Diseases of the immune
system. The principles of immune diagnosis, immunotherapy, immunorehabilitation, immunization.
The relative difficulty
of suppressing established immune responses is seen in animal models of
autoimmunity, in which methods able to prevent the induction of autoimmune
disease generally fail to halt established disease. Current treatments for
immunological disorders are nearly all empirical in origin, using
immunosuppressive drugs identified by screening large numbers of natural and
synthetic compounds. The drugs currently used to suppress the immune system can
be divided into three categories: first, powerful anti-inflammatory drugs of
the corticosteroid family such as prednisone; second, cytotoxic
drugs such as azathioprine and cyclophosphamide;
and third, fungal and bacterial derivatives, such as cyclosporin
A, FK506 (tacrolimus), and rapamycin
(sirolimus), which inhibit signaling events within T
lymphocytes. These drugs are all very broad in their actions and inhibit
protective functions of the immune system as well as harmful ones. Opportunistic
infection is therefore a common complication of immunosuppressive drug therapy.
The ideal immunosuppressive agent would be one that targets the specific part
of the adaptive immune response that causes tissue injury. Paradoxically,
antibodies themselves, by virtue of their exquisite specificity, might offer
the best possibility for the therapeutic inhibition of specific immune
responses. We will also consider experimental approaches to controlling
specific immune responses by manipulating the local cytokine environment or by
manipulating antigen so as to divert the response from a pathogenic pathway to
an innocuous one. We have discussed previously how the pathological responses
that cause allergy, autoimmunity, or graft rejection can be prevented by
innocuous, nonpathological T-cell responses.
Corticosteroids are
powerful anti-inflammatory drugs that alter the transcription of many genes.
Corticosteroid drugs are powerful anti-inflammatory agents that are used widely
to suppress the harmful effects of immune responses of autoimmune or allergic
origin, as well as those induced by graft rejection. Corticosteroids are
pharmacological derivatives of members of the glucocorticoid
family of steroid hormones; one of the most widely used is prednisone, which is
a synthetic analogue of cortisol. Cortisol
acts through intracellular receptors that are expressed in almost every cell of
the body. On binding
hormone, these receptors regulate the transcription of specific genes, as
illustrated. The expression of as many as 1% of genes in the genome may be
regulated by glucocorticoids, which can either induce
or, less commonly, suppress the transcription of responsive genes. The
pharmacological effects of corticosteroid drugs result from exposure of the glucocorticoid receptors to supraphysiological
concentrations of ligand. The abnormally high level
of ligation of glucocorticoid receptors causes
exaggerated glucocorticoid-mediated responses, which
have both beneficial and toxic effects. Given the large number of genes
regulated by corticosteroids and that different genes are regulated in
different tissues, it is hardly surprising that the effects of steroid therapy
are very complex. The beneficial effects are antiinflammatory
and are summarized; however, there are also many adverse effects, including
fluid retention, weight gain, diabetes, bone mineral loss, and thinning of the
skin. The use of corticosteroids to control disease requires a careful balance
between helping the patient by reducing the inflammatory manifestations of
disease and avoiding harm from the toxic side-effects of the drug. For this
reason, corticosteroids used in transplant recipients and to treat inflammatory
autoimmune and allergic disease are often administered in combination with
other drugs in an effort to keep the dose and toxic effects to a minimum. In
autoimmunity and allograft rejection, corticosteroids are commonly combined
with cytotoxic immunosuppressive drugs. Prednisone is
a synthetic analogue of the natural adrenocorticosteroid
cortisol. Introduction of the 1,2
double bond into the A ring increases anti-inflammatory potency approximately
fourfold compared with cortisol, without modifying
the sodium-retaining activity of the compound.
