MSOP1004 Vaccines L1 2024 PDF

An apparatus (4-5 cm length, with nine short needles) used for BCG vaccination in Japan. Shown with ampules of BCG and saline. Vaccination & antiviral drugs MSOP-1004  Lecture 1 contents Introduction to history of vaccination ‘Live’ and ‘Dead’ vaccines Types of immunity Exam...

An apparatus (4-5 cm length, with nine short needles) used for BCG vaccination in Japan. Shown with ampules of BCG and saline. Vaccination & antiviral drugs MSOP-1004  Lecture 1 contents Introduction to history of vaccination ‘Live’ and ‘Dead’ vaccines Types of immunity Examples of viral vaccines & disease eradication  Introduction to Vaccination In the treatment of disease ‘prevention is better than cure’ This is certainly true for infectious diseases, particularly where no effective drug against the infectious agent is available Prophylaxis is ‘a strategy designed to preserve health and prevent the spread of disease’ Prophylactic strategies include improvements in nutrition, sanitation, personal hygiene & public health A major approach to disease control is vaccination (administration of a vaccine)  Introduction to Vaccination A vaccine is a ‘preparation designed to elicit immunity to a disease’ (i.e. resistance to contracting a disease) A vaccine can be prophylactic (prevent a future infection) or therapeutic (e.g. against an existing cancer, rabies) Majority of vaccines are prophylactic, and aim to cause less disease than natural infection  History of Vaccination In Ancient Greece it was noticed that individuals who had survived smallpox (an often fatal virus infection), did not contract the disease again Over a thousand years ago, Chinese doctors developed the process of variolation, whereby healthy people were exposed to ‘matter’ from smallpox lesions (often dried scabs inserted into nose) This notably reduced risk of contracting virulent disease (mortality rate amongst affected dropped from ~30% to 1%)  History of Vaccination Variolation reached Turkey by 1700. In 1718, the wife of the British ambassador Lady Mary Wortley Montagu had her young son inoculated On return to England, she raised enough Mary Wortley Montagu, by Charles Jervas, after 1716. interest to initiate a trial Prisoners on death row were included in exchange for freedom. They all survived!  Jenner & Vaccination In 1790s, an English country doctor, Edward Jenner, noted that milkmaids usually didn’t contract smallpox and thus has clear complexions not ‘pocks’. Cows frequently contracted the mild ‘cow pox’. He postulated that pus from lesions on cow skin was conferring resistance to smallpox. In 1796 he inoculated a boy using the fluid from a cowpox blister on the hand of a milkmaid. He later ‘challenged’ the boy by inoculating his arms with ‘variolous material’ from smallpox sufferer. The boy developed a mild fever but no disease  Jenner & Vaccination Afterrepeating procedure with more subjects, Jenner’s findings published by Royal Society (1798). In 1840, smallpox ‘vaccination’ introduced (vacca Latin for cow) for free In 1853, smallpox vaccination was made compulsory in the UK Vaccination Act Jenner’s 1798 publication  Smallpox (from PHAM1054) Smallpox is caused by a poxvirus (Family Poxviridae; Genus Orthopoxvirus; Species Variola – DNA genome) Host range; human (though poxviruses infect range of vertebrates) Portal entry; inhalation/ingestion through direct contact with body fluids (saliva, pus), sometimes via skin lesions Target cells; skin epithelium and mouth mucosa, also virus in blood (viremia) Symptoms; ~12 days postinfection ‘flu-like, intestinal problems, vomiting Pathology; Pimples appear, becoming larger ’macules’ and spread over body. More macules, more fatalities through fluid loss, opportunistic infections etc. Fatality rate up to 40%. Survivors scarred with‘pockmarks’. Some individuals exhibit haemorrhagic smallpox - skin, eyes, organs - v. high mortality  Smallpox Vaccination Smallpox killed 300-500 million in 20th century! World Health Organisation instigated eradication program in 1967 - unparalleled worldwide effort The vaccine used was from a related orthopoxvirus, vaccinia virus (not coxpox virus). Vaccinia was isolated from the skin of infected animals and ‘freeze-dried’ (for transport and storage). Vaccine given by lightly piercing skin with a bifurcated needle. Vaccine protection ~ 10 years day-4-21  Smallpox Eradication The WHO strategy was focussed on countries where disease was endemic. Involved surveillance and containment by ‘Ring Vaccination’ of susceptible people in vicinity of outbreaks Strategy dramatically reduced # cases. After final few outbreaks, last natural case in Somalia in 1977 - first human disease to be eradicated!  