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As the SARS-CoV-2 virus continues to evolve, we explore what vaccine developers are doing to ensure their vaccines work against emerging variants and whether we need specifically adapted vaccines.

To date, 12 COVID-19 vaccines have received authorization for use in at least one country, and many more vaccine candidates are undergoing clinical trials to test their safety and efficacy.

Yet, like other viruses, SARS-CoV-2, the coronavirus that causes COVID-19, naturally undergoes mutations in time. These mutations can be negligible or affect how infectious or likely to cause severe disease a virus is.

With this in mind, and while the global vaccine rollout is currently underway, scientists and the public alike have raised a key concern: How will available vaccines and vaccine candidates hold up against emerging SARS-CoV-2 variants?

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The answer to this question lies in the definition of the word “work.” When vaccine developers set out the conditions of their clinical trials, they work closely with regulatory authorities, such as the Food and Drug Administration (FDA), to ensure they answer the most important questions.

For most experimental COVID-19 vaccines, the primary endpoints, or the main questions that a clinical trial asks, were the prevention of COVID-19. This meant that the developers would assess any case of COVID-19, including mild and moderate cases, when they were calculating how well their vaccine candidate performed.

In the case of the Pfizer-BioNTech vaccine, which was the first to receive emergency use authorization from the FDA, eight people who had received the vaccine and 162 people who had received the placebo developed COVID-19. This equates to a vaccine efficacy of 95%.

There were no deaths in either group in the clinical trial that the researchers could attribute to COVID-19 by the time the data became publicly available in the New England Journal of Medicine on December 31, 2020.

According to a recent study, real-world data from Israel suggest that this vaccine is highly effective in preventing COVID-19, including severe disease.

The authors of this paper could not provide a specific breakdown of how well the vaccine works at preventing COVID-19 in those who have the B.1.1.7 SARS-CoV-2 variant. However, they suggest that the vaccine is effective against the variant based on their overall data.

B.1.1.7 — a SARS-CoV-2 variant first identified in the United Kingdom — is one of a handful of emerging variants that have given rise to some concerns. Other variants that have caused some worry are B.1.351, first identified in South Africa, and P.1, which appears to originate in Brazil.

These variants are causing concern because they appear to be more transmissible than previous variants, and there is also some conjecture that some of them might give rise to more severe cases of COVID-19.

Given these concerns, two main questions have arisen: Will existing COVID-19 vaccines be able to match these emerging variants? And, how might vaccine producers modify their candidates to respond to new variants?

While data suggest that most COVID-19 vaccines might hold up reasonably well against B.1.1.7, the B.1.351 variant is causing significant concern.

When it comes to this variant, vaccine efficacy is lower, in some instances quite dramatically so.

Viral vector vaccines: Oxford-AstraZeneca and Johnson & Johnson

A sub-group analysis of data from the Oxford-AstraZeneca vaccine trial showed that the vaccine only had an efficacy of 10.4 % against COVID-19 in people who had an infection with B.1.351. However, it is worth noting that this study was small and has not been through peer review yet.

Nevertheless, in an interview for the BMJ from January 2021, Prof. Andrew Pollard, Director of the Oxford Vaccine Group and one of the leaders of the Oxford vaccine trials, explained that it would not be difficult to modify both mRNA and viral vector vaccines — of which the Oxford-AstraZeneca vaccine is one — to match emerging variants.

“For the RNA vaccines and the viral vectors, it’s relatively straightforward because you just have to synthesize a new bit of DNA in our case — or RNA in [the Pfizer and Moderna] cases — and then insert that into the new vaccine. Then there’s a bit of work to do to manufacture the new vaccine, which is a reasonably heavy lift. But the same processes would be used,” he told The BMJ.

“The second component,” he added, “is that there will almost certainly need to be some testing, whether it’s in animals or humans, to show that you can still generate immune responses, and then the regulator would have to approve that new product.”

Speaking to Reuters in February, the head of research and development at AstraZeneca, Sir Mene Pangalos, suggested that the company are already looking at a second-generation vaccine that would stand up to emerging variants.

This work could take at least until fall to complete. He declared: “We’re working very hard, and we’re already talking about not just the variants but also the clinical studies that we need to run, and we’re very much aiming to try and have something ready by the [fall].”

