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Biosimilar mRNA Vaccines, Part 1: Regulatory Revolution! – The Center for Biosimilars

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The COVID-19 pandemic has brought a remarkable shift in how we will prevent infections and autoimmune disorders in the future. The nucleic acid vaccines, including messenger RNA (mRNA) and DNA vaccines, have been under development for decades, but there was no opportunity to test their safety and efficacy; vaccines may take years and decades to provide sufficient proof of safety and efficacy. Then came COVID-19, caused by the SARS-CoV-2 virus. Fast data collection became possible because the virus was so widespread. Even with small infection numbers (n = 150) among study populations that averaged about 30,000 to 40,000, it was clear that mRNA vaccine efficacy was surprisingly high: 95% or better. The FDA would have approved the use of the mRNA vaccine at even at 50% efficacy.

The safety of the mRNA vaccines was confirmed clearly in multiple studies across the globe. However, not all COVID-19 vaccines fared well. The third mRNA vaccine, by CureVac, failed because its developers chose not to follow the teachings of the common wisdom. mRNA vaccines work by introducing a harmless piece of the virus into the body and triggering an immune response that conditions the body to recognize and attack the true virus. Moderna and Pfizer–BioNTech vaccines use modified RNA (pseudouridine); CureVac chose not to modify the RNA, and its vaccine uses normal uridine. It produced lower levels of antibodies than the Moderna and Pfizer-BioNTech vaccines and was just 47% effective at preventing COVID-19 infection. Incidentally, the name Moderna comes from “modified RNA.”

The Chinese Sinopharm vaccine, a traditional inactivated virus vaccine, also failed. This failure brought great misery because the Chinese government had used this vaccine as a diplomacy tool, supplying billions of doses to developing countries. As of today, none of the non-mRNA COVID-19 vaccines have come close to the efficacy of the mRNA vaccines.

We have 2 mRNA vaccines approved under Emergency Use Authorization (BNT162b2, mRNA-1273/NAID), and I anticipate their full approval soon. Pfizer has filed for the modification of storage temperature, and Moderna has filed for the reduction of dose; the Pfizer dose is 30 mcg, and the Moderna dose, 100 mcg. There are now newer lipid nanoparticle (LNP) formulations that can provide better temperature stability allowing only refrigeration storage.

Incidentally, Moderna has permitted the use of its patented LNP technologies to any company. Although the challenges to overcome IP issues remain, the humanitarian considerations make these challenges manageable. The US government has proposed to remove patent exclusivity relating to the COVID-19 vaccines. This action will require EU cooperation that is yet to come. However, as a patent law practitioner, I am confident that we can make COVID-19 vaccines without any patent infringement that remains in our way. mRNA vaccines have been under development for decades, so much of the base technology is already in the public domain. Both Pfizer and Moderna have shared their clinical protocol, and that is a rare event, as these protocols cost millions to produce and billions to execute. No other vaccine developer has shared these protocols in public. The mRNA vaccine developers now have a clear understanding of the regulatory process required to approve new mRNA vaccines.

Regulatory Pathway

At the time of the enactment of the Biologics Price Competition and Innovation Act (BPCIA, 2010), there was no indication that the introduction of mRNA vaccines would create a dilemma for the FDA in deciding an appropriate regulatory pathway.

The FDA’s Center for Biologics Evaluation and Research (CBER) jurisdiction includes biological products such as prophylactic and therapeutic vaccines, whole blood and blood products, cellular products and exosomal preparations, gene therapies, tissue products, and live biotherapeutic agents. CBER also regulates selected drugs and devices used to test and manufacture our biological products. In keeping with that mission, product approval applications filed with CBER include 351(a) filings, which are for “standalone” or original products, rather than biosimilars (21 Code of Federal Regulations [CFR] 601.2). The biologics license application (BLA) is regulated under 21 CFR 600 – 680.

