Vaccines

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Vaccines

• Material producing an immune reaction and an
  acquired immunity to a natural microorganism
• Dictionary of Biology, 1995

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• Immunisation is the most generally applicable
  way of preventing infectious disease.
• The control of so many important ... diseases by
  immunisation is arguably the most outstanding
  medical achievement of the twentieth century,
  recognised by the award of several Nobel prizes
• White Fenner, Medical Virology, 1994

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VACCINES

• One of the most important inventions ever
• Some of the most deadly diseases of recent times
  have been controlled by vaccination

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What is a Vaccine?

• Classical Vaccines can be
• crippled or attenuated organisms
• dead organisms (inactivated vaccines)
• individual proteins or other subunits
• synthetic or purified polymers eg polysaccharide,
  conjugated to a carrier
• A vaccine is introduced into people to give a
  protective immune response that mimics natural
  infection without causing disease SAFE
  EFFECTIVE

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Why Have Vaccines?

• Every year, up to three million children's lives
  are saved by immunization
• http//www.vaccinealliance.org/

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• Since the introduction of vaccines, rates of
  diseases such as polio, measles, hepatitis B,
  rubella, diphtheria, pertussis (whooping cough),
  and meningitis caused by Haemophilus influenzae
  type B (Hib) have declined by 90.
• Pertussis vaccine saves over 600 000 lives.
  Diphtheria has almost disappeared in some major
  regions. Hib infections in children have almost
  disappeared in the USA within 10 years of
  immunisation. Hepatitis B immunisation has caused
  a significant drop in the incidence of
  hepatocellular carcinoma.

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Bacterial Vaccines

• Brucella Vaccine
• Cholera Vaccine
• Diphtheria-Tetanus-Pertussis Vaccine
• Pertussis Vaccine
• Plague Vaccine
• Rickettsial Vaccines
• Staphylococcal Vaccines
• Tuberculosis Vaccines
• Diphtheria-Tetanus Vaccine
• Escherichia coli Vaccines
• Haemophilus Vaccines

• Anthrax Vaccines
• Diphtheria-Tetanus-acellular Pertussis Vaccines
• Salmonella Vaccines
• Shigella Vaccines
• Meningococcal vaccine
• Lyme Disease Vaccine
• Streptococcal Vaccines
• Toxoids
• Diphtheria Toxoid
• Staphylococcal Toxoid
• Tetanus Toxoid

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Viral Vaccines

• Rotavirus Vaccines
• Japanese Encephalitis Vaccines
• Parainfluenza Vaccines
• Respiratory Syncytial Virus Vaccines
• Herpesvirus Vaccines
• Cytomegalovirus Vaccines
• West Nile Virus Vaccines
• Ebola Vaccines
• Dengue Vaccines
• Papillomavirus Vaccines

• Influenza virus vaccine
• Measles Vaccine
• Mumps Vaccine
• Poliovirus Vaccines
• Rabies Vaccines
• Rubella virus vaccine
• Smallpox Vaccine
• Viral Hepatitis Vaccines
• Measles-Mumps-Rubella Vaccine
• AIDS Vaccines
• Pseudorabies Vaccines
• SAIDS Vaccines
• Yellow Fever Vaccine

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Conjugate Vaccines

• Semisynthetic vaccines consisting of
  polysaccharide antigens - from microorganisms or
  synthesised - attached to protein carrier
  molecules.
• The carrier protein is recognized by macrophages
  and T-cells thus enhancing immunity. Conjugate
  vaccines induce antibody formation in people not
  responsive to polysaccharide alone, induce higher
  levels of antibody, and show a booster response
  on repeated injection.
• Examples are H. influenza (Hib), N. meningitidis
  and S. pneumoniae

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and diseases with no vaccine or expensive
vaccines
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ERADICATION OF SMALLPOX - THE MOST SUCCESSFUL
VACCINE CAMPAIGN EVER

• Smallpox (variola) has been known for centuries
  and as recently as 1968 killed 2 million persons
  annually.
• Most people with smallpox would die or be
  severely disfigured or blinded
• In 1967 there were 10 million cases of small pox
  in 44 countries - 250 million vaccine doses were
  needed each year
• WHO decided to get rid of smallpox by embarking
  on a vaccine campaign to cover the whole planet
• The last cases of smallpox were in Somalia in
  1977 and in UK in 1978 (lab escape).

