The Promise of mRNA Vaccines for Disease Prevention

THE COVID-19 PANDEMIC was the catalyst scientists needed to complete their messenger Ribonucleic Acid (mRNA) research to develop the first mRNA-based vaccine. Now, vaccine manufacturers are using this new technology to produce novel vaccines for disease prevention of respiratory, tropical and latent viruses — and potentially cancer.

mRNA Vaccine Technology

Messenger RNA, also known as mRNA, is one of the types of RNA found in a cell. Like most RNA, it is made in the nucleus and then exported to the cytoplasm where the translation machinery, the machinery that makes proteins, binds to these mRNA molecules and reads the code on the mRNA to make a specific protein. In essence, the DNA for one gene can be transcribed into an mRNA molecule that will make one specific protein.¹

mRNA vaccines instruct the body to produce specific antigens called spike proteins that look physically similar to those of viruses. The antigens trigger the body’s immune system to create specific antibodies that fight off the real viruses should a body become exposed to them.

Research surrounding mRNA began decades ago, between 1947 and 1961, by several scientists around the world, separately but simultaneously.² However, mRNA research plateaued for approximately 30 years because it was unstable and caused a harmful inflammatory immune response. In 1994, James Eberwine, PhD, and his colleagues, were the first to “transfect” RNA into cells when they put RNA into a region of a neuron to determine what the protein made from that RNA did in that region. According to Dr. Eberwine, “We saw that if you put the RNA from cell A into cell B, then cell B will become cell A. RNA and mRNAs have a figurative cellular memory and a literal transformational quality.”

Then, in 2005, Drew Weissman, MD, PhD, and Katalin Kariko, PhD, made a breakthrough in their mRNA research. They altered one of mRNA’s four building blocks, known as nucleosides, and discovered that their modified synthetic mRNA no longer caused inflammation. This discovery solved the instability and inflammation challenges and allowed the mRNA research to continue. “mRNA vaccines are essentially plug and play,” explained Dr. Weissman. “We believe you can change the part of the mRNA that encodes a protein, plugging in new code specific to the virus we hope to protect against, and cause one’s body to produce proteins that match that virus’ proteins. We do not have to develop and manufacture an entirely new formula.”³

Pfizer and Moderna were the first vaccine manufacturers to utilize this novel mRNA vaccine technology to develop mRNA-based vaccines, both of which are COVID-19 vaccines. Initially recognized in Wuhan, China, in December 2019, China released the genome sequence for the SARS-CoV-2 virus on Jan. 11, 2020. Moderna then used this genome sequence to develop its COVID-19 vaccine (Spikevax) within two days, and Pfizer and BioNTech announced their partnership in March 2020 to develop their COVID-19 vaccine (Comirnaty), which moved into Phase I clinical trials by May 2020.⁴

Now that the first mRNA-based COVID-19 vaccines have been in use for more than a year, Pfizer and Moderna are moving forward with developing other mRNA-based vaccines for several well-known viruses.

Pfizer

Pfizer Inc., an American multinational pharmaceutical and biotechnology corporation, develops and produces vaccines for diseases using many technological platforms. Currently, Pfizer is developing two new mRNA-based vaccines and is investigating lipid nanoparticle (LPN) formulation technology for vaccine development.

In partnership with BioNTech, Pfizer was the first vaccine manufacturer to enter the marketplace with an mRNA-based COVID-19 vaccine, BNT162b2 (Comirnaty), to prevent infection with the SARS-CoV2 virus. Their COVID-19 vaccine received emergency use authorization from the U.S. Food and Drug Administration (FDA) on Dec. 11, 2020, and it received full approval on Aug. 23, 2021.⁵

In September 2021, Pfizer also started a Phase I study to evaluate the safety, tolerability and immunogenicity of an mRNA vaccine to prevent influenza. The trial included 615 healthy adults aged 65 years to 85 years old, with an FDA-approved standard quadrivalent influenza vaccine as a control. The completion date for this study is estimated to be July 26, 2022.⁶

