key: cord-0806257-o2jeau79
authors: Alshrari, A. S.; Hudu, Shuaibu Abdullahi; Imran, Mohd; Asdaq, Syed Mohammed Basheeruddin; Ali, Alreshidi Mateq; Rabbani, Syed Imam
title: Innovations and Development of Covid-19 Vaccines: A Patent Review
date: 2021-10-23
journal: J Infect Public Health
DOI: 10.1016/j.jiph.2021.10.021
sha: f5347d5e8bc4bd81bd73c04f40b6c7f8da03e8a7
doc_id: 806257
cord_uid: o2jeau79

More than 125 million confirmed cases of COVID-19 have been reported globally with rising cases in all countries since the first case was reported. A vaccine is the best measure for the effective prevention and control of COVID-19. There are more than 292 COVID-19 candidates’ vaccines being developed as of July 2021 of which 184 are in human preclinical trials. A patent provides protection and a marketing monopoly to the inventor of an invention for a specified period. Therefore, vaccine developers, including Moderna, BioNTech, Janssen, Inovio, and Gamaleya also filed patent applications for the protection of their vaccines. This review aims to provide an insight into the patent literature of COVID-19 vaccines. The patent search was done using Patentscope and Espacenet databases. The results have revealed that most of the key players have patented their inventive COVID-19 vaccine. Many patent applications related to COVID-19 vaccines developed via different technologies (DNA, RNA, virus, bacteria, and protein subunit) have also been filed. The publication of a normal patent application takes place after 18 months of its filing. Therefore, many patents/patent applications related to the COVID-19 vaccine developed through different technology may come into the public domain in the coming days.

In December 2019, a novel coronavirus associated with cluster pneumonia was identified in Wuhan, China. It spread rapidly, leading to a global pandemic [1] . The disease was named Coronavirus diseases 2019 (COVID-19) by the World Health Organization, and the virus was designated severe acute respiratory syndrome coronavirus two (SARS-CoV-2) [2] . COVID-19 outbreak poses a challenge to the global biomedical community and public health system [3] . The pandemic has now spread to every nation, infected millions, and murdered a considerable number of individuals [4, 5] . Because of this unprecedented and earnest health challenge, so many interventions from the use of off-label drugs, stem cell therapy, convalescent patient serum, and drug repurposed were mobilized.

More than 125 million confirmed cases of COVID-19 have been reported globally [6] . Cases have been on the rise in all countries since the first case was reported. However, only a negligible portion of acute infections was diagnosed, thereby underestimated the overall effects of COVID-19. The primary source of infection is infected patients during their prodromal period producing and shedding large quantities of the viruses from their upper J o u r n a l P r e -p r o o f respiratory tract [7] . All populations are susceptible to COVID-19 infection, but the most vulnerable are the health care workers, children, elderly and pregnant women [8] .

SARS-CoV-2 is an enveloped RNA virus of the β-coronavirus, with a hereditary succession the same as SARS-CoV-1 (80%) and bat coronavirus (96.2%) . The viral envelope is covered by spike (S) glycoprotein, envelope (E), and film (M) proteins. Host cell restricting and passage are interceded by the S protein [9] . Practically all SARS-CoV-2 vaccines developed and being developed focused on the spike (S) protein and the viral receptor-binding domain (RBD) [10] [11] [12] . This receptor binding domain bind to angiotensin-converting enzyme 2 (ACE2), a receptor on the surface of the host cells, thereby initiating the infection process [13] . SARS-CoV and SARS-CoV-2 share similar host receptor binding sites. However, the latter bind more than ten times higher than the former [14] . This may add to the higher contagiousness and infectiousness of SARS-CoV-2 when contrasted with SARS-CoV. The spike protein is highly immunogenic and capable of inducing neutralizing antibodies and serves as a significant virulence factor of coronaviruses [15, 16] .

Over 80% of COVID-19 sicknesses are asymptomatic or indicative of gentle side effects like respiratory manifestations, cough, fever, and difficulty breathing. In certain patients, COVID-19 outcomes in severe ailment will present with serious pneumonia, acute respiratory failure, pulmonary edema, acute respiratory syndrome (ARDS), sepsis, and numerous organ disappointment, leading to death [17, 18] . However, not every one of these symptoms is available in COVID-19 cases. Pregnant women having COOVId-19 will present with similar symptoms as that of non-pregnant women [19] .