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• Somalia, 1977 -
• Ali Maalim, last recorded case of
  naturally-caused smallpox
• http//www.cdc.gov/od/ogh/smallmaa.htm

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WHY DID THE SMALLPOX ERADICATION CAMPAIGN WORK?

• Effective vaccine which protected for many years
• Smallpoxvirus did not have a host besides man
• Symptoms of disease easy to identify - few
  subclinical cases and no reinfections
• It was such a dreaded disease that most people
  wanted to be vaccinated
• GOVERNMENTS GOT INVOLVED
• VACCINATION WAS FREE

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Smallpox Vaccines - old

• c. 1000 The Chinese inoculated their patients by
  snorting the powdered scabs of smallpox victims.
  Another method of their inoculation was by
  scratching the powder into their skin
  (variolation).
• By the 1700s, this method of variolation was
  common practice in China, India, and Turkey. In
  the late 1700s European physicians used this and
  other methods of variolation, but reported
  "devastating" results in some cases. 2 to 3 of
  people who were variolated died of smallpox, but
  this practice decreased the total number of
  smallpox fatalities by 10-fold
• Edward Jenner invented vaccination on May 14,
  1796, by inoculating James Phipps with material
  from the cowpox blisters of the hand of Sarah
  Nelmes, a milkmaid who had caught cowpox from a
  cow called Blossom.
• Dr. Kuwata, who was the pioneer of vaccination in
  Japan, vaccinated more than 70,000 people. He
  died with a vaccination needle in his hand in
  1868.

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Smallpox Vaccines - new

• At some time during the nineteenth century, the
  virus used for smallpox vaccination ceased to be
  cowpox and changed to vaccinia probably derived
  from camelpox.
• Dryvax (Wyeth) is a live-virus preparation of
  vaccinia virus prepared from calf lymph, first
  approved in 1931.
• Existing doses of Dryvax vaccine in USA were
  manufactured in the 1970s and early 1980s and
  stored frozen at -20C.
• 1,000 out of every 1,000,000 vaccinated people
  experienced reactions that were serious, but not
  life-threatening. Most of these reactions
  involved spread of vaccine virus elsewhere on the
  body.
• 14 - 52 people out of 1,000,000 vaccinated for
  the first time experienced potentially
  life-threatening reactions. These reactions
  included serious skin reactions and inflammation
  of the brain (encephalitis).

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History of
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Biotechnology of
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Monkeypox
Monkeypox was first identified in laboratory
monkeys in 1958, and the first human case was
reported in 1970 in a child in the Democratic
Republic of the Congo. It is now considered
endemic in parts of central and western
Africa. In May of 2003, the first cases in the
USA of monkeypox were reported among members of a
family in Wisconsin, who had bought two prairie
dogs as pets 11 days before the mother developed
fever, headache, sore throat, dyspnea, and
malaise along with a small papule, then a more
severe rash with more than 200 lesions. The
daughter presented with more severe illness that
included rash, lymphadenopathy, malaise, enlarged
tonsils, and fever. She eventually developed
encephalitis, became unresponsive, and required
intensive care. A fourth case was diagnosed in
the distributor of exotic animals who had sold
the two prairie dogs to the family first
affected, thus establishing an epidemiological
link between them (Reed et al., 2004). In this
outbreak, 72 cases of monkeypox were reported to
the CDC Epidemiological investigation revealed
that those two prairie dogs and others were
co-housed with an infected Gambian giant rat from
Ghana and other exotic rodent species.
Smallpox vaccine is effective at protecting
people against monkeypox when it is given before
they are exposed to monkeypox.
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• Jun 5, 2007 (CIDRAP News) US officials have
  announced the award of a 500 million contract to
  Bavarian Nordic A/S, a Danish firm, for 20
  million doses of a smallpox vaccine that's
  expected to be safe for people with weakened
  immune systems.
• The "next generation" smallpox vaccine, called
  Imvamune, is the company's version of modified
  vaccinia Ankara (MVA).
• MVA is a form of vaccinia virus weakened so that
  it can't replicate in humans, but does grow in
  eggs.