Preparation of Smallpox Vaccine Courtesy of the WHO WHO Declared smallpox eradicated 8th May 1980  Live & Dead Vaccines Smallpox was treated with a ‘Live vaccine’. Vaccinia virus is a related, non-pathogenic virus. However, most live vaccines are derived from organisms that have had their virulence (ability to produce severe disease) artificially reduced, or ‘attenuated’ ‘Dead vaccines’ can be derived from inactivated (e.g. formalin) pathogenic organisms or from subcellular components (e.g. surface proteins). Dead vaccines less common than live – used primarily where no safe live vaccine available.  Live & Dead Vaccines Vaccination is the ‘artificial induction of immunity’ or ‘immunisation’ with an ‘immunogen’. This ‘primes’ the immune system by eliciting ‘immune sensitisation’ and ‘memory’ in B-cell (antibodies) and T-cells (cell mediated). Short-term protection (e.g. tourists) may result from temporary increase in specific antibodies, whereas induction of memory is needed to combat much later exposure to the immunogen (i.e. pathogenic organism) via recognition and full immune response  Vaccines/Boosters Many vaccines are given to children, as their immune response is not fully developed and benefit from artificial stimulus before they become exposed to serious pathogens Often vaccines given several times to develop maximum immunity. These ‘boosters’ given in quick succession (e.g. Hepatitis B) or at regular intervals of a few years. Either to maximise immunity or for pathogens where immunity drops off with time (e.g. tetanus)  Vaccines/Boosters Contact with natural infection can also act as a booster The aim of vaccines can range from individual protection, to blocking of transmission, to eradication Vaccines must be effective, safe, stable and low-cost (and cause less disease than the infections they are used against!) Looking at these aspects for the smallpox vaccine…  Smallpox Vaccine Smallpox vaccine was very effective – worldwide eradication. As there were no asymptomatic ‘carriers’, outbreaks could be quickly identified and vaccination implemented The vaccinia virus vaccine used against smallpox was safe, usually producing a very mild infection; either asymptomatic or slight rash and/or fever. In patients with certain dermatological conditions (e.g. eczema) or in the immunocompromised, rash can become more widespread (1: 1000). Fatalities >1: 1M  Smallpox Vaccine Vaccine was stable as it was freeze-dried (lyophilised), enabling transport and storage even in hot countries Cost of mass vaccine production was a few pence Remaining cost in transport, storage, training and administration by staff, education, advertising etc  Immunity Active immunity is derived from exposure of the immune system to immunogens (antigens that lead to immunity), either natural or artificial (i.e. vaccines) Passive immunity can be similarly derived. IgG antibodies can cross the placenta from mother to foetus. Secreted antibodies (IgG, IgA, IgM) can by derived from breast milk  Immunity Passive immunity also from transfused human sera either prophalactically or in response to infection (e.g. rabies) – in both cases infections have to be antibody susceptible, not primarily sensitive to cell-mediated immunity Active immunity Passive immunity T cell B cell Naturally acquired Naturally acquired Artificially acquiredArtificially acquired  Immunity Some pathogens have both active and passive immunity vaccines Rabies vaccines are given to tourists to endemic countries If bitten by rabid animals a passive immunoglobulin vaccine is given as 100% fatal  Immunity ‘Herd Immunity’ is the principle of vaccination whereby enough members of a population are immunised (e.g. 90%), and thus the number of susceptible individuals is so low, that spread of a disease is slowed down, and eventually stops Conversely, if vaccine uptake becomes reduced in a population (e.g. recent MMR vaccine ‘scare’) the disease risk increases markedly in susceptible individuals  Immunity ‘Contact Immunity’ is where an individual receives a live (often attenuated) vaccine and causes the usually unintentional infection of another (nonimmune) person, leading to immunity in both. A prominent example of this is the live oral poliovirus vaccine, where virus is given to children and later excreted in faeces – source of infection for nonimmune parents  Polio (PHAM1054) Poliomyelitis (polio) is a human disease caused by poliovirus (Family Picornoviridae; Genus Enterovirus; RNA) Polio has been known since prehistory – depicted On Egyptian paintings/carvings. Detailed medical descriptions appeared in 18th/19th centuries, including the first polio epidemic Symptoms; In ‘immune competent’ individuals (95% cases) polio infection often subclinical or ‘abortive polio’ producing mild fever and intestinal problems. May get headache and temporary meningitis. However, in ‘immune suppressed’ (e.g. children have immature immune system) can lead to paralysis or even death Portal entry; oral via faeces-contaminated water or food – (‘faecal-oral