Candidate: Moderna COVID-19 Vaccine (mRNA-1273)

Category: RNAVAX

Type: Novel lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding for a prefusion stabilized form of the Spike (S) protein.

2021 Status: The Com-Cov trial led by the U.K.’s National Immunisation Schedule Evaluation Consortium (NISEC) and the Oxford Vaccine Group (University of Oxford) was expanded April 14 to include Moderna’s COVID-19 vaccine mRNA-1273 and Novavax’s NVX-CoV2373.

The trial was launched in February to assess the effect of combining doses of various vaccines. Participants initially received first doses of either AstraZeneca’s AZD1222 or Pfizer/BioNTech’s BNT162b2 (COMIRNATY® in Europe, with the vaccine switched for the second dose. Following the change, participants were to receive second doses of either the same vaccine as the first dose, AZD1222 or NVX-CoV2373.

Com-Cov’s six new arms each involve 175 people, bringing to 1,050 the total number of participants.

Moderna on April 13 announced an update on its Phase III COVE trial (NCT04470427), stating that mRNA-1273 showed “greater than 90%” against over 900 cases of COVID-19, and “greater than 95%” against over 100 severe cases of COVID-19, with a median follow-up of approximately 6 months after the second dose.

Moderna also announced preclinical results from a study of the company’s COVID-19 variant-specific vaccine candidates, mRNA-1273.351, designed to protect against the South African B.1.351 variant, and mRNA-1273.211, which combines mRNA-1273.351 with mRNA-1273. Both vaccines increased neutralizing titers against SARS-CoV-2 variants of concern.

In addition, Moderna said that through April 12, 2021, Moderna cumulatively delivered approximately 132 million doses globally, including approximately 117 million doses to the U.S. government.

Rollout in U.K.—The first doses of Moderna COVID-19 Vaccine were administered April 7 in the U.K., whose government has ordered 17 million doses of the two-dose vaccine. Moderna’s vaccine is the third approved for use in the country.

Six-Month Antibody Persistence—Data published April 7 in The New England Journal of Medicine from a Phase I trial showed antibody persistence through six months following the second dose of Moderna’s COVID-19 vaccine.

Thirty-three healthy adult participants in the NIH-led Phase I study were analyzed six months after receiving their second 100 μg dose (day 209). Persistence was detected by three distinct serologic assays. Antibody decay was estimated using two approaches and was consistent with published observations of convalescent patients with COVID-19 through eight months after symptom onset. Studies monitoring immune responses beyond six months are ongoing, Moderna said.

Moderna and Catalent said April 6 they agreed to expand their strategic collaboration by dedicating a new high-speed vial filling line for the manufacture of the Moderna COVID-19 Vaccine at Catalent’s biologics facility in Bloomington, IN. Under the expanded agreement, Catalent agreed to dedicate the filling line through June 2023 for manufacturing the COVID-19 vaccine and potentially additional Moderna pipeline programs. Catalent also agreed to provide inspection, labeling, cartoning, and final packaging for these programs.

The $50 million filling line was first announced in September 2020 as a third high-speed vial filling line. Catalent accelerated the overall project from a typical 18-month timeframe to approximately 10 months–including construction, procurement, installation, and CGMP qualification of the line, set to be completed in April 2021.

The European Medicines Agency (EMA) said March 26 that its Committee for Medicinal Products for Human Use recommended approval of a new manufacturing site for producing active substance and finished product intermediates for Moderna’s COVID-19 vaccine. The addition of the new manufacturing lines at the Lonza facility, located in Visp, Switzerland, together with other changes to the manufacturing processes that were greenlighted by the Committee are intended to scale-up production capacity and increase supply of the vaccine for the EU market, the EMA said.

Moderna on March 22 said the Philippines secured 7 million additional doses of COVID-19 Vaccine Moderna, as the vaccine is called outside the U.S., through a new supply agreement that brings its confirmed order commitment up to 20 million doses. The initial 13 million doses were secured on March 6. Under the agreement, whose value was not disclosed, deliveries are set to begin in mid-2021. The vaccine is not currently approved for use in the Philippines; Moderna said it will work with regulators to pursue approvals before distribution.

On March 5, Moderna said its development partner for Japan, Takeda Pharmaceutical, submitted a New Drug Application to Japan’s Ministry of Health, Labour and Welfare to import and distribute within the country Moderna’s vaccine candidate against COVID-19, known in Japan as mRNA-1273 or TAK-919. The companies previously said Takeda will import and distribute 50 million doses of the vaccine starting in the first half of 2021, pending licensure in Japan.

Takeda is conducting a placebo-controlled Phase I/II trial (NCT04677660) designed to evaluate the safety and immunogenicity of two vaccinations of mRNA-1273 at the 100 μg dose level given 28 days apart in 200 participants aged 20 years and above in Japan. Participants will be followed through 12 months after the second vaccination. Takeda completed enrollment for the study in February. Once available, the Phase I/II study results will be submitted to the Japan Pharmaceuticals and Medical Devices Agency (PMDA).