The diagnosis of COVID-19 starts with a good clinical evaluation. The clinical diagnosis can be dependent on signs and symptoms, history of exposure, and chest imaging. Even though COVID-19 presents various manifestations, there are no particular signs or symptoms that could be considered diagnostic [20] . Therefore an individual suspected of COVID-19 should be clinically assessed, and a confirmatory test should be done using real-time polymerase chain reaction (RT-PCR). The preferred specimen for this test is the respiratory tract samples like the throat swab. Other specimens that can be used include; cord blood, amniotic fluids in pregnant women [21] . Besides, chest CT may have high symptomatic worth in light of its ordinary pictures of infection contamination, high exactness with a low bogus negative rate, and time productivity.

J o u r n a l P r e -p r o o f Globally, researchers are attempting to discover and produce medicines for COVID-19. The optimum supportive patient care incorporates oxygen for seriously sick patients. Such patients are usually extremely sick and need respiratory help, such as ventilation for fundamentally ill patients. Dexamethasone is a corticosteroid that can help lessen the time allotment on a ventilator and save patients' lives with severe and primary disease [22] . WHO doesn't suggest self-prescription with any drugs, including anti-infection agents, as a counteraction or solution for COVID-19. An antiviral medication called remdesivir is the primary medication affirmed by the United States food and drug administration (FDA) to treat hospitalized COVID patients beyond 12 years old [23] . The FDA has also given emergency use approval (EUA) for two medications called monoclonal antibodies to treat COVID-19 [24] . Casirivimab and imdevimab can be given to high-chance patients who have as of late been determined to have gentle to direct ailment to bring down levels of the infection in their bodies and lower the danger of hospitalization [25] . The FDA has repealed its emergency approval to utilize hydroxychloroquine and chloroquine to treat individuals hospitalized with COVID-19 amid genuine worries about their safety and how well they neutralized the infection [26] . However, a vaccine is perhaps the best clinical measure for effective prevention and control, as recommended by WHO [27] . Therefore, making available an effective vaccine will help prevent susceptible populations and provide complex immunity to terminate the COVID-19 pandemic.

Vaccines are biologics that give dynamic, versatile invulnerability against explicit infections and contain drugs that look like the microorganisms that cause infection [28] . They are frequently produced using either killed or attenuated microorganisms, their surface proteins, or toxins, either ingested or inhaled, to stimulate the immune system to produce antibodies that will recognize and neutralize infecting microorganisms [29, 30] . There are different types of vaccines, each intended to teach our immune system how to get rid of invading pathogens. the Pfizer-BioNTech vaccine was 95% successful at forestalling confirmed cases of COVID-19 without evidence of past infection [31] . The mRNA is formulated in lipid particles to express and deliver the viral spike protein to the host immune system, eliciting an immune response that protects against COVID-19 [32] . Pfizer/BioNTech requires temperaturecontrolled shippers for transporting vaccines at the recommended storage temperature of −70 °C ± ten °C for up to 15 days. After thawing, the vaccine can only be stored at refrigerated conditions (2-8 °C) for up to 5 days [33] .

Moderna vaccine is also a USFDA approved mRNA vaccine recommended for 18 years and above with 94% efficacy with the administration of two doses of the vaccine [34]. It is a modified nucleoside mRNA vaccine. Its formulation is similar to that of the Pfizer-BioNTech vaccine and elicits an immune response to SARS-CoV-2 S antigen, which gives protection against COVID-19 [35] . The mRNA vaccine candidate of Moderna can remain stable at refrigerated conditions (2-8 °C) for 30 days; it can be stored for six months at −20 °C [33] .

Johnson & Johnson vaccine, a viral vector vaccine recommended for individuals above 17year and has 66% efficacy [36] . The vaccine was 66.3% viable in clinical trials at forestalling confirmed cases of COVID-19 in individuals who had no proof of earlier infection fourteen days after accepting the vaccine [37] . The vaccine had high adequacy at forestalling hospitalization and demise in individuals who became ill. Nobody who got COVID-19 should be hospitalized after 4week of vaccination. Early proof proposes that the vaccine may protect against asymptomatic infection, which is the point at which an individual is infected by the virus that causes COVID-19 yet doesn't become ill [38] . Un-punctured vials of Janssen COVID-19 Vaccine may be stored between 9°C to 25°C for up to 12 hours [33] .

