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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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Monkeypox may be spreading in Saskatchewan, says Shahab – Regina Leader Post

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The province’s chief medical health officer issued a public advisory about the virus on Saturday, asking people to be aware of the symptoms and to seek testing.

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Health officials are warning that the monkeypox virus may be spreading in Saskatchewan, after several out-of-province cases have been linked back to the province as a place of exposure.

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Chief medical health officer Dr. Saqib Shahab issued a public advisory about the virus on Saturday, asking people to be aware of the symptoms and to be diligent in seeking testing.

Three cases have been reported in Saskatchewan since early July, Shahab said, all linked to out-of-province transmission or travel.

Shahab said that in-province transmission has now been detected and reported by out-of-province travellers who were exposed in Saskatchewan, prompting the advisory.

“We’re at a stage where we think people are at high risk,” said Shahab. “We think the situation has changed in the last week (and) there is higher risk that we may see ongoing transmission in Saskatchewan.”

Monkeypox is transmitted primarily through prolonged skin-to-skin or face-to-face contact or with items like bedsheets or other surfaces contaminated by a person while infectious. A person can remain infectious for 5 to 21 days after exposure to the virus, said public health.

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Shahab said that transmission without close contact or with an asymptomatic person “is rare,” but public health is still looking to raise awareness about the virus.

He said it’s extremely important for people to know about transmission risk and visible symptoms to help keep the outbreak manageable.

“All of us should be aware of monkeypox symptoms right now, but especially if you think you’ve been in close contact,” said Shahab.

Communities at risk

Transmission so far has been reported in the LGBTQ2S+ and men who have sex with men (MSM) communities, which are currently considered to be at high risk for exposure to the virus.

People are advised to be especially cautious with anonymous sexual partners, and to be conscientious about monitoring for symptoms.

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“It’s very hard to let people know if you’ve had (anonymous) contact,” said Shahab. “It is advisable while this outbreak is happening to limit the number of partners and avoid having anonymous partners that are hard to contact.”

With risk of transmission rising, Shahab said that the province is making the monkeypox vaccine more available.

Vaccine eligibility expanded

Vaccine eligibility previously included only adult individuals who had already been in contact with monkeypox. Criteria will now expand to include individuals pre-exposure, who are considered to be at high risk.

“Having this more focused approach has really helped (other jurisdictions) get ahead of the outbreak,” said Shahab. “We hope that by taking this approach in Saskatchewan, we can try to avoid a quick or high surge of cases.”

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High risk individuals, according to public health, must be transgender, identify as two-spirit, bisexual, gay or MSM, and have either recently had a sexually transmitted infection, had or plan to have sexual contact with one or more partners within the last six months, or plan to travel to an area that is reporting monkeypox cases within the next three months.

The vaccine is currently delivered as one dose but could become a multi-dose immunization as public health follows recommendations made by the National Advisory Committee for Immunization.

Shahab said that when the federal government deployed 99,000 doses to provinces and territories, Saskatchewan was allotted 150 doses and has used seven to date, but more is on the way.

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“We have ordered additional vaccines now that we are offering pre-exposure prophylaxis (and) we will continue to do so on demand,” said Shahab.

Testing is important

People are strongly encouraged to contact HealthLine 811 with concerns about potential exposure, symptoms or vaccine questions, in order to facilitate testing.

“It is important to seek testing, exactly for the reason that we don’t want to miss cases,” said Shahab.

Testing volumes are currently low, said Shahab, but people are encouraged to seek testing if they have any concerns.

“We are monitoring the situation very closely, and we feel that so far that we haven’t missed any cases,” said Shahab. “We just want to do everything we can in that initial surge, and keep case numbers low.”

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Approximately 30,000 cases have been reported globally since the outbreak began in April, with around 1,000 cases identified in Canada, primarily in Quebec and Ontario but also in Alberta, B.C. and Saskatchewan.

Chief Public Health Officer Dr. Theresa Tam said Friday that wastewater analysis may be utilized to track transmission rates for monkeypox, similar to COVID-19. World Health Organization declared the virus an international emergency on July 23.

Shahab that tool is not currently in use in Saskatchewan, as case numbers remain too low, but could be used if necessary.

“If there was concern we were missing transmission, wastewater would be useful,” said Shahab.

lkurz@postmedia.com

  1. Saqib Shahab, chief medical health officer, speaks at the Legislative Building in Regina on Wednesday, March 18, 2020. Saskatchewan's Ministry of Health says there are no reported cases of monkeypox in the province and the risk of getting the disease remains low. However, it says if there were a case, vaccines could be offered to close high-risk contacts based on a public health assessment.

    Sask. offering monkeypox vaccines for close, high-risk contacts

  2. Chief Public Health Officer Theresa Tam listens to a question during a news conference, Tuesday, January 12, 2021 in Ottawa. Dr. Theresa Tam says Canada's public health agency is looking to make the most of Canada's waste, and plans to sift through the sewage to test for and measure new health threats like monkeypox, polio, antimicrobial resistant organism and more.

    Canadian wastewater surveillance expanding to new public health threats: Tam

  3. This 2003 electron microscope image made available by the Centers for Disease Control and Prevention shows mature, oval-shaped monkeypox virions, left, and spherical immature virions, right, obtained from a sample of human skin associated with the 2003 prairie dog outbreak. (Cynthia S. Goldsmith, Russell Regner/CDC via AP)

    Dyer: WHO’s monkeypox emergency serves as a reminder

The news seems to be flying at us faster all the time. From COVID-19 updates to politics and crime and everything in between, it can be hard to keep up. With that in mind, the Regina Leader-Post has created an Afternoon Headlines newsletter that can be delivered daily to your inbox to help make sure you are up to date with the most vital news of the day. Click here to subscribe. 

