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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

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Contemporary Challenges to the Immune System

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Contemporary challenges to the immune system l.jpg

Contemporary Challenges tothe Immune System

Ole Lund


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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


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Human Vaccines against pathogens

Immunological Bioinformatics, The MIT press.


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Deaths from infectious diseases in the world in 2002

www.who.int/entity/whr/2004/annex/topic/en/annex_2_en.pdf


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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


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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


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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


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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


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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


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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


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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


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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)


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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


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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)


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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


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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 intofour classes.Risk group 1 (RG1). Agents that are not associated with disease in healthy adult humansRisk group 2 (RG2). Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often availableRisk 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 columnclassification 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 threats3rd columnA 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.


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Pathogenic Bacteria

Adapted from Immunological Bioinformatics, The MIT press.Data derived from www.cbs.dtu.dk/databases/Dodo.


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Pathogenic Parasites

Adapted from Immunological Bioinformatics, The MIT press.Data derived from www.cbs.dtu.dk/databases/Dodo.


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BiodefenceTargets

www2.niaid.nih.gov/Biodefense/bandc_priority.htm


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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


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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


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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


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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


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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


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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


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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


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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


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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


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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


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