Many biological products are controlled by the Center for Drug Evaluation and Research (CDER), including biosimilar and interchangeable biologics. For example, in March 2020, insulin, glucagon, and human growth hormone regulated as drugs under the Food, Drug, and Cosmetic Act came into the CDER BLA program.

mRNA vaccines have a unique feature: They are manufactured chemically, not biologically, as are many other vaccines. As a result, the vaccine structure is completely known, unlike the therapeutic proteins. The variations in the secondary and tertiary structures and post-expression modifications require intensive evaluation of similarity to allow them a biosimilar status. A proposed biosimilar mRNA vaccine can provide a 100% match for a reference product sequence. Thus, mRNA vaccines are closer to generic chemical products than biological therapeutic proteins.

In my opinion, the traditional vaccines can stay within the jurisdiction of CBER, and the chemically synthesized vaccines be approved under BLA by CDER under the 351(k) filing where suitable.

Already, the FDA has issued a final guideline (February 2021) on the development of products for the treatment and prevention of COVID-19, which states:

“COVID-19 vaccine development may be accelerated based on knowledge gained from similar products manufactured with the same well-characterized platform technology, to the extent legally and scientifically permissible. Similarly, with appropriate justification, some aspects of manufacture and control may be based on the vaccine platform, and in some instances, reduce the need for product-specific data. Therefore, FDA recommends that vaccine manufacturers engage in early communications with [Office of Vaccines Research and Review] to discuss the type and extent of chemistry, manufacturing, and control information needed for development and licensure of their COVID-19 vaccine.”

This statement can be construed as pointing to the possibility of a biosimilar application filing for a licensed (BLA) product to meet all requirements of the BPCIA. If the sequence of a biosimilar mRNA vaccine matches a reference product sequence, then the need for extensive toxicology and efficacy testing can be reduced, on a case-by-case basis, depending on other factors of variation. In my earlier conversation with the FDA, I appreciated the broad encouragement I received to discuss the development plan in a Type B meeting first, where the possibilities of a modified 351(a) filing or a 351(k) filing for a biosimilar mRNA vaccine can be discussed; the 351(a) modified approach will be analogous to a 505(b)(2) new drug application under the FDC Act. I will keep my readers informed of any new indications from the FDA.

mRNA vaccines are now at the forefront of hundreds of possibilities, including preventing infections to preventing autoimmune disorders. Since the antigens focused on the design of mRNA vaccines cannot be patented, a biosimilar vaccine product may likely produce the product without any infringement issue. The testing proposal presented above will help expedite the approval of biosimilars without risking the safety and efficacy of biosimilar products.

For the first time, we have a scientific challenge to meet: how to classify mRNA vaccines as chemical drugs or as biosimilars rather than standalone biologics?

In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products generally derived from living material (humans, animals, or microorganisms) are complex in structure and, thus, are usually not fully characterized. However, this last consideration does not apply to mRNA vaccines.

To promote the idea of creating a new category of products, biosimilar vaccines, I have filed a citizen petition to the FDA advising the agency on creating new guidance for this new class of biosimilar products. In my opinion, the agency will agree to many of my suggestions because the issue of structural similarity with a reference product is no longer an issue. Preclinical toxicology studies can be waived based on in vitro and situ studies, requiring only comparable antibody production in animal species. The immunogenicity—stimulation of immune response—is not a significant issue because vaccines are supposed to be antigenic. A limited trial in animal species capable of showing antibody response that is comparable to findings with the reference mRNA vaccine will suffice to establish equivalent safety with the reference product.

I have also developed several mRNA vaccines, including COVID-19, flu, HPV, HIV, and tuberculosis, that are under advanced stages of development across the globe, including one with a biosimilar status. Today, the world needs about 8 billion doses of COVID-19 vaccines that work. I have concluded that we can make 1 billion doses using 30 L bioreactors in 6 months with our cost of goods not exceeding $0.50 per dose in bulk and $0.90 in final packaging if the vaccine is manufactured in the United States; the costs can be lower if manufactured in developing countries. For example, the cost of Moderna single dose is $32 to $37, and Pfizer’s, $22 in final packaging. I can confirm these costs of manufacturing that make the commercial manufacturing of COVID-19 vaccines a highly profitable project.

