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Mechanism of vaccine induced diabetes and autoimmunity

The mechanisms by which vaccines alter the risk of an autoimmune disease such as insulin
dependent diabetes (IDDM) is not known but there are probably several mechanisms. It is known
that killed vaccines can induce the formation of autoantibodies and autoimmunity in humans.
Research has focused primarily on vaccines containing molecules that immunologically mimic
autoantigens. The neural tissue derived rabies vaccine has historically been associated with most
frequently inducing autoimmunity, a condition which has been attributed to the contamination of
the vaccine with neural antigens that immunologically cross react to human antigens. Other
vaccines including the whole cell pertussis vaccine are known to contain autoantigens (Giudice,
Gervaix, Costantinoet al.1993). The presence of these autoantigens however does not readily
explain the wide divergence of autoantibodies that arise after vaccination (Hackett & Beech,
1960; Meiselas, Zingale, Leeet al.1961; Caspary, Field & Ball, 1964; Huang,YP, Gauthey,
Michelet al.1992) although cross reactivity could have some role (Sutjita, Hohmann, Comacchioet
al.1988). Live viral vaccines have been suggested to cause autoimmunity by infecting the
recipient's tissue and inducing an autoimmune response as is proposed with insulin dependent
diabetes associated with mumps and rubella (Sinaniotis, Daskalopoulou, Lapatsaniset al.1975;
Bodansky, Dean, Grantet al.1990; Fescharek, Quast, Maasset al.1990) vaccines. Recently
several investigators working on vaccines to control fertility used the diphtheria and tetanus
toxoids to break immunological tolerance to HCG, human chorionic gonadotropin, in humans
when the hormone is associated with the vaccine (Griffin, 1994). The ability of vaccines to induce
autoimmunity to autoantigens that associate with the vaccine can explain the development of a
number of autoimmune diseases following immunization.

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Mechanism of vaccine induced diabetes and autoimmunity

The mechanisms by which vaccines alter the risk of an autoimmune disease such as insulin
dependent diabetes (IDDM) is not known but there are probably several mechanisms. It is known
that killed vaccines can induce the formation of autoantibodies and autoimmunity in humans.
Research has focused primarily on vaccines containing molecules that immunologically mimic
autoantigens. The neural tissue derived rabies vaccine has historically been associated with most
frequently inducing autoimmunity, a condition which has been attributed to the contamination of
the vaccine with neural antigens that immunologically cross react to human antigens. Other
vaccines including the whole cell pertussis vaccine are known to contain autoantigens (Giudice,
Gervaix, Costantinoet al.1993). The presence of these autoantigens however does not readily
explain the wide divergence of autoantibodies that arise after vaccination (Hackett & Beech,
1960; Meiselas, Zingale, Leeet al.1961; Caspary, Field & Ball, 1964; Huang,YP, Gauthey,
Michelet al.1992) although cross reactivity could have some role (Sutjita, Hohmann, Comacchioet
al.1988). Live viral vaccines have been suggested to cause autoimmunity by infecting the
recipient's tissue and inducing an autoimmune response as is proposed with insulin dependent
diabetes associated with mumps and rubella (Sinaniotis, Daskalopoulou, Lapatsaniset al.1975;
Bodansky, Dean, Grantet al.1990; Fescharek, Quast, Maasset al.1990) vaccines. Recently
several investigators working on vaccines to control fertility used the diphtheria and tetanus
toxoids to break immunological tolerance to HCG, human chorionic gonadotropin, in humans
when the hormone is associated with the vaccine (Griffin, 1994). The ability of vaccines to induce
autoimmunity to autoantigens that associate with the vaccine can explain the development of a
number of autoimmune diseases following immunization.

Vaccines to prevent pregnancy which act by inducing an autoimmune response to HCG have
been used in at least four human clinical trials (Griffin, 1994). These vaccines consist of human
HCG holoprotein or peptides covalently bound to either a diphtheria or tetanus toxoid, the chief
component of the diphtheria and tetanus vaccine. The vaccine toxoids were successful in
breaking immunological tolerance and inducing autoimmunity to the human hormone as
demonstrated by the development of anti-HCG autoantibodies in the recipients. Detailed studies
in animals show that the association of beta HCG with vaccine toxoids greatly increase the
immune response to HCG as does the use of alum based adjuvants which are commonly used in
vaccines (Schutze, LeClerc, Jolivetet al.1987). HCG peptides were used instead of the
holoprotein in order to restrict the development of autoantibodies to epitopes unique to HCG
since HCG shares epitopes with other protein hormones. The ability of the vaccines antigens to
induce autoimmunity is not limited to HCG since a vaccine comprising a diphtheria toxoid
covalently linked to a peptide from human gastrin was able to induce antigastrin antibodies in
humans (Anonymous, 1994) .