AstraZeneca/Oxford vaccine against COVID-19 is a replication-defective viral vector vaccine with an average efficacy of 70.4% on a clinical trial. The effectiveness of the AstraZeneca/Oxford vaccine was evaluated in participants aged 18 years and older and confirmed its safety and efficacy against symptomatic COVID-19 [39] . The vaccine was found to possess similar immunogenicity across all age groups following the booster dose [40] . Although the average efficacy of the vaccine is lower than those produced by Moderna and Pfizer/BioNTech, its recommended storage conditions are worth consideration, most especially by scarce resource countries. The vaccine can be transported, stored, and J o u r n a l P r e -p r o o f distributed at refrigerated conditions (2-8 °C) for a minimum of six months using existing healthcare settings [33] .

As of July 2021, there are more than 292 candidates' vaccines being developed for COVID- 19 . Of these, about 184 are in human preclinical trials while the remaining are in the clinical trials of which the majority of them are protein subunit vaccines [41] [42] [43] . There are many others in clinical trial phase I/II, which will soon enter phase III clinical trials [44, 45] . Many of these vaccines will be assessed for safety and effectiveness before considering the human clinical trial. Only one in five is booming after the clinical trial. Therefore, having bunches of various vaccines being developed builds the odds that there will be at least one effective vaccine that will be demonstrated to be effective and safe to the population. [57] [58] [59] The global race to develop an effective and safe vaccine against COVID-19 is ongoing, and it involved many strategies and approaches which include but are not limited to: Live attenuated vaccine strategies that involved the use of live pathogen after long cell culture passaging in non-human cell lines to decreases its virulence [60] . This sort of vaccine typically evokes strong and long-haul memory invulnerable reactions after a single dosage.

Inactivated vaccine strategies involved using the entire microbe that has been weakened by chemicals or heat to the level that it cannot cause diseases [46] . Sub-unit vaccine strategies involved using purification of antigens of pathogens from recombinant expressed antigens or replicated via cell culture [61] . However, this type of vaccine needs an adjuvant to signal antigen-presenting cells and incite vigorous immune reactions. Virus-like particle strategies involved using recombinant yeast and an expression system. Viral vector strategies involved genetically modifying the virus to serves as a platform for expressing antigen of interest leading to stimulation of powerful cell and humoral reaction [62] . Finally, Nucleic acid (mRNA and DNA) vaccine strategies are swift to produce but untested as successful human vaccine systems. The immunogenic protein of the pathogen is being corded in mRNA or DNA upon administration. It is captured antigen-presenting cells that expressed and presented the antigen to the immune system to produce neutralizing antibodies [63] . This type of vaccine has been predicted to be safe and has little or no safety as the nucleic acid is immediately degraded in the body. [65] . Similarly, this type of vaccine's long-term side effect is unknown and cannot be predicted due to the shortening of the clinical trial period [66] .

The vaccine developer, including Moderna, BioNTech, Janssen, Inovio, and Gamaleya filed patent applications for the protection of their vaccines. A patent grants protection and marketing exclusivity to the inventor of an invention for a predetermined period. This review aims to provide an insight into the patent literature of COVID-19 vaccines.

The searched to know about vaccine patents assigned to them. and purification for obtaining the recombinant adenovirus. The administration of the recombined adenovirus is expected to generate the immunological response [68, 74] .

Currently, intramuscular is the recommended route for administering the COVID-19 vaccine.

However, considering the pathway through which the SARS-CoV2 enters the body, innovations have been trialed for the inhalation route of vaccine delivery [75] . Since, the approved COVID-19 vaccines are demonstrated to provide mostly the activation of T cells and serum neutralizing antibodies, without altering the mucosal immunity in the nasal cavity or lung tissue, the intra-nasal route was tested for this purpose. Moreover, drugs used to treat respiratory diseases are preferred to be given by the intra-nasal route; the COVID-19 vaccine is also tried by this route [76] . Various pharmaceutical companies such as CanSino Biologics, Bharat Biotech, AstraZeneca, and Codagenix are testing their COVID-19 vaccines for the intra-nasal route of delivery [75, 77] .

Many patents/patent applications on COVID-19 vaccines have been published. The summary of vaccines developed by the key players is provided in Table 2 . The cause of COVID-19 was described in the second week of January 2020. The publication of a normal patent application takes place after 18 months of its filing. Therefore, it is not possible to know exactly how many patent applications have been filed? how many have been published? and how many will be published in the coming days?. Accordingly, the list of some patents/patent applications related to the COVID-19 vaccine developed through different technology is provided in Table 3 . There are added intricacies with COVID-19, given that its seriousness shows up be diverse across sexual orientation and age. There's additionally proof that it has the captivity of having mutant strains.

