Vaccine Development

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Vaccine Development Polio Vaccine
Module 3 Vaccines PHB 4498 2003

Joseph B. McCormick, MD, MS Regional Dean and
James H. Steele Professor
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Iterative Steps to a Vaccine
Vaccine
Manufacture
Pivotal-Phase 3 trail
Phase 1, 2 trails
Pilot Lots
Preclinical
Process development
Pathogenesis
Basic Research
Epidemiology
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Basic Research
What causes the disease? HIV SARS Polio
Is it an infectious disease? Kochs postulates?
Is there recovery and what is the mechanism?
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Early History of Polio

• Egyptian Stele from 1580-1350 BC depicts a young
  man with a shortened
• and withered leg in a position typical of flaccid
  paralysis.
• Conclusion Polio has been plaguing humans for
  millennia

• 1789 Michael Underwood First description of
  polio as distinct disease

• 1907 After many different names poliomyelitis was
  finally accepted as the
• standard Polios gray (Greek word), myelos
  marrow, gray matter of
• spinal cord, Itisinflammation.

• Late 1900th and early 20th century endemic polio
  in Norway and Sweden
• Became epidemic. In New York in 1916 9000 cases
  were identified

• 1908 Landsteiner and Popper reported a
  filterable agent caused polio.

• 1931 Burnet and McNamara determined that 3
  strains of polio existed,
• And that serum was protective against homologous
  virus only.

• 1949 Enders Weller and Robbins grow poliovirus on
  non neural tissue

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Polio, the disease
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Polio, the disease
In 1921, outbreaks of poliomyelitis plagued
America. That summer, a young politician named
Franklin Delano Roosevelt, after a day fighting a
local forest fire, took cool swim for relief, and
later went to bed feeling as though he had
contracted a cold. In a few days Roosevelt
developed the paralytic form of polio.
Polio Natural History
Virus entry nose or mouth Incubation
intestine Symptoms Most are asymptomatic or
10 with flu-like symptoms, such as headache,
nausea, vomiting, and fever Infectious Patients
are infectious at this stage Transmission Contact
with infected feces or through infected
droplets, in food, or in water. Neurologic
1 develop the paralytic form of
polio Immmunity Lifelong to natural infection,
booster required after vaccine
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Polio, the disease
Roosevelt was one of the unlucky ones. His legs
were left permanently paralyzed. In such cases
the virus reaches the brain and spinal cord where
it multiplies and destroys the nerve tissue.
The disease becomes spinal or bulbar (involving
the last four or five cranial nerves), depending
on which nerves are affected. Both forms are
characterized by muscle pain, stiff neck and
back, and possible paralysis. The spinal form
affects the limbs. The bulbar form affects the
lungs so that patients cannot breathe (the iron
lung). There is no treatment for the paralytic
form, although muscular paralysis can be helped
with physical therapy.
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Earliest Questions Requiring answers

• What causes the disease Studies by Landsteiner
  and Popper 1905-1908

• The microscopic changes seen after autopsy of
  cases of polio
• were typical and unique, that is inflammation
  of the grey marrow
• of the spinal cord of humans.

• Landsteiner and Popper took some of the spinal
  cord from a
• fatal case of polio, ground it up, filtered it
  (to rule out bacterial causes)
• and injected the material into the cerebrospinal
  fluid of two monkeys.

• The monkeys came down with a clinical disease
  like polio. At autopsy
• they had the same lesions under the microscope as
  did humans who
• died of polio.

• This was a relative fufillment of Kochs
  postulates therefore the
• conclusion was that a filterable agent (virus)
  caused polio.

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Pathogenesis
Does the organism cause the disease
directly? HIV polio Lyme disease
Does the host response cause most of the
disease? Lyme HIV Polio Hantavirus
infections Dengue virus
Is the infection persistent? HIV Polio Herpes
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Earliest Questions Requiring answers

• Early experiments (by Sabin) to grow polio virus
  in tissue culture
• showed that it would only grow in neural tissue.
  Therefore thought
• to somehow mysteriously infect spinal cord.

• How does it cause disease 1940s two groups
  demonstrated
• oral transmission of polio virus to monkeys and
  showed they
• had subclinical infection and then were immune to
  further
• infection. Thus experimental evidence of oral
  transmission and immunity.