Animal and human experiments show that vaccine antigens, in killed vaccines, do not have
to be covalently attached to autoantigens to induce an autoimmune response. Autoimmunity to
the testis and thyroid have been induced in both humans and animals when autoantigens have
been administered with Freund's complete adjuvant, (Mancini, 1962; Gerfo, Feind, Weberet
al.1983). Autoimmunity has been induced in animals when Freund's complete adjuvant and the
autoantigen are administered in different locations but share the same draining lymph nodes
(Katsh, 1964; Levine & Wenk, 1967). Animal studies of this phenomenon show the induction of
autoimmunity is not limited to the use of Freund's complete adjuvant since the administration of
the swine flu vaccine in combination with an neural extract has lead to the development of
autoimmune neuritis and the administration of the pertussis vaccine with thyroid extract has lead
to the development of autoimmune thyroiditis in rodents (Hjorth, Bonde, Pineret al.1984; Greiner,
Mordes, Handleret al.1987) . In the later case a depot type adjuvant, Freund's incomplete
adjuvant, was necessary for the induction of autoimmunity. Administration of the pertussis
vaccine in the absence of autoantigens has been shown to exacerbate smoldering autoimmunity
in rodents (Levine & Wenk, 1966).

The ability of vaccines to induce an autoimmune response to antigens that are in proximity
to them explains the induction of autoimmunity in humans following immunization. The pertussis
vaccine is known to be an effective adjuvant, stimulating an immune response to antigens that
are in close proximity to it (Greenberg & Fleming, 1947). Vaccine antigens become closely
association with immunoglobulins after entering the body and this explains why rheumatoid
factor, an autoantibody against IgG antibodies, frequently develops after immunization (Aho,
Konttinen, Rajasalmiet al.1962; Aho, Somer & Salo, 1967; Palit, Chattopadhyay, Malaviyaet
al.1977; Welch, Fong, Vaughanet al.1982). Antigens from killed vaccines associate with a
number of other autoantigens besides IgG after being administered. For example antigens from
the DTP and other killed vaccines are known to circulate in the blood stream (Lewis, Jordan,
Cherryet al.1986) and associate with the membranes of blood cells causing acute lysis of these
cells (Brown, Blecher, Frenchet al.1973; Haneberg, Matre, Winsneset al.1978) . This explains
why some who receive vaccines develop an autoimmune response to these cells (Klemparskaya,
1973; Zupanska, Lawkowicz, Gorskaet al.1976; Kelton, 1981). Solid organs may also be effected
as well. Vaccination causes myocarditis in 3% of health patients (Helle, Koskenvuo, Heikkilaet
al.1978; Amsel, Hanukoglu, Friedet al.1986) . Part of this can be explained by circulating antigen
precipitating in the heart tissue however people often develop autoantibodies to myocardial tissue
after damage to the heart (Rose, Herskowitz, Neumannet al.1988) and this response may be
exacerbated by a vaccine draining into a lymphnode where the autoimmune process is
developing. In either case the myocarditis induced by vaccination can lead to chronic
autoimmune destruction of the myocardial tissue.

The mechanism for inducing autoimmunity appears to involve a lymphokine drive


phenomenon where the vaccine activates the immune systems and an immune response
develops to autoantigens that are attached to MHC molecules on the same antigen presenting
cells as the vaccine toxoids or MHCs on adjacent antigen presenting cells. This phenomenon
appears to occur in the draining lymph nodes (Katsh, 1964; Levine & Wenk, 1967) and is likely to
involve both the direct activation of macrophages (Mannhalter, Neychev, Zlabingeret al.1985) ,
the release of lymphokines capable of inducing autoimmunity (Gearing, Bird, Wadhaet al.1987)
and the up regulation of lymphokine receptors on cells (Tvede, Heilmann & Christensen, 1989).
Animal studies indicate that if the recipient has a smoldering autoimmune disease that the
vaccines do not have to be closely associated with autoantigens to exacerbate disease (Levine &
Wenk, 1966). This is especially troublesome since subclinical autoimmunity occurs in at least 2-3
% of children based on the presence of autoantibodies (Landin-Olsson, Karlsson, Dahlquistet
al.1989b) and is even more common in adults. While naturally acquired foreign antigens such as
infections (Rocken, Urban & Shevach, 1992) may also lead to induction of autoimmunity, animal
and human experiments have shown the use of depot type adjuvants as well as repetitive
administrations intensifies the induction of autoantibodies (Schutze, LeClerc, Jolivetet al.1987;
Griffin, 1994). This indicates vaccination is a greater risk factor for autoimmunity than many
natural infections of short duration.

Vaccines may alter the incidence of IDDM through mechanisms discussed above as well as
several other methods. Cytokines released following immunization may exacerbate subclinical
anti-islet cell autoimmunity however they may be directly toxic to the islet cells (Huang,X, Yuan,
Goddardet al.1995). It is also possible that immunization later in life causes the release of
diabetes inducing viruses which have chronically infected the host (Stanley, Ostrowski,
Justementet al.1996). Furthermore, certain vaccines such as the pertussis vaccine (Giudice,
Gervaix, Costantinoet al.1993) and the BCG have at least one antigen that cross react to islet
cells (Elias, Markovitis, Reshefet al.1990) and these antigens may stimulate an autoimmune
disease. Immunization starting at birth may have the opposite effect than immunization starting
after 2 months for several reasons. Interferon released following immunization at birth may inhibit
vertically transmitted Coxsakie B virus infections which have been attributed to causing 27% or
more cases of insulin dependent diabetes (Dahlquist, Frisk, Svanberget al.1995); (Hyoty,
Hiltunen, Knipet al.1995). It is possible that immunization at birth also alters the ratios of Th1/Th2
CD4 lymphocytes (Kolb, 1997).