Coronaviruses have a Spike protein or S-protein, which they use to append to receptors in 

A novel coronavirus from patients with pneumonia in China

Digital health strategies to fight COVID-19 worldwide: challenges, recommendations, and a call for papers

Disease and healthcare burden of COVID-19 in the United States

Disease burden and clinical severity of the first pandemic wave of COVID-19 in Wuhan, China

The novel zoonotic COVID-19 pandemic: An expected global health concern

SARS-CoV-2 viral load in upper respiratory specimens of infected patients

Current epidemiological and clinical features of COVID-19; a global perspective from China

SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography

Novel antibody epitopes dominate the antigenicity of spike glycoprotein in SARS-CoV-2 compared to SARS-CoV

Therapeutic strategies in the development of anti-viral drugs and vaccines against SARS-CoV-2 infection

The spike protein of SARS-CoV-a target for vaccine and therapeutic development

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

Monoclonal antibodies for the S2 subunit of spike of SARS-CoV-1 cross-react with the newly-emerged SARS-CoV-2

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment

A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in nonhuman primates

Clinical Features and Outcomes in Mechanically Ventilated Patients with COVID-19 and the

Acute Respiratory Distress Syndrome

Clinical features and risk factors of COVID-19-associated liver injury and function: A retrospective analysis of 830 cases

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

Clinical pathway for early diagnosis of COVID-19: updates from experience to evidence-based practice

COVID-19 diagnosis and management: a comprehensive review

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan

The place for remdesivir in COVID-19 treatment. The Lancet Infectious Diseases

Monoclonal Antibodies Receive EUA to Treat Mild to Moderate COVID-19. The American journal of nursing

Casirivimab-Imdevimab for Treatment of COVID-19 in Solid Organ Transplant Recipients: an Early Experience

Use of hydroxychloroquine and chloroquine in patients with COVID-19: a meta-analysis of randomized clinical trials. Pathogens and global health

World Health Organization declares global emergency: A review of the

Biotherapeutics and its applications in Microbiology

The effects of pre-existing antibodies on live-attenuated viral vaccines

Why and how vaccines work

The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine-United States

Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults

Refrigeration of COVID-19 Vaccines: Ideal Storage Characteristics, Energy Efficiency and Environmental Impacts of Various Vaccine Options

The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Moderna COVID-19 Vaccine-United States

A systematic review of SARS

Signal transduction and targeted therapy

The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Janssen COVID-19 Vaccine-United States

The Johnson & Johnson Vaccine for COVID-19

Singledose BNT162b2 vaccine protects against asymptomatic SARS-CoV-2 infection

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. The Lancet

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomized, controlled, phase 2/3 trial. The Lancet

SARS-CoV-2 vaccines in development

COVID-19: Current knowledge in clinical features, immunological responses, and vaccine development

Interim Results of a Phase 1-2a Trial of Ad26. COV2. S Covid-19 Vaccine

T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

Development of an inactivated vaccine candidate for SARS-CoV-2

Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials

Development of an inactivated vaccine candidate

An mRNA vaccine against SARS-CoV-2-preliminary report

Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates

SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

New vaccine production platforms used in developing SARS-CoV-2 vaccine candidates

I/II study of COVID-19 RNA vaccine BNT162b1 in adults

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomized, first-in-human trial

ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomized controlled trial. The Lancet

S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial

Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters

Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques

A live-vaccine-last schedule: saving an extra million lives a year? Clinical Infectious Diseases

Recombinant vaccines and the development of new vaccine strategies. Brazilian journal of medical and biological research

The 3Ds in virus-like particle basedvaccines: "Design, Delivery, and Dynamics

Genetic-Code-Expansion Strategies for Vaccine Development

Transforming vaccine development

Older adults may be left out of some COVID-19 trials. The New York Times

Exploring uncertainty and risk in the accelerated response to a COVID-19 vaccine: Perspective from the pharmaceutical industry

A network analysis of COVID-19 mRNA vaccine Patents

Global landscape of patents related to human Coronaviruses

Mrna Vaccines: Intellectual Property Landscape

How the 'Oxford' Covid-19 vaccine became the 'AstraZeneca' Covid-19

International Patent Office. IP trends on Covid-19 related vaccines

Covid-19 vaccine update

Sputnik V vaccine description

Chinese Patent Application for Coronavirus Vaccine Published

Inhalation Delivery for the Treatment and Prevention of COVID-19 Infection

Ivermectin Nasal Spray for covid19 Patients

A Study of Intranasal ChAdOx1 nCOV-19

Modified polynucleotides for the production of secreted proteins. United States patent number US10703789B2

