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Background Information
on Vaccines
Editorial BMJ 7040
British medical Journal
Page 1 of 3
BMJ
The legacy of Edward Jenner
More vaccines of different types are reaching ever more people
Two hundred years after the pioneering clinical experiments of Edward Jenner, who inoculated
humans with cowpox to prevent smallpox, we find ourselves at the threshold of a golden age of
vaccinology. Much attention has recently been directed at the advances in modern biotechnology that
are giving rise to exciting new vaccine candidates. Nevertheless, a long and arduous journey lies
between being an innovative concept and becoming a licensed product that can serve as a public
health tool. In fact, few concepts survive to become products. Less well appreciated are the advances
in clinical vaccine testing that allow a vaccine to progress towards licensing; the epidemiological
techniques devised to appraise its effectiveness after licensing, when the vaccine is used under real
life conditions; and the tactics used to achieve high levels of vaccine coverage, particularly in less
developed countries.
Biotechnology has opened entire new approaches to vaccine development, such as the rational and
precise attenuation of bacteria and viruses to serve as live vaccines, [i] the direct inoculation with
plasmid DNA encoding protective antigens ("naked DNA" vaccines), and the microencapsulation of
antigens to enhance immunogenicity and modulate the kinetics and type of immune response. [ii]
Consequently, at various stages in the pipeline we find vastly improved vaccines against infectious
diseases for which vaccines already exist - for example, acellular pertussis vaccines containing
purified antigens [iii] and a recombinant, single dose, live oral cholera vaccine [i] together with new
vaccines against diseases for which immunoprophylaxis was previously unavailable (malaria,
rotavirus [iv], and Lyme disease). Notably, several rotavirus vaccines that are advanced in clinical
trials follow a "Jennerian" approach in which an animal (rhesus monkey or bovine) rotavirus strain is
genetically manipulated (reassortant viruses) to express human rotavirus neutralisation antigens. [iv]
Vaccines are tested in a series of stepwise clinical trials. Phase 1 trials, performed in small numbers
of adults, are early dose-response tests to detect common adverse reactions and provide an initial
glimpse of whether relevant immune responses are generated. Most vaccine candidates never
progress beyond phase 1. Phase 2 trials, which assess the vaccine in increasingly larger numbers of
subjects, are typically placebo controlled to measure the rate of adverse reactions versus background
rates of complaints. The level of shedding of a live intranasal influenza vaccine or of a recombinant
live attenuated Vibrio cholerae 01 oral vaccine would also be examined in phase 2 trials, as would
their propensity to be transmitted to household contacts and to survive in the environment. For
vaccines that will ultimately be used in infants and children, phase 1 and 2 trials must be undertaken
in progressively younger subjects.
Particularly demanding is the design of phase 2 clinical trials to evaluate the reactogenicity and
immunogenicity of the new multivalent combination vaccines in infants. As additional vaccines -
such as hepatitis B, Haemophilus influenzae type b conjugate, and multiple component acellular
pertussis vaccines - enter infant immunisation regimens, a way must be devised to administer them
along with the fewest inoculations along with existing parenteral vaccines. The ultimate objective is
to combine vaccine antigens into a single inoculation. This raises the theoretical possibility of
interactions,[ so phase 2 trials must show that acceptable immune responses to all antigens can
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Editorial BMJ 7040
Page 2 of 3
indeed be stimulated without undue reactogenicity. Phase 1 and 2 trials of candidate AIDS vaccines
also require special considerations.
In some cases, as with vaccines to prevent influenza, shigella dysentery, [viii] or Plasmodium
falciparum malaria, [ix] preliminary assessments of efficacy can be obtained through carefully
performed experimental challenge studies with wild type organisms in fully informed adult
volunteers. Such modern day challenge studies are a direct legacy of Edward Jenner's experiments,
although today the study protocols undergo stringent ethical review, and children, such as Jenner's
young subject, James Phipps, would not be allowed to participate.
Large scale, randomised, controlled field trials remain the gold standard for showing the efficacy of a
vaccine. [iii,x] Such trials tend to be expensive, require several years to complete, and are subject to
the vagaries of year to year variation in the incidence of the disease. Moreover, in prelicensure
efficacy trials the protective activity of a vaccine is measured under ideal conditions, with extra staff
and with only fully vaccinated subjects included in calculations of efficacy. Therefore the practicality
of use of the vaccine within a programme is not readily estimated. Estimating efficacy after licensing
usually involves case-control studies, which are relatively inexpensive and simple to perform but
have inherent limitations that can distort the estimation of efficacy A few controlled
postlicensure trials have directly measured the effectiveness of vaccine under real life, programmatic
conditions.[xii]
Enhanced postlicensure epidemiological surveillance has proved its value by showing herd immunity
effects (as with H influenzae type b conjugate vaccine) and consequences in those who are not the
targets of the vaccine - for example, the rare occurrence of vaccine associated paralytic poliomyelitis
in household contacts of infants who have received Sabin live oral polio vaccine.
The ultimate triumph of vaccines is disease eradication. In the mid-1970s smallpox vaccine deployed
following special epidemiological strategies succeeded in eradicating the disease that Jenner
attempted to prevent in the 1790s. Polio has been eradicated from the western hemisphere, and
worldwide eradication is now a realistic goal. The World Health Organisation's expanded programme
on immunisation, descended from the smallpox eradication programme, has devised practical
solutions to maintaining a "cold chain" and delivering vaccines under field conditions in less
developed countries. During the past decade the percentage of the world's infants who receive the
basic vaccines of the expanded programme (BCG, DPT, oral polio, and measles) has risen from about
40% to over 80%.
Vaccines have come to be recognised by public health authorities as one of the most cost effective
interventions available. Across the world, in both industrialised and developing countries, more
vaccines of different types are being administered to increasingly larger segments of the population.
This is the greatest tribute to Edward Jenner, who started it all 200 years ago.
MYRON M LEVINE
Professor and director
Centre for Vaccine Development
University of Maryland School of Medicine
Baltimore
MD 21201
USA
i. Levine MM, Kaper JB. Live oral cholera vaccine: from principle to product.
Bull Inst Pasteur 1995; :93:243-353.
ii. Eldridge J H, Staas J K, Meubroek J A, McGhee J R, Gilley R M. Biodegradable
microspheres as a vaccine delivery system. Molec Immunol 1991, 25:287-94.
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Editorial BMJ 7040
Page 3 of 3
iii. Gustaffson L, Hallander H O, Olin P, Reizenstein E, Storsaeter J. A
controlled trial of two-component acellular, and a whole-cell pertussis vaccine.
N Engl J Med 1996;334:349-55.
iv. Rennels M B, Glass R I, Dennehy P H, Bernstein D I, Pichichero M E, Zito E T
et al Safety and efficacy of high-dose rhesus-human reassortant rotavirus
vaccine. Report of the national multicenter trial. Pediatrics 1996;97:7-13.
V. Simanjuntak C H, O'Hanley P, Punjabi N H, Moriega F, Pazzaglia G, Dykatra P.
et al. The safety, immunogenicity, and transmissibility of single-dose live oral
cholera vaccine CVD 1 03-HgR in 24 to 59 month old Indonesian children. J Infect
Dis 1993; 168: 1169-76.
vi. Clements JD, Ferreccio C, Levine MM, Horwitz I, Rao M, Edwards K, et al
Impact of Haemophilus influenza type b polysaceharide-tetanus protein conjugate
vaccine on responses to concurrently administered diphtheria-tetanus-pertussis
vaccine. JAMA 1992;267:673-8.
vii. Clements M L, Betts R F, Murphy B R. Advanyage of live attenuated
cold-adapted influenza virus over inactivated influenza A virus for
A/Washington/80 (H3N2) wild-type virus infection. Lancet 1984; i705-8
viii. Kotloff K L, Nataro J P, Losonsky G A, Wasserman S S, Hale T L, Taylor D N,
et al A modified Shigella volunteer challenge model in which the inoculum is
administered with bicarbonate buffer: clinical experience and implications for
Shigella infectivity. Vaccine 1995;13:1488-94.
ix. Herrington D A, Clyde D F, Losonsky G, Cortesia M, Murphy J R, Davis J, or al
Safety and immunogenicity in man of a synthetic peptide malaria vaccine against
Plasmodium falciparum sporozoites. Nature 1987;328:257-9.
X. Levin M M, Ferraccio C, Black R E Chilean Typhoid Committee, Germanier R.
Large-scale field trial of Ty 21a live oral typhoid vaccine in enteric-coated
capsule formulation. Lancet 1987, 1049-52
xi. Orenstein W A, Bernier R H, Hinman A R. Assessing vaccine efficacy in the
field: further observations. Epidemiol Rev 1988,10:212-41
xii. Lagos R, Horwitz I, Toro J, San Martin 0, Abrego P, Bustamante C, et al
Large scale, postlicensure, selective vaccination of Chilean infants with PRP-T
conjugate vaccine: practicality and effectiveness in preventing invasive
Haemophilus influenzae type b infections. Pediatr Infect Dis J 1996;15:216-22.
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Explore Vaccinology - A Brief History of Vaccination
Page 1 of 2
if
PASTEUR MÉRIEUX CONNAUGHT
AMONT POLICENCE GROUP
Canada
EXPLORING
IMMUNIZATION A Brief History of Vaccination
It has been 200 years since a country doctor from England named Edward Jenner first
discovered a way to vaccinate against the most dreaded disease of that time, smallpox.
On May 14, 1796, Jenner applied the first vaccine by using cowpox to immunize James
Phipps against smallpox.
Previous attempts for vaccinate date back to the 6th century. The first written record of
vaccination, The Correct Treatment of Smallpox, attributed the art to a Buddhist nun
practicing during the 11th century. And, it is widely accepted that vaccination was used in
ancient times, in China, India and Persia.
Edward Jenner's work with cowpox vaccination was the first scientific attempt to control
an infectious disease by means of a deliberate, systematic inoculation. Jenner's work laid
the foundations of modern vaccinology. However, nearly a century elapsed before a
French chemist, Dr. Louis Pasteur, previously noted for his studies of fermentation and
bacteria, disproved the theory of spontaneous generation and advanced the germ theory
of infection.
Pasteur was able to prove that protection against a disease could be afforded by the
infection of weakened germs which cause silent and relatively harmless infections. The
milestone in immunization for which Pasteur is most noted occurred in 1885. A boy
named Joseph Meister was bitten by a rabid dog, and, for the first time in history, was
successfully treated with a vaccine that prevented the development of rabies.
During the remainder of the 19th century, vaccine research continued. In addition to the
early discovery that vaccines could be made with weakened germs, it was discovered
during this time that vaccines could also be made with killed germs. Thus, at the turn of
the century, there existed two human virus vaccines: Jenner's smallpox vaccine and
Pasteur's rabies vaccine. Three human bacterial vaccines, typhoid, cholera and plague
(all killed) also existed.
However, vaccination was not without its opponents. The thought of deliberately and
routinely introducing a deadly virus - in any form - into a human being was met by many
with horror and outrage. By the turn of the century, these opponents had organized
against the new vaccines. Bitter battles were waged in the medical and scientific
community, as well as in the arena of public opinion over the merits of vaccines. But, by
the time World War I broke out, general vaccination was becoming routine. Soon
thereafter, tetanus toxoid, a vaccine based on an inactivated toxin, was introduced.
The Golden Age of vaccine development began in 1949. New discoveries and improved
techniques led to an explosion of creative activity in vaccinology. That interest,
commitment and study continues today. Two of the most famous products developed
during this period were the inactivated polio vaccine of Dr. Jonas Salk and the live polio
vaccine of Dr. Albert Sabin. Other discoveries included now widely used vaccines against
measles, mumps, rubella, hepatitis B and Haemophilus influenzae type b.
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Explore Vaccinology - A Brief History of Vaccination
Page 2 of 2
Recent vaccine development efforts have moved away from vaccines containing whole
organisms and toward safer subunit vaccines containing only the components necessary
to solicit satisfactory immune responses. Genetic engineering has been highly useful in
this process. In the next decade, with its dominant hope for the development of an AIDS
vaccine, the emphasis on safety will be paramount.
The 1990s and the early days of the 21st century may well mirror the 40 years after
Pasteur's important rabies experiment, with public reaction forcing scientists to find even
more ingenious and secure ways to protect humans against disease.
Copyright © Connaught Laboratories Limited, a Pasteur Mérieux Connaught Company
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Evolution of Vaccine Development, NIAID Fact Sheet
Page 1 of 4
FACT SHEET
Office of
Communications
and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Evolution of Vaccine Development
English physician Edward Jenner's observation that milkmaids
stricken with a disease called cowpox were rarely victims of
smallpox prompted him to devise the first vaccine 200 years ago.
One of the world's great medical successes, a modern-day version
of this vaccine led to the total eradication of smallpox by 1980. Since
Jenner's time, advances in the science of virology, bacteriology, and
immunology have led to an enhanced understanding of how the
human body defends itself against invading microorganisms. The
development of vaccines against more than 20 infectious diseases
has revolutionized our approach to public health. Since 1980, at
least 15 new or improved vaccines have become available. Today,
tremendous advances in molecular biology enable scientists to
devise new approaches to developing vaccines against diseases
that continue to plague the world's population.
Scientists in the laboratories of the National Institute of Allergy and
Infectious Diseases (NIAID) and NIAID-supported investigators at
research institutions around the country are pursuing novel
approaches to the development of new and improved vaccines. The
Institute has fostered the development of vaccines against such
diseases as influenza, pneumococcal pneumonia, pertussis, rubella,
rabies, bacterial meningitis, hepatitis B, and adenovirus-associated
respiratory disease. NIAID also supports innovative scientists who
are using vaccine technology to combat autoimmune disorders and
allergies.
Vaccines are made in a variety of ways, depending in part on the
nature of the organism and the disease it causes. Animal viruses,
weakened microbes, killed microbes, and toxins are the most
common components of the vaccines that have been in use
throughout much of the 20th century.
Animal Viruses
Unknown to Jenner, his vaccine worked because the cowpox virus
he used, which does not cause severe disease in healthy humans,
shares some proteins with its more virulent cousin, the variola virus
that causes smallpox. These proteins, called antigens, stimulate the
body's complex immune response, including the production of
memory cells. The next time that an individual encounters that same
antigen, the immune system is primed to destroy it quickly, before it
can cause disease.
Jenner's approach to vaccines is still being used today. NIAID
http://www.niaid.nih.gov/factsheets/vacevo.htm.
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Evolution of Vaccine Development, NIAID Fact Sheet
Page 2 of 4
investigators are using viruses that cause diseases in animals to
make vaccines designed to offer protection against rotaviruses, the
leading cause of infant diarrhea worldwide, and against
parainfluenza viruses, which cause severe respiratory tract
infections in children.
Weakened Microbes
In the late 19th century, the French microbiologist Louis Pasteur
used another approach to create a vaccine against human rabies.
The vaccine he developed, using weakened live rabies virus, was
later refined, but his idea has been used to create many highly
effective vaccines. Microbes weakened by growing them for many
cycles in animals or in tissue cultures in the laboratory can be used
to infect individuals without causing serious symptoms of the
disease. Scientists have also created vaccines from naturally
weakened strains of microbes that have been isolated from humans.
The oral polio vaccine is made from live, weakened virus as are
vaccines for mumps, measles, and rubella. In addition, NIAID-
supported researchers are using weakened viruses to create
vaccines designed to protect against diseases caused by
rotaviruses, respiratory syncytial virus, parainfluenza and influenza
viruses.