Medical News Todaycontacted both AstraZeneca and the Oxford Vaccine Group for comment, asking them about addressing concerns as to whether their COVID-19 vaccine can provide immunity against emerging variants. However, the company and the research group did not reply to our queries.

More recently, Johnson & Johnson reported their phase 3 clinical trial results ahead of gaining emergency use authorization for their single-shot viral vector COVID-19 vaccine from the FDA.

This vaccine demonstrated an overall efficacy of 66% at preventing moderate to severe COVID-19 across all clinical study sites. Johnson & Johnson have taken a different approach and studied moderate to severe disease at 14 and 28 days post-vaccination as their primary endpoints, rather than any COVID-19 disease.

When breaking down the data by region, the company reported efficacy against moderate to severe disease of 72% in the U.S., 66% in Latin America, and 57% in South Africa, indicating the drop in efficacy against COVID-19 caused by infection with B.1.351.

However, there were no cases of hospitalization or death in the group that had the vaccine from 4 weeks post-vaccination onward.

MNT contacted Johnson & Johnson for comment, but the company did not respond to our queries.

mRNA vaccines: Moderna and Pfizer BioNTech

Moderna are forging ahead with a variant-matched vaccine candidate. The company have already developed a new experimental vaccine specifically designed to match the B.1.351 variant.

In a press release from February 24, Moderna announced that they had shipped the first batch of this new vaccine candidate to the National Institutes of Health (NIH), who will be testing it in a new phase 1 trial.

The National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) told MNT that “NIAID plans to begin a phase 1 trial evaluating a vaccine against the B.1.351 variant developed by Moderna in (roughly) mid-March.”

“We will provide more information in an announcement once the trial has begun, per our usual process,” they said.

There will be a three-pronged approach to addressing the specific challenges of the B.1.351 variant.

The first will involve testing the variant-matched vaccine candidate as a booster in its existing clinical trial cohort. The second will test the new experimental vaccine as a booster in combination with the authorized Moderna vaccine. Scientists refer to such a combination as a multivalent vaccine.

The third approach will be a booster with the original vaccine. According to the press release, Moderna has already started this third booster approach.

Separately, the company are also planning on testing the variant-matched or the multivalent vaccine in people who have not received a vaccination yet.

Moderna did not reply to MNT‘s request for comments on their strategy regarding emerging SARS-CoV-2 variants.

Pfizer and BioNTech are currently testing a third dose of their mRNA vaccine in their clinical trial cohort to assess how well this strategy will prevent COVID-19 in light of emerging variants.

“Separately, in order to be prepared for any potential future strain changes, Pfizer and BioNTech are in ongoing discussions with regulatory authorities, including the [FDA] and the European Medicines Agency (EMA), regarding a registration-enabling clinical study to evaluate a variant-specific vaccine having a modified mRNA sequence,” the press release states.

“This study will evaluate the safety and immunogenicity of a third dose of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) to understand the safety and impact of a booster dose on immunity against COVID-19 caused by the circulating SARS-CoV-2 variants,” a spokesperson from Pfizer told MNT.

They continued:

“Based on in vitro studies conducted to date and observations from real-world evidence, we have not observed changes to neutralizing antibody levels that would predict a significant reduction in [the] protection provided by two doses of BNT162b2. [However], it is important to gather the clinical evidence to prepare in case an additional dose or an updated vaccine is needed.”

The companies are looking to test both the booster and new variant-matched experimental vaccines. “We are doing this to be prepared in case immunity wanes or a variant were to emerge that escapes protection from the current vaccine,” they explained.

They explained that a new vaccine with a modified mRNA sequence could facilitate a fast-paced updating process as new variants of concern emerge. Pfizer told us that they are already negotiating with the relevant authorities as to kickstarting a relevant evaluation study:

“Pfizer and BioNTech are in ongoing discussions with regulatory authorities regarding a potential registration-enabling study to evaluate an updated vaccine having a modified mRNA sequence. This could position us to update the current vaccine quickly if the need arises to protect against COVID-19 from emerging variants.

“Updated guidance issued by the FDA regarding emergency use of vaccines to prevent COVID-19 provides recommendations for evaluating a modified vaccine to address variants. By studying the effect of a booster vaccine now, the companies are hoping to inform the development of an efficient regulatory pathway for the validation of future modified mRNA vaccines, using the current pathways for influenza vaccines as models,” they added.

