Elasomeran - Moderna Therapeutics/National Institute of Allergy and Infectious Diseases

At a glance

Originator Moderna Therapeutics; National Institute of Allergy and Infectious Diseases
Developer Leiden University Medical Center; Moderna Therapeutics; National Institute of Allergy and Infectious Diseases; Regeneron Pharmaceuticals; Takeda
Class COVID-19 vaccines; RNA vaccines; Viral vaccines
Mechanism of Action Immunostimulants

Orphan Drug Status

Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

No
New Molecular Entity No
Available For Licensing Yes

Highest Development Phases

Marketed COVID 2019 infections
Phase III Human papillomavirus infections

Most Recent Events

05 Apr 2024 Arbutus Biopharma and Genevant Sciences issued statement regarding the claim construction ruling in the US District Court for the District of Delaware against Moderna for infringement of US patents in the manufacture and sale of elasomeran
15 Mar 2024 Moderna Therapeutics completes a phase II/III trial in COVID-2019 infections (Prevention, In children, In infants) in USA and Canada (IM) (NCT04796896)
12 Dec 2023 Merck Sharp & Dohme completes a phase III clinical trial in COVID-2019 infections (Prevention, In children) in USA (IM) (NCT05119855) (EudraCT2021-003591-13)

Development Overview

Introduction

Elasomeran (previously mRNA 1273) is an mRNA prophylactic vaccine, encoding for a prefusion stabilised form of the spike S protein, is being developed by Moderna Therapeutics and National Institute of Allergy and Infectious Diseases, for the prevention of COVID-2019 infections and human papillomavirus infections. Moderna Therapeutics will be utilising its proprietary in-house digital application suite, Drug Design Studio that contains a sequence designer module to create mRNAs for specific proteins, that are further optimised using bioinformatics algorithms. Elasomeran is launched in Canada, France, Poland, Spain, Sweden, Switzerland, United Kingdom. The vaccine is approved for the prevention of COVID-2019 infections in Argentina, Australia, Botswana, Brunei, Canada, European Union, Iceland, India, Israel, Japan, Liechtenstein, Norway, Paraguay, Philippines, Puerto Rico, Qatar, Singapore, South Korea, Switzerland, Taiwan, Thailand and US. Clinical development is underway in multiple countries. Clinical development for human papillomavirus infections is underway in US. Clinical development for transdermal patch is underway in Netherlands.

The company is seeking partnership opportunities for the development of its pipeline candidates (Moderna Therapeutics website, September 2020).

In April 2023, the US FDA amended the emergency use authorization (EUA) of the Moderna COVID-19 bivalent mRNA vaccine (original and omicron BA.4/BA.5 strains) [see AdisInsight drug profile800073610] and authorized it to be used for all doses administered to individuals 6 months of age and older, including for an additional dose or doses for certain populations in the US. The monovalent Moderna COVID-19 vaccine (elasomeran) is no longer authorized for use in the US^[1].

Company Agreements

In February 2022, Moderna Therapeutics and ROVI announced a long-term collaboration to increase capacities for the compounding, aseptic filling, inspection, labeling, and packaging of ROVI’s facilities located in Madrid. In addition to producing Moderna’s COVID-19 vaccine, ROVI’s platform could also be utilized to service future Moderna mRNA vaccine candidates. In April 2021, Laboratorios Farmacéuticos Rovi (ROVI) and Moderna Therapeutics further strengthened their collaboration for the latter's COVID-19 vaccine. ROVI will now, also manufacture the active substance of the vaccine and be responsible for compounding, filling and final packaging before the vaccine is distributed for administration to patients. Earlier in July 2020, the companies entered into an agreement for the large-scale, commercial fill-finish manufacturing of mRNA 1273 under which ROVI would provide vial filing and packaging capacity to support the production of vaccine doses, once approved. In January 2021, the company completed the manufacturing of the first batches of the COVID-2019 vaccine.^[2]^[3]^[4]^[5]

In May 2022, Moderna and Takeda announced to transfer the marketing authorization for Moderna’s COVID-2019 vaccine Spikevax™ (mRNA 1273) from Takeda to Moderna in Japan as of August 1, 2022. Under the terms of the agreement, Moderna will assume responsibility for all Spikevax™ activities, including import, local regulatory, development, quality assurance and commercialization. Companies concluded memorandum of understanding that Takeda will continue to provide distribution support for the Moderna COVID-2019 vaccines for a transitional period. Takeda will continue to provide distribution support under the current national vaccination campaign for Moderna COVID-2019 vaccines. Both companies will be responsible for ensuring proper implementation of operations associated with this transfer.^[6]

In March 2022, Moderna Therapeutics entered into a supply agreement with the Swiss Federal Government for seven million doses of Moderna's COVID-19 booster vaccine for anticipated delivery in 2023 and an additional option of seven million doses for delivery in 2023 and 2024. These doses are in addition to the seven million doses of Moderna's booster vaccine that are scheduled for supply to Switzerland in the second half of 2022, which the Government exercised its option to purchase in December 2021. Previously, in May 2021, Moderna reported that the Swiss Federal Government ordered for 7 million doses of booster vaccine in 2022, with an additional option for another 7 million doses for delivery during the second half of 2022 or first quarter of 2023. Purchase under the agreement is subject to regulatory approval of the booster vaccine candidate. Earlier, in February 2021, Moderna reported that the Swiss Federal Government increased its confirmed order commitment from 7.5 million to 13.5 million doses of mRNA 1273 vaccine for prevention of COVID-2019 infections in Switzerland. These additional 6 million doses will be delivered in the beginning of summer of 2021, with an option to receive doses in the first half of 2022 to address emerging variants. Earlier, Moderna as of September 2020, signed an agreement with the Swiss Federal Government to supply 4.5 million doses of its mRNA 1273 for prevention of COVID-2019 infections. Financial terms of deal were not disclosed. In December 2020, Swiss federal government increased its order of mRNA 1273 from 4.5 million to 7.5 million doses.^[7]^[8]^[9]^[10]

In March 2022, Moderna Therapeutics announced a new agreement with the Government of Japan’s Ministry of Health Labour and Welfare (MHLW) to supply Japan with an additional 70 million doses of mRNA 1273 booster vaccine or an updated booster vaccine candidate, if authorized, for anticipated delivery in the second half of 2022. This agreement is subject to the Ministry securing a budget for the additional supply. In 2022, 93 million doses of Moderna's COVID-19 vaccine are currently contracted for supply to Japan, with the potential for this to increase to 163 million doses with this new agreement. Earlier, in July 2021, Moderna Therapeutics expanded its agreement with the Government of Japan’s Ministry of Health Labour and Welfare (MHLW) and Takeda Pharmaceutical to supply additional 50 million doses of mRNA 1273 and its updated variant booster vaccine candidate (contingent to approval). Moderna will be responsible for the manufacture and supply of mRNA 1273 and booster dose vaccine as finished product and Takeda, with the support of the MHLW and Moderna, will be responsible for import, regulatory, development and distribution activities in Japan. Moderna will begin delivery of the vaccines in 2022. In October 2020, Moderna entered into a three-way agreement with the Government of Japan’s Ministry of Health Labour and Welfare (MHLW) and Takeda Pharmaceutical to import and distribute 50 million doses of Moderna’s COVID-19 vaccine candidate, mRNA 1273, starting in the first half of 2021, pending licensure in Japan. Under the terms of the agreement with the MHLW and Moderna, Takeda will be responsible for import and for securing the necessary regulatory approvals prior to distributing 50 million doses of mRNA 1273 in Japan, to ensure timely access starting during the first half of 2021. Financial details of the agreement have not yet been disclosed.^[11]^[12]^[13]^[14]^[15]

In February 2022, Moderna and Thermo Fisher Scientific entered into a 15 year strategic collaboration agreement to enable dedicated large-scale manufacturing in the US of Moderna’s COVID-2019 vaccine, Spikevax® (Elasomeran) and other investigational mRNA medicines in its pipeline. Under the terms of the agreement, Thermo Fisher will provide dedicated capacity for a range of aseptic fill-finish services including lyophilized and liquid filling. In addition, the company will provide inspection, labeling and final packaging services. Moderna will further utilize Thermo Fisher's and depth of capabilities to continue to transform its mRNA platform and bring new breakthrough medicines to patients around the world.

In June 2021, Moderna entered into an agreement with Thermo Fisher Scientific for fill/finish sterile manufacturing services and supply packaging for Moderna’s COVID-2019 vaccine. According to the terms of the agreement, Thermo Fisher’s commercial manufacturing site will be used for aseptic fill/finish, labelling and packaging to support the production of hundreds of millions of doses of COVID-2019 vaccine. Production will begin in the third quarter of 2021.^[16]^[17]

In February 2022, ASOFARMA Central America and the Caribbean, through its parent company ADIUM, and Moderna reached a collaboration agreement for the distribution and commercialization in the region of elasomeran (SPIKEVAX). As part of the agreement reached, ASOFARMA will collaborate with Moderna in the management of supply contracts already in force, as well as in vaccine registration processes, support for pharmacovigilance activities, continuing medical education, government affairs, marketing, and generation of new agreements that facilitate the availability of SPIKEVAX in the region. The agreement covers 18 countries in Latin America, including Brazil, Mexico, Colombia, and Argentina. Financial details of the deal were not disclosed.^[18]^[19]

In December 2021, Moderna announced an amendment to its existing contract with Gavi to accelerate supply of 20 million doses to COVAX by December 31, 2021 for a total of 54 million doses made available to COVAX in 2021. These doses are included in Moderna’s previously announced agreement with Gavi and were originally scheduled for delivery in the first quarter of 2022. Gavi retains the option to procure 233 million additional doses in 2022 under the original agreement. In addition, Moderna is also announcing a new supply agreement with Gavi for an additional 20 million doses for delivery in the second quarter of 2022 for a total of up to 136.5 million doses in the second quarter of 2022. Gavi retains options to purchase an additional 30 million doses in the second quarter of 2022 and an additional 100 million doses in the third quarter of 2022. Together, these two agreements allow Gavi to purchase up to 650 million doses of the Moderna COVID-19 vaccine for delivery through 2022. Earlier, in October 2021, Gavi, the Vaccine Alliance has exercised its option to purchase an additional 176.5 million doses of the Moderna COVID-19 vaccine for the COVAX Facility. Of these additional doses, 116.5 million doses are expected to be delivered in the first quarter of 2022 and 60 million doses are expected to be delivered in the second quarter of 2022. All doses are offered at Moderna’s lowest tiered price, in line with the Company’s global access commitments. COVAX retained the option to purchase 116.5 million doses for delivery in the third quarter of 2022 and an additional 116.5 million doses for delivery in the fourth quarter of 2022. These doses are in addition to the 34 million doses purchased for delivery in the fourth quarter of 2021. In May 2021, Moderna therapeutics entered into supply agreement with Gavi, the Vaccine Alliance to supply up to 500 million doses of the COVID-19 Vaccine to low- and middle-income countries. As a part of agreement, Moderna Therapeutics to send initial 34 million doses in the fourth quarter of 2021. Through this agreement, on behalf of the COVAX Facility, Gavi also retains the option to procure 466 million additional doses in 2022. All doses are offered at lowest tiered price, in line with the Moderna global access commitments. This agreement covers the 92 Gavi COVAX Advance Market Commitment (AMC) low- and middle-income countries.^[20]^[21]^[22]

In December 2021, Moderna announced a revised supply agreement with the UK government for up to 60 million doses of Moderna’s COVID-19 vaccine, which may include authorized booster vaccine candidates, with up to 29 million doses expected to be delivered in 2022 and up to 31 million doses expected to be delivered in 2023. Under the agreement, the UK government retains a right to increase its purchases in 2022 and 2023 by up to 20% above the contracted volumes, or to decrease by the same amount. Earlier in November 2020, Moderna announced a supply agreement with the UK government for an additional 2 million doses of mRNA 1273, Moderna’s vaccine candidate against COVID-19, to the United Kingdom beginning in March 2021. The UK government now secured 7 million doses of mRNA 1273. Earlier in November 2020, Moderna Therapeutics entered into a supply agreement with the Medicines and Healthcare products Regulatory Agency of United Kingdom to supply mRNA 1273, beginning in March 2021 if it is approved for use by United Kingdom regulatory authorities.^[23]^[24]^[25]

In October 2021, Moderna announce a memorandum of understanding (MoU) to make up to 110 million doses of the COVID-2019 vaccine (mRNA 1273) available to the African Union. Moderna aims to deliver the first 15 million doses in the fourth quarter of 2021, 35 million doses in the first quarter of 2022, and up to 60 million doses in second quarter 2022. Financial details were not disclosed.^[26]

In June 2021, United Nations Children's Emergency Fund (UNICEF) and Moderna Therapeutics signed a agreement to supply mRNA 1273 vaccine, on behalf of the COVAX facility. Under the agreement, Moderna will supply up to 34 million doses of mRNA 1273 vaccine, to be delivered in the fourth quarter 2021 and up to 500 million doses of the vaccine in 2022 to UNICEF and its procurement partners including the Pan American Health Organization (PAHO).^[27]^[21]

In September 2021, Moderna Therapeutics entered into a supply agreement with the government of Peru for 20 million doses of Moderna’s COVID-19 vaccine to begin delivery in the first quarter of 2022. mRNA 1273 is not currently approved for use in Peru, and the company will work with regulators to pursue necessary approvals prior to distribution.
^[28]

