Teacher 4- How viruses cause disease copy.pdf

How viruses cause diseases, vaccines, and prophylactic measures Viruses make us sick by killing cells or disrupting cell functi...

How viruses cause diseases, vaccines, and prophylactic measures Viruses make us sick by killing cells or disrupting cell function. Our bodies often respond with fever (heat inactivates many viruses), the secretion of a chemical called interferon (which blocks viruses from reproducing), or by marshaling the immune system's antibodies and other cells to target the invader. 1  What do we need to know about viruses in order to contain & control them? 9/9/2024 8:16 PM Medical virology 2 One Health approach! 2  Objectives: Definitions: Pathogenicity & Virulence What makes one strain of virus more virulent than another? Interactions between viruses and host cells: - Cellular factors - Cytopathic effects - New cell-surface antigen The spread of viruses in the host - Invasion routes - Patterns of viral disease: localized, generalized How infectious is a virus Control of virus disease by immunization: Vaccination Human antiviral vaccines currently in use What other new vaccines that are pretty far along in clinical trials? Vaccination Strategies: Sub-unit vaccines, Inactivated vaccines & live vaccines 9/9/2024 8:16 PM Medical virology 3 Pathogenicity vs. Virulence Pathogenicity refers to the ability of an organism to cause disease (ie, harm the host). This ability represents a genetic component of the pathogen and the overt damage done to the host is a property of the host-pathogen interactions. Commensals and opportunistic “pathogens” lack this inherent ability to cause disease. However, disease is not an inevitable outcome of the host-pathogen interaction and, furthermore, pathogens can express a wide range of virulence. Virulence, a term often used interchangeably with pathogenicity, refers to the degree of pathology caused by the organism. The extent of the virulence is usually correlated with the ability of the pathogen to multiply within the host and may be affected by other factors (ie, conditional). In summary, an organism (species or strain) is defined as being pathogenic (or not), and depending upon conditions, may exhibit different levels of virulence. 3  Pathogenicity: The ability of an organism to cause disease Virulence: the severity of disease caused by different strain of the same micro-organism (Or: A measure of the degree of the disease caused by a pathogen). typically used with viruses that cause gastroentritis Severity scoring system (e.g. Vesikari Scoring System): in Acute Gastroenteritis (AGE) you count for Dehydration, vomiting, diarrhea, fever, etc…. Each of Rotavirus/Norovirus genotype might lead to different illness. Infectivity is an organism's (a bacteria, virus, fungus, parasite, etc.) ability to infect you. You can be infected but not sick, and there are plenty of times when you're infected but the organism doesn't cause disease. Pathogenicity is a organism's ability to cause disease. Some organisms are harmless and can live on you or in you without you even noticing. But, if they do cause some sort of disease process, then they are called "pathogens". Some pathogens are less pathogenic than others. For example, E. coli is pathogenic depending on the strain. Others are pathogenic all the time, like HIV, where you will progress to AIDS almost 100% of the time. Virulence is a measure of the degree of disease that a pathogen causes. For example, there are some very virulent influenza viruses out there that will knock you out and might even kill you. On the other hand, you might catch a strain that infects you, causes disease, but the disease isn't so bad. In that case, the organism is infectious, pathogenic, but not very virulent. Ebola, on the other hand, is very infectious, very pathogenic (because most people who are infected develop disease), and very virulent (because it causes a severe, often fatal disease). 4  Differing manifestations of Viral infections 1. Viruses from the same family cause different diseases (E.g. ……..) 2. Viruses from different families might cause similar disease (E.g………) 3. Same virus might cause different diseases (E.g………). (Same virus infects multiple cell types) Herpes zoster EBV Measles Measles and RSV virus from Burkitt’s lymphoma Paramyxoviruses family EBV & VZV from same Herpesviruses family The Epstein-Barr virus (EBV), a member of the herpesvirus family (herpesvirus 4), is found throughout the world. Studies show that up to 95% of all adults have antibodies against this common virus, meaning that they were infected at some point in their lives. Even though most infections with EBV go unnoticed or produce only very mild symptoms, in some cases, it can be associated with the development of serious conditions, including several types of cancer. Diseases caused by EBV: infectious mononucleosis (not cancer), Burkitt's lymphoma, Hodgkin's lymphoma, gastric cancer, nasopharyngeal carcinoma, multiple sclerosis,[ and lymphomatoid granulomatosis. The term viral tropism refers to which cell types EBV infects. EBV can infect different cell