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Contemporary Challenges to
the Immune System
Challenges of the immune system
Outside
Infection
with
microbe A
Vaccine Infection Allergen ->
with
allergy
microbe B
Peptide
drugs
Time
Creation Creation
of self
of an
immune
system/
Tolerance
to self
Autoimmunity
(break of
tolerance to
self)
Inside
Cancer
Infectious Diseases
•More than 400 microbial agents are associated with disease
•Licensed vaccines in the United states for 22 microbial agents
•Vaccines for 36 pathogens have been developed
•Immunological Bioinformatics may be used to
•Identify immunogenic regions in pathogens
•These regions may be used as in rational vaccine design
•Which pathogens to focus on? Infectious diseases may be ranked
based on
•Impact on health
•Dangerousness
•Economic impact
Vaccines have been
made for 36 of >400
human pathogens
+HPV & Rotavirus
Immunological Bioinformatics, The MIT press.
Deaths from
infectious diseases
in the world in 2002
www.who.int/entity/whr/2004/annex/topic/en/annex_2_en.pdf
Pathogens with most impact on world
health
HIV/AIDS
•Acquired immunodeficiency syndrome (AIDS)
•Caused by the human immunodeficiency virus (HIV)
•AIDS develops ~10 years after infection as the concentration of
CD4+ T cells (the CD+ count) decreases below 20%
•WHO: tackling HIV/AIDS is the world’s most urgent public health
challenge
•HAART (highly active antiretroviral therapy )
•Combinations of viral protease inhibitors and nucleoside analogues
•Rapid decrease in virus levels
• A slower increase in CD4+ T cell counts
•Severe side effects
•Expensive
HIV
•Retrovirus
•HIV gp120 binds to CD4 on human cells
•Loss of CD4+ cells
•Escape mutants
•No vaccine
•No natural immunity – re-infection
•Escape from strain specific antibodies
•Broadly neutralizing antibodies are
rarely produced in patients
•Engineering of envelope protein to
produce such antibodies
•CTL vaccine may reduce viral load even if
it does not prevent infection
Figure by Drs. Louis E. Henderson and Larry Arthur, http://www.niaid.nih.gov/daids/dtpdb/virtarg.htm
Tuberculosis
•Mycobacterium tuberculosis bacteria (Mtb)
•Spread from by airborne droplets
•One third of the world’s population (1.86 billion people) is infected
•10% of the infected develop TB later in life
• 16.2 million people have TB
•Calmette-Guérin (BCG) vaccine used in most countries
•Need for improved anti-TB vaccines
•Spread of (multidrug resistant) MDR-TB
•Global burden of the TB epidemic/growing TB/HIV coepidemic
•Complicated and costly treatment regimens
•Inadequate diagnostic methods
•The relative ineffectiveness of the current BCG vaccines
Figure from: http://ucatlas.ucsc.edu/health/tb/tb_r2000.gif
Tuberculosis
•A recent study from South Africa published in Lancet reported:
•A recent outbreak of XDR-TB in an HIV-positive population in KwazuluNatal in South Africa was characterized by alarmingly high mortality rates.
•Of the 544 patients studied, 221 had MDR-TB. Of the 221 MDR-TB cases,
53 were defined as XDR-TB. Of the 53 patients, 44 had been tested for HIV
and all were HIV-positive.
•52 of 53 patients died, on average, within 25 days including those
benefiting from antiretroviral drugs.
•CDC is currently investigating a case of extensively drug resistant
tuberculosis (XDR TB). The case involves a U.S. citizen with potentially
infectious XDR TB who traveled to and from Europe on commercial flights
between May 12 and May 24, and then re-entered the U.S. at the CanadaU.S. border via automobile. Since May 25, the patient has been hospitalized
in airborne isolation or wearing an appropriate mask, and is now receiving
medical therapy for XDR TB.