Moderna and IBM on March 4 announced they planned to explore technologies—including artificial intelligence, blockchain, and hybrid cloud—that could help support smarter COVID-19 vaccine management. The companies said their goal was to identify ways technology can be used to help accelerate secure, information sharing between governments, healthcare providers, life science organizations, and individuals. Moderna and IBM expressed their intent to seek to improve confidence in vaccine programs and increase rates of vaccination, thereby reducing community spread.

Moderna said February 24 it making new capital investments of undisclosed value to increase capacity at its owned and partnered manufacturing facilities, which it expects will increase global 2022 capacity to approximately 1.4 billion doses of its COVID-19 vaccine, assuming a 100 μg dose. The company plans to study a dose range of 50 μg and lower for variant-based boosters and an additional booster of mRNA-1273, with 2022 output to depend on the dose of the booster. If the effective dose for a booster is 50 μg, then the 2022 supply could be significantly higher than 1.4 billion doses.

Should Moderna dedicate its entire 2022 capacity to a 50 μg boost, the company could supply up to 2.8 billion doses in fiscal year 2022. The maximum output will be determined as the Company more fully develops its booster product strategy. Moderna estimated that up to 12 months may be necessary before the additional production is available, based on a six- to nine-month timeframe to add capacity and an additional timeframe to permit regulatory validation and ramp-up.

Also on February 24, Moderna said it completed manufacturing of clinical trial material for its variant-specific vaccine candidate, mRNA-1273.351, against the South African SARS-CoV-2 variant (B.1.351), and has shipped doses to the NIH for a Phase I clinical trial to be led and funded by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

Moderna said it plans to evaluate three approaches to boosting, including:

  • mRNA-1273.351, based on B.1.351, at the 50 µg dose level and lower.
  • A multivalent booster candidate, mRNA-1273.211, which combines Moderna’s authorized vaccine and mRNA-1273.351 in a single vaccine at the 50 µg dose level and lower.
  • A third dose of the Moderna COVID-19 Vaccine, as a booster at the 50 µg dose level. The company said it has already begun dosing this cohort with the booster.

Moderna plans to evaluate mRNA-1273.351 and mRNA-1273.211 as a primary vaccination series for those who are seronegative, in a two-dose series at the 100 µg dose level and lower; and also plans to evaluate immunogenicity and safety in participants who have not received a COVID-19 vaccine, as well as participants in clinical studies who previously received mRNA-1273.

The European Union is in talks with Moderna to nearly double its number of doses purchased from the company, Reuters reported, citing two unnamed “senior EU officials.” According to the report, the EU would add 150 million additional doses to the 160 million that have already been bought and began being distributed in January 2021. Moderna declined comment while the EU had not responded to the report.

Moderna said February 12 that the Government of Canada increased by 4 million doses its confirmed order commitment of the COVID-19 Vaccine Moderna, bringing its confirmed order commitment to 44 million doses. Health Canada authorized the vaccine under an Interim Order in December 2020 for the immunization of people 18 years of age and older.

The FDA has told Moderna it can ship up to 40% more coronavirus vaccine—up to 14 doses instead of 10—into each of its vials, The New York Times reported on February 12, citing unnamed sources. Officials also want Moderna to submit more data showing that the change would not compromise vaccine quality.

Moderna’s production lines could conceivably be retooled to accommodate the change in fewer than 10 weeks, or before the end of April, the Times added.

A day earlier, Moderna said the U.S. government had purchased an additional 100 million doses of the Moderna COVID-19 Vaccine, bringing its confirmed order commitment to 300 million doses. As of that date, Moderna said, it had supplied 41 million doses to the U.S. government. More than 22 million Americans having received the vaccine in the U.S., according to the U.S. Centers for Disease Control and Prevention’s online tracker COVID-19 Vaccinations in the United States.

Moderna added that it remained on track to deliver the first 100 million doses in the first quarter of 2021 and the second order of 100 million doses in the second quarter of 2021.

Switzerland’s Federal Government has increased its confirmed order commitment from 7.5 million to 13.5 million doses of the COVID-19 Vaccine Moderna in Switzerland, Moderna said February 3. The additional 6 million doses will be delivered beginning in the summer of 2021, with an option to receive doses in the first half of 2022 as Moderna explores potential vaccine boosters to address emerging variants, the company added.

Moderna has asked the FDA for approval to fill its vials of the Moderna COVID-19 Vaccine (mRNA-1273) with 15 doses; the vials are now cleared to hold 10, CNBC reported January 29, citing an unnamed source. The FDA declined comment while Moderna had not responded to queries from the news outlet.

Moderna confirmed January 27 that it is in talks with the U.S. government to purchase an additional 100 million doses of mRNA-1273 for delivery in the third quarter of 2021. The planned purchase would bring the government’s confirmed order commitment to 300 million doses.

A day earlier, Moderna reported that that 30.4 million doses of its COVID-19 vaccine had been supplied to the U.S. government to date, and that the company remained on track deliver 100 million doses to the U.S. by the end of March.

During a presentation at the virtual J.P. Morgan 39th Healthcare Conference on January 11, Moderna said it planned in July to start a trial assessing the safety and immunogenicity in adults of a booster shot of mRNA-1273 to be given a year after the first of the vaccine’s two doses are administered.

“Our expectation is that the vaccination should last you at least a year. To the degree that you need a booster shot, we’ll make a data-based recommendation, and that will require us getting the data,” Tal Zaks, MD, PhD, Moderna’s chief medical officer, told attendees.