Subunit vaccines: Novavax

American vaccine development company Novavax have also developed a vaccine candidate — a subunit vaccine — that has shown a lot of promise against SARS-CoV-2.

According to a press release from January 29, 2021, the vaccine candidate was 89.3% efficient against the original strain in the context of a phase 3 trial conducted in the United Kingdom.

“Importantly, the timing of the trial overlapped [with] the emergence of the ‘U.K. variant,’ and over half the U.K. cases had this strain: the vaccine showed 86% efficacy in these patients,” Dr. Gillies O’Bryan-Tear, a fellow of the Faculty of Pharmaceutical Medicine in the U.K., who was not involved in the trial, explains.

In February, the EMA said they had started reviewing Novavax’s vaccine candidate for rollout in the European Union (EU).

A month later, on March 11, 2021, Novavax announced that their candidate was effective in protecting against disease caused by two variants, B.1.1.7 and B.1.351, first identified in the U.K. and South Africa, respectively.

However, some experts caution that despite these promising results, the candidate is still not as effective against newer variants as it is against the original ones.

For example, Prof. Lawrence Young, from Warwick Medical School in Coventry, U.K., notes that: “The Novavax protein-based vaccine is very effective against infection with the original virus variant (96.4% against symptomatic disease) with slightly reduced efficacy against the U.K. variant (B.1.1.7). However, the overall efficacy of this vaccine against the B.1.351 South African variant is significantly reduced at 48.6% — increasing to 55.4% if HIV-positive participants are excluded.”

“This study supports the need for modifying existing vaccines to provide better protection,” he adds.

In a comment for MNT, Novavax said they “initiated the development of new vaccine constructs in January 2021 as soon as some of the emerging variants’ (501Y.V1 and 501Y.V2) genetic sequences were available. [They] have begun the production process to make a purified variant recombinant spike protein for a bivalent vaccine.”

Similarly to Pfizer, they added that: “Preclinical studies are underway, and we plan to begin clinical testing of these new vaccine candidates in the first half of this year. The FDA has issued preliminary guidance on a regulatory pathway that provides clarity on the path forward.”

When asked how easy it would be to adapt their vaccine technology to match new variants, Novavax told MNT:

“A hallmark of our technology platform is that our manufacturing processes are easily adaptable to producing other versions of the coronavirus spike protein that match the new strains. Additionally, our platform uses a very small amount of antigen, which provides the ability to create a bi- or multivalent vaccine and also the rapid creation and large-scale production of vaccine candidates that could potentially address multiple circulating strains of [the coronavirus that causes] COVID-19.”

In light of both Moderna and Pfizer-BioNTech testing additional booster shots of their authorized vaccines, it stands to question whether variant-matched vaccines are necessary.

Prof. Jonathan Ball, a professor of molecular virology at the University of Nottingham in the U.K., recently made this argument on Twitter:

“Our own (so far unpublished) work show[s] that repeat boosting can generate antibodies that potently knock out [SARS-CoV-1] — which is far more antigenically different than variants of [SARS-CoV-2],” he said on the social media platform.

In his view, there is thus enough ground to test the potential of an additional booster dose in creating immunity against emerging SARS-CoV-2 variants, rather than developing second generation vaccines that match these variants.

Responding to MNT‘s queries, Novavax told us that they did expect that matched, bivalent, or multivalent vaccines against COVID-19 will become necessary in the future.

Another company looking at specifically targeting emerging variants are CureVac. With their mRNA vaccine candidate currently in phase 3 clinical trials, CureVac are currently studying how well it will perform against SARS-CoV-2 variants in “targeted in vitro studies,” Vice President of Communications Thorsten Schüller told MNT.

CureVac have teamed up with GSK and the U.K. government to develop second generation COVID-19 vaccines.

“Mutations are natural survival strategies of viruses, and SARS-CoV-2 variants are going to continue to occur throughout the world, and their number is likely to increase in the future,” Mr. Schüller explained. “There will be an enormous need for vaccines in general and particularly for multivalent vaccines.”

Vaccine developers are clearly taking the threat that new SARS-CoV-2 variants may pose risks seriously. Whether we face a future with variant-matched annual boosters akin to the flu shot remains to be seen.

For pharmaceutical companies, a steady demand for vaccines may also spell a guaranteed income.

Only as scientists continue to study how well the existing vaccines and those in development cope with SARS-CoV-2 variants will the full picture emerge.

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