Figure from: http://www.who.int/mediacentre/news/notes/2006/np23/en/index.htm http://www.cdc.gov/tb/XDRTB/travellerfactsheet.htm l
Malaria
•Four kinds of malaria parasites can infect humans:
•Plasmodium falciparum, P. vivax, P. ovale, and P. malariae
•Impact on word health
•300 to 500 million cases of malaria/year
•More than 1 million people die of malaria each year
•Mode of transmission
•Transmitted by bites by an female Anopheles
•Mosquito infected by a previous blood meal
•Malaria
•Anemia is also associated with malaria infections and is frequently severe
in children and pregnant women infected with P. falciparum.
•Immunity
•People residing in malaria-endemic regions acquire immunity to malaria
through natural exposure to malaria parasites.
From: http://www.cdc.gov/malaria/biology/humanhost/index.htm
Malaria life cycle
•The parasites grow and mature in the mosquito’s
gut for a week or more, then travel to the mosquito’s
salivary glands.
•When the mosquito next takes a blood meal, these
parasites mix with the saliva and are injected into the
bite
•Once in the blood, the parasites travel to the liver
and enter liver cells to grow and multiply
•The parasites leave the liver cells and enter red
blood cells
•Once in the cells, they continue to grow and
multiply.
•The infected red blood cells rupture, freeing the
parasites to attack and enter other red blood cells
•Toxins released when the red cells burst are what
cause the typical fever, chills, and flulike malaria
symptoms
•If a mosquito bites this infected person and ingests
certain types of malaria parasites (gametocytes), the
cycle of transmission continues
Figure from: http://www.malaria.org/images/lifecycle.gif
Childhood diseases
•Mumps, measles, rubella, chickenpox, whooping cough, smallpox,
diphtheria, tetanus, and polio*
•Successfully been controlled in the developed world through vaccines
•Over 1 million still die per year of these diseases
•Even in the developed world challenges still exist:
•Elimination of adverse side effects of vaccines
•Control of childhood diseases in immunologically compromised
children
•Development of more easily administered, "child-friendly" vaccines
•Better control of persisting childhood disease threats such as
infections caused by rapidly evolving organisms like streptococcus
and many microbes causing pneumococcal infection
*In Danish: Fåresyge, Mæslinger, Røde hunde, skoldkopper, kighoste, kopper, difteri, stivkrampe og polio
Respiratory infections
•Infections of the respiratory tract is a leading cause of illness
•Upper respiratory infections (URIs)
•Seldom have serious or life-threatening complications.
•Lower respiratory infections (LRIs) include more serious illnesses
•More than 4 million deaths each year
•Common causes (in addition to TB)
•Streptococcus pneumoniae (pneumococcus)
•At least 1 million children die of pneumococcal disease every
year.
•The currently licensed pneumococcal vaccine is based on the
23 most common serotypes
(http://www.who.int/vaccines/en/pneumococcus.shtml).
•Haemophilus influenzae
(http://www.who.int/mediacentre/factsheets/fs294/en/index.html)
•Respiratory syncytial virus (RSV)
Diarrheal Diseases
•More than half of the cases of diarrheal illness cannot be ascribed to a
particular agent.
•Important pathogens include
•Vibrio cholerae
•Shiga toxin–producing Escherichia coli (STEC)
•Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC)
•Shigella (S. boydii, S. dysenteriae, S. flexneri, S. sonnei)
•Salmonella typhi
• Helicobacter pylori
•Campylobacter
•Rotavirus
•Caliciviruses
Other classifications of
dangerousness
Recombinant DNA Advisory
Committee (RAC) classification
Risk group 1 (RG1) Agents that are not associated with disease in
healthy adult humans
Risk group 2 (RG2) Agents that are associated with human disease
which is rarely serious and for which preventive or therapeutic
interventions are often available
Risk group 3 (RG3) Agents that are associated with serious or lethal
human disease for which preventive or therapeutic interventions may
be available (high individual risk but low community risk)
Risk group 4 (RG4) Agents that are likely to cause serious or lethal
human disease for which preventive or therapeutic interventions are
not usually available (high individual risk and high community risk)
NIAID/CDC classification
•
•
•
Category A Diseases/Agents
•
Can be easily disseminated or transmitted from person to person
•
Result in high mortality rates and have the potential for major public health impact
•
Might cause public panic and social disruption; and
•
Require special action for public health preparedness.
