Lecture 19

Past, Present & FutureVaccines

The Lecture in a Single Slide

• Vaccines Have Been Used Since At Least the Beginning of the 19th

Century

• While Understanding about Infectious Agents and Vaccines Has Improved Dramatically, the Breadth of Agents Targeted with Vaccines Has Not Kept Pace

• The Anti-Vaccine Movement Foreshadowed the Return of Avoidable Childhood Diseases

A Glimpse From the Past:Smallpox

• Rates of Smallpox death in London documented since 1629• At its peak, 170 deaths (per 1,000 people) until 1800• Rapid decline thereafter• Why the decline?

Sanitation

• John Snow*• Mapped 1854 cholera deaths

to identify responsible wells

• Not believed & broke pump handle

• Founder or Epidemiology

• Hygiene improvements affected other diseases

Return to Smallpox

• Despite centuries of experience, the actual cause of death from smallpox remains largely unknown

• Respiratory transmission causes greatest viremia and death

Variolation

• Variolation• China: Nasal insufflation – Powdered scabs• Sudan: Cloth transferred from infected to

uninfected person’s arm; pustule contents into cut

• Introduced into UK by Lady Montagu and US by Cotton Mather

Lady Montagu Cotton Mather

Variolation to Inoculation

• Conventional Wisdom

• Gloucestershire doctor• mid-1796: Edward Jenner realizes

milkmaids resistant to smallpox• Immunizes James Phipps (8 yo boy)

with cowpox from “Blossom”

• 1774: Benjamin Jesty inoculates

wife & children with cowpox

• Did not publish data• John Fewster (1765) & Jobst Bose

(1769) correlate cowpox infection

with smallpox protection

Benjamin Jesty

EdwardJenner

Smallpox Eradication

• Smallpox lack non-human vectors• Global immunization• 1840: British Vaccination Act

• Mandatory vaccination, forbad variolation• 1843-1850: US States passed similar

laws• 1950: Pan American goal of smallpox

elimination from Western hemisphere• 1967: WHO worldwide effort• 1975: Last naturally occuring case

(Rahima Banu from Bangladesh)Rahima Banu

Directors of CDC Smallpox Eradication Program

Donald Millar, William Foege, Michael Lane

Well, Kind of (not really) Eradicated

• US & Soviet Union Agreed to Keep Smallpox vials for “defensive” use (future vaccines)

• Old samples periodically unearthed

• Soviets (& Russians) continued developing smallpox-based weapons

Growth in Immunotherapy

• Vaccine Growth in Parallel with Understanding of Disease & Immune Function

• FDA Approved 119 Different Immunotherapies (as of 2016)

• Major Trends:• Passive vs. Active• Live vs. Dead Vaccines• Diseases Targeted• Prophylaxis vs. Therapeutic

0

20

40

60

80

100

120

Through

1900

1901-1

910

1911-1

920

1921-1

930

1931-1

940

1941-1

950

1951-1

960

1961-1

970

1971-1

980

1981-1

990

1991-2

000

2001-2

010

2011-2

015

Cum

ulat

ive

Imm

unot

hera

pies

Passive

Active

A Quick Word on Passive Immunotherapy

• Concept: Transfer pre-existing immunity in human or non-human sources to patients

• Applications:• When quick immune defense is

needed• Animal Bites: Snakes, spiders, etc• Infectious Diseases: viral and

bacterial

Live vs. Dead Vaccines

• Dead Vaccines - Proteins, inactivated• Advantages:

• Low risk of infection• Target immune response towards epitopes

• Disadvantages: • Fewer epitopes • Incomplete inactivation

• Live Vaccines - Attenuated• Advantages:

• More epitopes• Physiological relevance

• Disadvantages• Potential for damage (immunosuppressed)• Manufacturing can be challenging

Poliomyelitis

• Old disease, traced back to Egypt• Ingested through mouth• Causes CNS paralysis, spinal damage

• Generally, not as dangerous if exposed at young age

• Improvements in santiation & hygiene delayed exposure• More severe disease in teens & adults

Alan Alda

Arthur C Clarke

Itzhak Perlman

Patrick PlayfairLaidlaw

Incapacitating Fear of Polio

• Debilitating fear of disease

• Spread in Summer• Parks and pools would close• People cautioned not to vacation (or

where to vacation)

• Schools Closed • Start Late in Season

Salk Vaccine

• Early vaccine attempts largely failed

• Breakthrough from virus propagation in

tissue culture (John Enders, Thomas

Weller, Frederick Robbins)

• Jonas Salk (Univ. Michigan) under

Thomas Francis before own lab at Univ

of Pittsburgh

• Developed killed version of polio• Clinical tests starting in 1953• Reported activity (13 Apr 1955)