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Poliomyelitis - Eradication in the New Millenium?

• Dreadful disease causing paralysis - in the 1950s
  many people were put in iron lungs in developed
  countries (and died elsewhere)
• In the late 1950s vaccines became available
• Poliomyelitis is almost eradicated!!

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• http//www.who.int/vaccines-polio/

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Things your children wont have to
worry about...
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• Three-year-old child in an iron lung in the
  1930s

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• In 1935 Maurice Brodie produced a
  formaldehyde-killed polio vaccine from ground-up
  monkey spinal cords. He gave the vaccine to three
  thousand children many developed allergic
  reactions, but none developed immunity to polio.
• In 1948 John Enders, Thomas H. Weller and
  Frederick C. Robbins successfully cultivated
  poliovirus in human tissue. They received a Nobel
  Prize in Physiology or Medicine in 1954.
• Other important findings were the identification
  of three poliovirus serotypes (Poliovirus type 1
  (PV1 or Mahoney), PV2 (Lansing), and PV3 (Leon))
  and
• preceding paralysis, the virus must be present in
  the blood, and
• the administration of antibodies in the form of
  gamma-globulin protects against paralytic polio.

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• The first effective polio vaccine was developed
  in 1952 by Jonas Salk. This inactivated
  poliovirus vaccine (IPV), is made from the wild
  Mahoney (type 1 poliovirus), MEF-1 (type 2
  poliovirus), and Saukett (type 3 poliovirus)
  strains, grown in monkey kidney tissue culture
  (Vero cell line) and inactivated with formalin.
• The injected Salk vaccine confers IgG-mediated
  immunity in the bloodstream, which prevents polio
  infection from progress to viraemia and protects
  the motor neurons.
• It offers no protection to the mucosal lining of
  the intestine, so vaccinated people can still
  carry the disease and spread it to unvaccinated
  individuals.
• Salk's vaccine was licensed in 1955, and
  immediately children's vaccination campaigns were
  launched.

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• Albert Sabin developed the oral polio vaccine
  (OPV) by 1961. This is a live-attenuated vaccine,
  produced by the passage of the virus through
  non-human cells at a sub-physiological
  temperature, which produces spontaneous mutations
  in the viral genome.
• The Sabin vaccine replicates very efficiently in
  the gut, the primary site of infection and
  replication, but not within nervous system
  tissue. OPV is superior in administration, and
  also provides longer lasting immunity than the
  Salk vaccine.
• As the incidence of wild polio diminishes,
  nations transition from use of the oral vaccine
  back to the injected vaccine because the risk of
  vaccine-related polio outweighs the risk of
  subclinical transmission.

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Contamination concerns

• In 1960, rhesus monkey kidney cells used to grow
  IPV were found to be infected with Simian Virus
  40.
• In 1961, SV40 was found to cause tumours in
  rodents. More recently, it was found in certain
  human cancers. However, it has not been
  determined that SV40 causes these cancers.
• SV40 was found in stocks of IPV used between 1954
  to 1962, but not in the OPV (licensed later).
• 10 - 30 million Americans may have received a
  dose of vaccine contaminated with SV40.

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• Vaccines produced by the former Soviet bloc
  countries until 1980, and used in the USSR,
  China, Japan, and several African countries, may
  have been contaminated meaning hundreds of
  millions more may have been exposed to SV40.
• A large study in Sweden examined cancer rates of
  700,000 individuals who had received potentially
  contaminated polio vaccine as late as 1957 the
  study revealed no increased cancer incidence
  between persons who received polio vaccines
  containing SV40 and those who did not.

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• In 1988, the 41st World Health Assembly - 166
  Member States - launched a global initiative to
  eradicate polio by the end of the year 2000.
• In 11 years the number of cases fell by more than
  90 percent from an estimated 350 000 cases (and
  even further since).
• Widely endemic on five continents in 1988, polio
  is now concentrated only in parts of the Indian
  sub-continent - and now Africa, again!

