RNA molecules have been utilized as therapeutic and research tools for more than two decades, with the usage ranging from in vitro transcribed (IVT) mRNA, small interference RNA (siRNA), RNA aptamers, riboswitches, and antisense RNA to the
recently developed mRNA vaccines. In 1978, nearly two decades after the discovery of messenger RNA (mRNA), the concept of a vaccine made from mRNA was materialized. mRNAs are messengers that can be directly delivered into cells for manipulating gene expression or producing proteins of interest. The application of mRNAs has been utilized in the prevention of cancer, infectious diseases, treatment of allergies and other diseases that need protein replacement.
The mRNA vaccine is emerging as a promising alternative to traditional vaccine platforms, as these vaccines can be manufactured quickly and tailored for a broad range of conditions. The mRNA vaccines have the potential to transform areas of medicine, including the prophylaxis of infectious diseases and are proven as clinically efficacious, safe and scalable. Numerous mRNA vaccines are under clinical trials or already available today against infectious pathogens such as Zika virus, cytomegalovirus, influenza virus, metapneumovirus, and parainfluenza virus as well as cancer. Although mRNA vaccines represent only 11% of all the vaccines developed on various platforms, two mRNA vaccines, mRNA-1273 (developed by Moderna) and BNT162b (developed by Pfizer and BioNTech Ltd.) were the first vaccines approved for emergency use in many countries.
mRNA vaccines for COVID- 19
The fundamental principle behind using mRNA as a technology is that it is based on a vehicle that enables the delivery of the transcript of interest, encoding one or more immunogen(s) or antigen of interest, into the host cell cytoplasm where expression generates translated protein(s) to be within the membrane, secreted or intracellularly located. In this way, upon invasion by a pathogen carrying the antigen, the immune system of the host can quickly trigger humoral and cellular immune responses, thereby preventing the disease. Three types of host cells can be transfected after administration of an mRNA vaccine intramuscularly, intracutaneously, or subcutaneously: (1) non-immune cells (such as muscle cells and epidermal cells) at the injection site; (2) immune cells found in the tissues at the injection site (such as dendritic cells and macrophages); (3) immune cells in peripheral lymphoid organs after the injected mRNA is transferred through the lymphatic system to adjacent lymph nodes or the spleen. As mRNA is a transient molecule by nature that is susceptible to degradation primarily through nuclease activity, efficient protection is required. Mitigation of both the effects of mRNA instability and the difficulty of mRNA passage through cell membranes can be achieved through the use of a suitable carrier able to deliver the encapsulated mRNA. The development of efficient and safe mRNA vaccine delivery systems has been critical to successful mRNA vaccines.
During the development of a SARS-CoV-2 vaccine, new delivery methods were introduced, among which the most widely used are lipid nanoparticles (LNPs). LNPs are typically a mixture of cholesterol, ionizable lipids, PEG lipids and co-lipids in various proportions. The LNP delivery systems serve multiple purposes in their applications. In addition to the sustained stability imparted through protection from nuclease degradation, they also facilitate organ specificity, and efficient cellular uptake, and provide endosomal escape properties that can enhance the successful delivery of the mRNA cargo to the cytoplasmic site of action. Some of the mRNA vaccines that have been developed so far are:
mRNA-1273: The vaccine was developed by American company Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA) and sold under the brand name Spikevax. It is an mRNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. It is encapsulated by patented LNPs with improved efficiency of mRNA delivery.
BNT162b mRNA: The Pfizer–BioNTech COVID-19 vaccine, BNT162b2, is an mRNA vaccine encoding a P2 mutant spike protein (PS 2) and formulated as an RNA–lipid nanoparticle of nucleoside-modified mRNA (modRNA). It elicits a blunted innate immune sensor activating capacity and thus augments antigen expression. It is encapsulated by patented LNPs with improved efficiency of mRNA delivery.
CVnCoV: The CureVac COVID-19 vaccine (abbreviated CVnCoV) is a COVID-19 vaccine candidate developed by CureVac N.V. and the Coalition for Epidemic Preparedness Innovations (CEPI). The vaccine comprises LNP-formulated, non-chemically modified, sequence-engineered mRNA encoding full-length S protein with two proline mutations (S-2P). It is formulated with a proprietary LNP, referred to as the RNActive® technology platform.
ARCoV: AWcorna, originally termed ARCoV and also known as the Walvax COVID-19 vaccine, is an mRNA COVID-19 vaccine developed by Walvax Biotechnology, Suzhou Abogen Biosciences, and the PLA Academy of Military Science. The vaccine primarily targets the Sars-CoV-2 receptor-binding domain of the spike protein, rather than the entire spike protein. It is encapsulated in LNPs of a proprietary composition using a preformed vesicle method and found thermostable at different temperatures.
ARCT-021: ARCT-021, also known as LUNAR-COV19, is a COVID-19 vaccine candidate developed by Arcturus Therapeutics. A lipid-enabled and Unlocked Nucleomonomer Agent modified RNA (LUNAR) of self-replicating RNA for vaccination against spike protein of SARS-CoV-2. Specifically, the vaccine combines two technologies, i.e., saRNA STARR™ and LUNAR® lipid-mediated delivery methods to enhance and extend antigen expression, enabling vaccination at lower doses.