While there is an excess of COVID-19 vaccine in the United States, the rest of the world is still starving for it. The WHO has also told me that the world needs 8 billion doses of COVID-19 vaccines and that they will be very proactive if anyone can supply the mRNA vaccines; the trust in all other vaccines has declined. This is a remarkable business opportunity for many companies since the capital expenditures (CAPEX) and operating expenditures (OPEX) are very small. In my next article on the topic, I will provide details of strategies to take the mRNA vaccines to market fast and reduce CAPEX and OPEX significantly. I want to enable newcomers to appreciate that mRNA technology will revolutionize health care, and there are many opportunities to join this revolution.

Summary

mRNA vaccines are chemically derived and have fixed chemical structures; it is possible to fully replicate a reference product sequence, reducing the burden of proving biosimilarity required for therapeutic proteins. The FDA has already suggested a new pathway for mRNA vaccines, but this path will only come into being when enough companies join in taking steps toward this strategy.

Watch for the second article in this series: Biosimilar mRNA Vaccines—Fast-to-Market Strategies.

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Health Canada approves updated Moderna COVID-19 vaccine

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TORONTO – Health Canada has authorized Moderna’s updated COVID-19 vaccine that protects against currently circulating variants of the virus.

The mRNA vaccine, called Spikevax, has been reformulated to target the KP.2 subvariant of Omicron.

It will replace the previous version of the vaccine that was released a year ago, which targeted the XBB.1.5 subvariant of Omicron.

Health Canada recently asked provinces and territories to get rid of their older COVID-19 vaccines to ensure the most current vaccine will be used during this fall’s respiratory virus season.

Health Canada is also reviewing two other updated COVID-19 vaccines but has not yet authorized them.

They are Pfizer’s Comirnaty, which is also an mRNA vaccine, as well as Novavax’s protein-based vaccine.

This report by The Canadian Press was first published Sept. 17, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

The Canadian Press. All rights reserved.

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These people say they got listeria after drinking recalled plant-based milks

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TORONTO – Sanniah Jabeen holds a sonogram of the unborn baby she lost after contracting listeria last December. Beneath, it says “love at first sight.”

Jabeen says she believes she and her baby were poisoned by a listeria outbreak linked to some plant-based milks and wants answers. An investigation continues into the recall declared July 8 of several Silk and Great Value plant-based beverages.

“I don’t even have the words. I’m still processing that,” Jabeen says of her loss. She was 18 weeks pregnant when she went into preterm labour.

The first infection linked to the recall was traced back to August 2023. One year later on Aug. 12, 2024, the Public Health Agency of Canada said three people had died and 20 were infected.

The number of cases is likely much higher, says Lawrence Goodridge, Canada Research Chair in foodborne pathogen dynamics at the University of Guelph: “For every person known, generally speaking, there’s typically 20 to 25 or maybe 30 people that are unknown.”

The case count has remained unchanged over the last month, but the Public Health Agency of Canada says it won’t declare the outbreak over until early October because of listeria’s 70-day incubation period and the reporting delays that accompany it.

Danone Canada’s head of communications said in an email Wednesday that the company is still investigating the “root cause” of the outbreak, which has been linked to a production line at a Pickering, Ont., packaging facility.

Pregnant people, adults over 60, and those with weakened immune systems are most at risk of becoming sick with severe listeriosis. If the infection spreads to an unborn baby, Health Canada says it can cause miscarriage, stillbirth, premature birth or life-threatening illness in a newborn.

The Canadian Press spoke to 10 people, from the parents of a toddler to an 89-year-old senior, who say they became sick with listeria after drinking from cartons of plant-based milk stamped with the recalled product code. Here’s a look at some of their experiences.

