Vaccines: Past, Present, and Future Tapani Ronni, PhD 1 About the - - PowerPoint PPT Presentation

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Vaccines: Past, Present, and Future Tapani Ronni, PhD 1 About the - - PowerPoint PPT Presentation

Feb 08, 2023 209 likes •707 views

Vaccines: Past, Present, and Future Tapani Ronni, PhD 1 About the Speaker PhD in Gene<cs, University of Helsinki, Finland Postdoctoral fellow, University of California, Los Angeles Scien<fic interests: gene therapy, microbial

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Vaccines: Past, Present, and Future

Tapani Ronni, PhD

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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)

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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

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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”

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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

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History of Vaccina<on (cont’d)

  • Un<l 19th 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”)

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Edward Jenner (1749-1823)

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Public Domain image. Pain8ng by James Northcote. Na8onal Portrait Gallery, London.

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History of Vaccina<on (cont’d)

  • Founda<on of Germ Theory: microscope

invented by a Dutch scien<st Antonie van Leeuwenhoek (1632-1732)

  • Magnifica<on of up to 250x
  • First person to see single-celled organisms

(micro-organisms)

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History of Vaccina<on (cont’d)

  • Germ Theory of Disease was firmly

established in the 19th century by Louis Pasteur and Robert Koch

  • Pathogenic microbes were now isolated and

studied systema<cally

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Louis Pasteur (1822-1895)

Public Domain image. Pain8ng by Albert Edelfelt. Musee D’Orsay, Paris.

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Robert Koch (1843–1910)

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Public Domain image. hLps://en.wikipedia.org/wiki/Robert_Koch

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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

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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

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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 2011

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Immunological Memory

  • Rapid, innate response (macrophages and
  • ther 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

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Immunological Memory (cont’d)

Response Time

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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

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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

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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

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An<body with An<gens

Public Domain image. hLps://en.wikipedia.org/wiki/An8body

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Classifica<on of Vaccines

  • Live, acenuated vaccines
  • Inac<vated vaccines
  • Toxoid vaccines
  • Subunit vaccines
  • Nucleic acid vaccines
  • Recombinant vector vaccines

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Live, Acenuated Vaccines

  • Viruses or bacteria that have been weakened

by repeated growth cycles (in case of viruses)

  • r 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

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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

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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

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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)

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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?

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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

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Nucleic Acid Vaccines (cont’d)

Courtesy: Na8onal Ins8tute of Allergy and Infec8ous Diseases

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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

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Recombinant Vector Vaccines (cont’d)

Courtesy: Na8onal Ins8tute of Allergy and Infec8ous Diseases

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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

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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

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Structure of HIV

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Courtesy: Na8onal Ins8tute of Allergy and Infec8ous Diseases

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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

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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. 2009 Dec 3;361(23):2209-20 36

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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

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Mycobacterium tuberculosis

Courtesy: Centers for Disease Control and Preven8on.

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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

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Case 3: Ebola (cont’d)

Courtesy: Centers for Disease Control and Preven8on. Image by Frederick A. Murphy.

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Case 3: Ebola (cont’d)

Ac<ve outbreak s<ll in 2015 in Liberia, Guinea, and Sierra Leone Public Domain Image

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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. 2015 Aug 29;386(9996):857-66

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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

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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

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Vaccine Safety and Herd Immunity (cont’d)

  • It is not necessary to be able to vaccinate 100%
  • f 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)

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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

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Selected References

1. de Kruif P. Microbe Hunters. 3th ed. Mariner Books; 2002 2. Delany I, Rappuoli R, De Gregorio E. Vaccines for the 21st Century. EMBO Mol Med. 2014 May 6;6(6):708-20 3. Carter, JB and Saunders VA. Virology: Principles and applica4ons. 2nd ed. Wiley; 2013 4. Delves PJ, Mar<n SJ, Burton DR, Roic IM. RoiG’s Essen4al Immunology, 12th ed. Blackwell Publishing Ltd; 2011 5. Vaccine.gov. Types of Vaccines. hcp://www.vaccines.gov/more_info/types/. Accessed September 11, 2015 6. Na<onal Ins<tute of Allergy and Infec<ous Diseases. HIV Vaccine Research. hcp://www.niaid.nih.gov/topics/HIVAIDS/Research/vaccines/Pages/ discovery.aspx. Accessed September 15, 2015 7. U.S. Food and Drug Administra<on. Vaccine Product Approval Process. hcp://www.fda.gov/BiologicsBloodVaccines/ DevelopmentApprovalProcess/BiologicsLicenseApplica<onsBLAProcess/ ucm133096.htm. Accessed September 15, 2015

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Thank you!

tapanironni@yahoo.com

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