Transcript PowerPoint Slides - CBS

Contemporary Challenges to
the Immune System
Ole Lund
Infectious Diseases
• More than 400 microbial agents are associated with disease
• Licensed vaccines in the United states for 22 microbial agents
• Vaccines for 34 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
Human Vaccines
against pathogens
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
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 – reinfection
• Escape from strain specific
antibodies
• Broadly neutralizing antibodies are
rarely produced in patients
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
TB kills one person every 15 seconds and is the leading killer of people living
with HIV. HIV/ TB co-infection rates are high (overall about 30% of HIV
patients have tuberculosis), but coinfection is only one concern. Growing
drug resistance, the inefficiency of diagnostic tools, and general U.S.
complacency all contribute to the loss of 2 million lives to TB each year.
The most common prophylaxis is the BCG vaccine against active TB in young
children. But BCG has shown little efficacy in most clinical trials.
Furthermore, vaccination in childhood impedes accurate TB diagnosis later in
life. BCG is not used in the United States.
S. Helen Labun,The Tuberculosis Initiative,Princeton, NJ
Figure from: http://ucatlas.ucsc.edu/health/tb/tb_r2000.gif
Malaria
• Four kinds of malaria parasites can infect humans:
• Plasmodium falciparum, P. vivax, P. ovale, and P. malariae
• 300 to 500 million cases of malaria/year
• More than 1 million people die of malaria each year
•Transmitted by bites by an female Anopheles
• Mosquito infected by a previous blood meal
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
• Haemophilus influenzae
• 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)
• Helicobacter pylori
• Rotavirus
• Caliciviruses
• Shigella (S. boydii, S. dysenteriae, S. flexneri, S. sonnei)
• Salmonella typhi
• Campylobacter
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
Pathogenic
Viruses
•1st column (and color of name)
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)
2nd column
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
3rd column
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)).
Adapted from Immunological Bioinformatics, The MIT press. Data derived from /www.cbs.dtu.dk/databases/Dodo.From number of identical
terms in Swissprot description.
Pathogenic
Bacteria
Adapted from Immunological Bioinformatics, The MIT press.
Data derived from www.cbs.dtu.dk/databases/Dodo.
Pathogenic
Parasites
Adapted from Immunological Bioinformatics, The MIT press.
Data derived from www.cbs.dtu.dk/databases/Dodo.
Biodefence
Targets
www2.niaid.nih.gov/Biodefense/
bandc_priority.htm
Bio defence 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
*In Danish: kopper
Plague
• Natural epidemics of
primarily bubonic plague
plague
have
been
• 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
approaches 100%
a
mortality
rate
that
• 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 foodborne 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
*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
• Tumor rejection antigens
• 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
protective, especially in response to parasitic worms
conditions
• 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