In September 2021, National Resilience entered an agreement with Moderna to manufacture mRNA 1273 vaccine. Under the terms of agreement, Resilience will manufacture mRNA for the Moderna COVID-19 vaccine at its facility in Mississauga, Ontario, for distribution worldwide.^[29]

In August 2021, Moderna Therapeutics announced a revised supply agreement with the Government of Canada for up to 105 million doses of mRNA 1273 vaccine and its booster vaccine candidate, if authorized, for delivery through 2024. The agreement provides for 20 million doses each year in 2022 and 2023, with an option for an additional 15 million doses each year. For 2024, the agreement provides an option for up to 35 million doses.^[30]

In July 2021, Moderna Therapeutics entered into a supply agreement with the government of Taiwan for 20 million doses of mRNA 1273 vaccine and its updated booster variant (if authorized), to begin delivery in 2022 and an additional 15 million doses in 2023. This new supply agreement is in addition to the prior agreement for 5 million doses in 2021.^[31]

In July 2021, Moderna announced a supply agreement with the government of Argentina for 20 million doses of Moderna’s mRNA 1273 COVID-19 vaccine or its updated variant booster vaccine candidate, if authorized, to begin delivery in the first quarter of 2022.^[32]

In June 2021, Moderna announced that the European Commission purchased an additional 150 million doses of Moderna’s COVID-19 vaccine, including the ability to purchase other COVID-19 vaccine candidates from Moderna’s pipeline. Under the terms of the agreement, delivery of Moderna’s updated variant booster vaccine candidate will begin in 2022. The purchase brings the European Commission’s confirmed order commitment to 460 million doses. Earlier, in February 2021, Moderna announced that the European Commission (EC) had purchased an additional 150 million doses of mRNA 1273, which are scheduled to be delivered in the third and fourth quarter of 2021. Under the terms of the agreement, EC has an option to purchase an additional 150 million doses for delivery in 2022. Previously, in December 2020, Moderna had unced that the European Commission exercised its option to purchase an additional 80 million doses of mRNA 1273, bringing its confirmed order commitment to 160 million doses. These deliveries are subject to receipt of the positive opinion from the European Medicines Agency’s (EMA) scientific committee for human medicines (CHMP) and the European Commission’s decision regarding the Conditional Marketing Authorisation (CMA) of mRNA 1273. In November 2020, European Commission approved an agreement to secure 80 million doses of mRNA 1273.^[33]^[34]^[35]^[36]

In June 2021, the US government purchased an additional 200 million doses of mRNA 1273, including the option to purchase other COVID-19 vaccine candidates from Moderna’s pipeline. To date, the US government ordered 500 million doses of the vaccine including 110 million doses anticipated to be delivered in the fourth quarter of 2021 and 90 million anticipated to be delivered in the first quarter of 2022. Moderna as of June 2021, supplied 217 million doses of vaccine to the US government. Earlier in December 2020, Moderna Therapeutics announced that the US government has exerciseds its option to purchase an additional 100 million doses of mRNA 1273, COVID-19 vaccine candidate, bringing its confirmed order commitment to 200 million doses. Of the first 100 million doses purchased by the U.S. government, approximately 20 million doses will be delivered by the end of December 2020. The US government has agreed to purchase supply of mRNA 1273 under US Department of Defense contract no. W911QY-20-C-0100. Under the terms of the agreement, Moderna will continue to leverage the Company’s US-based manufacturing infrastructure to supply mRNA 1273 to the US government. As part of Operation Warp Speed, the US government has the option to purchase up to an additional 300 million doses of mRNA 1273 from Moderna.^[37]^[38]

In June 2021, Moderna entered agreement with Magenta Investments to distribute mRNA 1273 and its updated booster variant in the United Arab Emirates. Financial details were not disclosed.^[39]

In June 2021, Moderna and Tabuk Pharmaceutical Manufacturing Company entered into an agreement to commercialise the Moderna COVID-19 Vaccine and future variant-specific booster candidates in Saudi Arabia. According to the terms of the agreement, Tabuk Pharmaceuticals will hold the marketing authorisation for the Moderna COVID-19 vaccine in Saudi Arabia. Beyond the Moderna COVID-19 Vaccine and Moderna’s updated variant booster candidates, the agreement also gives Tabuk the possibility to discuss opportunities to distribute other Moderna mRNA products if authorised in the future.^[40]

In June 2021, Moderna entered into a new agreement with Medison Pharma to commercialise Moderna's COVID-19 vaccine, mRNA 1273, across Central Eastern Europe and Israel. The agreement would cover countries like Poland, Czech Republic, Romania, Hungary, Bulgaria, Slovenia, Slovakia, Croatia, Estonia, Latvia, Lithuania, Serbia, Ukraine, Moldova, Albania, Bosnia and Herzegovina, Kosovo, North Macedonia, Montenegro, and Israel. Additional details of the agreement were not disclosed.^[41]

In June 2021, Government of Botswana and Moderna Therapeutics entered into a supply agreement to supply mRNA 1273 to Botswana and Africa. Financial details were not disclosed.^[42]

In June 2021, Moderna enters into an additional agreement with Lonza for the supply of an additional 300 million doses per year of Moderna’s updated booster variant vaccine candidate, upon authorization. Earlier in January 2021, Lonza announced that the production of active ingredient of the mRNA 1273 has been initiated. Earlier in May 2020, Moderna Therapeutics had entered into a 10-year strategic manufacturing agreement with Lonza to enable large scale manufacture of mRNA 1273 against COVID-2019 infections. Under the terms of the agreement, Moderna and Lonza intend to establish manufacturing sites in the US and Switzerland. Technology transfer will be initiated in June 2020, and the first batches of mRNA 1273 are expected to manufacture in the US in July 2020. A part of the funding for establishment of manufacturing operation in the US was covered under Moderna's contract with the BARDA. Further financial details were not disclosed.^[43]^[44]^[45]

In May 2021, Moderna therapeutics and Aldevron announced their expanded collaboration in support of the Moderna COVID-19 Vaccine and additional programs in Moderna’s clinical development pipeline. Under the terms of the agreement, Aldevron will supply plasmid DNA to serve as the genetic template for generating the COVID-19 mRNA vaccine and other investigational programs in Moderna’s pipeline.^[46]

In May 2021, Moderna Therapeutics and Samsung Biologics entered into manufacturing services and supply agreement in which Samsung Biologics will provide large scale, commercial fill-finish manufacturing for mRNA 1273 for prevention of COVID-19 infections. Upon execution of the deal, technology transfer will commence immediately at Samsung Biologics’ facilities in South Korea, utilizing a state-of-the-art production line equipped for aseptic fill-finish, labelling, and packaging services to support the production of hundreds of millions of doses of COVID-19 vaccine intended for the supply of markets outside of the U.S. starting in the third quarter of 2021^[47]^[48]

In May 2021, Moderna Therapeutics entered into a supply agreement with the government of Australia for 25 million doses of mRNA 1273 vaccine. This includes 10 million doses of Moderna’s COVID-19 vaccine against the ancestral strain (mRNA 1273) to be delivered in 2021 and 15 million doses of Moderna’s updated variant booster vaccine candidate to be delivered in 2022. Under the terms of the agreement the purchase is subject to regulatory approval of mRNA 1273 and booster vaccine candidates by the Therapeutic Goods Administration (TGA) of Australia.^[49]

In April 2021, Moderna therapeutics and Sanofi entered into a manufacturing and supply agreement for fill/finish sterile manufacturing services and supply packaging for up to 200 million doses of mRNA 1273 in the US beginning in September 2021. Sanofi will leverage its established manufacturing infrastructure at its site in Ridgefield, NJ.^[50]

In April 2021, Moderna entered into a supply agreement with Israel Ministry of Health for 2022. According to the terms of the agreement, Israel retains an option to purchase doses of vaccine candidates subject to regulatory approval. This agreement follows two earlier agreements to supply a total of 10 million doses of the COVID-2019 Vaccine.^[51]

In April 2021, As part of this expanded agreement, Catalent will now dedicate to Moderna’s use a new high-speed filling line at the site through June 2023, which can be used to manufacture the COVID-19 vaccine and potentially additional investigational programs in Moderna’s clinical pipeline. Catalent will also provide inspection, labeling, cartoning, and final packaging for these programs. In June 2020, Moderna Therapeutics entered into an agreement with Catalent for large-scale, commercial fill-finish manufacturing of Moderna’s mRNA-based COVID-19 vaccine candidate mRNA 1273 at Catalent’s biologics facility in Bloomington, Indiana. Under the terms of agreement, Catalent will provide vial filling and packaging capacity, as well as additional staffing required for 24x7 manufacturing operations at the site to support production of an initial 100 million doses of the vaccine candidate intended to supply the US market starting in the third quarter of 2020. The companies are in discussions to secure fill-finish capacity for continued production of hundreds of millions of additional doses.^[52]^[53]

In March 2021, Moderna Therapeutics entered into a supply agreement with the Government of The Philippines for 13 million doses of mRNA 1273 vaccine for treatment of COVID-2019 infection. Later, in the same month Government of Philippines has secured 7 million additional doses of mRNA 1273 vaccine through a new supply agreement with Moderna Therapeutics , bringing its confirmed order commitment up to 20 million doses. Under the terms of this agreement, deliveries would begin in mid-2021.^[54]^[55]

In March 2021, Moderna therapeutics entered into an agreement with Baxter BioPharma Solutions to provide fill/finish sterile manufacturing services and supply packaging for approximately 60-90 million doses of the Moderna COVID-19 Vaccine in 2021. The manufacturing of the Moderna COVID-19 vaccine will take place at the BioPharma Solutions fill/finish sterile manufacturing facilities located in Bloomington.^[56]

In March 2021, GC Pharma entered into a distribution agreement with Moderna Therapeutics and the Government of the Republic of Korea, for distribution of 40 million doses of Moderna’s mRNA 1273 in South Korea. Under the terms of agreement with Moderna, GC pharma is responsible for local regulatory activities, and under the terms of its agreement with the Korean government, GC Pharma, with support of the Korean government authorities, will be responsible for distribution activities in South Korea. Other details of the agreement were not disclosed.^[57]

In December 2020, Moderna therapeutics and Recipharm entered into a manufacturing and supply agreement to supply mRNA 1273 outside the US. This agreement will support formulation and fill finish a part of mRNA 1273 supply outside US. The manufacturing will take place at Recipharm’s manufacturing facility in France.^[58]

In December 2020, Modera and the Ministry of Health of Singapore entered into a supply agreement for mRNA 1273 to support ongoing efforts to secure access to the COVID-2019 infections vaccine for the people of Singapore. Further details of the agreement were not disclosed.^[59]

In December 2020, Moderna Therapeutics expanded its supply agreement with the Ministry of Health of Israel for an additional 4 million doses of mRNA 1273 vaccine for treatment of COVID-2019 infections. This agreement supports the ongoing efforts by the Ministry to secure early access to COVID-19 vaccine for the people of Israel.^[60]

In October 2020, Moderna enters into a supply agreement with the Ministry of Public Health of Qatar for mRNA 1273 to support the Ministry’s ongoing efforts to secure early access to a safe and effective COVID-19 vaccine for the people of Qatar.^[61]

In July 2020, Moderna Therapeutics and the Biomedical Advanced Research and Development Authority (BARDA) expanded its agreement for an additional $US472 million to support the clinical development mRNA-1273 for COVID-19 infections. Moderna received up to $US483 million contract to accelerate development of the vaccine and BARDA will fund the advancement of mRNA 1273 to FDA licensure. BARDA will also be responsible to support late-stage clinical development programs, as well as the scale-up of mRNA 1273 manufacture in 2020 to enable potential pandemic response. According to the terms of the revised agreement, BARDA is expanding the support which totals the award value of approximately $US955 million.^[62]^[63]

In July 2020, Medidata (a Dassault Systèmes company) signed collaboration with Moderna Therapeutics to support and accelerates the clinical trials including prospective phase III trial of mRNA 1273, for the treatment of COVID 2019. Under the collaboration, Moderna Therapeutics will utilise Medidata's "Rave clinical cloud platform" for electronic data capture (EDC); electronic clinical outcomes assessment (eCOA), and centralised statistical monitoring to detect efficacy signals to support and accelerates the clinical trials with mRNA 1273.^[64]

In January 2020, Moderna Therapeutics entered into a research and development agreement with Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID), to design a vaccine against COVID-2019 infections. Under the terms of the agreement, Moderna will manufacture an mRNA vaccine against coronavirus, which will be funded by Coalition for Epidemic Preparedness Innovations (CEPI). Moderna Therapeutics has a multi-year relationship with the NIH. IND-enabling studies and a phase I clinical study in the US will be conducted by NIAID.^[65]

Key Development Milestones

In August 2023, Elasomeran is available in the United Kingdom, Switzerland, France, Spain, Poland, Sweden and Canada for the treatment of COVID-2019 infections (Moderna Therapeutics pipeline, August 2023)

In September 2023, Health Canada has authorised and made commercially available the use of the SPIKEVAX™ COVID 19 vaccine targeting the Omicron XBB.1.5 subvariant for people six months of age and older. Health Canada received Moderna's regulatory application for its new COVID 19 vaccine on June 29, 2023. After a thorough, independent review of the evidence, Health Canada has determined that the vaccine meets the Department's stringent safety, efficacy and quality requirements^[66]^[67]

In April 2023, the US FDA amended the emergency use authorization (EUA) of the Moderna Covid-19 bivalent mRNA vaccine, simplifying the vaccination schedule for most individuals and authorizing the use of the current bivalent vaccine (original and omicron BA.4/BA.5 strains) for all doses administered to individuals 6 months of age and older, including additional doses for certain populations. The monovalent Moderna Covid-19 vaccine is no longer authorized for use in the United States^[1].