types, including B cells and epithelial cells. SAME VIRUS (EBV) DIFFERENT DISEASE BASED ON HOST CELL Measles Virus Infects both Polarized Epithelial and Immune Cells by Using Distinctive Receptor-Binding Sites on Its Hemagglutinin. Signaling lymphocyte activation molecule (SLAM, also called CD150), a membrane glycoprotein expressed on immune cells, acts as the principal cellular receptor for MV, accounting for its lymphotropism and immunosuppressive nature. MV also infects polarized epithelial cells via an as yet unknown receptor molecule, thereby presumably facilitating transmission via aerosol droplets. (SAME FAMILY LIKE RSV, BUT DISEASE MANIFESTATION IS DIFFERENT) 5 Herpes zoster (also known as Shingles or Zona) is a disease in humans. The same virus that causes chickenpox also causes shingles. The symptoms are pain and a rash with blisters. (SAME VIRUS DIFFERENT DISEASE; AGE RELATED). The causative agent for shingles is the varicella zoster virus (VZV)—a double-stranded DNA virus related to the Herpes simplex virus. Most individuals are infected with this virus as children which causes an episode of chickenpox. The immune system eventually eliminates the virus from most locations, but it remains dormant (or latent) in the ganglia adjacent to the spinal cord (called the dorsal root ganglion) or the trigeminal ganglion in the base of the skull. https://en.wikipedia.org/wiki/Varicella_zoster_virus. Paramyxoviridae (from Greek para-, beyond, -myxo-, mucus or slime, plus virus, from Latin poison, slime, thus meaning "slime beyond slime") is a family of viruses in the order Mononegavirales. Humans, vertebrates, and birds serve as natural hosts. There are currently 38 species in this family, divided among 7 genera. Diseases associated with this negative-sense single-stranded RNA virus family include: measles, mumps, respiratory tract infections. 5  What makes one strain of virus more virulent than another? Few nucleotides substitutions.. Or point mutation are enough …e.g. influenza In case of flu, mutations at the receptor binding domain that alter receptor binding specificity and/or mutations close to the fusion peptide that alter HA cleavage into HA1 and HA2, cause change in virulence. Receptor Binding Domain Multiple basic AA leavage site (H5N1) HA of the receptor virus 9/9/2024 8:16 PM Medical virology 6 What makes a virus strain (let us say Highly pathogenic H5N1) more virulent than other (seasonal H1N1): Typically specific mutations in specific proteins: 1. Mutation in the receptor binding domain of the HA surface glycoprotein: Bind more efficiently to the receptor. 2. Mutation in the Polymerase gene: Replicate more efficiently in the cells. 3. Mutation in fusion peptide: Make it more easy to cleave by enzyme during maturation (Multiple basic AA leavage site (H5N1)) 6  HOST-PATHOGEN INTERACTION Infection accelerates telomere erosion in immune cells. infection makes erosion faster as well as aging Telomere erosion limits the proliferative capacity of T cells in vitro and in vivo. A body with weak immune system is susceptible to infection https://royalsocietypublishing.org/doi/10.1098/rsbl.2019.0190 7  HOST-PATHOGEN INTERACTION 1.Cellular factors: Receptors, temperature (respiratory viruses; upper versus lower respiratory tract tropism), signaling molecules inside the host cell, type of immune cells, etc. 2. Viral cytopathic effects: CPE Cell lysis: the early viruses –coded proteins may shut down synthesis of macromolecules, particularly polypeptides, by the host cell. In some cases (adenovirus), accumulation of large amount of capsid protein abrupt both, cellular and viral synthetic activities. Death of cells followed by lysis would release large number of viruses. Cell fusion: Viral fusion proteins mediate the virus entry and cause formation of multinucleated giant cell (syncytia). Inclusion bodies: Are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins. These bodies that appear within cells as a result of infection with some virus and bacteria replication sites for the viruses https://www.histology.leeds.ac.uk/what-is- histology/H_and_E.php#:~:text=DNA%20(heterochro matin%20and%20the%20nucleolus,them%20and%2 0stains%20them%20purple.&text=Most%20proteins %20in%20the%20cytoplasm,proteins%20and%20sta ins%20them%20pink. H&E staining The most commonly used staining system is called H&E (Haemotoxylin and Eosin). H&E contains the two dyes haemotoxylin (Basic) and eosin (acidic). Eosin is an acidic dye: it is negatively charged (general formula for acidic dyes is: Na+dye-). It stains basic (or acidophilic) structures red or pink. This is also sometimes termed 'eosinophilic'. Thus the cytoplasm is stained pink in the picture below, by H&E staining. Haematoxylin can be considered as a basic dye (general formula for basic dyes is:dye+ Cl-). Haemotoxylin is actually a dye called hematein (obtained from the log-wood tree) used in combination with aluminium ions (Al3+). It is used to stain acidic (or basophilic; DNA) structures a purplish blue. Thus the nucleus is stained purple in the picture below, by H&E staining. The H&E stain provides a comprehensive picture of the microanatomy