U.K. APPROVES VACCINE—The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) on January 8 granted regulatory approval to mRNA-1273, following a positive recommendation by the independent Commission on Human Medicines.

EUROPE GRANTS CONDITIONAL AUTHORIZATION—The European Commission on January 6 granted conditional marketing authorization for mRNA-1273 to prevent COVID-19 in people 18 years of age and older. mRNA-1273 is the second COVID-19 vaccine to win a conditional nod from the European Union’s executive commission, a day after the European Medicines Agency recommended the action.

2020 Status: Researchers from Moderna and clinical partners published a study December 30 in The New England Journal of Medicine detailing data from the Phase III, 30,420-patient COVE trial (NCT04470427). The data echoed earlier announcements by Moderna by showing vaccine efficacy of 94.1%, and disclosing that 196 patients—185 in the placebo group, 11 in the mRNA-1273 group—showed symptomatic COVID-19. The 185 placebo patients with the virus included 30 with severe COVID-19; no severely ill patients were in the vaccine group.

“Overall, the safety of the mRNA-1273 vaccine regimen and platform is reassuring; no unexpected patterns of concern were identified,” the researchers wrote. They added that the trial was ongoing, with a two-year follow-up duration planned.

The U.S. Department of Defense disclosed December 28 that Moderna secured an approximately $1.967 billion contract from U.S. Army Contracting Command toward the purchase of an additional 100 million doses of mRNA-1273, after the U.S. government agreed to exercise its first option under its agreement with the company. That agreement calls for the purchase of 200 million doses, with options allowing for an additional up to 300 million doses to be purchased. The vaccine will be produced in Cambridge, Massachusetts, with an estimated completion date of June 30, 2021.

Health Canada on December 23 authorized mRNA-1273 for the immunization of people 18 years of age and older. The authorization came under Health Canada’s Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19, and was based on a rolling review of data announced on October 12. The rolling review includes data from Moderna’s 30,000-plus patient Phase III COVE trial (NCT04470427).

FDA AUTHORIZES EMERGENCY USE—The FDA on December 18 granted Moderna an emergency use authorization (EUA) for mRNA-1273 for the prevention of COVID-19 in individuals 18 years of age and older. The company quickly began distributing the two-dose vaccine, with 5.9 million doses set to be shipped the following week.

Moderna repeated earlier statements that it plans to produce 20 million doses of mRNA-1273 by the end of this month, and between 100 million and 125 million doses during the first quarter, of which between 85 million to 100 million doses will be available in the United States. The company has said previously that it plans to produce between 500 million and 1 billion doses in 2021.

“We remain positive on the technology platform and strong outlook for mRNA-1273, and believe the co[mpany] is likely to hit their 500M dose base guidance in 2021 or likely exceed this,” Michael J. Yee, equity analyst with Jefferies, said Thursday in a research note.

Yee projected that 500 million doses “equates to around $10B in sales in our 2021 model, which is above consensus $8B+, though buyside expectation is $10B,” Yee added.

The FDA set the stage for granting Moderna an EUA starting on Tuesday, when staff scientists issued a positive assessment of mRNA-1273 in a Briefing Document on the vaccine that was prepared for the agency’s Vaccines and Related Biologic Products Advisory Committee (VRBPAC). In the document, Moderna shared previously announced data from the COVE trial showing mRNA-1273 to be 94.5% effective in an interim analysis based on 27,817 studied as of the data cutoff of November 7, and 94.1% effective in the trial’s final analysis.

The 21-member VRBPAC recommended agency approval of mRNA-1273 by a 20–0 vote with one abstention: Through its recommendation, the advisory committee concluded that the benefits of Moderna’s vaccine outweighed its risks for use in individuals 18 years of age and older, based on the totality of scientific evidence available.

Adolescents ages 12–17 will be the focus of a new clinical trial announced December 10 by Moderna.  “Our goal is to generate data in the spring of 2021 that will support the use of mRNA-1273 in adolescents in advance of the 2021 school year,” CEO Stéphane Bancel said in a statement.

Moderna’s Phase II/III TeenCove trial (NCT04649151) will assess the safety, reactogenicity, and immunogenicity of two doses of mRNA-1273 given 28 days apart. Moderna aims to enroll 3,000 participants, randomizing them to the two 100 μg doses or placebo. Participants will be followed through 12 months after the second vaccination in the trial, which the company is conducting with the Biomedical Advanced Research and Development Authority (BARDA).

Moderna said December 4 it agreed with Israel’s Ministry of Health to supply an additional 4 million doses of mRNA-1273, enabling the Israeli government to secure 6 million doses of the vaccine. The value of the agreement was not disclosed.

A day earlier, Moderna researchers published interim durability data in The New England Journal of Medicine from an NIH-led Phase I study (NCT04283461) showing that 34 of the trial’s participants who were treated with mRNA-1273 (two injections of the 100 μg dose received 28 days apart) retained high levels of neutralizing antibodies through 119 days following first vaccination, and 90 days following their second vaccination. The results were consistent across all age cohorts (18–55, 56-70 and 71+), researchers added.