Killed Microbes
A number of other vaccines have been developed from whole
organisms that have been killed. Safe and relatively easy to
produce, these inactivated vaccines do not cause infection in people
who receive them, but they are able to stimulate the immune
system. However, the immunity produced may be less complete and
shorter lasting than that produced by a live vaccine or by natural
infection. Such vaccines in use today include those against polio,
whooping cough, and influenza.
Toxins
Some bacteria cause disease by producing toxins that invade the
bloodstream. Around the turn of the century, the identification of the
tetanus and diphtheria toxins led to another type of vaccine that
stimulates the production of antibodies against these toxins. The
diphtheria and tetanus vaccines are made from inactivated toxins
and have been used successfully to prevent these diseases since
the early 1900s. Improved vaccines against whooping cough
(caused by the pertussis bacterium) that are made up of inactivated
pertussis toxin and other toxic bacterial products of the pertussis
organism have recently been demonstrated to be both safe and
effective in preventing whooping cough in babies and young
children.
Subunit Vaccines
Recent research has focused on developing vaccines that use only
part of the infectious agent. Such subunit vaccines, which are now
available for meningitis, pneumonia, typhoid, and hepatitis B,
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Evolution of Vaccine Development, NIAID Fact Sheet
Page 3 of 4
produce the desired immunity without stirring up separate and
potentially harmful immune reactions to the many antigens carried,
for instance, on a single bacterium. Other subunit vaccines under
development include those for respiratory syncytial virus and
parainfluenza virus infections.
Conjugate Vaccines
Bacterial diseases such as pneumonia and meningitis cause
considerable illness, disability, and death among babies and children
in the United States. Some of the bacteria that cause these diseases
have an outer coat that cannot be recognized by the immature
immune systems of young infants, and therefore vaccines made
from these bacteria are not effective in babies. In addition, these
vaccines are of limited benefit to the elderly who have a diminished
immune response.
NIAID-supported researchers and scientists at the National Institute
of Child Health and Human Development devised a way to produce
vaccines that link together proteins or toxins from a second
organism to the outer coat of the bacteria. This enables a baby's
immune system to respond to the combined vaccine and produce
antibodies, immune system proteins that bind to the bacteria and
prevent disease. The first of this new breed of conjugate vaccines
was licensed in December 1986 to protect against Haemophilus
influenzae type b (Hib), the major cause of bacterial meningitis in
babies and young children. In 1990, two conjugate vaccines were
licensed to protect against Hib in babies as young as 2 months. The
widespread use of these vaccines has virtually eliminated Hib
meningitis in the United States.
Vaccines Through Biotechnology
Through genetic engineering, scientists can isolate specific genes
and insert them into the DNA of certain microbes or mammalian cells
grown in the laboratory, which become living factories, mass
producing the desired antigen. Then, using another product of
biotechnology, a monoclonal antibody that recognizes the antigen,
researchers can separate the antigen from all the other material
produced by the microbe or cell. This technique has been used to
produce safe vaccines that stimulate the human immune system
against such organisms as the hepatitis B virus.
In another approach, scientists have inserted genes for desired
antigens into the DNA of related but harmless viruses such as the
vaccinia virus, a relative of the cowpox virus that was used in
modern smallpox vaccines. When the re-engineered vaccinia virus is
inoculated, it stimulates an immune reaction to both the vaccinia and
the products of its passenger genes. These have included, in animal
experiments, genes from the viruses that cause hepatitis B,
influenza, rabies, and AIDS. Scientists similarly are using bacteria
such as salmonella as vaccine vectors to carry portions of microbes.
Instead of adding a gene, some scientists have snipped a key gene
out of an infectious organism. Thus crippled, the microbe can
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Evolution of Vaccine Development, NIAID Fact Sheet
Page 4 of 4
produce immunity but not disease. This technique has been tried
with the cholera bacterium and with herpes simplex virus.
DNA vaccines employ a new approach in which genes from disease-
causing microbes are isolated and injected directly into a person.
Some of these genes enter host cells, which then synthesize the
proteins encoded by the injected genes. The foreign proteins elicit
an immune response that may protect against subesequent infection
by the microbe. A DNA vaccine against AIDS is now being tested in
people.
A totally different approach to vaccine development lies in chemical
synthesis. Once scientists have isolated the gene that encodes an
antigen, they are able to determine the precise sequence of amino
acids that make up the antigen. They then pinpoint small key areas
on the large protein molecule, and assemble it chemical by
chemical. Wholly synthetic vaccines are being explored for malaria
and diarrheal diseases prevalent in developing countries.
Vaccines remain among the most powerful tools we have for
disease prevention. Advances in biotechnology have ushered in a
new era in vaccine development. NIAID has maintained a leadership
role in the basic research and development of new and improved
vaccines and will continue to nourish this exciting renaissance in
vaccine development.
NIAID, a component of the National Institutes of Health, supports research on
AIDS, tuberculosis and other infectious diseases as well as allergies and
immunology.
Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892
Public Health Service
U.S. Department of Health and Human Services
April 1996
Publications I Home
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Vaccines--How and Why?
Page 1 of 4
AGCESS
Classic
-Activities Exchange
Collection
Access Excellence Classic Collection
Vaccines--How and Why?
By: Bonnie A. Maybury Okonek and Pamela M. Peters, Ph.D.
History
Long before the causes of disease were known and long before the processes of recovery were
understood, an interesting thing was observed: if people recovered from a disease, rather than
succumbing to it, they appeared to be immune from a second bout with the same illness.
Perhaps it was these types of observations that led the Chinese to try to prevent smallpox--a
deadly disease characterized by pus-filled blisters--by exposing uninfected individuals to matter
from smallpox lesions. This process, known as "variolation," took a variety of forms. One form
consisted of removing pus and fluid from a smallpox lesion and using a needle to place it under
the skin of the person to be protected. Another method involved peeling scabs from lesions,
drying and grinding them to a powder, and letting an uninfected person inhale this powder. The
third method involved picking up a small amount of the scab powder with a needle and then
using the needle to place the powder directly into the individual's veins. Lady Mary Wortley
Montagu, wife of the British Ambassador to Turkey, observed this third method in the early
1700s and brought it back to England. Although the effects of variolation varied, ranging from
causing a mild illness in most individuals to causing death in a few, the mortality and morbidity
rates due to smallpox were certainly lower in populations that used variolation than in those
that did not.
One person who experienced variolation as a child in the late 1700s was Edward Jenner, a
young boy who survived the process and grew up to become a country doctor in England. As a
country doctor, Jenner noticed a relationship between the equine disease known as "grease" and
a bovine disease known as "cow pox." He saw that farmers who treated horses with grease
lesions often saw the development of cow pox in their cows, complete with blisters similar to
those seen in smallpox infection. Unlike lethal smallpox, however, the cowpox blisters
eventually disappeared, leaving only a small scar at the site of each blister.
At the same time, Jenner was interested when a milkmaid told him that she could not catch
smallpox because she had had cowpox. Jenner noted that there were many people like the
milkmaid - people who milked cows and who did not get smallpox even when exposed
repeatedly. With this in mind, Jenner undertook a daring experiment in 1796: he infected a
young boy with cowpox in hopes of preventing subsequent smallpox infection. After allowing
the boy to recover fully from cowpox, Jenner - in an experiment that would be considered
unethical by today's scientific community - intentionally infected the boy with smallpox by
injecting pus from a smallpox lesion directly under his skin. As Jenner had predicted, the boy
did not contract smallpox.
Although Jenner wanted to report his first case study in the Transactions of the Royal Society
of London, his study was rejected. Despite this, Jenner went on to collect 23 case histories over
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Vaccines--How and Why?
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the next months and published his own book detailing his observations. The book was called
"An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some
of the western counties of England, particularly Gloucestershire, and known by the name of
The Cow Pox." It soon became clear that Jenner's experiments had paid off, and that intentional
infection with cowpox protected people from much more serious infection with smallpox. As a
result, within a few years thousands of people protected themselves from the deadly smallpox
disease by intentionally infecting themselves with cowpox.
Jenner's process came to be called "vaccination," after "vacca," the Latin word for cow, and the
substance used to vaccinate was called a "vaccine." Now, some 200 years later, we have
progressed from a time when vaccination was a rare event, and Jenner's theories about
vaccination were not widely accepted, to the late 1900s when vaccines are so commonplace
that most children receive multiple vaccinations before they reach their first birthdays. The
result of such widespread vaccination has been a marked decrease in diseases which once
ravaged the world's population. An example of this is smallpox: once a major cause of death
world-wide, the smallpox virus is now found only in freezers in high-containment laboratories
at the Centers for Disease Control and Prevention (CDC) in Atlanta and the Institute for Viral
Preparations in Moscow.
How Vaccines Work
Disease causing organisms have at least two distinct effects on the body. The first effect is very
obvious: we feel sick, exhibiting symptoms such as fever, nausea, vomiting, diarrhea, rash, and
many others. Although the second effect is less obvious, it is this effect that generally leads to
eventual recovery from the infection: the disease causing organism induces an immune
response in the infected host. As the response increases in strength over time, the infectious
agents are slowly reduced in number until symptoms disappear and recovery is complete.
How does induction of the immune response occur? The disease causing organisms contain
proteins called "antigens" which stimulate the immune response. The resulting immune
response is multi-fold and includes the synthesis of proteins called "antibodies." These proteins
bind to the disease causing organisms and lead to their eventual destruction. In addition,
"memory cells" are produced in an immune response. These are cells which remain in the blood
stream, sometimes for the life span of the host, ready to mount a quick protective immune
response against subsequent infections with the particular disease causing agent which induced
their production. If such an infection were to occur, the memory cells would respond so quickly
that the resulting immune response could inactivate the disease causing agents, and symptoms
would be prevented. This response is often so rapid that infection doesn't develop - you are
immune from infection.
How to Make Vaccines
Obviously, a live, virulent organism cannot be used as a vaccine because it would induce the
very disease it should prevent. Therefore, the first step in making a vaccine is to separate the
two effects of disease causing organisms. In practice, this means isolating or creating an
organism, or part of one, that is unable to cause full blown disease, but that still retains the
antigens responsible for inducing the host's immune response. This can be done in many ways.
One way is to kill the organism using formalin; vaccines produced in this way are called
"inactivated" or "killed" vaccines. Examples of killed vaccines in common use today are the
typhoid vaccine and the Salk poliomyelitis vaccine.
Another way to produce a vaccine is to use only the antigenic part of the disease causing
organism, for example the capsule, the flagella, or part of the protein cell wall; these types of
vaccines are called "acellular vaccines." An example of an acellular vaccine is the Haemophilus
influenzae B (HIB) vaccine. Acellular vaccines exhibit some similarities to killed vaccines:
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Vaccines--How and Why?
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neither killed nor acellular vaccines generally induce the strongest immune responses and may
therefore require a "booster" every few years to insure their continued effectiveness. In
addition, neither killed nor acellular vaccines can cause disease and are therefore considered to
be safe for use in immunocompromised patients.
A third way of making a vaccine is to "attenuate" or weaken a live microorganism by aging it
or altering its growth conditions. Vaccines made in this way are often the most successful
vaccines, probably because they multiply in the body thereby causing a large immune response.
However, these live, attenuated vaccines also carry the greatest risk because they can mutate
back to the virulent form at any time. Such mutation would result in induction of the disease
rather than in protection against it. For this reason, attenuated vaccines are not recommended
for use in immunocompromised patients. Examples of attenuated vaccines are those that protect
against measles, mumps, and rubella. Immunity is often lifelong with attenuated vaccines and
does not require booster shots.
Some vaccines are made from toxins. In these cases, the toxin is often treated with aluminum
or adsorbed onto aluminum salts to decrease it's harmful effects; after such treatment the toxin
is called a "toxoid." Examples of toxoids are the diphtheria and the tetanus vaccines. Vaccines
made from toxoids often induce low level immune responses and are therefore sometimes
administered with an "adjuvant" - an agent which increases the immune response. For example,
the diphtheria and tetanus vaccines are often combined with the pertussis vaccine and
administered together as a DPT immunization. The pertussis acts as an adjuvant in this vaccine.
When more than one vaccine is administered together it is called a "conjugated vaccine."
Toxoid vaccines often require a booster every ten years.
Another way of making a vaccine is to use an organism which is similar to the virulent
organism but that does not cause serious disease, such as Jenner did with his use of the
relatively mild cowpox virus to protect against the similar, but often lethal, smallpox virus. A
more recent example of this type of vaccine is the BCG vaccine used to protect against
Mycobacterium tuberculosis. The BCG vaccine currently in use is an attenuated strain of
Mycobacterium bovis and requires boosters every 3 - 4 years.
In addition, biotechnology and genetic engineering techniques have been used to produce
"subunit vaccines" - vaccines which use only the parts of an organism yet which stimulate a
strong immune response. To create a subunit vaccine, researchers isolate the gene or genes
which code for appropriate subunits from the genome of the infectious agent. This genetic
material is placed into bacteria or yeast host cells which then produce large quantities of
subunit molecules by transcribing and translating the inserted foreign DNA. It is important to
note that these subunit molecules are encoded by genetic material from the infectious agent, not
from the host cell's genetic material. These "foreign" molecules can be isolated, purified, and
used as a vaccine. Hepatitis B vaccine is an example of this type of vaccine. Subunit vaccines
are safe for immunocompromised patients because they cannot cause the disease.
Vaccines are effective in preventing disease not only in individuals, but also in communities.
This type of protection is called "herd immunity." When a disease spreads from one human to
another, it requires both an infected individual to spread it and a susceptible individual to catch
it. Herd immunity works by decreasing the numbers of susceptible people. When the number of
susceptible people drops low enough, the disease will disappear from the community because
there are not enough people to carry on the catch-and-infect cycle. The greater the proportion of
vaccinated members of the community, the more rapidly the disease will disappear. This is the
reason that school children are often required to be vaccinated before attending school. This
required vaccination has resulted in the marked decrease of many once-common diseases
including pertussis (whooping cough), polio, smallpox, and others. Look for the story of the
Polio Vaccine in a future Classic Collection chapter. Viva la Vaccine!
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Vaccines--How and Why?
Page 4 of 4
For further information please see:
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The Role of US Government Agencies in Vaccine Research and Development
Page 1 of 7
The Role of US Government Agencies in Vaccine Research and
Development
by Gregory K. Folkers and Anthony S. Fauci
National Institute of Allergy and Infectious Diseases
Bethesda, Maryland
This article appeared in Nature Medicine Vaccine Supplement - May 1998
Contents
Abstract
Introduction
Successes and Challenges
Collaborations and Commitment
Government Players in Vaccine Research
Setting the Stage for Product Development
Successful Partnering
References/Acknowledgements
Abstract
Gregory Folkers and Anthony Fauci (National Institute of Allergy and Infectious Diseases)
discuss the role of US government agencies and the NIAID in particular, in the fight against
infectious diseases and the part that vaccine research plays in this fight. From long term
strategic decisions to specific research projects, Fauci and Folkers illustrate the federal
commitment to vaccine development and how it has and can impact both national and
international health. (Nature Med 1998; 4(5 Suppl): 491-494)
Introduction
In this century, vaccines have without question been among our most powerful tools for preventing
disease, disability and death and controlling health care costs. Recognizing the extraordinary benefits
of vaccines, US government agencies charged with protecting and improving the public health have
traditionally made vaccine research and development a top priority. Together with academic and
industrial partners, government-supported scientists have helped develop many of our most useful
vaccines, as well as several that will become available in the near future. These include new or
improved vaccines that protect against rabies, Haemophilus influenza type b, pneumococcal
pneumonia, pertussis, influenza, measles, mumps, rubella, hepatitis A and B, typhoid fever and
rotavirus
1,2
Successes and Challenges
Safe and effective vaccines, along with the operational expertise and political commitment to
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The Role of US Government Agencies in Vaccine Research and Development
Page 2 of 7
administer them, have facilitated some of the greatest successes in public health. Globally, smallpox
has been eradicated, poliomyelitis is on the verge of elimination, and other serious diseases such as
measles have been dramatically reduced in many regions. Each year, vaccines against these three
diseases alone save an estimated 7-8 million lives. By using measles vaccine in National
Immunization Days and more widespread administration of currently available vaccines against
rubella, hepatitis B, and Haemophilus influenza type b, another 3 million deaths could be prevented
every year³.
