Covid-19 sent the biotech industry into overdrive to develop vaccines that could tame the novel coronavirus. In relatively short order, and after different kinds of vaccines were researched, we have reached a state where the vast majority of U.S. vaccinations are messenger RNA shots. FDA guidance on booster shots for this fall is still developing, but the picture of what Covid-19 vaccines could look like in the years to come is already taking shape.

If the research pans out, people could get both less and more. The shots will come less frequently, meaning fewer boosters. But a single shot could also offer the potential to protect against more pathogens, such as influenza and respiratory syncytial virus (RSV). These combination shots are still in clinical development, research that is dominated by larger companies. And that’s another consequence of the Covid-19 vaccine race. The chase produced some clear winners — Pfizer/BioNTech and Moderna — and their market dominance, combined with a challenging financing environment, will make it difficult for competitors to catch up.

In the nearer term, companies that have already brought Covid-19 vaccines to the market are focusing on next fall. The FDA last week simplified the Covid-19 vaccination schedule. The original monovalent mRNA shots are no longer authorized. The bivalent vaccines, which protect against the original strain and the prevalent omicron variants, are now authorized for all doses for those age 6 months and older. In another change, the FDA also authorized another booster of the current bivalent shot for the elderly and immunocompromised.

An FDA advisory committee meeting is planned for June to discuss the composition of the vaccines that would be rolled out for the coming fall and winter. The agency said it hopes that making Covid-19 vaccination more closely resemble a seasonal flu shot will prompt more people to take them.

The companies still involved in Covid-19 vaccine research are making a bet that these vaccines will continue to have a healthy demand. The players made a reasonable assumption that the Covid-19 vaccine market would resemble the annual influenza vaccine market, said Lee Brown, global sector lead for healthcare at Third Bridge, an investment research firm. That’s between 500 million and 600 million doses in the developed world. According to Centers for Disease Control and Prevention data, 194.4 million flu vaccine doses were distributed during the 2020-2021 flu season.

The thinking has since shifted and estimates place the annual U.S. Covid-19 vaccine market at about 100 million doses, Brown told MedCity News. Though projections are lower, vaccine prices are going up, meaning it’s still a multi-billion dollar market. The easiest way for competitors to tap into it is by pricing below the mRNA shots, he said.

“The fact that the size of the market should be quite large and recurring makes it still an attractive marketplace,” Brown said. “If you have a competitive [vaccine] candidate that you can commercialize, you can still try to displace market leaders with price. Right now, you have a duopoly essentially.”

Pfizer’s Covid-19 shot accounts for about 65% of U.S. vaccinations while Moderna’s represents about 35%, Brown said. Other vaccines have not yet shown they can compete. The FDA last year limited use of Johnson & Johnson’s authorized shot due to safety concerns. In January, the pharmaceutical company slashed production of that vaccine.

Novavax was finally able to finally secure FDA authorization for its protein-based vaccine last July, and for its booster last October. But Brown said the Gaithersburg, Maryland-based company is too far behind Pfizer and Moderna to grab a meaningful share of the post-pandemic market. Novavax also has money problems. In February, the company revealed doubts about its ability to financially support its protein-based vaccine. Those problems are suggestive of the financial challenges other vaccine developers face. Sales of the Pfizer and Moderna vaccines have created huge revenue streams that can be reinvested into the development of the next generation of vaccines, Brown said. Potential rivals will need to raise capital to develop their products, and it’s much harder to raise money now compared to the height of the pandemic.

The transitioning vaccine market

The Covid-19 market is moving from the pandemic state into what Vignesh Ramesh, a partner at PA Consulting, describes as a “steady state.” The massive government support for developing novel vaccines and accelerating regulatory review is going away, he said in an interview. In the steady state, Covid-19 vaccines will more closely resemble seasonal flu vaccines. Flu vaccines are dominated by a handful of big pharma companies: Sanofi, GSK, and Novartis. Just as a large number of new vaccine companies aren’t trying to enter this space each flu season, a large number of Covid-19 vaccine developers won’t be entering the space either, he predicted.

Despite the dominance of mRNA vaccines in the U.S., Ramesh notes that AstraZeneca’s Vaxzevria, a viral vector vaccine, has more shots in arms globally compared to either the Pfizer or Moderna vaccines. That’s because AstraZeneca struck deals to distribute its shots in places like China, India, and Africa. While AstraZeneca last fall opted not to seek FDA authorization for its shot, saying the U.S. market was already well served, Ramesh said that this vaccine, which is less complex to manufacture and distribute compared to the mRNA shots, can be successful in a steady state environment.

However, Ramesh said there is still room to compete on the mRNA turf of Pfizer and Moderna. The immunity of those shots dissipates after about 90 days. The mRNA vaccine of GSK-partnered CureVac, still in early clinical development, could stand apart if it tops that, he said. The partners are also trying to differentiate by developing shots capable of protecting against multiple coronavirus strains and multiple pathogens, including flu and RSV. Pfizer and Moderna are both also pursuing these such multi-valent vaccines. In the steady state, multivalency will also play a role in reducing the overall number of vaccinations a person would need.

“If you can shrink that number of vaccines into combos, or better, more easily available [vaccines], there’s a domino effect on cost and adherence,” Ramesh said.

