Billions of doses of COVID-19 vaccines have been distributed worldwide since the beginning of the pandemic, with hundreds of millions of individuals having received a vaccine based on messenger RNA (mRNA) technology.1,2 Prior to the pandemic, however, few outside the world of scientific research and therapeutics development had more than a superficial understanding of how such a platform could make it into medical practice, if they knew anything at all about the technology. How did we get from a vaccine platform only experts were aware of to widespread use in such a seemingly short time? What can we expect from mRNA vaccines going forward?
A brief history of mRNA vaccines
Experiments showing that mRNA could be introduced into cells to generate an immune response against the encoded protein date to the 1990s, although technical challenges including the biological instability of mRNA and the induction of undesirable inflammatory responses by unmodified nucleic acid hampered development of this technology into clinical application.3,4 Advances including chemical modifications to the nucleoside constituents of the mRNA polymer and the use of a lipid outer coating for delivery of the mRNA formed the basis for this technology to enter human studies.5,6 These changes led to increased production of the target protein after inoculation with fewer inflammatory adverse effects (AEs), while retaining induction of an immune response.7-9 These technologic advances were the basis for the COVID-19 mRNA vaccines in widespread use today.
How mRNA vaccines work: a high-level overview
At a very basic level, the use of lipid nanoparticle–coated mRNA as a vaccine relies on 2 biologic mechanisms: the production of a usually nonnative (“heterologous”) protein in a cell and the stimulation of immune recognition of that protein. Each of the major components of the current vaccines contributes to these responses. The sequence of events that leads to induction of effective immunity includes the following:
- Creation of a nucleic acid sequence that results in production of the protein or a part of the protein against which a specific immune response is desired (“immunogen”)
- Delivery of that sequence into the cell to engage the cellular machinery for producing the immunogen
- Induction of inflammatory pathways to stimulate adaptive immunity leading to antibodies and T cells that respond to the immunogen
Immune protein sensors that initiate inflammation are present in all cell types. Some of these sensors can detect nucleic acid polymers, which led to initial challenges in the use of mRNA therapeutically because the resulting inflammation limited tolerability. Modifications to the coding sequence, including the use of nucleosides that are not used by normal human cells, limited the promotion of these undesired immune responses. At the same time, sequences of mRNA vaccines in use today are optimized to promote high levels of production of the desired protein product.
The lipid nanoparticle shell surrounding the mRNA is equally critical to the success of this platform.10 In addition to protecting the mRNA from degradation prior to cell entry, the nanoparticle enhances the delivery of the mRNA into the cell compartment in which protein will be produced. As this shell is minimizing detection of the encapsulated mRNA by inflammatory sensors, components of the nanoparticle stimulate immune signaling pathways that promote an appropriate response against the encoded protein sequence.11
The production of the target immunogen within a cell provides the mRNA platform with an immunologic advantage over some traditional vaccine platforms such as protein-based vaccines. When foreign proteins are present in an inflammatory reaction, the presentation of protein fragments to the responding immune cells favors production of antibodies, which are widely recognized to be an important source of protection against infection. Antibodies are a common correlate of protection after vaccination and have been a surrogate marker for the authorization of COVID-19 vaccines in children using an end point referred to as “immunobridging,” in which the levels of neutralizing antibodies produced in young, immunized children are compared with those in older children and adults; if similar, it is inferred that the vaccine will be protective. However, T-cell–mediated immunity is more strongly promoted when proteins are synthesized within a cell during an immune response, as they are with mRNA vaccines. In addition to helping minimize the spread of infection within an individual, the T cells generated after immunization can provide broad, long-lived protection against severe disease. This in large part explains why vaccines based on the initial SARS-CoV-2 strain continued to provide protection against hospitalization and death as newer variants able to escape antibody-mediated protection emerged.
What gave mRNA technology the upper hand in the COVID-19 pandemic
Traditional vaccine platforms include live-attenuated vaccines (such as measles-mumps-rubella), killed virus vaccines (such as inactivated poliovirus vaccine), and protein-based vaccines (including tetanus vaccine and polysaccharide conjugate vaccines such as Haemophilus influenzae type b). Each of these has been used as a platform for candidate COVID-19 vaccines, and some have made it to clinical usein various parts of the world. However, mRNA vaccines largely dominate in the United States. Reasons for the emergence of this platform are numerous and varied, but in some cases relate to specific scientific advantages that this platform holds over other options.
The nucleic acid sequence of SARS-CoV-2 was published within weeks of the outbreak, and knowledge about similar viruses led to focus on the spike protein as a target for vaccines.12 From a vaccine development standpoint, access to the sequence of the spike gene allowed preclinical work to begin nearly immediately on nucleic acid–based approaches to immunization, including mRNA and live virus platforms. Although to many it seemed as though Moderna and BioNTech appeared from nowhere, both companies had been actively developing mRNA-based vaccine (and therapeutic) candidates for at least 10 years, with candidate vaccines targeting respiratory pathogens and other indications in human trials for at least 5 years prior.13,14
Live attenuated vaccines can promote a similar range of antibody and T-cell–mediated protection as mRNA vaccines, and the adenovirus-based vaccines engineered to express the SARS-CoV-2 spike gene can be considered a subset of this category of vaccines. These were among the early candidates brought into clinical use. Concerns about rare AEs limited their uptake in the United States. This platform can also be at a disadvantage relative to mRNA vaccines because repeated administration can lead to immunity directed against the adenovirus vector, potentially decreasing the usefulness of live virus vector-based platforms as boosters.
A killed virus vaccine platform is the basis for Sinopharm and CoronaVac vaccines developed in China and the BBV152 vaccine made in India.15 Vaccines based on this platform have been given to billions of individuals worldwide.16 Manufacture of these vaccines early in the pandemic required the ability to grow infectious viruses in a controlled setting, which unlike manufacture of mRNA vaccines carries nonzero transmission risk. Because these vaccines do not produce proteins in the immunized individual, they tend to be better at inducing antibody-based protection than cellular responses. However, because they include whole inactivated virus, they can produce antibodies directed against a range of viral proteins, not only the spike protein.
Protein-based vaccines were at a disadvantage relative to mRNA vaccines early in the pandemic because production requires a system allowing generation of the target protein prior to construction of a testable vaccine. Like killed virus vaccines, these would also tend to favor generation of antibody-based protection over T-cell–mediated immunity. Nevertheless, a protein-based vaccine made by Novavax was recently authorized for use in adults in the United States.17
What does the future of mRNA-based vaccination potentially hold?
The spectacular success of the mRNA-based vaccines in controlling the COVID-19 pandemic has been extended to include their potential in immunizing against variants that have emerged. The FDA is expected to authorize mRNA vaccines based on variant sequences in fall 2022, demonstrating the ability of this platform to rapidly adapt the sequence to changing needs and quickly provide large amounts of vaccine.
Advantages of the mRNA platform also fuel expectations for future success of this platform in immunizing against other diseases. The mRNA vaccine pipeline includes development of vaccines against a range of viruses including influenza, respiratory syncytial virus, human metapneumovirus, endemic coronaviruses, parainfluenzavirus, and herpesviruses such as herpes simplex, varicella-zoster, cytomegalovirus, and Epstein-Barr virus. The platform also has a strong historical interest in development of cancer vaccines and in mRNA therapeutics for indications such as rare metabolic disorders in which delivery of mRNA encoding functional protein could correct the disorder. As additional knowledge is accumulated about how to prolong or otherwise alter the duration of protein production from delivered mRNA and how to influence the relevant immune pathways, it is reasonable to expect many additional applications could be envisioned.
References
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