“mRNA-1273 produced high levels of binding and neutralizing antibodies that declined slightly over time, as expected, but they remained elevated in all participants three months after the booster vaccination,” Alicia T. Widge M.D. of Vaccine Research Center, NIAID, NIH, and colleagues reported. “These results show that despite a slight expected decline in titers of binding and neutralizing antibodies, mRNA-1273 has the potential to provide durable humoral immunity.”

Seeking FDA Emergency Use Authorization — Moderna said November 30 it will seek FDA emergency use authorization (EUA) and a European conditional approval of mRNA-1273, after confirming its efficacy with additional positive Phase III data. The company cited a primary efficacy analysis by the study’s independent, NIH-appointed Data Safety Monitoring Board (DSMB) of data from the Phase III COVE trial, an analysis based on 196 cases of COVID-19. Of those cases, 185 were seen in patients randomized to placebo, and the other 11 in patients randomized to mRNA-1273.

The 196 COVID-19 cases included 33 adults ages 65+, and 42 participants identifying as being from diverse communities—including 29 Hispanic or LatinX, six Black or African Americans, four Asian Americans, and three multiracial participants. Moderna said the efficacy of mRNA-1273 was consistent across age, race and ethnicity, and gender demographics.

A day earlier, Moderna agreed to supply the UK government an additional 2 million doses of mRNA-1273 beginning in March 2021, through an amendment to an earlier supply agreement whose value was not disclosed. The amendment brings to 7 million the number of mRNA-1273 doses secured by the UK government.

The European Commission on November 25 approved an agreement to secure 80 million doses of mRNA-1273, with an option to increase its purchase of the vaccine to a total of up to 160 million doses. The price was not disclosed. Delivery of the vaccine could begin as early as the first quarter 2021 if it is approved for use by the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP), which started a rolling review of mRNA-1273 on November 17.

Upon regulatory approvals, Moderna said, it expects to begin shipping mRNA-1273 to the European Union beginning in December 2020. The EU told Reuters it wanted to come to terms with Moderna for a vaccine price of below $25 a dose, after CEO Stéphane Bancel told German weekly newspaper Welt am Sonntag that Moderna will charge governments between $25 and $37 per dose for mRNA-1273.

Moderna said November 16 that its COVID-19 vaccine candidate mRNA-1273 passed its most important test, the 30,000+ patient Phase III COVE trial (NCT04470427), by showing itself to be 94.5% effective in preventing COVID-19—an outcome hailed by CEO Stéphane Bancel as a “game changer.”

As a result, Moderna said, it will seek an emergency use authorization (EUA) from the FDA “in the coming weeks.” That EUA, Moderna said, is expected to be supported by final safety and efficacy data from the trial, with a median duration of at least two months.

The COVE trial’s independent, NIH-appointed Data Safety Monitoring Board (DSMB) has carried out a first interim analysis showing just five cases of COVID-19 in the mRNA-1273 group, compared with 90 seen in the placebo group. The study’s primary endpoint is significantly fewer COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine compared with patients randomized to placebo.

“This is a pivotal moment in the development of our COVID-19 vaccine candidate,” Bancel said in a statement. Appearing on CNBC the morning of the company’s announcement, Bancel said of the efficacy rate, “that’s a game changer, I believe,” given surveys in which respondents have expressed reluctance to take a COVID-19 vaccine.

Also positive on Moderna’s early Phase III data was Jefferies analyst Michael Yee: “These results are very strong and suggest mRNA-based technologies can deliver so far for COVID-19 protection.”

Moderna said November 11 it has completed case accrual for the first interim analysis of the Phase III COVE trial (NCT04470427), being conducted by the company with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA).

The Phase III COVE trial is designed to evaluate the safety of mRNA-1273 in 30,000 adult volunteers who do not have COVID-19, but are at the highest risk of severe COVID-19 disease. The company said it expects the trial’s first interim analysis will include “substantially more” than the originally planned 53 cases for the analysis. Data on these cases is being prepared for submission to the independent Data Safety Monitoring Board (DSMB) for analysis and recommendation.

Takeda Pharmaceutical agreed to import and distribute 50 million doses of mRNA-1273 beginning in the first half of 2021 pending licensure in Japan, under a three-way license agreement between among Takeda, Moderna, and Japan’s Ministry of Health Labour and Welfare (MHLW) announced by Takeda on October 29.

Two days earlier, Moderna said October 26 it signed a supply agreement of undisclosed value with Qatar’s Ministry of Public Health for mRNA-1273. Neither Moderna nor Abdullatif al-Khal, co-chair of Qatar’s National Pandemic Preparedness Committee and head of infectious diseases at Hamad Medical, disclosed how many doses Moderna will supply the country.

Four days earlier, Moderna completed enrollment of 30,000 participants for the Phase III COVE trial (NCT04470427). Moderna said COVE had enrolled more than 7,000 Americans over age 65, and more than 5,000 Americans who are under age 65 but have high-risk chronic diseases that put them at increased risk of severe COVID-19, such as diabetes, severe obesity and cardiac disease. Of the total participants in COVE, 42% are in high-risk groups.

More than 11,000 COVE participants from communities of color, representing 37% of the study population and, according to Moderna, similar to the diversity of the U.S. at large. These include more than 6,000 participants who identified as Hispanic or LatinX, and more than 3,000 participants who identified as Black or African American.

