Prof RN Basu • What is a Vaccine? • Vaccines are protective treatments that prevent disease by training the body’s immune system to recognise and respond to infectious pathogens such as bacteria, viruses and parasites to stop you getting sick. • This protection can be short-lived or life-long, depending on the type of vaccine and the disease. • Some vaccines contain weakened (attenuated) or inactivated versions of infectious agents, particularly viruses. • Others contain molecules that mimic specific components of pathogens or toxins produced by bacterial infections.
2 3 Name Vaccine Type Primary developer Country of origin Authorisation/Appr oval BNT162b2 mRNA based vaccine Pfizer, BioNTech;Fosun Multinational UK, Bahrain, Pharma Canada, Mexico, US
CoronaVac Inactivated vaccine (formalin Sinovac China China with alum adjuvant) Sputnik V Non-replicating viral vector Gamaleya Research Russia Russia Institute, Acellna Contract Drug Research and development BBIBP-CorV Inactivated Vaccine BeijingInstitute China China ofBiologicalProducts;Chi na National Phtil
4 Name Vaccine Type Primary developer Country of origin Authorisation/Appr oval No Name Inactivated vaccine Wuhan Institute of China China announced Biological Products; China National Pharmaceutical Group (Sinopharm) EpiVac Corona Peptide vaccine Federal Budgetary Russia Russia Research Institution State Research Centre of Virology and Biotechnology
5 Candidate Mechanism Sponsor Trial Phase Institution V591 Measles vector vaccine University of Pittsburgh’s Phase I University Centre for Vaccine ofPittsburgh;Themis Research Biosciences;Institut Pasteur VXA-CoV2-1 Recombinant vaccine Vaxart Phase 1 Vaxart (adenovirus type 5 vector AAVCOVID Gene-based vaccine Massachusetts Eye and Preclinical Ear; Massachusetts General Hospital;University of Pennsylvania AdCOVID Intranasal vaccine Altimmune preclinical University of Alabama at Birmingham 6 Candidate Mechanism Sponsor Trial Phase Institution ChAd—SARS- Adenovirus-based vaccine Washington University Pre-clinical WashingtonUniversi CoV-2-5 School of Medicine in ty Schoolof St.Louse Medicine in St.LouisHalo HaloVax Self-assembling vaccine VoltronTherapeutics,Inc.; Pre-clinical MGH Vaccine HothTherapeutics,Inc. andImmunotherapy Center HDT-301 RNA vaccine University Pre-clinical ofWashington;NationalIn stitutes ofHealth RockyMountainLaborator ies;HDT Bio Corp LinealDNA DNA Vaccine Takis Biotech Pre-clinical Pre-clinical
7 Candidate Mechanism Sponsor Trial Phase Institution HDT-301 RNA vaccine University Pre-clinical ofWashington;NationalIn stitutes ofHealth RockyMountainLaborator ies;HDT Bio Corp MRT5500 Recombinant Sanofi, Translate Bio Pre-clinical vaccine No name lii-Key Generex Biotechnology Generex announce peptideCOVID- d 19vaccine
8 Name Vaccine Type Primary developer Country of origin Authorisation/Appr oval BNT162b2 mRNA based vaccine Pfizer, BioNTech;Fosun Multinational UK, Bahrain, Pharma Canada, Mexico, US
CoronaVac Inactivated vaccine (formalin Sinovac China China with alum adjuvant) Sputnik V Non-replicating viral vector Gamaleya Research Russia Russia Institute, Acellna Contract Drug Research and development BBIBP-CorV Inactivated Vaccine BeijingInstitute China China ofBiologicalProducts;Chi na National Phtil
9 10 • Man always wanted to protect themselves from the scourge of disease • In this quest man was looking for the means to prevent disease • Thus concept of vaccine was born • King Mithridates (132 to 63 BC) VI of Pontus (Black Sea Region) immunised himself against fungal toxin by administering small non- toxin amounts • He wanted to protect himself from assassination attempts by poisoned food • He is considered as the first individual who applied the principle of immunology1
11 • In 1721, Dr Zabdiel Boylston variolated 240 people in Boston under persuasion by an evangelist minister, Cotton Mather2 • All excepting six survived i.e., the mortality from the procedure was 2.5% only • At that time more than 30% people died annually from naturally acquired small pox • This led to wide acceptance of variolation in Boston in 18th century • The vaccine era was actually began in 1774 when a farmer named Benjamin Jesty observed that milkmaids who had had cowpox did not get small pox
12 • This was about 22 years before Edward Jenner’s first inoculation and publication in 1798 • Sometime in 19th century vaccinia virus (a mouse pox virus) replaced cowpox in the vaccine • Many lessons were learnt from the small pox vaccine • Initially, small pox pus was used from one person to another and so on but syphilis was also passed along with • Loss of vaccine potency occurred after serial human passages • Many different types of animals were used for vaccine preparation • Ultimately by and large cattle were utilised for vaccine
13 • Subsequent work was done by Pasteur during the 19th century • It refined and consolidated the basis of vaccinology • The process involved the principles of isolation, inactivation, and administration of key components from disease-causing pathogens.
