The Journey of Vaccines from the Lab to Usage

Introduction: In this article we will discuss what vaccines are, how they work and an overview of the different types of vaccines, focussing on the Oxford, Pfizer and Moderna vaccines that have been ordered in the UK. Recently there has been positive news about the vaccines that have been developed to combat COVID-19, but what exactly are vaccines? Vaccines can be described as a suspension of an infectious agent or its components, modified to stimulate an immune response against diseases without inducing the disease. In the era of COVID-19 new technologies have facilitated the accelerated development of vaccines using structural and computational approaches.Moreover,single cell sorting sequencing and bioinformatics, which is the collection and analysis of biological data, has allowed the rapid identification of pathogen epitopes, which are regions of proteins that can trigger a cellular immune response. In addition the novel ‘plug and play’ viral platform has helped to slot in or ‘plug’ heterogeneous genes form different pathogens into an identical vector backbone or protein expression system.For example the SARS CoV-2 spike protein has been ‘plugged’ into the ChAdOx1 nCov-19 vaccine vector [1]. How do vaccines work? A key principle of vaccines is that they induce immunological memory so that upon exposure to the pathogen there is enhanced kinetics of the recall response, as shown in Fig.1[2]. Figure 1. A graph showing the enhanced kinetics of the secondary response, due to immunological memory. This figure is adapted from ABPI schools Vaccines can also prevent transmission to susceptible individuals and not just the people that are vaccinated, providing immunity to a community rather than individuals.This is because virus shedding, which is the expulsion and release of the virus after replication within the host, is reduced.The development of a COVID-19 vaccine that could successfully reduce virus shedding in the respiratory tract would have significant impact on the virus transmission dynamic.Vaccines can also provide herd immunity, which refers to the critical number of susceptible hosts that are required to maintain communicability of the virus.If this number is lowered, the virus may be eliminated. Overview of the different types of vaccines: There are many types of vaccines, as shown in Fig.2, each having their own advantages and disadvantages.These include live-attenuated, inactivated, subunit, nucleic acid and recombinant live viral vectored vaccines. Figure 2. A chart showing the major vaccine strategies Live attenuated: These contain whole viruses that have been weakened.The process involves taking a pathogenic virus and then undergoing serial passage in non-human host cells in tissue culture. Serial passage refers to the process of growing bacteria or a virus in iterations.When undefined mutations have been acquired, then a mutation that is less virulent than the host pathogen is chosen.They provide a strong, long-lived immune response for healthy individuals, inducing cellular and humoral immunity.An example of this is the BCG vaccine against TB.However,these are not suitable for individuals with a weakened immune system, such as immunosuppressant patients or pregnant women, as the virus may induce the disease in these individuals. Moreover,the vaccines may become genetically unstable or even contaminated with resident viruses, therefore be deemed ineffective. These vaccines are also relatively slower to produce and require a low temperature, known as cold chain, for stability and efficacy.This approach is not being considered by major biotechnology and pharmaceutical companies for COVID-19 [1]. Inactivated: These contain whole viruses that have been killed or small fragments of the virus, which cannot cause the disease.An example of the vaccine is the Polio vaccine. These are best for individuals with severely weakened immune system, as they cannot cause the disease. However the immune response is not long-lasting, hence require a repeated dose.Adjuvants may also be added, which are likely to cause local reactions, such as a sore arm.There is also a major challenge posed by the inactivation process, as sufficient inactivation of the virus must take place without changing the viral protein. Subunit protein vaccine: These use a fragment of a pathogen to trigger an immune response and the fragment is usually found on the surface of a protein.The gene of interest is isolated from the pathogen and cloned into a baculovirus, which are viral vaccine vectors and generates a high yield of the protein of interest.Cells are injected with the genetically engineered virus in fermenters, where rosettes, which