Category B Diseases/Agents (Second highest priority agents)
•
Are moderately easy to disseminate
•
Result in moderate morbidity rates and low mortality rates
•
Require specific enhancements of CDC's diagnostic capacity and enhanced
disease surveillance
Category C Diseases/Agents (Third highest priority)
•
Emerging pathogens that could be engineered for mass dissemination in the
future because of
•
Availability
•
Ease of production and dissemination
•
Potential for high morbidity and mortality rates and major health impact
http://www.bt.cdc.gov/agent/agentlist-category.asp#catdef
Biodefence
Targets
www2.niaid.nih.gov/Biodefense/
bandc_priority.htm
Dodo
Pathogenic Viruses
1st column: log10 of the number of deaths caused by the
pathogen per year
2nd column: DNA Advisory Committee (RAC)
classification
DNA Advisory Committee guidelines [RAC, 2002] which
includes those biological agents known to infect humans, as
well as selected animal agents that may pose theoretical risks
if inoculated into humans. RAC divides pathogens into
four classes.
Risk group 1 (RG1). Agents that are not associated with disease in
healthy adult humans
Risk group 2 (RG2). Agents that are associated with human disease
which is rarely serious and for which preventive or therapeutic interventions
are often available
Risk group 3 (RG3). Agents that are associated with serious or lethal
human disease for which preventive or therapeutic interventions may be
available (high individual risk but low community risk)
Risk group 4 (RG4). Agents that are likely to cause serious or lethal
human disease for which preventive or therapeutic interventions are not
usually available (high individual risk and high community risk)
3rd column: CDC/NIAID bioterror classification
classification of the pathogens according to the Centers for
Disease Control and Prevention (CDC) bioterror categories
A–C, where category A pathogens are considered the worst
bioterror threats
4th column: Vaccines available
A letter indicating the type of vaccine if one is available (A:
acellular/adsorbet; C: conjugate; I: inactivated; L: live; P:
polysaccharide; R: recombinant; S staphage lysate; T: toxoid).
Lower case indicates that the vaccine is released as an
investigational new drug (IND)).
5th column: G: Complete genome is sequenced
Data derived from /www.cbs.dtu.dk/databases/Dodo.
Biodefence targets
• Vaccines have only been made for 14 of the more than 123 agents on
the CDC/NIAID A–C list
• For many of the bacterial agents antibiotic treatment is possible, but
may be inefficient if the agent is inhaled
• Category A agents
• Bacillus anthracis (anthrax)
• Clostridium botulinum toxin (botulism)
• Yersinia pestis (plague)
• Variola major (smallpox)
• Francisella tularensis (tularemia)
• Viral hemorrhagic fevers
http://www.bt.cdc.gov/agent/agentlist-category.asp#catdef
Antrax
• Even with antibiotic treatment inhalation anthrax has 40-75% fatality
• An anthrax vaccine adsorbed (AVA) exists
• There are no data to support the efficacy of AVA for pulmonary
anthrax in humans
• The protective antigen (PA) of B. anthracis induces significant
protective immunity against inhalation spore challenge in animal
models
• Pilot lots of a recombinant PA vaccine are produced
*In Danish: miltbrand
Smallpox
• Eradicated in 1977
• The mortality from smallpox infections is approximately 30%
• The vaccine has serious side effects and is associated with
complications which may be life-threatening, especially in persons
with an impaired immune system
• A modified vaccinia Ankara (MVA) vaccine for evaluation in a phase I
clinical study is being produced by Bavarian Nordic and Acambis
• 1972 Yugoslavia outbreak
• Over a 9-week outbreak, 175 people were infected, 35 died
•
*In Danish: kopper
Emergency procedures included the isolation of Dakovica province,
shutting down borders, quarantining all persons suspected of coming into
contact with the virus, and prohibiting public events, meetings, and
weddings. 20 million people were vaccinated and 10,000 contacts were
quarantined.
