Vaccines

Vaccines. Dr. Hend Abdallah Al far H end.abdallah@pharma.asu.edu.eg.

Biologics. What are biologics: Biologics are the products manufactured, extracted from a biological source i.e. substance produced from a living organism rather than chemical reactions.

Biologics. If the underlying objective of these products: help in developing immunity in the person receiving them Immunobologics: biologics that induce immunization Immunization ,is the process by which an individual's immune system becomes fortified against an agent (known as the immunogen ). Immunization is done through various techniques, most commonly vaccination.

What Happens when a pathogen (Corona virus) enters our body The body’s natural immune response our bodies react and try to fight off the virus, often making us very sick in the process. Without a vaccine, here’s how our natural immune response plays out: The virus commonly enters the human body through the eyes, nose or mouth. When the body recognizes the virus as a foreign object, an immune cell engulfs and traps the virus so it cannot do harm to the body. The engulfing cell is known as an Antigen Presenting Cell (APC) because it displays the viral protein known as the antigen after engulfing the virus. The display activates T cells which examine the antigen and alert B cells of the intruder. Both immune cells multiply and some of the copies, known as memory cells , will form the basis of the body’s long-term immunity to the coronavirus. Some of the copied cells get to work immediately. B cells start making antibodies that match the antigen presented by the APC. The antibodies latch onto the virus to prevent it from entering cells and making more copies of itself. This whole process is the body’s primary immune response to the coronavirus. But it can take time for the immune system to recognize the intruder and stop it from multiplying. In the meantime, the body may undergo painful symptoms like fever, cough and difficulty breathing. Vaccines allow humans to build immunity without experiencing illness..

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T ypes of Immunity. Immunization, is the process by which an individual's immune system becomes fortified against an agent (known as the immunogen). When this system is exposed to molecules that are foreign to the body, called non-self, it will orchestrate an immune response, and it will also develop the ability to quickly respond to a subsequent encounter because of immunological memory .(antibodies) Therefore, by exposing an animal to an immunogen (vaccine) in a controlled way, its body can learn to protect itself this is called active immunization..

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VACCINES. A vaccine is a biological preparation given to provide immunity to a particular disease. A vaccine typically contains an agent that resembles a disease causing microorganism It works by developing antibodies that can quickly and effectively attack disease-causing microorganism when it enters the body thus prevent disease development Vaccination : It is the use of a biologic product “A Vaccine” to develop active immunity in a patient The first vaccine, against smallpox , was introduced by Edward Jenner in 1798 . Vaccines have been developed against diseases caused by bacteria (e.g., typhoid, whooping cough, tuberculosis) and by viruses (e.g., measles, influenza, rabies, poliomyelitis). Benefits of these products: Incidence of poliomyelitis fell dramatically after the use of inactivated polio vaccine and oral polio vaccine in the USA In the early 1950’s more than 20,000 cases per year By 1960 number dropped to 3000 case By 1979 number was about 10.

VACCINES. TYPES OF VACCINES Inactivated Killed Vaccines Live, attenuated vaccines Toxoids Subunit (surface proteins) 5. Conjugate Vaccines 6. Recombinant Vector Vaccines 7. DNA vaccines 8. Peptide vaccines.

1- Inactivated Killed Vaccines These are previously virulent micro-organisms that have been killed with chemicals or heat. Examples are vaccines against flu, cholera, and hepatitis A. Advantages :  The dead microbes can’t mutate back to their disease - causing state. Inactivated vaccines usually don’t require refrigeration, and they can be easily stored and transported in a freeze - dried form, which makes them accessible to people in developing countries. Disadvantages : Most such vaccines may have incomplete or short-lived immune responses and are likely to require booster shots to maintain a person’s immunity. This could be a drawback in areas where people don’t have regular access to health care and can’t get booster shots on time..

2- Live Attenuated Vaccines • Live, attenuated vaccines contain a version of the living microbe that has been weakened in the lab so it can’t cause disease. • Because a live, attenuated vaccine is the closest thing to a natural infection, these vaccines are good “teachers” of the immune system: • They elicit strong cellular and antibody responses and often confer lifelong immunity with only one or two doses. Examples include yellow fever, measles, rubella, and mumps..

Disadvan tages • The remote possibility exists that an attenuated microbe in the vaccine could revert to a virulent form and cause disease. • Also, not everyone can safely receive live, attenuated vaccines. For their own protection, people who have damaged or weakened immune systems — because they have undergone chemotherapy or have HIV, for example— cannot be given live vaccines. Another limitation is that live, attenuated vaccines usually need to be refrigerated to stay potent. If the vaccine needs to be shipped overseas and stored by health care workers in developing countries that lack widespread refrigeration, a live vaccine may not be the best choice..