• Finally in 1949 Enders, Robbins and Weller showed
  that virus
• could be grown in non-nervous tissue, opening the
  door to a
• vaccine. This required over 600 blind passages
  over a period
• of many years.

• This led to the capacity to quantitate virus, to
  quantitate antibody
• to the virus, to isolate virus from patients and
  to type virus.

• This also allowed cloning viruses,
  indispensable in the development
• of vaccines

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Pathogenesis-Recovery
Is recovery associated with immune
response? Polio HIV Lyme Herpes
Is the organism cleared by the immune
response? Polio HIV Lyme Herpes
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Prevention in animal or other model

• Are animals able to be infected?

• Does the disease, if any, mimic that in humans?

• Does the immune response in the animal
• correlate with clearance of virus or bacteria?

• Does the antibody neutralize virus or kill
  bacteria?

• Does the immune response in the animal protect
• from subsequent infection?

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The making of the vaccine

• Two approaches to making vaccine were taken
• Sabin, Cox and Koprowski took live attenuated
  vaccine approach
• Salk took inactivated vaccine approach

• Inactivated Vaccines
• Salk grew the 3 viruses in tissue monkey kidney
  tissue culture.
• Formalin for inactivation
• They titrated how much formalin was required to
  kill
• various amounts of virus

• Performed safety studies in monkeys to insure
  complete
• inactivation

• Conducted vaccine studies in animals (monkeys) to
  test the
• capacity of the inactivated virus to prevent
  infection.

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The Testing of the Vaccine

• By early 1954 sufficient steps were considered
  to have been taken
• to test the vaccine in humans

• Thomas Francis of the University of Michigan
  School of Public
• health led the trial. 1,829,916 children from
  the United States,
• Canada and Finland participated in the trial. It
  was the largest such
• trial ever conceived.

• Previous trials in 1939 had been ill conceived
  and disastrous with
• people inoculated with inactivated neural tissue
  getting polio in
• the inoculated limb.

• April 12, 1955 results presented showing 70
  efficacy and a
• Correlation between efficacy and antibody
  response.

• Based on the trials, products of 6 companies were
  licensed a few
• days later by the FDA.

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Attenuated Polio Vaccine- Development
The concept of attenuation of live organisms for
induction of immunity dates to Jenner (cowpox)
and Pasteur (Rabies).

• The first attenuation in tissue culture was by
  Theiler (Yellow fever)

• Assumed that infectons by live attenuated
  organisms more
• nearly approximated natural infections, giving
  lasting immunity.

• For Polio the characteristics sought for
  attenuated strains
• capacity to infect the gut and induce
  neutralizing antibody
• inability to infect the central nervous system
• genetic stability (no reversion to neurological
  virulence)

• Methods were trial and error, passing through
  tissue culture
• then animals. Outcome was lack of virulence and
  ability to produce
• antibody.

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Attenuated Polio Vaccine- Development

• Numerous tests of various candidate live vaccines
  were conducted
• Immunogenicity was a prime concern
• Genetic stability and neurological virulence
• Standard adopted for safety was intracerebral
• inoculation of monkeys

• Field Trials of various sizes were conducted
  throughout the world
• Few further trials conducted in the US

• At first types 1, 2 and 3 attenuated polioviruses
  were given seperately
• because of interference, latter the amounts were
  adjusted and
• they were given together.

• 1957 WHO recommended field trials with Sabin
  strains
• 1958 in Singapore (200,000 children)
• 1958-1959 Russian trials (Chumakov using Sabin
  strains)
• 15 million children vaccinated in Russia
• 1960 100 million in Russia and Eastern Europe

• 1960 the Sabin attenuated strains were licensed
• In 10 years from tissue culture isolation to
  effective vaccines

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Some stumbling blocks
What happens if some killed vaccine is still
alive?
Can there be other viruses hiding in the tissue
culture Of live attenuated vaccine? Simian virus
40 and the HIV controversy
Can the live vaccine be transmitted and can there
be disease associated with the live attenuated
Vaccine?
The vaccine cold chain, and use in tropical
countries.
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Polio Vaccine
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Polio Vaccine
University of Michigan
April 12, 1955 Result of Francis Field Trial
60-90 polio vaccine efficacy
Francis and Salk
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Polio Vaccine

• April 12, 1955 effective vaccine announced
• April 2526, 1955 cases seen after vaccination

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Polio Vaccine
Person

• Who?
• How many?
• Characteristics?