Vaccines to prevent pregnancy which act by inducing an autoimmune response to HCG have
been used in at least four human clinical trials (Griffin, 1994). These vaccines consist of human
HCG holoprotein or peptides covalently bound to either a diphtheria or tetanus toxoid, the chief
component of the diphtheria and tetanus vaccine. The vaccine toxoids were successful in
breaking immunological tolerance and inducing autoimmunity to the human hormone as
demonstrated by the development of anti-HCG autoantibodies in the recipients. Detailed studies
in animals show that the association of beta HCG with vaccine toxoids greatly increase the
immune response to HCG as does the use of alum based adjuvants which are commonly used in
vaccines (Schutze, LeClerc, Jolivetet al.1987). HCG peptides were used instead of the
holoprotein in order to restrict the development of autoantibodies to epitopes unique to HCG
since HCG shares epitopes with other protein hormones. The ability of the vaccines antigens to
induce autoimmunity is not limited to HCG since a vaccine comprising a diphtheria toxoid
covalently linked to a peptide from human gastrin was able to induce antigastrin antibodies in
humans (Anonymous, 1994) .

Animal and human experiments show that vaccine antigens, in killed vaccines, do not have
to be covalently attached to autoantigens to induce an autoimmune response. Autoimmunity to
the testis and thyroid have been induced in both humans and animals when autoantigens have
been administered with Freund's complete adjuvant, (Mancini, 1962; Gerfo, Feind, Weberet
al.1983). Autoimmunity has been induced in animals when Freund's complete adjuvant and the
autoantigen are administered in different locations but share the same draining lymph nodes
(Katsh, 1964; Levine & Wenk, 1967). Animal studies of this phenomenon show the induction of
autoimmunity is not limited to the use of Freund's complete adjuvant since the administration of
the swine flu vaccine in combination with an neural extract has lead to the development of
autoimmune neuritis and the administration of the pertussis vaccine with thyroid extract has lead
to the development of autoimmune thyroiditis in rodents (Hjorth, Bonde, Pineret al.1984; Greiner,
Mordes, Handleret al.1987) . In the later case a depot type adjuvant, Freund's incomplete
adjuvant, was necessary for the induction of autoimmunity. Administration of the pertussis
vaccine in the absence of autoantigens has been shown to exacerbate smoldering autoimmunity
in rodents (Levine & Wenk, 1966).

The ability of vaccines to induce an autoimmune response to antigens that are in proximity
to them explains the induction of autoimmunity in humans following immunization. The pertussis
vaccine is known to be an effective adjuvant, stimulating an immune response to antigens that
are in close proximity to it (Greenberg & Fleming, 1947). Vaccine antigens become closely
association with immunoglobulins after entering the body and this explains why rheumatoid
factor, an autoantibody against IgG antibodies, frequently develops after immunization (Aho,
Konttinen, Rajasalmiet al.1962; Aho, Somer & Salo, 1967; Palit, Chattopadhyay, Malaviyaet
al.1977; Welch, Fong, Vaughanet al.1982). Antigens from killed vaccines associate with a
number of other autoantigens besides IgG after being administered. For example antigens from
the DTP and other killed vaccines are known to circulate in the blood stream (Lewis, Jordan,
Cherryet al.1986) and associate with the membranes of blood cells causing acute lysis of these
cells (Brown, Blecher, Frenchet al.1973; Haneberg, Matre, Winsneset al.1978) . This explains
why some who receive vaccines develop an autoimmune response to these cells (Klemparskaya,
1973; Zupanska, Lawkowicz, Gorskaet al.1976; Kelton, 1981). Solid organs may also be effected
as well. Vaccination causes myocarditis in 3% of health patients (Helle, Koskenvuo, Heikkilaet
al.1978; Amsel, Hanukoglu, Friedet al.1986) . Part of this can be explained by circulating antigen
precipitating in the heart tissue however people often develop autoantibodies to myocardial tissue
after damage to the heart (Rose, Herskowitz, Neumannet al.1988) and this response may be
exacerbated by a vaccine draining into a lymphnode where the autoimmune process is
developing. In either case the myocarditis induced by vaccination can lead to chronic
autoimmune destruction of the myocardial tissue.

The mechanism for inducing autoimmunity appears to involve a lymphokine drive


phenomenon where the vaccine activates the immune systems and an immune response
develops to autoantigens that are attached to MHC molecules on the same antigen presenting
cells as the vaccine toxoids or MHCs on adjacent antigen presenting cells. This phenomenon
appears to occur in the draining lymph nodes (Katsh, 1964; Levine & Wenk, 1967) and is likely to
involve both the direct activation of macrophages (Mannhalter, Neychev, Zlabingeret al.1985) ,
the release of lymphokines capable of inducing autoimmunity (Gearing, Bird, Wadhaet al.1987)
and the up regulation of lymphokine receptors on cells (Tvede, Heilmann & Christensen, 1989).
Animal studies indicate that if the recipient has a smoldering autoimmune disease that the
vaccines do not have to be closely associated with autoantigens to exacerbate disease (Levine &
Wenk, 1966). This is especially troublesome since subclinical autoimmunity occurs in at least 2-3
% of children based on the presence of autoantibodies (Landin-Olsson, Karlsson, Dahlquistet
al.1989b) and is even more common in adults. While naturally acquired foreign antigens such as
infections (Rocken, Urban & Shevach, 1992) may also lead to induction of autoimmunity, animal
and human experiments have shown the use of depot type adjuvants as well as repetitive
administrations intensifies the induction of autoantibodies (Schutze, LeClerc, Jolivetet al.1987;
Griffin, 1994). This indicates vaccination is a greater risk factor for autoimmunity than many
natural infections of short duration.