Corticosteroids are lipid-soluble molecules that
enter cells by diffusing across the plasma membrane and bind to their receptors
in the cytosol. Binding of corticosteroid to the
receptor displaces a dimer of a heat-shock protein
named Hsp90, exposing the DNA-binding region of the receptor. The steroid:receptor complex then
enters the nucleus and binds to specific DNA sequences in the promoter regions
of steroid-responsive genes. Corticosteroids exert their numerous effects by
modulating the transcription of a wide variety of genes. Corticosteroids regulate
the expression of many genes, with a net anti-inflammatory effect. First, they
reduce the production of inflammatory mediators, including cytokines,
prostaglandins, and nitric oxide. Second, they inhibit inflammatory cell
migration to sites of inflammation by inhibiting the expression of adhesion
molecules. Third, corticosteroids promote the death by apoptosis of leukocytes and lymphocytes. Azathioprine
was developed as a modification of the anti-cancer drug 6-mercaptopurine; by
blocking the reactive thiol group, the metabolism of
this drug is slowed down. It is slowly converted in vivo to 6- mercaptopurine, which is then metabolized to
6-thio-inosinic acid, which blocks the pathway of purine
bio-synthesis. Cyclopho-sphamide was similarly
developed as a stable pro-drug, which is activated enzymatically
in the body to phosphoramide mustard, a powerful and
unstable DNA-alkylating agent. Cytotoxic
drugs cause immunosuppression by killing dividing
cells and have serious side-effects. The two cytotoxic
drugs most commonly used as immunosuppressants are azathioprine and cyclophosphamide
Both interfere with DNA synthesis and have their major pharmacological action
on dividing tissues. They were developed originally to treat cancer and, after
observations that they were cytotoxic to dividing
lymphocytes, were found to be immunosuppressive as well. The use of these
compounds is limited by a range of toxic effects on tissues that have in common
the property of continuous cell division. These effects include decreased
immune function, as well as anemia, leukopenia,
thrombocytopenia, damage to intestinal epithelium, hair loss, and fetal death
or injury. As a result of their toxicity, these drugs are used at high doses
only when the aim is to eliminate all dividing lymphocytes, and in these cases
treated patients require subsequent bone marrow transplantation to restore
their hematopoietic function. They are used at lower doses, and in combination
with other drugs such as corticosteroids, to treat unwanted immune responses. Azathioprine is converted in vivo to a purine
antagonist that interferes with the synthesis of nucleic acids and is toxic to
dividing cells. It is metabolized to 6-thioinosinic acid, which competes with inosine monophosphate, thereby
blocking the synthesis of adenosine monophosphate and
guanosine monophosphate and
thus inhibiting DNA synthesis. It is less toxic than cyclophosphamide,
which is metabolized to phosphoramide mustard, which alkylates DNA. Cyclophosphamide
is a member of the nitrogen mustard family of compounds, which were originally
developed as chemical weapons. With this pedigree goes a range of highly toxic
effects including inflammation of and hemorrhage from the bladder, known as
hemorrhagic cystitis, and induction of bladder neoplasia.
Cyclosporin A, FK506 (tacrolimus),
and rapamycin (sirolimus)
are powerful immunosuppressive agents that interfere with T-cell signaling.
There are now relatively nontoxic alternatives to the cytotoxic
class of drugs that can be used for immunosuppression
in transplant patients.
The systematic study of
products from bacteria and fungi has led to the development of a large number
of important medicines including the two immunosuppressive drugs cyclosporin A and FK506 or tacrolimus,
which are now widely used to treat transplant recipients. Cyclosporin
A is a cyclic decapeptide derived from a soil fungus
from
Cyclosporin A and tacrolimus are both toxic to kidneys and other organs.
Finally, treatment with these drugs is expensive because they are complex
natural products that must be taken for prolonged periods. Thus there is room
for improvement in these compounds, and better and less expensive analogues are
being sought. Nevertheless, at present, they are the drugs of choice in
clinical transplantation, and they are also being tested in a variety of
autoimmune diseases, especially those that, like graft rejection, are mediated
by Tcells. Immunosuppressive drugs are valuable
probes of intracellular signaling pathways in lymphocytes. The mechanism of
action of cyclosporin A and tacrolimus
is now fairly well understood. Each binds to a different group of immunophilins: cyclosporin A to
the cyclophilins, and tacrolimus
to the FK-binding proteins (FKBP).
