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.
The Canadian government says it will donate up to 200,000 vaccine doses to fight the mpox outbreak in Congo and other African countries.
It says the donated doses of Imvamune will come from Canada’s existing supply and will not affect the country’s preparedness for mpox cases in this country.
Minister of Health Mark Holland says the donation “will help to protect those in the most affected regions of Africa and will help prevent further spread of the virus.”
Dr. Madhukar Pai, Canada research chair in epidemiology and global health, says although the donation is welcome, it is a very small portion of the estimated 10 million vaccine doses needed to control the outbreak.
Vaccine donations from wealthier countries have only recently started arriving in Africa, almost a month after the World Health Organization declared the mpox outbreak a public health emergency of international concern.
A few days after the declaration in August, Global Affairs Canada announced a contribution of $1 million for mpox surveillance, diagnostic tools, research and community awareness in Africa.
On Thursday, the Africa Centres for Disease Control and Prevention said mpox is still on the rise and that testing rates are “insufficient” across the continent.
Jason Kindrachuk, Canada research chair in emerging viruses at the University of Manitoba, said donating vaccines, in addition to supporting surveillance and diagnostic tests, is “massively important.”
But Kindrachuk, who has worked on the ground in Congo during the epidemic, also said that the international response to the mpox outbreak is “better late than never (but) better never late.”
“It would have been fantastic for us globally to not be in this position by having provided doses a much, much longer time prior than when we are,” he said, noting that the outbreak of clade I mpox in Congo started in early 2023.
Clade II mpox, endemic in regions of West Africa, came to the world’s attention even earlier — in 2022 — as that strain of virus spread to other countries, including Canada.
Two doses are recommended for mpox vaccination, so the donation may only benefit 100,000 people, Pai said.
Pai questioned whether Canada is contributing enough, as the federal government hasn’t said what percentage of its mpox vaccine stockpile it is donating.
“Small donations are simply not going to help end this crisis. We need to show greater solidarity and support,” he said in an email.
“That is the biggest lesson from the COVID-19 pandemic — our collective safety is tied with that of other nations.”
This report by The Canadian Press was first published Sept. 13, 2024.
Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.
HALIFAX – The Nova Scotia government says it could be months before it reveals how many people are on the wait-list for a family doctor.
The head of the province’s health authority told reporters Wednesday that the government won’t release updated data until the 160,000 people who were on the wait-list in June are contacted to verify whether they still need primary care.
Karen Oldfield said Nova Scotia Health is working on validating the primary care wait-list data before posting new numbers, and that work may take a matter of months. The most recent public wait-list figures are from June 1, when 160,234 people, or about 16 per cent of the population, were on it.
“It’s going to take time to make 160,000 calls,” Oldfield said. “We are not talking weeks, we are talking months.”
The interim CEO and president of Nova Scotia Health said people on the list are being asked where they live, whether they still need a family doctor, and to give an update on their health.
A spokesperson with the province’s Health Department says the government and its health authority are “working hard” to turn the wait-list registry into a useful tool, adding that the data will be shared once it is validated.
Nova Scotia’s NDP are calling on Premier Tim Houston to immediately release statistics on how many people are looking for a family doctor. On Tuesday, the NDP introduced a bill that would require the health minister to make the number public every month.
“It is unacceptable for the list to be more than three months out of date,” NDP Leader Claudia Chender said Tuesday.
Chender said releasing this data regularly is vital so Nova Scotians can track the government’s progress on its main 2021 campaign promise: fixing health care.
The number of people in need of a family doctor has more than doubled between the 2021 summer election campaign and June 2024. Since September 2021 about 300 doctors have been added to the provincial health system, the Health Department said.
“We’ll know if Tim Houston is keeping his 2021 election promise to fix health care when Nova Scotians are attached to primary care,” Chender said.
This report by The Canadian Press was first published Sept. 11, 2024.
ST. JOHN’S, N.L. – Newfoundland and Labrador‘s chief medical officer is monitoring the rise of whooping cough infections across the province as cases of the highly contagious disease continue to grow across Canada.
Dr. Janice Fitzgerald says that so far this year, the province has recorded 230 confirmed cases of the vaccine-preventable respiratory tract infection, also known as pertussis.
Late last month, Quebec reported more than 11,000 cases during the same time period, while Ontario counted 470 cases, well above the five-year average of 98. In Quebec, the majority of patients are between the ages of 10 and 14.
Meanwhile, New Brunswick has declared a whooping cough outbreak across the province. A total of 141 cases were reported by last month, exceeding the five-year average of 34.
The disease can lead to severe complications among vulnerable populations including infants, who are at the highest risk of suffering from complications like pneumonia and seizures. Symptoms may start with a runny nose, mild fever and cough, then progress to severe coughing accompanied by a distinctive “whooping” sound during inhalation.
“The public, especially pregnant people and those in close contact with infants, are encouraged to be aware of symptoms related to pertussis and to ensure vaccinations are up to date,” Newfoundland and Labrador’s Health Department said in a statement.
Whooping cough can be treated with antibiotics, but vaccination is the most effective way to control the spread of the disease. As a result, the province has expanded immunization efforts this school year. While booster doses are already offered in Grade 9, the vaccine is now being offered to Grade 8 students as well.
Public health officials say whooping cough is a cyclical disease that increases every two to five or six years.
Meanwhile, New Brunswick’s acting chief medical officer of health expects the current case count to get worse before tapering off.
A rise in whooping cough cases has also been reported in the United States and elsewhere. The Pan American Health Organization issued an alert in July encouraging countries to ramp up their surveillance and vaccination coverage.
This report by The Canadian Press was first published Sept. 10, 2024.
