Coronavirus: what will the second generation vaccines against Covid-19 be like

December 8, 2021

As news leaked out that the Covid-19 vaccine being developed by Pfizer and BioNTech was about to roll out around the world, Todd Zion couldn’t help but feel a bit deflated.

It was November 2020 and, for the first time, news of hope in the fight against Covid-19.

Not just Pfizer-BioNTech, but Moderna and later Oxford-AstraZeneca reported Phase III clinical trial results for their vaccines with efficacy that exceeded the expectations of the most optimistic scientists.

What followed was an avalanche of political deals and vaccine diplomacy. World leaders were quick to be the first to get their hands on the new vaccines.

While Zion, an entrepreneur and CEO of a small startup called Akston Biosciences, was personally relieved that the tide was turning against the global pandemic, he faced the unenviable task of trying to convince his employees that His hard work had not been in vain.

Nine months earlier, Akston Biosciences had joined the global vaccine race as one of more than 40 teams competing to develop the first vaccine against the Covid-19 of the world.

Now, like dozens of others, they had been completely defeated by the speed and efficiency of their rivals’ technologies, who had completed clinical trials while their own products were still in development.

But Zion still felt that the race was far from over. “Those vaccines helped enormously, but if you are an innovator, you know that products that come first tend to have a lot of problems that are not sustainable, «he says.

“So for that reason I stayed motivated. But for a small company it was a challenge to keep developing our vaccine while most of the world thought the problem was solved. «

Second generation

Twelve months later, Akston Biosciences is among a plethora of companies hoping to bring a second generation vaccines Covid-19 to the clinic for the next year and a half.

The challenges are plentiful: Many vital vaccine raw materials are desperately in short supply, while more than two years into the pandemic, they must convince regulators that new products are still needed.

But they come with a variety of novel innovations. There is, for example, the French biotech company Valneva, whose vaccine contains an adjuvant chemical that is added to the vaccine to stimulate the immune response. This, in particular, has the objective of provoking a better immune response in the elderly.

Also adding to the list is California-based Vaxart, which is developing a vaccine in pill form that could address the problem of needle phobia.

Each second-generation vaccine has its own specific target markets.

The appearance of new mutated versions of the virus that causes Covid-19 during the last year, such as the Delta and Omicron variants, create a potential requirement for different technologies of provide a stronger immune system response.

«We have some data that your immune system’s response to natural infection, but also to vaccination, declines over time,» says Andrew Ustianowski, clinical leader of the Covid Vaccine Research Program at the National Institute for Health Research in the United States. United Kingdom.

“We can see the antibody responses and, to some extent, the T cell responses decreasing over time. Therefore, one of the hopes of second-generation vaccines is that they can provide us with protection for a longer period than these first vaccines. «

The strict refrigeration requirements for many of the first-generation vaccines have also posed significant challenges in reaching many of the world’s poorest communities. For example, currently, only 28% of India’s population is fully vaccinated.

Akston Biosciences recently received approval to conduct a Phase II / III clinical trial, the second stage of human trials, to verify the safety and efficacy of an intervention, in India over the next year.

The nature of its vaccine, which can be kept at room temperature for at least 6 months, is expected to help reach regions with limited infrastructure needed to store and transport less stable vaccines.

Although it may not be widely available until 2023, Zion is confident that it will remain highly relevant in the fight against Covid-19.

«We just signed a manufacturing development and license agreement with an Indian company,» he says. “They have about 100 countries on their list that they are targeting, mainly in the Southeast Asia, Middle East and Africa Sub-Saharan. We see that primary vaccines continue to be an opportunity in some of the underserved regions. «

Being late to the party

In early 2020, Filip Dubovsky was working for AstraZeneca when he learned of another pharmaceutical company called Novavax, which was developing a particularly inventive way to create a flu vaccine.

Company scientists had discovered a powerful adjuvant called Matrix-M, which comes from the inner bark of an endemic tree in Chile, the Quillaja Saponaria, known as the soap tree.

In a phase III trial, usually the final stage of the initial trial, involving large numbers of people, it not only produced a stronger antibody response than existing flu vaccines, but also provided cross-protection against multiple strains of influenza.

Dubovsky was intrigued, so much so that in June 2020 he joined Novavax as its medical director to work on the company’s Covid-19 vaccine. Yours recently became in the first of the second generation vaccines to hit the market, initially receiving an emergency clearance in Indonesia and the Philippines.