are glycoprotein subunits, are produced.This is then purified and formulated into a vaccine.This method is relatively easy to scale up in fermenters and is more stable than live virus vaccines.Moreover,it is safe to be administrated to immunosuppressed individuals.However, subunit protein vaccines are less immunogenic and do not activate the innate system, providing a comparatively weaker immune response.This strategy is being used for COVID-19 spike protein vaccine by Sanofi and GSK.The Spike protein is cloned into a baculovirus and an adjuvant is added to enhance the immune response, hence creating a stronger and longer lasting outcome. The recombinant subunit protein produced, has undergone Phase 1/2 clinical trials and the results are anticipated in December 2020 [3]. Nucleic acid (DNA) vaccine: In this method the gene of interest is cloned into an eukaryotic expression plasmid.This is then purified and injected into the patient.The encoded protein is then expressed.The DNA vaccines have many positives: they are non-infectious, minimising safety concerns; can be administrated to immunosuppressed individuals; easy to manufacture; thermally stable, therefore less dependent on cold chain and so more transportable.However,these DNA vaccines are less immunogenic than live vaccines and problems have occurred regarding the inefficient cellular uptake of the vaccine.There are currently no such vaccines licensed however many are under development for COVID-19. Nucleic acid (m-RNA) vaccine: RNA vaccines work by introducing an mRNA sequence coded for a disease specific antigen.The antigen is produced within the body and is recognised by the immune system.There are 2 major types: non-replicating conventional mRNA vaccines and self-amplifying mRNAs (SAM).The conventional mRNA vaccine has the basic structural elements of a mature mRNA – 5’cap, 5’ UTR, OFR, 3’ UTR and poly (A) tail structure-, as shown in Fig.3. Figure 3. A diagram showing the structure of a mature mRNA. This is used in non-replicating conventional mRNA vaccines. This figure is adapted from Wikimedia On the other hand SAM is based on an alphavirus genome, where the genes encoding the RNA replication machinery are intact but the genes encoding the structural proteins are replaced with the antigen of interest.Therefore a small dose of the vaccines can produce huge amount of antigens. RNAm vaccines have similar advantages to DNA vaccines, such as being safer for the patient, as they are not produced using infectious elements, and being administrated to immunosuppressed individuals.However, unlike DNA vaccines, mRNA vaccines do not need to enter the nucleus and so avoid the problem of integration.The main problems posed by this process are that mRNA cellular uptake is very inefficient and can be easily degraded, hence making a naked mRNA vaccine very unstable. However,these problems can be overcome by using lipid nanoparticles for better cellular uptake and increased stability [4]. Both the BNT162b1 vaccine developed by Pfizer& BioNTech and the mRNA-1273 vaccine developed by Moderna are mRNA vaccines. Recombinant live viral vectored vaccine: In this method a small piece of DNA is extracted from the pathogenic virus and then inserted into a vector, before being replicated.There are many examples of this, including the HPV vaccine. Advantages of this type of vaccine includes not requiring adjuvants as the virus vector backbone can stimulate innate immune system. In addition a strong T cell and B cell response is activated. However,the immunogenicity of such a vaccine can be lowered due to pre-existing antibodies against the vector backbone. The Oxford& AstraZeneca vaccine(ChAdOx1 nCov-19) uses this technology. Vaccines for COVID-19: For SARS-CoV-2, antibodies that bind to and block the spike protein are thought to be effective for protection from disease since the spike protein attaches to human cells, allowing the virus to enter. Blocking this entrance will prevent infection [5].Many companies have targeted this in the development for COVID-19 vaccinations;three such vaccines are shown in Fig.3 below. Figure 4. A table showing the three of the major COVID-19 vaccines The Oxford& AstraZeneca vaccine: Figure 5. A diagra showing how the Oxford COVID-19 vaccine works. A chimpanzee adenovirus is used in the ChAdOx1 viral vector, engineered to match the SARS-CoV-2 spike protein. This figure is adapted from the University of Oxford ChAdOx1 nCov-19 is a type of live replication-deficient adenovirus vectored vaccines.The ChAdOx1 vaccine uses a chimpanzee adenovirus vaccine vector (simian) to express the SARS -nCoV-19 Spike protein, as shown in Fig.5 [7].The vaccine is replication-deficient because