of organs and tissues. Hematoxylin precisely stains nuclear components, including heterochromatin and nucleoli, while eosin stains cytoplasmic components including collagen and elastic fibers, muscle fibers and red blood cells. Inclusion bodies: Are nuclear or cytoplasmic aggregates of stainable 8 substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins. These bodies that appear within cells as a result of infection with some virus and bacteria 8  Rabies Virus Herpes virus Measles Virus exception:RNA but replicates in nucleus Negri bodies are eosinophilic, sharply outlined, pathognomonic inclusion bodies (2– 10 µm in diameter) found in the cytoplasm of certain nerve cells containing the virus of rabies, especially in Ammon's horn of the hippocampus. They are also often found in the cerebellar cortex of postmortem brain samples of rabies victims. They consist of ribonuclear proteins produced by the virus. eosinophilic color is mainly due to cytoplasm (proteins). 9 Interactions between viruses and host cells 3. New cell-surface antigen: Induction of new (foreign) antigen on the cell surface Particularly with enveloped viral infections (WHY????????????) e.g.: herpes, orthmyxo, paramyxo and retroviruses The infected cell is susceptible for cytotoxic T cells Can be laboratory detected by immunoflourescence staining as marker for malignant change https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2184260/ 10 The spread of viruses in host: Important events in pathogenesis: Invade the host; Establish a bridgehead by replicating in susceptible cells at the site of inoculation (A virus might have more than one site for replication). Overcome the local defenses, e.g. lymphocytes, macrophages, and interferon; viruses have to have mechanisms to overcome interferone from interfering in its replication process Spread from the site of inoculation to other areas, often via the blood stream (viremia). Undergo further replication in its target area, whether this be localized (e.g. adenovirus conjunctivitis) or generalized (e.g. measles); Exit from the host in numbers large enough to infect other susceptible hosts and thus ensure its own survival 11 The spread of viruses in host: Polio life cycle + stand rna virus transmitted through fecal oral route first replicates in the intestine 12  Viral infections caused by viruses can be classified under two main heading: Those localized to tissue at site of entry (acute); EXAMPLE! Those that spread to one or more organs remote from this area (Generalized/Systemic) and can establish infection that persist for years or even for life; EXAMPLE! Patterns of disease In a host, viruses cause 3 basic patterns of infection: localized, disseminated, and inapparent. Localized - viral replication remains localized near the site of entry e.g. skin, respiratory or the GI tract) Systemic (disseminated) - systemic infections usually take place through several steps; Entry of virus Spread to regional lymph nodes Primary viraemia ® spread to other susceptible organs such as the liver and spleen More intense secondary viraemia ® dissemination to other organs, such as the skin. 13  Systemic infection: Measles (two receptors) virus infection cycle virimeia is when the virus transmits through lood The time course of MV infection and receptor usage. (A) MV enters humans through the respiratory route and initiates its infectious cycle in lymphoid organs in the upper respiratory tract by using SLAM (found on immune cells) as a receptor. (B) MV-infected lymphocytes enter the bloodstream, and MV propagates in lymphoid organs throughout the body. (C) MV- infected immune cells appear to transmit MV to epithelial cells in various organs (e.g., airway, intestine, bladder). A putative epithelial cell receptor appears to play an important role in MV infection of epithelial cells. (D) MV then replicates in epithelial cells and actively releases progeny viruses into the airway. Consequently, respiratory aerosols of patients contain large amounts of MV particles for the virus to be systemic transmit through the blood 14 Localized infections: e.g. enteroviruses 9/9/2024 8:16 PM Medical virology 15 15  (some!) Any virus that goes viremia, it might cause generalized infection. 16  Invasion routes: The ability of some viruses to infect more than on route (e.g. hepatitis) Enter via: -Abrasion (e.g. ……) - inoculation with contaminated needle (e.g. ……) - insect of animal bites (e.g. ……) - respiratory tract (e.g. ……) - gastrointestinal tract (e.g. ……) - via conjunctiva (e.g. ……) - genital tract (e.g. ……) FIND THREE EXAMPLES FOR EACH ROUTE 17  http://www.sciencedirect.com/science/article/pii/S1931312813001200#fig2 Understand virus pathogenicity : Virus Entry Routes into the CNS they invade different parts therefore causing different disease Alpha herpesviruses Rare infect pseudounipolar sensory neurons of PNS ganglia when the immune system is weak it comes back and reinfects the Rabis virus and poliovirus cells spread via neuromuscular junctions (NMJs) from muscles into somatic motor neurons in the spinal cord (reach CNS). it might reach the brain and cause seziure