In the US, dramatic progress has been made against many serious diseases (Table 1). Age-appropriate
vaccine coverage in the period June 1996 to June 1997 reached an all-time high, meeting or
exceeding each of the targets set in President Clinton's 1993 Childhood Immunization Initiative⁴
The impact of vaccines in the United States
Disease
Peak incidence (year)
1996 cases
Diphtheria
206,939 (1921)
2
Measles
894,134 (1941)
508
Mumps
152,209 (1968)
751
Pertussis
265,269 (1934)
7,796
Polio, paralytic
(wild poliovirus)
21,269 (1952)
0
Rubella
(German measles)
57,686 (1969)
238
Rubella, congenital
syndrome
20,000 (1964-5)
4
Table 1. Impact of vaccines in the US.
Despite these encouraging developments, infectious diseases remain the leading cause of death
worldwide, and the third leading cause of mortality in the US. Of approximately 52 million deaths
worldwide from all causes in 1996, more than 17 million were due to infectious diseases, including
approximately 9 million among children. In 1996 alone, an estimated 4.5 - 6 million deaths were
attributed to two diseases, tuberculosis and malaria, for which no effective vaccines are available⁵.
Vaccines also are lacking for many other serious infectious diseases that exact an enormous toll
worldwide, such as sexually transmitted diseases (other than hepatitis B), respiratory syncytial virus
and dysentery due to Shigella spp².
In addition to endemic diseases, we face the ongoing threat of new and re-emerging diseases and the
widespread development of antimicrobial resistance, which underscore the need for a strong
commitment to the development of new and improved vaccines. At least 30 newly recognized
diseases and syndromes have been identified since 1980, including the acquired immunodeficiency
syndrome (AIDS) and its etiologic agent, the human immunodeficiency virus (HIV). As a vivid
reminder of the ever-present threat of disease emergence, the first known human cases of H5N1 avian
influenza were identified in Hong Kong in 1997⁶. The multinational response to this outbreak has
been extraordinary, including the US government's collaboration with industry in producing a
recombinant vaccine for use in at-risk laboratory and health care personnel.
Resistance to antimicrobial agents has been observed in virtually all classes of organisms, resulting in
a diminished capacity to treat many serious infections. For example, more than one-third of
nosocomial Staphylococcus aureus infections in the US are resistant to methicillin, leaving
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The Role of US Government Agencies in Vaccine Research and Development
Page 3 of 7
vancomycin as the only reliable therapy 7 We were given pause for thought in recent months when S.
aureus isolates with increased resistance to vancomycin were identified for the first time in Japan and
the
US 7,8 The threat of malaria also has been exacerbated by the widespread development of drug
resistance. Among the 100 countries and territories where Plasmodium falciparum malaria is
endemic, only Central America and Egypt have not recorded cases of chloroquine-resistance9.
Resistance to fansidar and mefloquine is also common in many areas. As is the case with many
diseases that disproportionately affect the developing world, an effective malaria vaccine is essential
if this disease is to be controlled.
Collaborations and Commitment
Most currently available vaccines, as well as those in the development "pipeline," have resulted from
collaborations between partners in the public and private sector, including federal and state
governments, small and large companies, academic research institutions and non-governmental
organizations
10-12
The importance of vaccine development and the necessity for strong cross-sector partnerships have
been recognized at the highest levels of government, both internationally and in the US. Last year, for
example, the participants in the Denver Summit of Eight stressed their shared commitment to
developing an HIV vaccine. Both Congress and President Clinton have made immunization,
including vaccine research and development, a top priority, and the President has articulated the goal
of developing an HIV vaccine within ten years. At the National Institutes of Health (NIH), funding
for vaccine research and development has increased approximately 65 percent overall from fiscal year
1993 to fiscal year 1999¹³ NIH and other national research agencies are partners in the Children's
Vaccine Initiative (CVI), launched in 1990 with the goal of developing safe, affordable and heat-
stable vaccines that can protect children against the infectious killers of childhood with a minimum of
doses given orally early in life³ Congress has twice targeted funds in support of the CVIs work in
facilitating the development, production, technology transfer, procurement and introduction of new
vaccines. More recently, NIH helped establish the Multilateral Initiative on Malaria (MIM), an
international consortium of government agencies, research organizations and donor agencies working
to mobilize the scientific resources and political will needed to develop malaria control strategies and
notably, a vaccine 14
The private sector also has demonstrated a renewed commitment to vaccine development, thanks in
part to revisions in product liability laws and new technology transfer legislation which have
facilitated interactions between government, academia and industry 15,16,17 Moreover, recent
advances in gene cloning and expression, peptide synthesis and other technologies have created
unprecedented opportunities for developing patentable "bioengineered" vaccines that promise a
substantial return on research and development costs 15
The Government Players in Vaccine Research
Within the federal government, more than 20 different agencies have a role in vaccine research
10-12
Among these, the Centers for Disease Control and Prevention (CDC), the Department of Defense
(DoD), the Food and Drug Administration (FDA), the United States Agency for International
Development (USAID) and the NIH are the federal agencies with the largest investment in vaccine
development
10-12
http://www.niaid.nih.gov/director/nature/1998/nature98text.htm.
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The Role of US Government Agencies in Vaccine Research and Development
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The roles of these different agencies in vaccine development are related and complementary, and
span the spectrum from basic research to licensure and program implementation
10-12
For example,
CDC conducts epidemiologic studies and surveillance needed to define health priorities, and
develops recommendations for vaccine use through the Advisory Committee on Immunization
Practices (ACIP). DoD performs research into vaccines that will protect against pathogens likely to
be encountered by military personnel. USAID supports research on vaccines of particular relevance
to young children in developing countries. The FDA establishes standards for the processes, facilities
and pre- and post-licensing studies needed to insure the safety and effectiveness of vaccines. And the
NIH supports much of the basic and clinical research in fields such as immunology and microbiology
that leads to vaccine development. In addition, the NIH supports Vaccine Evaluation Units (VEU)
and AIDS VEUs around the country, with broad capabilities to conduct prophylactic and therapeutic
studies in children, adults and the elderly, as well as specific high-risk populations.
At the NIH, we have identified three broad goals in vaccine research:
Identifying new vaccine candidates to prevent diseases for which no vaccines currently exist
Improving the safety and efficacy of existing vaccines
Designing novel vaccine approaches, such as new vectors and adjuvants.
The federal government also has an important coordinating function through the National Vaccine
Program Office which is responsible for the coordination of government and nongovernment
activities on research, licensing, production, distribution and use of vaccines 10-12 As
noted
above,
several government agencies are partners in the CVI, a global coalition working to maximize
protection against infectious diseases through the development and use of safe, effective, easy-to-
deliver and widely available vaccines. Coordination of national malaria vaccine efforts is conducted
through the Malaria Vaccine Coordinating Committee, which has developed new collaborations
among federal agencies. In addition, programs such as the National Cooperative Vaccine Discovery
Group bring together experienced investigators from academia, industry and government to facilitate
the conceptualization, discovery and development of HIV vaccines. These consortia follow leads
from basic studies of virology, microbiology, molecular biology, immunology, genetics and
structural biology to design vaccine strategies 18
Decisions regarding the federal government's vaccine priorities are made on the basis of current
morbidity and mortality data, recommendations by advisory groups such as the National Vaccine
Advisory Committee, and evaluations made by the Institute of Medicine (IOM) of the National
Academy of Sciences. In this regard, a new IOM study on Vaccine Research Priorities for the 21st
Century, to be published in 1998, will provide a useful roadmap for developing vaccines for both
infectious and non-infectious diseases such as cancer and autoimmune diseases.
Setting the Stage for Product Development
NIH and other agencies actively pursue research portfolios that involve interaction with industry and
academia and the transfer of technology to the private sector for commercialization. Historically, an
important focus of these efforts has been to further explore concepts that may not be of immediate
financial interest, including those for which the principal market might be less developed nations, but
nonetheless are of great potential public health importance.
For example, 25 years ago, when very little was known about viruses that cause gastrointestinal
diseases, NIH researchers helped identify rotavirus as the leading cause of severe diarrhea in infants
and young children I They embarked on the development of a rotavirus vaccine, and after a series of
pivotal discoveries developed a rhesus rotavirus-tetravalent (RRV-TV) vaccine to protect against the
four clinically important strains of the virus. Having demonstrated the feasibility of this approach,
which probably would not have been pursued alone by industry, the NIH team signed a Cooperative
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The Role of US Government Agencies in Vaccine Research and Development
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Research and Development Agreement (CRADA) with a leading vaccine manufacturer in 1987,
which began commercial development of the RRV-TV vaccine. Subsequently, the vaccine has
proven safe and efficacious in both developed and developing countries. Widespread use of the RRV-
TV vaccine promises to reduce the enormous global burden of rotavirus diarrhea, which claims the
lives of an estimated 870,000 children annually 19
The government also plays a critical role in vaccine development by providing scientists with
reagents that might not otherwise be shared because of proprietary interests. Of growing importance
are repositories such as the AIDS Research and Reference Reagent Program of the NIH, which now
stocks over 1,100 reagents for public distribution, including viruses, proteins/peptides, cell lines,
recombinant DNA clones and antibodies²⁰. Other repositories provide genetically altered mice and
research materials relevant to malaria and other diseases. The critical role of such repositories was
cogently demonstrated most recently during the Hong Kong outbreak of H5N1 avian influenza.
Fortuitously, as part of NIH's long-standing research into respiratory viruses, the specific antiserum
needed to identify the H5N1 avian influenza strain was available in sufficient quantities from the NIH
to quickly develop test kits for detecting the avian influenza virus. CDC, WHO, the Hong Kong
Department of Health and other collaborators used these kits in their extraordinarily successful public
health response to the outbreak²¹
DOE
A number of government agencies, including DoD and NIH, support projects to sequence the
genomes of medically important pathogens. Sequence information can be used in many ways,
including identifying antigens to incorporate into vaccines. The success of the first microbe
sequencing project-the delineation of the complete Haemophilus influenzae genome in 1995-
encouraged the current government-sponsored efforts to sequence the full genomes of many other
pathogens, such as Plasmodium spp., Mycobacterium spp., Chlamydia trachomatis, Vibrio cholerae
and Neisseria gonorrhoeae²². These sequencing efforts have beenfacilitated by technologies such as
DNA chip technology and microarrays that enable the rapid, simultaneous analysis of tens of
thousands of genes and hold particular promise in the development of libraries of immunologically
important genes. Among many possible uses, such gene libraries will provide a powerful tool to
rapidly identify DNA vaccine candidates.
Successful Partnering
Vaccines are complex products, and the process whereby a vaccine is developed and tested requires
many steps (Fig. 3). The various partners in vaccine development bring perspectives, resources and
skills that are sometimes unique, but more often overlapping and complementary. Industry provides
expertise in product development and manufacturing, while many governmental efforts focus on
creating and expanding the scientific base in disciplines that underlie product development 10-12
A prototypic example of a successful partnership across sectors is the development of acellular
pertussis vaccines²³. In the 1930s, the US recorded more than 200,000 cases of pertussis each year.
With the development and widespread use of whole-cell pertussis vaccines, morbidity and mortality
related to pertussis declined dramatically wherever the vaccines were widely used. However, despite
their proven record, concerns about the side effects of whole-cell vaccines resulted in a decrease in
their use in many parts of the world, and a concomitant increase in pertussis cases¹.
These and other concerns stimulated the search for an effective acellular vaccine that would have
fewer side effects, thereby removing barriers to the immunization of infants and perhaps adults as
well. Basic research in government and university laboratories helped provide the insights that
enabled industry to develop candidate vaccines. Phase I and Phase II clinical trials of these products,
supported by industry and government, were conducted at academic medical centers. International
efficacy trials, funded and overseen by industry and government through CRADAs and other
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The Role of US Government Agencies in Vaccine Research and Development
Page 6 of 7
mechanisms, and facilitated by public health officials through intergovernmental channels, helped
provide the safety and efficacy data necessary for licensure²³. These new vaccines are at least as
effective, and less reactogenic than "whole-cell" pertussis vaccines. Acellular pertussis vaccines are
now recommended for all doses in the childhood immunization schedule in the US²⁴. The
widespread availability of these well tolerated vaccines will remove a major disincentive to pertussis
immunization in the US and abroad.
The integration of expertise brought to the vaccine development process by various partners will
continue to be crucial to dealing with the challenges posed by infectious diseases. As we prepare for
the public health challenges of endemic, emerging and re-emerging diseases, it is imperative that a
robust commitment to basic research and cross-sector collaboration be maintained. Only with such
collaborations can we successfully translate basic research findings and technological advances into
improved health through immunization.
As we approach the 21 st century there is a growing awareness that we are increasingly living in a
global community. The concept of the US government playing a contributory role in the fostering of
global health has been the subject of increased attention. This was evident in the justification of the
FY 1999 National Institute of Allergy and Infectious Diseases budget before the House
Appropriations Subcommittee on the Departments of Labor, Health and Human Services, Education,
and Related Agencies²⁵ In this regard, the contribution of the federal government to vaccine research
and development will be critical.
References/Acknowledgements
Acknowledgements
The authors thank Regina Rabinovich and John La Montagne for helpful discussions.
1. Levine, M.M. et al. eds. New Generation Vaccines, 2nd edition. New York: Marcel Dekker
Inc., 1997.
2. Gellin, B. (ed.) The Jordan Report: Accelerated Development of Vaccines. Bethesda,
Maryland: National Institute of Allergy and Infectious Diseases, 1998.
3. Children's Vaccine Initiative. The CVI strategic plan: managing opportunity and change: a
vision of vaccination for the 21st century. Geneva, 1997.
4. Centers for Disease Control and Prevention. National, state and urban areas vaccination
coverage levels among children aged 19-35 months-United States, July 1996-June 1997.
MMWR 47(6), 108-116 (1998).
5. World Health Organization. World Health Report 1997, Geneva.
6. Centers for Disease Control and Prevention. Update: isolation of avian influenza A (H5N1)
viruses from humans-Hong Kong, 1997-1998. MMWR 46(52-53), 1245-7 (1998).
7. Centers for Disease Control and Prevention. Reduced susceptibility of Staphylococcus aureus
to vancomycin-Japan, 1996. MMWR 46(27), 624-626 (1997).
8. Centers for Disease Control and Prevention. Staphylococcus aureus with reduced susceptibility
to vancomycin-United States, 1997. MMWR 46(33), 765-766 (1997).
9. World Health Organization. World malaria situation in 1994. Weekly Epidemiological Record
72, 269-274 (1997).
10. Bloom, BR. The United States needs a national vaccine authority. Science 265, 1378-80
(1994).
11. Douglas, RG. Fostering partnerships for vaccine development: a delicate fabric. Bull NY Acad
Med (Summer) 113-123 (1996).
12. National Vaccine Advisory Committee. United States vaccine research: a delicate fabric of
public and private collaboration. Pediatrics 100(6), 1015-1020 (1997).
