The urgent need to develop an effective vaccine to provide individuals and populations worldwide with immunity against the COVID-19 disease caused by the novel coronavirus, SARS-CoV-2, has led several biotechnology companies to leverage messenger RNA (mRNA) technology and take a novel approach to vaccine development.

As the COVID-19 pandemic continues to unfold, there are a multitude of biotechnology companies, governments and research institutions concentrating their efforts on developing a prophylactic vaccine against the novel coronavirus known as SARS-CoV-2. Many conventional vaccine development approaches are problematic because they involve prolonged lead times of between 2 to 5 years and require significant capital investment, making them poorly-adapted to responding to a rapidly spreading pathogen. By contrast, mRNA-based vaccines can be developed, clinically trialled and scaled-up into production and distribution relatively quickly – with the possibility of mass-immunisation commencing within 18 months of vaccine development commencing.

The premise of mRNA vaccines is simple: a vaccine that utilises a synthetic strand of mRNA, the minimum genetic instruction that allows human cells to make and express the target viral protein, which then triggers an adaptive immune response against the virus. This approach enables a rapid and scalable response to new viral pathogens as it bypasses the need to work directly with the virus itself.

US-based mRNA pioneers Moderna and Arcturus Therapeutics, as well as Germany’s BioNTech, each have a candidate mRNA vaccine. Moderna’s mRNA-1273 vaccine was produced 42 days following the sequencing of the SARS-CoV-2 genome – a response that is unprecedented in vaccine development. It is the first candidate COVID-19 vaccine to commence human trials, with a Phase I clinical trial under way in the US in collaboration with the National Institutes of Health (NIH). The study is aimed at assessing the vaccine’s safety, reactogenicity (common adverse reactions) and immunogenicity (ability to elicit an immune response) in a limited number of healthy volunteers.[1]

Coronavirus genome and proteins

The coronaviruses are a large family of viruses consisting of spherically-shaped viral particles covered with spike proteins protruding from their surface, which give the virus its crown-like appearance (corona being Latin for crown). The coronavirus uses its spike proteins to attach to and penetrate the surface of host cells by binding to ACE2 receptors on these cells.[2]

Researchers in China have sequenced the genome of the novel coronavirus (SARS-CoV-2), which has allowed mRNA sequences against viral proteins to be rapidly developed. Of particular interest has been the genetic sequence encoding the spike protein, which Moderna and Arcturus Therapeutics have incorporated into their respective candidate vaccines.

COVID-19 mRNA vaccine candidates

  • Moderna’s first-in-class mRNA-1273 vaccine encodes for a stabilised form of the spike protein, formulated with a lipid nanoparticle carrier.[3] The US Food and Drug Administration has allowed the vaccine to proceed to a Phase I study in humans under an Investigational New Drug (IND) application filed by the NIH, in parallel with animal studies.[4] The NIH commenced a Phase I trial on 16 March 2020. The study will enrol 45 healthy adults in order to evaluate the vaccine’s safety and immunogenicity at three dosage levels (25mcg, 100mcg and 250 mcg) to be administered by intramuscular injection on a 2-dose vaccination schedule given 28 days apart.[5] If the Phase I trial proves successful, Moderna expects to commence larger Phase II efficacy trials (enrolling several hundred participants) under its own IND filing within a few months.[6] If all Phase II clinical endpoints are met, then Phase III clinical trials may occur towards the end of 2020, but any approved vaccine is anticipated to be 12 to 18 months away by both industry and health authorities.
  • Arcturus Therapeutics and Duke-NUS Medical School have partnered in the development of a candidate self-replicating mRNA vaccine, currently in preclinical testing.[7] The partnership will receive up to US$10 million from the Singapore Government to co-develop the vaccine, which utilises mRNA encoding the viral spike protein, delivered by a lipid nanoparticle delivery system.
  • BioNTech is collaborating with Pfizer to co-develop its mRNA-based vaccine candidate BNT162, leveraging an earlier agreement between the parties to jointly develop an mRNA-based influenza vaccine. The agreement with Pfizer excludes distribution rights within China, where Shanghai-based Fosun Pharma will distribute and market any COVID-19 vaccine developed by BioNTech.[8] BNT162 is currently in pre-clinical testing with clinical trials expected to begin in April 2020.[9]

The rationale for mRNA vaccines

Vaccine platforms using mRNA-based technologies utilise two approaches: non-replicating and self-replicating mRNA. Non-replicating mRNA vaccines only code for the antigen required to elicit the desired immune response (such as the spike protein of SARS-CoV-2), making them relatively simple to develop and often more economical to administer (particularly where direct intradermal injection is feasible). Self-replicating mRNA vaccines include not only the genetic sequence of the antigen required but also the RNA replication machinery required for the mRNA to be amplified, thereby enabling a large amount of antigen production from a small dose, potentially reducing reactogenicity but complicating the development, manufacture and administration of the vaccine.