In January 2022, Pfizer and BioNTech partnered to research, develop and commercialize a potential first mRNA-based shingles vaccine. Shingles is caused by the varicella zoster virus (VZV), the virus that causes chicken pox. VZV is a latent virus that can reactivate later in life, causing shingles. Adults aged 50 years and older, as well as vulnerable populations such as cancer patients, are at an increased risk of shingles, a debilitating, disfiguring and painful disease that impacts approximately one in three people in the United States. Pfizer and BioNTech’s clinical trials for its mRNA-based shingles vaccine are set to start in the second half of 2022. According to Pfizer, while there are currently approved vaccines for shingles, there is an opportunity to develop an improved vaccine that potentially shows high efficacy and better tolerability and is more efficient to produce globally by utilizing mRNA technology.”⁷

Also in January 2022, Pfizer announced its agreement with Acuitas Therapeutics that will expand its access to LPN formulation technology for up to 10 targets for vaccine or therapeutic development, which offers a strong strategic fit with Pfizer’s mRNA strategy to develop potential new breakthrough vaccines. Acuitas’ mRNA-LNP technology is used in Pfizer’s COVID-19 vaccine.⁸

Moderna

Moderna Inc., an American pharma-ceutical biotechnology company, is focused on developing RNA therapeutics, primarily mRNA vaccines and therapies spanning several therapeutic areas.

Cytomegalovirus (CMV), a type of herpes virus that usually produces very mild symptoms in an infected person, may cause severe neurological damage in people with weakened immune systems and newborns. CMV is a latent virus that remains in the body for life after infection. The Centers for Disease Control and Prevention (CDC) estimates more than half of adults have been infected with CMV by age 40.⁹ In addition, CMV is the most common infectious cause of birth defects in the United States. CDC estimates about one out of every 200 babies is born with congenital CMV and approximately one out of five of these babies will have long-term health problems such as hearing loss, intellectual disability, vision loss, seizures and lack of coordination or weakness.¹⁰

Moderna’s vaccine candidate, CMV mRNA-1647, combines six mRNAs in one vaccine that encode for two proteins located on the surface of CMV: five mRNAs encoding the subunits that form the membrane-bound pentamer complex and one mRNA encoding the full-length membrane-bound glycoprotein B (gB). Both the pentamer and gB are essential for CMV to infect barrier epithelial surfaces and gain access to the body, which is the first step in CMV infection. The vaccine is designed to produce an immune response against both the pentamer and gB to prevent CMV infection. Moderna believes a vaccine that protects women from CMV infection should protect against congenital CMV infection. Currently, there is no approved CMV vaccine.

The Phase I and II studies of CMV mRNA-1647 vaccine demonstrated functional antigen-specific responses that support the vaccine’s potential to prevent CMV infection. Interim seven-month data from the Phase II study at 50 ug, 100 ug and 150 ug dose levels showed the vaccine was generally well-tolerated. The most common local adverse reaction was injection site pain, and the most common systemic adverse reactions were headache, fatigue, myalgia, arthralgia and chills. Based on the interim analysis of the Phase II study, the 100 ug dose was chosen for the Phase III study.

Moderna is currently recruiting participants for its Phase III study, known as CMVictory, to evaluate the safety and efficacy of the CMV mRNA-1647 vaccine against primary CMV infection in women aged 16 years to 40 years old. This study is anticipated to enroll up to 8,000 participants, including 6,900 women of child-bearing age, from approximately 150 global sites beginning in the United States. The U.S. demographic will include 58 percent white women and 42 percent persons of color.¹¹

Respiratory syncytial virus (RSV) is one of the most widespread respiratory viruses in young children and older adults in the United States. In children younger than 1 year old, RSV is the most common cause of bronchiolitis and pneumonia. In older adults, RSV can result in pneumonia and respiratory distress. There is currently no approved vaccine for RSV.