In June 2022, Moderna Therapeutics announced that it has received emergency use authorization (EUA) from the US Food and Drug Administration (FDA) for elasomeran in young children ages 6 months through 5 years of age at a dose level of 25 µg. It has also received emergency use authorization for a 50 μg two-dose regimen of elasomeran for children ages 6 through 11 years old and a 100 μg two-dose regimen for adolescents aged 12 through 17 years old ^[68] ^[69]. In February 2022, the US FDA granted full approval to Mderna’s messenger RNA (mRNA) COVID19 shot, Spikevax™, for persons age 18 and older^[70]. In January 2022, the US FDA approved the Biologics License Application (BLA) for elasomeran (SPIKEVAX) to prevent COVID-19 in individuals 18 years of age and older^[68]. In August 2021, Moderna Therapeutics completed the rolling submission process for its Biologics License Application (BLA) to the US FDA for the full licensure of the elasomeran mRNA vaccine for active immunization to prevent COVID-2019 infections in participants, 18 years of age and older. As part of the completed BLA submission, the company has requested priority review designation. Earlier, in June 2021, Moderna Therapeutics initiated the rolling submission process with the US FDA for the BLA^[71]^[72]^[73].

In October 2021, the US FDA approved the emergency use authorisation of elasomeran for the administration of a booster dose, in individuals 18 years of age and older. To support the authorization for emergency use of a single booster dose of the Moderna COVID-19 Vaccine, the FDA analyzed immune response data from 149 participants 18 years of age and older from the original clinical studies who received a booster dose at least 6 months after their second dose and compared it to the immune responses of 1 055 study participants after completing their two-dose series. The antibody response of the 149 participants against SARS-CoV-2 virus 29 days after a booster dose of the vaccine demonstrated a booster response. Earlier in the same month, the US FDA plans to hold an advisory committee meeting plans to discuss an amendment to the emergency use authorisation of the Moderna's COVID-19 vaccine for the administration of a booster dose, in individuals 18 years of age and older^[74]^[75]. In January 2022, the US FDA amended the emergency use authorization (EUA) granted to ModernaTx for elasomeran, to shorten the time between the completion of a primary series of the vaccine and a booster dose to at least five months for individuals, aged 18 years and older^[76].

In December 2023, Merck Sharp completed a phase III trial which evaluated safety and immunogenicity of 2-dose regimens of 9vHPV co-administered with mRNA-1273 SARS-CoV-2 vaccines for treatment of papillomavirus infections and COVID-2019 infections (9-11 years of age) (NCT05119855; V503-076). This open label, ramdomised trial was initiated in March 2022, enroled 165 volunteers in US^[77].

In September 2022, the EMA’s human medicines committee (CHMP) recommended converting the conditional marketing authorisations of the elasomeran mRNA vaccine into standard marketing authorisations. These no longer need to be renewed annually. The companies provided all requested additional data on the pharmaceutical quality of the vaccines. The CHMP recommended their conversion to standard marketing authorisations as an outcome of the second annual renewal procedure. This recommendation covers all existing and upcoming adapted Spikevax vaccines, including the recently-approved adapted Spikevax bivalent Original/Omicron BA.1^[78]. As at March 2022, the EMA approved the conditional marketing authorization (CMA) application of a 50µg two-dose series of elasomeran mRNA vaccine (Spikevax) in children ages 6-11 years. The application was submitted in November 2021, based on phase II/III KidCOVE study [see below] of mRNA 1273 in children ages 6 to 11^[79]^[80]. In July 2021, the European commission granted conditional marketing authorisation based on EMA’s human medicines committee (CHMP) positive opinion on extending indication for the elasomeran mRNA vaccine (Spikevax) to include use in children aged 12 to 17 years, to be given as two injections in the muscles of the upper arm, four weeks apart. The results from the TeenCove trial [see below] allowed the CHMP to conclude that the efficacy was similar to that in adults^[81]^[82]. In July 2021, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending marketing authorization for elasomeran mRNA vaccine COVID-19 vaccine to include adolescents 12 years of age and older^[83]. In June 2021, Moderna had submitted application for conditional marketing approval of the vaccine for the use of the vaccine in adolescents with the EMA^[84]. In January 2021, the European Commission granted a conditional marketing authorization for active immunisation to prevent COVID-2019 infections caused by SARS-CoV-2 virus in individuals 18 years of age and older, in the European Union, including Iceland, Liechtenstein and Norway. The authorisation was based upon the recommendation of the European Medicines Agency (EMA). The EMA’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for the vaccine based on the totality of scientific evidence shared by Moderna, including a data analysis from the pivotal phase III trial^[85]. Ealier in January 2021, Moderna submitted the last outstanding data package needed for the assessment of the application to the CHMP for marketing authorisation. This contains information that is specific to the manufacturing of the vaccine for the EU market^[86]. In December 2020, EMA received an application for conditional marketing authorisation (CMA) for elasomeran mRNA vaccine by Moderna Biotech. The EMA has already reviewed some data on the vaccine during a rolling review. EMA will assess the data submitted as part of the formal application for conditional marketing authorisation. EMA will communicate on the outcome of its assessment accordingly^[87]. Earlier, in November 2020, EMA’s Committee for Medicinal Products for Human Use (CHMP) started a rolling review of data of elasomeran mRNA vaccine, for the prevention of COVID-2019 infections. The CHMP’s decision to start the rolling review of elasomeran mRNA vaccine was based on preliminary results from non-clinical studies and early clinical studies in adults, which suggested that the vaccine triggered the production of antibodies and T cells that target the virus. The CHMP evaluated the first batch of data on the vaccine, which come from preclinical studies. Large-scale clinical trials involving several thousands of people are ongoing. The results will provide information on how effective the vaccine is in protecting people against COVID-2019 and will be assessed once submitted to the agency. All the available data on the safety of the vaccine as well as its pharmaceutical quality will also be reviewed as they become available. The rolling review will continue until enough evidence is available to support a formal marketing authorisation application^[88]. In October 2020, Moderna Therapeutics received written confirmation from the European Medicine Agency (EMA) that elasomeran mRNA vaccine is eligible for submission of an application for a European Union Marketing Authorisation under centralised procedure. Confirmation of eligibility was given in response to the submission of a letter of intent enabling Moderna to evaluate the opportunity for submitting a marketing authorisation application (MAA) for elasomeran mRNA vaccine with the EMA. This submission followed positive results from a preclinical viral challenge study and the positive interim analysis of the phase I trial in healthy adults and older adults [see below]^[89]. In February 2022, EMA’s safety committee (PRAC) was assessing reported cases of heavy menstrual bleeding (heavy periods) and absence of menstruation (amenorrhea) with the COVID-19 vaccines Comirnaty and Spikevax. The PRAC decided to request an in-depth evaluation of all available data, including reports from spontaneous reporting systems, clinical trials and the published literature. At this stage, it was not yet clear whether there is a causal link between the COVID-19 vaccines and the reports of heavy periods or amenorrhea^[90].

In November 2022, EMA’s human medicines committee (CHMP) recommended authorising elasomeran/davesomeran (an adapted Spikevax COVID-2019 vaccine) targeting the omicron subvariants BA.4 and BA.5 in addition to the original strain of SARS-CoV-2. The adapted vaccine, Spikevax bivalent original/omicron BA.4-5, is recommended for adults and children from 12 years of age who have already had a primary vaccination course against COVID-2019. The CHMP’s opinion on Spikevax bivalent Original/Omicron BA.4-5 will be sent to the European Commission, which will adopt a final decision. Moderna submitted an application (called a variation application) to change the current marketing authorisation of Spikevax and include the use of the adapted vaccine targeting the Omicron subvariants BA.4 and BA.5 in addition to the original strain of SARS-CoV-2^[91]^[92].

In April 2023, Therapeutic Goods Administration (TGA) approved elasomeran, from provisional to full registration on the basis of long-term follow-up data from a number of studies that confirmed the safety and efficacy for elasomeran ^[93] (TGA website, May 2023). In August 2022, TGA provisionally approved a paediatric dose (25mcg in 0.25ml vial) of the SPIKEVAX, for use in children aged six months to less than six years (6 months to 5 years). Provisional approval of SPIKEVAX in this age group is valid for two years. This approval was based on the data from the KidCOVE trial which enrolled 6000 participants aged six months up to six years. The vaccine is provisionally approved for immunisation to prevent COVID-19 in individuals aged six years and older (primary series of 2 doses administered at least 28 days apart), and as a booster dose for adults aged 18 years and older^[94]. In August 2021, Moderna Therapeutics announced that Therapeutic Good Administration (TGA) granted provisional registration for elasomeran mRNA vaccine for the prevention of COVID-2019 infection aged 18 years of age and older. Australian government has secured 10 million doses in 2021 and has option to procure 15 million does in 2022^[95].

In March 2022, Health Canada approved the 50µg two-dose series of elasomeran mRNA vaccine (SPIKEVAX™) in children, aged six to 11 years. The application was submitted in November 2021, based on the phase II/III KidCOVE trial [see below] that evaluated the safety, tolerability, reactogenicity and effectiveness of two 50 µg doses of the vaccine in healthy children 28 days apart^[79]^[96]

In March 2022, the Therapeutic Goods Administration approved the 50µg two-dose series of elasomeran mRNA vaccine (SPIKEVAX™) in children, aged six to 11 years^[79].

In October 2021, Moderna announced that the Swissmedic granted authorisation to a booster dose of Spikevax at the 50 µg dose level in volunteers aged 12 years and older, in Switzerland. The Swissmedic also approved a third dose of Spikevax at the 100 µg dose level for people with a weakened immune system at least 28 days after the second dose. The approval was supported by clinical evidence that a 50 µg booster dose induces a strong immune response against COVID-19^[97].

In October 2021, Moderna announced that the European Medicines Agency (EMA) granted authorization for a third dose of elasomeran mRNA vaccine (SPIKEVAX™) given at least 28 days after the second dose to severely immunocompromised individuals 12 years of age or older^[98].

In September 2021, Health Canada approved the New Drug Submission (NDS-CV) for elasomeran mRNA vaccine (SPIKEVAX™ or elasomeran mRNA vaccine) for the prevention of COVID-2019 infections in Canada in individuals 12 years of age and older. The approval was based on clinical data from the phase III COVE study. In August 2021, Health Canada had expanded the Interim Order authorization for the elasomeran mRNA vaccine COVID-19 vaccine to include adolescents 12 years of age and older ^[99]. In June 2021, Moderna had submitted for authorisation of its COVID-19 vaccine in adolescents with Health Canada. The submission was based on the phase II/III TeenCOVE trial [see below] in adolescents 12 to less than 18 years old in the US ^[84]. In December 2020, the Health Canada approved mRNA 1273 under an Interim Order for prevention of COVID-2019 infections in individuals 18 years of age or older, in Canada. The Interim Order of the Health Canada allows the importation, sale and advertising of drugs for use in relation to COVID-2019 in Canada. Earlier in October 2020, Moderna Therapeutics initiated a rolling submission to the Health Canada for elasomeran mRNA vaccine in the indication. This submission was based on the positive results from a preclinical viral challenge study of mRNA 1273, the positive interim analysis of the phase I study of mRNA 1273 in healthy adults and older adults and included data from phase III COVE study [see below] ^[100] ^[101].

In June 2023, Moderna announced that it has initiated the filing of a rolling New Drug Submission (NDS) to Health Canada for its updated monovalent COVID-19 vaccine, SPIKEVAX® XBB.1.5 (mRNA-1273.815) targeting the omicron subvariant XBB.1.5 of SARS-CoV-2 ^[102]

In August 2021, it was announced that recently, the elasomeran mRNA vaccine for COVID-2019 infections was approved for emergency use in the context of the pandemic in Argentina and it also received a donation of 3.2 million doses of the vaccine from the US government (NCT05027672).

In October 2021, Moderna Therapeutics requested authorization of a 50 µg booster dose from global regulators in low income countries^[21].

In October 2021, Moderna announced that the US Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) voted to recommend the use of a booster dose of the Moderna COVID-19 vaccine at the 50 µg dose level for people aged 65 and older; people aged 18 to 64 who are at high risk of severe COVID-19; and people aged 18 to 64 with frequent institutional or occupational exposure to SARS-CoV-2 under the Emergency Use Authorization (EUA) issued by US FDA). Moderna estimates that the authoriSation of a booster dose of elasomeran mRNA vaccine at the 50 µg dose level and subsequent approval could result in up to 1 billion extra doses being available for distribution in 2022^[103]. In September 2021, Moderna initiated its submission of initial data of a phase II trial [see below] to the US Food and Drug Administration (FDA) for the evaluation of a booster dose of the vaccine at the 50µg dose level^[104].

In August 2021, Moderna announced that the US FDA has approved an update to the emergency use authorisation to elasomeran mRNA vaccine, to prevent COVID-2019 infections, to include a third dose for immunocompromised individuals, aged 18 years and older, in the US, who have undergone solid organ transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of immuno-compromise. Moreover, the National Kidney Foundation (NKF) has urged the Centers for Disease Control and Prevention (CDC) to officially recommend a third dose so that immune compromised participants can start preventing themselves from the virus^[105]^[106].