Dubovsky considered that the technology, which combines the Matrix-M adjuvant with a more traditional protein-based vaccine, would always take longer to develop than the methods used by the first wave of covid-19 vaccines, based on messenger RNA (mRNA). and adenovirus. However, it says that Getting to the party a little late may have given Novavax certain perks.

While Novavax’s clinical trials were being conducted, new variants of Covid-19 began to emerge, allowing them to show that their vaccine was still effective against a variety of different strains.

Their data so far shows that their vaccine is 93% effective against the Alpha and Beta variants, although no efficacy has been published for the dominant Delta strain and it is still too early to say whether it will be effective against Omicron.

Neutralizing antibodies

Dubovsky says that, as with the Novavax flu vaccine, the use of the adjuvant means that the vaccine stimulates the production of neutralizing antibodies which are of higher quality.

“It is not just about how high the antibodies go, but how good they are«Explains Dubovsky.NeN» We have data from early clinical studies showing that our vaccine was capable of generating very high-level neutralizing antibodies. So these are not just antibodies that can recognize the spicule, they can actually stop the spread of the virus. «

Dubovsky hopes his new adjuvant can help prevent calls «Progressive infections», whereby fully vaccinated people can become infected.

Progressive infections remain a major ongoing problem, particularly in the wake of the Delta variant, with studies estimating that advanced infection rates can range from 1 in 100 to 1 in 5,000, depending on the population.

(From the interview with Dubovsky, the strongly mutated Omicron variant has also emerged, which early signs suggest may also lead to a significantly higher rate of recurrent infections).

Generate more and better quality antibodies it is one of the main ways in which second-generation vaccines hope to stand out, as a possible booster option in the US and Europe, but also as a primary vaccine in many parts of the world.

Brian Ward, a medical officer at the Canadian biotech company Medicago, told the BBC that they are preparing to publish data from their phase III clinical trial and that they intend to apply for regulatory approval for their vaccine in a few weeks.

Medicago claims they can produce antibody titers (a measure of the concentration of antibodies) much higher than current vaccines.

«MRNA vaccines [producen títulos de anticuerpos que] are between two and a half and four times higher [que en alguien que se está recuperando de Covid-19]Ward says. «The Novavax vaccines and ours are 10 to 15 times higher.»

Vaccines that are further behind in development, such as Vaxart, which are currently enrolling for their Phase II trial, hope that offering new technologies or novel delivery mechanisms will still make them commercially viable.

Vaxart’s vaccine, which comes in tablet form, produces antibody responses in the nose that are believed to be better at preventing the spread of the virus. Additionally, the company has compiled survey data that found that 32% of Americans would be more likely to take a Covid-19 vaccine if it were offered in pill form.

According to The Lancet, since January 2021, 20% of American adults have consistently reported that they will get vaccinated only if necessary for work or they won’t be vaccinated at all. Vaxart founder Sean Tucker believes that having an oral vaccine can help with this problem. «At the end of the day, a lot of people are afraid of needles,» he says.

Another key way these vaccines can compete with first generation vaccines is in price, much more affordable than the more expensive Pfizer / BioNTech and Moderna vaccines.

«Our goal is $ 3-5 per dose, and we think that’s where it all happens in the future,» says Zion. “The amount of government subsidy at these $ 25-30 for dose price ranges (for mRNA vaccines) simply it will not be sustainable ”.

However, in such a competitive landscape, it remains to be seen whether there will be room for all second-generation vaccines in development. On the one hand, the market for drivers in high-income countries is highly uncertain.

Scientists are still unclear if the emergence of new variants will make regular immunizations against the virus a necessity, or if their threat will slowly decline in the coming years.

«Indeed, the manufacturers of the newer vaccines have to show a profit on top of what we already have,» says Ustianowski. «And that is not final.»

The risks

The successful implementation of Covid-19 vaccines over the past year has been widely hailed as an «unprecedented» achievement.

Vaccine development is a notoriously precarious business, with two-thirds of vaccines proving inadequate in clinical trials. However, experts have warned that the success of the first wave of covid-19 injections is no guarantee that the second wave will overcome it.

One of the first victims was the German company CureVac, whose mRNA vaccine showed disappointing results in a phase III trial in June, demonstrating an efficacy of only 47% in the prevention of diseases.

The news was seen as a setback as the vaccine, which used smaller doses of mRNA, was expected to be cheaper and last longer in storage than the Pfizer / BioNTech and Moderna equivalents.