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Polio eradication is based on four strategies

• Routine immunization of infants starting with
  four doses of oral live polio vaccine in the
  first year of life
• National Immunization Days (NIDs), which
  vaccinate all children FREE under five years of
  age (2 rounds per year for at least three
  consecutive years)
• Effective disease surveillance
• House-to-house 'mopping-up' to ensure that every
  child is vaccinated.
• The target date for certification of the world as
  polio-free WAS 2005.

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Influenza
KILLED WHOLE-VIRUS VACCINE
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• The virus is injected into the fluid surrounding
  the embryo.
• The egg is resealed, the embryo is infected.
• The virus is harvested and purified
• The virus is inactivated with sodium
  deoxycholate and formaldehyde for split vaccines
  for injection.

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Live Flu Vaccines

• These strains are
• cold-adapted (ca) (i.e., they replicate
  efficiently at 25C, a temperature that is
  restrictive for replication of many wild-type
  viruses)
• temperature-sensitive (ts) (i.e., they are
  restricted in replication at 37C (Type B
  strains) or 39C (Type A strains), temperatures
  at which many wild-type influenza viruses grow
  efficiently) and
• attenuated (att) so as not to produce classic
  influenza-like illness in the ferret model of
  human influenza infection.
• They are grown in eggs like split vaccines, but
  administered nasally and not by injection

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Number of U.S. flu cases per season 29 million
to 58 million Number of Americans hospitalized
per season 114,000 Number of deaths
36,000 Number of vaccine doses produced in a
season 87.1 million

• World maximum capacity of 450 million doses/yr

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Drawbacks

• Vaccine companies must place their egg orders
  six months in advance
• Each egg is inoculated with only one virus strain
  and produces enough for 1-2 doses, so
  approximately two to three eggs are required per
  vaccine. This process consumes 270 million or
  more for the United States alone
• When a pandemic is looming, vaccine companies
  must manufacture as much as ten times more
  vaccine than they would normally produce.
• The egg method isnt very flexible if you need
  to rapidly ramp up vaccine supply - you cant
  tell a chicken to lay more eggs.

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Nature (26 May 2005) Erica Check explains that
pharmaceutical companies have little incentive to
invest large sums of money making a vaccine for a
pandemic that might never happen. Developing
countries in Asia, which are most likely to be
the source of pandemic, have little capacity to
make vaccines or buy stocks from other countries.
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US
Developed world
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Successful New Vaccines.
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Hepatitis
Recombinant / killed vaccine

• More than 2 billion people alive today have at
  some time been infected with the hepatitis B
  virus (HBV). Of these, about 350 million remain
  chronically infected carriers. Every year there
  are over 4 million acute clinical cases of
  hepatitis B and about a million deaths.
• Get vaccinated! Hepatitis B is preventable.

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Hepatitis A
KILLED WHOLE- VIRUS VACCINE

• The virus is spread through the faecal-oral
  route, most often through person-to-person
  transmission. It may also be spread through
  contaminated food or water.
• An estimated 1.4 million cases of HAV infection
  occur worldwide each year. The overall case
  fatality rate is estimated to be 0.3.
  http//www.cdc.gov/ncidod/diseases/hepatitis/slide
  set/httoc.htm

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Rotavirus

• Acute diarrhoea is responsible for nearly 1.9
  million deaths per year in children under age
  five. Rotavirus is responsible for as much as 25
  of these, almost all of which occur in developing
  countries.
• GlaxoSmithKline and Merck both have new rotavirus
  vaccines licenced.
• These have been introduced in the public sector
  immunization programmes of Brazil, El Salvador,
  Mexico, Panama, Nicaragua and Venezuela
  http//www.who.int/mediacentre/factsheets/fs289/e
  n/index.html

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Papillomavirus

• Gardasil, recently licensed by Merck, covers the
  cancer-causing types 16 and 18 and types 6 and 11
  for genital warts. A second vaccine, developed by
  GSK, covers HPV types 16 and 18 alone and is
  expected to be licensed in 2007.
• The Merck vaccine sells for US120 / doseand 3
  doses are required

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Pneumococcus

• Pneumococcus causes serious infections in adults
  and children, including pneumonia, blood
  infections, meningitis, sinusitis and ear
  infections.
• Prevnar, or heptavalent pneumococcal conjugate
  vaccine (PCV7), is newly available (2000) and can
  be given to younger children. It includes seven
  purified capsular polysaccharides of S.
  pneumoniae, each coupled with a nontoxic variant
  of diphtheria toxin
• A 23-valent polysaccharide vaccine (23PS) is
  recommended for people over age 65 and children
  over age two who are at high risk.

