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The Moderna COVID‑19 vaccine (pINN: elasomeran ), codenamed mRNA-1273 and sold under the brand name Spikevax, is a COVID-19 vaccine developed by Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA). It is authorized for use in people aged 12 years and older in some jurisdictions and for people 18 years and older in other jurisdictions to provide protection against COVID-19 which is caused by infection by the SARS-CoV-2 virus. It is designed to be administered as two 0.5 mL doses given by intramuscular injection at an interval of 29 days apart.

It is an RNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles.

The Moderna COVID‑19 vaccine is authorized for use at some level in 53 countries, including Canada, European Economic Area countries, Singapore, Philippines, South Korea, Thailand, the United Kingdom, and the United States.

On 15 March 2021, Moderna's second COVID‑19 vaccine (mRNA-1283) started phase I clinical trials.

Medical uses
The Moderna COVID‑19 vaccine is used to provide protection against infection by the SARS-CoV-2 virus in order to prevent COVID‑19.

The vaccine is given by intramuscular injection into the deltoid muscle. The initial course consists of two doses. The World Health Organization (WHO) recommends an interval of 28 days between doses. Data show that first dose efficacy persists for up to ten weeks. Therefore, to avoid deaths where supplies are limited, the WHO recommends delaying the second dose by up to 12 weeks to achieve high coverage of the first dose in high-priority groups.

Efficacy
Evidence of vaccine efficacy starts about two weeks after the first dose. High efficacy is achieved with full immunization, two weeks after the second dose, and was evaluated at 94.1%: at the end of the vaccine study that led to emergency authorization in the US, there were eleven cases of COVID‑19 in the vaccine group (out of 15,181 people) versus 185 cases in the placebo group (15,170 people). Moreover, there were zero cases of severe COVID‑19 in the vaccine group, versus eleven in the placebo group. This efficacy has been described as "astonishing" and "borderline historic" for a respiratory virus vaccine, and it is similar to the efficacy of the Pfizer–BioNTech COVID-19 vaccine.

Efficacy estimates were similar across age groups, sexes, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID‑19. Only individuals aged 18 or older were studied. Studies are underway to gauge efficacy and safety in children aged 0–11 (KidCOVE) and 12–17 (TeenCOVE).

A further study conducted by the US Centers for Disease Control and Prevention (CDC) between December 2020 and March 2021, on nearly 4thousand health care personnel, first responders, and other essential and frontline workers concluded that under real-world conditions, mRNA vaccine effectiveness of full immunization (14 days or more after second dose) was 90% against SARS-CoV-2 infections, regardless of symptoms, and vaccine effectiveness of partial immunization (14 days or more after first dose but before second dose) was 80%.

The duration of protection provided by the vaccine is unknown, and a two-year followup study is underway to determine the duration.

Specific populations
Limited data are available on the safety of the Moderna COVID‑19 vaccine for people who are pregnant. The initial study excluded pregnant women or discontinued them from vaccination upon a positive pregnancy test. Studies in animals found no safety concerns and clinical trials are underway to evaluate the safety and efficacy of COVID‑19 vaccines in pregnant people. Real-world observations through the CDC v-safe tracking program have not uncovered unusual numbers of adverse events or outcomes of interest. Based on the results of a preliminary study, the US CDC recommends that pregnant people get vaccinated with the COVID‑19 vaccine.

Adverse effects


The World Health Organization (WHO) stated that "the safety data supported a favorable safety profile" and that the vaccine's AE (adverse event) profile "did not suggest any specific safety concerns". The most common adverse events were pain at the injection site, fatigue, headache, myalgia (muscle pain), and arthralgia (joint pain).

The US Centers for Disease Control and Prevention (CDC) has reported anaphylaxis (a severe allergic reaction) in 2.5 cases per million doses administered and has recommended a 15-minute observation period after injection. Delayed cutaneous reactions at injection sites resulting in rash-like erythemas have also been observed in rare cases but are not considered serious or contraindications to subsequent vaccination.

On June 23, 2021, the US CDC confirmed that myocarditis or pericarditis occurs in about 13 of every 1 million young people, mostly male and over the age of 16, who received the Moderna or the Pfizer–BioNTech vaccine. Most affected individuals recover quickly with adequate treatment and rest.