13. Office of Financial Management, Office of the Director, National Institutes of Health.
14. [Editorial]. Two cheers for the multilateral malaria initiative. Nature; 388(6639), 211 (1997).
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The Role of US Government Agencies in Vaccine Research and Development
Page 7 of 7
15. Tanouye, E. Vaccine business is heating up; drug companies see sales surge. Wall Street
Journal, Feb. 25, 1998.
16. >P.L. 104-113, the National Technology Transfer and Advancement Act of 1995.
17. Jenks, S. Varmus strikes "reasonable pricing" clause in CRADAs. JNCI 87(9), 642 (1995).
18. National Institute of Allergy and Infectious Diseases. HIV/AIDS Research Agenda. Bethesda,
Md., (1995).
19. Marwick, C. Rotavirus vaccine a boon to children. JAMA 279(7), 489-490 (1998).
20. National Institute of Allergy and Infectious Diseases. NIH AIDS Research and Reference
Reagent Program Catalog. Rockville, Md., 1998.
21. Belshe, RB. Influenza as a zoonosis: how likely is a pandemic? Lancet 351(9101), 460-1
(1998).
22. The Institute for Genomic Research, http://www.tigr.org.
23. Fauci, A S. Biomedical research in an era of unlimited aspirations and limited resources.
Lancet 348, 1002-3 (1996).
24. Centers for Disease Control and Prevention. Pertussis vaccination: use of acellular pertussis
vaccines among infants and young children. Recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR 46(RR-7), 1-25 (1997).
25. Department of Health and Human Services. Fiscal Year 1999 Justification of Estimates for
Appropriations Committees, National Institutes of Health, Volume II.
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
Director's Page I NIAID Home | Search NIAID
Last Updated January 20, 1999 (kap)
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Why and AIDS Vaccine?, NIAID Division of AIDS, AIDS Vaccine Site
Page 1 of 2
The NIAID Division of AIDS
General Info
NEWS OVERVIEW I GENERAL INFORMATION FUNDING OPPORTUNITIES
SCIENCE RESOURCES & LINKS
Why an AIDS Vaccine
Basic Information about
HIV and AIDS
Basic Information about
Although recent treatment advances have led to an encouraging
AIDS vaccines
downturn in the number of new AIDS cases and AIDS-related deaths
How Vaccines Work
in this country, the epidemic continues to accelerate elsewhere in the
Why an AIDS Vaccine
world. In 1997 alone, approximately 5.8 million people globally
is Necessary
were newly infected with HIV, including approximately 590,000
How AIDS Vaccines are
children under age 15.
Developed
Developing a Safe and
According to a detailed, country-by-country analysis of HIV
Effective AIDS Vaccine
prevalence released earlier this year by UNAIDS, approximately 5.8
Challenges in
million people worldwide were newly infected with HIV in 1997
Developing AIDS
Vaccines
alone. More than 90 percent of these new infections occurred in
NIAID's Role in AIDS
developing countries, where antiretroviral therapy is beyond the
Vaccine Development
reach of all but the privileged few. Alarmingly, in 27 developing
Clinical Trials of
countries, HIV prevalence more than doubled between 1995 and
Candidate AIDS
1997. The prevalence of HIV infection is highest in the African
Vaccines
nations of Botswana and Zimbabwe, where more than 25 percent of
HIV Vaccine Glossary
adults are now HIV-infected.
Globally, one in every 100 adults 15 to 49 years of age is HIV-
infected; at least 80 percent of these infections are due to
heterosexual transmission. By the end of 1997, an estimated 30.6
million people worldwide were living with HIV/AIDS, including 1.1
million children younger than 15 years of age. Since the beginning of
the HIV/AIDS epidemic, at least 8.2 million children younger than
15 have been orphaned because of the premature deaths of HIV-
infected parents.
Current worldwide statistics can be found at the WHO.
Other information sources:
Intensifying the Global Response to HIV/AIDS - Statement by
Dr. Peter Piot, Executive Director UNAIDS to the United
states House of Representatives International Relations
Committee, September 16, 1998
UNAIDS Report July 1998 - HIV preventive vaccine trials in
developing countries
UNAIDS report October 1998
The Need for a Vaccine Against HIV-AIDS - Edward
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Katongole-Mbidde, MBCHB
World Health Report, 1999
Contact Us
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Diseases That Vaccines Prevent
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Discoses that voccines prevent
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Program Office
Table of Contents
Main Menu
Smallpox: The beginning of vaccines, the end of a disease
Welcome Center
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Get the facts on other vaccine-preventable diseases
If we stop
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Smallpox: The beginning of vaccines, the end of a disease
Throughout history, there has never been anything small about smallpox,
Immunization Laws
except perhaps the variola virus that causes it. A very old, deadly, and virulent
disease, smallpox was often portrayed as the Grim Reaper himself. It occurred
in two forms: variola major, which killed 20% or more of its victims, and variola
Vaccine Safety
minor, which killed 1%.(1) In its typically widespread epidemics, one percent
was often rendered in the thousands.
Publications
Smallpox began somewhat like the flu, with chills, high fever, nausea, and
aches. Within a few days, however, its characteristic rash of unsightly, painfully
swollen pustules declared itself. The disease spread with devastating ease from
Q and A
one individual to another by way of droplets from the nose and mouth (for
example, in sneezing), contact with the dried scabs of the pustules, or even
Diseases that
contact with clothing or articles used by people with smallpox. It took about 12
vaccines prevent
days from exposure to the time the disease became evident; consequently, care
givers of people with smallpox often caught the disease and then followed the
Some of the
first wave of victims to the grave within a matter of weeks.
people who stand
behind vaccinations
The numbers of people killed by smallpox in previous centuries are so large that
they are numbing. Some authors credit smallpox with the collapse of both the
Aztec and Incan empires, (2) civilizations that had prospered for centuries in
The things you may
South America, Mexico, and nearly halfway into the North American continent.
have been hearing
Some historians think smallpox emerged when humans first began to grow their
own food, around 12,000 years ago. (3) From that time forward, every human era
Calendar
was marked by the presence of smallpox. Anthropologists have determined that
eruptions evident on the skin of an Egyptian mummy of the 20th dynasty (1200-
The future
1100 B.C.) originated in smallpox. (4) From the earliest days of Europe,
of vaccines
epidemics hung like a perpetual thundercloud over human society. As Thomas
Babington Macaulay, a 19th-century British historian and statesman, (5)
observed, "The havoc of the [bubonic, or "black"] plague had been far more
rapid: but plague had visited our shores only once or twice within living memory;
and the smallpox was always present. "(6) In 1519, the Spanish brought the
disease to Mexico, where three and a half million Indians died. (7) In the 17th
and 18th century, entire tribes in North America were wiped out by smallpox. (8)
In the North American colonies, those who could, would flee to the countryside
when the first case in a new epidemic appeared. (9) Epidemics often followed
the course of a river or trails taken by traders and explorers. Many people who
survived this highly contagious disease bore its mark forever in unsightly scars,
and many were left blind. However, survivors truly triumphed, because having
the disease and surviving it made them immune to having it again. Recognizing
a similar, cross-over effect in milkmaids who contracted cowpox-they appeared
to be immune to smallpox--Dr. Edward Jenner began late 17th- and early 18th-
century efforts to rid humanity of this scourge.
On May 14, 1796, Dr. Jenner performed an experiment that demonstrates how
desperate people were to find some way to prevent this terrible scourge. He
innoculated (vaccinated) a boy with matter taken from pustular cowpox lesions.
Several weeks later, he challenged the success of the first inoculation by
vaccinating the boy with smallpox. It was a tremendous risk, but it worked. The
boy didn't develop smallpox. Following publication of the results in June, 1798,
Jenner predicted the eventual eradication of smallpox. It took more than two
centuries to prove him correct.
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Jenner was hardly the first to observe that inoculation could prevent disease.
Folk methods had been tried in many cultures, most of them relying herbs,
magic, religious objects, prayers, incantations, and ultimately, luck. In some
countries where more than one God was worshiped, there were gods to whom
one prayed specifically for protection against smallpox. (11) Medical practitioners
in a number of ancient cultures had made observations about resistance to
smallpox and had experimented with methods of immunization. Around 1700,
nearly a century before Dr. Jenner's experiment, the practice of variolation--
inoculation of a healthy person with pus from an infected person's smallpox
lesions--was first tried in England, but the practice is believed to have originated
in Africa and was learned from slaves. (12) In 1716, Cotton Mather, a member of
the clergy, author, scholar, and physician in Boston, (13) sent Dr. John
Woodward, an English physician, a vivid description of inoculation, as it had
been described to him by one of his slaves, Anesimus. (14) The difference
between the African method and Jenner's method was that Jenner involved a
third party (cows) and a milder form of the disease (cowpox). His work opened
the door to immunization as we know it today.
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Why we don't need smallpox vaccinations today
Through massive vaccination efforts, smallpox has been wiped out. This historic
victory occurred in this century, in the lifetimes of today's grandparents, parents,
and children.
The one weakness of the variola (smallpox) virus is that it survives by being
passed from one person to another. Public health officials worldwide joined
together in the 1970s to take advantage of this weakness. They undertook to
interrupt the cycle of smallpox through an intensive immunization and
monitoring effort. In effect, by immunizing humans, they were removing the
human incubator from the cycle, one vaccination at a time.
This was a huge task, involving many densely populated countries with limited
health, technology, and communications facilities. Nevertheless, the effort
succeeded. The last case of variola major occurred on Bhola Island in
Bangladesh in October, 1975. The last case of variola minor was in Ethiopia in
August, 1976. Although smallpox had been a nearly constant companion for
twelve millennia, no one grieved over its quiet departure.
Because smallpox has been eradicated, smallpox vaccination has ceased
everywhere. Travelers no longer need certificates to prove vaccination against
this disease (15) The children born at the end of this century may be puzzled by
the small, round scars on their parents' and grandparents' upper left arms, the
last scars left by smallpox.
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Pneumococcal disease
Streptococcus pneumoniae (pneumococcus) bacteria is a leading cause of
illness in young children. In the elderly, such infections can be deadly.
The terms pneumoniae, pneumococcus, and pneumococcal refer to the S.
pneumoniae bacteria, not to the illness pneumonia, although pneumococcal
bacteria can indeed cause a form of pneumonia. S. pneumoniae sets up camp
in the upper respiratory tract: nose, sinuses, ears, and throat. From there, they
launch widespread invasive infections in the blood, central nervous system,
brain, upper and lower respiratory tracts, and ears. They have a particular
affinity for the environment in the respiratory tracts and ears of little children.
The ear infections they cause account for more than 24 million visits to
pediatricians each year. The chart below shows the annual tally of human
miseries that begins with S. pneumoniae.
Table. Annual number of cases of diseases associated with Streptococcus
pneumoniae bacteria, and the groups in the United States most at risk of having
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these diseases*
Disease
Affecting
Group(s) most at risk of
Number of
having the disease
cases each
year
Meningitis
Brain, central
Certain Native American
3,000
nervous
tribes; Alaskan natives,
system
especially children under age
2 yrs.; other children age 6-24
months; all adults 65 yrs. or
older
Bacteremia
Blood
Certain Native American
50,000
tribes; Alaskan natives,
African Americans; all
children, all adults 65 yrs. or
older.
Pneumonia
Lungs
Certain Native American
500,000
tribes; Alaskan natives, all
ages; all children; all adults
65 yrs. or older
Otitis media
Ears
Children under age 4 yrs.
7,000,000
*Source: Advisory Committee on Immunization Practices. Prevention of
pneumococcal disease. Morbidity and Mortality Weekly Review April 4, 1997;
46(RR-8):1-25.
The highest incidence rates for invasive pneumococcal disease (such as
meningitis or bacteremia) in any U.S. population have been reported among
specific American Indian groups, such as the Apache.
Alaskan Natives of all ages have an eight- to ten-fold higher risk of meningitis or
bacteremic pneumonia than do any other groups in the U.S. population.
Black adults have three to five times greater incidence of bacteremia, compared
with white adults.
The worst of the S. pneumoniae infections, of course, are those that get into the
bloodstream or central nervous system. Pneumococcal infection causes death
in 40,000 people per year, making S. pneumoniae the number one killer among
all vaccine-preventable bacterial diseases. About half of the lives lost to
pneumococcal infections could be saved through use of the pneumococcal
vaccine.
Meningitis and bacteremia are the most lethal of the pneumococcal diseases.
The highest proportion of deaths from pneumococcal infections occurs among
the elderly and people who have underlying medical conditions. As many as
91% of adults who have invasive pneumococcal infection have at least one of
the conditions described in the chart below.
Table 2. Underlying health problems that place people at greater risk of
pneumococcal infections or severe pneumococcal disease*
Type of health
Age group
Explanation/examples
problem
affected
Chronic
Adults
Congestive heart failure
cardiovascular
(especially
disease
elderly)
Cardiomyopathy
Chronic pulmonary
Adults
Chronic obstructive pulmonary disease
disease
(especially
(COPD)
elderly)
Emphysema
Chronic liver
Adults
Cirrhosis
disease
(especially
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alcohol
abusers)
Some diabetes
Adults
Cardiovascular dysfunction
mellitus
complications
Kidney dysfunction
Asthma, but only
Adults
Only if associated with chronic
as indicated
bronchitis, emphysema, or long-term
use of systemic corticosteroids
Asplenia
Children and
Spleen surgically removed
adults
Spleen in place but not functioning due
to disease such as sickle cell anemia
People who are
All ages
Congenital (inherited)
unresponsive to
immunodeficiency
the pneumococcal
HIV infection
vaccine or who
Some cancers: leukemia, lymphoma,
have certain types
multiple myeloma, Hodgkins' disease,
of reduced
generalized malignancy
immune resistance
Organ or bone marrow transplantation
Certain drug treatments: alkylating
agents, antimetabolites, systemic
corticosteroids
Chronic kidney failure or nephrotic
syndrome
* Source: Advisory Committee on Immunization Practices. Prevention of
pneumococcal disease. Mortality and Morbidity Weekly Review April 4, 1997;
46(RR-8):1-25.
People in this group are at the highest risk of all for pneumococcal infection,
because of the vital role that the spleen plays in filtering impurities (in the case
of pneumococcal disease, encapsulated bacteria) from the blood.
Children with sickle cell disease or who have had their spleen removed are at
increased risk for widespread, severe pneumococcal infection in the blood and
death from that infection.
S. Pneumoniae is the most common source of bacterial pneumonia in people
with HIV infection.
Since introduction of a vaccine to prevent Haemophilus influenzae type b (Hib
disease), S. pneumoniae has also taken the lead as the most common cause of
bacterial meningitis in the United States. Nevertheless, among children, death
from pneumococcal infection is relatively uncommon, except in those who have
meningitis, those whose immune system is compromised (for example, by AIDS
or by chemotherapy treatments), and those who have had spleen removal and
develop severe bacteremia.
The pneumococcal vaccine is given in one injection. Repeat doses are not
needed in people who received a first dose at age 65 or older, but vaccination
can be repeated after five years in people over 65 who had the first dose before
turning 65. Some people find it convenient to get this vaccine at the same time
as an influenza injection, but the injections are separate and in different arms.
Pneumococcal vaccine can also be combined with other vaccines in the same
way. The vaccine is especially appropriate for: children over age 2 years,
people 65 years or older, people aged 2 to 64 years who are at increased risk of
pneumococcal disease because they have chronic illness, especially those
listed in Table 2; and people aged 2 to 64 years who live in settings where risk
of pneumococcal disease is increased (for example, Alaskan Natives, Native
Americans, and people in nursing homes). The vaccine is not recommended for
routine use in healthy children who attend day-care facilities.
