Vaccine_Lec1_SP_EUC_2023-2024_REVISION.pptx

Vaccines: Reshaping Global Health Vaccine Technologies MED320 Dr Stavros Panagiotou Vaccine Immunity • Once a vaccine is injected, dendritic cells (DCs) and macrophages will take up the components of the vaccine, with the help of their pattern recognition receptors (PRRs) • PRRs will recognise th...

Vaccines: Reshaping Global Health Vaccine Technologies MED320 Dr Stavros Panagiotou Vaccine Immunity • Once a vaccine is injected, dendritic cells (DCs) and macrophages will take up the components of the vaccine, with the help of their pattern recognition receptors (PRRs) • PRRs will recognise the pathogen-associated molecular patterns (PAMPs) • After that, Antigen-presenting cells (APCs) will get activated and start to move towards lymph nodes in near areas • The antigen processed by the APCs will be presented to lymphocytes, where antigen will get recognised and proper stimulatory signals will get received in order to become activated • Thereafter, antigen-specific B and T-lymphocytes will clonally expand to generate antibodies which recognise the same antigen • Long-term protection against the pathogen will be provided when memory B and T cells will be formed. Figure adopted from: (Crommelin et al., 2013, Elder, 2020). Can vaccines make a difference? Table 1: Comparison of morbidity and mortality of vaccine-preventable diseases before and after introduction of vaccines in the US Vaccine-preventable disease Prevaccine estimated annual morbidities* Postvaccine estimated annual morbidities ** Reduced morbidities postvaccine (%) Smallpox 29,005 0 100 Diphtheria 21,053 0 100 Measles 530,217 69 >99 Mumps 162,344 5,311 97 Pertussis 200,752 15,737 92 Polio 16,316 0 100 Rubella 47,745 5 >99 Tetanus 580 33 94 Haemophilus influenza 20,000 22 (Type B) < 5 years old >99 *Prevaccine estimated annual morbidities of 20th century. ** Postvaccine estimated morbidities of 2016. 2-3 million lives are saved every year because of vaccines! An example highlighting the importance of vaccines Ebola Virus Outbreak • Ebola virus disease (EVD) causes haemorrhagic fever with extremely high case-fatality rates, which can reach up to 90% • The world’s largest Ebola outbreak was in West Africa in 2013-2016, while the world’s second largest Ebola outbreak was in the Democratic Republic of the Congo (DRC) in 2018-2020 • As a response to 2018-2020’s Ebola outbreak, the DRC’s ministry of health, with the support of WHO and more than 50 partners, had enhanced surveillance in place, systematically screened millions of travellers, and rapidly rolled out a recombinant vesicular stomatitis virus (rVSV-ZEBOV-GP) vaccine • The rVSV-ZEBOV-GP vaccine was designed to effectively work in postexposure situations in a ring strategy to recognise contacts and contacts of contacts. • Although this vaccine was yet to be licensed, a conditional marketing authorisation was provided to distribute the vaccine to control the number of Ebola cases Ebola Virus Outbreak: Outcome post vaccinations? 2013-2016 Ebola outbreak Cases: 28,646 Deaths: 11,323 20182020* Ebola outbreak Cases: 3,481 Deaths: 2,299 Up to ~98% effective in stopping Ebola virus transmission! Vaccine Technologies Live attenuated vaccines • Live, attenuated vaccines contain a version of the living pathogenic microbe that has been attenuated or weakened in the lab so that it has lost its significant pathogenicity • This is accomplished by serial passages through a foreign host (tissue culture, embryonated eggs, or live animals for multiple generations) • This extended passaging introduces one or more mutations into the new host. The mutated pathogen is significantly different from the original pathogenic form, so it can’t cause disease in the original host but can effectively induce the immune response • Live, attenuated virus vaccines are prepared from attenuated strains that are almost or completely devoid of pathogenicity but can induce a protective immune response. Live attenuated vaccines Advantages of live, attenuated vaccines • Since a live, attenuated vaccine is the closest thing to a natural infection, these vaccines are good “teachers” of the immune system • The attenuated vaccines elicit strong immunoprotective cellular and antibody responses, and often confer lifelong immunity with only one or two doses Disadvantages of Live, Attenuated Vaccines • Secondary mutations can lead to reversion to virulence and can thus cause disease • Interference by related viruses (as is suspected in the case of oral polio vaccine in developing countries) • Immune-compromised, damaged, or weakened immune systems (due to chemotherapy, HIV infection, or even pregnancy) cannot be given live vaccines • They need the cold chain to stay potent, and skilled health care workers to handle them Inactivated/Inert/Killed (antigen) • Heat, chemicals (such as formaldehyde or β-propiolactane), or radiation are typically used to inactivate antigens • Chemical treatment destroys a pathogen’s ability to replicate but keeps the immunogenic structure intact in its natural form • It is crucial to ensure the integrity of the structure of antigenic epitopes of surface antigens • Inactivated, whole-pathogen vaccines provide protection by