(https://www8.georgetown.edu/centers/cndls/applications/posterTool/inde
x.cfm?fuseaction=poster.display&posterID=881)
Plague
• Natural epidemics of plague have been primarily bubonic plague
• Transmitted by fleas from infected rodents
• Inhalation of aerosolized bacilli can lead to a pneumonic plague that
can spread through the air from person to person
•
Untreated has a mortality rate that approaches 100%
• A formalin-killed whole-cell vaccine (USP) was available until 1999
• It could prevent bubonic plague but could not prevent pneumonic
plague
• Candidate vaccines based on the F1 and V antigens are in clinical
trial
*In Danish: pest
Botulism
• Caused by Botulinum toxin
• Characterized by peripheral neuromuscular blockade.
• Seven antigenic types (A-G) of the toxin exist
• All seven toxins cause similar clinical presentation and disease
• botulinum toxins A, B, and E are responsible for the vast majority of
food borne botulism cases in the United States.
• The heavy chain is not toxic, and has been shown to evoke complete
protection against the toxin.
• Sequencing of the C. botulinum Hall strain A bacterium genome has
been completed
•
DynPort Vaccine Company LLC (DVC) vaccine in phase I clinical trials
*In Danish: pølseforgiftning
Tularemia
• Caused by Francisella tularensis
• If untreated, the disease can lead to respiratory failure
• Treatment with antibiotics reduces mortality for naturally acquired
cases by 2 to 60%
• A live attenuated tularemia vaccine has been administered under an
investigational new drug (IND) application to thousands of volunteers
• In vivo studies demonstrate that either CD4 or CD8 T cells can
mediate resolution of live vaccine strain (LVS) infections
• Antibodies appear to contribute little, if anything, to protective
immunity
*In Danish: harepest
Viral hemorrhagic fevers (VHFs)
• Viral hemorrhagic fevers encompass a group of similar diseases
caused by four types of viruses:
Arenaviruses, associated with Argentine, Bolivian, and Venezuelan
hemorrhagic fevers, Lassa fever, and Sabia virus–associated
hemorrhagic fever
Bunyaviruses, including Crimean-Congo hemorrhagic fever, Rift
Valley fever, and Hantavirus infection
Filoviruses, comprising Ebola and Marburg hemorrhagic fevers
Hemorrhagic flaviviruses, including yellow fever, dengue
hemorrhagic fever, West Nile virus, Kyasanur Forest disease, and
Omsk hemorrhagic fever
• With very few exceptions (yellow fever), no vaccines or proven
treatments exist
• Many of the diseases are highly fatal
Cancer
• One of the three leading causes of death in industrialized countries
• Caused by cells which grow progressively without any regulation
• Antigens
• Self – changed expression
• Neoantigens
• No successful treatment based on immune responses, except for a
few types of cancer (see e.g., de Leo [2005]).
• Tumors are generally genetically unstable, and they can lose their
antigens by mutation
• Moreover, some tumors lose expression of a particular MHC
molecule, totally blocking antigen presentation.
• These tumors may become susceptible to a natural killer (NK) cell–
mediated response, but, tumors that lose only one or two MHC
molecules may avoid recognition by NK cells
Allergy
• Allergic reactions are caused by a special class of antibodies called
immunoglobulin E (IgE) antibodies
• IgE responses are, under normal physiological conditions protective,
especially in response to parasitic worms
• Almost half of the inhabitants of North America and Europe have
allergies to one or more common environmental antigens
• Allergic reactions occur when allergens cross-link preexisting IgE
bound to the mast cells
• Treatment
• Desensitization: the aim is to shift the antibody response from IgE
to IgG
• IgG antibodies can bind to the allergen and thus prevent it from
causing allergic reactions
• Patients are injected with escalating doses of allergen
Autoimmune diseases
• Infections can trigger autoimmune disease
• Susceptibility to autoimmune disease is associated mostly with the
MHC genotype
• susceptibility is linked most strongly with MHC class II alleles, but in
some cases there are strong associations with particular MHC class I
alleles
• For many years immunologists have sought to develop methods for
preventing and treating autoimmune diseases by
• Identifying those self antigens that are the target of autoimmune
processes
•
Using vaccines based on these antigens to revert the dangerous
immune response to a non harmful one
• All of these attempts entail risk, and require exact dosage to get any
benefit