Betacoronavirus mRNA vaccine. United States patent number US10702600B1

Modified nucleosides, nucleotides, and nucleic acids, and uses thereof

Betacoronavirus mRNA vaccine. United States patent number US10933127B2

Formulation for administration of RNA. United States patent application publication number US20190321458A1

Particles comprising protamine and RNA in combination with endosome destabilizing agents. United States patent number US10729785B2

Lipid nanoparticles for delivery of nucleic acids. PCT patent application publication number WO2021123332A1

Vaccination with mRNA-coded antigens. United States patent application publication number US20210023199A1

Methods of immunostimulation with complexes of RNA and cationic carriers

Compositions and methods for preventing and treating coronavirus infection-SARS-COV-2 vaccines. PCT patent application publication number WO2021155323A1

Compositions and methods for preventing and treating coronavirus infection -SARS-COV-2 vaccines. Canadian patent application publication number CA3101131A1

MERS-CoV vaccine. United States patent number US10548971B2

Pharmaceutical agent and method for use thereof for inducing specific immunity to virus of severe acute respiratory syndrome SARS-CoV-2 (Embodiments)

Expression vector for creating immunobiological agent for inducing specific immunity to virus of severe acute respiratory syndrome SARS-CoV-2 (Embodiments)

Pharmaceutical agent and method for use thereof for inducing specific immunity to virus of severe acute respiratory syndrome SARS-COV-2 (Embodiments)

Coronavirus vaccine formulations. PCT patent application publication number WO2021154812A1

Coronavirus vaccine formulations. United States patent number US10953089B1

Method of creating a live vaccine against COVID-19 based on the probiotic strain

Enterococcus Faecium L3 and a live vaccine Enterococcus Faecium L3-PENTF-COVID-19

Russian patent number RU2745626C1

Hansenula polymorpha recombinant COVID-19 viruslike envelope particle vaccine cell strain. Chinese patent application publication number CN112048445A

Bimolecular DNA vaccine of virus antigen-immune coactivator. Chinese patent application publication number CN111588843A

Corona virus disease 2019 (COVID-19) DNA vaccine and preparation method and application thereof. Chinese patent application publication number CN111569057A

SARS-CoV-2 vaccine based on lentiviral coat modification and mRNA delivery and preparation method of SARS-CoV-2 vaccine. Chinese patent application publication number CN112168958A

Polypeptide and application thereof to novel coronavirus detection and antibody or vaccine screening. Chinese patent application publication number CN111647053A

Adenovirus carrier vaccine used for preventing SARS-COV-2 infection. PCT patent application publication number WO2021000968A2

Preparation method of antisense RNA polyvalent vaccine for COVID-19

Chinese patent application publication number CN111330003A

mRNA and vaccine for coding a SARS-CoV-2 viral antigen and preparation method of vaccine

Cold-adapted live attenuated severe acute respiratory syndrome coronavirus and vaccine containing the same. United States patent number US11020475B1

Bat-derived coronavirus vaccine for preventing COVID-19

Chinese patent application publication number CN111437384A

Use of membrane inhibitors to enhance vaccine development against enveloped viruses. PCT patent application publication number WO2021092392A1

SARS-CoV-2 attenuated strain and application of SARS-CoV-2 attenuated strain in prevention of novel coronavirus pneumonia. Chinese patent application publication number CN112175913A

Expression of SARS-CoV-2 spike protein receptor binding domain in attenuated salmonella as a vaccine. United States patent number US10973908B1

Expression vector for expressing COVID-19

antigen and construction method of genetically engineered lactobacillus oral vaccine. Chinese patent application publication number CN111944837A

SARS-CoV-2 polypeptide vaccine using papillomavirus (PV) virus-like particle (VLP) presentation antigen. Chinese patent application publication number CN112300290A

Recombinant subunit vaccine of novel coronavirus and application of same. Chinese patent application publication number CN112480268A

Preparation and application of novel coronavirus subunit nanovaccine. Chinese patent application publication number CN111603556A

Adenovirus vector vaccine for preventing SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 vaccine based on novel adenovirus vectors Sad23L and/or Ad49L. Chinese patent application publication number CN111778264A