CureVac is now seeking a new Covid-19 vaccine in partnership with GSK, which it attempts to target multiple variants of coronavirus at once. This has shown better results in animal studies and appears to elicit ten times more antibodies than your first try.

However, Klaus Edvardsen, development director at CureVac told the BBC that it is unlikely that they will be in a position to apply for regulatory approval before the end of 2022.

This example serves to illustrate the many obstacles and challenges that second-generation vaccine developers face.

Many companies are already finding that the road to regulatory approval is much more difficult, and the US Food and Drug Administration says there will be no more vaccine authorizations for emergency use.

The billions of doses of vaccines that have already been given (now 29.92 million are given every day) are also exerting unprecedented pressure on the vaccine supply chain.

With manufacturers of glass vials and other key raw materials choosing to prioritize first-generation vaccines, second-generation developers are struggling to get what they need.

«We are definitely among the second-class citizens when it comes to the supply chain,» says Zion.

“Vials, glass, plastic, everything is being consumed by the approved vaccines. We had some filters in order, which were in the truck, and then they were diverted to one of the approved vaccine companies through some government edict. It’s like that all the time. «

For Akston Biosciences and the other new competitors that are vying for a share of the market, the price of business failure is potentially too high.

Two years ago, Novavax saw a clinical trial for an RSV vaccine that collapsed and burned. The process cost them tens of millions of dollars, resulted in the layoff of employees and the sale of two development and manufacturing facilities.

The future

To date, it is estimated that 47.7% of the world’s population, including large swaths of South America, Africa and Asia, have yet to receive even a dose of coronavirus vaccine.

The great hope for second-generation vaccines is that they can make great strides on this problem, especially since unvaccinated populations are at even greater risk than any new variants that may emerge.

William Hanage, an epidemiologist at Harvard’s TH Chan School of Public Health, has been trying to quantify the impact of the Delta variant in unvaccinated people and recently discovered a surprising statistic.

«I was looking at death rates in the US and Florida had a delta wave after the vaccines became available,» he says.

“More than 30% of all Covid-19 deaths in Florida have occurred since vaccines, because delta is more dangerous and Florida has a lot of unvaccinated seniors. And that’s just in the US We know that there are large parts of the world that are not vaccinated. «

One company that is specifically focusing on bringing Covid-19 vaccines to low-income countries is Lund-based biotech Ziccum, which has developed a technology to air dry existing vaccines and turn them into powder forms that do not need to be stored or transported in cold temperatures.

Ziccum is collaborating currently with Janssen, whose first-generation Covid-19 vaccine was approved in February 2021, to study whether it will be possible to create dry powder forms from one of Janssen’s vaccine platforms.

In the near future, this could be used to try to improve the vaccine situation throughout the African continent.

Ziccum CEO Göran Conradson told the BBC that talks are taking place about the use of his technology in Rwanda, where less than 20% of the population is fully vaccinated.

«We have been invited to Rwanda to see what we can do,» says Conradson. “There have been many initiatives in Africa at this time. We have had so many contacts from the African CDC, the African Development Bank, the African vaccine manufacturers, there are a lot of initiatives ”.

Even if some of the second-generation vaccines never make it to the market for Covid-19, the vast investments in research and acceleration manufacturing processes, can bring significant health benefits in the field of other diseases.

Vaxart is also looking to create vaccine-based pills for flu and norovirus, while CureVac and GSK aim to produce one that vaccinates against coronaviruses and flu at the same time.

California-based biotech Gritstone recently launched a phase I clinical trial in Manchester, using a method known as self-amplifying RNA (saRNA), a newer form of mRNA technology.

Initially designed for use against cancer, it produces copies of itself once inside the cells of the body, which means that it can induce the same response as an mRNA vaccine, but with a dose 50 or 100 times lower, which makes the vaccine cheaper and easier to apply.

Andrew Allen, president, CEO and co-founder of Gritstone, says the vaccine technology could also be used to help develop universal vaccines against other viruses such as the flu.

It might even help accelerate your existing work on cancer vaccines, which uses biopsies to try to predict different targets for the immune system to attack, as the tumor evolves.

But one of the greatest legacies of this new wealth of vaccine research could be making the world much more prepared. for future coronavirus outbreaks, something that many scientists believe is inevitable based on the trends of the last two decades.

«We have had three coronavirus outbreaks in the last 20 years,» Allen says. “We had Sars in 2002, Mers in 2012, and then Covid-19. I think we can all agree that there will be another coronavirus outbreak, and we must be prepared for it. We need to be better prepared than last time«.

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