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3- Toxoid Vaccines Bacterial toxins are inactivated by treating them with formalin, a solution of formaldehyde and sterilized water. Such “ detoxified ” toxins, called toxoids , are safe for use in vaccin es. It is a vaccine made from a toxin (poison) that has been made harmless but that elicits an immune response against the toxin  These vaccines are used when a bacterial toxin is the main cause of illness.  When the immune system receives a vaccine containing a harmless toxoid , it learns how to fight off the natural toxin.  The immune system produces antibodies that block the toxin. Example : Vaccines against diphtheria and tetanus are examples of toxoid vaccin es..

4- Subunit Vaccines Instead of the entire microbe, subunit vaccines include only the antigens that best stimulate the immune system.  In some cases, these vaccines use epitopes — the very specific parts of the antigen that antibodies or T cells recognize and bind to. Advantages: Because subunit vaccines contain only the essential antigens and not all the other molecules that make up the microbe, the chances of adverse reactions to the vaccine are lower. They can safely be given to immunosuppressed people. Disadvantages: 1- I dentifying which antigens best stimulate the immune system is a tricky, time - consuming process. 2- Isolated protein does not stimulate the immune system as well as a whole organism vaccine. Example : Vaccine against HBV.

5- Conjugate Vaccines [outer polysaccharide + proteins] Consists of poor antigens (polysaccharides or oligosaccharides) that are chemically coupled to a protein carrier (PC)(Strong antigens). Coupling of the saccharides to protein converts polysaccharides to T-dependent antigens, which elicit robust immune responses in infants and adults. This technique for the creation of an effective immunogen is most often applied to bacterial polysaccharides for the prevention of invasive bacterial disease. Conjugate vaccines are a special type of subunit vaccine to get around this problem..

Conjugate Vaccines Polysaccharide coatings disguise a bacterium’s antigens so that the immature immune systems of infants and younger children can’t recognize or respond to them .  When making a conjugate vaccine, scientists link antigens or toxoids from a microbe that an infant’s immune system can recognize to the polysaccharides.  The linkage helps the immature immune system to react to polysaccharide coatings and defend against the disease - causing bacterium.  The vaccine that protects against Haemophilus influenzae type B ( Hib ) is a conjugate vaccine and other e.g are Pneumoccocal Vaccine and Meningococcal Vaccine.

6- Recombinant Vector Vaccines • Recombinant vector vaccines are experimental vaccines similar to DNA vaccines, but they use an attenuated virus or bacterium to introduce microbial DNA to cells of the body. • “Vector” refers to the virus or bacterium used as the carrier. • In nature, viruses bind to cells and inject their genetic material into th em. • In the lab, scientists take advantage of this process. The carrier viruses then transport that microbial DNA to cells. • Recombinant vector vaccines closely mimic a natural infection and therefore do a good job of stimulating the immune system. In effect, the harmless bacterium mimics a harmful microbe, provoking an immune response.  Researchers are working on both bacterial and viral - based recombinant vector vaccines for HIV, rabies, and measles ..

7- DNA Vaccines Introduce pieces of laboratory-made viral or bacterial DNA into the body. Unlike recombinant vector vaccines, DNA vaccines do not rely on a viral or bacterial vector. Instead, "naked" DNA is injected directly into the body. Cells take up this DNA and use it to produce proteins. The proteins trigger the body to produce immune response.

8- Peptide vaccines Based on identification of the peptide sequences that trigger a protective immune response and to use completely synthetic versions of these as the vaccine substance.  1) No risk of mutation or reversion, 2) little or no risk of contamination by pathogenic or toxic substances. 3)chemical manipulation of the peptide structure increases stability and decreases unwanted side effects seen in the native sequence..

Long road ahead There are more than 240 vaccine candidates worldwide in various stages of development as of Sept. 21, according to the Vaccine Centre at the London School of Hygiene and Tropical Medicine. Around 40 or so have advanced to clinical trials, a stage where the vaccines are tested on people – and where most vaccines wash out..

An ideal Vaccine should be ….. Good immune response Both Cell Mediated Immunity and antibody responses. Immunity is long lived Single dose Safety Danger of reversion to virulence, or Severe disease in immunocomprised Stability Organisms in the vaccine must remain viable in order to infect and replicate in the host Vaccine preparations are therefore very sensitive to adverse storage conditions Maintenance of the cold chain is very important. Expense Cheap to prepare.