The protocol for the COVE trial has been posted online. Moderna said it will determine whether to submit a dossier to FDA requesting Emergency Use Authorization (EUA) after assessing whether the potential benefit of the vaccine outweighed potential risks once the two months of median safety follow-up have accrued.

On October 14, Moderna received written confirmation from the European Medicine Agency (EMA) that mRNA-1273 is eligible for submission of a European Union Marketing Authorization Application under the Agency’s centralized procedure. The submission followed positive results from a preclinical viral challenge study and two positive interim analyses of data from a Phase I open-label study (NCT04283461) assessing mRNA-1273 in healthy adults ages 18-55 years, published in July in The New England Journal of Medicine (NEJM); and in older adults ages 56-70 and 71+, published in September in NEJM.

Moderna President Stephen Hoge, MD, told The Wall Street Journal the company will not enforce at least seven U.S. patents related to mRNA-1273, including one for the invention of a vaccine that applies a gene-based technology to protect against the family of coronaviruses that includes COVID-19. “We’re quite studiously not asserting infringement,” Hoge said. “We’re not interested in using that IP to decrease the number of vaccines available in a pandemic.”

Speaking September 30 at the Financial Times U.S. Pharma and Biotech Summit 2020, CEO Stephane Bancel said Moderna would not be ready to apply for a U.S. EUA for mRNA-1273 before November 25—three weeks after Election Day, “assuming that the safety data is good, ie a vaccine is deemed to be safe.” The company cannot file for a limited EUA before November 1, because it agreed with the FDA that at least half of trial participants must undergo two months of screening after their final injection with the vaccine. Bancel added that Moderna does not expect approval to distribute mRNA-1273 to the whole U.S. population until March 2021 at the earliest.

A day earlier, researchers from Moderna and clinical partners published a second interim analysis of data in The New England Journal of Medicine (NEJM) from the open-label Phase I trial (NCT04283461) of its mRNA-1273 that is being conducted by NIAID. The analysis assessed a two-dose vaccination with mRNA-1273, with the doses given 28 days apart in 40 healthy adult participants across two dose levels (25 and 100 µg) in two age cohorts (ages 56–70 and ages 71) with the results reported through Day 57, one month after the second dose.

At both the 25 µg and 100 µg dose levels, mRNA-1273 induced dose-dependent binding antibody responses after two vaccinations that reached the upper quartile of the distribution of convalescent sera. At Day 57, geometric mean titers (GMT) exceeded the median of those seen in convalescent sera from 41 individuals with confirmed COVID-19 diagnosis, Moderna said.

One of Moderna’s manufacturing partners, Lonza, expects to begin delivering doses of mRNA-1273 starting in December, Torsten Schmidt, head of Lonza’s facility in Visp, Switzerland, told Reuters on September 29. As of that date, the three production lines that will manufacture the doses in Visp were 50% completed. Once operational, they will produce doses using vaccine ingredients made at Lonza’s Portsmouth, NH, facility.

The ingredients include a synthetic version of messenger RNA (mRNA), genetic material, which is packed inside tiny fat droplets called nanolipids, to instruct human cells to make a non-replicating form of the coronavirus’s spike protein and trigger an immune response in the body. The ingredients will be frozen at -70 degrees Celsius (-94 degrees Fahrenheit), then shipped from Visp to another European manufacturing partner of Moderna, Spain’s Laboratorios Farmacéuticos Rovi, for fill and finish.

Moderna disclosed in a September 18 regulatory filing that it anticipates producing approximately 20 million doses of mRNA-1273 by the end of 2020, and restated earlier estimates that it expects to manufacture “in the range of between 500 million and 1 billion doses” in 2021.

Also that day, Moderna said it established its first regional hub and commercial organization outside of North America in Switzerland. The company’s activities in Sewitzerland will be overseen by Dan Staner, who was appointed Vice President and General Manager, Switzerland, effective that day. Staner will build a team to cover functions for the Swiss market that include medical, regulatory, pricing, reimbursement, market access, government affairs, and commercial operations, Moderna said. Staner will also work closely with Nicolas Chornet, who the company recently named SVP International Manufacturing, Europe, based in Basel.

Switzerland has been a focus of Moderna activity in recent months. The country’s federal government has agreed to procure 4.5 million vaccine doses of mRNA-1273, while Moderna partners with Basel-based Lonza on larger scale global manufacturing of mRNA-1273 and said it will do so with future Moderna products.

On August 28, Moderna said it was in talks with Japan’s government to supply a potential 40 million or more doses of mRNA-1273. The vaccine would be distributed within Japan in the first half of 2021 via a partner company, Takeda Pharmaceutical, upon regulatory approval.

Four days earlier, Moderna confirmed that it was in advanced talks with the European Commission to supply 80 million doses of mRNA-1273. The potential purchase agreement provides for an option for EU Member States to purchase an additional 80 million doses for a total of up to 160 million doses.

The company said it is scaling up global manufacturing to be able to deliver approximately 500 million doses per year—and possibly up to 1 billion doses per year beginning in 2021. In Europe, Moderna’s strategic manufacturing partners include Lonza and ROVI, which will oversee manufacturing and fill-finish outside of the U.S.