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Polio Vaccine
Persons

• Who (age, sex)?
• How many (6, 60 or 600)?
• Characteristics (case definition,
• vaccinated, paralytic or no)?

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Polio Vaccine
Person

• Who (age, sex) (School Children, Both sexes)
• How many (From April 17 to May 24 1955
• there were 81 cases associated with
  vaccination)?
• Characteristics (48 paralytic, 33
  non-paralytic)?

• 4,869,000 doses of vaccine given or a rate
• of 1.7 cases per 100,000 vaccine doses

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Polio Vaccine
Cases of Polio after Vaccination April 17 to May
14 1955
Nathanson and Langmuir Am. J. Hyg. 1963
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Polio Vaccine
Cases of Polio after Vaccination April 17 to May
14 1955
Nathanson and Langmuir Am. J. Hyg. 1963
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Polio Vaccine
Poliomyelitis cases associated with Cutter
Vaccine April 17-June 30, 1955
Place
Nathanson and Langmuir Am. J. Hyg. 1963
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Polio Vaccine
Nathanson and Langmuir Am. J. Hyg. 1963
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Polio Vaccine
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Polio Vaccine
Per Cent
Incubation Period (days)
From Nathanson and Langmuir Am. J. Hyg. 1963
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Polio Vaccine
Correlation between sites of inoculation and
firstparalysis among paralytic vaccinated polio
cases
Nathanson and Langmuir Am. J. Hyg. 1963
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Selection of Vaccine Candidates

• Is this disease amenable to prevention by a
  vaccine
• Does natural infection confer immunity?
• Have protective vaccines been developed
  before?
• Do immune responses correlate with protection?

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Selection of Vaccine Candidates

• Does the disease burden warrant investment
  
• of resources to develop a vaccine?
• Can the vaccine attract financial
• resources needed for development to
• licensure and use as a public health tool?

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Priority Setting for Health Related
Investments Vaccine Priorities in Developing
Countries

• Multiattribute Accounting Requires least
  quantification and fewest assumptions

Step 1 Specify alternatives (disease candidates
for vaccine) Step 2 Define criteria (costs,
benefits) this defines a table Step 3 Fill in
the values in the table Step 4 Determine a
relative order of alternatives based on all
objectives Step 5 Ranking of projects (by
decision makers)
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Hypothetical Table of Multiattribute Accounting
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Vaccine Prediction Table
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Accessing Likely Utilization of New Vaccines

• Availability (manufacture, profits, legal
  concerns, humanitarian)
• Capacity of health care system to deliver vaccine
• Statutory Requirements (e.g school immunization
  requirements, travellers)
• Target population
• access to health care
• socioeconmic status
• education status
• perception of vaccine efficacy and safety
• perception of chance of getting disease
• Vaccine characteristics (route, storage, delivery
  cost etc)
• Patient acceptance (route, doses, reactions,
  cost)
• Provider attitudes (efficacy, safety, liability,
  simplicity, profits)

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Calculation of Potential Health Benefits
Disease Burden Estimates
(Adjust for disease undesirability (IME))
Total disease Burden Value
(Adjust for proportion vaccine preventable)
Vaccine preventable Illness Value
(Adjust for vaccine efficacy)
Expected annual reduction in morbidity and
mortality
(Adjust for estimated success And time of
benefits)
Present Value of annual potential health benefits
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Calculation of expenditures on vaccines
Define Target population Estimates annual
number of New vaccinees (cost per dose
doses) Cost of vaccines for immunzation Program
(Adjust for success and time) Annualized value
of vaccine costs
Estimation of vaccine development cost Adjust
for discount rate Annualized cost of
development
Annualized present value of potential
expenditures on vaccines
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Central Analysis
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Ranking
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Tuberculosis Vaccine Action Plan- NIAID