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Canadian wastewater surveillance expanding to new public health threats: Tam – CP24

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Laura Osman, The Canadian Press


Published Friday, August 12, 2022 2:53PM EDT


Last Updated Friday, August 12, 2022 4:53PM EDT

OTTAWA – Plans are underway to sift through Canadian sewage to test for and measure monkeypox, polio and other potential health threats, the country’s chief public health officer said Friday.

Over the course of the COVID-19 pandemic, wastewater detection became a key way to track the spread of the virus, especially as free lab tests for individuals were phased out for all but a few in later waves.

Dr. Theresa Tam said the experts at the National Microbiology Lab have now discovered a promising approach to detect monkeypox in wastewater and will use the infrastructure developed during the pandemic to look for it.

“Moving forwards, it could form part of our monitoring of the disease activity going up and down across the country,” Tam said at a media briefing.

Tam said the method is complicated, but they’ve landed on something that can “probably” be used more broadly. How that monitoring fits into the Public Health Agency of Canada’s surveillance efforts on monkeypox is not yet clear.

The monkeypox disease comes from the same family of viruses that cause smallpox, which the World Health Organization declared eradicated around the globe in 1980.

Cases of monkeypox began to appear around the world in non-endemic countries in May.

Just this week the number of Canadian cases surpassed 1,000, though there are early signs the virus may now be spreading at a slower rate, Tam said.

The Public Health Agency of Canada also intends to start testing for polio as “soon as possible” after U.S. health officials found the polio virus in New York City’s wastewater.

The devastating virus was eradicated from Canada in 1994 and until very recently has not been found in the United States since 1993. Cases have now freshly emerged in Western nations with traditionally high rates of vaccinated people.

A positive case was discovered in New York last month.

The presence of the polio virus in the city’s wastewater suggests the virus is likely circulated locally, health authorities from the city, New York state and the U.S. federal government said Friday.

“We’re already starting to look at what the options are,” Tam said of monitoring for polio in Canada.

Polio tests are just now coming online in Ontario, said Eric Arts, a microbiology and immunology professor at Western University.

The COVID-19 pandemic proved how useful waste can be compared to person-by-person tests, he said, especially when it comes to early detection.

“Instead of testing hundreds of thousands of people kind of randomly to determine if they’re infected with a specific pathogen, or one that we don’t even know is circulating, you can just get a wastewater sample and test 100,000 people with one test,” he said.

Wastewater surveillance can be adapted for other things as well, she said. Even before the pandemic, Tam said the public health agency was looking at ways to scan for antimicrobial resistant organisms, or superbugs as they’re often called.

Wastewater detection is still imperfect though, Tam warned.

“You’re dealing with a slurry of many things with a lot of DNA, RNA, all sorts of things,” Tam said, putting it politely.

That slurry includes countless viruses and virus mutations. Some vaccines, like the oral vaccine for polio given in some countries that includes a live, attenuated virus, can also be confused with the real thing in a wastewater sample.

“It’s not terribly easy,” she said.

Different countries use different methods, Tam said, and even within Canada there’s a lot of innovation happening.

“I think one of the roles of our lab is to then look at the best methods and try and bring some standardization and guidance to that testing,” she said.

This report by The Canadian Press was first published Aug. 12, 2022.

– With files from Adina Bresge in Toronto and The Associated Press

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Foreigners flock to Canada for monkeypox vaccine – Medical Xpress

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Credit: Pixabay/CC0 Public Domain

With the monkeypox vaccine in short supply in the United States, thousands of foreigners, including Americans are flocking to Montreal to get their shots.

Canada’s second-largest city, located about 70 kilometers (43 miles) north of the US border in Quebec province, has decided to make the vaccine available to all those who consider themselves to be at risk.

ackRobb Stilson, an art director from Denver, Colorado, took advantage of the opportunity during a visit to Montreal last week.

“It’s very difficult in the States to get vaccinated,” Stilson said as he lined up to get a shot at a pop-up vaccination center together with his husband and two daughters. “I’ve friends who have waited 8 or 9 hours to get in.”

Because contact tracing is difficult, authorities in Montreal decided to offer the vaccine to all those who are at risk to stem the spread of the virus.

“As tourists, they may participate in activities that may expose them and so in a way, we’re combatting the pandemic by letting them become vaccinated here so that they don’t transmit the infection either here or when they go back home,” Donald Vinh, infectious disease specialist at the McGill University Health Center, told AFP.

Since the vaccination campaign was launched in mid-May, as soon as the first cases of monkeypox were detected, Montreal has inoculated 18,500 people, 13 percent of them foreigners.

The goal is to administer 25,000 doses and vaccinate some 75-80 percent of the population deemed to be at risk, in particular men who have sex with men or with multiple partners.

“I hope the strategy used by the public health agency of Montreal is a beacon for other public health agencies to use as a vaccination strategy,” Vinh added.

In the western province of British Columbia, health authorities decided last week they will no longer offer the vaccine to foreigners citing limited supplies and the fact that it was becoming more available in the United States.

Faced with a lack of available doses, American health authorities on Tuesday authorized a new injection procedure which will make it possible to inoculate five times the number of people with the same amount of the drug.

As of August 11, Canada has registered 1,059 confirmed cases of monkeypox, but authorities see signs of infections beginning to slow.


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Foreigners flock to Canada for monkeypox vaccine (2022, August 12)
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