In August 2021, Moderna Therapeutics announced that the Conditional Marketing Authorisation (CMA) extension was granted by the Medicines and Healthcare products Regulatory Agency (MHRA) for elasomeran in 12-17 year olds in the UK. The approval was granted via the european commission Decision Reliance route. In January 2021, Moderna Therapeutics had announced that Medicines and Healthcare products Regulatory Agency (MHRA), under Regulation 174, had authorised the use of elasomeran mRNA vaccine for the prevention of COVID-2019 infections, in the United Kingdom. The temporary authorisation permits the supply of COVID-19 Vaccine Moderna in Great Britain and is based upon the advice of the UK Commission on Human Medicines. The authorisation is based on the data from the Phase III COVE study^[107]^[108]^[109]. Earlier in October 2020, Moderna received confirmation that the MHRA in the United Kingdom initiated the rolling review process of elasomeran mRNA vaccine , for the prevention of COVID-2019 infections^[23].

In July 2021, a conditional marketing authorisation extension was granted by the Medicines and Healthcare products Regulatory Agency (MHRA) for elasomeran mRNA vaccine in 12-17 year olds in Northern Ireland^[107]

In June 2021, Moderna requested an emergency use authorization (EUA) for its COVID-19 vaccine in adolescents with the US Food and Drug Administration (FDA). The submission was based on phase II/III TeenCOVE study [see below] in adolescents ages 12 to less than 18 in the US^[110]^[111].

In December 2020, the US FDA authorised the emergency use of elasomeran mRNA vaccine against COVID-19 in individuals 18 years of age or older. The FDA based its recommendation on the totality of scientific evidence shared by the Company, including a data analysis from the pivotal Phase 3 clinical study In the same month, the US FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) recommended that the US FDA should grant an Emergency Use Authorisation (EUA) to elasomeran mRNA vaccine . 20 VRBPAC members recommended for EUA, zero members voted against, and one abstained. In November 2020, Moderna Therapeutics filed for Emergency Use Authorization with the US FDA for elasomeran mRNA vaccine, for the prevention of COVID-2019 infections. In December 2020, a frontline health care worker was immunised with the vaccine in the US within the emergency use authorisation. Unlike Pfizer-BioNTech vaccine [see AdisInsight drug profile 800057858], Moderna COVID-19 vaccine requires only routine cold storage, up to 10 shots can be administered from a single vial and a second booster shot must be administered 28 days later. In the same month, a community health center in US received the vaccine under the emergency use authorization. In December 2020, the US Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommended vaccination for individuals, 18 years or older, under US FDA's emergency use authorisation^[112]^[113]^[114]^[115]^[37]^[116].

In January 2021, Israel’s Ministry of Health (MOH) authorised the use of elasomeran mRNA vaccine for prevention against COVID-2019 infections. The authorisation is given according to Regulation 29 (A)(9): Medical product designated for pharmaceutical treatment of local citizens in case of epidemic or contagious disease or protection from chemical or radioactive substances, according to Regulation 29 of the Pharmacists’ Regulations (Medical preparations) – 1986. The decision from the MOH is based on a rolling submission of data initiated by Moderna prior to November 2020 and is based on the totality of scientific evidence shared by the company, including a data analysis from the pivotal phase III clinical study (see below)^[117]^[118].

In August 2021, Swissmedic reviewed accelerated rolling procedure application and approved the extension for elasomeran mRNA vaccine for adolescent population (12-17 years old). Earlier, in June 2021, Moderna therapeutics filed accelerated rolling procedure for the indication extension of temporary authorised the vaccine in the prevention of COVID-2019 infections. The approval was based on phase III trials [See below] which was conducted in 3,732 children aged 12 to 17 old. In January 2021, Moderna Therapeutics announced that Swissmedic, based upon the recommendation of the Human Medicines Expert Committee (HMEC), has authorized the use of the vaccine for the prevention of COVID-2019 infections, in Switzerland. The authorization was given according to the ordinary approvals procedure and was based on a rolling submission of data and the totality of scientific evidence shared by the Company, including a data analysis from the pivotal Phase 3 clinical study^[109]. Earlier in November 2020, Swissmedic initiated the rolling review for the prevention of COVID-2019 infections^[119]^[120].

In June 2021, Botswana Medicines Regulatory Authority (BMRA) granted emergency use authorization for elasomeran mRNA vaccine in Botswana for use in adults aged 18 years and older^[42].

In June 2021, Moderna announced that the government of India issued a registration certificate and a permission to import the elasomeran mRNA vaccine for restricted use in an emergency situation in India^[121].

As of June 2021, Moderna received emergency (or other conditional, interim or provisional) authorisation for use of elasomeran mRNA vaccine from health agencies in more than 50 countries^[121].

As at May 2021, Moderna received emergency (or other conditional, interim or provisional) authorization for its elasomeran mRNA vaccine from health agencies in Thailand and Paraguay^[122]

As at May 2021, Moderna received authorization for its elasomeran mRNA vaccine from health agencies in Taiwan and the Philippines and Brunei^[49]^[9].

In May 2021, the Ministry of Food and Drug Safety of South Korea (MFDS) approved the Conditional Marketing Authorization for Moderna's mRNA vaccine against COVID-19 infections. The approval is based on the totality of scientific evidence shared by the company, including a data analysis from the pivotal Phase III clinical trial (see below)^[122]

In May 2021, the World Health Organization (WHO) issued Emergency Use Listing (EUL) for elasomeran mRNA vaccine for the prevention of COVID-19 infections, in individuals 18 years of age and older. The decision was based on the totality of scientific evidence shared by the Company, including a data analysis from the pivotal phase III clinical trial (see below)^[123].

Prior to June 2021, elasomeran mRNA vaccine was approved in Puerto Rico.

In June 2021, Moderna Therapeutics submitted an authorisation application to Swissmedic for use of elasomeran mRNA vaccine in adolescents. The submission is based on phase II/III trial of mRNA 1273 in adolescents in the US^[124]

In May 2022, Moderna announced to transfer the marketing authorization for elasomeran (Spikevax^TM) from Takeda to Moderna in Japan, as of August 2022. Companies concluded a memorandum of understanding that Takeda will continue to provide distribution support for the Moderna COVID-19 vaccines for a transitional period^[125]. In December 2021, the Ministry of Health, Labour and Welfare (MHLW) of Japan granted approval for 50µg booster dose of elasomeran to prevent COVID-2019 infections (Takeda investor review; February 2022). In July 2021, the Ministry of Health, Labour and Welfare (MHLW) of Japan granted approval for the use of elasomeran mRNA vaccine in adolescents 12+ years (expanded age) to prevent COVID-2019 infections^[126]. In May 2021, Moderna Therapeutics announced that the Ministry of Health, Labour and Welfare (MHLW) of Japan granted special approval under article 14-3 of the Pharmaceuticals and Medical Devices Act for emergency use of the vaccine in adults. The approval is based on Moderna’s phase III COVE trial [see below] results and positive initial clinical data from the Takeda-led placebo-controlled phase I/II trial [see below]^[13]. Earlier, in March 2021, Takeda had submitted the new drug application (NDA) to the MHLW to import and distribute the vaccine in Japan^[127]^[128].

In February 2021, Moderna announced that the Qatar Ministry of Public Health has issued an emergency use authorization for mRNA 1273 for the prevention of COVID-2019 infections. The approval is based on the totality of scientific evidence shared by the Company, including a data analysis from the pivotal phase III clinical study (see below) announced on November 2020. Qatar has secured access to the vaccine through a supply agreement announced on October 2020^[129].

In February 2021, Moderna announced that the Singapore Health Sciences Authority (HSA) has approved the interim authorization of its elasomeran mRNA vaccine (COVID-19 Vaccine Moderna) for the prevention of COVID-2019 infections for use under the Pandemic Special Access Route (PSAR) for the prevention of COVID-2019 infections. The decision from the HSA is based on the totality of scientific evidence shared by the company, including a data analysis from the pivotal phase III clinical study (see below)^[130]. Earlier, in November 2020, Moderna initiated the rolling review process of elasomeran mRNA vaccine, for the prevention of COVID-2019 infections to the Health Sciences Authority in Singapore^[118].
As at February 2021, Moderna Therapeutics supplied 45.4 million doses to the US government and targets to deliver first 100 million doses by the end of March 2021 and 200 million doses by the end of June 2021. In the same month the company increased its base-case global production estimate from 500 to 600 million doses for 2021. Also, U.S government agreed to purchase 200 million doses of vaccine and in discussion for additional purchase of 100 million doses by the third quarter of 2021^[131]^[132]^[133]^[134].

In May 2020, the US FDA granted a fast track designation to elasomeran mRNA vaccine for prevention of COVID-2019 infections^[49]^[135].

As of October 2020, Moderna is scaling up global manufacturing of elasomeran mRNA vaccine for prevention of COVID-2019 infections with plans to deliver approximately 500 million doses per year and up to about 1 billion doses per year, beginning in 2021^[89].

Moderna Therapeutics, in November 2020, reported data that demonstrated that elasomeran mRNA vaccine remained stable at temperatures of 2°C to 8°C, for a period of 30 days. The vaccine was also found to remain stable at -20°C for up to 6 months, and at room temperature for up to 12 hours. The company intends to submit the extended stability data for approval^[136].

As of June 2022, Moderna reported that mRNA 1273.351 (Beta variant) is in phase I clinical development, mRNA 1273.617 (Delta variant), mRNA 1273.211 (Beta variant+wild type) and mRNA 1273.213 (Beta-delta variant) are undergoing phase II clinical development worldwide (Moderna pipeline, June 2022).

In March 2022, Leiden University Medical Center initiated a phase II clinical trial to evaluate safety and immunological response against COVID-2019 infections after revaccination with mRNA 1273 with a ceramic skin patch (EudraCT2021-006754-31; 80101). The open-label, randomised trial intends to enrol approximately 20 patients in the Netherlands.

In June 2023, Moderna therapeutics completed a phase II/III trial which was designed to evaluate the immunogenicity, safety, and reactogenicity of mRNA 1273.529 (B.1.1.529, Omicron variant) in comparison with mRNA 1273 booster vaccine for the prevention of COVID-2019 infections (NCT05249829; mRNA-1273-P305). The randomised, observer-blind, double-blind, active-controlled trial was initiated in February 2022 and enrolled 3557 volunteers in the UK^[137].

In December 2021, National Institute of Allergy and Infectious Diseases initiated a phase II/III trial to assess the safety, tolerability, and immune responses of Moderna mRNA-1273 in preventing COVID-19 disease in people who are living with HIV (PLWH) or have comorbidities associated with elevated risk of severe COVID-19 (CoVPN 3008; NCT05168813). The randomised trial has enrolled 14232 patients in Botswana, Kenya, Malawi, Swaziland, South Africa, Uganda, Zambia and Zimbabwe^[138]. In February 2023, results from the study were presented at the 30th Conference on Retroviruses and Opportunistic Infections (CROI-2023)^[139].

In August 2021, National Institute of Allergy and Infectious Diseases (NIAID), in collaboration with PPD, initiated a phase II CPAT trial to assess the immunogenicity of a third dose of either the elasomeran vaccine or Pfizer-BioNTech COVID-19 vaccine (tozinameran) in kidney transplant recipients, who have failed to respond to two doses (DAIT NIAID; 38865; NIAID CRMS ID 38865; DAIT COVID19-TB-02; NCT04969263). In October 2021, this open-label, non-randomised COVID-19 protection after transplant pilot (CPAT) study completed enrollment of 81 patients in the US^[140].

In April 2021, Regeneron Pharmaceuticals initiated a phase II trial to assess the immunogenicity, safety, and tolerability of single intramuscular (IM) injection of elasomeran mRNA vaccine, administered with casirivimab/imdevimab [see AdisInsight drug profile 800058539] in healthy volunteers (R10933-10987-COV-2118; NCT04852978). The randomised, open-label, parallel group study intends to enrol approximately 180 participants in the US^[141].

In April 2021, National Institute of Allergy and Infectious Diseases (NIAID), in collaboration with Immune Tolerance Network and Rho Federal Systems Division Inc, initiated a phase II trial to assess the proportions of systemic allergic reactions to elasomeran mRNA vaccine (SARS-CoV-2 vaccination) versus Pfizer-BioNTech's COVID-2019 vaccine (tozinameran) [see AdisInsight Drug profile 800057858], in two populations, including the individuals with a history of allergic reactions or mast cell disorder (HA/MCD), and a non-atopic population (DAIT COVID-19-004; NCT04761822). This randomised, double-blind study is enrolling approximately 3 400 patients in the US^[142].

In May 2023, Moderna Therapeutics completed a phase IIIb COVE Transplant trial which was designed to evaluate the safety, reactogenicity and immunogenicity of elasomeran mRNA vaccine Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) vaccine in adults with a kidney or liver transplant and in healthy adult participants (NCT04860297; mRNA-1273-P304). The open-label trial initiated in April 2021 enroled 234 volunteers in the US^[143]. In September 2021, Moderna initiated dosing and administered the extra vaccine dose to the first set of volunteers in the US^[144].