On August 20, NIAID Director Anthony S. Fauci, MD, said on CNN that he wanted COVE and other Phase III trials for COVID-19 vaccine candidates to enroll minorities at levels that are at least double their percentages in the population.

The COVE trial’s primary endpoint is the prevention of symptomatic COVID-19 disease. Key secondary endpoints include prevention of severe COVID-19 disease, as defined by the need for hospitalization), and prevention of infection by SARS-CoV-2. Data will be reviewed by an independent Data Safety Monitoring Board (DSMB) chartered by NIH. Formal study efficacy analysis will be triggered at 151 cases, with two earlier, interim analyses after 53 and 106 cases

Moderna on August 11 joined the U.S. government in announcing that the company was awarded an additional up to $1.525 billion toward manufacturing and delivering 100 million doses of mRNA-1273. The new funding, combined with up to $955 million previously committed to Moderna, more than doubles Washington’s investment in the company to potentially up to $2.48 billion. The new funding includes an unspecified amount of incentive payments “for timely delivery of the product,” Moderna added. The company did say, however, that the U.S. government holds an option to purchase from it up to an additional 400 million doses of mRNA-1273.

Also on August 11, Moderna disclosed in its Form 10-Q quarterly regulatory filing that it “cannot be certain that we were the first to make the inventions claimed in our patents or pending patent applications, or that we were the first to file for patent protection of such inventions, including mRNA-1273,” since “third parties may have filed patent applications for technology covered by our pending patent applications without our being aware of those applications, and our patent applications may not have priority over those applications,” In addition, “publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all.”

The disclosure—which had not been included in earlier filings—followed a report by Axios and Public Citizen that the NIH may hold joint ownership claims to the vaccine, had filed a patent application to that effect, and had maintained that “mRNA coronavirus vaccine candidates [are] developed and jointly owned” by NIH and Moderna.

On August 5, Moderna CEO Stéphane Bancel told analysts on the quarterly conference call that the company will charge some “small-order” customers seeking “in the millions” of doses between $32 and $37 per dose for mRNA-1273, adding that Moderna is in talks with some governments worldwide for larger-volume agreements at lower per-dose prices: “We are working with governments around the world and others to ensure a vaccine is accessible regardless of ability to pay.” Pfizer and BioNTech, by comparison, agreed to a $19.50 per-dose price with the U.S. government.

Moderna disclosed in its second-quarter results that it received approximately $400 million of customer deposits as of July 31, 2020 for potential supply of mRNA-1273.

Also on August 5, researchers from Moderna, NIAID, and collaboration partners published a preclinical study in Nature showing that mRNA-1273 protected mice from infection with SARS-CoV-2. mRNA-1273 induced neutralizing antibodies in mice when given as two intramuscular injections of a 1-microgram (mcg) dose three weeks apart. Mice given two injections of the 1-mcg dose and later challenged with SARS-CoV-2 virus either 5 or 13 weeks after the second injection were protected from viral replication in the lungs and nose.

mRNA-1273 also induced robust CD8 T-cell responses in mice—but did not induce the type of cellular immune response linked to vaccine-associated enhanced respiratory disease (VAERD). In addition, mice challenged 7 weeks after only a single dose of 1 mcg or 10 mcg of mRNA-1273 were also protected against viral replication in the lung.

The investigators also vaccinated mice with sub-protective doses of mRNA-1273, then challenged the mice with SARS-CoV-2. The mice showed no evidence of enhanced lung pathology or excessive mucus production, indicating the vaccine did not cause enhanced disease, the researchers reported.

Wang Wenbin, a spokesman for China’s foreign ministry, on July 31 denied a Reuters report that hackers linked to the Chinese government attempted to steal data from Moderna earlier this year—a report Reuters attributed to “a U.S. security official tracking Chinese hacking” speaking on condition of anonymity.

The report and denial came a week after the U.S. Justice Department made public its indictment of two Chinese nationals on charges of spying on the U.S. that entailed three unnamed U.S.-based targets involved in medical research to fight the novel coronavirus. Moderna confirmed to Reuters that it was in contact with the FBI and informed of the suspected “information reconnaissance activities” by the hacking group.

“Moderna remains highly vigilant to potential cybersecurity threats, maintaining an internal team, external support services and good working relationships with outside authorities to continuously assess threats and protect our valuable information,” the company stated July 31.

Three days earlier, researchers for Moderna and NIAID published a study in The New England Journal of Medicine (NEJM)  reporting that two doses of mRNA-1273 induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2.

Three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. The researchers also noted that macaques receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19.

On July 27, Moderna and NIAID launched the approximately 30,000-patient Phase III COVE trial  of mRNA-1273, a study being funded among late-stage clinical activity for which the company has won an additional up-to-$472 million from BARDA.

The additional funding nearly doubles the original up-to-$483 million commitment made by BARDA to Moderna in April toward supporting development and manufacturing of mRNA-1273 through FDA licensure, bringing the agency’s funding to a potential of approximately $955 million. Moderna said the extra funding followed the company decision to expand the patient population of the Phase III study, following talks with the FDA and officials with Operation Warp Speed, the federal effort through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.