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Haemophilus influenzae type B (Hib)

• Illnesses caused include meningitis, pneumonia,
  and infections of the blood, bones, and joints.
  Serious infections are most common in children 6
  to 12 months old, but may also occur in older
  children.
• Conjugate vaccines introduced in 1992 purified
  polysaccharide capsule conjugated to diphtheria
  or tetanus toxoid.

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South Africa vaccines

• In South Africa, the last polio case due to the
  wild poliovirus was reported in 1989.
• The final countdown to a polio free South Africa
  was launched on 11 April 2002.
• Vaccines are free of charge at local clinics and
  community health centres in South Africa.
• All children have a right to basic health care.
  NB. Immunisation is one of the health care
  components.
• The government of South Africa currently devotes
  more than R80 million/yr to vaccines.
• The birth cohort in SA each yr is 1.1 million

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So Things are Fine?

• ...almost three million ... lives worldwide are
  lost from diseases that are preventable with
  existing vaccines.
• http//www.vaccinealliance.org/

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• Of children who die before their fifth birthday,
  98 are in the developing world.
• Of people who are HIV positive, some 95 are in
  poor countries.
• Of the millions who die prematurely of
  tuberculosis, malaria, measles, tetanus and
  whooping cough, nearly all live in the poor
  world.
• Tuberculosis alone kills more people each year
  than lung cancer, the terror of the West. The
  Economist, 14th August 1999

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Effective Vaccines Not Commonly Used in
Developing Countries

• Japanese encephalitis virus
• Hib
• Typhoid
• Rubella
• (Cholera)
• HBV
• HAV

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What Cheap Vaccines Do We Need?
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How Vaccines are Developed
Preclinical development Manufacture (GMP)
Basic research
Clinical trials
Phase I/II
Phase III
Laboratory
Human research
in vitro animal studies
Safety, Immunogenicity
Discovery
Exploration
Efficacy
Vaccine concept
Experiments in rodents and primates
Human trials
Safety, immunogenicity
Likelihood of protection in humans
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Challenges for Public Health Sector to Global
Vaccine Use

• Safe Vaccines
• Cost Effective Vaccines
• Vaccine administration must be easily implemented
• infants (eg routine childhood vaccines)
• targeted populations (eg rubella vaccine
• Vaccine Supply should be assured
• Procurement and financial sustainability

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36 million children not immunized (DTP3), 2001
3 million children die of EPI vaccine preventable
diseases every year
Source WHO/UNICEF estimates, 2002
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Global Immunisation 1980-2001, DTP3
coverage global coverage at 73 in 2001
Source WHO/UNICEF estimates, 2002
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Vaccine Safety

• Vaccine production
• Production quality control safety
• Batch lot consistency
• Delivery systems
• Needle free delivery
• Multi-dose vials
• Stability of vaccine (eg. cold chain)
• Vaccine-related adverse events
• Public perception, as much as reality

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Vaccine Safety Public Perception

• Vaccine-associated perception
• Autism and measles vaccine
• Hepatitis B vaccine and multiple sclerosis
• OPV in Nigeria today
• RotaShield and intussusception
• Reported association forced withdrawal of vaccine
• Resulted in new dimensions of vaccine trials for
  second generation candidates

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Vaccine Cost-effectiveness

• Global regional burden of disease
• Vaccine production costs
• Purification of vaccine antigens
• Quality control and regulatory costs
• Filling and formulation
• Clinical trials
• Production plants for GMP vaccine
• Competition with pharmaceutical industry
• Financial sustainability - elusive 1 per dose

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Vaccine Administration

• Currently we have cost effective vaccines against
  a range of childhood illnesses
• Challenge is getting the vaccine to the children
  who need it most
• Vaccines such as measles, hepB and Hib are not
  yet administered routinely