The first generation of vaccines for Covid-19 is edging closer to the market. But are these vaccines able to withstand the force of viral evolution?

The race to commercialize the first Covid-19 vaccines in the US and EU is intensifying, with frontrunner developers such as AstraZeneca, Moderna, and BioNTech now in phase III. They are already taking preorders for millions of vaccine doses for when their vaccines are cleared by regulators. This could be as early as November in the case of AstraZeneca. 

Most of the leading vaccines programs train the immune system to detect antigens on the surface of SARS-CoV-2 — the RNA virus responsible for causing Covid-19. The most frequently used antigen is a protein called spike, which is seen as most likely to protect from the infection. 

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However, viruses can rapidly mutate, leading to changes in their structure that allow them to become no longer recognizable by the immune system. The Covid-19 virus is no exception, and laboratory experiments have shown the spike protein can mutate. If the viral surface proteins change enough in the wild, we could be faced with new Covid-19 strains that these vaccines are unable to protect us from.

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We are starting to see a few mutations of the SARS-CoV-2 virus that impact the spike surface antigen,” said Alexandre Le Vert, Executive Chairman and co-founder of the French vaccine firm Osivax. 

If these mutation trends persist and increase with the worldwide spread of the virus, we believe that the vaccines targeting the spike surface antigen might have limited efficacy.

Furthermore, Le Vert pointed out that mutations in surface proteins on the SARS-CoV-2 virus could even cause some vaccines to exacerbate the infection. This can happen via a phenomenon known as antibody-dependent enhancement, where certain antibodies stick to the virus incorrectly and make it even better at infecting cells.

So how can we make sure that Covid-19 vaccines won’t get outpaced by an evolving virus? According to the UK company Emergex, a key clue lies in studying vaccines for other viral infections that have proved effective for decades.

Last week, Emergex released the results of an investigation into immune responses to the yellow fever vaccine, which is a weakened form of the live virus. Like Covid-19, yellow fever is caused by an RNA virus.

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Emergex and its collaborators were surprised to discover that immune cells that recognize and destroy virus-infected cells — T cells — largely ignored the surface antigens of the yellow fever virus. Instead, they recognized antigens within the virus. 

Many of the vaccines currently being developed for Covid-19 are targeting surface proteins and particularly the spike [protein],” said Thomas Rademacher, co-founder and CEO of Emergex Vaccines. “Our results suggest that this may not produce an equivalently safe, effective, and long-lived immune response compared to that seen with live attenuated vaccines.” 

Rademacher told me that the company is “exploring the development of a SARS-CoV-2 [vaccine] candidate,” but details are pending.

Few companies are developing live attenuated vaccines for Covid-19. Though they can provide very strong protection, these vaccines are tricky to transport and may be unsafe for people with weakened immune systems. Most developers are opting for alternative approaches such as inactivated vaccines, recombinant viral vectors, and mRNA vaccines. 

If live attenuated vaccines are off the table, then how could other types of vaccines achieve long-lasting protection? According to Le Vert, the answer lies in aiming vaccines at antigens within the SARS-CoV-2 virus. His company, Osivax, is developing a vaccine candidate that consists of nanoparticles carrying copies of internal Covid-19 antigens. 

We believe that targeting internal antigens such as the nucleocapsid presents an advantage over surface antigens as they have a much lower mutation rate,” said Le Vert. He added that an immune T-cell response against these internal antigens could protect against both current and future strains of Covid-19.

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Innate pharma Covid-19

Innate pharma Covid-19

The company raised €32M in July to fund the development of the vaccine, which is expected to reach phase I trials by 2021. Additionally, the funding will allow Osivax to develop a vaccine capable of universal protection against flu — a virus that mutates far more rapidly than coronaviruses.

Another company going beyond the viral surface is the Belgian company eTheRNA. It is developing a vaccine made of mRNA molecules, like those of the German companies CureVac and BioNTech. The mRNA molecules deliver genetic instructions that cause the patient’s cells to produce the viral antigen. In this way, the vaccines can be manufactured without the complex production facilities needed for other vaccines. 

Unlike CureVac and BioNTech, eTheRNA makes the patient’s cells produce a mix of SARS-CoV-2 antigens both on the surface and inside the virus. In addition to making the immune system produce antibodies, the vaccine activates T cells, which are a key part of our immune ‘memory’ for future infections. 

The viral surface is more sensitive to mutation and strain drift – and an antibody-based approach is potentially vulnerable to such changes,” said Wim Tiest, eTheRNA’s Director of Infectious Disease Programme Strategy.

That is why an approach like ours that targets a broader part of the virus and triggers a multi-angled immune response offers a valuable alternative despite the longer development timelines.”

Using the proceeds of a €34M Series B round closed in June, eTheRNA is developing the vaccine with the aim of entering phase I trials in late 2020.

Emergex, Osivax, and eTheRNA are part of a minority of companies that target internal viral antigens as part of their vaccine strategy. “Based on the WHO official list, there are only about 10 companies out of 170 developing a vaccine targeting internal antigens,” noted Le Vert.

The rest seem confident that spike and other surface targets will protect over the long term. For Valneva in France, which is developing an inactivated vaccine for Covid-19, the benefits of targeting surface antigens for Covid-19 generally outweigh the risks. 

Coronaviruses have a lower mutation rate than, for example, influenza viruses, for which a yearly adaptation of vaccines is necessary,” said Thomas Lingelbach, CEO of Valneva. 

SARS-CoV-2 has had very few genetic changes since it emerged in late 2019. In other words, regular strain adaptation is currently not expected to be a requirement for a SARS-CoV-2 vaccine.”

With so much unknown about the new virus, it remains unclear which vaccines will prove successful over the years to come. And as the first Covid-19 vaccines near approval, it seems prudent to continue studying how they can provide long-term protection. We’ll likely have plenty of time, since some believe that the virus will never truly go away.


Images from Elena Resko and Shutterstock

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