepa<<s C Onen the problem is poor an<genicity or high variability of the pathogen Three case studies: HIV/AIDS, tuberculosis, Ebola 32

33 Case 1: HIV/AIDS HIV is a complex retrovirus that causes AIDS Highly variable virus an<gens Virus can stay latent inside host genome for years Goal: iden<fy an<genic structures on the HIV surface that would provide broad immunity against different HIV strains 33

34 Structure of HIV Courtesy: Na8onal Ins8tute of Allergy and Infec8ous Diseases 34

35 Case 1: HIV/AIDS (cont d) HIV is a complex retrovirus that causes AIDS Highly variable virus an<gens Virus can stay latent inside host genome for years Killed HIV not an<genic; weakened HIV unsafe Goal: iden<fy an<genic structures on the HIV surface that would provide broad immunity against different HIV strains 35

36 Case 1: HIV/AIDS (cont d) Many vaccine trials have been disappoin<ng Thai vaccine study used two recombinant vectors as prime / boost combina<on Efficacy 31% (in preven<ng HIV infec<on) among 16 thousand par<cipants Next goal: efficacy >50% Enough for licensing? Rerks-Ngarm S, Pi8suYthum P, Nitayaphan S, et al. Vaccina8on with ALVAC and AIDSVAX to prevent HIV-1 infec8on in Thailand. N Engl J Med Dec 3;361(23):

37 Case 2: Tuberculosis Major public health problem in developing countries Predominantly lung disease caused by Mycobacterium tuberculosis BCG vaccine inefficient in adults Slow infec<on efficacy? Mul<valent vaccines in development 37

38 Mycobacterium tuberculosis Courtesy: Centers for Disease Control and Preven8on. 38

39 Case 3: Ebola Deadly viral hemorrhagic fever caused by a filovirus Primary host not human (fruit bat?) Mortality rate over 50% Recent epidemic prompted intense vaccine development efforts 39

40 Case 3: Ebola (cont d) Courtesy: Centers for Disease Control and Preven8on. Image by Frederick A. Murphy. 40

41 Case 3: Ebola (cont d) Ac<ve outbreak s<ll in 2015 in Liberia, Guinea, and Sierra Leone Public Domain Image 41

42 Case 3: Ebola (cont d) Recent paper in Lancet detailed a vaccine trial in Guinea where vaccina<on was safe and 100% effec<ve VSV vector with Ebola glycoprotein an<gen Due to ethical concerns, the control group got delayed vaccina<on instead of placebo Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy and effec8veness of an rvsv-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccina8on cluster-randomised trial. Lancet Aug 29;386(9996):

43 Regulatory Framework for Vaccines Food and Drug Administra<on (FDA) Center for Biologics Evalua<on and Research (CBER) Inves<ga<onal New Drug (IND) applica<on for any clinical trial If all trial phases successful, submit Biologics License Applica<on (BLA) Approved BLA -> marke<ng launch VAERS system to monitor adverse events In Europe: European Medicines Agency, CHMP 43

44 Vaccine Safety and Herd Immunity The benefit/risk balance of current vaccines is good However, some recipients unsuitable (immunocompromised or allergic persons) Claimed link between vaccina<ons and au<sm has been thoroughly debunked 44

45 Vaccine Safety and Herd Immunity (cont d) It is not necessary to be able to vaccinate 100% of the target popula<on to stop infec<ous diseases. A concept called herd immunity protects the unvaccinated individuals in the target popula<on as long as the vaccina<on coverage is adequate (WHO recommends coverage of 95%). Measles epidemic of 2015 in US is an example of what can happened if vaccina<on coverage is inadequate (189 cases) 45

46 Future Challenges Cold chain in developing countries Highly variable microbes (influenza, HIV) Many pediatric vaccines not affordable to people in poorest countries Global Vaccine Alliance 46

47 Selected References 1. de Kruif P. Microbe Hunters. 3 th ed. Mariner Books; Delany I, Rappuoli R, De Gregorio E. Vaccines for the 21 st Century. EMBO Mol Med May 6;6(6): Carter, JB and Saunders VA. Virology: Principles and applica4ons. 2 nd ed. Wiley; Delves PJ, Mar<n SJ, Burton DR, Roic IM. RoiG s Essen4al Immunology, 12 th ed. Blackwell Publishing Ltd; Vaccine.gov. Types of Vaccines. hcp:// Accessed September 11, Na<onal Ins<tute of Allergy and Infec<ous Diseases. HIV Vaccine Research. hcp:// discovery.aspx. Accessed September 15, U.S. Food and Drug Administra<on. Vaccine Product Approval Process. hcp:// DevelopmentApprovalProcess/BiologicsLicenseApplica<onsBLAProcess/ ucm htm. Accessed September 15,

48 Thank you! 48

Vaccines and other immunological antimicrobial therapy 1

Vaccines and other immunological antimicrobial therapy 1 Vaccines Vaccine: a biological preparation that provides active acquired immunity to a particular disease. Vaccine typically contains an agent that