transmission’). Poliovirus resistant to stomach acid. Target cells; primarily infects epithelium of pharynx and gut. Can cross into lymphatic system, blood cells and finally neurons  190px-Polio_sequelle Poliomyelitis Pathology; in the paralytic disease, the poliovirus infects the ventral (front) grey matter of spinal cord /CNS, which controls numerous motor functions (e.g. limbs, ribcage/diaphragm). Infection causes destruction and inflammation of motor neuron ganglia. This effects the neuronal axons which control muscle movement, leading to paralysis (often asymmetric) Virus release (‘egress’) from infected cells following replication produces the ‘cytopathic effect’. As neurons do not regenerate, if the number destroyed is large, affected limbs often atrophy If damage is not too extensive, paralysis often temporary with surviving neurons ‘re-innervating’ the This iron lung was donated to the CDC by the family of Mr. Barton Hebert of Covington, Louisiana, who’d used the device from the late 1950s until his death in 2003. paralysed muscle If paralysis effects breathing, patients can be placed in a negative pressure ventilator or ‘iron lung’  Major illness Occurs in less than 1% of all poliovirus infections Flaccid paralysis— weakness Inflammation and sometimes destruction of neurons Recovery can take up Adapted from Werner, J. Disabled Village Children: A Guide for Community Health Workers, to two years and may Rehabilitation Workers, and Families, Second Edition. The Hesperian Foundation, 1999. be incomplete.  Grey matter in spinal cord cell body ganglion axon Normal motor unit Reinnervation Pathology in acute polio  Treatment of polio No currently available drug treatments for enteroviral (including poliovirus) infections. The drug Pleconaril has been through Phase II clinical trial – interferes with virus capsid protein, inhibiting uncoating 1st effective vaccine developed in the USA by Jonas Salk in 1952. The Salk ‘inactivated’ or ‘dead’ polio vaccine was produced by formalin- inactivating all 3 poliovirus serotypes (different surface antigens). Vaccine licensed in 1955 and mass immunisation campaign lead to huge drop in number of cases  ‘Inactive’ Polio vaccine However, there were some cases of polio (and a few deaths) after vaccination, due to incomplete virus inactivation. Problem now solved – 70-90% protection. Two intramuscular administrations, one month apart, then ‘boosters’ every 5 years. Increases numbers of lymphocytes stimulated. Can be used in immune compromised individuals  Salk’s Inactivated Vaccine (IPV) Licensed in 1955 by the FDA 70% effective in preventing poliovirus infection  ‘Live’ Polio Vaccine To overcome problems with Salk vaccine, a ‘live’ vaccine was developed by Albert Sabin in 1957. Contained of non-virulent, attenuated poliovirus serotypes (one in each vaccine) Attenuation achieved by serial passage in non- human cell culture – enriches ‘weaker’ mutated viruses By 1963 tri-valent (all 3 serotypes) Sabin vaccine produced  ‘Live’ Oral Polio Vaccine Oral administration several times in infancy (>1 month apart to allow previous infection to subside). Lifelong immunity. Not used in immune compromised. Salk was used in USA. Sabin was used in some other countries However, there was a problem with ‘reversion to virulence’ of mainly types 2 & 3 poliovirus (1 in a million) passing through gut – some attenuated strains have single base change. Non-immunised individuals advised not to be exposed to recently inoculated A child receives oral Polio vaccine. children  Attenuation of virulence An example of how a virulent pathogen can be attenuated to produce a vaccine strain (e.g. polio)  Treatment of polio Both vaccines stimulate ‘neutralising’ antibody (IgG, IgM) production IPV – inactivated polio vaccine Last case of polio in Americas in 1991 OPV – oral polio vaccine Last case in Europe in 2002 Polio still endemic in Nigeria, India, Pakistan, Afghanistan Polio is one of few diseases Where both live and dead vaccines compete for use In UK new inactivated combination vaccine (next lecture) World Health Assembly adopted resolution to eradicate declared polio worldwide Initiative involves WHO, governments, Bill Gates Foundation..  Militants preventing polio vaccination in Pakistan Armed militants are killing health workers in Pakistan, tasked with protecting children against polio, because of suspicion over western made vaccines. The World Health Organisation says that it is vital that young children are vaccinated as concern grows over a possible resurgence of the disease. 