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The Public Health Emergency Is Expiring, So What Is The Future Of Covid-19 Vaccines?

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.

Image by Flickr user NIAID via a Creative Commons license

MRNA Vaccines – Just The Beginning?

By Dr. Myriam Mendila, chief development officer of CureVac

World Immunization Week is April 24-30, and it's an important week to highlight the action needed and to promote the use of vaccines to protect people around the world, of all ages, against infectious diseases.

World Immunization Week aims to promote the use of vaccines to protect people of all ages from diseases and deliver immunization. Although vaccination is one of the most effective public health interventions to prevent, control and even eradicate diseases, and has made one of the greatest contributions to human health and life expectancy, there continues to be a global need for new and improved vaccines available to everyone. 

Over the past 60-70 years, great strides in vaccine development have been made and delivered enormous benefits to human health. With the application of the mRNA technology to combat the devastating impact of coronavirus infection being one of the most recent, can this technology have a similar impact on other diseases?

Dr. Myriam Mendila, chief development officer of CureVac, explains how we are likely to have just scratched the surface on how mRNA vaccines have the potential to improve outcomes for many other diseases beyond COVID-19.

The global coronavirus pandemic brought about unprecedented cooperation and collaboration to address this significant global threat. Scientists around the world looked for a technology that could be rapidly adapted into a vaccine and advanced into development.

Luckily, mRNA was poised and ready to make, what we now know, a monumental impact on the severity of coronavirus infection and enabled the world to return to normal.

mRNA not a new technology

Unlike the general perception of being a new technology, the use of mRNA for medical purposes has been in development for about 20 years, with multiple clinical studies conducted, including its use as a vaccine for infectious diseases and cancer. Ever since the founder of CureVac, Dr. Ingmar Hoerr, was able to show that mRNA could be stabilized and introduced to the body without being destroyed, extensive research has been conducted to design an optimal mRNA backbone that could possibly be adapted for therapeutic use.

mRNA itself is unstable and rapidly broken down by enzymes in the body. To solve this challenge, lipid nanoparticles (LNPs) are typically used to provide a protective coating, enabling efficient delivery of the mRNA into cells.

Following the sequencing of the coronavirus spike protein, which grants the virus entry into human cells, an mRNA strand coding for that given spike protein could be tailored to create a vaccine. Following administration of the mRNA vaccine, an immune response is triggered against the coronavirus spike protein. The vaccine can be generated in days, which demonstrates the power and flexibility of the mRNA technology. Not only is this important for future pandemic preparedness, but also in responding to other infectious diseases that continue to impact global health, including seasonal influenza, respiratory syncytial virus (RSV), malaria and many others. The advantage of mRNA technology is that it lends itself extremely well to combining different antigens into one vaccine. Already, there are studies with multivalent vaccines combining influenza and COVID-19, RSV and COVID-19 as well as the potential to include all three into one vaccine.

In some respects, the clinical development timelines for mRNA technology to obtain regulatory approval for use in a given disease, and then entry into the market, are very similar to those of other technologies in the same indication, such as other vaccine types, monoclonal antibodies, RNA interference, antibody-drug conjugates, etc. The difference during the pandemic, was the condensed clinical development timeline for vaccine product development and the unique situation where many stakeholders joined forces to achieve a common goal. Many people are now wondering, if this can be achieved with COVID-19, why can't a similar effort work with other diseases?

Still early days for mRNA vaccines

Despite a couple of decades of research, in many respects, we are still in the early days of understanding the potential of mRNA for medical use. Following COVID-19, evaluating the impact that mRNA can have on other diseases is still in its infancy. The development of new generation COVID-19 vaccines was a great place to start, as well as expanding the technology into influenza, RSV and other respiratory diseases. But the real indicator of the impact that mRNA can have on human health will be success in other major therapeutic areas. Most companies developing mRNA technology are also looking at oncology, including at CureVac, which was the original focus of the company on founding. The concept of developing a vaccine for cancer isn't new, but development of an effective product has been elusive.

In oncology – like with prophylactic vaccines for infectious diseases – a cancer vaccine teaches the immune system to recognize cancer cells and kill them. As cancer cells are so close to normal healthy cells, this has proven very difficult and can only be achieved by mimicking specific proteins found on the surface of cancer cells.

Over the last decade, major technological advancements, such as next-generation sequencing, have been made that enable precise data from patient tumor samples to be extracted, including the identification of point mutations that give rise to tumor specific antigens that can only or mostly be found in tumor cells and so serve as targets for cancer vaccine candidates. With the ability to sequence the entire exome (only protein coding sequences of the genome) of every patient, the inventory of genomic changes in a tumor can be seen. This information provides the foundation for using mRNA technology encoding for specific tumor antigens as the basis for cancer vaccine development and hopefully the success that previous technologies have not achieved.