Several viruses may infect receptor neurons in the nasal olfactory epithelium. Infiltration through the BBB. May virus reach the brain? Virus Entry Routes into the CNS (A) Alpha herpesviruses (e.g., HSV-1, VZV, and PRV) infect pseudounipolar sensory neurons of PNS ganglia. CNS spread is rare and requires anterograde axonal transport of progeny virions toward the spinal cord. (B) RABV and poliovirus spread via neuromuscular junctions (NMJs) from muscles into somatic motor neurons in the spinal cord. (C) Several viruses may infect receptor neurons in the nasal olfactory epithelium. Spread to the CNS requires anterograde axonal transport along the olfactory nerve into the brain. (D) Infiltration through the BBB (Blood brain barrier). The BBB is composed of brain microvascular endothelium cells (BMVECs) with specialized tight junctions, surrounding basement membrane, pericytes, astrocytes, and neurons. Infected leukocytes can traverse this barrier carrying virus into the brain parenchyma. (E) Alternatively, virus particles in the bloodstream can infect BMVECs (Brain Microvascular Endothelial Cells ), compromising the BBB. Transport from the soma to the distal axon is known as anterograde transport, whereas transport from distal regions back to the soma is known as retrograde 18 transport. Axonal transport is an energy-dependent process that involves microtubules and the microtubule-based motor proteins, the dyneins and kinesins. 18  Understand virus pathogenicity : Through immune cells 9/9/2024 8:16 PM Medical virology 19 Main idea is the virus could have multiple virimia 19 Acute VS Chronic Viral Infection 20  Group 1 Acute Rapid recovery gastroentritis +influnzae Patterns of disease Apparent recovery with early CNS complications Rapid death Ebola + rabies Group 2 persistent Symptom free periods punctuated with reactivation chronic- herpes Long symptom free period followed by illness and death Chronic disease with periodic exacerbations (CMV) Long incubation period followed by long illness and death Group 3 Slow-fatal HIV, HTLV Find examples, Congenital illness followed late in life by acute illness and death And if persistent, identify the mechanisms Oral herpes is an infection of the lips, mouth, or gums due to the herpes simplex virus. It causes small, painful blisters commonly called cold sores or fever blisters. Oral herpes is also called herpes labialis. Oral herpes is a common infection of the mouth area. It is caused by the herpes simplex virus type 1 (HSV-1). Most people in the United States are infected with this virus by age 20. After the first infection, the virus goes to sleep (becomes dormant) in the nerve tissues in the face. Sometimes, the virus later wakes up (reactivates), causing cold sores. A slow virus disease is a disease that, after an extended period of latency, follows a slow, progressive course spanning months to years, frequently involving the central nervous system and ultimately leading to death. Eg. HTLV, HIV, and rare cases of Measles 21  Limited persistence: Molluscum contagiosum small, raised, pink lesions with a dimple in the center. a type of pox virus the virus is infectious and is replicating Molluscum contagiosum is a skin infection caused by the virus Molluscum contagiosum (MCV-a pox virus). It produces benign raised bumps, or lesions, on the upper layers of your skin. Most cases of molluscum contagiosum will clear up naturally within two years (typically 9 months). Unlike herpesviruses, which can remain inactive in the body for months or years before reappearing, molluscum contagiosum does not remain in the body when the growths are gone from the skin and will not reappear on their own. Molluscum contagiosum (MC), sometimes called water warts, is a viral infection of the skin that results in small, raised, pink lesions with a dimple in the center. They may occasionally be itchy or sore. They may occur singly or in groups. Any area of the skin may be affected, with abdomen, legs, arms, neck, genital area, and face being most common. Onset of the lesions is around 7 weeks after infection. It usually goes away within a year without scarring. MC is caused by a poxvirus called the molluscum contagiosum virus (MCV). The virus is spread either by direct contact including sexual activity or via contaminated objects such as towels. The condition can also be spread to other areas of the body by the person themselves. Risk factors include a weak immune system, atopic dermatitis, and crowded living conditions. Following one infection, it is possible to get reinfected. Diagnosis is typically based on the appearance. Most cases of molluscum contagiosum will clear up naturally within two years (usually within nine months). So long as the skin growths are present, there is a possibility of transmitting the infection to another person. When the growths are gone, the possibility of spreading the infection is ended. Unlike herpesviruses, which can remain inactive in the body for months or years before reappearing, molluscum contagiosum does not remain in the body when the growths are gone from the skin and will not reappear on their 22 own. 22 23  How