• 1) Vaccine-targeted Laboratory Research
• Improved animal models of tuberculosis,
• persistent infection and reactivation disease.
• Elucidate mechanisms
• 1) M. tuberculosis bacteria, and the host
  response to those bacteria, cause tissue
  damage and
• 2), model animals and the human host protect
  themselves immunologically from disease.
• Identification of immunologic correlates of
  animal and human protection
• Identification of protective antigens and
  virulence genes of M. tuberculosis
• .
• Development of diagnostic tools that distinguish
  individuals infected with M. tuberculosis
  infection from individuals with active
  tuberculosis disease from individuals previously
  vaccinated with BCG.
• Necessary expertise for this research will likely
  be drawn largely from the academic community with
  contributions from interested industry
  scientists. To effectively streamline the vaccine
  development process, the above areas of basic
  research should be pursued simultaneously with
  limited empiric testing of vaccine candidates in
  the best available animal models.

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Tuberculosis Vaccine Action Plan- NIAID

• .2) Production Of Vaccine Candidates for Animal
  and Human Testing
• Establish pilot manufacturing facilities that
  meet Good Manufacturing Practice (GMP) standards
  for products to be delivered to human subjects.
  GMP facilities may be most readily found in
  industrialized countries, but developing country
  scientists should be involved in the
  manufacturing process to increase trust in the
  product in countries where efficacy trials may be
  held.
• NOTE A successful scale-up manufacturing plan
  should be developed for each candidate that will
  enter a large efficacy trial before the start of
  the trial.
• Establish repositories for human and animal
  samples acquired during trials.
• Identify and develop adequate reagent sources and
  supplies.
• Develop assays for the efficient evaluation of
  vaccine candidates in animal and human trials.
• Manufacturing expertise will likely be drawn
  primarily from industry.

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Tuberculosis Vaccine Action Plan- NIAID
3. Testing in Human Subjects

• Phase I (safety and immunogenicity) trials will
  require protocol development and preparation of
  trial sites. These could be in the US, other
  industrialized nations and/or developing
  countries. Such trials typically involve 10-60
  human subjects. The necessary preparations may
  include infrastructure development, training, and
  epidemiological and surveillance groundwork,
  depending on the needs of the site.
• Phase II (expanded safety and immunogenicity)
  trials may require establishment of data
  coordinating centers, central laboratory
  facilities and/or standardized methodologies, a
  Data and Safety Monitoring Board and a
  coordinated mechanism for candidate vaccine
  selection. These trials typically involve a few
  hundred human subjects.
• Phase III (large efficacy) trials involving
  thousands of subjects
• require more substantial infrastructure,
  sophisticated trial design, and intensive
  pre-trial epidemiologic studies and surveillance
  to determine the local prevalence and incidence.

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Tuberculosis Vaccine Action Plan- NIAID

• Phase III trials will need to occur in
  populations with high prevalence and incidence of
  tuberculosis, and therefore are likely to involve
  sites in developing (as well, perhaps, as in
  industrialized) countries.
• Phase III trial sites may be used initially
  (while new candidate vaccines are in earlier
  stages of development) to learn more about BCG
  and what factors are responsible for its variable
  efficacy against tuberculosis in different
  settings and in childhood extrapulmonary versus
  in adult pulmonary tuberculosis.
• Understanding the failure of BCG in some parts
  of the world would contribute a great deal to
  the ability to create a more effective
  tuberculosis vaccine. Successful Phase III
  trials will likely require a pre-established an
  agreement and cooperative effort among
  international and US funding and regulatory
  agencies, industry, academic scientists,
  tuberculosis control programmes, and involved
  governments.

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Tuberculosis Vaccine Action Plan- NIAID

• All phases of vaccine testing in human volunteers
  will likely require
• Staff training at clinical trial sites located in
  developing and industrialized countries.
• IRB and ethical reviews by all involved
  countries.
• Optimization through expanded animal model
  testing.
• Disease monitoring and treatment.
• HIV testing and subsequent counseling of human
  volunteers.
• Workshops for government and health care staff in
  trial site countries.
• Adequate sources of reagents and supplies.
• Core laboratory facilities for use of
  standardized methods and assays.

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Iterative Steps to a Vaccine
Vaccine
Manufacture
Pivotal-Phase 3 trail
Phase 1, 2 trails
Pilot Lots
Preclinical
Process development
Pathogenesis
Basic Research
Epidemiology