the essential early virus genes, such as E1 and E3, are deleted.This means that there is minimal expression of the adenovirus’ own protein and so the expression of the foreign transgene is focussed.The Oxford vaccine has shown promising results and induces a strong B and T cell response after a single vaccination. Also,the adenovirus vector has natural tropism for mucosal tissues so there is a possibility for internasal delivery.However,adenovirus vectors require a helper virus in manufacture and are of low titer, meaning very little antibody is present in the serum [1]. Pfizer & BioNTech and Moderna:mRNA vaccines: The mRNA vaccinations developed by Pfizer & BioNTech and Moderna have showed extremely positive results during clinical trials of 90% and 94.5% efficacy, respectively. The major advantage between traditional and mRNA vaccines is that the mRNA is taken up by our body cells, and then our own cells produce the protein that stimulates an immune response.They elicit B cell and T cell immune responses since our cells make the spikes.Moreover,people cannot have immunity to RNA- unlike in adenoviruses used in vectored vaccines, such as the Oxford vaccine.Although no RNA-based vaccine is yet on the market, Moderna has been working with the NIH on developing RNA vaccines to prevent other viral diseases, such as MERS and Zika [6]. Comparison: The efficacy of the Oxford & AstraZeneca vaccine is lower compared to the other two mRNA based vaccines, as it has an average efficacy rate between 70% to 90%. However it has a much higher shelf life of 6 months compared to Pfizer, which has only around 5 days at -70 °C . Storage is a logistical problem for the Pfizer vaccine, as it has to be stored in ultra-cold freezers, which are not readily available everywhere around the world. With this comes the cost of electricity needed to power the freezers and the safe transportation of the vaccines. Moreover much of the world’s current cold chain capacity is already in use, hence this is a vital issue that has to be resolved. Moderna has a shelf life of 1 month and needs to be stored between 2° C to 4° C.Therefore,there is no need for ultra-cold freezers, unlike Pfizer. Oxford vaccine will be able to deliver significantly more doses than the other two [7]. Conclusion: Vaccines are a necessity to combat COVID-19 and there are many advantages and disadvantages to the vaccines that have been developed thus far, so it is unclear which vaccine strategies will be most successful.However,after promising results in the clinical trials, the development of various vaccine platforms and strategies in parallel has resulted in the rapid development of new technologies, such as nucleic acid base vaccines [8]. ✵COPYRIGHT: This text is the property of We Communicate Science, a non-profit establishment co-founded by Dr. Detina Zalli and Dr. Argita Zalli. The article is written by Shanthavi Wijayakumar, King’s College London, UK. ✵References : 1.Linda Klainskis(2020), Lecture 18- Vaccines. Available at:https://keats.kcl.ac.uk/enrol/index.php?id=78944 [Accessed8 Dec. 2020]. 2.www.abpischools.org.uk. (n.d.). How medicines work. [online] Available at: https://www.abpischools.org.uk/topic/howmedicineswork/5 [Accessed 8 Dec. 2020]. 3.https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-14-13-00-00. (n.d.). Sanofi: Press Releases, Tuesday, April 14, 2020. [online] Available at: https://www.sanofi.com/en/media-room/press-releases/2020/2020-04-14-13-00-00 [Accessed 9 Dec. 2020]. 4.University of Cambridge (2018). RNA vaccines: an introduction. [online] PHG Foundation. Available at: https://www.phgfoundation.org/briefing/rna-vaccines [Accessed 8 Dec. 2020]. 5.Johns Hopkins Coronavirus Resource Center. (n.d.). A Primer on COVID-19 Vaccine Development, Allocation and Deployment. [online] Available at: https://coronavirus.jhu.edu/vaccines/reports/types-of-covid-19-vaccines [Accessed 8 Dec. 2020]. 6.DNA Science. (2020). How the Various COVID Vaccines Work. [online] Available at: https://dnascience.plos.org/2020/09/10/how-the-various-covid-vaccines-work/#:~:text=Moderna%20Therapeutics [Accessed 9 Dec. 2020]. 7. www.research.ox.ac.uk. (n.d.). Researchers find very high rates of Covid-19 in the Brazilian Amazon. [online] Available at: https://www.research.ox.ac.uk/Article/2020-12-09-researchers-find-very-high-rates-of-covid-19-in-the-brazilian-amazon [Accessed 13 Dec. 2020]. 8.American Council on Science and Health. (2020). Comparing COVID Vaccines: Pfizer vs. Moderna vs. AstraZeneca/Oxford. [online] Available at:https://www.acsh.org/news/2020/11/23/comparing-covid-vaccines-pfizer-vs-moderna-vs-astrazenecaoxford-15170 [Accessed 7 Dec. 2020].

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