In March 2024, Moderna Therapeutics completed a phase II/III KidCOVE trial that evaluted safety, tolerability, reactogenicity and effectiveness of elasomeran mRNA vaccine in healthy children (six months-12 years) (mRNA-1273-P204; NCT04796896). The open label, randomised trial was initiated in March 2021 and enrolled 11950 participants in the US and Canada. First patient was dosed in March 2021^[145]^[146]. In April 2021, Moderna reported that, expects to enrol 6,750 healthy paediatric participants in the U.S and Canada. Trial is a two-part, dose escalation study, which includes, each participant ages 2 years to less than 12 years receives one of two dose levels (50 µg or 100 µg) and each participant ages six months to less than 2 years receives one of three dose levels (25 µg, 50 µg and 100 µg) (part 1). An interim analysis will be conducted to determine recommended dose (part 2)^[147]. As of October 2021, the enrollment for the 6 years to under 12 years is complete, but the phase II/III study continues to enroll children ages 6 months to under 6 years of age. The Company has enrolled approximately 5,700 pediatric participants in the US. In October 2021, top-line efficacy and safety data from the trial were released by the Company^[148]. In November 2021, Moderna released data from children six years to under 12 years given two 50 µg doses of elasomeran. In March 2022, results from this trial were released by Moderna Therapeutics^[80].

In February 2022, Takeda completed a phase I/II trial that evaluated safety and immunogenicity of two doses of elasomeran mRNA vaccine by intramuscular injection in healthy Japnese volunteers (U1111-1261-9040; TAK-919-1501; NCT04677660; jRCT2071200069). The randomised, observer-blind, placebo controlled trial completed enrollment of 200 participants in Japan in February 2021. In January 2021, first patient was dosed in the trial^[149]^[150]. Company intends to submit the results from the trial to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) as part of the NDA filing process^[151]. In February 2021, Takeda completed enrollment in this study^[127].

In October 2021, Moderna Therapeutics, in collaboration with Biomedical Advanced Research and Development Authority completed a phase II trial which was designed to evaluate the safety, reactogenicity, and immunogenicity of 2 doses ofelasomeran mRNA vaccine for prevention of COVID-2019 infections in adults 18 years of age or older (mRNA-1273-P201; 75A50120C00034; NCT04405076). The study comprised Part A (Blinded Phase), Part B (Open-labeInterventional Phase), and Part C (Rollover Proof of Concept). Participants in Part A received either 2 active mRNA 1273 vaccine doses or placebo. Part B was an open-label phase in which the participant who received placebo in Part A would be unblinded and would be administered two dose of the vaccine. Part C was a proof-of-concept rollover study which was designed to evaluate a vaccine to treat mutations of SARS-CoV-2, such as the S-protein of the B.1.351 variant. Part C included participants who were enrolled in the phase III mRNA-1273-P301 study (NCT04470427). The randomised, observer-blind, placebo controlled, dose-confirmation study was initiated in May 2020 and enrolled 660 healthy volunteers and older adults, in the US^[152]. The US FDA approved Investigational New Drug (IND) application of elasomeranfor initiating a phase II trial in prevention of COVID-2019 infections in May 2020. In the same month, Moderna received initial feedback from the US FDA regarding design of the planned phase II study. Earlier, in April 2020, Moderna Therapeutics submitted an IND application for the same^[153]^[135]^[154]^[155]^[156]^[157]. In May 2021, the company released preliminary positive immunogenicity and adverse events data from the individual who received single booster dose of elasomeran and mRNA 1273.351. In September 2021, Moderna released data of boster dose^[104]^[158].

In May 2021, Moderna announced that the phase II/III TeenCove trial met its primary endpoint of non-inferior immunogenicity versus the phase III adult study comparator group^[159]. In December 2020, Moderna, in collaboration with Biomedical Advanced Research and Development Authority initiated the randomised, observer-blind, dose-expansion, placebo controlled trial to evaluate the safety and reactogenicity of a single dose level of elasomeran mRNA vaccine administered in 2 doses 28 days apart to an adolescent population (NCT04649151; mRNA-1273-P203). In February 2021, Moderna announced completed enrolment of 3 732 participants, aged 12 to less than 18 years, in the US. The study is being carried out in accordance with paediatric investigation plan (PIP), which was agreed by EMA's Paediatric Committee (PDCO). Data from the trial were released by Moderna in May 2021. In July 2021, additional safety and immunogenicity data were released^[82]^[160]^[161]^[162]^[163].

In November 2020, the US NIH-appointed Data Safety Monitoring Board (DSMB) for the study of elasomeran mRNA vaccine informed Moderna that the trial has met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%. In December 2022, Moderna Therapeutics completed a phase III trial in collaboration with Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases (NIAID). Earlier in July 2020, Moderna Therapeutics announced initiation of dosing in phase III COVE study to evaluate the efficacy, safety and immunogenicity of elasomeran 100 µg for the prevention of COVID-2019 infections (NCT04470427, mRNA-1273-P301,75A50120C00034; UM1AI68614HVTN; UM1AI148684-03). The randomised, stratified, observer-blind, placebo-controlled trial completed enrolment of 30 000 patients in the US, in October 2020^[164]^[165]. The trial is conducted in collaboration with the National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority. The primary endpoint will be the prevention of symptomatic COVID-19 disease. In June 2020, Moderna reported that company has finalised the phase III study protocol based on feedback from the US FDA. The 100 µg dose level was chosen as the optimal dose level to maximise the immune response while minimising adverse reactions, based on the results of the phase I study. Moderna has completed manufacture of vaccine required to start the phase III study^[166]^[167]^[168]^[153]^[135]^[154]^[169]. As of October 2020, the company completed enrollments of 28 618 patients in the trial and 22 194 patients received their second vaccination dose. Case accrual for the first interim analysis was completed in November 2020^[170]^[120]^[101]. Data from the trial were released by Moderna in November and December 2020. Data demonstrated that the 100 µg two-dose regime of the elasomeran mRNA vaccine given 28 days apart was well-tolerated and demonstrated vaccine efficacy against COVID-19^[171]^[115]^[118]^[172]. In February 2021,the company reported that the all participants in the COVE study will be monitored for two years after their second dose to assess long-term protection and safety^[161]. As of April 2021, all placebo participants have been dosed COVID-19 Vaccine and 98% of those have received the vaccine^[147]. In May 2021, Moderna released the adverse events and immunogenicity data for the trial in the Japanese population^[13]. In September 2021, the company released new analysis data from a open-label part of the trial^[173].

In May 2022, ModernaTX initiated a phase I clinical trial to evaluate the safety, reactogenicity and immunogenicity of modified mRNA vaccines using a systems biology approach in healthy adults (NCT05397223; mRNA-CRID-001). The open-label, randomised trial intends to enrol 300 volunteers in the US.

In April 2022, National Institute of Allergy and Infectious Diseases completed a phase I trial that evaluated the safety and immunogenicity of elasomeran mRNA vaccine, in 120 healthy volunteers (1UM1AI148373-01; 20-0003; NCT04283461).The primary objective was to evaluate the safety and reactogenicity of a two-dose vaccination schedule of the vaccine. The secondary objective was to evaluate the immunogenicity to the SARS-CoV-2 S protein^[174]. In March 2020, The trial was initiated and dosed first patient. As of April 2020, enrolment of three dose cohorts (25 µg, 100 µg and 250 µg) was completed with 45 adults patients (aged 18 - 55) in the US. However as per the latest amended protocol by NIH, enrolment was underway in additional six cohorts (60 participants) that included three cohorts of 30 older adults (aged 56 - 70) and three cohorts of 30 elderly adults (aged 71 - above). Favourable interim results from the 25 µg and 100 µg cohorts were released in May 2020. Based on these results, the trial is proposed to be amended to include two dose levels, 50 µg and 100 µg, to select a dose for pivotal studies. A 50 µg dose level cohort will be included across each of the three age groups^[175]^[176]^[177]^[65]. In July 2020, Moderna Therapeutics completed enrollment in the cohorts of older adults and elderly adults of 30 patients each, in this tudy^[157]. In July 2020, interim results from this trial were released by Moderna Therapeutics^[178]. In October 2020, immunogenicity data from the trial was released by Moderna Therapeutics^[89]. In December 2020, interim immunogenicity data from a trial was released by Moderna Therapeutics and it also reported that, no serious adverse events were noted in the trial and no prespecified trial-halting rules were met^[179]. In April 2021, Moderna Therapeutics released antibody persistence data out of six months following second dose of elasomeran^[147]. In June 2021, the company released interim results of the trial^[180].

In January 2021, Moderna Therapeutics released results from in vitro neutralization studies of sera from individuals vaccinated with Moderna COVID-19 vaccine^[181].

In August 2020, Moderna Therapeutics in collaboration with National Institute of Allergy and Infectious Diseases announced positive results from the preclinical studies in mouse for prevention of COVID-2019 infections^[182].

In May 2020, Moderna Therapeutics reported favourable preclinical data from a mouse challenge model of COVID-2019 infections^[175].

Safety information

In April 2021, Moderna Therapeutics released a new safety data on cerebral venous sinus thrombosis (CVST) of elasomeran mRNA vaccine after over 64.5 million doses administered globally. The reports showed that elasomeran mRNA vaccine does not suggest an association with cerebral venous sinus thrombosis (CVST) or thrombotic events, based on analyses performed using data through March 2021^[147].

Supply arrangement

In February 2021, the European Commission (EC) purchased an additional 150 million doses of elasomeran mRNA vaccine, which are scheduled to be delivered in the third and fourth quarter of 2021. The total confirmed order commitment for delivery to the EC in 2021 is 310 million doses. Under the terms of the agreement, EC has an option to purchase an additional 150 million doses for delivery in 2022^[35].

In January 2020, the Swiss Federal Government secured 7.5 million doses of the elasomeran mRNA vaccine and the deliveries are expected to begin by the end of January, in Switzerland^[109].

In December 2020, Moderna entered into a supply agreement with the government of the South Korea to provide 40 million doses of the elasomeran mRNA vaccine for the prevention of COVID-2019 infections. Under the terms of the agreement, deliveries would begin in May 2021, and the company is aiming to get the marketing approval prior to the distribution^[183].

In December 2020, the Canadian Government increased its confirmed order commitment by 20 million doses of elasomeran mRNA vaccine, bringing its confirmed order commitment to 40 million doses for prevention of COVID-2019 infections^[184].

In September 2020, the Canadian Government increased its confirmed order commitment to 20 million doses of elasomeran mRNA vaccine for prevention of COVID-2019 infections. In October 2020, Moderna Therapeutics announced that it remains on track and will deliver up to 56 million doses of this vaccine in 2021. The Canadian vaccine supply will be sourced from Moderna's European production capacity, in collaboration with its partners Lonza, and ROVI^[101].

Financing information

In December 2020, Biomedical Advanced Research and Development Authority (BARDA) awarded a grant of $US 955 million (contract no. 75A50120C00034) for continued research and development of elasomeran. BARDA is reimbursing 100 percent of the allowable costs incurred by Moderna for conducting the programme described in the BARDA contract^[185].

In August 2020, the US government, under the US Department of Defense contract (number W911QY-20-C-0100) granted an award worth approximately $US1.525 billion, for the manufacturing and delivery of 100 million doses of elasomeran, including incentive payments for timely delivery of the therapy. The agreement also granted an option to the US government, under the Operation Warp Speed, to purchase up to an additional 400 million doses of the vaccine^[186].

As of August 2020, the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract number HHSN272201500002C, are funding this project in whole or in part with federal funds^[187].

In May 2020, Moderna Therapeutics announced an underwritten public offering of $US1.25 billion in shares of its common stock with a 30 day purchase option of an additional $US187.5 million. The net proceeds will be utilized for manufacturing of elasomeran mRNA vaccine^[188].

In January 2020, Moderna Therapeutics announced that Coalition for Epidemic Preparedness Innovations (CEPI) will be funding the manufacture of an mRNA vaccine against COVID-2019 infections^[65].

Patent Information

As of December 2022, the US Patent and Trademark Office (USPTO) issued patents to Moderna Therapeutics for composition of matter of spikevax with patent numbers 11,524,023 (2041), 11,485,972 (2038), 10,703,789 (2033), 10,702,600 (2036), 10577,403 (2033), 10,442,756 (2036), 10,266,485 (2036), 10064,959 (2031), 9,868,692 (2036) and compositions of matter and use 10,898,574 (2032) in the US. The composition of matter patent number 3718565 (203)6 and composition of matter and method of use 3590449 (2031) in Europe ^[189]

As of December 2020, Moderna Therapeutics issued two US patents, two pending US patent applications and pending patent applications in Europe, Canada, Australia, Brazil, China, Hong Kong, India, Japan, Russia, and Singapore covering claims to lipid nanoparticle-encapsulated mRNAs encoding infectious disease antigens and methods using such compositions for vaccination. Issued US Patent Nos. 10 022 435 and 10 709 779 feature claims directed to methods of vaccinating subjects against infection with lipid nanoparticle-encapsulated mRNAs encoding infectious disease antigens^[190].

In October 2020, Moderna Therapeutics declared that it will not enforce its patent rights for elasomeran (US 10 703 789; US 10 702 600; US 10 577 403; US 10 442 756; US 10 266 485; US 10 064 959; US 9 868 692) during the pandemic if the vaccine gets approval by the US FDA^[191]^[192]^[193]^[194].

Moderna Therapeutics holds broad and deep patent estate that include foundational patents in modified mRNA technologies and delivery technologies for mRNA vaccines and therapeutics in the USA, Japan, Europe and other jurisdictions (Modern Therapeutics website, January 2020).