Moderna’s vaccine candidate, RSV mRNA-1345, encodes for a stabilized profusion F glycoprotein that elicits a superior neutralizing antibody response compared to the postfusion state. This vaccine candidate uses the same LNP as Moderna’s COVID-19 vaccine and contains optimized protein and codon sequences.

The Phase I study of RSV mRNA-1345 enrolled participants aged 65 years to 79 years. Results released in September 2021 showed neutralizing antibodies were confirmed to be present at baseline in all participants and that a single vaccine of 50 ug, 100 ug or 200 ug boosted neutralizing antibody titers against RSV-A by approximately 14-fold and against RSV-B by approximately 10-fold. In addition, it was well-tolerated in older adults through the first month.

The Phase II/III study, known as ConquerRSV, commenced in November 2021 and expects to enroll approximately 34,000 participants. Conducted in multiple countries with locations selected by RSV epidemiology, the primary purpose of the Phase II study is to evaluate the safety of the RSV mRNA-1345 vaccine in adults older than 60 years of age for initiation

of the large-scale Phase III study.¹² In February 2022, the National Institute of Allergy and Infectious Diseases’ Data and Safety Monitoring Board endorsed the start of the Phase III study after an independent review of preliminary Phase II data, which suggests the vaccine has an acceptable safety profile in older adults at the selected dose. The primary purpose of the Phase III study is to establish the safety and efficacy of the vaccine in support of licensure. According to a Moderna spokesperson, “An mRNA vaccine against RSV could have a positive impact on individuals, communities and global public health. Our ultimate goal is to combine our RSV vaccine with our COVID-19 and flu boosters into a single-dose booster.”¹³

Epstein-Barr virus (EBV) is a member of the herpes virus family, which includes CMV, herpes simplex virus (HSV) and VZV. EBV is a major cause of infectious mononucleosis and can lead to lifelong medical conditions. It is also associated with an increased risk of developing multiple sclerosis, certain lymphoproliferative disorders, cancers, autoimmune diseases and long COVID. Currently, there is no approved vaccine to prevent EBV.

Moderna’s EBV mRNA-1189 vaccine candidate contains four mRNAs that encode EBV envelope glycoproteins — gH, gL, gp42 and gp220 — that mediate viral entry into B cells and epithelial surface cells, the major targets of EBV infection. In January 2022, Moderna dosed its first participant in its Eclipse study, which will be conducted at 15 sites in the United States and will enroll 270 participants. The primary purpose of the study is to assess the safety and tolerability of the EBV mRNA-1189 vaccine candidate in healthy adults aged 18 years to 30 years. The study aims to demonstrate whether the vaccine has the potential to induce protection from both cell types — inhibiting viral entry into B cells and epithelial cells.¹⁴

Also in January 2022, Moderna, and its partner IAVI — a nonprofit scientific research organization dedicated to addressing urgent, unmet global health challenges, including HIV, tuberculosis and emerging infectious diseases — announced first doses were administered in a Phase I clinical trial of its experimental mRNA-based HIV vaccine. The Phase I trial, IAVI G002, will test the hypothesis that sequential administration of priming and boosting HIV immunogens delivered by mRNA can induce specific classes of B-cell responses and guide their early maturation toward broadly neutralizing antibody (bnAb) development. The induction of bnAbs is widely considered to be a goal of HIV vaccination, and this is the first step in that process. The immunogens being tested in IAVI G002 were developed by scientific teams at IAVI and Scripps Research and will be delivered via Moderna’s mRNA technology. The primary purpose of the Phase I trial is to build on the response seen in a proof-of-concept trial. Participants will be monitored for safety for six months after their last vaccination. Participants’ immune responses to the vaccine candidates will then be examined in molecular detail to evaluate whether the targeted responses were achieved.¹⁵