Vaccines may alter the incidence of IDDM through mechanisms discussed above as well as
several other methods. Cytokines released following immunization may exacerbate subclinical
anti-islet cell autoimmunity however they may be directly toxic to the islet cells (Huang,X, Yuan,
Goddardet al.1995). It is also possible that immunization later in life causes the release of
diabetes inducing viruses which have chronically infected the host (Stanley, Ostrowski,
Justementet al.1996). Furthermore, certain vaccines such as the pertussis vaccine (Giudice,
Gervaix, Costantinoet al.1993) and the BCG have at least one antigen that cross react to islet
cells (Elias, Markovitis, Reshefet al.1990) and these antigens may stimulate an autoimmune
disease. Immunization starting at birth may have the opposite effect than immunization starting
after 2 months for several reasons. Interferon released following immunization at birth may inhibit
vertically transmitted Coxsakie B virus infections which have been attributed to causing 27% or
more cases of insulin dependent diabetes (Dahlquist, Frisk, Svanberget al.1995); (Hyoty,
Hiltunen, Knipet al.1995). It is possible that immunization at birth also alters the ratios of Th1/Th2
CD4 lymphocytes (Kolb, 1997).

Types of Vaccines

Active Immunization

* Live Vaccines
* Inactivated or Killed Vaccines
* Toxoids
* Cellular Fractions
* Combinations

Passive Immunization

* Immunoglobulins
* Anitisera

Live Vaccines

Live vaccines are prepared from live organisms. These organisms are passed through chick
embryos or other such media repeatedly till they lose their capacity to induce the disease fully,
but retain the capacity to trigger off the defence mechanism. Live vaccines are usually more
potent than inactivated vaccines. They multiply within the host and produce more antigens.

Live vaccines should not be given to people with immune deficiency or people being treated for
certain chronic ailments or pregnant women (unless absolutely necessary).

Live virus vaccines are used for tuberculosis ( BCG), measles and polio. Usually one dose of live
vaccine is enough for immunity. Some, as in the case of polio, need more. These should be
spaced out. Effective storage is crucial for live vaccines. Do not receive vaccination from a centre
that you suspect has poor storage facility.

Inactivated or Killed Vaccine

Certain organisms when killed by heat or chemicals and then introduced into the body induce
immunity. Killed vaccines are not as effective as live vaccines. For instance the pertussis vaccine,
after three doses is about 80% effective in the first three years and after 12 years not at all.
Inactivated vaccines may require two or three doses. These are administered by injections.

Diphtheria, pertussis, tetanus, cholera, rabies, and hepatitis B are some diseases that are
combated with killed vaccines.

Toxoids

Certain organisms when killed by heat or chemicals and then introduced into the body induce
immunity. Killed vaccines are not as effective as live vaccines. For instance the pertussis vaccine,
after three doses is about 80% effective in the first three years and after 12 years not at all.
Inactivated vaccines may require two or three doses. These are administered by injections.

Cellular fractions

Some vaccines are prepared from fractions of the cell. The meningococcal vaccine is produced
from the polysaccharide antigen on the cell wall. These vaccines are safe and effective but for a
limited duration.

Combination Vaccines

This is a mix of two or more types of vaccines. This enables easier administration, reduces cost
and avoids repeated contact with the patient. DPT (Diphtheria, Pertussis and Tetanus) vaccine is
given in a single shot. Some vaccines combine two strains of the same species. Polio and
influenza vaccines are prepared this way.

Immunoglobulins

Immunoglobulins are specific protein substances that are produced by certain cells in the body to
help in fighting infection. They are also referred to as antibodies and are a vital part of the body's
defence mechanism. Immunoglobulins are of five different types - Immunoglobulin G, A, M, D and
E. These are classified based upon the speed with which they are formed in response to the
infection, as well as their mechanism and site of action. The invading organisms or vaccines
promote the production of immunoglobulins (antibodies) against that particular disease-causing
organism which is then destroyed. The body also retains in its memory the template of the
disease-causing organism so that the next time it attacks, the antibodies are quick to counter any
threat to the body and the person does not develop the disease.
Antisera, antitoxins

Materials prepared in animals are called antisera. Since human immunoglobulin preparations are
not available for all diseases, we rely on antitoxins produced from animal sources. These are
used to fight tetanus, diphtheria, gas gangrene, snakebite and botulism. Antisera can produce
serum sickness due to the recipient's sensitivity. So, today the preference is toward
immunoglobulins.

Some Processes associated with preparation of Vaccines

Attenuation

To "attenuate" is to weaken a live micro-organism by ageing it or altering its growth conditions.