Sanniah Jabeen, 32, Toronto

Jabeen says she regularly drank Silk oat and almond milk in smoothies while pregnant, and began vomiting seven times a day and shivering at night in December 2023. She had “the worst headache of (her) life” when she went to the emergency room on Dec. 15.

“I just wasn’t functioning like a normal human being,” Jabeen says.

Told she was dehydrated, Jabeen was given fluids and a blood test and sent home. Four days later, she returned to hospital.

“They told me that since you’re 18 weeks, there’s nothing you can do to save your baby,” says Jabeen, who moved to Toronto from Pakistan five years ago.

Jabeen later learned she had listeriosis and an autopsy revealed her baby was infected, too.

“It broke my heart to read that report because I was just imagining my baby drinking poisoned amniotic fluid inside of me. The womb is a place where your baby is supposed to be the safest,” Jabeen said.

Jabeen’s case is likely not included in PHAC’s count. Jabeen says she was called by Health Canada and asked what dairy and fresh produce she ate – foods more commonly associated with listeria – but not asked about plant-based beverages.

She’s pregnant again, and is due in several months. At first, she was scared to eat, not knowing what caused the infection during her last pregnancy.

“Ever since I learned about the almond, oat milk situation, I’ve been feeling a bit better knowing that it wasn’t something that I did. It was something else that caused it. It wasn’t my fault,” Jabeen said.

She’s since joined a proposed class action lawsuit launched by LPC Avocates against the manufacturers and sellers of Silk and Great Value plant-based beverages. The lawsuit has not yet been certified by a judge.

Natalie Grant and her seven year-old daughter, Bowmanville, Ont.

Natalie Grant says she was in a hospital waiting room when she saw a television news report about the recall. She wondered if the dark chocolate almond milk her daughter drank daily was contaminated.

She had brought the girl to hospital because she was vomiting every half hour, constantly on the toilet with diarrhea, and had severe pain in her abdomen.

“I’m definitely thinking that this is a pretty solid chance that she’s got listeria at this point because I knew she had all the symptoms,” Grant says of seeing the news report.

Once her daughter could hold fluids, they went home and Grant cross-checked the recalled product code – 7825 – with the one on her carton. They matched.

“I called the emerg and I said I’m pretty confident she’s been exposed,” Grant said. She was told to return to the hospital if her daughter’s symptoms worsened. An hour and a half later, her fever spiked, the vomiting returned, her face flushed and her energy plummeted.

Grant says they were sent to a hospital in Ajax, Ont. and stayed two weeks while her daughter received antibiotics four times a day until she was discharged July 23.

“Knowing that my little one was just so affected and how it affected us as a family alone, there’s a bitterness left behind,” Grant said. She’s also joined the proposed class action.

Thelma Feldman, 89, Toronto

Thelma Feldman says she regularly taught yoga to friends in her condo building before getting sickened by listeria on July 2. Now, she has a walker and her body aches. She has headaches and digestive problems.

“I’m kind of depressed,” she says.

“It’s caused me a lot of physical and emotional pain.”

Much of the early days of her illness are a blur. She knows she boarded an ambulance with profuse diarrhea on July 2 and spent five days at North York General Hospital. Afterwards, she remembers Health Canada officials entering her apartment and removing Silk almond milk from her fridge, and volunteers from a community organization giving her sponge baths.

“At my age, 89, I’m not a kid anymore and healing takes longer,” Feldman says.

“I don’t even feel like being with people. I just sit at home.”

Jasmine Jiles and three-year-old Max, Kahnawake Mohawk Territory, Que.

Jasmine Jiles says her three-year-old son Max came down with flu-like symptoms and cradled his ears in what she interpreted as a sign of pain, like the one pounding in her own head, around early July.

When Jiles heard about the recall soon after, she called Danone Canada, the plant-based milk manufacturer, to find out if their Silk coconut milk was in the contaminated batch. It was, she says.

“My son is very small, he’s very young, so I asked what we do in terms of overall monitoring and she said someone from the company would get in touch within 24 to 48 hours,” Jiles says from a First Nations reserve near Montreal.