Phase III trial participants will receive two intramuscular injections approximately 28 days apart, and will be randomly assigned 1:1 to receive either two 100 µg injections of mRNA-1273 or two shots of a saline placebo. Moderna disclosed plans for the Phase III trial in mid-July on the same day that researchers from NIAID, Moderna, and their clinical research partners reported that mRNA-1273 induced rapid and strong immune responses against SARS-CoV-2, in an interim analysis of results from their Phase I study (NCT04283461).

“These safety and immunogenicity findings support advancement of the mRNA-1273 vaccine to later-stage clinical trials,” the researchers concluded in “An mRNA Vaccine against SARS-CoV-2 — Preliminary Report,” published in The New England Journal of Medicine (NEJM).

At the 100 µg dose, they reported, the geometric mean titers seen among patients were 2.1-fold higher than those seen in convalescent sera obtained from 38 individuals with confirmed COVID-19 diagnoses. Also at 100 µg, the geometric mean titer levels were 4.1-fold above those seen in reference convalescent sera.

Moderna said via Twitter on July 8 that it completed enrollment of its Phase II trial of mRNA-1273 (NCT04405076). The study is designed to evaluate the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273, given 28 days apart. Moderna enrolled 600 healthy participants across two cohorts: 300 adults ages 18-55 years, and 300 ages 55 years and up. Participants are assigned to placebo, a 50 μg or a 100 μg dose at both vaccinations, and will be followed through 12 months after the second vaccination.

The Phase II trial does not include a 250 μg dosage, Moderna has said, since the dosages under study showed neutralizing antibody titers at or above convalescent sera and were generally well tolerated in the company’s Phase I trial.

Six days earlier, Moderna said via Twitter on July 2 that its planned 30,000-patient Phase III trial of mRNA-1273 is still expected to begin in July, “and we expect to be the first to start a Phase III trial,” despite changes to the trial’s protocol following talks with the NIH that pushed back the start from an expected July 9 launch.

Also in July, The Wall Street Journal reported CEO Stéphane Bancel’s projection that mRNA-1273 could be available for limited use as soon as this fall in a profile of the company that recounted its meteoric rise and included a description of him as being “very rigorous, and he’s very demanding at the same time.”

World Health Organization (WHO) Chief Scientist Soumya Swaminathan, MD, MBBS, told reporters June 26 she considered mRNA-1273 “not far behind” what she called “probably the leading candidate” among COVID-19 vaccine candidates in development worldwide, AZD1222 by AstraZeneca, University of Oxford and Vaccitech.

A day earlier, Moderna said it would partner for large-scale, commercial fill-finish manufacturing of mRNA-1273 with Catalent at its biologics facility in Bloomington, IN. Undert the agreement, whose value was not disclosed, Catalent agreed to provide packaging capacity and vial filling work under barrier isolator technology, as well as additional staffing required for 24×7 manufacturing operations at the site to support production of an initial 100 million doses of the vaccine candidate, which are intended to supply the U.S. market starting in the third quarter.

The companies are in talks to secure fill-finish capacity for continued production of hundreds of millions of additional doses, Moderna said, while Catalent also agreed to provide clinical supply services from its facilities in Philadelphia—including packaging and labeling, as well as storage and distribution to support Moderna’s Phase III clinical study for mRNA-1273.

“We know our platform. It works on MERS, Zika and CMV and so on. When you have the right sequence … you will get neutralizing antibodies,” CEO Bancel told CNBC, predicting mRNA-1273 had an 80% to 90% chance of success.

Earlier in June, BARDA said it was expanding its collaboration with Moderna in order to increase the domestic manufacturing capacity of mRNA-1273 by accelerating manufacturing scale-up. “While large investments in manufacturing and vaccine supplies before FDA approval presents a financial risk, continuing to make these investments is critical to shave months to years off the vaccine development timeline and meet the Administration’s directive to make vaccine available more rapidly,” BARDA stated.

mRNA-1273 was the first COVID-19 product to be shifted for advanced development from NIH to BARDA, which said expansion activities are expected to begin with delivering material for manufacturing “mid-year.” BARDA has partially supported the research and development of mRNA-1273 with federal funding under Contract no. 75A50120C00034.

On June 3, The New York Times reported that Moderna was among developers of five COVID-19 vaccines identified by President Donald Trump’s administration as most likely to produce a vaccine for the virus, citing unnamed “government officials.” According to the report, the five will receive additional government funding, assistance with clinical trials, and financial and logistical support for manufacturing. A formal announcement is expected in coming weeks.

In May, Moderna reported positive interim Phase I data showing that all 45 participants across the study’s three dose levels produced antibodies of the virus by day 15 following treatment, with eight of the participants in two of the dose levels reaching or exceeding neutralizing antibody titers generally seen in convalescent sera. The data disclosed by Moderna touched off a 911.95 (3.85%) surge of the Dow Jones Industrial Average.

NIAID led the Phase I trial (NCT04283461), an open-label, dose-ranging study in males and non-pregnant females, 18 to 55 years old. The 45-patient study is assessing the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 3 dosages in healthy adults.

All participants across all three dose levels seroconverted by day 15 after a single dose, Moderna said. At day 43, two weeks following the second dose, levels of binding antibodies for the 15 participants dosed at the 25 µg level were at levels seen in blood samples from people who have recovered from COVID-19. At day 43, 10 participants at the 100 µg level showed levels of binding antibodies that significantly exceeded the levels seen in convalescent sera.