infectious is a virus the higher the reproduction number the higher the infection Reproduction number (Ro): is the average number of secondary cases generated by one primary case in susceptible community ; The higher the number, the more persona can be infected from one case e.g. Ro value of: SARS & smallpox is 2; influenza is 6-8; 1 indvidual can infect up to 8 and measles is 10 Incubation period: Dangerous of influenza high Ro no. and short incubation period What is Rt? R0 is less than 1: Each existing infection is causing less than one new infection. In this case, the disease will decline and eventually die out. R0 is equal to 1: Each existing infection is causing one new infection. The disease will stay alive and stable, but there won’t be an outbreak or epidemic. R0 is more than 1: Each existing infection is causing more than one new infection. The disease will spread between people and there may be an outbreak or an epidemic. 24 Immunization 25 Control of virus disease by immunization Vaccination: The development and use of vaccines against some serious human viruses was certainly one of the great success stories of 20'th century biological science. In the early decades of the 20'th century, viral diseases such as yellow fever, polio, and rabies were greatly feared, because there was no effective way of preventing the very serious diseases caused by these easily transmissible viruses. The development of new vaccines remains one of the main goals of much virology research. Latin vacca: cow, infection with cowpox prevent infection with smallpox, because it contain viral epitopes that induce B cell and T cell immunity for this poxvirus. Identify the different types of vaccines and the pros and cons of each! REF: http://phrma-docs.phrma.org/sites/default/files/pdf/PhRMA_Vaccine_FactBook_2013.pdf 26  Four generations of virus vaccine Identify the different types of vaccines and the pros and cons of each! Yellow fever vaccine! Virtually every infection with rabies resulted in death until two French scientists, Louis Pasteur and Émile Roux, developed the first rabies vaccination in 1885. This vaccine was first used on a human on July 6, 1885, on nine-year-old Joseph Meister (1876–1940), who had been mauled by a rabid dog. Their vaccine consisted of a sample of the virus harvested from infected (and necessarily dead) rabbits, which was weakened by allowing it to dry for 5 to 10 days. Similar nerve tissue-derived vaccines are still used now in some countries, and while they are much cheaper than modern cell culture vaccines, they are not as effective.[citation needed] Neural tissue vaccines also carry a certain risk of neurological complications. Yellow fever vaccine: The vaccine consists of a live, but attenuated, strain of the yellow fever virus called 17D. The 17D vaccine has been used commercially since the 1950s. The mechanisms of attenuation and immunogenicity for the 17D strain are not known. However, this vaccine is very safe, with few adverse reactions having been reported and millions of doses administered, and highly effective with over 90% of vaccinees developing a measurable immune response after the first dose. In 2013, the World Health Organization concluded, "a single dose of vaccination is sufficient to confer life-long immunity against yellow fever disease." It is on 27 the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system. 27 Recombinant vaccine 28 Human Antiviral Vaccines Currently in Use Recombinant / Virus: Administered: Attenuated: Inactivated: Sub-unit: Hepatitis A im X Hepatitis B im/sc X 1. IM 2. IN is Live Influenza 1. IM is inactivated 2. IN attenuated Japanese B sc X encephalitis Measles, Mumps, im X Rubella (MMR) Poliovirus o/im X X Rabies im X (X) Smallpox sc X Tick-borne im X encephalitis Varicella-Zoster im X Yellow fever sc X Administration Oral: o Subcutaneous or scarification: sc Intramuscular: im IN: Intranasal 29  Bacterial vaccines Bacterial vaccines Subcutaneous injections are administered in the fat layer, underneath the skin. Intramuscular injections are delivered into the muscle. Intradermal injections are delivered into the dermis, or the skin layer underneath the epidermis (which is the upper skin layer). The dermis is, on most places of the human body, only a few mm thick. 30  Route of Vaccination Route of vaccination defines the type of immune response generated? Can you explain & give examples? IgM vs IgG vs IgA (MUCOSAL?!) http://www.who.int/immunization/documents/Elsevier_Vaccine_immunology.pdf Route of vaccination affects the type of immune response generated (e.g. types of Antibodies produced) IgG- This class of antibody is the most important class of immunoglobulin in secondary immune responses. IgG crosses the placenta, conferring protection to the new born and is able to activate the complement system through the classical pathway. IgM is the predominant antibody in the primary immune responses. It can also activate the classical pathway complement. IgA is found primarily in secretions such as breast milk, tears, saliva and mucosal membranes. IgE – evolved to provide protection against certain parasitic infections however in developed countries it is more commonly associated with allergic diseases such as asthma and hayfever. IgD – there is little known about this antibody. 