Composition of vaccine formulations. Manufacturing residues: DNA or Nutrient medium comp. Adjuvant Buffering agent: e.g. Sodium borate. Toxin inactivator : e.g. Formalin. Protein stabilizer : e.g. BSA. Freeze drying stabilizer : e.g. Gelatin. Preservatives Thiomerosal Hg  Autism.

Definition It is an agent which, while not having any specific antigenic effect in itself, may stimulate the immune system, increasing the response to a vaccine . adjuvants help vaccines work better. WHY? Improve the immunogenicity of antigens/vaccine specially recombinant Proteins/peptides which lack most of the features of the original pathogen and often weak immunogens . Reduce the dose of antigen or the number of immunizations needed for protective immunity. Improve the efficacy of vaccines in newborns, the elderly or immuno-compromised persons. As Antigen delivery systems for the uptake of antigens by the mucosa. However Adjuvanted vaccines can cause more local reactions (such as redness, swelling, and pain at the injection site) and more systemic reactions (such as fever, chills and body aches) than non-adjuvanted vaccines.

Adjuvants have been used safely in vaccines for decades. for more than 70 years. Aluminum salts were initially used in the 1930s, 1940s, and 1950s with diphtheria and tetanus vaccines after it was found they strengthened the body’s immune response to these vaccines. Newer adjuvants have been developed to target specific components of the body’s immune response, so that protection against disease is stronger and lasts longer. In all cases, vaccines containing adjuvants are tested for safety and effectiveness in clinical trials before they are licensed for use in the United States, and they are continuously monitored by CDC and FDA once they are approved..

First way an adjuvant can work to activate various cells involved in the immune response , either directly or indirectly. A second way an adjuvant may aid the immune response is by forming a depot of Ag at the injection site resulting in the sustained release of small quantities of Ag over a long period of time. A third way an adjuvant can work is to serve as a vehicle to help in delivering the Ag to the spleen and/or lymph nodes where Ag is trapped by the follicular dendritic cells where necessary cell to cell interactions take place to generate plasma cells ( Ab-secreting cells )..

Adjuvant industry is to maintain a balance between:.

Toxicity Stability Bioavailability Cost Production difficulty Pre-existing immunity to adjuvant.

1) Local Reactions: local injection site Pain, inflammation, swelling , and necrosis, lymphadenopathy, granulomas, Ulcers and the generation of sterile abscesses. 2) Systemic reactions: induction of Acquired immunodeficiency, immunosuppression, eosinophilia, allergy, anaphylaxis, Nausea, fever, adjuvant arthritis , organ specific toxicity and immuno-toxicity..

According to their mechanism of action Active immunostimulants : substances that increase the immune response to the antigen; 2) Vehicle adjuvants; being oil emulsions or liposomes that serve as a matrix for antigens as well as stimulating the immune response. 3) Carriers, being immunogenic proteins According to the route of administration: Mucosal Parenteral According to physicochemical properties:.

Cell wall peptidoglycan of Gram + ve or lipopolysaccharide of Gram - ve bacteria enhance the immune response against co-administered antigens despite themselves not being very immunogenic. LPS (lipopolysaccharides) enhance cellular and humoral immune responses Prepared at low acidic condition….. Why?! The major structural element responsible for their toxicity and adjuvant effect is Lipid A . In low acid conditions, Lipid A can be hydrolyzed to obtain Monophosphoryl lipid A , a compound which retains the adjuvant activity of Lipid A with reduced toxicity.

Nanocrystal of inulin (plant derived polysaccharide, linear chain of fructose capped with glucose ) Gamma inulin is effective at boosting cellular immune responses without the toxicity exhibited by other adjuvants such as FCA (Freund's Complete Adjuvant) Algammulin is a combination of gamma-inulin and aluminium hydroxide. It exhibits a higher ratio of antibody response to cell mediated activity than -inulin alone. Glucans, Dextrans , Glucomannans , Galactomannans and xylans Macrophages have glucan and mannan receptors. Their activation stimulates phagocytosis and cytokine secretion plus release of leukotrienes and prostaglandins..

Tensoactive adjuvants. Saponins They are tenso -active glycosides. Eg : QS-21 (Quill A derived Saponin) They integrate into cell through interaction with membrane of macrophages, forming pores through which antigens enter macrophages , stimulating a strong lymphocytes response. Limitations: Severe injection site pain, granulomas and toxicity includes severe hemolysis are major limiting factor in QS-21 use. ( Kept for veterinary vaccines and severe fatal diseases like HIV infection ).