“I never got a call back. I never got an email”

At home, her son’s fever broke after three days, but gas pains stuck with him, she says. It took a couple weeks for him to get back to normal.

“In hindsight, I should have taken him (to the hospital) but we just tried to see if we could nurse him at home because wait times are pretty extreme,” Jiles says, “and I don’t have child care at the moment.”

Joseph Desmond, 50, Sydney, N.S.

Joseph Desmond says he suffered a seizure and fell off his sofa on July 9. He went to the emergency room, where they ran an electroencephalogram (EEG) test, and then returned home. Within hours, he had a second seizure and went back to hospital.

His third seizure happened the next morning while walking to the nurse’s station.

In severe cases of listeriosis, bacteria can spread to the central nervous system and cause seizures, according to Health Canada.

“The last two months have really been a nightmare,” says Desmond, who has joined the proposed lawsuit.

When he returned home from the hospital, his daughter took a carton of Silk dark chocolate almond milk out of the fridge and asked if he had heard about the recall. By that point, Desmond says he was on his second two-litre carton after finishing the first in June.

“It was pretty scary. Terrifying. I honestly thought I was going to die.”

Cheryl McCombe, 63, Haliburton, Ont.

The morning after suffering a second episode of vomiting, feverish sweats and diarrhea in the middle of the night in early July, Cheryl McCombe scrolled through the news on her phone and came across the recall.

A few years earlier, McCombe says she started drinking plant-based milks because it seemed like a healthier choice to splash in her morning coffee. On June 30, she bought two cartons of Silk cashew almond milk.

“It was on the (recall) list. I thought, ‘Oh my God, I got listeria,’” McCombe says. She called her doctor’s office and visited an urgent care clinic hoping to get tested and confirm her suspicion, but she says, “I was basically shut down at the door.”

Public Health Ontario does not recommend listeria testing for infected individuals with mild symptoms unless they are at risk of developing severe illness, such as people who are immunocompromised, elderly, pregnant or newborn.

“No wonder they couldn’t connect the dots,” she adds, referencing that it took close to a year for public health officials to find the source of the outbreak.

“I am a woman in my 60s and sometimes these signs are of, you know, when you’re vomiting and things like that, it can be a sign in women of a bigger issue,” McCombe says. She was seeking confirmation that wasn’t the case.

Disappointed, with her stomach still feeling off, she says she decided to boost her gut health with probiotics. After a couple weeks she started to feel like herself.

But since then, McCombe says, “I’m back on Kawartha Dairy cream in my coffee.”

This report by The Canadian Press was first published Sept. 16, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

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B.C. mayors seek ‘immediate action’ from federal government on mental health crisis

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VANCOUVER – Mayors and other leaders from several British Columbia communities say the provincial and federal governments need to take “immediate action” to tackle mental health and public safety issues that have reached crisis levels.

Vancouver Mayor Ken Sim says it’s become “abundantly clear” that mental health and addiction issues and public safety have caused crises that are “gripping” Vancouver, and he and other politicians, First Nations leaders and law enforcement officials are pleading for federal and provincial help.

In a letter to Prime Minister Justin Trudeau and Premier David Eby, mayors say there are “three critical fronts” that require action including “mandatory care” for people with severe mental health and addiction issues.

The letter says senior governments also need to bring in “meaningful bail reform” for repeat offenders, and the federal government must improve policing at Metro Vancouver ports to stop illicit drugs from coming in and stolen vehicles from being exported.

Sim says the “current system” has failed British Columbians, and the number of people dealing with severe mental health and addiction issues due to lack of proper care has “reached a critical point.”

Vancouver Police Chief Adam Palmer says repeat violent offenders are too often released on bail due to a “revolving door of justice,” and a new approach is needed to deal with mentally ill people who “pose a serious and immediate danger to themselves and others.”

This report by The Canadian Press was first published Sept. 16, 2024

The Canadian Press. All rights reserved.

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