Under Moderna’s intra-tumoral immune-oncology program, the company has two investigational cancer vaccines currently in clinical trials. These vaccines are designed to stimulate a patient’s immune system with antigens derived from tumor-specific mutations to enable the immune system to elicit a more effective anti-tumor response. Through next-generation sequencing, the mRNA-based personalized cancer vaccines have the potential to direct a patient’s cells to express the selected neoepitopes (mutations found on a patient’s cancer cells) that might help a patient’s immune system better recognize cancer cells as foreign and destroy them. Using algorithms developed by its in-house bioinformatics team, Moderna predicts 20 neoepitopes present on a patient’s cancer should elicit the strongest immune response based on unique characteristics of a patient’s immune system and the cancer’s particular mutations.

The randomized, placebo-controlled Phase II study investigating a 1 mg dose of the mRNA-4157 vaccine in combination with Merck’s pembrolizumab (KEYTRUDA), compared to pembrolizumab alone, for the adjuvant treatment of high-risk resected melanoma is fully enrolled. The primary endpoint of the Phase II study is recurrence-free survival at 12 months. Moderna expects the Phase II data results in the fourth quarter of 2022. The Phase I study in multiple cohorts is ongoing, including in the expanded head and neck cohort.¹⁶

Moderna’s mRNA-2752 vaccine candidate is currently in a Phase I study to evaluate it as a single agent in patients with advanced solid tumor malignancies and lymphoma. Enrollment in additional cohorts is ongoing. Interim data from the ongoing Phase I study showed mRNA-2752 in combination with AstraZeneca’s durvalumab (IMFINZI) was tolerated at all dose levels tested and elicited evidence of anti-tumor activity.¹⁷

In February 2022, Moderna announced it is expanding its mRNA-based vaccine pipeline with three new development programs: mRNA-1608 vaccine candidate for HSV, mRNA-1468 vaccine candidate for VZV and mRNA-4359, a new checkpoint cancer vaccine to explore initial indications for advanced or metastatic cutaneous melanoma and non-small cell lung carcinoma.¹⁸

A New Vaccine Landscape

Although the mRNA-based vaccine technology is still novel, the research behind the science has existed for several decades and shows great promise for disease prevention. Both Pfizer and Moderna are excited about this new vaccine landscape — with its multiple benefits over traditional vaccine technology — that they believe could prevent diseases, as well as reduce suffering and death around the world.

According to Pfizer, “mRNA-based influenza vaccine design requires only the genetic sequence of the virus. The flexibility of mRNA technology and its rapid manufacturing could potentially allow better strain match, greater reliability of supply and the potential opportunity to improve upon the efficacy of current flu vaccines. Furthermore, in a pandemic influenza situation, mRNA technology could allow rapid, large-scale manufacturing of effective vaccines.”¹⁹

According to Moderna, “mRNA provides many competitive advantages to other methods of vaccine development. For one, it allows for accelerated research and development timelines and rapid iteration cycles. We create our mRNA vaccines and mRNA therapeutics using the same, cell-free manufacturing processes and facilities. Other benefits include low fixed costs and flexible resource allocation.”

Moderna also believes the potential implications of using mRNA as a drug are significant and far-reaching and could meaningfully improve how medicines are discovered, developed and manufactured: “For Moderna, priority one is our pan-respiratory annual single-dose booster vaccine. Respiratory viruses are a major cause of mortality worldwide, with an estimated 2.7 million deaths in 2015, and many more millions hospitalized and sick at home. Building on our continued focus on mRNA-1273, our COVID-19 vaccine, we want to prevent people who are at high risk — 50 years of age and older, healthcare workers and the immunocompromised — from being hospitalized due to respiratory infection. We will not stop until that goal is achieved.”

Priority two for Moderna is to go after the most impactful latent viruses and develop first-in-class vaccines against them: “We want to protect our fellow human beings from suffering from the long-term damage caused by these viruses. Too many people have the quality of their health impacted because, decades before, they were infected with a latent virus. We envision a world where vaccines against all the most important latent viruses are available to all.”