These immunophilins are peptidyl-prolyl
cis-trans isomerases but
their isomerase activity does not seem to be relevant
to the immunosuppressive activity of the drugs that bind them. Rather, the immunophilin:drug complexes bind
and inhibit the Ca2+-activated serine/threonine phosphatase calcineurin. Calcineurin is activated in T cells when intracellular
calcium ion levels rise after T-cell receptor binding; on activation it dephosphorylates the NFATc family
of transcription factors in the cytoplasm, allowing them to migrate to the
nucleus, where they form complexes with nuclear partners including the
transcription factor AP-1, and induce transcription of genes including those
for IL-2, CD40 ligand, and Fas
ligand. This pathway is inhibited by cyclosporin A and tacrolimus,
which thus inhibit the clonal expansion of activated
T cells. Calcineurin is found in other cells besides
T cells but at higher levels; T cells are therefore particularly susceptible to
the inhibitory effects of these drugs. Rapamycin has
a different mode of action from either cyclosporin A
or tacrolimus. Like tacrolimus,
it binds to the FKBP family of immunophilins.
However, the rapamycin:immunophilin
complex has no effect on calcineurin activity but,
instead, blocks the signal transduction pathway triggered by ligation of the
IL-2 receptor. Rapamycin also inhibits lymphocyte
proliferation driven by IL-4 and IL-6, implying a common postreceptor
pathway of signaling by these cytokines. The rapamycin:immunophilin complex acts by binding to a protein kinase named mTOR (mammalian
target of rapamycin; also known as FRAP, RAFT1, and
RAPT1).
This kinase phosphorylates two
downstream intracellular targets. The first is another kinase,
p70 S6 kinase, which in turn regulates the translation
of many proteins. The second is PHAS-
The potential of
antibodies for removal of unwanted lymphocytes is demonstrated by antilymphocyte globulin, a preparation of immunoglobulin
from horses immunized with human lymphocytes, which has been used for many
years to treat acute graft rejection episodes.
Anti-lymphocyte globulin does not, however, discriminate between useful
lymphocytes and those responsible for unwanted responses. Moreover, horse
immunoglobulin is highly antigenic in humans and the large doses used in
therapy are often followed by the development of serum sickness, caused by the
formation of immune complexes of horse immunoglobulin and human anti-horse
immunoglobulin antibodies. Nevertheless, anti-lymphocyte globulins are still in
use to treat acute rejection and have stimulated the quest for monoclonal
antibodies to achieve more specifically targeted effects. Immunosuppressive
monoclonal antibodies act by one of two general mechanisms. Some monoclonal
antibodies trigger the destruction of lymphocytes in vivo, and are referred to
as depleting antibodies, whereas others are nondepleting
and act by blocking the function of their target protein without killing the
cell that bears it. IgG monoclonal antibodies that
cause lymphocyte depletion target these cells to macrophages and NK cells, which bear Fc receptors
and which respectively kill the lymphocytes by phagocytosis
and antibody-dependent cytotoxicity. Many antibodies
are being tested for their ability to inhibit allograft rejection and to modify
the expression of autoimmune disease. We will discuss some of these examples
after looking at the measures being taken to prepare monoclonal antibodies for
therapy in humans. Antibodies can be engineered to reduce their immunogenicity
in humans. The major impediment to therapy with monoclonal antibodies in humans
is that these antibodies are most readily made by using mouse cells, and humans
rapidly develop antibody responses to mouse antibodies. This not only blocks
the actions of the mouse antibodies but leads to allergic reactions, and if
treatment is continued can result in anaphylaxis. Once this has happened,
future treatment with any mouse monoclonal antibody is ruled out. This problem
can, in principle, be avoided by making antibodies that are not recognized as
foreign by the human immune system, and three strategies are being explored for
their construction. One approach is to clone human V regions into a phage
display library and select for binding to human cells, as described in Appendix
I In this way, monoclonal antibodies that are entirely human in origin can be
obtained. Second, mice lacking endogenous immunoglobulin genes can be made
transgenic for human immunoglobulin heavy- and light-chain loci by using yeast
artificial chromosomes. B cells in these mice have receptors encoded by human
immunoglobulin genes but are not tolerant to most human proteins. In these
mice, it is possible to induce human monoclonal antibodies against epitopes on human cells or proteins.