Moderna Therapeutics has in-licensed patents for modified mRNA technologies and delivery technologies from Harvard University and University of Pennsylvania (Modern Therapeutics website, January 2020).

Patent disputes

In August 2023, two of the asserted Alnylam patents were the subject of an order from the Delaware Court on interpreting certain claim language. Alnylam and Moderna have concurred to a final judgement of non-infringement of two of Alnylam's patents as a result of that order. Alnylam respectfully objects to the Delaware Court's decision and plans to file an appeal. Alnylam hopes that its second infringement lawsuit against Moderna will proceed in the Delaware Court. In March 2022, Alnylam filed a lawsuit against Moderna, alleging patent infringement in the United States District Court for the District of Delaware. Alnylam has so far filed two separate lawsuits against Moderna in an effort to recoup appropriate damages for the company's infringement of five of its patents, which are essential lipid technologies used in Moderna's COVID-19 vaccine, SPIKEVAX®^[195]..

In June 2023, Promosome LLC filed major patent infringement actions against Moderna for infringement of US Patent No. 8 853 179 (the "179 patent") entitled "Reengineering mRNA primary structure for enhanced protein production" which relates to messenger RNA technology utilized for Spikevax vaccine. The lawsuit describes how, under a 2013 confidential disclosure agreement, Promosome taught its method to Moderna's highest levels of leadership without out-licensing the '179 Patent which generated more than $US35 billion in revenue with sales of Spikevax vaccine^[196].

In April 2024, Arbutus Biopharma issued the statement regarding the claim construction ruling of the U.S. District Court for the District of Delaware in the lawsuit brought by Arbutus and its licensee Genevant Sciences (Plaintiffs) against Moderna. Moderna affiliate seeking damages for infringement of U.S. Patent Nos. 8 058 069, 8 492 359, 8 822 668, 9 364 435, 9 504 651 and 11 141 378 in the manufacture and sale of MRNA 1273^[197]. In February 2022, Arbutus Biopharma Corporation and Genevant Sciences filed a lawsuit in the US District Court for the District of Delaware against Moderna and a Moderna affiliate seeking damages for infringement of US Patent Nos. 8 058 069, 8 492 359, 8 822 668, 9 364 435, 9 504 651, and 11 141 378 in the manufacture and sale of Moderna's elasomeran (MRNA 1273). The patents relate to nucleic acid-lipid particles and lipid vesicles, as well as compositions and methods for their use. Arbutus and its licensee Genevant do not seek an injunction or otherwise seek to impede the sale, manufacture or distribution of MRNA 1273 but seek fair compensation for Moderna’s use of their patented technology. In December 2021, the United States Court of Appeals for the Federal Circuit rejected Moderna’s appeal of a prior decision of the US Patent Trial and Appeal Board (PTAB) holding all claims of the asserted 8 058 069 patent to be patentable and dismissed Moderna’s appeal challenging a similar finding of patentability with respect to certain claims of the asserted 9 364 435 patent. Moderna had initiated inter partes review (IPR) challenges against these patents in 2018 and 2019 ^[198]. In July 2020, the US PTAB had ruled the 8 058 069 patent related to Moderna’s challenge to certain legacy patents held by Arbutus, that commenced before the development of elasomeran. Through its actions, Moderna overturned one legacy patent held by Arbutus and invalidated the broadest claims of a second one^[199].
This patent family includes two issued U.S. patents, two pending U.S. patent applications and pending patent applications in Europe, Canada, Australia, Brazil, China, Hong Kong, India, Japan, Russia, and Singapore. Issued U.S. Patent Nos. 10 022 435 and 10 709 779 feature claims directed to methods of vaccinating subjects against infection with lipid nanoparticle-encapsulated mRNAs encoding infectious disease antigens.

Drug Properties & Chemical Synopsis

Route of administration IM, Transdermal
Formulation Injection, Patch
Class COVID-19 vaccines, RNA vaccines, Viral vaccines
Mechanism of Action Immunostimulants
WHO ATC code
J07B-X03 (Covid-19 vaccines)
EPhMRA code
J7E9 (All other viral vaccines)

Indication	Biomarker Function	Biomarker Name	Number of Trials
COVID 2019 infections	Outcome Measure	vitronectin Tumor necrosis factor alpha (TNF-alpha) Thromboxane T-cell surface antigen CD4 T-Cell differentiation antigen CD8 seryl-tRNA synthetase Rheumatoid factor Protein S Picolinic acid PD-L1/CD274 PD-1/CD279 Monocyte chemoattractant protein-1 (MCP-1/CCL2) MIP-1 alpha membrane-bound transcription factor peptidase, site 2 Interleukin-8 (IL-8) Interleukin-6 (IL-6) Interleukin-23 (IL-23) Interleukin-22 (IL-22) Interleukin-21 (IL-21) Interleukin-2 (IL-2) Interleukin-18 (IL-18) Interleukin-17 (IL-17) Interleukin-10 (IL-10) interleukin 37 interleukin 33 Interleukin 1 Beta (IL-1Î²) Interferon Gamma (IFNg) Interferon alpha (IFN-alpha) GTP binding protein 1 fuzzy planar cell polarity protein FK506 binding protein 4 Eotaxin (CCL11) CXCL9 CXCL1 Creatinine Creatine Chemokine IFN-Î³-inducible protein10 (IP-10/CXCL10) CD40/TNFRSF5 Cardiac Troponin I C-X-C motif chemokine ligand 5 C-X-C motif chemokine ligand 11 C-reactive protein (CRP) C-C motif chemokine ligand 8 C-C motif chemokine ligand 20 C-C motif chemokine 5 (CCL5 C-C motif chemokine 4 (CCL4 Bilirubin ATP citrate lyase 46 more biomarker names Show less	4 2 1 7 6 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 9 2 1 2 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 1
COVID 2019 infections	Brief Title	seryl-tRNA synthetase PD-L1/CD274	1 1
COVID 2019 infections	Arm Group Description	T cell receptor beta variable 20/OR9-2 (non-functional) protein tyrosine phosphatase, non-receptor type 6 Cytokeratin 20 CD22 calcineurin binding protein 1 B-lymphocyte antigen CD20 B-lymphocyte antigen CD19 B-cell lymphoma 2 (Bcl-2) 6 more biomarker names Show less	1 1 2 1 1 2 1 1
COVID 2019 infections	Detailed Description	vitronectin T-cell surface antigen CD4 Renin Protein S Interleukin-22 (IL-22) Interleukin-21 (IL-21) Interferon Gamma (IFNg) Fumaric acid Cytokeratin 20 Calprotectin C-reactive protein (CRP) B-lymphocyte antigen CD20 10 more biomarker names Show less	2 1 1 1 1 1 1 1 1 1 1 1
COVID 2019 infections	Eligibility Criteria	T-cell surface antigen CD4 PD-L1/CD274 PD-1/CD279 Glycerophosphocholine FSH Apolipoprotein H antibodies 4 more biomarker names Show less	1 1 1 1 2 1
COVID 2019 infections	Official Title	PD-L1/CD274	1
COVID 2019 infections	Brief Summary	seryl-tRNA synthetase	1
COVID2019 infections	Arm Group Label	B-lymphocyte antigen CD19	1
hepatitis B	Arm Group Description	B-cell lymphoma 2 (Bcl-2)	1
herpes zoster	Arm Group Description	B-cell lymphoma 2 (Bcl-2)	1
herpes zoster	Outcome Measure	vitronectin myasthenia gravis, familial infantile, 1	1 1
influenza virus infections	Arm Group Description	B-cell lymphoma 2 (Bcl-2)	1
influenza virus infections	Outcome Measure	suppression of tumorigenicity 14 (colon carcinoma) serine peptidase inhibitor, Kunitz type 1	1 1
pneumococcal infections	Arm Group Description	Cytokeratin 20 B-lymphocyte antigen CD20 B-cell lymphoma 2 (Bcl-2) 1 more biomarker names Show less	1 1 1
SARS-CoV-2 acute respiratory disease	Outcome Measure	PD-L1/CD274 PD-1/CD279 Interleukin-22 (IL-22) Interleukin-21 (IL-21) Interferon Gamma (IFNg) 3 more biomarker names Show less	1 1 1 1 1
SARS-CoV-2 acute respiratory disease	Brief Title	PD-L1/CD274	1
SARS-CoV-2 acute respiratory disease	Detailed Description	Interleukin-22 (IL-22) Interleukin-21 (IL-21) Interferon Gamma (IFNg) 1 more biomarker names Show less	1 1 1
SARS-CoV-2 acute respiratory disease	Eligibility Criteria	PD-L1/CD274 PD-1/CD279	1 1
SARS-CoV-2 acute respiratory disease	Official Title	PD-L1/CD274	1

Drug Name	Biomarker Name	Biomarker Function
Elasomeran - Moderna Therapeutics/National Institute of Allergy and Infectious Diseases		Apolipoprotein H antibodies	Eligibility Criteria
	ATP citrate lyase	Outcome Measure
	B-lymphocyte antigen CD19	Arm Group Label
	B-lymphocyte antigen CD20	Arm Group Description, Detailed Description
	Bilirubin	Outcome Measure
	C-reactive protein (CRP)	Detailed Description, Outcome Measure
	calcineurin binding protein 1	Arm Group Description
	Calprotectin	Detailed Description
	Cardiac Troponin I	Outcome Measure
	Creatine	Outcome Measure
	Creatinine	Outcome Measure
	Cytokeratin 20	Arm Group Description, Detailed Description
	FSH	Eligibility Criteria
	Fumaric acid	Detailed Description
	fuzzy planar cell polarity protein	Outcome Measure
	Glycerophosphocholine	Eligibility Criteria
	GTP binding protein 1	Outcome Measure
	Interferon alpha (IFN-alpha)	Outcome Measure
	Interferon Gamma (IFNg)	Outcome Measure
	Interleukin-2 (IL-2)	Outcome Measure
	membrane-bound transcription factor peptidase, site 2	Outcome Measure
	myasthenia gravis, familial infantile, 1	Outcome Measure
	PD-1/CD279	Eligibility Criteria, Outcome Measure
	PD-L1/CD274	Brief Title, Eligibility Criteria, Official Title, Outcome Measure
	Protein S	Detailed Description
	protein tyrosine phosphatase, non-receptor type 6	Arm Group Description
	Rheumatoid factor	Outcome Measure
	serine peptidase inhibitor, Kunitz type 1	Outcome Measure
	seryl-tRNA synthetase	Brief Summary, Brief Title, Eligibility Criteria, Outcome Measure
	suppression of tumorigenicity 14 (colon carcinoma)	Outcome Measure
	T cell receptor beta variable 20/OR9-2 (non-functional)	Arm Group Description
	T-Cell differentiation antigen CD8	Outcome Measure
	T-cell surface antigen CD4	Outcome Measure
	Thromboxane	Outcome Measure
	Tumor necrosis factor alpha (TNF-alpha)	Outcome Measure
	vitronectin	Arm Group Description, Detailed Description, Outcome Measure

Indication	Phase 0	Phase I	Phase II	Phase III	Phase IV
Influenza virus infections	-	1	2	-	2
Herpes zoster	-	-	-	1	1
COVID-19 respiratory infection	-	1	3	-	6
Hepatitis B	-	-	-	-	1
Pneumococcal infections	-	-	-	1	2
Human papillomavirus infections	-	-	-	1	-
Chronic myeloid leukaemia	-	-	-	-	1
SARS-CoV-2 acute respiratory disease	-	1	2	-	3
Cytomegalovirus infections	-	1	-	-	-
COVID 2019 infections	1	8	89	23	471
Systemic lupus erythematosus	-	-	-	-	1
Cancer	-	-	-	-	2
Respiratory syncytial virus infections	-	1	-	-	-