This approach is now beginning to show potential. Earlier in April at the American Academy for Cancer Research (AACR) annual meeting, Merck and Moderna presented encouraging clinical data using their mRNA cancer vaccine plus Keytruda in the treatment of early melanoma, and further data in other cancer settings are eagerly awaited. While the development of mRNA cancer vaccines based on the information from whole exome sequencing is advancing towards phase III clinical trials, technology is already progressing to the next stage. Whole-genome-sequencing, combined with short as well as long-range RNA sequencing, has the potential to provide an innovative approach for broader cancer antigen discovery, enabling the detection of the full inventory of genomic alterations in a given tumor as the basis for a cancer vaccine.

Reaching the patient

The successful development of a vaccine in general, regardless of disease setting, is a huge achievement but is only the beginning. It then needs to reach the patient. Despite many advances, the distribution of new vaccines globally, remains a challenge. Traditional vaccine production entails multiple steps, from manufacture of drug substance to fill & finish, as well as the logistics needed to ship the product to the point of need.

During COVID, there was the additional challenge of needing to keep the vaccines in cold storage, at temperatures much lower than the regular cold supply chain. However, this issue has now been partially addressed, enabling easier distribution to all parts of the world.

Once again, the power and flexibility of mRNA in vaccine development could dramatically disrupt the status quo. Manufacturing infrastructure is now in place to rapidly produce new mRNA vaccines at large industrial scale, which could potentially lead to a lower price per vaccine and enable companies to supply low-income countries more cost effectively.

Our colleagues at BioNTech have also taken a more direct approach in Africa to boost manufacturing capacity and supply with the introduction of a container solution. The first containers are now in place in Rwanda.

At CureVac, we are pioneering a mobile integrated and automated platform, a "printer" for the small-scale manufacture of mRNA vaccines and therapeutics in Good Manufacturing Practice (GMP) standard. The printer, which covers all steps for rapid and standardized manufacturing, has been designed to potentially facilitate broad access to mRNA technology and is expected to accelerate the transition of innovative product concepts from science to the clinic across different therapeutic areas, such as new mRNA-based vaccines in pandemic situations, mRNA product production for clinical studies as well as personalized mRNA-based therapies in oncology. The printer is RNA agnostic, meaning that users can produce any RNA sequence, not just those from CureVac.

The development of a new product addressing the current challenges of manufacturing relies on the effective design of the mRNA strand. For example, the 5′ and 3′ UTR elements flanking the coding sequence profoundly influence the stability and translation of mRNA, both of which are critical for the efficacy of vaccines. These regulatory sequences also impact the half-life and expression of therapeutic mRNAs. Technology innovation is enabling the development of a new generation of mRNA vaccines addressing not only the current challenges, but also providing foundations for multiple avenues of future research.

The potential of mRNA is enormous, and it has already changed industry policies. Three main companies with expertise in the development and manufacturing of mRNA are shaping the regulatory environment, and they define new standards for the field to enable continuous innovation. But innovation is not limited to a handful of high-profile companies that have developed or are developing COVID-19 vaccines. Partnering and collaboration has always played a key role in technology development, with start-ups and academia often providing innovation and larger biotech/pharma companies the funding, infrastructure and expertise for development and commercialization. Collaboration was key to the success of mRNA vaccines in COVID-19 and will be essential in the future because the development of mRNA vaccines and therapeutics is not easy.

In summary, we are only just beginning to realize the potential of mRNA vaccines. Over the next several years, we could see the technological advances needed to overcome existing limitations – multivalent vaccines deliverable in a single shot for infectious disease, additional success in cancer vaccines and therapeutic application in other major diseases, such as heart disease, metabolic disorders and neurological conditions. 

Beyond vaccines, the mRNA platform could be the next transformation in medicine addressing the unmet needs for many patients around the world.

Vaccine Printer Could Help Vaccines Reach More People

Getting vaccines to people who need them isn't always easy. Many vaccines require cold storage, making it difficult to ship them to remote areas that don't have the necessary infrastructure.

MIT researchers have come up with a possible solution to this problem: a mobile vaccine printer that could be scaled up to produce hundreds of vaccine doses in a day. This kind of printer, which can fit on a tabletop, could be deployed anywhere vaccines are needed, the researchers say.

"We could someday have on-demand vaccine production," says Ana Jaklenec, a research scientist at MIT's Koch Institute for Integrative Cancer Research. "If, for example, there was an Ebola outbreak in a particular region, one could ship a few of these printers there and vaccinate the people in that location."