31 Route of Vaccine Administration Alters Antigen Trafficking, Innate immunity but not Adaptive Immunity the site of injection determines where the Ag will go and how close it is to the lymph node and which lymph node 9/9/2024 8:16 PM Medical virology 32 32  Struggle with Vaccines development Reasons for not having an HIV vaccine: secretes proteins that distract the immune system 1. Virus mutates very rapidly. 2. Very few glycoproteins (gp120) are expressed on the surface. 3. Expression of free glycoproteins to disguise immune system. 4. Glycoprotein is highly glycosylated (Masked). 5. The virus integrates its genome into host cells Text Text 33 33  Struggle with Vaccines development : What are a couple other new vaccines that are pretty far along in clinical trials? For several years, vaccines have been in clinical trials for the two most common sexually- transmitted viruses, HPV and HSV-2. As described in these two NEJM article abstracts, the HPV vaccine is a "virus-like-particle" vaccine, whereas the HSV-2 vaccine is a "glycoprotein D- adjuvant" vaccine. A February 2005 article in J. of Infectious Diseases titled "Role of Herd Immunity in Determining the Effect of Vaccines against Sexually Transmitted Disease" considered the forthcoming use of these vaccines. Human papilloma virus (HPV) vaccines may prevent infections by certain types of human papillomavirus associated with the development of cervical cancer, genital warts, and other cancers. Two vaccines have market approval in many countries as of 2014 (called Gardasil and Cervarix in the US). Both vaccines protect against the two HPV types (HPV- 16 and HPV-18) that cause 70% of cervical cancers, 80% of anal cancers, 60% of vaginal cancers, and 40% of vulvar cancers.[ In two clinical trials, a vaccine containing herpes simplex virus (HSV) type 2 glycoprotein D (gD2) and a novel adjuvant AS04 comprising alum (Al) and 3-deactylated monophosphoryl lipid A (3-dMPL) afforded HSV-seronegative women significant protection against HSV-2 genital disease (vaccine efficacy, 73% in study 1 and 74% in study 2) and limited protection against infection (46% in study 1 and 39% in study 2). https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet Look up for its makeup, safety, method of Adminstration, and whether it protects if was taken after infection? http://www.nature.com/news/failed-herpes-vaccine-puzzles-virologists-1.9739 Three vaccines are approved by the FDA to prevent HPV infection: Gardasil, Gardasil 9, and Cervarix. All three vaccines prevent infections with HPV types 16 and 18, two high-risk HPVsthat cause about 70% of cervical cancers and an even higher percentage of some of the other HPV-associated cancers (9, 10). Gardasil also prevents infection with HPV types 6 and 11, which cause 90% of genital warts (17). Gardasil 9 prevents infection with the same four HPV types plus five additional high-risk HPV types (31, 33, 45, 52, and 58). In addition to providing protection against the HPV types included in these vaccines, the vaccines have been found to provide partial protection against a few additional HPV types that can cause cancer, a phenomenon called cross- protection. The vaccines do not prevent other sexually transmitted diseases, nor do they treat existing HPV infections or HPV-caused disease. HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia. HSV-1 tends to reside in the trig It has been notoriously difficult to develop effective vaccines against herpes viruses, many of which have complex life cycles and can lie dormant in the body for long periods of time. The only vaccine that can successfully prevent infection by a member of the herpes virus family is 34 the chickenpox vaccine, which uses a live, weakened virus. Early tests of the glycoprotein D vaccine suggested that it protected more than 70% of women against HSV-2. The vaccine did not work in men https://en.wikipedia.org/wiki/Herpes_simplex_research 34  HPV VLP vaccine looks like a virus but is not because it does not have the same genome Similar strategies have been used with other viruses example Chikungunya The HPV vaccines are based on hollow virus-like particles (VLPs) assembled from recombinant HPV coat proteins. The virus possesses circular double stranded DNA and a viral shell that is composed of 72 capsomeres. Every subunit of the virus is composed of two proteins molecules, L1 and L2. The reason why this virus has the capability to affect the skin and the mucous layers is due to its structure. The primary structures expressed in these areas are E1 and E2, these proteins are responsible for the replication of the virus. E1 is a highly conserved protein in the virus, E1 is in charge of the production of viral copies is also involved in every step of replication process. The second component of this process is E2 ensures that non- specific interaction occurs while interacting with E1. As a result of these proteins working together is assures that numerous amounts of copies are made within the host cell. The structure of the virus is critical because this influence the infection affinity of the virus. Knowing the structure of the virus allowed for the development of an efficient vaccine, such as Gardasil and Cervarix. The vaccines target the two high-risk HPVs, types 16 and 18 that cause the most cervical cancers. Gardasil's proteins are synthesized by the yeast Saccharomyces cerevisiae. Its protein makeup allows it to target four types of HPV. Gardasil contains inactive L1 proteins from four different HPV strains: 6, 11, 16, and 18.. 