Moderna’s multi-valent vaccine strategy includes a triple vaccine — Covid-19, flu, and RSV in a single shot. That vaccine is in Phase 1 testing. The company is also testing a flu and RSV combination. If these vaccines succeed in clinical trials and receive regulatory approvals, Moderna projects commercial launches starting in 2025, executives said during the company’s annual vaccines day event earlier this month.

One of the limitations of mRNA shots is the need for ultra-cold storage. Once thawed, they can be stored in a refrigerator for up to 30 days, according to FDA guidance to vaccine providers. Moderna is testing formulation changes that could improve how the vaccine is stored and administered. A new version of the bivalent vaccine that is refrigerator stable has started Phase 3 testing. Moderna did not respond to an inquiry seeking additional comment, but Jacqueline Miller, Moderna’s senior vice president of infectious disease development, said during the vaccines day presentation that in addition to improving the vaccine’s refrigerator shelf life, the changes also offer the potential for distributing these shots in pre-filled syringes.

“This is really important for people on the front lines of vaccinating because it will increase their ease of use,” Miller said.

The move to multivalent vaccines will come with greater use of artificial intelligence and machine learning technologies, according to Venkata Indurthi, chief scientific officer of Aldevron, a company that makes DNA, RNA, and proteins that are used in cell and gene therapies. AI tools predict the viral mutations that need to be addressed into new vaccines in development, Indurthi said. The technology also helps vaccine developers better understand RNA molecules and optimize their design.

“It’s going to be extremely critical for design optimization of these molecules, manufacturing optimization,” Indurthi said in an interview. “AI, machine learning significantly accelerates the speed of development moving forward.”

BioNTech has already leveraged AI via a partnership with startup InstaDeep. The alliance developed an early warning system that analyzed sequencing data to identify new, high-risk SARS-CoV-2 variants. Seeking to apply InstaDeep’s AI capabilities more broadly, BioNTech in January announced a £362 million deal to buy the company.

Vaccine challenges and opportunities

Some of the limitations facing RNA vaccines are outside of science. Economics and geopolitical tensions also affect production and distribution of vaccines, Indurthi said. Kevin Coker, CEO of the contract research organization Proxima Clinical Research, said the clear advantage of mRNA technology is the ability to quickly create a vaccine candidate compared with other technologies. But the ultra-cold storage requirements makes them a challenge even in some pockets of the U.S., he said.

“To distribute a vaccine like that, the infrastructure costs are significant,” Coker told MedCity News. “With DNA vectors, with protein vaccines, the stability of the products is much better. So you can get them into areas, underserved populations, much easier.”

As long as new vaccine technologies can provide advantages in efficacy and price, they can still provide competition in the U.S. and around the world, Ramesh said. The market opportunity in Southeast Asia and Africa is particularly large. As examples of technologies that could offer competition to current vaccines, Ramesh cited plant-derived vaccines and oral vaccines. But both types of technologies have encountered setbacks. Medicago’s Covifenz vaccine is made with a virus-like particle that resembles the coronavirus’s spike protein. One advantage of Medicago’s plant-derived vaccines is that they only need standard refrigerator temperatures. Last year, Canada approved the Quebec-based company’s vaccine.

The virus-like particle in Covifenz is produced in a plant closely related to the tobacco plant. Tobacco giant Philip Morris International was a minority shareholder in Medicago, a relationship that led the World Health Organization to turn down the company’s request for emergency authorization last year. The WHO and United Nations have a policy barring them from engaging with the tobacco industry. Philip Morris divested, selling its Medicago shares to the company’s majority shareholder, Mitsubishi Chemical Group. But in February, that Japanese company said it will close Medicago. Mitsubishi’s announcement said investing in the commercialization of Medicago’s products was no longer viable. The company did not respond to a message seeking further comment.

The changing Covid-19 landscape is also affecting oral vaccine research. In mid-March, Vaxart suspended mid-stage clinical trial plans for its Covid-19 pill vaccine, opting to focus instead on norovirus, where it can more quickly validate and differentiate its technology. However, CEO Andrei Floroiu said during an investor call that the technology can still offer advantages over injectable Covid-19 vaccines, which have so far shown limited ability to protect broadly against multiple variants and other viruses. Vaxart is continuing preclinical research of a pill vaccine that could offer cross reactivity — protection against SARS-CoV-2 as well as other coronaviruses. This approach builds on data Vaxart has observed in clinical testing of its pill vaccine candidates, Floroiu said.

Covid-19 revamped clinical research, leading many companies to adopt technologies that enable patients to participate remotely. But Coker, whose company has run clinical trials for Covid-19 therapies, sees another challenge for Covid-19 studies: the sites. Hospitals continue to grapple with turnover of a workforce exhausted by Covid-19, he explained. When hospitals look for places to save money, clinical research is one of the first places they cut. Consequently, clinical research is delayed, he said.

In the steady state world, Ramesh expects that Covid-19 vaccine developers will find recruiting patients and running clinical trials will be similar to conducting studies for other infectious diseases, such as flu or pneumococcal disease. In other words, it won’t be anything like it was at the height of the pandemic when Covid-19 studies were able to recruit large numbers of patients very quickly. Vaccine companies will need to plan for their trials to take much longer, he said.

Ramesh does not see a significant amount of investment going toward vaccine research beyond what’s being done by the market leaders. But looking at the Covid-19 market broadly, he sees more opportunity in research of new therapeutic options, particularly for treating moderate-to-severe disease.

“I don’t believe that space has been adequately served during the pandemic, and in the steady state environment, I see more opportunity in the treatment side,” he said.

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