4- ISCOMs (Immuno-stimulating complexes) A mixture of different adjuvants in the same formulation . Two or more adjuvants with different mechanisms of action are combined to enhance the potency and type of the immune response to the vaccine antigen. ISCOMS are virus like particles of 30–40 nm , composed by Quil A, lipids and cholesterol. Antigens can be inserted in the membrane or encapsulated. ISCOMS are particularly effective in activating cellular immunity and cytotoxic T cells.

5- Oil-in-Water emulsion The mechanism of action of adjuvant emulsions includes the formation of a depot at the injection site, enabling the slow release of antigen and the stimulation of antibody producing plasma cells They are irritants, local inflammation, granulomas and ulcers at the injection site A) Freund’s complete Adjuvant (initial immunization) Non specific immune potentiation Non metabolized oil such as mineral oil + surfactant + mycobacterium. B) Freund’s incomplete Adjuvant (Booster) (Without mycobacterium).

LIMITATIONS : 1) Severe local and systemic side-effects including sterile abscesses and eosinophilia. 2) Granulomas when the SC or ID route is used rather than IM injection . 3) Local injection site Pain, inflammation, lymphadenopathy . 5) Bone and Neurotoxicity ..

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mRNA vaccine. mRNA vaccine A mRNA vaccine is made using mRNA that gives your cells instructions for how to make the spike protein found on the surface of the COVID-19 virus. After vaccination, your immune cells begin making the spike protein and displaying them on cell surfaces. This causes your body to create antibodies that can fight the COVID-19 virus..

Viral vector vaccine. Viral vector vaccine A viral vector vaccine is made when genetic material from a COVID-19 virus is inserted into a unrelated, harmless virus. When the viral vector gets into your cells, it delivers genetic material from the COVID-19 virus that gives your cells instructions for how to make the spike protein found on the surface of the COVID-19 virus. Once your cells displace the spike proteins on their surfaces, your immune system creates antibodies that can fight the COVID-19 virus..

Protein subunit vaccine.

Types of SARS-CoV-2 vaccines for COVID-19 Genetic vaccines (nucleic acid vaccines) irimuriolog$ www.immunology.org DNA antibodies immune cells RNA Contain a segment of SARS-CoV-2 virus genetic material that codes for a specific protein. Can be DNA or RNA. Our cells use the genetic material to make the SARS-CoV-2 protein, which is recognised by the immune system to trigger a response. This response builds immune memory, so your body can fight off SARS-CoV-2 in future. Considerations Low cost and fast to develop. May need to be stored at specific low temperatures. Approved in the UK for COVID-19 Pfizer/BioNTech & Moderna In clinical trials for COVID-19 CureVac, Inovio Pharmaceuticals.

Types of SARS-CoV-2 vaccines for COVID-19 Inactivated vaccines immunolog$ www.immunology.org immune Contain killed SARS-CoV-2 virus. c The killed virus is recognised by the immune system to trigger a response without causing illness. This response builds immune memory, so your body can fight off SARS-CoV-2 in future. antibodies Considerations May need to be administered with an adjuvant to boost immune response. Examples in human use for other disease Influenza vaccine Approved elsewhere in the world for COVID-19 Sinovac, Sinopharm, Bharat Biotech In clinical trials for COVID-19 Shifa-Pharmed, Chinese Academy of Medical Sciences.

Types of SARS-CoV-2 vaccines for COVID-19 Attenuated vaccines inhnhÜriolog$ www.immunology.org immune cells Contain weakened SARS-CoV-2 virus. The weakened virus is recognised by the immune system to trigger a response without causing illness. This response builds immune memory, so your body can fight off SARS-CoV-2 in future. antibodies Considerations A well-known approach which requires time and extensive testing. The immune response resembles the natural infection. Examples in human use for other disease Oral Polio vaccine In clinical trials for COVID-19 Codagenix.

Types of SARS-CoV-2 vaccines for COVID-19 Viral vector vaccines irrimÜholog$ www.immunology.org antibodies Use an unrelated harmless virus, modified to deliver SARS-CoV-2 genetic material. The delivery virus is known as a viral vector. Our cells use the genetic material to make a specific SARS-CoV-2 protein, which is recognised by the immune system to trigger a response. This response builds immune memory, so your body can fight off SARS-CoV-2 in future. immune cells Considerations Generate strong immune response. May need to be stored at specific low temperatures. Examples in human use for other diseases Ebola vaccine Approved in the UK for COVID-19 AstraZeneca/Oxford Approved elsewhere in the world for COVID-19 Jannsen, CanSino, Gamaleya.