SW0123: This vaccine is developed by stamina, encodes the full-length SARS-CoV-2 spike protein and is delivered using lipoprotein particles. It has good protective effects against SARS-CoV-2 and its D614G and N501Y variants.
Further, recently Gennova Biopharmaceuticals Limited, an Indian company announced its mRNA Covid-19 booster vaccine, ‘Gemcovac Om’, against the Omicron variant of Covid. The vaccine is developed by Biotechnology Industry Research Assistance Council (BIRAC) using Gennova Biopharmaceuticals Limited in collaboration with HDT Biotech Corporation, USA. The vaccine GEMCOVAC-OM is a thermostable vaccine and does not require ultra-cold chain infrastructure as used for other approved mRNA-based vaccines. Also, the vaccine could be administered into the skin via a “needle-free” PharmaJet system.
Patent Filing of Covid-19 mRNA Vaccines and Litigation
The patent-filing activity has grown dramatically over the past 5years for both infectious diseases and cancer. However, it is pertinent to mention that the number of applications for infectious disease indications surpassed those for cancer over the past 3 years, which could reflect increased interest in vaccines following epidemic outbreaks of MERS-CoV, Ebola virus and Zika virus. The patent landscape of assignees claiming a Covid-19 mRNA vaccine was generated and it was observed that the majority 70% of the patent families were filed by industry, followed by companies and the remaining are research institutions or independent inventors. The patent filing activity also indicates that patents are being filed to protect methods to improve mRNA delivery efficiency for mRNA that is delivered by a carrier, namely lipid nanoparticle (LNP) compositions. Also, various patent applications are being filed to protect pharmacological modifications to reduce mRNA instability and innate immunogenicity.
According to World Intellectual Property Organization (WIPO), a staggering number of almost 7,800 COVID-19 patents were filed, encompassing approximately 1,300 patents related to vaccines and 4,800 focused on therapeutics. Moderna, CureVac, BioNTech and GSK collectively own nearly half of the mRNA vaccine patent applications.
Further, before the COVID-19 pandemic, the U.S. National Institutes of Health (NIH) and Moderna collaborated on developing vaccines for other coronaviruses. However, when the SARS-CoV-2 outbreak was imminent, Moderna and NIH collaborated on developing a functional vaccine for COVID-19 but a U.S. patent application was filed by Moderna, with no NIH scientists included as inventors. Further, Moderna recently sued Pfizer and BioNTech alleging patent infringement of three out of eight patents that cover its Covid 19 vaccine (Spikevax). Particularly, Moderna’s lawsuit involved three patents that claim priority to applications filed between 2011 and 2016 covering its foundational intellectual property wherein Moderna alleged that “despite having many different options”, Pfizer and BioNTech “copied Moderna’s approach to encoding for the full-length spike protein in a lipid nanoparticle formulation”.
On 10 January 2022, Pfizer claimed that it entered into an agreement with Acuitas Therapeutics for a lipid nanoparticle delivery system for mRNA vaccines and therapeutics. However, on 28 February 2022, Arbutus Biopharma and Genevant Sciences, two biotech companies specializing in developing lipid nanoparticles, claimed to own the intellectual property of nanoparticle lipids used by Moderna for COVID-19 vaccines. Thus, Arbutus and Genevant sued Moderna for allegedly infringing on their nanoparticle formulations.
Further, in the year March 2022, Alnylam Pharmaceuticals, an American biopharmaceutical company also sued Moderna and Pfizer (separately) alleging that both infringed its patent concerning one of the four lipid components encapsulating an mRNA payload in commercialized lipid nanoparticles.
Furthermore, the German company CureVac, filed suit against BioNTech in July 2022, seeking compensation for infringement of four CureVac patent claims concerning the features of the mRNA payload and lipid formulation used to make the BioNTech coronavirus vaccine.
Although the rationale for mRNA technology is relatively simple, it is evident that the researchers have had to work for years developing technologies to allow mRNA to work inside our cells and produce proteins for evoking an immune response that protects us against diseases. The mRNA vaccines are considered safe as mRNA is non-infectious, non-integrating in nature, and degraded by standard cellular mechanisms. Further, they are highly efficacious because of their inherent capability of being translatable into the protein structure inside the cell cytoplasm. Additionally, mRNA vaccines are fully synthetic and do not require a host for growth, e.g., bacteria.
Therefore, they can be quickly manufactured inexpensively to ensure their “availability” and “accessibility” for mass vaccination on a sustainable basis. Thus, vaccine development using mRNA technology would be a promising and studied approach to produce safe and effective new vaccines, not only for prophylaxis but also as a treatment. Furthermore, it is imperative to note that even the overall patent filing activity indicates the filing of documents with claims to protect methods to improve mRNA delivery efficiency and protect pharmacological modifications to reduce mRNA instability and innate immunogenicity.
Accordingly, it is anticipated that the filing of patent applications would be growing exponentially as a result of increased investment in mRNA vaccine platforms. Further, the ongoing, accelerated clinical trials are potentially a proof of concept for mRNA vaccines. Therefore, gaining positive results in these trials would not only solve an immediate urgent need for a vaccine against SARS-CoV-2 but also provide a potent and versatile therapeutic tool for future outbreaks of many infectious diseases. Overall, with significant advances in mRNA biology, delivery, and manufacturing, the biotechnology and vaccine industries are poised for further investment in the development of novel products.