14 • Some concepts were developed • These were: • Attenuation (weakening the capacity to produce disease) of bacteria and viruses • Killed or inactivated (normally by chemicals such as formalin) vaccine • Live attenuated vaccine • Late in 19th century and early 20th century serum and cellular immunity were recognised • This gave rise to the concepts of active (body actively produces) and passive (immune serum from other human and animal was injected) immunity
15 • In Diphtheria and tetanus toxins were recognised as the cause of these diseases • Antiserum was made in horses (antitoxin) that could neutralise toxin effects of these diseases • Antitoxin was first used to prevent diphtheria in a child in 1891 • Early vaccines against diphtheria and tetanus were developed at the beginning of the 20th century • These vaccines combined toxin with antitoxin • In the second half of 20th century many vaccines were developed that could prevent many childhood diseases
16 • It was demonstrated that the strategy of ring immunization for small pox was a success story for eradication of small pox in 1980 • The last case of small pox had occurred 4 years earlier • Ring immunization means: identification, immunization of all contacts of cases and the contacts of contacts • Some countries like USA and Russia still holds the virus as the WHO repository laboratories • But there is a concern that some other countries could be holding surreptitiously stocks of the virus • These countries could possibly use the virus as a biological weapon
17 • Because of the concern of bioterrorism, the US government started a programme in 2001 for development of small pox vaccine • These vaccines were to be developed using modern techniques • This technique involved: • Development of a new plaque purified seed virus • Cultivated in tissue culture, and • Development and testing of a safer human replication deficient strain of virus • This was termed as “modified vaccine Ankara”
18 • Vaccine • The term vaccine is derived fro the word, vacca • This is a Latin word meaning cow • Because cowpox pus was used in prevention of small pox • Vaccination • It is a procedure deliberately undertaken for preventing an infectious diseases by sensitizing the body’s immune system to deploy its acquired defences against that infectious agent • Some vaccines are used to enhance existing immune system – therapeutic vaccination
19 • Vaccines developed by trial and error • Small pox vaccine was developed because of direct observation • First variolation of used for vaccination • Sometimes there was fatal outcome in this procedure • But this was of lower risk than when small pox was acquired in an epidemic • It was later recognised that cowpox could provide immunity against small pox • The vaccines for tetanus, diphtheria and pertussis were prepared by trial and error • These were successful experimentation but some other trial failed and sometimes the consequences were quite adverse
20 • Diphtheria • Causative organism for this disease is Corynerbacterium diphtheriae • It produces toxins that cause cell death at the site as well as elsewhere in the body • The toxin causes many effects that ultimately cause death • Serum from horses immunised with diphtheria toxin was used for immunising and treating diphtheria • In early experiments production was not supervised and controlled causing deaths • This prompted enactment of Biologics Control Act of 1902 in USA • In India, CDSCO controls the biologics
21 • Active immunization using diphtheria toxin was effective • But it cased many adverse events • In early 1920, it was shown that toxins treated with heat and formalin lost its potency but still was immunogenic • Diphtheria toxoid was evolved since then • Vaccination with diphtheria toxoid was highly effective to prevent the disease • A fully immunised person very rarely can become infected as a carrier or may suffer from mild disease • But if a person is not fully immunised, the risk of becoming severely ill after exposure is 30 times higher page
22 Vaccine Development Pathway
23 • Introduction3 • Vaccines represent a relatively small proportion of the entire pharmaceutical industry • Several new vaccines have achieved an enormous success • In the US alone, the annual sales exceeded $500 million • The timeline for development of a vaccine and its approval from the regulatory authorities is long and may be 15 years or more • Moreover, it needs a considerable amount of investment
24 • To get approval from regulatory authorities, the primary aspects that are looked at are: • Safety • Immunogenicity, and • Efficacy • This means that when used on healthy or diseased individuals he vaccine will not be producing any harmful effect • People who receive the vaccine would expect that the disease for which the vaccine is given would be able to prevent the disease
25 • Earlier the relative importance between safety and efficacy varied at different points in time • At present expectations of vaccine recipients are that the vaccine: • Must be absolutely safe, and • It must be highly efficacious • It is very challenging to meet these expectations because a vaccine is a complex biological product • Vaccination produces its effect by activating multiple components of recipient’s of immune response
26 • Most drugs are used to treat a sick person • In contrast, vaccines are used on healthy individuals and also for immunising children to prevent disease • The manufacturers and regulator face the challenges of balancing the expectations of safety and efficacy, and timely licencing, and • Controlling the cost by not unnecessarily increasing the duration of nonclinical and clinical phases of testing
27 A schematic of the typical phases of vaccine development and approval4
28 • Safety • Relative freedom from harmful effects • Purity • Relative freedom from extraneous matter • Efficacy • Reasonable expectation that when administered under adequate direction for use will serve a clinically significant function in diagnosis, cure, mitigation, treatment, or prevention of disease
29 • Immunogenicity • Ability of a vaccine to stimulate an immune response. • Measurement of immunogenicity may include: • antigen specific antibody titres, • seroconversion rates, • cellular immunity. • cytokine responses, or • other immune parameters
