Both Moderna and Pfizer’s Covid-19 bivalent vaccines have landed in Korea as a booster shot against the Omicron variants.

Moderna is expanding the mRNA scope beyond Covid-19 vaccines to tackle other global health issues, said Moderna’s Senior Director of Bacteriology and Infectious Disease Research, Dr. Obadiah Plante, in a recent interview with Korea  Biomedical Review. 

Dr. Plante, who graduated from the Massachusetts Institute of Technology (MIT) with a Ph. D in Organic Chemistry, leads the discovery of novel mRNA-based vaccines at Moderna.

Addressing global unmet needs

Plante mentioned Moderna's three priority areas.

“Moderna is focusing on vaccine candidates to address respiratory viruses, latent viruses, and global health threats. Simultaneously, we are advancing our mRNA therapeutic pipeline to tackle cancer and rare diseases,” he said.

Accordingly, the company is specifically targeting respiratory infections with vaccine candidates aimed at the major causative agents, including the SARS-CoV-2 virus, influenza virus, respiratory syncytial virus (RSV), and the four endemic human coronaviruses (HCoVs).

“Currently, we have influenza and RSV vaccine candidates in phase 3 clinical trials and are already seeing early clinical benefits in two rare disease programs from our therapeutic mRNA medicines portfolio,” said Plante. “We expect to report on data from our personalized cancer vaccine trial later this year. “

To address global health threats, Moderna plans to advance a portfolio of 15 vaccine programs by 2025 internally and externally through partnerships with researchers in its mRNA Access program to explore new vaccines against emerging or neglected infectious diseases.

Internally, the company is conducting phase 1 trials for a Nipah virus (NiV) vaccine candidate, mRNA-1215, he said.

Concerning latent infections, he mentioned that three of Moderna’s five vaccine candidates are in clinical trials.

Latent viruses exist in a resting state, without causing any noticeable symptoms and reactivate during times of stress or compromised immunity.

The capacity for latency is a defining feature of human immunodeficiency virus (HIV) and members of the Herpesviridae family, including Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV), and herpes simplex virus (HSV).

He stated that his company is targeting both the potential short and long-term health impacts of infection for each aforementioned latent virus.

Multi-pathogen vaccines with the mRNA platform and trade-off considerations

Addressing another anticipated area of research, he turned topics to multi-pathogen vaccines. Moderna’s mRNA platform is designed to accommodate multiple vaccine antigens in a single formulated product, according to Plante.

Considerations of the number of mRNA vaccine antigens for multi-pathogen vaccines include the immunogenicity of each component and potential immune interference.

“Each disease requires a threshold immune response, so the assessment of the immune response to each component in a multi-pathogen vaccine determines if components interfere with the immune response to individual components," he said. "Therefore, pathogens of interest and their respective vaccine antigens, dictate the level of immunogenicity needed for a given multi-pathogen vaccine.”

Beyond combination respiratory vaccines for SARS-CoV-2, influenza and RSV, Moderna is exploring combination vaccines with both viral and bacterial pathogens, like pertussis in the preclinical space, he went on to say.

Asked about an approximate timeline for these multi-pathogen vaccines, he responded, “We can’t predict when a commercialized combination vaccine will be released as yet but are successfully advancing several combination vaccine candidates through clinical development.”

Solutions to mRNA challenges

Subsequently, he highlighted some challenges of the mRNA platform.

He said multiple biological barriers must be overcome to deliver mRNA medicines and maximize its clinical potential.

Effective delivery of mRNA-based medicines is enabled by encapsulating the mRNA into tiny lipid (fat) droplets, known as lipid nanoparticles (LNPs) in order to protect it against degradation and facilitate better cell uptake, Plante explained. 

Accordingly, Moderna has invested in numerous proprietary LNPs for systemic, intramuscular, intratumoral, and pulmonary delivery of mRNA, which each target different cell types and are optimized for different administration routes.

“With Moderna’s focus on respiratory diseases,” he said, "we have invested in delivery of mRNA medicines directly to the lungs by inhalation to maximize its concentration in the lungs.”

He quickly noted that Moderna’s optimization of pulmonary delivery of mRNA presents other opportunities to address unmet medical needs.

In response to mRNA’s inherent instability issues, he said researchers at Moderna have found that the formation of lipid-mRNA complexes, called adducts, were responsible for mRNA activity loss.

"Since mRNA must be intact to be translated, adduct formation renders mRNA untranslatable, leading to a decrease in protein expression needed to treat or prevent disease,” he added.

In addition to the clinical benefits of stabilizing mRNA integrity, manufacturing protocols that limit the formation of lipid-mRNA adducts can improve product shelf-life, Plante said.

“Robust analytical methods and stringent manufacturing controls are critical to ensure mRNA stability, improved product activity within LNP delivery systems, and higher storage temperatures.”

However, despite all these achievements in the field of mRNA, Plante acknowledged that mRNA vaccine hesitancy still persists globally but emphasized his company’s stance is to lead the mRNA field with scientific and clinical data to provide accurate information and education.