For both non-replicating and self-replicating mRNA vaccines, the mRNA is formulated with a carrier such as a lipid-nanoparticles that encapsulates the mRNA to protect it from degradation and to allow uptake into human cells. There are various possible modes of delivery of the mRNA to the patient, including direct intradermal injection and more complex cellular therapies (removing, modifying and reintroducing target cells). Once within the cytoplasm of a patient’s host cell, the mRNA is translated by the host cell’s translational machinery (ribosomes) to produce the target protein, which then undergoes further post-translational modifications such as folding to produce a functional protein. This protein mimics the SARS-CoV-2 spike protein and therefore has the ability to elicit an adaptive immune response to the SARS-CoV-2 virus. As noted above, self-replicating mRNA constructs additionally have the ability to be translated by ribosomes to produce the replicase machinery necessary for self-amplification of the mRNA itself.[10]

This mRNA vaccine approach offers potential advantages over conventional inactivated and live-attenuated whole virus vaccines and subunit vaccines (which use a specific part of the virus such as its proteins, sugars, or capsule) in its simplicity and capacity to bring into effect a rapid and scalable response to novel pathogens. There is also likely to be potential for improved vaccine safety and efficacy:[11], [12]

  • mRNA vaccines allow for rapid, cost-effective and scalable manufacture of vaccines as there is no need for viral growth and expansion or the development of viral-specific cell cultures.
  • Once the viral genome has been sequenced, the target mRNA can be produced by a standardised process, rendering production faster and more cost-effective.
  • Delivery of mRNA into a human cell can be achieved by formulating the mRNA onto carrier molecules, allowing for rapid uptake and expression within cells.
  • Modifications to mRNA vaccine constructs can make them more stable and highly translatable.
  • Vaccines containing mRNA are capable of inducing both a T-cell (cellular) and B-cell (antibody) immune response.
  • The use of mRNA confers no risk of infection from the vaccine itself.

This approach also has advantages over DNA-based vaccines because mRNA does not need to enter the host cell nucleus in order to be transcribed. This means the dosage of vaccine can be significantly lower and no special delivery mechanisms are required. Additionally, there is no risk of DNA integrating into the host cell genome, avoiding concerns about the possibility of insertional mutagenesis.

Other candidate vaccines

A number of other COVID-19 candidate vaccines are currently in pre-clinical testing and also hold promise of a viable vaccine being produced during the next 1-2 years, most notably:[13]

  • Janssen’s (Johnson & Johnson) intranasally delivered recombinant adenovirus-based vaccine, incorporating a SARS-CoV-2 protein and utilising the vaccine platform it developed for the Zika and Ebola viruses;
  • Sanofi’s recombinant vaccine expressed in a baculovirus system and incorporating a SARS-CoV-2 protein;
  • LinealRx’s DNA vaccine encoding a SARS-CoV-2 protein;
  • Inovio Pharmaceuticals’ DNA vaccine encoding the SARS-CoV-2 spike protein;
  • Clover Biopharmaceuticals’ and GlaxoSmithKline’s recombinant SARS-CoV-2 spike protein subunit vaccine; and
  • the University of Queensland’s recombinant subunit vaccine incorporating the SARS-CoV-2 spike protein.

A number of these candidates have expectations of moving into Phase I clinical trials within 3 to 6 months.

Concluding remarks

Vaccines utilising mRNA platforms remain an unproven technology, with no vaccine approved for use to date. However, mRNA vaccine technology holds great promise and, if ultimately proven successful, could reduce vaccine lead-time and cost of development and manufacture and thereby shorten the time to product regulatory approval and implementation. While still too early to predict, the outcome of this race to develop a successful COVID-19 vaccine appears destined to yield a variety of improved techniques and new technologies, while also providing important lessons on how best to develop a vaccine in the face of future rapidly emerging global epidemics and pandemics.