The Cutter Incident

• Cutter Laboratories (1955)• Company did not fully inactivate virus

• 40,000 cases of polio• 200 cases of paralysis• 10 deaths

• Salk’s Enemies Pounced• No Nobel prize• Sabin vaccine accelerated

Sabin Vaccine

• Attenuated Poliovirus developed by Albert Sabin• University of Cincinnati

• Virus passaged through animals to weaken its activity against humans

• Oral administration (via sugar cube)

Live versus Dead Vaccines

• “Dead” or subunit antigens capture majority of faccines

• Ratio has remained at roughly 3:1 through history

0

2

4

6

8

10

12

Through

1900

1901-1

910

1911-1

920

1921-1

930

1931-1

940

1941-1

950

1951-1

960

1961-1

970

1971-1

980

1981-1

990

1991-2

000

2001-2

010

2011-2

015

Vacc

ines

App

rove

d

Live

Dead

Vaccine-Preventable Diseases

• Virus and Bacterial Diseases Targeted by Vaccines• Relative ratio has remained

remarkably steady since 1950s

• Neurologic, respiratory and gastrointestinal indications capture most vaccines

0

2

4

6

8

10

12

Through 1900

1901-1910

1911-1920

1921-1930

1931-1940

1941-1950

1951-1960

1961-1970

1971-1980

1981-1990

1991-2000

2001-2010

2011-2015

Vacc

ine

Appr

oval

s

VirusBacteriumCancer

0

2

4

6

8

10

12

Through 1900

1901-1910

1911-1920

1921-1930

1931-1940

1941-1950

1951-1960

1961-1970

1971-1980

1981-1990

1991-2000

2001-2010

2011-2015

Vacc

ine

Appr

oval

s

Nervous SystemRespiratoryGastrointestinalOther

Killed Influenza Vaccine

• Developed by Thomas Francis, Jr, Jonas Salk and others

• Influenza Virus incoluated into allantoic cavity of eggs• Working seed bank developed (month 2)• Cell culture methods approved

• Utilized virus grown and killed • Formalin or beta-propiolactone• Reagents standardized• Filling, safety release

Influenza Virus Vaccine Cycle Northern Hemisphere

• February: • WHO recommends influenza

strains for next year• Three strains selected for

trivalent vaccine

• FDA provides seed strains to manufacturers• Goal: Final product testing

by 1 Aug• Final approval by or in Sept http://www.nature.com/news/2009/090512/full/459144a/box/1.html

Breadth of Application

• The net number of infectious diseases targeted has remained steady since 1981

• Most advancements have arisen from improvements of existing vaccines

-1

0

1

2

3

4

5

Before…

1901-1

910

1911-1

920

1921-1

930

1931-1

940

1941-1

950

1951-1

960

1961-1

970

1971-1

980

1981-1

990

1991-2

000

2001-2

010

2011-2

015

Indi

catio

ns T

arge

ted

0

5

10

15

20

25

Before 1900

1901-1

910

1911-1

920

1921-1

930

1931-1

940

1941-1

950

1951-1

960

1961-1

970

1971-1

980

1981-1

990

1991-2

000

2001-2

010

2011-2

015

Infe

ctio

us D

iseas

es (N

et)

Vaccine Withdrawals

• Most vaccines withdrawn due to Obsolescence (replacement by a superior product)

• Remarkably few withdrawn due to toxicity Obsolescence, 41

Efficacy, 5

Toxicity, 2Market, 3

What Evidence Links Vaccines to Autism?

Vaccine Deniers

• Anti-vaccine movement

• Provoked by scandalous report linking vaccines to autism• Suggested link with thimerosol (mercury)

preservatives• Andrew Wakefield study thoroughly

discredited

• Movement surprisingly active

amongst educated Americans

• Increasing US incidence of measles, whooping cough, other preventable infections Council on Foreign Relations

MeaslesWhooping cough

Vaccines for Cancer:

• Gardasil Approved for Prevention of HPV infection• Linked to cervical and other cancer

• Virus Like Particle (VLP) that self-assembles into a virion lacking nucleic acid

• Other Cancer Vaccines the Subject of Next Lecture http://www.discoverymedicine.com/Richard-Roden/files/2009/08/roden_35_fig2.jpg.jhtml?id=2

The Lecture in a Single Slide

• Vaccines Have Been Used Since At Least the Beginning of the 19th

Century

• While Understanding about Infectious Agents and Vaccines Has Improved Dramatically, the Breadth of Agents Targeted with Vaccines Has Not Kept Pace

• The Anti-Vaccine Movement Foreshadowed the Return of Avoidable Childhood Diseases