Joshua Schimmer, a senior managing director on Evercore ISI’s biotech team, said in an investor note that mRNA-1273 may be “good enough” to be first among COVID-19 candidates to win FDA approval, but is unlikely to be better than other candidates that appeared likely to offer higher immunogenicity, fewer doses and less reactogenicity, according to Seeking Alpha.

The same day as the interim Phase I data release, Moderna announced plans to raise about $1.34 billion in gross proceeds through an underwritten public offering. Morgan Stanley is acting as sole book-running manager for the offering, from which the company said it intended to use proceeds toward working capital needs (raw materials, labor and capital equipment purchases) related to manufacturing mRNA-1273 for distribution in and outside the U.S. upon receiving approvals.

Moderna said any remaining proceeds will fund clinical development and drug discovery in existing and new therapeutic areas; further development of its mRNA technology platform; the creation of new modalities; or working capital and other general corporate purposes.

The public offering consisted of 17.6 million shares of common stock at a public offering price of $76.00 per share, before underwriting discounts and commissions. Moderna also granted the underwriters a 30-day option to purchase up to an additional 2.64 million shares of common stock at the public offering price, less underwriting discounts and commissions.

Earlier in May, Moderna received the FDA’s Fast Track designation for mRNA-1273, six days after the company received FDA clearance to begin a Phase II trial of mRNA-1273.

Cautioned Philipp Rosenbaum, PhD, Infectious Diseases Analyst at GlobalData. “mRNA-based vaccines have yet to be proven to work in humans, and the history of vaccine development shows that setbacks and roadblocks are almost certain.”

However, Anthony S. Fauci, MD, Director of the NIH’s National Institute for Allergy and Infectious Diseases, told National Geographic in an interview published May 4 that mRNA-1273 and University of Oxford-led vaccine candidate ChAdOx1 nCoV-19 have generated “rather substantial immune responses, particularly the mRNA vaccine. When we look at the immune response that you can induce with a modest dose—one that’s feasible to be translated into humans—and the amount of time it takes to get to that level of immunity, it is really quite impressive.”

Moderna accelerated its manufacturing capacity for mRNA-1273 and additional future products through a 10-year agreement with Lonza announced by the companies on May 1. The companies agreed to establish manufacturing suites at Lonza’s facilities in the U.S. and Switzerland for the production of mRNA-1273. Technology transfer is expected to begin in June, with the first batches of mRNA-1273 set to be manufactured at Lonza’s U.S. site in July. Moderna and Lonza said they intend to establish additional production suites across Lonza’s worldwide facilities, ultimately allowing for the manufacture of material equivalent to up to 1 billion doses of mRNA-1273 per year for use worldwide, based on the currently expected dose of 50 µg.

An unspecified portion of funding for establishing manufacturing operations at Lonza U.S. is covered by Moderna’s contract with BARDA, announced April 16. BARDA committed up to $483 million toward supporting development and manufacturing of mRNA-1273 through FDA licensure.

“Our ability to design our antigens in silico allows us to rapidly produce and test antigens and move vaccine development candidates quickly into the clinic,” Tal Zaks, MD, PhD, Moderna’s chief medical officer, told GEN in April. “Multiple mRNAs encoding for multiple viral proteins can be combined in a single vaccine, permitting production of complex multimeric antigens that are more difficult to achieve with traditional technologies.”

Also in April, Moderna also launched a partnership with Ginkgo Bioworks, which agreed to provide resources for potential optimizations to Moderna’s processes for generating some of the key raw materials used in the manufacturing of mRNA-1273 and other Moderna mRNA vaccines. Ginkgo agreed to contribute its microbial discovery, production, and fermentation infrastructure to companies and academic researchers working on coronavirus response. The company said it intended to provide $25 million in free work at its Boston-area location.

In March, Moderna said it was accelerating work on mRNA-1273 and was engaged in discussions for outside funding of such activities. CEO Stéphane Bancel detailed that acceleration during a Synbiobeta “town hall” presentation. He said a reason the SARS-CoV-2 vaccine development had been so fast was the work Moderna had done over the past two years in an existing collaboration with NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC) to develop a vaccine against MERS-CoV.

Moderna’s platform is based on injecting mRNA into cells to produce protein in human cells—an idea Bancel first viewed as crazy before realizing that making a human protein in a human cell is probably not going to be worse than making it in bacteria: “We don’t guess the biology—we use the biology of nature.”

Moderna was among developers of COVID-19 drug and vaccine candidates highlighted March 22 on CBS’ “60 Minutes.”

Also in March, Moderna disclosed in a regulatory filing that Bancel told Goldman Sachs representatives that while a commercially-available vaccine probably won’t be available for 12–18 months, a vaccine might be available in the fall of 2020 under emergency use authorization. He also said the Company was scaling up manufacturing capacity toward producing millions of doses per month, in the potential form of individual or multi-dose vials.

The first batch of mRNA-1273 was shipped in February to the VRC, which partnered with Moderna in designing the vaccine.

COVID-19: 300 Candidates and Counting

To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:

FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.

DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.

KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.

TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.

GEN has also tagged the most common treatment types: