mRNA Vaccines

Messenger RNA (mRNA) vaccines have been shown to have a greater specificity and efficacy than traditional vaccines, and with the recent speed of COVID-19 vaccine development, this success can only grow. mRNA vaccines have a long history; developed by Robert Malone in late 1987, he mixed strands of mRNA with droplets of fat for transfection. However, scientists were using liposomes to transport mRNA into murine and human cells to induce protein expression as far back as 1978 [1].

mRNA vaccines against influenza viruses are among the most extensively studied because they are the most ideal technology compared to what is currently used. The wide availability of tools to measure T and B cell responses and the ease of testing efficacy in small-animal models also contribute largely to the efficacy of trials. The speed of manufacturing these types of vaccines is faster than other types of vaccines, such as inactivated viruses, due to the ease of modifying the RNA sequence for new variants [2]. Individuals who get an mRNA vaccine are not exposed to the virus, nor can they become infected by the vaccine. Using a specific mRNA blueprint, cells can produce the respective viral protein necessary for immunity. As part of a normal immune response, the immune system recognizes that the protein is foreign and produces specialized proteins called antibodies [2]. mRNA vaccines can be used to help protect against a host of different illnesses but have most-notably focused on influenza, COVID-19, Zika, and respiratory syncytial virus (or RSV).

MRNA vaccines against influenza were the first to be developed, with the first clinical trial of mRNA vaccines used to treat mice in 1993 [1,3]. However, complete protection from influenza after vaccination was not actualized until 2012. Researchers in this study showed that intradermal injection with unmodified mRNA encoding various influenza virus antigens combined with a protamine-complexed RNA adjuvant facilitated immunity against the virus in mice, ferrets, and domestic pigs [2]. This was the first of many studies that showed that mRNA vaccines can induce broadly protective T and B cell immune responses.

More recently, mRNA lipid nanoparticle (LNP) delivery has been used for the development of a “universal” influenza vaccine capable of inducing potent immune responses against viral epitopes conserved among influenza virus strains. The first human trial of an mRNA-based influenza vaccine, using an LNP-formulated, nucleoside-modified mRNA encoding an H10N8—the strain that affects humans—HA antigen, has been recently reported. In this study, individuals vaccinated showed that the vaccine produced an immune response to the virus in all subjects at 43 days after vaccination [4].

Under normal circumstances like with the diseases listed previously, creating and manufacturing a vaccine can take up to 10–15 years due to the complexity of vaccine development and the length of clinical trials. However, due to the nature of the COVID pandemic, researchers were able to uncover the viral sequencing of SARS-CoV-2 about 10 days after the first reported cases in Wuhan, China. The timely turnaround for vaccine development came from worldwide cooperation, specifically the Gulf Cooperation Council and the WHO [5].

One study from 2021 measures efficacy of the COVID vaccine from Moderna, mRNA-1273. Vaccine recipients were assessed for neutralizing and binding antibodies as correlated of risk for COVID-19 and of protection. These immune markers were measured at the time of second vaccination and four weeks later, with values reported in standardized World Health Organization international units. Vaccine recipients had estimated vaccine efficacies of 78%, 91%, and 96%, depending on the titer [6].

The Pfizer-BioNTech vaccine, BNT162b2, is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine. The body of evidence for the Pfizer-BioNTech COVID-19 vaccine was primarily informed by one large, randomized, double-blind, placebo-controlled Phase II/III clinical trial that enrolled >43,000 participants. Oliver et al. found consistent high efficacy of ≥92% across age, sex, race, and ethnicity categories, among persons with underlying medical conditions, and among participants with evidence of previous SARS-CoV-2 infection [7].

These studies are bringing mRNA vaccines to the forefront of medicine. As of March 10, 2022, more than 10.9 billion doses of COVID vaccines have been administered worldwide, with 4.45 billion people fully vaccinated [8]. The number of cases has steadily decreased, with symptoms significantly less impactful for those who have been vaccinated [9]. The success rate of COVID-19 vaccines has lit a flame under researchers who strive to create efficient vaccines as quickly and safely as possible, making the impending creation of preventative treatments against the Zika virus and RSV within arm’s reach.

The Zika virus (ZIKV) has recently triggered global concern due to severe health complications, with the worst complications found in newborn babies. Although there’s no specific antiviral that has been proven safe enough to prevent this disease, the success of mRNA vaccine technology in facing the COVID-19 pandemic has provided hope. Moderna's current mRNA-1893 vaccine candidate for Zika contains an mRNA sequence encoding for the structural proteins of the Zika virus [10]. Preclinical data published in the Journal of Infectious Diseases have shown that vaccination with mRNA-1893 provided protected against Zika virus transmission during pregnancy in mice. This revolutionary information that a modified mRNA vaccine can prevent ZIKV disease also brings hope that the vaccine can be adapted to reduce the risk of sensitizing individuals to subsequent exposure to the Dengue virus (DENV)—a disease spread from the bite of an infected Aedes species mosquito—should this become a clinically relevant concern [11].

RSV causes a respiratory tract infection that affects 64 million people per year worldwide. It hospitalizes three million children under five years old and approximately 336,000 older adults annually. The global healthcare costs of RSV-associated infections in young children in 2017 were estimated to be US $5.45 billion [12]. RSV tends to be a seasonal illness; however, the COVID-19 pandemic has led to increased interseasonal RSV infection in children and the elderly [13].

Like the Zika vaccine, there is no approved preventative measures for RSV. However, four mRNA vaccine candidates and one monoclonal antibody treatment are in late-stage clinical trials to find an efficient RSV vaccine. Current running studies are working to evaluate the safety and tolerability of Moderna’s mRNA-1345 vaccine, a vaccine against RSV encoding for a prefusion F glycoprotein, and to demonstrate the efficacy of a single dose in the prevention of a first episode of RSV. This trial is directed at 34,000 randomized participants ages 60 years and older across multiple countries. The trial vaccine uses the same LNPs as Moderna’s COVID-19 vaccine and has optimized protein and codon sequences. Due to the success Moderna researchers have found with their COVID vaccine, they are starting to focus on boosters that combine flu, COVID-19, and RSV protection [13].

There have been some recorded issues with mRNA vaccines, such as increasing production while also following good manufacturing practices (GMP), establishing regulations, further documenting safe procedures in rapidly changing environments, and increasing efficacy [14,15]. These vaccines are also sensitive to storage and transportation, rendering it substantially inaccessible to a country like India. However, scientists are currently at work to clear up any issues and clarify future approaches to make these vaccines more accessible to those who need them. There has been recent discourse and research on how to safely transport mRNA vaccines by freezing them, which allows for transportation more than one time [16]. Important future directions of research will be to compare and elucidate the immune pathways activated by various mRNA vaccine platforms, to improve current approaches based on these mechanisms and to initiate new clinical trials against additional disease targets [17].

mRNA vaccines have proven to be the most quickly produced and effective when there is a world-wide effort. Moderna has recently partnered with Thermo Fisher Scientific for a 15-year production pact to further manufacture COVID vaccines and more. Thermo Fisher Scientific is a leader in supporting the development of mRNA for today’s applications and the research shaping solutions for tomorrow, proving their dedication to resolving issues with mRNA. The future of safe mRNA production is brighter than ever, especially with current and future collaborations with Thermo Fisher Scientific.

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