The Vaccines. 01.06.20
Welcome to The Plague Pit – number 25
For this ‘silver anniversary’ issue, I’m delighted to welcome a new student contributor, Xavier Machado. Xavier is currently in the lower sixth at Winchester College studying maths, further maths, biology and chemistry. He’s also head of the Medical Society and hopes to study medicine at university. He has sent in this fine article about the science behind immunization – and the work in progress towards a COVID-19 vaccine.
With countries and nations across the world starting to reduce some of the original measures to combat the spread of SARS-CoV-2, we need to ask ourselves if we are prepared. In one of many of the Government’s briefings addressing their strategy to ease lockdown, the Prime Minister said that the “only feasible long-term solution” to end the coronavirus pandemic is the creation of an effective vaccine or treatment, but warned this was not an inevitability. So how are scientists around the world developing the vaccine to stop this global health crisis that has affected so many of us?
A vaccine is designed to protect people before they are exposed to the virus – not as a treatment. Before talking about the current developments regarding the vaccine against SARS-CoV-2, I will first outline how a vaccine works. When a pathogen invades us, the immune system triggers a series of response in an attempt to remove them from our bodies. Our first line of defence offered by the immune system helps prevent pathogens from entering the body at all. This would be our skin to block entry, or secretions in the linings of our airways that trap or kill the pathogens. Once a pathogen has made it through, the immune system must first recognise the foreign particles, distinguishing between self and non-self. To do this the immune cells produce receptor molecules that bind specifically to molecules from foreign cells to activate defensive responses. The specific binding is a type of molecular recognition.
Two types of molecular recognition provide the basis for the two types of immune defence: innate immunity and adaptive immunity. In innate immunity, molecular recognition relies on a small set of receptor proteins that bind to molecules or structures that are absent in human bodies, but common to groups of viruses or other pathogens. In adaptive immunity, molecular recognition relies on a vast arsenal of receptors, each of which recognizes a feature which is much more specific, since the receptors produced only bind to a particular part of a certain pathogen. As the name suggests, the adaptive immunity response is enhanced by previous exposure to the pathogen, which is part of how the vaccine works, by using this adaptive immunity mechanism.
Adaptive immunity works using T cells and B cells – types of white blood cells called lymphocytes. Recognition occurs when a B cell or T cell binds to an antigen, via a protein called an antigen receptor. This then activates the two types of cells, which simply start to produce antibodies which target the pathogens for further biochemical pathways resulting in the death or removal of these pathogen in some way, and this is the natural activity of your immune system which vaccines harness.
So, what happens when we inject the vaccine? First, I would like to note that there are several different types of vaccines, but these all result with the individual becoming immunized. Vaccines try to mimic viral infection. They are usually manufactured using inactivated or killed viral particles. These contain the antigens which the pathogens produce. Once in the blood stream, the adaptive immunity defence system kicks in. T cells bind to the antigens, causing them to become activated and proliferate into cytotoxic T cells, suppressor T cells, or helper T cells. The helper T cells express the antigen receptors, playing a major role in antibody generation and memory B cell activation. B cells also bind to the antigens. Once they have binded, later they can present this antigen on their cell surface membrane. Helper T cells then interact with this, which causes the helper T cells to produce cytokines. This stimulates activated B cell proliferation, leading to further differentiation: either plasma cells producing antibodies, or to memory B cells – aiding with future immune response, and this is what the vaccine aims to achieve.
Like the SARS coronavirus, COVID-19 is believed to have originated from bats and that both of these viruses bind to the similar ACE2 receptors found in the human lung and both exhibit genomes of approximately same length, with 89% nucleotide similarity to the SARS-like coronaviruses in Chinese bats. On this basis, early shaping of the potential SARS-CoV-2 vaccine strategies will be based on those which worked for SARS previously. [1]
One of the major hurdles that researchers have struggled with early on, is similar to problems faced when trying to develop the SARS outbreak before, where the vaccine would actually enhance the disease and immunopathology of the virus [2].