Indication	Qualifier	Patient Segment	Phase	Countries	Route / Formulation	Developers	Event Date
COVID 2019 infections	-	In children, Prevention	Marketed	Canada, United Kingdom	IM / Injection	Moderna Therapeutics	08 Aug 2023
COVID 2019 infections	-	In adolescents, In adults, In children, Prevention	Marketed	France, Poland, Spain, Sweden, Switzerland	IM / Injection	Moderna Therapeutics	08 Aug 2023
COVID 2019 infections	conditional marketing approval Authorised under an Interim Order	In adolescents, Prevention	Marketed	Canada, United Kingdom	IM / Injection	Moderna Therapeutics	08 Aug 2023
COVID 2019 infections	rolling submission; Great Britain	In adults, Prevention	Marketed	Canada, United Kingdom	IM / Injection	Moderna Therapeutics	08 Aug 2023
COVID 2019 infections	age 6 months and older	In infants, Prevention	Marketed	Canada	IM / Injection	Moderna Therapeutics	12 Sep 2023
COVID 2019 infections	in children aged 6 months to 6 years	In children, In infants, Prevention	Registered	Australia	IM / Injection	Moderna Therapeutics	15 Aug 2022
COVID 2019 infections	rolling submission	In adults, In the elderly, Prevention	Registered	Australia, Switzerland	IM / Injection	Moderna Therapeutics	10 Aug 2021
COVID 2019 infections	Emergency use authorisation Emergency Use Authorization Conditional Marketing Authorisation Authorised under an Interim Order	Prevention	Registered	Argentina, Botswana, Brunei, European Union, Iceland, India, Israel, Liechtenstein, Norway, Paraguay, Philippines, Puerto Rico, Qatar, Singapore, South Korea, Taiwan, Thailand	IM / Injection	Moderna Therapeutics	30 Aug 2021
COVID 2019 infections	12-17 yrs Provisional registration (12-18 years of age)	In adolescents, Prevention	Registered	Australia, European Union, Iceland, Liechtenstein, Norway, Switzerland	IM / Injection	Moderna Therapeutics	21 Apr 2023
COVID 2019 infections	-	In children, Prevention	Registered	Australia, European Union, Iceland, Liechtenstein, Norway	IM / Injection	Moderna Therapeutics	17 Mar 2022
COVID 2019 infections	Emergency use authorization (special approval under article 14-3 of the Pharmaceuticals and Medical Devices Act for emergency use)	In adolescents, In adults, Prevention	Registered	Japan	IM / Injection	Takeda	21 May 2021
COVID 2019 infections	-	In children, Prevention	Phase III	USA	IM / Injection	Moderna Therapeutics	28 Mar 2022
COVID 2019 infections	6 months to 11 years 6 months - 12 years	In children, In infants, Prevention	Phase II/III	Canada, USA	IM / Injection	Moderna Therapeutics	15 Mar 2021
COVID 2019 infections	-	Prevention	Phase II/III	Kenya, Malawi, South Africa, Swaziland, Uganda, Zambia	IM / Injection	National Institute of Allergy and Infectious Diseases	30 Sep 2022
COVID 2019 infections	-	Prevention	Phase II	Netherlands	Transdermal / Patch	Leiden University Medical Center	22 Mar 2022
COVID 2019 infections	Administered with casirivimab/imdevimab	Combination therapy, Prevention	Phase II	USA	IM / Injection	Regeneron Pharmaceuticals	29 Apr 2021
COVID 2019 infections	EUA amended, monovalent vaccine no longer authorized for use in the US	In adolescents, In children, In infants	Discontinued (Registered)	USA	IM / Injection	Moderna Therapeutics	18 Apr 2023
COVID 2019 infections	EUA amended, monovalent vaccine no longer authorized for use in the US	Prevention	Discontinued (Registered)	USA	IM / Injection	Moderna Therapeutics, National Institute of Allergy and Infectious Diseases	18 Apr 2023
COVID 2019 infections	EUA amended, monovalent vaccine no longer authorized for use in the US	In adolescents, Prevention	Discontinued (Preregistration)	USA	IM / Injection	Moderna Therapeutics	18 Apr 2023
Human papillomavirus infections	-	In children, Prevention	Phase III	USA	IM / Injection		28 Mar 2022

Adverse drug reaction	Total safety reports	Serious reports	First reports
Behaviour and behaviour mechanisms	6	6	-
Breast disorders	2	-	-
Cardiovascular disorders	311	298	-
Chemically induced disorders	32	28	-
Congenital disorders	6	6	-
Digestive system disorders	51	49	-
Disorders of environmental origin	10	6	-
Drug response related complications	154	153	-
Ear nose and throat disorders	16	14	1
Endocrine disorders	33	33	-
Eye disorders	62	60	-
Female urogenital diseases and pregnancy complications	4	4	-
Genitourinary disorders	71	70	-
Haematological disorders	175	151	-
Immunological disorders	297	266	-
Infections	67	63	-
Male urogenital diseases	2	1	-
Mental disorders	12	12	-
Miscellaneous disease terms	6	5	-
Multisystem disorders	15	14	-
Musculoskeletal disorders	80	70	-
Neurological disorders	224	204	1
Nutritional and metabolic diseases	7	7	-
Pathological conditions signs and symptoms	354	303	1
Pathology and biological functions	13	11	-
Pigmentation	4	1	-
Psychiatric disorders	1	1	-
Respiratory tract disorders	50	46	1
Sclerosis	5	5	-
Sedation	1	1	-
Signs symptoms and ill defined conditions	112	75	-
Skin and connective tissue diseases	235	168	-
Stomatognathic disorders	20	17	-
Tissue disorders	25	25	-
Tumours	22	21	-

Scientific Summary

Adverse Events

Phase III

Updated results from phase III COVE trial in Japanese population (n = 200) demonstrated that the vaccine injected at 100 µg dose given 28 days apart in the participants aged 20 years and above was generally well tolerated with no significant safety concerns reported. Participants will be followed through 12 months after the second vaccination. Previously, treatment with elasomeran in patients with COVID-2019 infections in a phase III COVE study was observed to be safe and well tolerated. The most common solicited adverse reactions (ARs) after the two-dose series included injection site pain (88.2%), erythema (8.6%), swelling (12.2%), and ipsilateral lymphadenopathy (14.2%). The majority of these ARs were grade 1 (mild) or grade 2 (moderate). A higher occurrence of grade 3 (severe) reactions as observed in the elasomeran group after the first (2.9%) and second (15.8%) injections. The majority of local solicited ARs occurred within the first one to two days after injection and generally persisted for a median of one to two days. Solicited systemic adverse events occurred more often in the vaccine group (54.9% and 79.4%) than in the placebo (42.2% and 36.5%) group after both the first dose and the second dose respectively and were most commonly headache, fatigue and myalgia. The majority of local solicited ARs occurred within the first one to two days after injection and generally persisted for a median of one to two days^[171]. Earlier reported adverse events were observed to be of mild or moderate in severity. Grade 3 (severe) events greater than or equal to 2% including injection site pain (2.7%) following first dosage and fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%) and erythema/redness at the injection site (2.0%) following second dose were reported from the patients and were reported to be short-lived. Solicited adverse reactions increased in frequency and severity in the elasomeran group after the second dose. There was one COVID-19-related death in the study to date, which occurred in the placebo^[13]^[115]^[118]^[172]^[165]

Phase II/III:

In updated results from a phase II/III TeenCove trial of elasomeran, the most common side effects in children aged 12 to 17 were similar to those in people aged 18 and above. They included pain and swelling at the injection site, tiredness, headache, muscle and joint pain, enlarged lymph nodes, chills, nausea, vomiting and fever. These effects were usually mild or moderate and improve within a few days from the vaccination. Due to the limited number of children and adolescents included in the study, the trial could not detect new uncommon side effects or estimated the risk of known side effects such as myocarditis and pericarditis^[82]. Previously, treatment with elasomeran was generally well tolerated with a safety and tolerability profile generally consistent with the phase III COVE study in adults. The majority of adverse events were observed to be mild or moderate in severity. No serious safety concerns were reported. The most common solicited local adverse event was reported to be injection site pain. The most common solicited systemic adverse events following second dose of elasomeran were observed to be headache, fatigue, myalgia and chills^[160]^[163].

Results from a phase II/III KidCOVE trial in children aged six years to under 12 years demonstrated that, elasomeran was generally well tolerated with a safety and tolerability profile generally consistent with the phase III COVE study in adolescents and adults. The majority of adverse events were mild or moderate in severity. The most common solicited adverse events were fatigue, headache, fever, and injection site pain^[148]^[146].

Updated interim results from a phase I trial in healthy volunteers showed that treatment withelasomeran was generally safe and well-tolerated, with no serious adverse events reported through day 57. Adverse events (AEs) were generally transient and mild to moderate in severity. The most notable adverse events were seen at the 250µg dose level, with three of those 14 participants (21%) reported one or more severe events. Solicited systemic adverse events were more common after the second vaccination and occurred in seven of 13 (54%) participants in the 25µg group, all 15 participants in the 100µg group and all 14 participants in the 250µg group. The most commonly reported systemic adverse events following second vaccination at the 100 µg dose were fatigue (80%), chills (80%), headache (60%) and myalgia (53%), all of which were transient and mild or moderate in severity. The most common solicited local adverse event at the 100µg dose was pain at the injection site (100%), which was transient and mild or moderate in severity. Earlier, results from a phase I trial established a generally safe and well tolerated profile for elasomeran, which was consistent with the company's earlier infectious disease vaccine clinical studies. A solitary grade 3 adverse event of erythema at the injection site was seen in one volunteer, in the 100 µg dose cohort. The 250 µg dose level reflected the most notable adverse events in three volunteers with grade 3 systemic symptoms, only after the second dose. The adverse events were predominantly transient and self-resolving. Grade 4 adverse events or serious adverse events were not reported^[178]^[175]^[174].

In a phase II/III CoVPN3008 trial, elasomeran was well tolerated by persons living with HIV (PLWH) with more reactogenicity (solicited adverse events [AEs]) in females. A total of 14% (172/1262) and 12% (64/542) of PLWH reported moderate/severe reactogenicity after the 1st and 2nd vaccination, with no hospitalisations. Female PLWH and CD4 count >500 had 35% (p=0.03) and 44% (p=0.04) increased odds of moderate/severe reactogenicity, respectively. Other baseline characteristics were not associated with the odds of reporting moderate/severe reactogenicity among PLWH after 1st vaccination^[139]^[138].

Phase II

In a phase II trial, safety profile of booster dose of single 50µg of elasomeran or mRNA 1273.351 when given to previously vaccinated individuals was similar as reported in previous trials of mRNA 1273. The majority of adverse events were mild or moderate in severity. After the third dose of the vaccine, any Grade 3 solicited local or systemic adverse events was reported in 15% individuals and 10.5% individuals after the third dose of mRNA 1273.351. No Grade 4 solicited local or systemic adverse events were reported. The most common solicited local adverse event was injection site pain in both groups. Fatigue, headache, myalgia and arthralgia were the most common solicited systemic adverse events after the third dose (Booster) of mRNA 1273.351 or mRNA 1273. The data suggest that mRNA 1273.351 had a lower reactogenicity profile than mRNA 1273 in this study^[158]^[152].

Pharmacodynamics

Summary

Immunogenicity

Summary

Phase III

New analysis data from a open-label part of the phase III COVE trial, demonstrated 88 breakthrough cases of COVID-19 in the more recently vaccinated group (49 cases per 1000 person-years) and 162 cases in the group vaccinated last year (77.1 cases per 1000 person-years). The reduction in incidence rates for participants vaccinated more recently compared to participants vaccinated last year was 36% (95% CI: 17-52%). A Cox proportional hazards model reported 19 severe cases after adjusting for age and risk factors for severe COVID-19. A numerical trend towards a lower rate of severe cases in the group vaccinated more recently (3.3 per 1000 person-years) and to the group vaccinated last year (6.2 per 1000 person-years)^[173]. The final analysis of phase III COVE study data showed that elasomeran exhibited 93% efficacy, with the efficacy remaining durable through six months after administration of the second dose. The vaccine maintained antibodies through six months, including against variants such as the delta variant. After two doses of the vaccine, binding and neutralising antibodies were generated against ancestral strain of the virus and against the variants of concern, Alpha, Beta, Gamma, Delta, Epsilon and Iota. Earlier, data from the trial in Japanese population (n = 200) demonstrated that the vaccine injected at 100µg dose given 28 days apart in the participants aged 20 years and above showed an immune response comparable to the data of participants in USA. Binding and neutralizing antibody titers were elevated at 28 days after the second dose of the vaccine in 100% of participants. Previously, data from a phase III COVE trial demonstrated a point estimate of vaccine efficacy of 94.1% (95% CI 89.3-96.8%; p<0.0001. The primary analysis was based on 196 cases, of which 185 cases of COVID-19 were observed in the placebo group versus 11 cases observed in the mRNA-1273 group. A secondary endpoint analysis of severe cases of COVID-19 showed that all cases (n = 30) occurred in the placebo group and none in the elasomeranvaccinated group. Efficacy was consistent across age, race and ethnicity, and gender demographics. Interim analysis showed the trial met statistical criteria with a vaccine efficacy of 94.5% (p <0.0001)^[72]^[13]^[171]^[118]^[172]^[165].

Phase II/III:

In a phase II/III TeenCove trial, no cases of COVID-19 were observed in the vaccine group (n=2163) who had received two doses of the vaccine compared with 4 cases in the placebo group (n=1073), resulting in a vaccine efficacy of 100% starting 14 days after the second dose in 2500 adolescents. The trial demonstrated a vaccine efficacy rate of 93% in seronegative adolescent population starting 14 days after the first dose. Elasomeran produced a comparable antibody response in 12- to 17-year-olds to that seen in young adults aged 18 to 25 years (as measured by the level of antibodies against SARS-CoV-2)^[82]^[159]^[160]^[163].

Results from a phase II/III KidCOVE trial, demonstrated a robust neutralising antibody response in the 6 months through 5 years of age group consistent with young adults, even at the lower 25 μg dose, along with a favorable safety profile consistent with other age groups. The antibody titeres in the pre-specified 6 months to 23 months and 2 years to 5 years age sub-groups met the success criteria for similarity to the adults in the COVE study, which satisfied the primary objective of the study. The secondary endpoint of vaccine efficacy was observed to be 51% and 37% based on RT-PCR confirmed COVID-19 and CDC case definition in the 6 months through 23 months and 2 years through 5 years age groups, respectively, comparable to the vaccine efficacy observed in adults receiving elasomeran during the same omicron prevailing period. The secondary endpoint of vaccine efficacy in the 6 to 11 years of age during the delta wave was observed to be 88% based on CDC case definition^[68]. Results from a phase II/III KidCOVE trial in children aged six years to under 12 years demonstrated that, the study met its primary immunogenicity endpoints. In the trial, the SARS-Cov-2-neutralizing antibody geometric mean ratio (GMR) comparing the response in children to the response in young adults from the phase III COVE study was 1.5 (95% Cl: 1.3, 1.8), with a seroresponse rate of 99.3%, representing a difference of 0.6% (95% CI: -2.8%, 2.8%) to the phase III benchmark. These results demonstrate strong immune response in this cohort of children one month after the second dose and met the co-primary immunogenicity endpoints for 6 to less than 12 years old's in KidCOVE. Vaccine efficacy of 100% using the P301 primary case definition for COVID-19 was observed two weeks after the first dose of elasomeran at the 50 µg dose level. For asymptomatic infection two weeks after the first dose, vaccine efficacy was 65% (95% CI: .16, .85). For SARS-CoV-2 infection regardless of symptoms, vaccine efficacy was 80% (95% CI: .62, .90) two weeks after the first dose^[80]^[148]^[146].