Finally, one can graft
the complementarity-determining regions (CDRs) of a mouse monoclonal antibody, which form the
antigen-binding loops, onto the framework of a human immunoglobulin molecule, a
process known as humanization. Because antigen-binding specificity is
determined by the structure of the CDRs (see Chapter
3), and because the overall frameworks of mouse and human antibodies are so
similar, this approach produces a monoclonal antibody that is antigenically identical to human immunoglobulin but binds
the same antigen as the mouse monoclonal antibody from which the CDR sequences
were derived. These recombinant antibodies are far less immunogenic in humans
than the parent mouse monoclonal antibodies, and thus they can be used for the
treatment of humans with far less risk of anaphylaxis. Monoclonal antibodies
can be used to inhibit allograft rejection. Antibodies specific for various
physiological targets have been used in attempts to prevent the development of
allograft rejection by inhibiting the development of harmful inflammatory and cytotoxic responses. One approach is to perfuse the organ
before transplantation with antibodies that react with antigen-presenting cells
and thus target them for destruction within the mononuclear phagocytic
system. Depletion of antigen-presenting cells in the graft by this method is
effective at preventing allograft rejection in animal models, although there is
no convincing evidence that it is successful in humans. Antibodies have,
however, been used to treat episodes of graft rejection in humans. Anti-CD3
antibodies are moderately effective as an adjunct to immunosuppressive drugs in
the treatment of episodes of transplanted kidney rejection. A further approach
to inhibiting allograft rejection is the blockade of the co-stimulatory signals
needed to activate T cells that recognize donor antigens. In animal studies of
graft rejection, a fusion protein made from CTLA-4 and the Fc
portion of human immunoglobulin, which binds to both B7.1 and B7.2, has allowed
the longterm survival of certain grafted tissues.
Even more effective in a primate model of renal allograft rejection was the use
of a humanized monoclonal antibody against the CD40 ligand
(CD154), present on T cells. CD40 ligand binds to
CD40, expressed on dendritic and endothelial cells,
stimulating these cells to secrete cytokines such as IL-6, IL-8, and IL-12. The
mechanism of the immunosuppressive effect of anti-CD40 ligand
antibody is not known, but it is most likely to be a consequence of blocking
the activation of dendritic cells by T helper cells
recognizing donor antigens. Monoclonal antibodies against other targets have
also had some success in preventing graft rejection in animals.
Of particular interest are
certain nondepleting anti-CD4 antibodies: when given
for a short time during primary exposure to grafted tissue, these lead to a
state of tolerance in the recipient. This tolerant state is an example of the
dominant immune suppression discussed in Section 13-27. It is long-lived and
can be transferred to naive recipients by CD4 T cells producing cytokines
typical of TH2 cells, although T cells producing other patterns of cytokines
might also be involved. The presence of anti-CD4 antibody at the time of
transplantation might favor the development of a nondamaging
TH2 response, rather than an inflammatory TH1 response, because of a reduced
strength of interaction between the graft cell antigens and responding naive T
cells. In human bone marrow transplantation, depleting antibodies directed at
mature T lymphocytes have proved particularly useful. Elimination of mature T
lymphocytes from donor bone marrow before infusion into a recipient is very
effective at reducing the incidence of graft-versus-host disease. In this
disease, the T lymphocytes in the donor bone marrow recognize the recipient as
foreign and mount a damaging alloreaction against the
recipient, causing rashes, diarrhea, and pneumonia, which is often fatal. Mice
grafted with tissue from a genetically different mouse reject that graft.
Having been primed to respond to the antigens in the graft, they then reject a
subsequent graft of identical tissue more rapidly (left panels). Mice injected
with anti-CD4 antibody alone can recover immune competence when the antibody
disappears from the circulation, as shown by a normal primary rejection of
graft tissue (center panels). However, when tissue is grafted and anti-CD4
antibody is administered at the same time, the primary rejection response is
markedly inhibited (right panels). An identical graft made later in the absence
of anti-CD4 antibody is not rejected, showing that the animal has become
tolerant to the graft antigen. This tolerance can be transferred with T cells
to naive recipients (not shown). Antibodies can be used to alleviate and
suppress autoimmune disease. Autoimmune disease is detected only once the
autoimmune response has caused tissue damage or has disturbed specific
physiological functions. There are three main approaches to treatment. First,
anti-inflammatory therapy can reduce tissue injury caused by an inflammatory
autoimmune response; second, immunosuppressive therapy can be aimed at reducing
the autoimmune response; and third, treatment can be directed specifically at
compensating for the result of the damage.
For example, diabetes, which
is induced by autoimmune attack on pancreatic β cells, is treated by
insulin replacement therapy. Anti-inflammatory therapy for autoimmune disease includes the use of anti-cytokine antibodies;
anti-TNF-α antibodies induce striking temporary
remissions in rheumatoid arthritis. Antibodies can also be used to block cell
migration to sites of inflammation; for example, anti-CD18 antibodies prevent
leukocytes adhering tightly to vascular endothelium and reduce inflammation in
animal models of disease. The ultimate goal of immunotherapy for autoimmune
disease is specific intervention to restore tolerance to the relevant autoantigens. Two experimental approaches are under
investigation. The first aims at blocking the specific response to autoantigen. One way to attempt this is to identify the
clonally restricted T-cell receptors or immunoglobulin carried by the
lymphocytes that cause disease, and to target these with antibodies directed
against idiotypic determinants on the relevant
antigen receptor. Another way is to identify particular MHC
class I or class II molecules responsible for presenting peptides from autoantigens and to inhibit their antigen-presenting
function selectively with antibodies or blocking peptides. This approach has
been successful in some animal models of autoimmunity, for example experimental
autoimmune encephalomyelitis (EAE), in which it seems
that a limited number of clones of T cells, responding to a single peptide,
might cause disease. However, autoimmune disease in humans and most animal
models is driven by a polyclonal response to autoantigens
by T and B lymphocytes. For this reason, immunotherapy based on the
identification of specific receptors carried by pathogenic lymphocytes is
unlikely to succeed. Immunotherapy based on the identification of the
particular MHC molecules that drive an autoimmune
response is more likely to be effective, but such therapy would also inhibit
some protective immune responses. The clinical course of 24 patients was
followed for 4 weeks after treatment with either a placebo or a monoclonal
antibody against TNF-α at a dose of 10 mg kg-1.
The antibody therapy was associated with a reduction in both subjective and
objective parameters of disease activity (as measured by pain score and
swollen-joint count, respectively) and in the systemic inflammatory acute-phase
response, measured as a fall in the concentration of the acute-phase reactant
C-reactive protein. In mice with experimental autoimmune encephalomyelitis (EAE), macrophages process myelin basic protein (MBP) and present MBP peptides to
TH1 lymphocytes in conjunction with co-stimulatory signals. Activated TH1 cells
secrete cytokines, which activate macrophages. The activated macrophages can,
in turn, injure the oligodendrocytes.
Antibodies against MHC class II molecules block this process by blocking the
interaction between TH1 cells and antigen-presenting macrophages. Modulation of
the pattern of cytokine expression by T lymphocytes can inhibit autoimmune
disease. The second approach to immunotherapy for autoimmune disease is to try
to turn a pathological autoimmune response into an innocuous one. This approach
is being pursued experimentally because, as we learned in Chapter 13, tolerance
to tissue antigens does not always depend on the absence of a T-cell response;
instead, it can be actively maintained by T cells secreting cytokines that
suppress the development of a harmful, inflammatory T-cell response. As the
pattern of cytokines expressed by T lymphocytes is critical in determining the
perpetuation and expression of autoimmune disease, the manipulation of cytokine
expression offers a way of controlling it. There are various techniques,
collectively known as immune modulation, that can
affect cytokine expression by T lymphocytes. These involve manipulating the
cytokine environment in which T-cell activation takes place, or manipulating
the way antigen is presented, as these factors have been observed to influence
the differentiation and cytokine-secreting function of the activated T cells.
As discussed in earlier chapters, CD4 T lymphocytes can be subdivided into two
major subsets, the TH1 cells, which secrete interferon (IFN)-γ,
and the TH2 cells, which secrete IL-4, IL-5, IL-10, and transforming growth
factor (TGF)- β. In
many cases, autoimmune disease is associated with the activation of TH1 cells,
which activate macrophages and drive an inflammatory immune response. In animal
models of experimentally induced autoimmune disease, such as EAE, the relative activation of the TH1 and TH2 subsets of T
lymphocytes can be manipulated to give either a TH1 response and disease, or a
TH2 response that confers protection against disease.
The preferential activation of TH1 or TH2
cells can be achieved by direct manipulation of the cytokine environment or by
administering antigen by particular routes, for example by feeding. Recent
evidence shows that patterns of cytokines secreted by T lymphocytes are very
complicated and that the TH1 and TH2 subdivision of T lymphocytes is a
considerable oversimplification. For example, CD4 T cells have been identified
that develop in a cytokine environment rich in IL-10, and in turn secrete high
levels of IL-10 and little IL-2 and IL-4. This pattern of cytokine secretion
has bystander effects on other T cells and suppresses antigen-induced
activation of other CD4 T lymphocytes. These cells have been provisionally
designated Tr1 cells (T regulatory cells 1). Another subset of T cells with
immunosuppressive bystander effects secretes TGF-β
as the dominant cytokine and has been
designated TH3. Such cells might be predominantly of mucosal origin and
activated by the mucosal presentation of antigen. A further subset of T cells
also seems to be implicated in immunoregulation.
These are the NK1.1+ CD4 T cells, so named because they bear the receptor
NK1.1, which is usually found on NK cells. NK1.1+ T
cells, which we discussed, recognize antigens, including lipid antigens,
presented by the class I-like molecule CD1 (and respond by secreting IL-4.
Thus, when stimulated, the NK1.1+ T cells can act to promote TH2 responses.
Although there is no direct evidence that NK1.1+ T cells are involved in immunomodulation in humans, in mice that suffer spontaneous
autoimmune disease this population of cells is either missing or decreased.
Furthermore, transfer of NK1.1+ T cells into such mice prevents the onset of
the autoimmune disease. Immune modulation aims to alter the balance between
different subsets of responding T cells such that helpful responses are
promoted and damaging responses are suppressed. As a therapy for autoimmunity
it has the advantage that one might not need to know the precise nature of the autoantigen stimulating the autoimmune disease. This is
because the administration of cytokines or antigen to modulate the immune
response causes changes in the pattern of cytokine expression that have
bystander effects on lymphocytes with the presumed autoreactive
receptors. However, the drawback of this approach is the unpredictability of
the results. In murine models of diseases such as diabetes
and EAE, most of the results suggest that a TH2
response can protect against TH1-mediated disease, but there is evidence that
TH2 lymphocytes can also contribute to the pathology of these diseases. An
additional problem is the difficulty of modulating established immune
responses.
Vaccination
Vaccination is the
administration of antigenic material (a vaccine) to
stimulate an individual's immune system to develop adaptive immunity to a
pathogen. Vaccines can prevent or ameliorate morbidity from infection. The
effectiveness of vaccination has been widely studied and verified; for example,
the influenza vaccine,[1] the HPV vaccine, and the chicken pox vaccine. Vaccination is
the most effective method of preventing infectious diseases; widespread
immunity due to vaccination is largely responsible for the worldwide
eradication of smallpox and the restriction of diseases such as polio, measles,
and tetanus from much of the world.
The active agent of a vaccine may be intact but
inactivated (non-infective) or attenuated (with reduced infectivity) forms of
the causative pathogens, or purified components of the pathogen that have been
found to be highly immunogenic (e.g., outer coat proteins of a virus). Toxoids are produced for immunization against toxin-based
diseases, such as the modification of tetanospasmin
toxin of tetanus to remove its toxic effect but retain its immunogenic effect.
In common speech, 'vaccination' and
'immunization' have a similar meaning. This distinguishes it from inoculation,
which uses unweakened live pathogens, although in
common usage either is used to refer to an immunization. Vaccination efforts
have been
met
with some controversy since their inception, on scientific, ethical, political,
medical safety, and religious grounds. In rare cases, vaccinations can injure
people and, in the
Generically, the process of artificial induction
of immunity, in an effort to protect against infectious disease, works by
'priming' the immune system with an 'immunogen'.
Stimulating immune responses with an infectious agent is known as immunization.
Vaccination includes various ways of administering immunogens.
Some vaccines are administered after the patient
already has contracted a disease. Vaccinia given
after exposure to smallpox, within the first three days, is reported to
attenuate the disease considerably, and vaccination up to a week after exposure
likely offers some protection from disease or may modify the severity of
disease.[13] The first rabies immunization was given by Louis
Pasteur to a child after he was bitten by a rabid dog. Subsequent to this, it
has been found that, in people with uncompromised immune systems, four doses of
rabies vaccine over 14 days, wound care, and treatment of the bite with rabies
immune globulin, commenced as soon as possible after exposure, is effective in
preventing the development of rabies in humans.[ Other examples
include experimental AIDS, cancer and Alzheimer's disease vaccines. Such
immunizations aim to trigger an immune response more rapidly and with less harm
than natural infection.
Most vaccines are given by hypodermic injection
as they are not absorbed reliably through the intestines. Live attenuated
polio, some typhoid and some cholera vaccines are given orally to produce
immunity in the bowel.
Adjuvants and preservatives
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This
presents the antigen in such a way as to produce a greater action than the
simple aqueous tetanus toxoid. People who get an
excessive reaction to adsorbed tetanus toxoid may be
given the simple vaccine when time for a booster occurs.
In the preparation for the 1990 Gulf campaign, Pertussis vaccine (not acellular)
was used as an adjuvant for Anthrax vaccine. This produces a more rapid immune
response than giving only the Anthrax, which is of some benefit if exposure
might be imminent.
Vaccines may also contain preservatives to
prevent contamination with bacteria or fungi. Until recent years, the
preservative thiomersal was used in many vaccines
that did not contain live virus. As of 2005, the only childhood vaccine in the
U.S. that contains thiomersal in greater than trace
amounts is the influenza vaccine,[2] which is currently recommended only for
children with certain risk factors.[15] Single-dose Influenza
vaccines supplied in the UK do not list Thiomersal
(its UK name) in the ingredients. Preservatives may be used at various stages
of production of vaccines, and the most sophisticated methods of measurement
might detect traces of them in the finished product, as they may in the
environment and population as a whole.
Vaccination versus inoculation
Many times these words
are used interchangeably, as if they were synonyms. In fact, they are different
things. As doctor Byron Plant explains: "Vaccination is the more commonly
used term, which actually consists of a "safe" injection of a sample
taken from a cow suffering from cowpox... Inoculation, a practice probably as
old as the disease itself, is the injection of the variola
virus taken from a pustule or scab of a smallpox sufferer into the superficial
layers of the skin, commonly on the upper arm of the subject. Often inoculation
was done "arm to arm" or less effectively "scab to arm"...
Vaccination
began in the 18th century with the work of Edward Jenner.
Types
Vaccines work by presenting a foreign antigen to
the immune system to evoke an immune response, but there are several ways to do
this. Four main types are currently in clinical use:
1. An inactivated vaccine consists of
virus or bacteria that are grown in culture and then killed using a method such
as heat or formaldehyde. Although the virus or bacteria particles are destroyed
and cannot replicate, the virus capsid
proteins or bacterial wall are intact
enough to be recognized and remembered by the immune system and evoke a
response. When manufactured correctly, the vaccine is not infectious, but
improper inactivation can result in intact and infectious particles. Since the
properly produced vaccine does not reproduce, booster shots are required
periodically to reinforce the immune response.
2.
In an attenuated vaccine, live virus or bacteria
with very low virulence are administered. They will replicate, but locally or
very slowly. Since they do reproduce and continue to present antigen to the
immune system beyond the initial vaccination, boosters may be required less
often. These vaccines may be produced by passaging,
for example, adapting a virus into different host cell cultures, such as in
animals, or at suboptimal temperatures, allowing selection of less virulent strains, or by mutagenesis or targeted deletions in genes
required for virulence. There is a small risk of reversion to virulence, which
is smaller in vaccines with deletions. Attenuated vaccines also cannot be used
by immunocompromised individuals. Reversions of
virulence were described for a few attenuated viruses of chickens (infectious bursal disease virus, avian infectious bronchitis virus,
avian infectious laryngotracheitis virus [3], avian metapneumovirus
3.
Virus-like particle vaccines consist of viral
protein(s) derived from the structural proteins of a virus. These proteins can
self-assemble into particles that resemble the virus from which they were
derived but lack viral nucleic acid, meaning that they are not infectious.
Because of their highly repetitive, multivalent structure, virus-like particles
are typically more immunogenic than subunit vaccines (described below). The
human papillomavirus and Hepatitis B virus vaccines
are two virus-like particle-based vaccines currently in clinical use.
4.
A subunit vaccine presents an antigen to the immune
system without introducing viral particles, whole or otherwise. One method of
production involves isolation of a specific protein from a virus or bacterium
(such as a bacterial toxin) and administering this by itself. A weakness of
this technique is that isolated proteins may have a different three-dimensional
structure than the protein in its normal context, and will induce antibodies
that may not recognize the infectious organism. In addition, subunit vaccines
often elicit weaker antibody responses than the other classes of vaccines.
A number of other vaccine strategies are under experimental
investigation. These include DNA vaccination and recombinant viral vectors.
Routes
of administration
A
vaccine administration may be oral, by
injection (intramuscular, intradermal,
subcutaneous),
by puncture,
transdermal or
intranasal.
Vaccine
A vaccine is a
biological preparation that improves immunity to a particular disease. A
vaccine typically contains an agent that resembles a disease-causing microorganism,
and is often made from weakened or killed forms of the microbe, its toxins or
one of its surface proteins. The agent stimulates the body's immune system to
recognize the agent as foreign, destroy it, and "remember" it, so
that the immune system can more easily recognize and destroy any of these
microorganisms that it later encounters.
Vaccines may be prophylactic (example: to prevent or
ameliorate the effects of a future infection by any natural or "wild"
pathogen), or therapeutic (e.g. vaccines against cancer are also being
investigated; see cancer vaccine).
The term vaccine derives from Edward
Jenner's 1796 use of cow pox (Latin variola
vaccinia, adapted from the Latin vaccīn-us, from vacca,
cow), to inoculate humans, providing them protection against
smallpox.
"With the exception of safe water, no other
modality, not even antibiotics, has had such a major effect on mortality
reduction and population growth."
Effectiveness
Vaccines do not guarantee
complete protection from a disease. Sometimes, this is because the host's
immune system simply does not respond adequately or at all. This may be due to
a lowered immunity in general (diabetes, steroid use, HIV infection, age) or
because the host's immune system does not have a B cell capable of generating
antibodies to that antigen.
Even if the host develops antibodies, the human
immune system is not perfect and in any case the immune system might still not
be able to defeat the infection immediately. In this case, the infection will
be less severe and heal faster.
Adjuvants are
typically used to boost immune response. Most often aluminium
adjuvants are used, but adjuvants
like squalene are also used in some vaccines and more
vaccines with squalene and phosphate adjuvants are being tested. Larger doses are used in some
cases for older people (50–75 years and up), whose immune response to a given
vaccine is not as strong.
The efficacy or performance of the vaccine is dependent on a
number of factors:
the disease itself (for some diseases
vaccination performs better than for other diseases)
the strain of vaccine (some vaccinations are for
different strains of the disease)
whether one kept to the timetable for the
vaccinations (due to Vaccination
schedule)
some individuals are "non-responders"
to certain vaccines, meaning that they do not generate antibodies even after
being vaccinated correctly
other factors such
as ethnicity, age, or genetic predisposition.
When a vaccinated individual does develop the disease
vaccinated against, the disease is likely to be milder than without vaccination
The following are important considerations in the
effectiveness of a vaccination program:
1.
careful modelling to
anticipate the impact that an immunization campaign will have on the
epidemiology of the disease in the medium to long term
2.
ongoing surveillance for the relevant disease
following introduction of a new vaccine and
3.
maintaining high
immunization rates, even when a disease has become rare.