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Vaccines. “Material producing an immune reaction and an acquired immunity to a natural microorganism” Dictionary of Biology, 1995. “Immunisation is the most generally applicable way of preventing infectious disease.

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“Material producing an immune reaction and an acquired immunity to a natural microorganism”

Dictionary of Biology, 1995

“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

  • One of the most important inventions ever
  • Some of the most deadly diseases of recent times have been controlled by vaccination
what is a vaccine
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
why have vaccines
Why Have Vaccines?

“Every year, up to three million children's lives are saved by immunization“

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.
bacterial vaccines
Bacterial Vaccines
  • Anthrax Vaccines
  • Diphtheria-Tetanus-acellular Pertussis Vaccines
  • Salmonella Vaccines
  • Shigella Vaccines
  • Meningococcal vaccine
  • Lyme Disease Vaccine
  • Streptococcal Vaccines


    • Diphtheria Toxoid
    • Staphylococcal Toxoid
    • Tetanus Toxoid
  • Brucella Vaccine
  • Cholera Vaccine
  • Diphtheria-Tetanus-Pertussis Vaccine
  • Pertussis Vaccine
  • Plague Vaccine
  • Rickettsial Vaccines
  • Staphylococcal Vaccines
  • Tuberculosis Vaccines
  • Diphtheria-Tetanus Vaccine
  • Escherichia coli Vaccines
  • HaemophilusVaccines
viral vaccines
Viral 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
  • 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
conjugate vaccines
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

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).
Somalia, 1977 -

Ali Maalim, last recorded case of naturally-caused smallpox

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
smallpox vaccines old
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.
smallpox vaccines new
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 -20°C.
  • ~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).

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.

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.
poliomyelitis eradication in the new millenium
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!!





have to



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.
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.
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.
contamination concerns
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.
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.
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!
polio eradication is based on four strategies
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….


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.
live flu vaccines
Live Flu Vaccines
  • These strains are:
    • cold-adapted (ca) (i.e., they replicate efficiently at 25°C, a temperature that is restrictive for replication of many wild-type viruses);
    • temperature-sensitive (ts) (i.e., they are restricted in replication at 37°C (Type B strains) or 39°C (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

Number of U.S. flu cases per season:

29 million to 58 million

Number of Americans hospitalized per season:


Number of deaths:


Number of vaccine doses produced in a season:

87.1 million

World maximum capacity of 450 million doses/yr

  • 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 isn’t very flexible if you need to rapidly ramp up vaccine supply - you can’t tell a chicken to lay more eggs.”

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.



Developed world…


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.

Recombinant / killed vaccine

hepatitis a
Hepatitis A





  • 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%.

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
  • 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 US$120 / dose…and 3 doses are required
  • 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.
haemophilus influenzae type b hib
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.
south africa vaccines
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
so things are fine
So Things are Fine…?
  • “...almost three million ... lives worldwide are lost from diseases that are preventable with existing vaccines.”

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. TheEconomist, 14th August 1999
effective vaccines not commonly used in developing countries

“At present, vaccine development is based on current market demand rather than epidemiological realities.”

- WHO Vaccines Report, 1996

Effective Vaccines Not Commonly Used in Developing Countries
  • Japanese encephalitis virus
  • Hib
  • Typhoid
  • Rubella*
  • (Cholera)
  • HBV
  • HAV
how vaccines are developed
How Vaccines are Developed

Preclinical development

Manufacture (GMP)

Clinical trials

Basic research

Phase I/II

Phase III


Human research

in vitro & animal studies






Vaccine concept

Experiments in rodents and primates

Human trials

Safety, immunogenicity

Likelihood of protection

in humans

challenges for public health sector to global vaccine use
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

36 million children not immunized (DTP3), 2001

3 million children die of EPI vaccine preventable diseases every year

Source: WHO/UNICEF estimates, 2002


Global Immunisation 1980-2001, DTP3 coverage

global coverage at 73% in 2001

Source: WHO/UNICEF estimates, 2002

vaccine safety
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
vaccine safety public perception
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
vaccine cost effectiveness
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
vaccine administration
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