mRNA Vaccine Technology Update

Moderna, Pfizer, and Boehringer Ingelheim are among the pharmaceutical companies investigating the applicability of mRNA vaccines to treat and prevent other conditions. In addition to a vaccine for HIV, mRNA is being explored as a potential vehicle to create vaccines for several other conditions.¹

Influenza

A messenger RNA (mRNA) influenza vaccine has the potential to improve on the current flu vaccine paradigm. Three mRNA flu vaccines began phase 1 clinical trials in 2020.

Together, Sanofi and Translate Bio are investigating a monovalent flu vac- cine candidate for the hemagglutinin protein of the A/H3N2 strain of the in- fluenza virus.² When the A/H3N2 strain is most dominant, flu activity may be more severe, particularly among at-risk groups, such as older adults and younger children.

Pfizer’s phase 1 trial (NCT05052697)³ is evaluating the response to their mRNA flu vaccine in a group of healthy adults between 65 and 85 years across the United States. Participants will randomly receive 1 of 4 dose lev- els of the company’s monovalent vaccine candidate (A or B strain of the virus), 1 of 4 dose levels of the bivalent candidate (A and B strains of the virus), the quadrivalent candidate, or a currently approved quadrivalent flu vaccine.

In July 2020, Moderna announced the dosing of the first participants in a phase 1/2 study of mRNA-1010, a quadrivalent flu vaccine candidate⁴ to eval- uate the safety and immunogenicity of 3 levels of doses of the vaccine targeting hemagglutinin surface proteins from 4 World Health Organization–recom- mended influenza strains. Moderna is also investigating an mRNA candidate (mRNA-1073) combining vaccines for COVID-19 and the flu.⁵

Respiratory Syncytial Virus

Previous investigations into a vaccine for respiratory syncytial virus (RSV) have been unsuccessful, with early candidates ultimately strengthening rather than protecting against the disease.⁶ Currently, no vaccine against RSV exists.

Moderna is now studying mRNA-1345,5 an RSV vaccine candidate that uses the same lipid nanoparticle as their COVID-19 vaccine. In late 2021, the company announced interim data⁷ from a phase 1 trial (NCT04528719) evaluating the tolerability and reactogenicity of mRNA-1345 in groups of par- ticipants between 18 and 49 years, 65 and 79 years, and 12 and 59 months. Results showed that at 1-month post vaccination, 50-μg and 100-μg doses were “generally well tolerated” in the study’s cohort of younger adults. Moderna expects the study to be completed in 2023.

Cytomegalovirus

Moderna’s cytomegalovirus (CMV) vaccine candidate^,8 mRNA-1647, combines 6 mRNAs into 1 vaccine aimed at protecting against CMV—a significant unmet need, according to a company press release. CDC estimates suggest 1 in 200 babies are born with CMV, 1 of 5 of whom will experience “devastating sequelae,” such as hearing loss, seizures, and blindness, as well as potential complications later in life.⁹

The phase 3 CMVictory study (NCT05085366) will evaluate safety and efficacy of mRNA-1647 against primary CMV infection in women between 16 and 40 years. Investigators are aiming to enroll 8000 participants (6900 of childbearing age) across 150 global sites.

Epstein-Barr Virus

In January 2022, Moderna announced¹⁰ the dosing of the first candidate in the company’s phase 1 Eclipse study (NCT05164094) of mRNA-1189, an Ep- stein-Barr virus (EBV) vaccine candidate. Although EBV—which causes infec- tious mononucleosis—affects “millions of adolescents globally,” there is no vaccine currently available.

The goal of mRNA-1189 is to prevent EBV-induced infectious mononucleosis and potentially EVB infection itself. The vaccine contains 4 mRNAs that en- code EBV envelope glycoproteins gH, gL, gp42, and gp220.

Cancer

Cancer vaccines are currently being studied both alone and in combination with chemotherapy and immunotherapy. Some of these vaccines are personalized¹¹—created for individual patients based on their tumor samples—whereas others target the proteins found in cancer cells more globally.¹

BioNTech and Regeneron Pharmaceuticals are currently collaborating on an mRNA cancer vaccine for advanced melanoma.¹² The vaccine, BNT111, is currently in a phase 2 clinical trial (NCT04526899). In late 2021, BioNTech was granted an FDA fast track designation based on “available preclinical and clinical data showing the potential of BNT111 to overcome current limitations in the treatment of inoperable therapy-resistant advanced-stage melanoma,” according to a press release.¹²

BioNTech is also collaborating with investigators at the University Medical Center Groningen in the Netherlands in the phase 1 OLIVIA clinical trial (NCT04163094)¹³ to evaluate the W_ova1 mRNA vaccine in combination with neoadjuvant chemotherapy for ovarian cancer. The first-in-human study is estimated to be completed in late 2023.

Boehringer Ingelheim, CureVac, and Ludwig Cancer Research have joinedforces to study mRNA vaccine BI 1361849 (CV9202), a self-adjuvanting mRNA-based immunotherapeutic cancer vaccine to “mobilize the immune system” to fight tumors.”¹⁴ It contains 6 mRNAs coded for 6 different antigens commonly expressed in non–small cell lung cancer (NSCLC).¹⁴ It is being investigated in a phase 1/2 clinical trial (NCT03164772)¹⁵ as a combination treatment with durvalumab or durvalumab plus tremelimumab for NSCLC.

