All the Way with mRNA?

Before the advent of mRNA vaccines to SARS-CoV-2 (COVID-19) the technology was already under investigation for several decades, mainly for the delivery of therapeutics. Laboratory studies began in the early 1960s, but success was ultimately made possible by a series of breakthroughs in nucleoside modification and in lipid nanoparticle (LNP) delivery systems (here). 

mRNA vaccines differ fundamentally from traditional vaccines. Rather than injecting an antigen, synthetic mRNA encoding the target antigen is delivered into host cells within lipid nanoparticles (LNPs). After host cell ribosomes translate the mRNA into the target protein, it is then presented to the immune system, stimulating both cellular and antibody responses. As only the genetic sequence of the pathogen or target antigen is required, vaccine development to an emerging infectious agent can begin quickly.

In response to the COVID-19 pandemic, the extraordinary rapid development, clinical evaluation and deployment of mRNA vaccines to SARS-CoV-2 demonstrated that these novel vaccines were safe and effective (here). Less than a year after the publication of the viral genome in January 2020, COVID-19 vaccines received emergency regulatory approvals, launching unprecedented successful global vaccination campaigns against the pandemic (here). 

This achievement fundamentally changed vaccine science and has given humanity a unique tool to fight any emerging pandemic or any infectious disease with a high disease burden. It has also accelerated research into mRNA vaccines for seasonal and pandemic influenza viruses, respiratory syncytial virus (RSV), cytomegalovirus, HIV, malaria, bacterial and protozoan infections as well as numerous cancer immunotherapies (here). An mRNA vaccine for RSV has already been registered by the FDA and TGA, and an mRNA vaccine for seasonal influenza was found to be more effective than standard-dose licensed influenza vaccines in phase 3 clinical trials in adults aged 50 years or older (here).

Despite the overwhelming scientific success of mRNA vaccines, public confidence has been undermined. The reasons include rapid early rollouts of a new type of vaccine, mandates, side effects, the politicisation of public health and pervasive misinformation especially through influencers on social media and other platforms. Extensive clinical data involving billions of administered doses, reaffirms that mRNA vaccines are safe and highly effective, consistently reducing hospitalisation and death, but misinformation and an unbalanced emphasis on very rare side effects like myocarditis continues to influence vaccine acceptance (here). 

The medical consensus remains firm — that the benefits of mRNA COVID-19 immunisation substantially outweigh the risks (here). At the same time, challenges remain, including improving the durability of immune responses and overcoming the cold-chain requirements that may limit accessibility to some geographical areas.

Should mRNA vaccines replace traditional vaccines? 

Not yet! Traditional vaccines to serious infectious diseases have protected humanity for many decades, some for more than a century, and their development usually requires several years because pathogens must be cultured, purified and manufactured before clinical testing. Each platform requires production of either the pathogen itself or purified antigen, processes that are often lengthy, expensive and technically demanding. Depending on the vaccine type, their production may involve the use of master cell banks, embryonated eggs, bioreactors, specialised purification systems, various chemical treatments and a high level of quality control to ensure a safe, pure and consistent product (here). 

Advantages of mRNA Vaccines

The greatest advantage is speed. Once the genome of a new threat is published, vaccine design and subsequent animal studies and human clinical trials can be commenced quickly under regulatory authority supervision (here).

mRNA vaccines use essentially the same manufacturing process regardless of the antigen encoded and changing from one vaccine to another or updating a vaccine generally requires only an alteration of the nucleotide sequence. As RNA viruses, like SARS-CoV-2 and Influenza viruses, rapidly evolve, this "plug-and-play" capability offers enormous advantages, including molecular precision in the fight against emerging infectious diseases (here). 

mRNA vaccines can stimulate multiple arms of immunity resulting in broad immune responses. Unlike purified protein vaccines that predominantly induce antibody responses, intracellular antigen production leads to presentation through both major histocompatibility complex class I and class II pathways stimulating neutralising antibodies, CD4+ helper T cells, CD8+ cytotoxic T cells and immune memory, resulting in remarkable effectiveness against severe COVID-19 (here). 

mRNA vaccines are safe. Large observational studies consistently demonstrate favourable safety profiles with over 13 billion COVID-19 vaccine doses administered globally (here). The adverse event attracting greatest attention has been myocarditis, which occurs predominantly in adolescent and young adult males after the second dose usually within one week. Most cases are mild and recovery is usually rapid (here). However, it is important to note that COVID-19 infection itself carries a substantially greater risk of myocarditis than vaccination (here). Population studies consistently demonstrate that the benefits of vaccination greatly outweigh this rare complication (here). Anaphylaxis has also rarely occurred with mRNA vaccines. Whenever administered, the appropriate treatments for anaphylaxis must be at hand (here).

