Over the last few months spent in and out of lockdown, we have seen cycles of the easing and then tightening of restrictions, and decreases and then spikes in the incidence rate of Covid-19. Many have begun to wonder how long we can sustain this new life, and it has become clear that until a vaccine is introduced any change is unlikely. Now, as clinical trials conclude for several coronavirus vaccines, the wait for approval from regulatory bodies and subsequent distribution begins.
The race for a vaccine is currently dominated by frontrunners from Moderna, Pfizer/BioNTech, AstraZeneca/Oxford, and Johnson and Johnson, with the Pfizer vaccine having already received approval for emergency use from several regulatory authorities. The main technologies used are different from the conventional live attenuated vaccines, which use weakened versions of the pathogen, or inactivated vaccines, such as the flu shot, which contains a killed virus.
Vaccines are created to trigger an immune response to an adapted form of a pathogen without causing illness, so the body has the correct systems in place in case it ever encounters the actual pathogen. The protein spikes on the surface of SARS-CoV-2 are antigens and when they are detected by cells in the immune system, specific proteins called antibodies are produced to attack the virus. Once these antibodies have been created, they remain in the bloodstream looking for pathogens to attack, and the immune system will quickly fight off any SARS-CoV-2 it encounters. The body is also able to produce more antibodies quickly, as the groundwork was already carried out on first exposure to the antigen. This provides long-term immunity to the disease.
“The mRNA used in these vaccines encodes the SARS-CoV-2 spike protein.”
The Pfizer/BioNTech and Moderna vaccines differ from traditional vaccines as they do not directly contain the specific antigen, but instead contain viral mRNA (messenger RNA); a type of genetic material that carries information about what proteins are to be made between parts of the cell. The mRNA used in these vaccines encodes the SARS-CoV-2 spike protein. When injected into the body, cells cannot differentiate between viral and human mRNA and proceed to build the protein spikes. The body can now recognise the SARS-CoV-2 virus without having encountered the actual virus at all, and with no risk of catching the disease. This causes antibody production and leads to immunity.
The Johnson and Johnson and Oxford/AstraZeneca vaccines use another method called viral vectors, where a different virus is modified genetically so that it can produce the SARS-CoV-2 protein spikes. A similar technique has been used for vaccines against the Zika virus. Oxford/AstraZeneca has used a common cold virus that used to infect chimpanzees. The virus itself cannot replicate in humans, but the protein spike on it still causes an immune response against the SARS-CoV-2 virus.
Due to the unstable nature of RNA, the Pfizer and Moderna vaccines must be stored at a low temperature, which is a concern for vaccine distribution and administration as we reach this critical stage. “The logistics of vaccine administration will depend on the specific vaccine used”, says Trinity immunologist, and Head of the School of Biochemistry and Immunology, Professor Ed Lavelle. “For example, the Oxford/AstraZeneca vaccine can be stored at fridge temperature. At the other end of the scale, the Pfizer/BioNTec RNA vaccine must be stored at -70C but can be stored in a fridge for 5 days.”
“The speed at which these vaccines have been developed and trialed is an incredible feat.”
Chains of distribution that keep the vaccines at these temperatures will be key, explains Lavelle: “Thermal shipping boxes have been developed that will allow storage for 15 days so if there are central facilities with low-temperature freezers, the vaccines can then be transported to standard vaccine administration sites, for example, GP surgeries. The Moderna vaccine (another RNA vaccine) is stable at -20C (the temperature of a household freezer) for 6 months and it is thought to be stable in a fridge for 30 days. We will likely use a number of vaccines next year so there will be different protocols for the specific vaccine concerned.”
The speed at which these vaccines have been developed and trialed is an incredible feat: “This has been remarkable, and a testament to the transformation in vaccine development facilitated by new technologies including RNA vaccines and viral vectors. This is likely to have a major impact on the development of new vaccines in the future. However, in addition to the advantages of new technologies, other factors, particularly the enormous financial investment to support Covid-19 vaccine initiatives have been vital.”
These vaccines have been developed very quickly, but that does not mean they have rushed through safety protocols or are unsafe. The effect Covid-19 has had on the world means that the research and testing for these vaccines became the number one priority, resulting in the elimination of many barriers that usually slow down developments. Traditionally much of the time spent developing vaccines consists of writing grant applications, coordinating with manufacturers, and waiting for approval for trials. These processes accelerated as they were prioritised, and proposals for research related to Covid-19 were reviewed before anything else.
“These newer, gene-based vaccines are much quicker to develop than live attenuated vaccines, as only the genetic code is needed.”
In addition to this, previous experiences with other coronaviruses, namely SARS-CoV-1, meant that scientists had a good understanding of how the immune system responded to the virus and could quickly select the protein spike as a focus for the vaccine, saving significant amounts of time that would have otherwise been spent determining the antigen to focus on. The genetic sequence was made publicly available on January 10 before the World Health Organisation had even declared a public health emergency, meaning research could begin straight away. These newer, gene-based vaccines are much quicker to develop than live attenuated vaccines, as only the genetic code is needed. Massive amounts of funding have been dedicated to developing these vaccines as quickly as possible, which has alleviated any financial barrier that would have slowed down research, trials, or testing.
Usually, companies will not fund development unless they believe their product is likely to succeed. They only fund each stage when the previous phase is completed and the results are promising, which slows down development. In the race to produce a Covid-19 vaccine, money was allocated before previous phases were completed, so planning and preparation could begin in anticipation of a positive result. In short, the next phase was ready to go as soon as the go-ahead was clear from the earlier trial phase. No time was wasted, but no steps were skipped. In some cases, phases of trials were running simultaneously. This overlap of trials did not cut down the time allocated but simply overlapped some parts of them. For example, Moderna began its first phase of clinical trials on humans while still testing on primates.
With the final stretch of the marathon in sight, some vaccines are finished clinical trials and are being approved by regulatory bodies, so companies have begun to estimate the number of doses they will be capable of manufacturing. The overestimation of capacity “is a possibility but the first vaccines, likely to be approved soon, are based on technologies that are very amenable to scale up so we hope that the ambitious targets set by these companies are achievable”, says Lavelle. Pfizer plans to manufacture 100 million doses in 2020 and 1.3 billion in 2021, with each person needing two doses to be adequately protected.
As the public, we can be confident that the Covid-19 vaccines are being tested as rigorously as any others, with the eyes of the entire medical and immunology community firmly fixed on ensuring their efficacy and safety. The speed of their development can be accredited, not to any oversights or carelessness, but to global collaboration and a shared goal of bringing an end to this pandemic.