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Get the facts on other vaccine-preventable diseases
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The home page of the National Immunization Program offers information about
the following diseases and vaccines:
Pertussis (whooping cough) Varicella (chicken pox, shingles)
Diphtheria Meningococcal
Tetanus Influenza
Diphtheria-tetanus-pertussis (DTP) vaccine Cholera
Acellular pertussis vaccine Bacillus Calmette Guérin (tuberculosis vaccine)
Polio Japanese encephalitis
Measles Typhoid
Mumps (Bubonic) plague
Rubella Rabies
Haemophilus influenzae type b Vaccinia (smallpox)
Hepatitis A Yellow fever
Click here to go the National Immunization Program's site
Table of contents
Footnotes
1. Henderson DA. A victory for all mankind. World Health. 1980;1:3-5.
2. McNeill WH. Plagues and People. Garden City, NY: Anchor
Press/Doubleday, 1976.
3. McNeill WH. Plagues and People. Garden City, NY: Anchor
Press/Doubleday, 1976. Cited in Henderson DA, Fenner F. Chapter 2: Smallpox
and vaccinia. In: Plotkin and Mortimer book.
4. Duffy J. Epidemics in Colonial America. Baton Rouge: Louisiana State
University Press, 1953: 18.
5. Barnhart CI. New Century Cyclopedia of Names. Vol. 2.
6. Macaulay TB. The History of England from the Accession of James II, 5 vols.
(Philadelphia, 1887 ed.), IV, 575. Cited in Duffy, p. 19.
7. Hoehling, p. 70.
8. Hoehling, p. 92.
9. Duffy.
10. Grolier's Online Encyclopedia: Jenner, Edward.
11. Henderson DA, Fenner F. Smallpox and vaccinia. In Plotkin & Mortimer. Pp
13-40.
12. Duffy, p. 24. Also Abercrombie TF. History of Public Health in Georgia,
1733-1950. Atlanta: Georgia Department of Public Health: 1953:24-25.
13. Barnhart CL, ed. New Century Cyclopedia of Names. Vol. 2.
14. Mather C. Letter to John Woodward, December 16, 1716. Cited in Duffy,
p.28.
15. Henderson in World Health.
16. ACIP. Prevention of pneumococcal disease. MMWR April 4, 1997;46(RR-
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8):1-25.
Top
National Vaccine Program Office
Centers for Disease Control and Prevention (CDC)
Updated: 01/19/1999 15:12:28
CDC
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I'm hearing so many different things about vaccines. I don't know whom
to believe.
Immunization
Are vaccines effective?
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Is it true that vaccines can cause side effects?
If we stop
Is it true that polio vaccination causes polio?
vaccinating
Can I or my child get AIDS, or the HIV virus, or chronic fatigue syndrome
from vaccines?
Do vaccines cause fibromyalgia, rheumatoid arthritis, arthritis, or lupus?
Immunization Laws
Who should not have vaccinations
Do vaccines cause cancer?
Vaccine Safety
Do vaccines cause autism?
Can I get animal diseases from vaccines that are made using animal
Publications
cells?
Can't I just "wait and see" on my child's vaccinations?
Q and A
Can epidemics occur today? In the United States?
Are we safe from epidemics?
Diseases that
Why must my child have so many shots?
vaccines prevent
Aren't there some chemicals and other substances added to vaccines?
I got a flu shot and I still came down with the flu. Why?
Some of the
people who stand
If you didn't find the answer you need in this section
behind vaccinations
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The things you may
have been hearing
Are vaccines safe?
Calendar
Yes, vaccines are very safe. Today, the United States has the safest, most
effective vaccine supply in history.
The future
of vaccines
Table of contents
I'm hearing so many different things about vaccines. I don't know whom to
believe.
Studies have shown that most parents rely on their child's physician for advice
on vaccination decisions. In particular, pediatricians and family practitioners
have taken special, intensive training in infant and child health. No one knows
your child's health and medical needs better than the health professional who
routinely cares for your child.
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Are vaccines effective?
Vaccines are both effective and cost-effective. "Effective" does not mean that
every individual who has vaccination is 100% protected. No vaccine can
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accomplish that kind of guarantee. Effective means that most vaccinated people
will be protected, particularly when a high proportion of people in a population
are immunized. That is why protection from disease involves more than one
step. As explained in the Immunization Concepts section of this page, three
steps are needed: immunization of the individual, community immunity, and
practical measures to prevent disease outbreaks.
Table of contents
Is it true that vaccines can cause side effects?
There is some risk associated with any medical procedure or medication, and
immunization is no exception. Side effects of immunizations range from redness
and warmth of the skin where a vaccine was injected, to more serious effects,
including damage to the central nervous system or death. However, the risk of
such a serious event is extremely small. As a rule, the risk of contracting the
disease, and of dying or suffering serious or permanent complications of that
disease, is far greater than the risk of dying from the immunization.
Table of contents
Is it true that polio vaccination causes polio?
It is true that in extremely rare cases, one of the two types of polio vaccine can
cause polio. This type of polio is referred to as vaccine-associated paralytic
polio, or VAPP.
The two types of vaccine are oral polio vaccine (OPV), which was introduced in
1961 and contains live but weakened polio virus, and inactivated polio vaccine
(IPV), in which the virus is killed. OPV, as the name implies, is given orally. IPV
is injected. With each type, four doses must be given.
About eight or nine people per year develop VAPP as a result of the OPV
vaccine. The estimated rate of cases is one per 2.4 million doses distributed, or
one case to every 750,000 children receiving their first dose of OPV.
In hopes of eliminating this risk altogether, the Advisory Committee on
Immunization Practices (ACIP) published recommendations on January 24,
1997, for a transition period in which use of OPV would be reduced, and use of
IPV would be increased.
Specifically, ACIP recommended:
1. Use of IPV, followed by OPV. On this schedule, resistance to
polio would develop as a result of the IPV injection; therefore, it
would be safe to have OPV in the second, third, or fourth dose.
2. OPV alone, for certain cases. For example, ACIP stated that
this schedule would be better for children who begin the primary
vaccination schedule after 6 months of age.
3. IPV alone, for certain cases. For example, ACIP recommended
IPV alone for children with immune suppression.
The preferred method recommended by ACIP is two doses of IPV, followed by
two doses of OPV. Implementation of these recommendations should reduce
the risk for VAPP and would help providers to make the transition to using only
IPV, says ACIP.
To visit the home page of a consumer group dedicated to reducing the risk of
VAPP, click here.
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Table of contents
Can I or my child get AIDS, or the HIV virus, or chronic fatigue syndrome from
vaccines?
No. There is no evidence that vaccine supplies today are contaminated or that
they are capable of causing HIV, AIDS, chronic fatigue syndrome, or other
health problems.
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Do vaccines cause fibromyalgia, rheumatoid arthritis, arthritis, or lupus?
After decades of vaccine use in the U.S., current research shows no definitive
evidence proving vaccines cause chronic illness.
According to the Arthritis Foundation, there is no known link between vaccines
and fibromyalgia, rheumatoid arthritis, or lupus, and while the number of
persons with these conditions has been rising, the statistics do not support
alarm over these increases. (1) In considering the increases, it's important to
remember that rheumatoid arthritis (a type of arthritis that causes systemic
inflammation, as well as joint problems), arthritis, and lupus are primarily
diseases of middle and older age. A very large segment of the American
population--the so-called "baby boomers"--are now entering the ages when
these diseases occur, so an increase in the numbers of cases is to be
expected.
Perception of increases in fibromyalgia incidence may be because this disease
has only recently been defined, and it is just in the past decade that physicians
have known that the various symptoms of fibromyalgia (chronic muscle aches
and pains, "trigger points" of pain, and chronic, sometimes overwhelming
fatigue) do constitute a specific disease. Thus, it is not possible to know
whether the number of cases detected these days represents an increase over
that which occurred previously.
Arthritis, on the other hand, is not a "new" disease. Evidence of osteoarthritis
(arthritis confined to the joints, where one bone meets another) has been found
as far back as the mummies of ancient Egypt. Its incidence increases with age.
In a comprehensive 1994 study of adverse events associated with vaccination,
the Institute of Medicine reviewed the possibility of a link between diphtheria
and tetanus vaccines--these vaccines are generally given in combination--and
arthritis. The Institute found that it is biologically possible for these
immunizations to be associated with arthritis, primarily because the tetanus
toxoid has the potential to induce serum sickness, which is a source of a
temporary form of arthritis. However, the Institute also found that the evidence
available in scientific studies up to 1994 was inadequate to determine whether
this biologically possible link actually occurs. Since those findings were
reported, one group of researchers found a link between rubella vaccine and
temporary, acute arthritis, arthralgia (joint pain) or myalgia (muscle pain) when
the vaccine was administered within 12 months of giving birth. (2)Another group
found no evidence of any increased risk of developing chronic arthritis,
arthralgia, or myalgia within the 12 months following vaccination; the women in
this study were of childbearing age.(3)
Similarly, the Institute found that a link between hepatitis B vaccine and acute or
chronic arthropathy (inflamed, painful joints) also is biologically plausible, but
the studies available are inadequate to accept or reject a causal link to
vaccination. A link between the disease, hepatitis B, and arthropathy has been
proven.(4)
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Who should not have vaccinations
If you have questions or concerns about the appropriateness of a particular
immunization for yourself or your child, you should consult with your health care
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provider, who knows your individual circumstances best.
In general, any person who has had an anaphylactic (shock) reaction to an
immunization should not have that vaccine again. A mild to moderate local
reaction, such as soreness, redness, or swelling after injection of a vaccine, is
not an indication for withholding a vaccination.
Any person who has had an anaphylactic reaction to an ingredient contained in
a vaccine (for example, egg protein, which is contained in influenza and yellow
fever vaccines) should not have that vaccine.
The Advisory Committee on Immunization Practices recommends that "All
vaccines can be administered to persons with minor illness such as diarrhea,
mild upper-respiratory infection with or without low-grade fever, or other low-
grade febrile illness. "(7) Anyone who currently has a moderate or severe illness,
with or without a fever, should delay vaccination until restored to health.
Live vaccines, such as oral polio vaccine, should not be given to people whose
immune system is suppressed by congenital immunodeficiency, HIV infection or
AIDS, leukemia, lymphoma, generalized cancer, cancer therapies, or high-dose
corticosteroids. (8)
The complete general recommendations on immunization are spelled out in the
Recommendations of the Advisory Committee on Immunization Practices, (9)
which are available on the CDC National Immunization Program home page.
*For additional information on this topic, click here to go to the National
Immunization Program site.
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Do vaccines cause cancer?
As explained by the National Immunization Program in its Vaccine Safety Fact
Sheet, after decades of vaccine use in the United States, current research
shows no reliable evidence proving that vaccines cause chronic illness. The
term "chronic illness" includes cancer.
Questions have been raised from time to time, by various researchers, about
the role of components or unique substances that may be found in vaccines and
cancer. The most current questions are addressed in a technical document,
"Selected Issues on Immunizations."
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Do vaccines cause autism?
Autism is a neurologic condition--a problem that occurs in the brain and central
nervous system. It is usually identified at the ages of 18 months to 30 months,
the same ages at which some vaccinations are given. For example, a child who
is receiving vaccinations on the recommended schedule would receive three
doses of diphtheria, tetanus, and acellular pertussis (or pertussis) vaccines,
plus a "booster" of the DtaP or DTP combination; three doses of oral polio
vaccine; at least one dose of the measles/mumps/rubella combination; two or
three doses of the Haemophilus influenzae type B vaccine; and the hepatitis B
vaccine by 30 months. (10) The symptoms are absence or delay of speech
development and lack of interest in interacting with others. Sometimes autism
results in loss of already acquired speech and social skills, which gives the
impression that some external event may have caused damage that leads to
autism. There is no scientific evidence to date that autism and immunizations
are linked. According to very recent findings of experts in the field of neurology,
autism appears to result from prenatal dysgenesis; that is, a specific set of brain
abnormalities that occur while the fetus is developing in the womb. (11)
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Can I get animal diseases from vaccines that are made using animal cells?
This question arises from time to time because animal cells are used in the
manufacture of some vaccines. Today, manufacturers are required to test cell
lines used for the presence of a variety of infectious agents, to prevent
contamination of vaccine products. There is no evidence that currently available
vaccines are contaminated with infectious agents that cause disease.
Although it is quite biologically possible for animal viruses to be transmitted to
human beings, it is not a simple matter. Viruses that establish themselves and
then thrive in one species are dependent upon the genetic and biochemical
make-up of that species to continue to survive. They may--but do not always--
find an acceptable genetic and biochemical environment in another animal
species. To cross species, the virus may have to evolve--possibly over
thousands of years and millions of spontaneous "trial-and-error" mutations--to
become sufficiently adaptable to cross to another species, and adequately
matched to the environment of the second species to survive there. New strains
of influenza, which can develop in birds, adapt in pigs, and then be
transmittable to humans is one example of a virus that can do this. This topic is
more fully discussed in the Vaccine Safety.
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Can't I just "wait and see" on my child's vaccinations?
Delaying a child's vaccinations is inadvisable for several reasons. First, the
recommended schedule for childhood vaccinations is not an arbitrary schedule.
In developing vaccines, scientists must take into account:
The ages at which the vaccine is safe for a child, taking into account a
number of developmental factors, including height and weight
The age at which certain diseases are most likely to strike
The situations in which the child might be exposed to diseases, for
example, by entering day care or kindergarten
The period of time in which the vaccination continues to provide
protection or a booster shot becomes necessary
Second, disease outbreaks occur even in vaccinated populations, and children
who are not vaccinated are at risk of getting the disease and of infecting others.
Some diseases that are typically not too severe in children can have serious
consequences in adults. Varicella (chicken pox), for example, is usually
(although not always) not severe in children, but it can be quite serious in
adults. Between January and April, 1997, state health departments reported
three fatal cases in which women of ages 23, 25, and 32 died. The two younger
women had previously been in good health. The 23-year-old contracted the
disease from her children (ages 2 and 5), who were not vaccinated against the
disease. The 32-year-old woman, who had Crohn's disease (a condition that
can be managed with diet and medication) caught chicken pox from 4-year-old
niece, who also had not been vaccinated against the disease, (12)
Mumps can cause sterility in men. While rubella (German measles) is usually
mild in children and adults, up to 90% of infants born to mothers infected with
rubella during the first three months of pregnancy will develop congenital rubella
syndrome, resulting in heart defects, cataracts, mental retardation, and
deafness. (13) A decision to withhold vaccinations from your child puts your
child, other children, adults, and even your future grandchildren at risk of
diseases that can be prevented.
Third, unless you qualify for a religious or philosophical exemption (the laws
vary among states), your child's entry into school could be delayed until you
comply with your state's school vaccination requirements. If you do qualify for
an exemption, you must take responsibility for the health of your own child and
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for the children and adults who come into contact with your child. An
unvaccinated child will be at risk of becoming infected even when other children
are not yet ill but are incubating the infection and able to spread the disease. In
the event of an outbreak of vaccine-preventable disease in the community,
schools usually require that children who are not protected by vaccination
remain at home, from the first case through the last--which may mean 30 to 60
days at home. Any child with an infectious disease should be isolated at home
to prevent its spread to others. Keep in mind that there are many people in any
community whose resistance to disease is low: for example, people who are
being treated for cancer, people who have immune disorders, and elderly
people. To protect these people, a parent of an unvaccinated child must take
constant precautions. Realistically, since the symptoms of many childhood
illnesses look much like cold or flu symptoms, even the most cautious parent
will not always be able to recognize symptoms that merit isolation.