Moderna is studying at least 3 mRNA vaccines for cancer in clinical trials, 2 of which are personalized. KEYNOTE-942 (NCT03897881) is studying mRNA-4157 as an adjuvant therapy to pembrolizumab in patients with high- risk melanoma.¹⁶ KEYNOTE-603 (NCT03313778) is studying the safety, toler- ability, and immunogenicity of mRNA-4157 in patients with solid tumors, both alone in those with resected solid tumors and in combination with pembroli- zumab in those with unresectable solid tumors.¹⁷

A third Moderna vaccine—mRNA-5671/V941—is in a phase 1 study (NCT03948763)¹⁸ as both a monotherapy and in combination with pembrolizumab to target a specific cancer cell protein found in NSCLC, colorectal cancer, and pancreatic cancer.

References

1. Billingsley A. More than COVID-19: 6 other promising mRNA vaccines in the pipeline. GoodRx Health. November 5, 2021. Accessed February 7, 2022. https://www.goodrx.com/health-topic/vaccines/other-mrna-vaccines
2. Sanofi and Translate Bio initiate phase 1 clinical trial of mRNA influenza vaccine. News release. Sanofi; June 22, 2021. Accessed February 7, 2022. https://www.sanofi.com/en/media-room/press-releases/2021/2021-06-22-07-00-00-2250633
3. Abbasi J. Pfizer launches phase 1 mRNA flu vaccine trial. JAMA. 2021;326(18):1784. doi:10.1001/jama.2021.19634
4. Abbasi J. Moderna’s mRNA vaccine for seasonal flu enters clinical trials. JAMA. 2021;326(14):1365. doi:10.1001/jama.2021.17499
5. Moderna announces significant advances across industry-leading mRNA portfolio at 2021 R&D day. News release. Moderna, Inc; September 9, 2021. Accessed February 7, 2022. https://investors.modernatx.com/news/news-details/2021/Moderna-Announces-Significant-Advances-Across-Industry-Leading-mRNA-Portfolio-at-2021-RD-Day-09-09-2021/default.aspx
6. Su S, Du L, Jiang S. Learning from the past: development of safe and effective COVID-19 vaccines. Nat Rev Microbiol.2021;19(3):211-219. doi:10.1038/s41579-020-00462-y
7. Moderna receives FDA fast track designation for respiratory syncytial virus (RSV) vaccine (mRNA-1345). News release. Moderna, Inc; August 3, 2021. Accessed February 7, 2022. https://investors.modernatx.com/news/news-details/2021/Moderna-Receives-FDA-Fast-Track-Designation-for-Respiratory-Syncytial-Virus-RSV-Vaccine-mRNA-1345-08-03-2021/default.aspx
8. Moderna announces clinical progress from its industry-leading mRNA vaccine franchise and continues investments to accelerate pipeline development. News release. Moderna, Inc; April 14, 2021. Accessed February 7, 2022. https://investors.modernatx.com/news/news-details/2021/Moderna-Announces-Clinical-Progress-from-its-Industry-Leading-mRNA-Vaccine-Franchise-and-Continues-Investments-to-Accelerate-Pipeline-Development-04-14-2021/default.aspx
9. Moderna announces first participant dosed in phase 3 pivotal registration study of its mRNA cytomegalovirus (CMV) vaccine. News release. Moderna, Inc; October 26, 2021. Accessed February 7, 2022. https://www.businesswire.com/news/home/20211026006165/en/Moderna-Announces-First-Participant-Dosed-in-Phase-3-Pivotal-Registration-Study-of-Its-mRNA-Cytomegalovirus-CMV-Vaccine
10. Moderna announces first participant dosed in phase 1 study of its mRNA Epstein-Barr Virus (EBV) vaccine. News release. Moderna, Inc; January 5, 2022. Accessed February 7, 2022. https://investors.modernatx.com/news/news-details/2022/Moderna-Announces-First-Participant-Dosed-in-Phase-1-Study-of-its-mRNA-Epstein-Barr-Virus-EBV-Vaccine/default.aspx
11. mRNA-based personalized cancer vaccines. Moderna. Accessed February 7, 2022. https://www.modernatx.com/pipeline/therapeutic-areas/mrna-personalized-cancer-vaccines-and-immuno-oncology
12. BioNTech receives FDA fast track designation for its FixVac candidate BNT111 in advanced melanoma. News release. BioNTech SE; November 19, 2021. Accessed February 7, 2022. https://investors.biontech.de/news-releases/news-release-details/biontech-receives-fda-fast-track-designation-its-fixvac
13. Ovarian cancer treatment with a liposome formulated mRNA vaccine in combination with (neo-)adjuvant chemotherapy (OLIVIA). ClinicalTrials.gov. Updated May 14, 2021. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04163094
14. mRNA-based cancer vaccine (BI 1361849). Boehringer Ingelheim. Accessed February 7, 2022. https://www.inoncology.com/us/ourpipeline/mrna-based-icv
15. Phase 1/2 study of combination immunotherapy and mRNA vaccine in subjects with NSCLC. ClinicalTrials.gov. Updated November 16, 2021. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03164772
16. An efficacy study of adjuvant treatment with the personalized cancer vaccine mRNA-4157 and pembrolizumab in participants with high-risk melanoma (KEYNOTE-942). ClinicalTrials.gov. Updated December 21, 2021. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03897881
17. Safety, tolerability, and immunogenicity of mRNA-4157 alone in participants with resected solid tumors and in combination with pembrolizumab in participants with unresectable solid tumors (KEYNOTE-603). ClinicalTrials.gov. Updated December 21, 2021. Accessed February 7, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03313778
18. A study of mRNA-5671/V941 as monotherapy and in combination with pembrolizumab (V941-001). ClinicalTrials.gov. Updated January 13, 2022. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03948763