This is accomplished by serial passage, that is, passing the live micro-organism through animal
tissue several times to reduce its potency. For example, measles virus is passed through chick
embryos, poliovirus through monkey kidneys, and the rubella virus through human diploid cells -
the dissected organs of an aborted foetus.

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.

Detoxification

Some vaccines are made from toxins. In these cases, the toxin is often treated with aluminium or
adsorbed onto aluminium salts to decrease the toxin's harmful effects. After the 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 that increases the immune response. For
example, the diphtheria and tetanus vaccines are often combined with the pertussis vaccine and
administered together as a DPT vaccination. The pertussis acts as an adjuvant in this vaccine.

Examples of common human diseases caused by viruses include the common cold, influenza,
chickenpox and cold sores. Many serious diseases such as ebola, AIDS, avian influenza and
SARS are caused by viruses. The relative ability of viruses to cause disease is described in terms
of virulence. Other diseases are under investigation as to whether they too have a virus as the
causative agent, such as the possible connection between human herpes virus six (HHV6) and
neurological diseases such as multiple sclerosis and chronic fatigue syndrome. There is
controversy over whether the borna virus, previously thought to cause neurological diseases in
horses, could be responsible for psychiatric illnesses in humans.

Viruses have different mechanisms by which they produce disease in an organism, which largely
depends on the viral species. Mechanisms at the cellular level primarily include cell lysis, the
breaking open and subsequent death of the cell. In multicellular organisms, if enough cells die the
whole organism will start to suffer the effects. Although viruses cause disruption of healthy
homeostasis, resulting in disease, they may exist relatively harmlessly within an organism. An
example would include the ability of the herpes simplex virus, which causes cold sores, to remain
in a dormant state within the human body. This is called latency and is a characteristic of the all
herpes viruses including the Epstein-Barr virus, which causes glandular fever, and the varicella
zoster virus, which causes chickenpox. Most people have been infected with at least one of these
types of herpes virus. However, these latent viruses might sometimes be beneficial, as the
presence of the virus can increase immunity against bacterial pathogens, such as ''Yersinia
pestis''. On the other hand, latent chickenpox infections return in later life as the disease called
shingles.

Some viruses can cause life-long or chronic infections, where the viruses continue to replicate in
the body despite the host's defence mechanisms. This is common in hepatitis B virus and
hepatitis C virus infections. People chronically infected are known as carriers, as they serve as
reservoirs of infectious virus. In populations with a high proportion of carriers, the disease is said
to be endemic. In contrast to acute lytic viral infections this persistence implies compatible
interactions with the host organism. Persistent viruses may even broaden the evolutionary
potential of host species.
Epidemiology

Viral epidemiology is the branch of medical science that deals with the transmission and control
of virus infections in humans. Transmission of viruses can be vertical, that is from mother to child,
or horizontal, which means from person to person. Examples of vertical transmission include
hepatitis B virus and HIV where the baby is born already infected with the virus. Another, more
rare, example is the varicella zoster virus, which although causing relatively mild infections in
humans, can be fatal to the foetus and newly born baby.

Horizontal transmission is the most common mechanism of spread of viruses in populations.


Transmission can be exchange of blood by sexual activity, e.g. HIV, hepatitis B and hepatitis C;
by mouth by exchange of saliva, e.g. Epstein-Barr virus, or from contaminated food or water, e.g.
norovirus; by breathing in viruses in the form of aerosols, e.g. influenza virus; and by insect
vectors such as mosquitoes, e.g. dengue.

The rate or speed of transmission of viral infections depends on factors that include population
density, the number of susceptible individuals, (i.e. those who are not immune), the quality of
health care and the weather.

Epidemiology is used to break the chain of infection in populations during outbreaks of viral
diseases. Control measures are used that are based on knowledge of how the virus is
transmitted. It is important to find the source, or sources, of the outbreak and to identify the virus.
Once the virus has been identified, the chain of transmission can sometimes be broken by
vaccines. When vaccines are not available sanitation and disinfection can be effective. Often
infected people are isolated from the rest of the community and those that have been exposed to
the virus placed in quarantine. To control the outbreak of foot and mouth disease in cattle in
Britain in 2001, thousands of cattle were slaughtered. Most viral infections of humans and other
animals have incubation periods during which the infection causes no signs or symptoms.
Incubation periods for viral diseases range from a few days to weeks but are known for most
infections. Somewhat overlapping, but mainly following the incubation period, there is a period of
communicability; a time when an infected individual or animal is contagious and can infect
another person or animal. This too is known for many viral infections and knowledge the length of
both periods is important in the control of outbreaks. When outbreaks cause an unusually high
proportion of cases in a population, community or region they are called epidemics. If outbreaks
spread worldwide they are called pandemics.
Epidemics and pandemics
Native American populations were devastated by contagious diseases, particularly smallpox,
brought to the Americas by European colonists. It is unclear how many Native Americans were
killed by foreign diseases after the arrival of Columbus in the Americas, but the numbers have
been estimated to be close to 70% of the indigenous population. The damage done by this
disease significantly aided European attempts to displace and conquer the native population.

A pandemic is a worldwide epidemic. The 1918 flu pandemic, commonly referred to as the
Spanish flu, was a category 5 influenza pandemic caused by an unusually severe and deadly
influenza A virus. The victims were often healthy young adults, in contrast to most influenza
outbreaks, which predominantly affect juvenile, elderly, or otherwise weakened patients.