Phase II:

In updated data of a phase II trial, a booster dose of elasomeran at the 50µg dose level (n=344) boosted neutralising titers significantly above the phase III benchmark. After a third dose, a similar level of neutralising titers was achieved across age groups, notably in older adults (ages 65 and above). Robust antibody responses were induced and significantly increased geometric mean titers (GMT) for all variants of concern including Beta (B.1.351) by 32- fold, Gamma (P.1) by 43.6-fold and Delta (B.1.617.2) by 42.3-fold^[104]. In a phase II trial, increased pseudovirus neutralisation (PsVN) antibody titer against SARS-CoV-2 virus and two variants, B.1.351 and P.1 were exhibited post two week after booster dose of single 50µg of elasomeran or mRNA 1273.351 when given to previously vaccinated individuals (who have completed two dose of vaccines). Booster dose increased geometric mean titers (GMT) against the wild-type, B.1.351, and P.1 variants to levels similar to or higher than the previously reported peak titers against the D614G strain following primary vaccination. Booster with mRNA-1273.351 showed higher antibodies against the B.1.351 variant and more efficacy than a booster dose of mRNA 1273 (GMT = 1400 for mRNA 1273.351; GMT = 864 for mRNA 1273). mRNA 1273.351 booster showed balance immune response against the variants as evident by improvement in neutralizing titers between the wild-type (D614G) and B.1.351, post 15 days (a 7.7-fold difference prior to boost to a 2.6-fold difference 15 days after boost)^[158]^[152].

Phase I:

Interim results from the phase I trial showed activity against variants of SARS-CoV-2 in vitro neutralisation studies of sera from individuals (n = 8) vaccinated with elasomeran vaccine. Neutralisation assays against additional variant strains showed minimal impact on neutralising titers against the alpha and A.23.1 variants, relative to those against the ancestral strain (D614G). This analysis showed a modest reduction in neutralising titers against the delta (2.1-fold), gamma (P.1, 3.2-fold), kappa (3.3-3.4-fold), and eta (4.2-fold) variants relative to those against the ancestral strain. A 7.3 or 8.4-fold reduction in neutralising titers was observed with the additional versions of the beta variant relative to the ancestral strain. An 8-fold reduction in neutralising titers relative to the ancestral strain was observed with A.VOI.V2 variant (first identified in Angola)^[180].Interim durability data from participants in the phase I trial of elasomeran showed that, it produced high levels of binding and neutralizing antibodies that declined slightly over time and remained elevated in all participants three months after the booster vaccination. At day 119, 3 months post-second 100 µg dose, binding and neutralizing antibody titers remained high in all participants and results were consistent across all age groups (18-55, 56-70 and 71+)^[179]. Interim results from a phase I trial showed that in the 18-55 age group, neutralising antibody titers were observed in 100% of evaluated participants and at the 100 µg dose level selected for phase III, the geometric mean titers were above those seen in convalescent sera. mRNA 1273 induced consistently high levels of pseudovirus neutralisation antibody titers in all participants in the 56-70 and 71+ age groups. Vaccination with elasomeran elicited Th1-biased CD4 T cell responses in all age groups^[89]. Earlier data showed dose-dependent increases in binding titers across 25 µg, 100 µg and 250 µg dosage levels, and between prime and boost within the 25 µg and 100 µg dose levels. All volunteers aged 18-55 (n=15 per cohort) across all three dose levels seroconverted by day 15, after administration of a single dose. mRNA 1273 induced binding antibodies to the full-length SARS-CoV-2 Spike protein in all participants after the first vaccination, with all participants seroconverting by day 15. After two vaccinations, at day 57, geometric mean titers exceeded those seen in convalescent sera obtained from 38 individuals with confirmed COVID-19 diagnosis. Of the 38 individuals in the convalescent sera group, 15% were classified as having severe symptoms (hospitalization requiring intensive care and/or ventilation), 22% had moderate symptoms and 63% had mild symptoms. After the second vaccination, PsVNA neutralising antibody titers were detected in all participants in all dose cohorts. The day 57 geometric mean titers at the 100 µg dose were 2.1-fold higher than those seen in convalescent sera (n=38). Strong correlations were observed between the binding and neutralisation assays, and between the live virus and pseudovirus neutralization assays. A clear dose response was seen in geometric mean titers between the 25µg and 100µg dose levels, with minimal additional increases at the 250µg dose. Moreover, following second vaccination, mRNA 1273 elicited Th1-biased CD4 T-cell responses without significant elevation of Th2-biased CD4 T-cell responses. Earlier, results from the trial at day 43, at the 25 µg dose level (n=15), the binding antibody levels matched the levels observed in convalescent sera (blood samples from people who have recovered from COVID-19), tested in the same assay. At day 43, at the 100 µg dose level (n=10), binding antibody levels significantly surpassed the levels in convalescent sera. Samples were unavailable for remaining volunteers. Neutralising antibody data from first four volunteers in each of the 25 µg and 100 µg dose level cohorts, also exhibited an evoking of neutralising antibodies in all eight volunteers, as determined by plaque reduction neutralization (PRNT) assays against live SARS-CoV-2, following administration of mRNA 1273. Antibody persistence data out to 6 months following the second dose 100 µg dose (day 209) of the elasomeran showed that, among 33 healthy adult participants, antibodies elicited by the vaccine persisted through 6 months after the second dose. Antibody decay was estimated using two approaches and was consistent with of convalescent patients with COVID-19 through 8 months after symptom onset^[147]^[178]^[175]^[174].

Preclinical studies:

Preclinical results from a mice viral challenge study showed prevention of viral replication in the lungs of animals challenged with SARS-CoV-2, following vaccination with mRNA 1273. Protective neutralising titres seen in this model displayed consistency with those seen at the 25 µg and 100 µg dose levels in volunteers, in a phase I trial^[175].

In non-human primates, a two dose vaccination schedule of mRNA 1273 induced potent immune response and protection against the SARS-CoV-2 infection in the upper and lower airways, without causing vaccine associated enhanced respiratory disease. The geometric mean titer (GMT), as measured in a pseudovirus neutralization assay, was 103 at the 10µg dose, similar to a previously reported GMT of 109 for a panel of convalescent sera, and lower than the GMT of 231 for humans at the 100µg dose. Higher doses of 100µg increased the GMT to 1 862, with a further increase in neutralizing antibody titers. Significant increases in T cell responses, including Th1 CD4 T cells, was observed following vaccination. Following a viral challenge with SARS-CoV-2, mRNA 1273 protected against lung inflammation, at the 10µg and 100µg doses, with both doses also providing protection against viral replication in the lungs, and the 100µg dose also protecting against viral replication in the nose. Detectable viral replication was observed in six of eight placebo treated animals at Day 2, versus no animal (out of eight) in the 100µg cohort^[200].

Preclinical results indicate that mRNA 1273 induced neutralizing antibodies in mice when administered as two intramuscular injections of a 1 µg (mcg) dose three weeks apart. Administration of injections of the 1-mcg dose and later challenging with SARS-CoV-2 virus, either 5 or 13 weeks after the second injection, protected the vaccinated mice from viral replication in the lungs and nose. Single dose of 1 µg or 10 µg of mRNA-1273 also protected the vaccinated mice against viral replication in the lung, upon challenge after 7 weeks of vaccination. mRNA 1273 induced robust CD8 T-cells response in mice, but not vaccine-associated enhanced respiratory disease (VAERD). sub-protective doses of mRNA 1273 and then challenged the mice with SARS-CoV-2. Sub-protective doses of mRNA-1273 in mice showed no evidence of enhanced lung pathology or excessive mucus production, indicating that the vaccine did not cause VAERD^[182].

In in vitro studies conducted in the B.1.1.7 variant, neutralising antibody titers remained high and were generally consistent with neutralising titers relative to prior variants. There was no significant impact on neutralisation from either the full set of mutations found in the B.1.1.7 variant or from specific key mutations of concern. It was observed that the sera from the phase I participants and NHPs immunised with the vaccine were able to neutralise the B.1.1.7 variant to the same level as prior variants. In the studies conducted in B.1.351 variant, the vaccine produced neutralising antibody titers that remained above the neutralising titers that were shown to protect NHPs against wildtype viral challenge. Pseudovirus neutralising antibody titers were approximately 6-fold lower relative to prior variants^[181].

Expected Date	Event Type	Description	Updated
01 Aug 2022	Regulatory Status	Moderna plans to transfer the marketing authorization of elasomeran (Spikevax™) from Takeda to Moderna in Japan ^[125]	30 Jun 2022
18 Mar 2022	Trial Update	Merck Sharp & Dohme plans a phase III trial for Human papillomavirus infections and COVID-2019 infections (Prevention, In adolescents) in March 2022 (NCT05119855)	05 Jan 2024
28 Feb 2022	Trial Update	Murdoch Childrens Research Institute, PATH, Coalition for Epidemic Preparedness Innovations and he Peter Doherty Institute for Infection and Immunity plans a phase III trial in COVID-2019 infections (Prevention, In adults, In the elderly) in Australia in February 2022 (IM) (NCT05228730)	10 Feb 2022
31 Dec 2021	Regulatory Status	Takeda expects approval of mRNA 1273 in Japan in FY2021 ^[128]	26 May 2021
14 Oct 2021	Regulatory Status	The US FDA committee plan to discuss an amendment to the emergency use authorisation for mRNA 1273 vaccine for the administration of a booster dose (In adults) (9336832)	25 Oct 2021
31 Aug 2021	Trial Update	National Institute of Allergy and Infectious Diseases (NIAID) plans a phase II trial in COVID-2019 infections (Prevention) in USA (IM) (NCT04969263)	14 Feb 2022
31 Aug 2021	Regulatory Status	Moderna Therapeutics announces intention to complete the rolling BLA submission for COVID-2019 infections (Prevention)in USA in August 2021 ^[72]	27 Aug 2021
31 Jul 2021	Regulatory Status	Moderna Therapeutics intends to launch mRNA 1273 outside of the USA in early second half of 2021	27 May 2021
30 Jun 2021	Regulatory Status	Takeda intends to start distribution of mRNA 1273 in Japan by first half of 2021 ^[151]	03 Aug 2021
31 May 2021	Regulatory Status	Moderna Therapeutics plans to file BLA with US FDA for COVID-19 infections in May 2021 (9292023) (9311798) ^[160]	03 Aug 2021
01 May 2021	Regulatory Status	Moderna Therapeutics announces intention to launch mRNA 1273 in South Korea for COVID-2019 infections in May 2021 ^[183]	04 Jan 2021
31 Mar 2021	Regulatory Status	Moderna Therapeutics announces intention to launch mRNA 1273 in United Kingdom for COVID-2019 infections (Prevention) in March 2021 ^[23]	25 Nov 2020
01 Mar 2021	Trial Update	National Institute of Allergy and Infectious Diseases (NIAID) plans a phase II SARS trial for COVID-2019 infections in USA (IM) (NCT04761822) (700334022)	29 Apr 2021
12 Jan 2021	Regulatory Status	Moderna Therapeutics expects EMA’s Committee for Medicinal Products for Human Use will conclude its assessment of safety and effectiveness of mRNA 1273 during an extraordinary meeting, in January 2021, which is based on the context of the rolling review and may be subject to change as evaluation proceeds ^[87]	07 Jan 2021
06 Jan 2021	Regulatory Status	The CHMP schedule an extraordinary meeting to conclude assessment on MAA of mRNA-1273 COVID-2019 vaccine ^[86]	07 Jan 2021
31 Dec 2020	Regulatory Status	Moderna announces intention to submit emergency use authorization to US FDA for COVID-2019 infections by end of 2020 ^[172]	16 Dec 2020
17 Dec 2020	Regulatory Status	The US FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) schedules a meeting to review the safety and efficacy data package for mRNA-1273 for December 2020 ^[118]	21 Dec 2020
27 Jul 2020	Trial Update	Moderna Therapeutics plans a phase III trial for COVID-2019 infections (Prevention) in USA (IM) in July 2020 (NCT04470427) (700320962) ^[175]	29 Jul 2020
30 Jun 2020	Trial Update	Moderna Therapeutics plans a phase II trial for COVID-2019 infections (Prevention) in USA in the second quarter of 2020 ^[62]	01 Jun 2020
30 Jun 2020	Trial Update	Moderna therapeutics plans to files an IND application with the US FDA for COVID-2019 infections in the second quarter of 2020 ^[62]	29 Apr 2020
19 Mar 2020	Trial Update	National Institute of Allergy and Infectious Diseases (NIAID) plans a phase I trial for COVID-2019 infections (Prevention) in USA (IM, Injection) (NCT04283461) (700318512) ^[65]	12 Mar 2020

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