35  A vaccine called Gardasil is used in the national NHS cervical cancer vaccination programme. Gardasil protects against multiple types of HPV, between them responsible for more than 70% of cervical cancers in the UK. A bonus of using Gardasil to prevent cervical cancer is that it prevents genital warts too. https://www.merckvaccines.com/Products/Gardasil9 GARDASIL 9 is a vaccine indicated in females 9 through 26 years of age for the prevention of cervical, vulvar, vaginal, and anal cancers caused by human papillomavirus (HPV) Types 16, 18, 31, 33, 45, 52, and 58; precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11. 36  HSV Vaccine candidate https://en.wikipedia.org/wiki/Herpes_simplex_research#Vaccine_research Chickenpox is also a herpes virus but vaccine is available. he chickenpox vaccine is a shot that can protect nearly anyone who receives the vaccine from catching chickenpox. It's also called the varicella vaccine, because chickenpox is caused by the varicella-zoster virus. The vaccine is made from a live but weakened, or attenuated, virus. EBV is also a Herpes virus, vaccine has been tested in preclinical trials 37 Vaccination Strategies There are three basic types of vaccine: 1) Sub-unit Vaccines The newest type; completely safe, except for rare adverse reactions. Problems: (Relatively) poor antigenicity (especially short peptides) Vaccine delivery (carriers/adjuvants needed) a) Synthetic Vaccines (Novartis influenza vaccine for H1N1) b) Recombinant Vaccines (hepatitis B surface antigen (HBsAg) Produced in yeast) HBV c) Virus Vectors (Astrazenica!) d) mRNA Vaccine (Moderna). Understand why it is difficult to make vaccines in many time, and why it does not work 38 2) Inactivated Vaccines Method of production - exposure to denaturing agent by heat/cold shock or by serial passage - results in loss of infectivity without loss of antigenicity. Advantages: More effective than above - better immunogens. Stable. Little or no risk (if properly inactivated) Disadvantages: Not possible for all viruses; denaturation may lead to loss of antigenicity, e.g. measles. Not as effective at preventing infection as live viruses (mucosal immunity - IgA). May not protect for a long period ? 39 3) Live Virus Vaccines The use of virus with reduced pathogenicity to provide immune response without disease. May be naturally occurring virus (e.g cowpox, 1776), artificially attenuated (oral poliovirus vaccine (OPV)) and Live attenuated influenza vaccine (MedImmune). Advantages: Good immunogens Induce long-lived, appropriate immunity Disadvantages: Unstable: biochemically (live virus) and genetically (reversion to virulence) Not possible to produce in all cases Contamination possible Inappropriate vaccination e.g. immunocompromised hosts / rubella in pregnancy may lead to disease 40  Not important 41 protein vax 42  9/9/2024 8:16 PM Medical virology 43 A pentavalent vaccine is five individual vaccines conjugated in one intended to actively protect infant children from 5 potentially deadly diseases: Haemophilus Influenza type B, Whooping Cough, Tetanus, Hepatitis B and Diphtheria. Pneumococcal conjugate vaccine (PCV) is a pneumococcal vaccine and a conjugate vaccine used to protect infants, young children, and adults against disease caused by the bacterium Streptococcus pneumoniae (the pneumococcus). There are currently three types of PCV available on the global market, which go by the brand names: Prevnar (called Prevenar in some countries), Synflorix and Prevnar 13. The BCG vaccine protects against tuberculosis, which is also known as TB. TB is a serious infection which affects the lungs and sometimes other parts of the body such as the bones, joints and kidneys. It can also cause meningitis. 43 Passive immunization: Injection of human immunoglobulin (polyclonal or monoclonal) preparation containing various antibodies immediate partial or complete protection against infection by certain viruses. For who? -Patient at especial risk (pregnant, immunosuppresed patient..etc); RSV SYNAGIS (palivizumab): Anti Fusion protein of RSV. - For preventive of HAV for traveler for endemic country. - Rapid protection after exposure until vaccine immunity develops; Rabbis antibodies. 44 killed vrius vaccine does not have good immunity we have to put molecules that provide good immunity called adjuvants ??? 