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On this day in 2020, the Moderna COVID-19 vaccine entered phase 1 trials, making it the first COVID vaccine to do so. This came less than a week after the World Health Organisation declared COVID-19 a global pandemic. How was it possible for this to happen so quickly? The third part of the #ChemVsCOVID series, produced with the Royal Society of Chemistry, gives a brief overview of the prior work and what the phase 1 trials looked at.

Moderna’s vaccine, like that of Pfizer/BioNTech, is an RNA vaccine, a technology which had not previously been used in an approved product. Similarly, the viral vector technology used in the Oxford/AstraZeneca vaccine had not previously been approved for immunisation against other diseases. However, research on both of these vaccine technologies has been being carried out for decades now – vital work which allowed these vaccines to be produced so quickly in response to the pandemic.

The concept of a vaccine based on RNA was first suggested back in 1990. Over the subsequent years, it was shown in laboratory tests that various types of immunity could be induced by mRNA. The first attempt at producing a vaccine based on mRNA was in 1993, where an RNA vaccine coding for an influenza antigen produced an immune response in mice.

Despite this success, a challenge for the success of mRNA vaccines was the fragility of the synthetic mRNA. Our bodies’ immune systems are extraordinarily effective at spotting interlopers, and the synthetic mRNA was quickly identified and dismantled before it could reach the target cells, rendering any vaccine useless.

The solution was to develop a form of camouflage for the mRNA. mRNA is made up of building blocks called nucleosides. Biochemist Katalin Karikó and immunologist Drew Weissman discovered that by swapping out on of these nucleosides for one that was similar but subtley different in structure, the mRNA could fly under our immune system’s radar.

However, this didn’t entirely solve the problem. Though the immune system was no longer being triggered by the mere presence of the mRNA, enzymes in our bodies woud still be able to break it down before it was able to reach our cells. Another innovation was needed: a way of encapsulating the mRNA and ferrying it to the cells.

A number of methods have been developed for this, but the one use by the current COVID RNA vaccines is lipid nanoparticle encapsulation. Lipid nanoparticles are very small fat droplets, and their use to transport mRNA in our cells has been being researched for the past decade. This research has identified the best combination of different lipids to adequately protect the mRNA, and it has been vital to the success of the COVID RNA vaccines.

The viral vector vaccines, of which the Oxford/AstraZeneca vaccine is an example, also owe much to prior research. The roots of these vaccines go back even further than those of the RNA vaccines, to the 1980s.

Initially, the focus of research on viral vectors was on the treatment of rate genetic diseases, with the hope being that the viral vectors could deliver a gene that could in some way correct the mutations causing them. The issue was that this approach required high doses, which acted like a flare to the body’s immune system, potentially sparking massive inflammation.

While this wasn’t useful for gene therapy approaches, the immune response was potentially useful to vaccine developers, and work began on how viral vectors could be used to produce vaccines. In the 2000s, viral vector vaccine development focused on HIV, malaria, and tuberculosis, with limited success. Though a vaccine was produced for HIV, and it was shown to be safe, further human testing showed that it didn’t work.

Incremental improvements did follow, however. In 2017, China approved a vaccine against Ebola which used viral vectors, the first such vaccine to be approved. Though trials showed it produced an immune response, there was not sufficient evidence to show it prevented infections.

A concern around the failed HIV vaccine, and to a lesser extent the Ebola vaccine, was the the type of virus used to create the viral vector may have had a negative on the immune response it generated. For both of these examples, human adenovirus vectors were used – specifically a virus called Ad5. This is one of the number of viruses which can cause the common cold. Inevitably, this means that some of us have been exposed to it, and consequently have preexisting immunity. This is bad news for viral vector vaccines, as it can reduce their effectiveness.

For this reason, some viral vector vaccines for COVID-19, including the Oxford/AstraZeneca vaccine, use primate adenovirus vectors. The vast majority of people will have no preexisting immunity to these viruses, meaning that they won’t have a negative impact on virus effectiveness.

It’s not just the prior research on vaccines which has been useful in producing vaccines against COVID-19. Previous research on other coronaviruses has also helped focus vaccine production efforts. The SARS epidemic of 2003 and the MERS outbreak in 2012 were both caused by different coronaviruses.

Vaccinations were never produced against the coronaviruses that caused these outbreaks; this is partly a consequence of their lower prevalence compared to COVID-19, and also a result of the lack of incentives for pharmaceutical companies to produce a vaccine for diseases which are not widespread. However, vaccine development efforts still took place, and lessons learned from these efforts were taken into account when designing vaccines for COVID-19.

All of the COVID vaccines went through pre-clinical trials – these don’t involve humans, and instead test the vaccines in isolated cells and in animals to ensure that they’re safe and produce an immune response. Usually, vaccines need to complete this stage before they progress to phase 1 trials, but in the case of the COVID vaccines, the urgency of producing them meant that some early phase 1 trials were done concurrently with pre-clinical tests to speed things up. It’s important to emphasise that these tests were still completed, so overall no corners were cut.

The phase 1 trials are simply intended to check the vaccine is safe in humans. They can also be used to get some idea of the optimum dose of the vaccines in humans, something that Moderna’s phase 1 trial examined by splitting participants into different groups who received varying amounts of the vaccine. These trials can also help identify common side effects, something which continues to be monitored in the later phases of testing.

Ultimately, the phase 1 trials showed that the COVID-19 vaccine currently approved are safe to use in humans. Some vaccine candidates did fall at the first hurdle: the Merck vaccine candidate was withdrawn in January 2021 after phase 1 trials showed the immune responses in those who received the vaccine were worse than those seen in those who’d had COVID, and also inferior to the responses seen for other vaccines.

The hope is that the efforts to create COVID vaccines will also aid vaccine development for other diseases in the future. For example, there is already an RNA vaccine in development for malaria. And now that we have vaccines, it’s also hoped that if variants of SARS-CoV-2 emerge which the current vaccines are less effective against, it should be relatively easy to tweak the existing vaccines to combat these.

This graphic was developed in partnership with the Royal Society of Chemistry. See the full #ChemVsCOVID series of graphics here.

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References/further reading

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