The Spanish flu pandemic lasted from 1918 to 1919. Older estimates say it killed 40–50 million
people, while more recent research suggests that it may have killed as many as 100 million
people, or 5% of the world's population in 1918.

Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century;
it is now a pandemic, with an estimated 38.6 million people now living with the disease worldwide.
The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization
(WHO) estimate that AIDS has killed more than 25 million people since it was first recognised on
June 5, 1981, making it one of the most destructive epidemics in recorded history. In 2007 there
were 2.7 million new HIV infections and 2 million HIV-related deaths.

Several highly lethal viral pathogens are members of the ''Filoviridae''. Filoviruses are filament-
like viruses that cause viral hemorrhagic fever, and include the ebola and marburg viruses. The
Marburg virus attracted widespread press attention in April 2005 for an outbreak in Angola.
Beginning in October 2004 and continuing into 2005, the outbreak was the world's worst epidemic
of any kind of viral hemorrhagic fever.
Cancer

Viruses are an established cause of cancer in humans and other species. Viral cancers only
occur in a minority of infected persons (or animals). Cancer viruses come from a range of virus
families, including both RNA and DNA viruses, and so there is no single type of "oncovirus" (an
obsolete term originally used for acutely transforming retroviruses). The development of cancer is
determined by a variety of factors such as host immunity and mutations in the host. Viruses
accepted to cause human cancers include some genotypes of human papillomavirus, hepatitis B
virus, hepatitis C virus, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus and human
T-lymphotropic virus. The most recently discovered human cancer virus is a polyomavirus
(Merkel cell polyomavirus) that causes most cases of a rare form of skin cancer called Merkel cell
carcinoma.

Hepatitis viruses can develop into a chronic viral infection that leads to liver cancer. Infection by
human T-lymphotropic virus can lead to tropical spastic paraparesis and adult T-cell leukemia.
Human papillomaviruses are an established cause of cancers of cervix, skin, anus, and penis.
Within the ''Herpesviridae'', Kaposi's sarcoma-associated herpesvirus causes Kaposi's sarcoma
and body cavity lymphoma, and Epstein–Barr virus causes Burkitt's lymphoma, Hodgkin’s
lymphoma, B lymphoproliferative disorder and nasopharyngeal carcinoma. Merkel cell
polyomavirus closely related to SV40 and mouse polyomaviruses that have been used as animal
models for cancer viruses for over 50 years.
Host defence mechanisms

The body's first line of defence against viruses is the innate immune system. This comprises cells
and other mechanisms that defend the host from infection in a non-specific manner. This means
that the cells of the innate system recognise, and respond to, pathogens in a generic way, but
unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the
host.
RNA interference is an important innate defence against viruses. Many viruses have a replication
strategy that involves double-stranded RNA (dsRNA). When such a virus infects a cell, it releases
its RNA molecule or molecules, which immediately bind to a protein complex called dicer that cuts
the RNA into smaller pieces. A biochemical pathway called the RISC complex is activated, which
degrades the viral mRNA and the cell survives the infection. Rotaviruses avoid this mechanism
by not uncoating fully inside the cell and by releasing newly produced mRNA through pores in the
particle's inner capsid. The genomic dsRNA remains protected inside the core of the virion.

When the adaptive immune system of a vertebrate encounters a virus, it produces specific
antibodies that bind to the virus and render it non-infectious. This is called humoral immunity. Two
types of antibodies are important. The first called IgM is highly effective at neutralizing viruses but
is only produced by the cells of the immune system for a few weeks. The second, called, IgG is
produced indefinitely. The presence of IgM in the blood of the host is used to test for acute
infection, whereas IgG indicates an infection sometime in the past. IgG antibody is measured
when tests for immunity are carried out.

A second defence of vertebrates against viruses is called cell-mediated immunity and involves
immune cells known as T cells. The body's cells constantly display short fragments of their
proteins on the cell's surface, and if a T cell recognises a suspicious viral fragment there, the host
cell is destroyed by ''killer T'' cells and the virus-specific T-cells proliferate. Cells such as the
macrophage are specialists at this antigen presentation. The production of interferon is an
important host defence mechanism. This is a hormone produced by the body when viruses are
present. Its role in immunity is complex, but it eventually stops the viruses from reproducing by
killing the infected cell and its close neighbours.

Not all virus infections produce a protective immune response in this way. HIV evades the
immune system by constantly changing the amino acid sequence of the proteins on the surface of
the virion. These persistent viruses evade immune control by sequestration, blockade of antigen
presentation, cytokine resistance, evasion of natural killer cell activities, escape from apoptosis,
and antigenic shift. Other viruses, called ''neurotropic viruses'', are disseminated by neural spread
where the immune system may be unable to reach them.
Prevention and treatment

Because viruses use vital metabolic pathways within host cells to replicate, they are difficult to
eliminate without using drugs that cause toxic effects to host cells in general. The most effective
medical approaches to viral diseases are vaccinations to provide preventative immunity to
infection, and antiviral drugs that selectively interfere with viral replication.
Vaccines