*The Advisory Committee on Immunization Practices is a panel of experts who
convene regularly to review current vaccine schedules and new and improved
methods of administering vaccines. Based on their recommendations,
vaccination schedules may change. For information on the current
recommended schedule of vaccinations for children, call the National
Immunization Program's hotline at 1-800-232-2522 (English) or 1-800-232-0233
(Spanish), or click here to go to the National Immunization Program's
homepage.
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Can epidemics occur today? In the United States?
They can and they do. In every country and every region where immunization
levels drop, fresh outbreaks of disease follow. Thanks to the protection provided
by immunizations, few young people living in the United States today have any
idea of what it's like to live through an epidemic of a highly infectious, deadly
disease. Our grandparents may well remember the dread they felt when their
child--or a neighbor's child--developed a summer cold, which often signaled a
developing case of polio. Fortunately, we now have vaccines to prevent polio
and many other diseases. All of the generations of people who lived on earth
before this century lived under constant threat of diseases that spread rapidly
into epidemic proportions, sweeping away entire families, tribes, or towns. Even
today, millions of people who do not have immunization in their community
experience this threat.
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Are we safe from epidemics?
We are safe from many diseases, in large measure because we have the
technology and good fortune in this country to develop and distribute vaccines
quickly and routinely, and because the majority of our population has been
vaccinated and community immunity is in effect.
The diseases that we have controlled through vaccination still exist, and there is
no safety in hiding, especially in today's world. Increasingly, national borders
are blurred and the separation created by geographic distances is minimized.
We may travel more in a week, and rub shoulders with more people, than our
grandparents did in a lifetime. Travel and travelers are increasingly a source of
exposure to diseases. Early data analysis showed, for example, that in 1996,
488 confirmed cases of measles were reported in the U.S., and a substantial
proportion of these cases had been "international importations" (cases brought
into the U.S. by persons who had traveled). The sources of the imported cases
included Germany, Greece, Japan, Austria, India, the Philippines, China, Italy,
Russia, England, Kenya, Liberia, Nepal, Somalia, Tahiti, and Turkey (14)
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Q and A
Page 7 of 9
Another set of outbreaks was linked to school-aged American children who
were not required to receive a second dose of measles vaccine to attend
school. To read the complete text of these reports, click here.
We conduct business around the world, travel to distant nations where
vaccinations are not widely available, vacation in exotic places where we may
plunge into jungles, climb isolated mountains, and explore hidden caves--or we
work with people who do these things. As our suburbs expand into fields and
woods, we are pressing into the abodes of living things we have not
encountered in many years, or may never have encountered, and some of them
harbor viruses that can cause sickness in people. A chance encounter may be
just that--a chance to acquire a disease that can result in sickness and death.
Table of contents
Why must my child have so many shots?
As we have increased the number of vaccinations that are available, the
number of shots a child receives has indeed gone up. The miracles of
technology have created a "crisis of opportunity." While there is no known
consequence of having so many injections, (15) no one wants to subject children
to unnecessary discomfort. For this reason, vaccine developers are working on
alternative and less discomforting methods of administering vaccines. Among
those being tried are combination vaccines, which will reduce the number of
injections required. New ways to give vaccines, such as by mouth or by inhaling
an aerosol, are also being explored. Also, pediatricians and vaccine experts are
working together to develop new schedules that will reduce the number of
injections that are needed at any one visit or altogether.
Table of contents
Aren't there some chemicals and other substances added to vaccines?
Yes, chemicals are added to some vaccines in very small amounts and for
specific purposes (for example, to boost the action and strength of the vaccine).
Details on the additives used are available in a fact sheet posted on the CDC
National Immunization Program site.
Table of contents
I got a flu shot and I still came down with the flu. Why?
Influenza vaccine has an excellent track record in preventing disease. It is 70%
to 90% effective in healthy people younger than 65, if a good match has been
made between the vaccine and the circulating viruses, and if the vaccinated
individual's immune system is functioning properly (16)
There are several possible explanations for getting a flu-like illness after an
influenza immunization.
One is that you didn't have the flu at all-that you acquired another virus,
disease, or condition that caused flu-like symptoms, which are common
to a number of other ailments. There are many viruses that can cause
flu-like symptoms that wouldn't be prevented by influenza vaccine.
Diseases like fibromyalgia, rheumatoid arthritis, and chronic fatigue
syndrome can cause aches, pains, and fatigue that resemble the flu.
Second is that for any of a number of reasons, your immune system
didn't respond properly, or as folks sometimes say, "Your vaccination
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Q and A
Page 8 of 9
didn't 'take'."
Second is that for any of a number of reasons, your immune system
didn't respond properly, or as folks sometimes say, "Your vaccination
didn't 'take'."
A fourth possibility is that the vaccine you received was not strong
enough or had not been stored properly. This has occurred occasionally.
And yet a fifth is that you had already been exposed to the flu before you
received the vaccine.
Table of contents
If you didn't find the answer you need in this section
Call the CDC National Immunization Program hotline at 1-800-232-2522
(English) or 1-800-232-0233 (Spanish), or visit the National Immunization
Program's home page .
Table of contents
Do you have a question you think should be answered here?
Submit your question on our comments line. We are unable to answer inquiries
individually, but will do our best to respond by improvements and additions to
this web site. Click here to go to the comments line.
Table of contents
Footnotes
1. Arthritis Foundation. Letter of May 15, 1997: "There is no evidence that
defects in vaccine administered to newborns and children are contributing to a
current explosion of chronic neurological and immune system dysfunction in the
American population including lupus and rheumatoid arthritis. This certainly is
not true in lupus, rheumatoid arthritis, or juvenile arthritis Certainly the term
explosion is not justified. The current scientific data reveals that the causes of
lupus and rheumatoid arthritis are a combination of genetic susceptibility and
then a variety of factors stimulating the immune process I am not aware of any
findings linking childhood immunizations with lupus or rheumatoid arthritis."
2. Tingle AJ, Mitchell LA, Grace M, et al. Randomised double-blind placebo-
controlled study on adverse effects of rubella immunisation in seronegative
women. Lancet 1997;349:1277-1281.
3. Ray P, Black S, Shinefield H, et al. Risk of chronic arthropathy among
women after rubella vaccination. Journal of the American Medical Association
August 20, 1997;278(7):1-7. An abstract of this article is available on the
American Medical Association homepage.
4. Institute of Medicine. Adverse events associated with childhood vaccines:
evidence bearing on causality. Stratton KR, Howe CJ, Johnston RB Jr, editors.
http://www.cdc.gov/od/nvpo/qa.htm
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Q and A
Page 9 of 9
Washington, DC: National Academy Press, 1994:222-227.
5. Plotkin SA, Mortimer Jr., EA (editors). Vaccines. 2nd edition. Philadelphia: W.
B. Saunders Company, 1994: Appendix 6, pages 973-974 [information in public
domain].
6. Centers for Disease Control and Prevention. General recommendations on
immunization: Recommendations of the Advisory Committee on Immunization
Practices. Morbidity & Mortality Weekly Review January 24, 1994; 43(RR-1):21.
This article can be viewed online on the CDC site.
7. Centers for Disease Control and Prevention. General recommendations on
immunization: Recommendations of the Advisory Committee on Immunization
Practices. Morbidity & Mortality Weekly Review January 24, 1994; 43(RR-1):26.
This article can be viewed online on the CDC site.
8. Centers for Disease Control and Prevention. General recommendations on
immunization: Recommendations of the Advisory Committee on Immunization
Practices. Morbidity & Mortality Weekly Review January 24, 1994; 43(RR-1):21.
This article can be viewed online on the CDC site.
9. Centers for Disease Control and Prevention. General recommendations on
immunization: Recommendations of the Advisory Committee on Immunization
Practices. Morbidity & Mortality Weekly Review January 24, 1994; 43(RR-1):1-
40. This article can be viewed online on the CDC site.
10. Centers for Disease Control and Prevention. General recommendations on
immunization: Recommendations of the Advisory Committee on Immunization
Practices. Morbidity & Mortality Weekly Review January 24, 1994; 43(RR-1):8.
This article can be viewed online on the CDC site.
11. Rapin I. Current concepts: Autism [review article]. New England Journal of
Medicine July 10, 1997; 337(2):97-104. The full text of this review article can be
purchased through the Journal's online service at http://www.nejm.org.
12. Centers for Disease Control and Prevention. Varicella-related deaths among
adults: United States, 1997. Morbidity & Mortality Weekly Review May 16, 1997;
46(19):409-412. This article can be viewed online at the Centers for Disease
Control and Prevention home page.
13. National Vaccine Program Office. Selected issues on immunizations:
Background information for the Natonal Medical Association Vaccine Task
Force Meeting. Atlanta: National Vaccine Program Office, April 20, 1997: 2-3.
This can be viewed online in the publications section of this site.
14. Centers for Disease Control and Prevention. Measles: United States, 1996,
and the interruption of indigenous transmission. Morbidity & Mortality Weekly
Review March 21, 1997; 46(11):242-246.
15. Orenstein W. Quoted in Vaccine danger: more kids missing shots.
Immunization News Service June 30, 1997:1.
16. Advisory Committee on Immunization Practices. Prevention and control of
influenza: Recommendations of the Advisory Committee on Immunization
Practices. Morbidity & Mortality Weekly Review April 25, 1997;46(RR-9):3.
Top
National Vaccine Program Office
Centers for Disease Control and Prevention (CDC)
Updated: 04/06/1999 15:56:45
CDC
http://www.cdc.gov/od/nvpo/qa.htm
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6/7/99
TRENDS IN PREVENTIVE MEDICINE
Better Than a Cure
by Tim Beardsley, staff writer
W
hen cholera started killing
thousands of Rwandan refu-
gees in camps in Zaire last
summer, nobody was more frustrated
than Jerald C. Sadoff of the Walter Reed
Army Institute of Research in Washing-
ton, D.C. As chair of a World Health Or-
ganization (WHO) committee on vac-
cines for diarrheal diseases, Sadoff had
been trying unsuccessfully for months
to raise about $200,000 for research
into vaccines against a newly identified
strain of cholera. It took pictures of
sickness and death beamed around the
world from the camps to focus interna-
tional attention on the disease; relief
agencies eventually spent $140 million
in emergency aid to contain the out-
break. "It did seem ironic," Sadoff recalls.
The episode highlights some of the
difficulties faced by vaccine science. The
benefits of immunization are invisible,
yet governments as well as ordinary
citizens are most easily persuaded to
reach into their purses for medical re-
search when they see suffering. Like-
wise, even though it is in the public in-
terest for people to be well immunized,
healthy individuals are unwilling to pay
much for vaccines. Most pharmaceuti-
cal companies therefore avoid making
them. In consequence, the global effort
to develop new and more effective vac-
cines is small in comparison with other
areas of medical research.
Infectious disease is still the number-
one cause of death worldwide. Microbes
of one kind or another kill more than
13 million every year, mostly infants.
Acute respiratory infections take the
biggest toll among the young; in 1992
they killed about 2.8 million children
younger than five years. Diarrheal dis-
eases took another 2.2 million, and ma-
laria carried off a million.
Vaccines offer the best hope for re-
ducing the appalling toll. Immunization
is, simply, the best medicine. Not even
antibiotics can touch it in terms of cost-
effectiveness. According to David Park-
er and Terrel Hill of UNICEF, immuni-
zation against measles, tetanus and tu-
berculosis costs from $2 to $15 per
"discounted year of healthy life" gained
VACCINATIONS against measles are administered to Rwandan refugees
(a statistical measure of the value of a
at a camp in Tanzania. Such immunization campaigns assume an espe-
vaccine). Other common interventions
cially high priority in situations where there is crowding and poor sanita-
cost from $25 to $1,000 for the same
tion. Vaccines save lives and prevent disease more cost-effectively than
88
SCIENTIFIC AMERICAN January 1995
The World Health Organization wants industry to step up
its efforts to dévelop new vaccines. Can big business
and a public health bureaucracy see eye to eye?
benefit. Moreover, vaccination is ex-
tremely safe. Although some serious re-
actions have been linked to the current
generation of pertussis (whooping
cough) vaccines, the risk is tiny in com-
parison with the threat posed by con-
tracting the disease itself, which in the
1980s killed more than 500,000 a year
worldwide. Pertussis vaccines now in
clinical trials should be even safer.
Some public health experts have wor-
ried that the large reductions in death
rates brought about by immunization
might in poor countries be offset by
children dying at greater rates from
other causes, such as starvation. But the
available data do not support that no-
tion, Parker and Hill say. They even sug-
gest that decreasing death rates from
disease seem to lead to lower birth
rates, presumably because women feel
the need to have fewer children when
more survive.
Much could be achieved merely by
ensuring that today's vaccines reached
all the people who could benefit from
them. That step alone would save about
two million lives every year, WHO calcu-
lates. Even in the U.S., an estimated 500
children die every year from diseases
that could have been prevented by vac-
cination. Influenza, hepatitis B and
pneumococcal pneumonia kill more
than 500,000 adults annually in the
U.S.; many of those deaths could have
been avoided if available vaccines were
more widely used.
There seems to be no argument
among the players in the vaccine busi-
ness that even larger gains against mi-
crobes are achievable with new and im-
proved products. In the past, vaccine
development was as much an art as a
science. But scientific advances in recent
years have pointed to fresh approach-
es, some of which are already proving
themselves. "From an immunologic per-
spective, the state of knowledge is such
STEVE LEHMAN SABA
that the art of vaccination can soon be
grounded on a rational rather than an
empirical basis," declares the 1993 edi-
tion of The Jordan Report, a survey of
vaccine developments published once
other form of medication. The technical means for developing new
a year by the National Institute of Aller-
vaccines for a variety of fatal illnesses are improving steadily. Money for
gy and Infectious Diseases (NIAID).
vaccine research remains a limiting factor, however, and often vaccines
At present, only about 20 different
fail to reach those whom they would benefit most.
types of vaccine are in widespread use.
SCIENTIFIC AMERICAN January 1995
89
DIPHTHERIA-PERTUSSIS-TETANUS
IMMUNIZATION COVERAGE
100%
40%-59%
80%-99%
20%-39%
60%-79%
0%-19%
DATA UNAVAILABLE
SOURCE WHO,
NOSNHOR ANNHOR
IMMUNIZATION RATES vary widely. The map shows the pro-
Health Organization recommends for use globally. Rates for
portion of infants receiving all three doses of diphtheria-per-
poliomyelitis, measles and tuberculosis tend to track those
tussis-tetanus vaccine. The vaccine is one of five the World
shown here; for hepatitis B, coverage is more patchy.