directly generating TH and humoral immune response against the pathogenic immunogen Inactivated/Inert/Killed (antigen) Advantages of Inactivated Whole Virus Vaccines • 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 freezedried form, which makes them cheap and easily accessible to people in developing countries Disadvantages of Inactivated Whole Virus Vaccines • Most inactivated vaccines stimulate a weaker immune response than do live vaccines, so it likely requires multiple booster doses to maintain a protective immunity level • A drawback in areas where people don’t have regular access to health care and can’t get booster shots on time • Excessive treatment can destroy immunogenicity, whereas insufficient treatment can leave infectious virus capable of causing disease • In addition, there is an increased risk of allergic reactions due to the presence of large amounts of unrelated structural antigens of microbes Toxoid vaccines • Toxoid vaccines (such as the diphtheria and tetanus vaccines) are made by purifying the bacterial exotoxin • Toxicity of purified exotoxins is then suppressed or inactivated either by heat or with formaldehyde (while maintaining immunogenicity) to form toxoids • Vaccination with toxoids induces anti-toxoid antibodies that can bind with the toxin and neutralize its deleterious effects • It is extremely important to achieve detoxification/inactivation without excessive modification of the antigenic epitope structure Subunit Vaccines (selected antigens) • Identification of an immunoprotective antigen and its antigenic epitopes (up to 20 different antigens) • The microbe can be grown in the laboratory, and the important antigens can then be purified and used as subunit vaccines • The antigen molecules can be manufactured from the microbe using recombinant DNA technology Subunit Vaccines (Conjugate vaccines) • If a bacterium possesses an outer coating of sugar molecules called polysaccharides, as many harmful bacteria do, researchers can try developing a conjugate vaccine for it • Polysaccharide coatings disguise bacterial antigens so that the immature immune systems of infants and younger children can’t recognize or respond to them • Therefore, conjugate vaccines have been developed by attaching the polysaccharide to a stronger protein • When the immature immune system responds to the linked protein, it also responds to the polysaccharide and defends against the disease-causing bacterium. Next generation technologies Reverse vaccinology • Adjacent to other technologies • Sequencing of the genome of a pathogen, to specifically select a virulence factor, proven to be responsible for causing disease • Once this target is selected, it can then be progressed under different vaccine technologies Nucleic acid vaccines • Can be in the form of either DNA, or mRNA • Easy and quick to make • Less expensive to make compared to the traditional vaccines DNA vaccines • DNA vaccination is a relatively recent development in vaccine technology • It involves the direct introduction of a plasmid into the appropriate tissue containing the complete expression cassette independently encoding the antigens against which the immune response is • DNA immunization is a novel technique used to efficiently stimulate humoral and cellular immune responses to protein antigens • DNA vaccines usually consist of plasmid vectors (derived from bacteria) that contain heterologous genes (transgenes) inserted under the control of a eukaryotic promoter, thus allowing protein expression in mammalian cells DNA vaccines Mechanism of action 1) Injection of DNA vaccine 2) Transfer of DNA sequence to cells (either naked or through a vector) 3) Transfection of cells exposing viral epitopes on the cell’s surface 4) Recognition by T-cells → B-cells → Antibodies RNA Vaccines Non-replicating mRNA (NRM) Self-amplifying mRNA (SAM) DNA vs RNA vaccine • DNA vaccines need to transcribe its sequence to an mRNA sequence in the nuclei first. It will then initiate the process to express the viral antigen • An RNA vaccines “skip” the transcription process and begin antigen expression immediately • DNA is a much more stable nucleic acid, whereas RNA sequences require super cooling conditions to remain stable Nucleic Acid Vaccines Advantages of DNA/mRNA Vaccines • It can induce the expression of antigens that resemble native viral epitopes more closely than standard vaccines do since live attenuated and killed vaccines are often altered in their protein structure and antigenicity • Sequences can be produced quickly, and the coding sequence can be manipulated in many ways • DNA/mRNA vaccines encoding several antigens or proteins can be delivered to the host in a single dose • Rapid, large-scale production is available at costs considerably lower than traditional vaccines • DNA/mRNA vaccinations may provide an important tool for stimulating an immune response in HBV, HCV, and HIV patients Disadvantages of DNA/mRNA Vaccines • Although DNA/mRNA can be used to raise immune responses against pathogenic proteins, certain microbes have outer capsids made up of polysaccharides. This limits the extent of the usage of DNA vaccines because they cannot be the substitute for polysaccharide-based subunit vaccines