Vaccination is a cheap and effective way of preventing infections by viruses. Vaccines were used
to prevent viral infections long before the discovery of the actual viruses. Their use has resulted in
a dramatic decline in morbidity (illness) and mortality (death) associated with viral infections such
as polio, measles, mumps and rubella. Smallpox infections have been eradicated. Vaccines are
available to prevent over thirteen viral infections of humans, and more are used to prevent viral
infections of animals. Vaccines can consist of live-attenuated or killed viruses, or viral proteins
(antigens). Live vaccines contain weakened forms of the virus that causes the disease. Such
viruses are called attenuated. Live vaccines can be dangerous when given to people with a weak
immunity, (who are described as immunocompromised), because in these people, the weakened
virus can cause the original disease. Biotechnology and genetic engineering techniques are used
to produce subunit vaccines. These vaccines use only the capsid proteins of the virus. Hepatitis B
vaccine is an example of this type of vaccine. Subunit vaccines are safe for immunocompromised
patients because they cannot cause the disease.

The yellow fever virus vaccine, a live-attenuated strain called 17D, is probably the safest and
most effective vaccine ever generated.
Antiviral drugs

Over the past twenty years, the development of antiviral drugs has increased rapidly. This has
been driven by the AIDS pandemic. Antiviral drugs are often nucleoside analogues, (fake DNA
building blocks), which viruses incorporate into their genomes during replication. The life-cycle of
the virus is then halted because the newly synthesised DNA is inactive. This is because these
analogues lack the hydroxyl groups, which, along with phosphorus atoms, link together to form
the strong "backbone" of the DNA molecule. This is called DNA chain termination. Examples of
nucleoside analogues are aciclovir for Herpes simplex virus infections and lamivudine for HIV and
Hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral
drugs.

Other antiviral drugs in use target different stages of the viral life cycle. HIV is dependent on a
proteolytic enzyme called the HIV-1 protease for it to become fully infectious. There is a large
class of drugs called protease inhibitors that inactivate this enzyme.

Hepatitis C is caused by an RNA virus. In 80% of people infected, the disease is chronic, and
without treatment, they are infected for the remainder of their lives. However, there is now an
effective treatment that uses the nucleoside analogue drug ribavirin combined with interferon. The
treatment of chronic carriers of the hepatitis B virus by using a similar strategy using lamivudine
has been developed.
Further Reading

* What is a Virus?
* Virus History
* Virus Origins
* Virus Microbiology
* Virus Classification
* Virus Infection in Other Species
* Virus Uses

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses
material from the Wikipedia article on "Virus" All material adapted used from Wikipedia is
available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia®
itself is a registered trademark of the Wikimedia Foundation, Inc.
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Dangers of HPV Vaccine Production in Plants, Microbes, and Viruses

Widespread releases of hazardous transgenes and vaccines have the potential to create viruses
more deadly than the ones the vaccines protect against

Prof. Joe Cummins and Dr. Mae-Wan Ho

The Rainbow And The Worm. The Physics of Organisms. By Dr. Mae-Wan Ho Human papilloma
virus (HPV) vaccines are already commercialised and promoted worldwide in a bid to protect
young girls and women from cervical cancer [1, 2] (Recombinant Cervical Cancer Vaccines, SiS
29; The HPV Vaccine Controversy, SiS 41), while there is still major uncertainty over their
efficacy and safety, especially in the long term. One obstacle to the adoption of the vaccines by
developing countries is that the two available are very costly. There appears to have been a rush
to create cheap oral HPV vaccines in transgenic plants, microbes and viruses that do not require
refrigeration and can be distributed relatively inexpensively, but would involve widespread
releases of hazardous transgenes and products into the open environment. Some of these are
near commercialization, and regulators must be warned against the approval of such production
methods unless and until strict containment and safeguards are put in place.
HPV vaccines in crop plants

The main concern over the vaccines produced in crop plants is that transgenes from tests sites or
production farms can readily spread by pollen or by mechanical dispersal of seeds. Debris from
transgenic crops can also spread transgenes and vaccine proteins through contaminating surface
and groundwater. Debris in the form of dust in the air can impact on the respiratory mucosa
directly, with the potential of triggering acute and delayed immune reactions in humans and
animals exposed. HPV vaccines have already been associated with various adverse acute
immune reactions some of which resulted in death [2]. People subject to persistent exposure to
the crop vaccine are likely to develop oral tolerance rendering them susceptible to virus infection
[3] (Pharm Crops for Vaccines and Therapeutic Antibodies, SiS 24)..

There have been reports since 2006 that HPV virus and L1 proteins were produced in plants
including transgenic potato, tobacco and a wild tobacco N. benthamiana [4]. HPV L1 virus-like
particles were expressed in transgenic potatoes and these particles were found to immunize
animals fed the potatoes. The gene for the particle protein L1 had been optimized for activity in
potato by codon alterations. The full length message had a C-terminal signal sequence for
nuclear localization of the protein and production of the L1 protein is enhanced by removal of the
signal sequence for nuclear localization. The oral immunization using transgenic potato had to be
enhanced by ingesting LI protein produced from insect cell (baculovirus) cultures.[5]. Comparing
the production of HPV19 L1 in cytoplasm or chloroplast of Nicotiana benthamiana showed that
the vaccine was produced most effectively in the chloroplasts. Adjustments in codon preferences
showed that the human codon preference was most effective in enhancing production of the
vaccine. The optimally engineered gene configuration produced up to 11 percent of the plant’s
soluble protein as L1 vaccine protein [6]. The HPV 16 L1 protein produced in N. benthamiana
proved very immunogenic following injection in mice [7]. Another N. benthamiana chloroplast
transformation produced up to 1.5 percent total leaf protein as HPV L1 whose half life in the leaf
was at least 8 hours [8].