Yet there is no shortage of leads for
portable refrigerators is of varying qual-
search laboratory to the field-"from
novel products. A survey conducted by
ity and availability. The cold chain is one
bench to bush," in the argot of the busi-
the NIAID has identified 192 vaccine
reason why in developing countries the
ness-has not been as rapid as it should
candidates that are ready for early test-
cost of delivering a vaccine is far great-
be. Many vaccine researchers feel the
ing in people or animals. New disease
er than the cost of the vaccine itself.
same way. "There has existed for some
targets aside, there is plenty of room for
time the belief that even more could be
improvement in existing products. Mea-
From Bench to Bush
accomplished if ways could be found to
sles vaccine, for example, does not work
bring greater cohesion" to vaccine de-
in infants younger than nine months,
so many children die from the illness
O
ne of the biggest problems with
velopment, the recently published U.S.
current products is simply that
National Vaccine Plan states.
before that age. Typhoid vaccine is un-
most have to be given several times to
The obstacles are complex. Manufac-
reliable. The bacillus Calmette-Guérin
be effective. A full course of all the
turers have to be convinced that the in-
(BCG) vaccine against tuberculosis is
WHO-recommended vaccines, for exam-
vestment necessary to develop a new
only partly effective; as a result, more
ple, requires five visits to a provider. In-
product-which may be anywhere from
than three million people die of that in-
evitably, many children do not receive
$10 million to more than $100 million-
fection every year, most of them young
all the required doses, especially in re-
is likely to produce a good return. Vac-
adults. With the spread of multidrug-
mote places. Yet although workers in
cines, they say, are much harder than
resistant strains, that total seems likely
the field agree that reducing the number
the average drug to manufacture. Some
to increase.
of necessary doses is one of the most
involve the use of dangerous microor-
Purely practical considerations con-
promising ways to improve protection,
ganisms. "You can't imagine the num-
nected with delivering vaccine to its re-
manufacturers have been slow to de-
ber of steps it takes to make a new vac-
cipients are often a major hurdle. Most
velop such vaccines, in the opinion of
cine," says R. Gordon Douglas, Jr., pres-
vaccines are sensitive to heat, so a re-
Philip K. Russell, a former head of the
ident of the vaccine division at Merck &
frigerated "cold chain" stretching from
U.S. Army medical research and devel-
Co. To make a batch of poliomyelitis
the manufacturer to the patient has to
opment command, who is now presi-
vaccine takes at least nine months, he
be established. The challenge can be
dent of the Albert B. Sabin Vaccine
notes.
daunting in regions where tempera-
Foundation.
A product is likely to generate hefty
tures may reach more than 40 degrees
Russell is not alone in believing that
returns, however, only if it can be sold
Celsius and where the kerosene fuel for
the progress of vaccines from the re-
in rich countries or if the market will be
90
SCIENTIFIC AMERICAN January 1995
extensive. Many potential disease tar-
gets are not economically justifiable.
"Take Crimean hemorrhagic disease-
o's going to develop a vaccine for
?" Douglas asks rhetorically. Many
international development agencies, in-
cluding the U.S. Agency for Internation-
al Development, have been hesitant to
get involved in early-stage vaccine re-
HIII
search, Russell observes. Most agencies
have seen their primary role as deliver-
ing existing vaccines to the needy. "One
of the sad problems is that implement-
ers and researchers and manufacturers
hardly ever got together, and when they
did they didn't talk the same language,"
remarks John R. La Montagne, head of
vaccine research at the NIAID.
Vaccine Czar
T
he task of breaking that logjam has
fallen to Jong Wook Lee, a soft-spo-
ken former vaccine researcher from
South Korea, who is director of the new
WHO Global Program for Vaccines and
Immunization. The program, which is
STEVE MUREZ Black Star
run out of a cramped annex behind
WHO headquarters in Geneva, brings
the organization's vaccine research and
JONG WOOK LEE is head of the new Global Program for Vaccines and Immunization
delivery operations together for the first
at WHO and also runs the Children's Vaccine Initiative. Lee declares he is "flinging
time. It will, Lee predicts, wield enough
open the door to industry" in order to speed the development of new vaccines.
fluence over manufacturers to per-
de them to cooperate. "We are fling-
g open the door to industry," he
announces.
Even if Lee's program meets only
some of its targets for the remainder of
the decade, the effort could save mil-
lions of lives. "Never in the field of hu-
man medicine will so much be owed by
so many to so few," he beams in a rare
immodest moment.
If Lee's ambitions seem unrealistic, it
is worth remembering that WHO, in col-
laboration with UNICEF, has a success-
ful history when it comes to getting vac-
cines to where they are needed. The or-
ganizations eradicated smallpox in 1977
and boosted global immunization lev-
els for six major killing diseases from 5
percent in 1974 to more than 80 percent
in 1990. Lee's program estimates that
vaccination against just three of those
six-measles, neonatal tetanus and per-
tussis-is now preventing almost three
million deaths a year. Although immu-
nization rates have started to flag in re-
cent years in some countries, most of
them in western and central Africa, Lee
has plans to reverse that trend.
WHO has also made impressive
ides against polio and estimates that
JOHN PINDERHUGHES
cination prevents 550,000 cases of
that crippling disease annually. WHO's
American wing, the Pan American Health
R. GORDON DOUGLAS, JR., president of Merck & Co.'s vaccine division, is angry
Organization, announced last Septem-
about price controls Congress has imposed on vaccines supplied to the govern-
ber that an unrelenting surveillance ef-
ment. "This means we're not doing all the things we're capable of," he states.
SCIENTIFIC AMERICAN January 1995
91
fort combined with "vaccination days"
(stocks of virus may exist in laborato-
there are dangers. In August 1990, WHO,
for the entire juvenile populations of
ries after then). Lee is planning to ease
the World Bank, UNICEF, the U.N. Devel-
high-risk countries has already eradicat-
that passage by stepping up surveil-
opment Program and the Rockefeller
ed polio from the Western Hemisphere:
lance and vaccination efforts in coun-
Foundation launched a campaign called
the last recorded case there occurred
tries where polio is still well known.
the Children's Vaccine Initiative (CVI).
in Peru in 1991. Lee's team at WHO be-
Close collaboration with industry on
The CVI was intended to catalyze the
lieves polio could follow smallpox to
vaccine development is a new venture
creation of heat-stable, affordable vac-
extinction in the wild by the year 2000
for WHO, however. And history suggests
cines that could be administered orally
Many Ways to Make a Vaccine
As
S long ago as the early 18th century, people sought pro-
cause their immune systems do not recognize as foreign the
tection against smallpox by pressing infectious "matter"
sugars in the bacterial cell walls. During the past two de-
from patients' lesions into breaks in their own skin. The high-
cades, however, researchers have learned how to combine
ly dangerous practice was intended to cause a mild case of
these sugars with protein carriers. The resulting "conjugate"
the disease and so bestow immunity.
vaccines work well even in infants. In 1986 the first conju-
Immunization became a more reasonable proposition in
gate vaccine, against Hemophilus influenzae type B, was li-
1798, when Edward Jenner demonstrated how the illness
censed in the U.S., and current versions are effective in chil-
could be prevented by inoculations of cowpox, a related but
dren as young as two months. Conjugate vaccines for pneu-
less dangerous disease. The principle of using a related
mococcal pneumonia and meningococci groups A and C are
pathogen to provoke immunity is still being explored today in
under development. "They could have a tremendous impact
vaccines designed to protect children from rotaviruses, which
in a number of diseases," says John R. La Montagne of the Na-
cause often fatal diarrhea in millions of children. But many
tional Institute of Allergy and Infectious Diseases.
other approaches to vaccination are used as well.
Adjuvants and microspheres.
Killed whole organisms and weakened toxins.
Many improvements in vaccines expected over the next
Several widely used vaccines, including those targeted at
decade are likely to be the result of better adjuvants or carri-
influenza and pertussis, are based on killed microbes. In-
ers. Adjuvants are substances that potentiate an immune re-
jectable poliomyelitis vaccines also work this way. A variant
sponse. The only adjuvant licensed for use in humans at pre-
of this approach, used in diphtheria and tetanus immuniza-
sent is alum, an aluminum salt, but other chemicals, including
tion, is to inject people with chemically modified versions of
some complex organic ones, are being studied. Among them
toxins produced by the infectious agent. Such toxoids, as
are muramyl dipeptide, squalene, lipid spheres known as li-
they are called, allow the immune system to learn how to in-
posomes and cagelike organic structures called immunostimu-
activate the poison from a real infection.
latory complexes (ISCOMs).
An approach that has long captured the
Subunit vaccines.
imagination of researchers puts immunogenic
Vaccines consisting of molecular subunits
chemical fragments into minute polymer
of pathogens can avoid some of the compli-
spheres that only slowly let the immune sys-
cations of using whole organisms. Subunit
tem "see" their contents as they diffuse out.
vaccines are now available for meningitis,
The scheme might be able to confer long-last-
pneumonia and hepatitis B; vaccines em-
ing immunity for some diseases with a single
ploying this approach against respiratory
inoculation. Recently workers have success-
syncytial virus and parainfluenza virus, both
fully stabilized tetanus toxoid in polyester mi-
major killers, are in development. Subunit
preparations are also being investigated as
candidates for protection against infection
HANK MORGAN Photo Researchers, Inc.
crospheres, thus pointing the way to a one-
dose tetanus vaccine.
with HIV (the AIDS virus) as well as malaria.
Oral vaccines.
Most vaccines are thought to exert their ef-
Altered pathogens.
fects in the bloodstream. Oral polio vaccine,
Some diseases require a more powerful
however, seems to work by triggering a differ-
immune stimulus. In such cases, favorable
ent kind of immune response that can be
results can sometimes be obtained with live microorganisms
elicited only when immunostimulatory molecules reach spe-
that have been weakened, or attenuated, so that they do not
cial cells in the lining of the gut. Immunity generated this way
produce significant illness. This is still the basis of the oral po-
is termed mucosal immunity. Many researchers believe vac-
lio vaccine and the combined vaccine against measles, mumps
cines designed to stimulate mucosal immunity-which would
and rubella. Modified pathogens might be even more com-
probably be administered orally-might protect against dis-
monly used in the future. Genetic engineering has made it
eases that have so far proved resistant to vaccination. Sexual-
possible to introduce immune-stimulating proteins from a
ly transmitted diseases, including HIV infection, are a major
range of pathogens into tried and trusted carrier organisms
focus of research interest, as are pathogens that enter the
such as vaccinia (derived from the cowpox virus with which
body through the gut, such as Vibrio cholerae (which causes
Jenner countered smallpox) and various bacteria.
cholera) and Shigella (dysentery).
Conjugates.
Naked DNA.
Vaccines for some bacterial diseases, such as pneumococ-
The most recent and surprising development was the dem-
cal pneumonia and meningitis, cannot be used in babies, be-
onstration that DNA, when injected into muscle, can by itself
92
SCIENTIFIC AMERICAN January 1995
early in life and would protect against
has secured international agreement on
lio vaccine that is stable for up to a
a wide range of diseases.
procedures for manufacturing vaccines
week at 37 degrees C. (The product is
The plan was to cajole manufacturers
and checking their quality, an important
now in industrial development.)
to making innovative products by es-
step toward being able to make novel
Russell believes that the CVI's great-
blishing priorities for research, orga-
combinations. It also stimulated a
est achievement was to persuade man-
nizing clinical trials and raising money.
promising project that demonstrated
ufacturers to make vaccines that com-
Ciro A. de Quadros of the Pan American
how deuterium oxide, better known as
bine protection against hepatitis B and
Health Organization says the initiative
heavy water, can be used to make a po-
Hemophilus influenzae type B (Hib)-a
common and dangerous cause of men-
ingitis-with the existing combination
vaccines for diphtheria, pertussis and
confer immunity. Workers at Vical, a biotechnology company in San Diego, Calif.,
tetanus. "There was tremendous embed-
collaborating with Merck and U.S. Navy investigators, have shown that such "naked
ded resistance" from people who saw
DNA" can immunize mice against malaria and influenza. The DNA, which encodes
no need to disturb the status quo, Rus-
a protein displayed by the pathogen, apparently stimulates host tissues to synthe-
sell recalls. "If you look at the CVI as a
size proteins that the immune system recognizes as foreign.
global intellectual movement, it's been
By continuously stimulating the immune system, naked DNA vaccines could pro-
a substantial success."
duce responses as strong as those induced by attenuated organisms. In particular,
Others have a different assessment.
they seem able to stimulate the arm of the immune system that employs cells to
"European industry was quite upset
kill invaders. Naked DNA technology "has an immensely powerful capability," says
with the CVI because it ignored our
Philip K. Russell of the Albert B. Sabin Vaccine Foundation.
achievements," explains Walter S. Van-
dersmissen, director of government af-
fairs for SmithKline Beecham in Brus-
SOME VACCINES IN DEVELOPMENT
sels. "It was a dream, and we tried to in-
Disease/Pathogen
Technology
still a sense of realism. Today not much
has been achieved." The ambitions were
Respiratory syncytial virus
Attenuated virus;
slowly scaled back, but friction still de-
subunit in microspheres
veloped between the CVI and WHO
when workers for those agencies start-
Influenza
Attenuated virus and naked DNA
ed giving conflicting advice to govern-
ments. Moreover, the CVI failed to raise
Group B streptococci
Conjugates
more than a few million dollars toward
a planned $300-million fund for vac-
fluenza
Subunits and attenuated virus;
cine development.
inactivated virus in microspheres
Mounting disagreements among the
CVI's sponsors over what the initiative
Meningococci group B
Modified polysaccharide
should be doing were finally resolved
last August. The sponsors agreed to let
Measles
Subunits in ISCOMs and in vaccinia;
the initiative be advised by the same
attenuated virus; naked DNA
committee that oversees WHO's new
program, thus effectively bringing them
Pneumococcal pneumonia
Subunits and conjugates
under one command. Lee was given the
additional appointment of executive
Typhoid
Subunits and conjugates
secretary of the CVI, which makes him
almost a global vaccine czar. The CVI
Cholera
Inactivated and attenuated pathogens;
will now concentrate on raising aware-
subunit combinations
ness of research results and gaining
political commitments to improved vac-
Shigella
Bacterial vector; subunits and conjugates
cines, according to Roy Widdus, an ad-
viser to Lee on the project.
Tuberculosis
Mycobacterial vector; subunit
Whether the new WHO effort can
forge a consensus on vaccine develop-
Malaria
Subunit and naked DNA
ment will depend on the ability of Lee
and his team to better the record of the
Dengue
Yeast, yellow fever and vaccinia vectors;
CVI in building constructive links with
attenuated and chimeric viruses
industry. Lee acknowledges that WHO
has in the past been coy, even "a little
Rotavirus
Attenuated and modified viruses
paranoid," about close relations with
manufacturers, fearing that its impar-
Tetanus
Single dose: toxoid in microspheres
tiality might seem to be tainted. But he
now has good reason to want to change
Schistosomiasis
Subunit
that stance.
Last year WHO received the results
immunodeficiency
Subunits; vaccinia vectors; inactivated
of a confidential study conducted by
virus
Mercer Management Consulting on the
SOURCES: Global Program for Vaccines and Immunization, World Health Organization;
economics of the $3-billion global vac-
The Jordan Report, National Institute of Allergy and Infectious Diseases
cine industry. A central finding was that
the $60 million that UNICEF spends ev-
SCIENTIFIC AMERICAN January 1995
93
ery year to buy vaccines for poor coun-
encourage more countries to make or
technology [see box on pages 92 and
tries-at discount prices-was enough
buy vaccines rather than appeal to the
93]. The amounts are small, but man-
for the deals to be profitable for manu-
charity of UNICEF. At present, UNICEF
ufacturers can "feel they are partners,"
facturers, provided they could charge
purchases fully 40 percent of the
says Paul-Henri Lambert, head of the
higher prices elsewhere. The study thus
world's pediatric vaccines for countries
vaccine R&D division.
made clear that UNICEF-which acts as
that have not made their own arrange-
U.S. vaccine producers, however, are
the purchasing arm of WHO-could ex-
ments. Some of those countries could
unlikely to become suppliers for UNICEF.
ert pressure on manufacturers. "We are
buy for themselves, Lee says, and a
According to Ronald J. Saldarini, presi-
writing the guidelines, so we have lever-
few-including China and India-will
dent of Lederle-Praxis Biologicals, an-
age," Lee declares. "No one country can
be told to start doing so immediately.
other major U.S. vaccine manufacturer,
perform this function, and industry can-
Others will be given a grace period. The
the prices are simply too low. "I can't
not ignore the process."
move is likely to be well received by
afford to supply" UNICEF, he states.
manufacturers: because many poor
Merck's Douglas blames the U.S. gov-
Building Bridges
countries are unlikely to establish their
ernment for making it hard for domes-
own plants, Lee's policy means more
tic. manufacturers to bid on UNICEF
Le
ee is keen to stimulate vaccine pro-
vaccines will be sold at higher prices.
contracts. Merck would do so, he says,
duction in developing countries as
Vaccine makers have noticed the new
if it could charge lower prices than it
well as in the industrial world. About 60
industry-friendly stance in Geneva. "It's
charges the federal government for vac-
percent of the global supply of diphthe-
a major change for a group that has a
cines. But back in 1982, Merck execu-
ria-pertussis-tetanus vaccine-a relative-
tendency to denigrate the profit-mak-
tives were lambasted by a congression-
ly simple product-is made in develop-
ing sector," reflects Thomas M. Vernon,
al committee for proposing to do just
ing countries; Lee explains that he would
Jr., executive director for medical, sci-
that, and the company wants to avoid a
be quite happy to see manufacturers
entific and public health affairs at Mer-
repeat episode. Overseas manufacturers
outside the industrial world grab a larg-
ck. "There has been a wind of change,"
that have supplied UNICEF programs
er slice of the pie for other products. "In
Vandersmissen agrees. "Now industry
were encouraged to do so by their gov-
the developing world, they are not just
can frankly state its point of view, in-
ernments as a matter of foreign policy,
driven by profit motivations," he says.
cluding financial concerns."
