Coronaviruses are a group of related RNA viruses known to cause respiratory tract infections in humans and other animals. Although all viruses mutate while replicating and infecting host cells, RNA viruses are particularly unstable, meaning they are more prone to mutation during replication.

The majority of viral mutations are minor and have no impact on the virus or the disease it causes.  However, multiple mutations can lead to a new variant of a virus emerging and sometimes it is possible these new variants are more transmissible or deadly as they can better evade the immune system.

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The emergence of SARS-CoV-2 variants

SARS-CoV-2, the coronavirus causing Covid-19 and wreaking havoc across the globe for the last year, has also been mutating.

There are now three new concerning variants of SARS-CoV-2 circulating globally. The first was identified in the UK in September using genomics sequencing, and has been dubbed B117. Another variant, known as B1351, was discovered in South Africa in October and contains many of the same mutations to B117 in the spike, although it emerged independently. The third, which is called P1 and believed to have emerged in Brazil in December, contains many similar mutations to the other two variants.

The three variants are believed to be spreading more easily and quickly than other SARS-CoV-2 variants, but there is no evidence that they are causing more severe illness or higher death rates. It is possible, however, that these variants could escape the immune system and therefore mean those who have previously contracted Covid-19 are susceptible to reinfection.

The threat of these variants has caused many countries to close their borders to stop the further spread of these highly virulent and transmissible Covid-19 variants. For instance, the UK has closed its borders to South American countries and Portugal, while many countries across Europe have banned visitors from the UK.

This situation has also led to concerns that approved Covid-19 vaccines, which are the world’s main exit strategy from the pandemic, may not be effective against these emerging variants. Thankfully, for these mutations and variants, this likely to not be the case for the Pfizer/BioNTech Covid-19 vaccine. On 20 January, Pfizer and Biotech announced results of an in vitro study showing that their vaccine elicits antibodies to neutralise the UK variant spike protein, while acknowledging that more data will be needed to monitor the vaccine’s efficacy against new viral variants.

In addition, on 25 January, Moderna confirmed its Covid-19 vaccine was similarly able to neutralise the UK and South Africa variant. It remains unclear if the other approved vaccines, including AstraZeneca/University of Oxford vaccines and Russia’s Sputnik V, are also still effective against these three viral variants.

Despite some promising signs, the world is not out of the woods yet. It remains possible that these variants could continue to mutate – or other variants could emerge – to be resistant to the vaccines.

Enter next-generation vaccines to tackle Covid-19 variants

When SARS-CoV-2 emerged on to the global stage in early 2020, many pharma groups leapt into action. After receiving the genetic code of the emerging coronavirus from researchers in Australia and China in mid-January, these companies signed deals and started to apply existing technology – often used for previous coronaviruses like SARS and MERS – to develop vaccines targeting the S protein used by SARS-CoV-2 to infect human cells.

Thanks to these efforts, within nine months of the pandemic’s outset, three vaccines had completed Phase III trials and began to be approved across the world.

Given the likelihood that SARS-CoV-2 would mutate, and new viral variants would emerge, other vaccine developers took their time and decided to look beyond the obvious target, the spike (S) protein, when designing their Covid-19 vaccines. Two examples of companies with next-generation vaccines designed to hold up better against new variants are California-based Vaxart and France’s OSE Immunotherapeutics.

Beyond the S protein: Vaxart’s oral Covid-19 vaccine

Vaxart founder and chief scientific officer Sean Tucker states: “We know from history with coronaviruses, you can be reinfected every two to five years and that is generally not because of waning immunity, but because the strains mutate to get around the pre-existing immunity.”

Tucker adds that during the spring as the pandemic spread, it became clear to him that “the S protein was likely to be highly susceptible to mutations”. Therefore, Tucker explains, when applying its oral vaccine technology to the Covid-19 pandemic, Vaxart decided to also include the nucleocapsid (N) protein – an area “which is historically highly conserved among…coronaviruses” in its VXA-CoV2-1 vaccine.

“The idea was that as the S mutated, we would still be able to elicit a strong T cell response against the N proteins” to protect against emerging variants, Tucker says. This concept bore fruition in Vaxart’s ongoing Phase I trial where orally administered VXA-CoV2-1 was found to activate strong T cell responses against both the S and the N proteins. Now Vaxart needs to continue to collect data to confirm that VXA-CoV2-1 remains effective against variants as they emerge and continue to mutate.

As it is an oral vaccine, Vaxart’s VXA-CoV2-1 could also overcome one of the other challenges facing the first-generation vaccines: logistics. Vaxart CEO Andrei Floroiu noted in a release: “Our room temperature-stable oral tablet vaccine has the potential to ease many of the problems associated with distribution and administration of cold chain-dependent injectable vaccines and may make herd immunity more achievable by making it much easier to vaccinate more people faster.”

OSE’s 11-target Covid-19 vaccine

Similarly to Vaxart, OSE Immunotherapeutics noticed that all the first-generation vaccines were targeting the same antigens on the S protein, according to the company’s chief scientific officer Nicolas Poirier. Poirier was concerned by this as “we know when you have a lot of immune response against the same antigens you have a pressure selection effect, which could favour the emergence of variants or mutations”, as well as the fact that the S protein is prone to mutation.

OSE decided to focus on “targets that are not exposed to the body as they are inside the capsid of the virus”, Poirier notes.

To decide on which epitopes, or small protein fragments, to target with its vaccine, OSE screened “the T lymphocytes memory response in convalescent symptomatic and severe patients” and 46,000 sequences of SARS-CoV-2 to avoid mutation hotspots.

OSE used its Memopi technology to settle on 11 different targets that are outside these high-mutation regions and are naturally immunogenic in humans to include in its CoVepiT vaccine. These targets focus on areas of SARS-CoV-2 including S, M, N and non-structural proteins and also aim to confer not antibody-based immunity, but a long-term lymphocyte response to SARS-CoV-2.

As CoVepiT moves towards starting Phase I studies, Poirier notes that OSE is continuing to regularly screen hundreds of thousands of sequences of SARS-CoV-2 to check there were no mutations in the regions the vaccine targets.

This vaccine design approach also means that even if one of the variants were to mutate to compromise OSE’s S targeting epitopes, “there are still 10 other targets designed to elicit a T lymphocyte response against SARS-CoV-2,” Poirier says. “Outside of Spike, no SARS-CoV-2 mutation has been observed in our other 10 targets.”