The plant chloroplast system not only produces satisfactorily high levels of HPV L1 protein but
avoided the spread of the transgene in pollen for the most part. But the spread of L1 protein in
plant debris polluting surface and ground water and in dust to the respiratory tracts of humans
and other animals cannot be avoided unless the transgenic plants are carefully confined in a
secure greenhouse facility
Transgenic microbes as oral Vaccines

The transgenic yeast, Schizosaccharomyces pombe, modified to produce HPV 16 L1 [1].


Currently, a lyophilized preparation of S. pombe containing HPV 16 L1 as an oral vaccine was the
subject of a patent application [9]. S. pombe is a native of Africa and has been used there to
make beer. The potential pollution of the African environment with transgenic pombe yeasts
requires fuller consideration.

A bacterial system has been developed for both a prophylactic and a therapeutic treatment for
cervical cancer. Bacterial expression vectors are designed to produce coat protein ( L1) or
tumour associated proteins of HPV. These proteins are displayed on the surface of the modified
bacterium. The bacteria-based vaccine is potentially capable of preventing viral infection and of
targeting cancer cells. Gram positive bacteria such as Lactobacilli, or gram negative bacteria
such as Salmonella, may both serve as display vectors [10].
Vaccine production from viruses

A rabbit papilloma virus similar to the human virus served as a model for producing vaccine using
tobacco mosaic virus (TMV). The DNA codes for epitopes (protein amino acid sequences that
are recognized by elicited antibodies) were identified and used to modify coat proteins from TMV.
The modified TMV proteins were capable of eliciting antibodies that were active against the rabbit
papilloma virus. The modified TMV coat proteins served as a vaccine to prevent rabbit
paillomavirus infection. The modified vaccine was produced rapidly and in quantity by infecting N.
benthamiana with modified TMV [11]. Using modified TMV to produce recombinant vaccines is
convenient, but inherently hazardous, as the recombinant virus may give rise to new pathogens.

A potyvirus (potato virus A) coat protein gene was modified by fusing an epitope from the HPV L2
minor protein to its N terminus, and an epitope from E7 oncooprotein (cancer gene) to its C
terminus. That construct was cloned into a potato virus X vector, and used to transform N.
benthamiana and the food crop Brassica rapa variety Rapa (turnip tops). Both transformed crops
produced edible vaccine believed to be capable of both preventing and treating HPV cancers
[12]. The purified HPV vaccine was most stable as freeze dried material stored at minus 20
degrees C [13]. N. benthamiana is not a food crop nor is it used to produce tobacco. B. rapa is
both a food crop and a weed known to spread transgenic pollen great distances, and is almost
certain to cross pollinate Brassica food crops. No transgenic crops producing vaccines and drugs
should be allowed in open fields for reasons stated earlier.

The Cervarix vaccine available commercially [2] is produced by GlaxoSmithKline using a


baculovirus vector propagated in an insect cell line. A number of other vaccines are also being
produced using baculovirus vectors. Baculoviruses are soil inhabiting viruses that infect insects.
Baculovirus expression vectors propagated in insect cells were originally hampered by the
appearance of many interfering baculovirusese with chromosomal deletions, which arise as an
intrinsic property of the native baculovirus [14,15]. The intrinsic deletions in the viral chromosome
may provide a source of diversity as the virus faces environmental challenges. Such instability is
undesirable in producing vaccines. Some progress has been achieved in making more stable
baculovirus expression vector lines [16]. Nevertheless, regulators and the vaccine producer have
not made public comment about the genetic stability of the baculovirus lines producing Cervarix
vaccine, nor the fact that baculovirus is capable of infecting mammalian cells and tissues. If the
GM baculovirus infects mammalian cells and tissues in vivo, they would also transfer transgenes
to those infected cells as gene therapy experiments have demonstrated since 2001 [17].
Baculovirus can also serve as a gene delivery vector for stem cell and bone tissue engineering
[18].

The use of GM viruses to produce HPV vaccines in yeast, insect cells, crop plants and bacteria
has proceeded without much warning. And the pharmaceutical corporations commercializing
such products appear to have scant regard over the safety of their products.
Hazards of horizontal transfer of transgenes

A safety issue that has been persistently ignored by regulators is horizontal transfer of transgenes
to unrelated species. GM microbes and viruses have the strongest potential to transfer
transgenes horizontally and contribute to creating new pathogenic bacteria and viral strains
Recent evidence confirms that transgenic DNA does jump species to bacteria and even plants
and animals [19] (Horizontal Gene Transfer from GMOs Does Happen, SiS 39), as some of us
had predicted. The widespread use of eukaryotic cell cultures and crops plants to produce
vaccines in conjunction with viruses creates abundant opportunities for horizontal gene transfer
and recombination to generate potentially more deadly viruses than the vaccines are meant to
protect against.
References