The printer produces patches with hundreds of microneedles containing vaccine. The patch can be attached to the skin, allowing the vaccine to dissolve without the need for a traditional injection. Once printed, the vaccine patches can be stored for months at room temperature.

In a study appearing today (April 24) in Nature Biotechnology, the researchers showed they could use the printer to produce thermostable COVID-19 RNA vaccines that could induce a comparable immune response to that generated by injected RNA vaccines, in mice.

Jaklenec and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, are the senior authors of the study. The paper's lead authors are former MIT postdoc Aurelien vander Straeten, former MIT graduate student Morteza Sarmadi '21, and postdoc John Daristotle.

Printing vaccines

Most vaccines, including mRNA vaccines, have to be refrigerated while stored, making it difficult to stockpile them or send them to locations where those temperatures can't be maintained. Furthermore, they require syringes, needles, and trained health care professionals to administer them.

To get around this obstacle, the MIT team set out to find a way to produce vaccines on demand. Their original motivation, before COVID-19 arrived, was to build a device that could quickly produce and deploy vaccines during outbreaks of diseases such as Ebola. Such a device could be shipped to a remote village, a refugee camp, or military base to enable rapid vaccination of large numbers of people.

Instead of producing traditional injectable vaccines, the researchers decided to work with a novel type of vaccine delivery based on patches about the size of a thumbnail, which contain hundreds of microneedles. Such vaccines are now in development for many diseases, including polio, measles, and rubella. When the patch is applied to the skin, the tips of the needles dissolve under the skin, releasing the vaccine.

"When COVID-19 started, concerns about vaccine stability and vaccine access motivated us to try to incorporate RNA vaccines into microneedle patches," Daristotle says.

The "ink" that the researchers use to print the vaccine-containing microneedles includes RNA vaccine molecules that are encapsulated in lipid nanoparticles, which help them to remain stable for long periods of time.

The ink also contains polymers that can be easily molded into the right shape and then remain stable for weeks or months, even when stored at room temperature or higher. The researchers found that a 50/50 combination of polyvinylpyrrolidone and polyvinyl alcohol, both of which are commonly used to form microneedles, had the best combination of stiffness and stability.

Inside the printer, a robotic arm injects ink into microneedle molds, and a vacuum chamber below the mold sucks the ink down to the bottom, making sure that ink reaches all the way to the tips of the needles. Once the molds are filled, they take a day or two to dry. The current prototype can produce 100 patches in 48 hours, but the researchers anticipate that future versions could be designed to have higher capacity.

Antibody response

To test the long-term stability of the vaccines, the researchers first created an ink containing RNA that encodes luciferase, a fluorescent protein. They applied the resulting microneedle patches to mice after being stored at either 4°C or 25°C (room temperature) for up to six months. They also stored one batch of the particles at 37°C for one month.

Under all of these storage conditions, the patches induced a strong fluorescent response when applied to mice. In contrast, the fluorescent response produced by a traditional intramuscular injection of the fluorescent-protein-encoding RNA declined with longer storage times at room temperature.

Then, the researchers tested their COVID-19 microneedle vaccine. They vaccinated mice with two doses of the vaccine, four weeks apart, then measured their antibody response to the virus. Mice vaccinated with the microneedle patch had a similar response to mice vaccinated with a traditional, injected RNA vaccine.

The researchers also saw the same strong antibody response when they vaccinated mice with microneedle patches that had been stored at room temperature for up to three months.

"This work is particularly exciting as it realizes the ability to produce vaccines on demand," says Joseph DeSimone, a professor of translational medicine and chemical engineering at Stanford University, who was not involved in the research. "With the possibility of scaling up vaccine manufacturing and improved stability at higher temperatures, mobile vaccine printers can facilitate widespread access to RNA vaccines."

While this study focused on COVID-19 RNA vaccines, the researchers plan to adapt the process to produce other types of vaccines, including vaccines made from proteins or inactivated viruses.

"The ink composition was key in stabilizing mRNA vaccines, but the ink can contain various types of vaccines or even drugs, allowing for flexibility and modularity in what can be delivered using this microneedle platform," Jaklenec says.

More information: Robert Langer, A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines, Nature Biotechnology (2023). DOI: 10.1038/s41587-023-01774-z. Www.Nature.Com/articles/s41587-023-01774-z

This story is republished courtesy of MIT News (web.Mit.Edu/newsoffice/), a popular site that covers news about MIT research, innovation and teaching.

Citation: Vaccine printer could help vaccines reach more people (2023, April 24) retrieved 26 April 2023 from https://medicalxpress.Com/news/2023-04-vaccine-printer-vaccines-people.Html

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