30 • The decision to develop a vaccine is usually based on assessment of market need, i.e., whether the developer would be able to sell the product at a reasonable price • The government may assess the market need but most often altruistic • This may be based on relative public health importance, or global incidence of a particular disease • However the ultimate decision is almost always based upon financial consideration
31 • Regulation and approval of vaccine • Approval for a vaccine is the responsibility of the national regulatory authority • In India, the Central drug standardisation and Control Organisation (CDSCO) is the regulatory authority for drugs and biological products • The CDSCO has issued the New Drugs and Clinical Trials Rules, 2019.6 • These rules also covers regulatory aspects of vaccines and biologicals • Specifically for COVID-19 vaccine the CDSCO has issued Draft regulatory guidelines for development of vaccines with special consideration for covid-19 vaccine 7
32 • In USA, the Food and Drug Authority is the regulator • In UK, it is the MHRA that regulates the drug and vaccine development • In European Union, the medicinal products are licensed by the European Medicine Agency • Licencing of vaccines like other medical products is generally based on an assessment of relative risks versus benefits for the product • In Australia, the authority for licencing, the Therapeutic Goods administration uses a risk management approach
33 • Basic Research and Development • Initial development of a candidate vaccine needs detailed information and understanding of: • Target disease • Infectious or other agent responsible for the disease • Basis of protective immunity • These studies are performed in basic research laboratories • From these preliminary studies, candidate immunogens and other related issues emerge
34 • The related issues include: • Evaluation of available adjuvants and stabilisers that will be included in the final product • Adjuvants8 • An adjuvant is an ingredient used in some vaccines that helps create a stronger immune response in people receiving the vaccine. • In other words, adjuvants help vaccines work better. • Some vaccines are made from weakened or killed germs • They contain naturally occurring adjuvants and help the body produce a strong protective immune response
35 • Most vaccines developed today do not use the whole germ • They include just small components of germs, such as their proteins, rather than the entire virus or bacteria. • Adjuvants help the body to produce an immune response strong enough to protect the person from the disease he or she is being vaccinated against. • Adjuvanted vaccines can cause local and systemic reactions than nonadjuvanted vaccines • Local reactions • Such as redness, swelling, and pain at the injection site • Systemic reactions • Such as fever, chills and body aches.
36 • Some adjuvants that are used in vaccine development are: • Aluminium • Used in vaccines such as anthrax, DT, DTaP, DTaP-HepB-IPV, Japnese encephalitis, Pneumococcal (Prevnar13) • Monophosphoryl lipid A (MPL) + aluminum salt • Eg. Cervarix used forX [Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant] • MF59 • E.g. Fluad (Adjuvanted flu vaccine)
37 • Vaccine Platform • At the early stage the decision also need to include the most appropriate vaccine platform for the development of vaccine • Example: • Live attenuated vaccines are most efficacious, but • These organisms can occasionally revert to increase virulence, or • May cause disease in a small proportion of people with underlying health problems • (virulence is the ability of the organism to cause severe disease)
38 • Inactivated or non replicating antigens are safer but they are less efficacious • They may need multiple doses and will require an adjuvant in the final product • These basic research also has to aim at determining the likely efficacy of the candidate vaccine • Typically, this needs animal models of disease, and • Identification of immunological markers indicating protection such as neutralising antibodies
39 • Classical Vaccine Platform • Most vaccines currently in use are basically of two types: • Virus-based • Protein based • Virus based vaccine can consist of: • inactivated virus that is no longer infectious, or • Live attenuated virus • Live attenuated virus is generally by passaging in cell culture until it loses its pathogenic capabilities and may cause only a mild illness
40 • Protein based vaccine can consist of • Purified protein from the virus • Virus infected cells • Recombinant protein • Virus like particles • These particles consist of the structural viral protein necessary to form a virus particle • The lack the viral genome and non structural protein • Protein based vaccine require addition of adjuvants
41 • The classical vaccine platform have some deficiencies that is less amenable to fast development of vaccine in a pandemic • In the case of SARSpCov-2, large quantities of virus need to be grown in Bio-safety Level 3 conditions for a whole inactivated vaccine • Extensive safety testing is required to be sure that the virus is safe and do not revert to wild type • Several recombinant proteins need to be produced at the same time for virus-like particle vaccine • Next-generation vaccine platforms • Using these platforms, vaccines can be developed based on sequence information alone • If the viral protein that is important to provide protection is known then its coding sequence is sufficient to development of vaccine • This helps in speedier development of vaccine in a pandemic
42 A schematic representation is shown of the classical vaccine platforms that are commonly used for human vaccines, and next-generation platforms, where very few have been licensed for use in humans.9
An overview of the different vaccine platforms in development against COVID-19. 43 • Manufacturing and process development • It is a complex process • Needs scale-up from a small quantity of production in laboratory setting to production of gallons of vaccine production in industry setting • The process of large scale production also to be included in the nonclinical development of experimental vaccine • This will accelerate experimental production from laboratory setting to industrial process based manufacture of vaccine • Vaccine production process is quite complex • The process needs identification and purity of each component
44 45