19th December 2013 Potential ‘solution’ on polio vaccination being tested 16 September 2014 th An innovative vaccine delivery method called the Nanopatch is being evaluated by the World Health Organisation in the hope it can be used to help eradicate polio. The Nanopatch, which contains thousands of tiny pins and avoids the need for cold storage or to be administered by medical professionals, could offer a means to get the vaccine to more remote areas of the world. Oliver Rosenbauer, spokesperson for the Polio Eradication Initiative at the WHO, explained to Today programme presenter John Humphrys that "any vaccine is only as good as the number of children it reaches... Traditionally vaccines are given with needles via injections and to reach remote populations can be very difficult.  Polio eradication programme reaches 'major milestone' A "major milestone" in the battle to eliminate polio globally has been reached, the US Centres for Disease Control (CDC) has said Its experts think a second of the three forms of poliovirus has been eliminated after mass vaccination campaigns. Wild poliovirus type 3 has not been detected for more than two years. Type 2 was eradicated in 1999. Experts said the world was "closer than ever" to defeating polio but the situation in Pakistan was worrying. Polio is highly infectious and causes paralysis in up to one in 200 people. Some children die when the muscles that help them breathe stop working. But there has been huge progress in eliminating the disease. Cases have fallen from 350,000 in 1988 to 416 in 2013. The last case of type 3 poliovirus was detected in Pakistan in November 2012, according to the CDC report. 15th November 2014  Milestone in polio eradication acheived The second of three forms of the polio virus has been eradicated, experts have announced. There are three types of the wild polio virus, which, while scientifically different, cause the same symptoms, including paralysis or even death, The world was declared free of type 2 four years ago - and now the World Health Organization has said type 3 has also been eradicated. But type 1 is still circulating in Afghanistan and Pakistan. Polio usually affects children under five. The WHO estimates one in 200 cases leads to irreversible paralysis. Death can occur when breathing muscles are affected by the paralysis. There is no cure but the polio vaccine protects children for life. Cases of wild polio have fallen by 99% since 1988. The declaration type 2 had been wiped out was made in 2015, a full 16 years after the last case was seen in India. 24th November 2019  Poliovirus found in London sewage samples 22 June 2022 nd The virus that causes polio has been detected in a concerning number of sewage samples in London, health officials have said. The disease was common in the UK in the 1950s but was eliminated by 2003. The UK Health Security Agency (UKHSA) says it was probably imported to London by someone who was recently vaccinated overseas with a live form of the virus. Scientists believe the virus originated from someone who was immunised abroad with the live oral polio vaccine, which hasn't been used in the UK since 2004. That person then shed traces of the virus from their gut which were detected by the sewage sampling. In rare cases, that form of the virus can then be transmitted to others and mutate into what is known as "vaccine-derived" polio. Although weaker than the original or "wild" form of the disease, it can still cause serious illness, including paralysis, in people who are unvaccinated. It says the risk is low, but parents should ensure their children have been fully immunised against the disease. "Most of the UK population will be protected from vaccination in childhood, but in some communities with low vaccine coverage, individuals may remain at risk," said Dr Vanessa Saliba, consultant epidemiologist at UKHSA. An inactivated polio vaccine is used in the UK as part of the routine childhood programme. It is given to children three times before the age of one, and then again at three and 14 years of age. Take-up of the first three doses is about 86% in London, well below target levels, with the rest of the UK over 92%.  Poliovirus antivirals There are no commonly used poliovirus antiviral agents, however there are several in development, clinical trials and limited ‘field’ usage The most advanced is V-073 (pocapivir), which inhibits capsid uncoating This antiviral has been employed in the global eradication campaign in particular countries/incidences Also for ‘compassionate use’ in immune deficient vaccinated individuals – can be susceptible to poliomyelitis and also be virus excreters Another antiviral is V-7404 – a virus-specific protease inhibitor, which is in clinical trials Aim to use both drugs simultaneously to reduce development of resistance  Literature & Websites Course textbooks: Korsman ‘Virology: an illustrated colour text’ Also Schors ‘Understanding Viruses’ Denyer et al ‘Pharmaceutical Microbiology’ Greenwood ‘Antimicrobial Chemotherapy’ Mims et al ‘Medical Microbiology’ BNF! Moodle weblinks: World Health Organisation immunization The Big Picture Book of Viruses: http://www.virology.net/Big_Virology