Limitations of mRNA Vaccines

The limited durability of neutralising antibodies and issues with cold-chain and shelf life compared to traditional vaccines have often been cited as limitations for the mRNA platform (here).

While neutralising antibody concentrations decrease over several months following vaccination, resulting in the need for regular boosters, immune memory through B cells and T cells remains considerably longer than circulating antibody titres and protection against severe disease, hospitalisation and death has remained consistently high (here). Nevertheless, mRNA vaccines granting longer-lasting immunity remain an important research priority.

Cold-chain logistics are important as they increase costs, complicate rural delivery and limit deployment in developing countries. The first-generation mRNA vaccines initially required storage near −70°C, however, second-generation formulations showed improved stability at refrigerator temperatures and lyophilised formulations, and importantly those using advanced LNPs, can be stored at standard refrigerator temperatures (here).

The shelf life of mRNA vaccines continues to improve as manufacturing technology advances, and varies depending on the storage temperature (frozen vs. refrigerated) and the specific manufacturer formulation. Ultra-low frozen mRNA vaccines can be generally stored for 24 months and held in refrigerated storage for 10 weeks. Regulators frequently update these timelines based on ongoing stability studies (here).

Misinformation

Misinformation spreads quickly. It is worth emphasising that there is no infectious material in mRNA vaccines so there is no possibility of vaccine-derived infection. Moreover, there is no evidence of genomic integration as mRNA cannot enter the cell nucleus and is rapidly degraded by normal cellular processes (here). Nor do mRNA vaccines cause infertility, autism, weaken immunity or remain permanently in the body. (Such misinformation is often reported and emphasised by ‘antivaxxers’ and internet influencers).

For many people in the community speed of development generated suspicion, and rapid development was equated with inadequate testing. However, the fact is that manufacturing occurred concurrently with trials, shortening timelines without compromising scientific standards (here).

There were also communication failures as evolving recommendations sometimes appeared to be contradictory to the public and changing of advice regarding boosters and emerging variants was interpreted by some as inconsistency rather than adaptation to new evidence. Moreover, public health recommendations were sometimes interpreted through political/ideological perspectives rather than a scientific lens, resulting in reduced trust in expert advice (here). In addition, different Australian states did not have consistent advice and guidelines, which eroded public trust (here).

Future directions 

In order to enhance immune durability of mRNA vaccines, researchers are focusing on self-amplifying RNA vaccines (saRNA) (resulting in smaller doses of vaccine being needed), improved lipid nanoparticles, pan-coronavirus vaccines, circular RNA vaccines, universal influenza vaccines, and multivalent vaccines (eg COVID-19, influenza, human metapneumovirus, RSV combinations). 

Japan has already approved the world's first saRNA COVID-19 vaccine for use in adults as primary and booster vaccinations, giving an efficacy of 100% against severe disease (here). 

mRNA beyond infectious diseases

Cancer vaccines represent one of the fastest growing areas of mRNA research. Numerous clinical trials are evaluating mRNA vaccines for melanoma, pancreatic cancer, lung cancer, ovarian cancer, personalised neoantigen vaccines and autoimmune disease modulation (here). mRNA based gene editing tools and protein replacement therapies based on mRNA are also being explored (here). 

Conclusion

mRNA vaccines have transformed modern vaccinology and (together with protein subunit and viral vector vaccines) led the fight against COVID-19. Compared with traditional vaccine platforms, they offer unprecedented speed of development, precision antigen design, flexible manufacturing, strong humoral and cellular immunity, and exceptional adaptability to emerging pathogens. Their success has accelerated research across infectious diseases and oncology (here). Confidence is growing that mRNA can "go all the way" to fundamentally transform preventive medicine and immunotherapy.

Professor Gary Grohmann is a Board member and a member of the Scientific Advisory Committee of the Immunisation coalition. He is a former Director of Immunobiology at the Therapeutic Goods Administration and currently works as an independent consultant.

Professor Robert Booy is an infectious diseases paediatrician. He is a Senior Professorial Fellow at the University of Sydney Children’s Hospital Westmead Clinical School and a member of the Scientific Advisory Committee of the Immunisation Coalition.

Acknowledgement: Gratitude to Dr John McEwen for reviewing the manuscript.