45  Proposed mechanisms of action of adjuvants Available evidence suggests that adjuvants employ one or more of the following mechanisms to elicit immune responses: (1) sustained release of antigen at the site of injection (depot effect), (2) up-regulation of cytokines and chemokines, (3) cellular recruitment at the site of injection, (4) increase antigen uptake and presentation to antigen presenting cells (APC), (5) activation and maturation of APC [increased major histocompatibility complex (MHC) class II and co-stimulatory molecules expression] and migration to the draining lymph nodes, and (6) activation of inflammasomes 46 Problems regarding vaccines Sensitization, reversion, rare possible complications. Attenuated vaccines not given to pregnant or immune compromised. Developing effective vaccines to some viruses is proving very difficult e.g. influenza, common cold viruses, HIV-1, herpes and more. Common problems include the existence of many serotypes, antigenic drift and shift. The Future? Genetic engineering DNA vaccines (plasmids) Synthetic peptides (T-cell based vaccines) Improved adjuvants, liposomes, TLR-agonists 47  Success stories: Smallpox: WHO/Eradicated 1980. Next targets - polio, measles. Polio: Could be eliminated by vaccination? 48 Measles: Two vaccines available, live and inactivated. Attenuated vaccine is used in combination with mumps and rubella (MMR) (below). Great success in USA. 49  Rubella: Live attenuated vaccine: CRS: congenital rubella syndrome: Congenital rubella syndrome (CRS) is an illness in infants that results from maternal infection with rubella virus during pregnancy. When rubella infection occurs during early pregnancy, serious consequences–such as miscarriages, stillbirths, and a constellation of severe birth defects in infants–can result. Congenital rubella syndrome (CRS) can occur in a developing fetus of a pregnant woman who has contracted rubella, usually in the first trimester. If infection occurs 0–28 days before conception, the infant has a 43% chance of being affected. If the infection occurs 0–12 weeks after conception, the chance increases to 51%. If the infection occurs 13–26 weeks after conception, the chance is 23% of the infant being affected by the disease. Infants are not generally affected if rubella is contracted during the third trimester, or 26–40 weeks after conception. Problems rarely occur when rubella is contracted by the mother after 20 weeks of gestation and continues to disseminate the virus after birth. It was discovered in 1941 by Australian Norman McAlister Gregg. The molecular basis for the causation of congenital rubella syndrome are not yet completely clear, but in vitro studies with cell lines showed that rubella virus has anapoptotic effect on certain cell types. There is evidence for a p53- dependent mechanism. 50 Extra Reading (Optional) What were some "early 2005" updates on research and development towards new viral vaccines? Extra Let's look at three March 2005 journal articles. reading Can a vaccine based on gp120 protect against HIV? In March 2005 J. of Infectious Diseases: "Placebo-Controlled Phase 3 Trial of a Recombinant Glycoprotein 120 Vaccine to Prevent HIV-1 Infection." This study concludes that "There was no overall protective effect". Information on the various ongoing approaches toward an effective HIV vaccine can be found at the HIV Vaccine Trials Network. Where do things stand on developing a vaccine to protect against dengue? In March 2005 J. of Infectious Diseases: "rDEN4delta30, a Live Attenuated Dengue Virus Type 4 Vaccine Candidate, Is Safe, Immunogenic, and Highly Infectious in Healthy Adult Volunteers." Can cloning a SARS gene into Vaccinia be the basis of a vaccine to protect against the SARS virus? In March 2005 Journal of Virology: "Recombinant Modified Vaccinia Virus Ankara Expressing the Spike Glycoprotein of Severe Acute Respiratory Syndrome Coronavirus Induces Protective Neutralizing Antibodies Primarily Targeting the Receptor Binding Region." In general, attenuated live vaccines are longer lasting and produce both humoral and cell-mediated immunity, whereas inactivated or sub-unit vaccines produce only humoral immunity. A risk factor for an attenuated live vaccine strain, however, is the possibility that it could genetically revert back to being pathogenic. This is an important issue, because this situation actually took place (albeit very rarely) for the live polio vaccine. So, we ask.... For polio, how different genetically is the attenuated viral strain (the Sabin vaccine) from the wild-type virulent strain (that causes paralysis)? What is the genetic structure of one rare revertant strain that arose from the vaccine strain several decades ago? As shown here, the Sabin vaccine strain is different from the wild-type "Leon" virulent strain at only 10 of the 8000 nucleotides of the poliovirus genome. Administration of the Sabin strain to many millions of children resulted in virulent revertant strains causing paralytic disease at a frequency of about 1 child in 4 million. One such revertant strain that arose from the vaccine strain is different at only 9 nucleotides (here). Comparing the two figures shows that at only one of these sites (nucleotide position 472) is the revertant change the exact reversal of the original attenuation change 51 Thank you for your attention 52