Douglas maintains.
At present, technical problems mean
Within the past year the Global Pro-
Constraints on vaccine prices also lie
some vaccines manufactured in devel-
gram for Vaccines and Immunization
at the heart of a separate bitter argu-
oping countries "may be completely
has awarded $400,000 to industrial and
ment U.S. manufacturers have with their
useless," Lee admits. But WHO has in-
academic researchers to investigate how
government. The amount of vaccine
troduced standards of good manufac-
a heat-stable oral polio vaccine might be
that U.S. producers sell to the Public
turing practice that should eliminate
manufactured. It has also entered into
Health Service can fluctuate drastically
such variations. Lee argues that if man-
contracts worth more than $300,000
from year to year as a consequence of
ufacturers in Asian countries can make
with companies in the U.S. and Europe
the rules used to apportion purchases.
cars suitable for the U.S. market, Asian
to develop improved vaccines for group
Yet under the Vaccines for Children pro-
pharmaceutical companies can proba-
A and C meningococci and for tubercu-
gram [see box on opposite page], which
bly make vaccines to WHO's standards.
losis and leprosy, as well as a single-
started last October, the price the gov-
Lee is also spearheading an effort to
dose tetanus toxoid using microsphere
ernment pays is capped, with increases
only for inflation. The combination is
anathema to industry. Barry R. Bloom,
a researcher at the Albert Einstein Col-
lege of Medicine in Bronx, N.Y., argued
recently in Science for the creation of a
national vaccine commission to try to
bring some stability to the rocky rela-
tions between the U.S. government and
its suppliers. The commission would
assess vaccine supply and demand and
be able to respond to emergencies, such
as an outbreak of infectious disease. "If
there were an outbreak of yellow fever
in New Orleans, we would be out of vac-
cine in two weeks," Bloom declares. "We
are not prepared."
Others are not convinced that a com-
mission would help. Saldarini of Leder-
le-Praxis sees no need for another gov-
PETER SABA
ernment committee. "I'm committeed
out," he complains. In any event, Con-
gress recently directed the nearest thing
the government had to a central author-
ity on vaccines-the National Vaccine
Program Office-to cut 30 people from
its staff of 35. Russell calls the effective
MOBILE VACCINATION CLINIC near Chang Rai, Thailand, is visited by hill tribe vil-
dismantling of the office "a disaster."
lagers. In such remote areas lacking electricity and modern refrigeration, distribu-
Lee seems anxious to avoid similar
tion efforts are complicated by the need to keep the vaccines cool.
disasters in the international arena. But
94
SCIENTIFIC AMERICAN January 1995
Born in the U.S.A.
E
ven in a rich country such as the U.S., getting vaccines
the VFC program because it has increased the fraction of
to infants is difficult. Almost all American children are
domestic vaccine bought by the government (at a half-
fully vaccinated by the time they enter school, since vacci-
price discount) from about 50 to 80 percent. At the same
nation is a condition for enrollment. Still, many do not re-
time, Congress put a cap on prices, so makers cannot
ceive all their shots by the recommended age. Henry D.
compensate for the fall in revenues. The result, they say,
Mustin and his colleagues at the University of Washington
will be less research and fewer new products.
published in a recent issue of the Journal of the American
R. Gordon Douglas, Jr., of Merck notes that the project-
Medical Association a study showing that in a nationally
ed shortfall is already constraining the company's choices
representative sample only 46 percent of white infants
about which projects to pursue. "These decisions will af-
and 34 percent of black infants had received adequate im-
fect health 10 years from now, and I can only tell you that
munizations by the age of eight months. According to the
this means we're not doing all the things we are capable
Centers for Disease Control and Prevention, 67 percent of
of," he insists. Christine M. Grant of Connaught Laborato-
U.S. youngsters have received all the recommended doses
ries, which is owned by Pasteur-Merieux, remarks that the
of diphtheria-pertussis-tetanus, measles-mumps-rubella
price-capping provisions of the program "send a message
and poliomyelitis vaccines by the time they are two years
that is 180 degrees opposed to support for research and
old. But only 55 percent had received the three recom-
development." Ronald J. Saldarini, president of Lederle-
mended Hemophilus influenzae type B shots, and only 16
Praxis Biologicals, charges that the VFC program "is an at-
percent had been properly vaccinated against hepatitis B.
tempt to virtually nationalize the industry and take us out
The vaccine-policy joke (there is only one) is that there are
of the private sector."
counties in Texas where the cattle are better immunized
Even if the VFC program is fully implemented, Douglas
than the children are.
argues that it will not significantly increase the number of
Missed vaccinations can have serious consequences.
children in the U.S. who receive their immunizations on
Poor measles vaccination rates resulted in a 55,000-case
time. The reason some children fall behind is not cost,
outbreak in the U.S. in 1989-1991, causing 136 deaths.
Douglas maintains, but a lack of education and ready op-
Concern about the low rates prompted the government to
portunities in impoverished inner-city areas. Douglas's
implement last year the Vaccines for Children (VFC) pro-
proposed solution to U.S. vaccination woes is to require
gram, which was intended to make it easier for uninsured
that every health insurance package cover preventive ser-
or inadequately insured children to obtain free vaccines
vices for children.
from private physicians. (Private pediatricians
typically charge $270 for a full course of 11
shots, although vaccinations have also been
free for the asking in public health clinics.) But
the program has gotten off to a shaky start.
Initially the government had proposed dis-
tributing vaccines for the program to private
physicians from a single warehouse in Bur-
lington, N.J. Officials realized belatedly, how-
ever, that they could not establish the neces-
sary tracking and handling system by the pro-
gram's October I starting date; consequently,
that plan was scrapped. Some states with ex-
perience in vaccine distribution have agreed
to disburse VFC vaccines to physicians them-
GENERAL SERVICES ADMINISTRATION
selves, but as of early November, 24 states
had still not done so.
U.S. vaccine manufacturers bitterly oppose
The VFC vaccine distribution center that wasn't
whether the new WHO/CVI combined
depend on other factors, not least on
bureaucracy can really spur the develop-
how much money the program can raise.
FURTHER READING
ment of more effective vaccines is still
"Unless some other source of funds is
THE JORDAN REPORT: ACCELERATED DE-
an open question. Despite Lee's over-
found, none of this can really work,"
VELOPMENT OF VACCINES IN 1993. Na-
tures to industry, difficulties remain.
Bloom says. The Global Program for Vac-
tional Institute of Allergy and Infec-
Lambert says industry's penchant for
cines and Immunization now has a bud-
tious Diseases, National Institutes of
secrecy about its plans-especially when
get of less than $30 million; Lee would
Health, 1993.
it scents profits-is still a problem. Van-
like to increase that to $50 million.
FRONTIERS IN MEDICINE: VACCINES. Spe-
dersmissen argues that WHO would be
More important still will be whether
cial section in Science, Vol. 265, pages
1371-1404; September 2, 1994.
most effective if it concentrated on or-
WHO adopts economically sustainable
VACCINES AND PUBLIC HEALTH: ASSESS-
nizing clinical trials.
policies that will keep the industry con-
ING TECHNOLOGIES AND PUBLIC POLI-
Lee has his own measure of progress
nection strong. It is still too early to
CIES. Special section in International
relations with industry. "When we in-
judge the program, but Lee at least ap-
Journal of Technology Assessment in
vite, they always come," he observes
pears to have a clear vision. "Whatever
Health Care, Vol. 10, No. 1, pages 1-196;
with satisfaction. "They are never too
else," he admonishes, "we must not kill
Winter 1994.
busy." But in the long term, success will
the goose that lays the golden eggs."
SCIENTIFIC AMERICAN January 1995
95
Scientific American Exploration: AIDS Moonshot?: June 2, 1997
Page 1 of 3
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EXPLORE!
AIDS Moonshot?
Under President Clinton's command, researchers step
up the search for an HIV vaccine
PRESIDENT BILL
CLINTON vows to speed the
pace of AIDS vaccine research
Medical science is still far from conquering AIDS, but a number of
and make cutting-edge drugs
recent events give reason for hope. Within the past 18 months, clinical
more widely available to the
studies have shown that protease inhibitors and other powerful new
infected through the Medicaid
drug treatments can virtually halt replication of HIV, the virus that
program.
causes AIDS. These successes have led to marked improvements in the
condition of many suffering from the disease. The drugs are expensive,
however, and nobody knows how long they will hold the virus at bay.
To halt the spread of HIV around the world, researchers believe that it
is necessary to discover a vaccine, and an affordable one at that.
President Bill Clinton gave AIDS vaccine research a shot in the arm on
MORE
May 19, 1997, when he called for scientists to develop a vaccine for the
EXPLORATIONS
disease within ten years--and invoked the spirit of John F. Kennedy's
1961 declaration that the U.S. would set a man on the moon within ten
years. Although activists criticized Clinton for not promising new
money to support the initiative, having a vaccine as a presidential goal
is likely to help boost funding for vaccine research in future federal
budgets. In the meantime, the Administration says it plans to propose
extending federal Medicaid coverage to buy costly and potent drugs for
infected low-income people who have not yet developed the symptoms
of full-blown AIDS. Medicaid recipients are now excluded from early
access to these drugs.
Although some researchers are concerned about the demoralizing
consequences if Clinton's timetable proves impossible, many are
optimistic that the campaign might spur drug companies to step up their
efforts to protect against HIV. Manufacturers have tested dozens of
potential vaccines in small groups of people. These small trials are
aimed at establishing that the preparations are safe and that they
stimulate the immune system. But the results so far have not persuaded
pharmaceutical companies to organize large "phase 3" trials involving
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Scientific American Exploration: AIDS Moonshot?: June 2, 1997
Page 2 of 3
thousands of volunteers--the kinds of tests which will be necessary to
prove that a vaccine is safe for widespread use and effective and
preventing infection.
Researchers do not yet understand what aspects of the immune response
are necessary to confer protection against HIV; some even worry that
no highly effective vaccine is possible. And development efforts have
slowed since 1994, when the National Institutes of Health decided that
small tests had produced insufficient evidence to justify large-scale
U.S. trials of two candidate vaccines based on an HIV protein called
gp-120.
AIDS vaccines have largely fallen out of the spotlight since then, but
very recent findings suggest possible ways to overcome some of the
widely-recognized obstacles to developing an effective vaccine. One of
the big problems bedeviling such efforts is that there are multiple
strains of HIV, and different ones predominate in different regions. As a
result, a vaccine that works acceptably in one part of the world might be
useless elsewhere. Recently, however, Kent Weinhold of Duke
University Medical Center demonstrated that several vaccine candidates
in development could actually elicit immune responses to a variety of
HIV strains. In the tests, immune-system cells known as cytotoxic T
lymphocytes, taken from a group of volunteers, were exposed to cells
harboring various strains of HIV. Having thus been "trained" to
recognize the characteristic proteins of HIV, the lymphocytes often
were then able to kill HIV-infected cells.
The vaccines that Weinhold investigated were based on a modified
canarypox virus (a virus that causes disease in canaries but not in
humans) that had been genetically engineered to contain a gene from
HIV. These vaccines are more sophisticated than the gp-120 vaccines
that NIH declined to test in 1994. In the newer tests, vaccinated
volunteers were injected first with the canarypox preparation, and
subsequently given a booster shot consisting of just HIV's gp-120
protein, a protein that HIV uses as a gateway to enter the human cells.
Consequently, the body's immune cells were exposed to HIV proteins
from two different sources--both the ones manufactured by the
canarypox virus, and the gp-120 protein that was injected directly--to
assist the cells in identifying and destroying the invading AIDS virus.
The encouraging results from laboratory tests do not yet prove the
vaccines will work in people. "The only way to establish protection is
to do a phase 3 trial," notes Carole A. Heilman, associate director of the
division of AIDS at the National Institutes of Health. But the latest
finding show that the new candidates have potential. "There seems to
be more activity going on in AIDS vaccines in general," Heilman
comments.
David B. Weiner the University of Pennsylvania recently announced
another encouraging discovery. He and his colleagues were able to
make two chimpanzees resistant to HIV infection (like humans, chimps
are susceptible to the virus) by vaccinating them with a preparation
based on "naked" DNA encoding HIV genes. Conventional vaccines
employ killed or modified pathogens, or proteins made by them, rather
than DNA. In contrast, a DNA vaccine like the one used by Weiner
works by allowing the body's cells to make viral proteins in a harmless,
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Scientific American Exploration: AIDS Moonshot?: June 2, 1997
Page 3 of 3
non-infectious form; the immune system then gets sensitized to them,
which helps prevent subsequent infection by the actual virus. Weiner's
result provides evidence that a naked DNA vaccine might work in
people, although there are substantial differences between chimpanzees
and humans: most notably, chimps usually do not become sick with
AIDS when infected with HIV.
Scientists have also learned a lot in recent years
CD4
about the molecular-level interactions between
Incoming HIV
HIV and the receptors on cells of the body,
which provide the virus with its foothold for
entering the cells. "We can work to find the best
immunogens," Heilman declares. Moreover,
researchers have acquired new tools in the form
DEADLY
of genetically-engineered small animals, such as
LIFECYCLE
rabbits, that are susceptible to infection with HIV. (Non-primates are
normally immune to infection with HIV and its close viral relatives.)
These animals will speed the testing of anti-AIDS therapies and
vaccines.
Plans are moving ahead to test various types of HIV vaccine in humans
in intermediate and large-scale trials; studies are now being planned in
Uganda, Thailand and the U.S. And despite the past gloom in the field,
Heilman says there is no reason to believe that President Clinton's goal
is out of reach. Most successful vaccines are the end result of trail and
error modifications, she notes. But HIV researchers have a more
sophisticated understanding of their quarry than did previous
generations of immunologists. "This is not very different from how
vaccines generally are developed," she points out: "Everything is
consistent with our enthusiasm."
--Tim Beardsley, staff writer
RELATED LINKS:
President Clinton's call for an AIDS vaccine
AIDS vaccine R&D overview
AIDS research at Duke University
AIDS-related research at NIH
NIH support for an AIDS vaccine
HIV InSite--informational site at the University of California, San
Francisco
Exhibit: Cracking Open AIDS's Shell from Scientific American
In Search of AIDS-Resistance Genes from Scientific American
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6/7/99