The overall dwindling of Covid-19 cases has caused countries globally to lower their emergency responses to the virus. Korea, although much later than other countries, is no exception, lowering the infectious disease grade of Covid-19 to level 2, the same as the flu in August. However, a resurgence of new Omicron strains could signal trouble ahead of the upcoming fall and winter seasons.

Korea Biomedical Review got a hold of Galit Alter, recently appointed Vice President of Moderna’s Immunology Research Division, to understand Moderna’s strategy to stay ahead of the changing variants for Covid-19 and other infectious diseases, its platform technology, and ongoing efforts to reduce the adverse effects of mRNA-based vaccines.

Alter is currently leading research involving the use of conventional as well as new cutting-edge immunological tools for vaccine development to understand how mRNA vaccines program the immune system to fight infectious diseases, cancer, and autoimmune diseases.

As a Professor of Medicine in Systems Immunology at the Ragon Institute of MGH, MIT, and Harvard for 19 years, she shared that biopharmaceutical companies often approach her to conduct immune profiling analyses of their drug candidates. However, when the chance to join Moderna came knocking, Alter jumped at the opportunity to become actively involved in developing solutions that could directly impact lives.

“The allure of Moderna was like the Tesla of vaccines,” she said. “While there are many tools available for vaccine development, I believe it is important to explore how to use them strategically by leveraging mathematical modeling, computational tools, and others to make better vaccines.”

Immunobridging to keep up with virus variants and pathogen X

Instigated by the recent pandemic, there has been a global effort through the Coalition for Infectious Disease Innovation (CEPI), the World Health Organization (WHO), and other organizations to understand the mechanistic correlates of immunity to enable the development of vaccines that can be used universally, regardless of Covid-19 variants. Consequently, most Covid-19 vaccine developers are using immunobridging strategies to advance the next product, as it is well-known that neutralizing antibodies correlate with protection against severe disease and death. 

Immunobridging assesses the effectiveness of a new drug or vaccine candidate by using an accepted surrogate measure for efficacy. 

“As a result of this robust correlative immunity, all booster vaccines that we're developing within Moderna currently are using an immunobridging approach to essentially establish that we are reaching neutralizing antibody cutoff levels that are associated with protection against breakthrough infections and disease,” explained the VP. 

The CEPI 100-day calls on immunologists to develop a solution by measuring the immune responses that are associated with protection against a novel pathogen X and use this in the therapeutic product profile of the vaccine against that pathogen.  

As Covid-19 cases are starting to peak again in some regions, the immunologist shared her thoughts on the different responses required in a pandemic compared to an endemic situation. 

“In a pandemic, we need everyone to build immunity against the virus and we use the boosters to continuously educate the immune system to anticipate future variants in circulation,” she said. “In endemics, however, we prioritize the vulnerable populations to ensure they can scale their immune system fast enough so that their antibody or T-cell levels are ready to fight back.”

It is precisely the platform’s ability to scale to provide suitable quantities for an endemic or pandemic that makes it so versatile. 

“This mRNA vaccine can essentially make small numbers of doses or billions of doses and we can now use it to fight infections, tumors, or deliver genes to replace genetic defects,” said the expert.

Speaking to the other advantages of the platform, she noted its ability to rapidly use digital information to develop vaccines that can induce broad durable immune responses that are safe. 

Working to silence the adverse effects

However, Alter attempted to clear the air on adverse events such as myocarditis and pericarditis, anaphylaxis caused by polyethylene glycol anti-PEG antibodies, and LNP-related thermostability which have collectively triggered vaccine hesitancy and mistrust toward mRNA vaccines.   

Alter was quick to note that among the vaccine platforms tested during the pandemic, it was the vectored vaccines that resulted in side effects such as thrombocytopenia, but mistakenly all Covid-19 vaccines were labeled as driving these potential complications.

Regarding myocarditis and pericarditis, the immunologist first stated that both were very rare after mRNA vaccine administration, adding that most cases are mild and resolve within a short time. However, she argued that epidemiological studies have also shown a 45-fold increase in myocarditis due to Covid-19 infection as the spike protein from the virus attaches to the angiotensin-converting enzyme 2 (ACE2) receptor and eventually gets into the systemic circulation thus causing adverse heart conditions. 

Despite popular belief, she said that the vaccine itself lowered the risk of myocarditis which further decreased with subsequent rounds of boosting. 

“This is because the spike protein delivered with mRNA is stabilized and expressed on the surface of an antigen-presenting cell (APC) so it cannot be released into the systemic circulation,” reasoned Alter. “The more antibodies that are built up with every boost dose enables the spike antigen to be cleared more effectively.”

Addressing adverse events related to anaphylaxis associated with anti-PEG antibodies, she noted that this was observed very early on in the first vaccine rollouts in 2021 and led to close monitoring of putative causes of anaphylaxis. She dispelled this claim by pointing out that a large consortium of investigators, run by the National Institutes of Health (NIH) in the U.S. studied individuals who had a high predisposition towards allergy or autoimmune diseases to investigate the relationship between anti-PEG antibodies and adverse reactions and found no association.

“We are working on improving lipid nanoparticles (LNPs) to reduce the -20 degrees Celsius cold storage requirement so that the mRNA vaccine can remain thermostable at four degrees Celsius and are hoping to roll this out next year,” Alter said.

Driving continuous improvements

Alter explained that Moderna has a team of clinicians and immunologists monitoring vaccine safety, and surveillance to facilitate constant improvements to its Covid-19 vaccine based on real-world data, large clinical studies, and observed vaccine responses, to lower the mRNA antigen dose used in its booster shots.

She pointed to the results of its respiratory syncytial virus (RSV) vaccine which has not shown any signs of post-vaccine effects as a sign of the quick evolution of the mRNA platform.

“This is just the beginning of the mRNA story but we at Moderna are committed to improving the vaccine platform to reduce side effects,” said Alter.

Moderna is also looking at developing different ways of applying mRNA to drive mucosal immunity and cellular immunity to try to tune and manipulate the immune response. 

As respiratory diseases are one of the diseases with the highest disease burden globally, Moderna is developing combination vaccines including three against Covid-19, influenza, and RSV, two against Covid-19 and influenza, two against human metapneumovirus (hMPV) and human parainfluenza virus (hPIV), and another two against RSV and HMPV, all in phase 1 clinical trials. 

“As an immunologist, I believe that the ability to treat multiple diseases with a single vaccine holds great promise for preventing a wide range of diseases, not just respiratory,” said the vaccine expert.

However, with one foot still inside the academic world and another in the industry, she explained how each world brings its unique advantages and corresponding solutions. 

“In academia, you can imagine any component of a vaccine and try to deliver the vaccine in different ways considering all the different immune responses but at Moderna, we have a unified mission to consider how our platform can program the immune response to modify multiple different disease outcomes," said Alter.