Contemporary Challenges to the Immune System Challenges of

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 Creationof Creation of self 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 CD 4+ 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 CD 4+ T cell counts • Severe side effects • Expensive

HIV • Retrovirus • HIV gp 120 binds to CD 4 on human cells • Loss of CD 4+ 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_r 2000. gif

Tuberculosis • A recent study from South Africa published in Lancet reported: • A recent outbreak of XDR-TB in an HIV-positive population in Kwazulu. Natal 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 Canada. U. 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/np 23/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/fs 294/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 (RG 1) Agents that are not associated with disease in healthy adult humans Risk group 2 (RG 2) Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available Risk group 3 (RG 3) 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 (RG 4) 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/agentlist-category. asp#catdef

Biodefence Targets www 2. niaid. nih. gov/Biodefense/ bandc_priority. htm

Dodo Pathogenic Viruses 1 st column: log 10 of the number of deaths caused by the pathogen per year 2 nd 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 (RG 1). Agents that are not associated with disease in healthy adult humans Risk group 2 (RG 2). Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available Risk group 3 (RG 3). 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 (RG 4). 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) 3 rd column: CDC/NIAID bioterror 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 4 th 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)). 5 th 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/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: //www 8. georgetown. edu/centers/cndls/applications/poster. Tool/ind ex. cfm? fuseaction=poster. display&poster. ID=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 F 1 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 • Dyn. Port 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 CD 4 or CD 8 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 (Ig. E) antibodies • Ig. E 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 Ig. E bound to the mast cells • Treatment • Desensitization: the aim is to shift the antibody response from Ig. E to Ig. G • Ig. G 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