Another important element which researchers and governments must consider is the intended target population for the vaccine. Presently, those with highest risk of contracting the virus, or being severely affected by this, are frontline healthcare workers, those above the age of sixty, or the individuals with underlying conditions such as diabetes. This might mean that these populations would be prioritized. [1]
Furthermore, the current vaccine completion date is unknown at the moment but we have been given the rough timeline as a vaccine to be widely available – the government has said that up to 30 million COVID-19 doses could be available by September. This means that the vaccine must be prepared so it is easily produced in large quantities quickly, so that large numbers of the population can receive it quickly.
So how are researchers approaching the vaccine manufacturing process? Many of the paths that researchers are taking are currently looking at the spike protein. This protein is part of the outer layer of the virus and it is how the virus enters our cells – have a look at Alfred Beadman’s article where he mentions the spike protein with more depth. Antibodies which target this can potentially block the virus from ever entering our cells.
Scientists at the University of Oxford have modified an adenovirus vector to carry the spike protein gene. This way, when the modified vector invades human cells, the gene will be integrated into the cell’s genome, and the spike protein will be produced, without the harmful effects of the virus. This will possibly trigger an immune response, for memory B cells to be produced aiding in future infections. [3]
Scientists have also thought to repurpose other vaccines, making them combat the novel coronavirus. There is one vaccine which is thought at the moment to be able to be repurposed for this function – the BCG vaccine. This is usually used to control tuberculosis, but it stimulates broad components of the immune response, so offers protection against a range of diseases including influenza. [3]
Imperial researchers are also working to produce a vaccine against COVID-19, in a different way to the other methods mentioned. They still harness that same immune system pathway, just through different methods. Within weeks of the first cases of the coronavirus, scientists in China had sequenced the genetic code of the virus. A team at imperial then used this code to produce strands of the DNA in a lab. They specifically used the gene which coded for the spike proteins on the outside of the virus. They inserted this gene into plasmids to make a self-amplifying RNA vaccine. When injected the vaccine will deliver the genetic instructions to muscle cells to manufacture the spike protein, which in theory should provoke an immune response.
While in theory these vaccines all sound promising and seem to be going well, the reality is that these vaccines take a lot of time, a lot of money and there are several hurdles to overcome. As of 23rd April, the World Health Organization has announced that 83 potential covid-19 candidate vaccines are being assessed, with seven being approved for human testing. Of these seven, three are in China, one of which has the only vaccine in a phase II trial [4] (There are 3 main phases of a clinical trial. Phase I is usually quite small, only a few patients. Aim is to find out how much of a drug is safe to give, the possible side effects and how the body gets rid of the drug. Phase II includes a few more patients ranging from 10-100 where its aim is to establish the preliminary efficacy of the drug. Phase III involves the final confirmation of safety and efficacy of the drug, involving hundreds or thousands of people.)
Another company is amid testing its inactivated virus COVID-19 vaccine in phase 1 with 144 adults – a rather large phase I trial. It hopes to move to phase II with another 600 people soon and a preprint looking at the vaccine’s efficacy found that it offered “complete protection” against SARS-CoV-2 strains circulating worldwide. [5]
In the US there are two approved for human trials. The first company, Inovio Pharmaceuticals began testing its DNA platform vaccine in April. They estimate that the vaccine will be ready in 12 to 18 months – a much larger number than the UK government’s estimate. The second company, Moderna, had developed a vaccine called mRNA-1273 with the first patients being tested in March, and the trials expanding to 60 adults. [5]
Vaccines are continually being investigated globally, with countries coming together on 24th April (with the US not being present and announcing that they would be freezing funding to the WHO), however, WHO has cautioned nations against relying on a vaccine to end the current situation we are all facing. Ohid Yaqub, a senior lecturer at the University of Sussex also noted that “there is a long history of over-optimistic vaccine predictions” and that even if a vaccine became available it was “too early even to speculate whether it will have high efficacy or low efficacy.” There may be some truth to Omid’s statement, however the fact remains we are currently living in unprecedented times, and with vaccines being developed at unprecedented rates, there is a possibility we may see a successful vaccine developed in the near future, although it is critical that we must ensure its quality and safety before widespread use.
Xavier Machado
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094941/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586247/
[3] https://www.bmj.com/content/369/bmj.m1790.long