Pharmacology
Moderna's technology uses a nucleoside-modified messenger RNA (modRNA) compound codenamed mRNA-1273. Once the compound is inside a human cell, the mRNA links up with the cell's endoplasmic reticulum. The mRNA-1273 is encoded to trigger the cell into making a specific protein using the cell's normal manufacturing process. The vaccine encodes a version of the spike protein with a modification called 2P, in which the protein includes two stabilizing mutations in which the original amino acids are replaced with prolines, developed by researchers at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. Once the protein is expelled from the cell, it is eventually detected by the immune system, which begins generating efficacious antibodies. The mRNA-1273 drug delivery system uses a PEGylated lipid nanoparticle drug delivery (LNP) system.

Chemistry
The vaccine contains the following ingredients:

The active ingredient is an mRNA sequence containing a total of 4101 nucleotides that encodes the full-length SARS-CoV-2 spike (S) glycoprotein, with two mutations (K986P and V987P) designed to stabilize the pre-fusion conformation. The sequence is further optimized by:
 * all uridines (U) substituted with N1-methylpseudouridine (U → m1Ψ),
 * flanked by an artificial 5' untranslated region (UTR) and a 3' UTR derived from the human alpha globin gene (HBA1),
 * introduction of two additional stop codons,
 * terminated by a 3' poly(A) tail.

A putative sequence of the vaccine has been published on a forum for professional virologists, obtained by direct sequencing of residual vaccine material in used vials.

The vaccine mRNA is dissolved in an aqueous buffer containing tromethamine, tromethamine hydrochloride, sodium acetate, and sucrose. The mRNA is encapsulated in lipid nanoparticles that stabilize the mRNA and facilitate its entry into cells. The nanoparticles are manufactured from the following lipids:
 * 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),
 * cholesterol,
 * PEG2000-DMG (polyethylene glycol (PEG) 2000-dimyristoyl glycerol (DMG)), and
 * SM-102

Manufacturing
In June 2020, Moderna entered a partnership with Catalent in which Catalent will fill and package the vaccine candidate. Catalent will also provide storage and distribution.

On 9 July 2020, Moderna announced an in-fill manufacturing deal with Laboratorios Farmacéuticos Rovi, in the event that its vaccine is approved.

Moderna is relying extensively on contract manufacturing organizations to scale up its vaccine manufacturing process. The first step of the process—synthesis of DNA plasmids (to be used as a template for synthesis of mRNA)—has been handled by a contractor called Aldevron based in Fargo, North Dakota. For the remainder of the process, Moderna contracted with Lonza Group to manufacture the vaccine at facilities in Portsmouth, New Hampshire in the United States, and in Visp in Switzerland, and purchased the necessary lipid excipients from CordenPharma. Besides CMOs, Moderna also manufactures the vaccine at its own production facility in Norwood, Massachusetts.

For the tasks of filling and packaging vials (fill and finish), Moderna entered into contracts with Catalent in the United States and Laboratorios Farmacéuticos Rovi in Spain. In April 2021, Moderna expanded its agreement with Catalent to increase manufacturing output at the latter's plant in Bloomington, Indiana. The expansion will allow Catalent to manufacture up to 400 vials per minute and fill an additional 80million vials per year. Later that month, Moderna announced its plans to spend billions of dollars to boost production of its vaccines, potentially tripling the output in 2022, claiming as well that it would make no less than 800million doses in 2021. The increase in production is in part attributed to improvements made by the company in manufacturing methods.

The Moderna news followed preliminary results from the Pfizer-BioNTech vaccine candidate, BNT162b2, with Moderna demonstrating similar efficacy, but requiring storage at the temperature of a standard medical refrigerator of 2 - 8 C for up to thirty days or -20 C for up to four months, whereas the Pfizer-BioNTech candidate requires ultracold freezer storage between -80 and -60 C. Low-income countries usually have cold chain capacity for only standard refrigerator storage, not ultracold freezer storage. In February 2021, the restrictions on the Pfizer vaccine were relaxed when the US Food and Drug Administration (FDA) updated the emergency use authorization (EUA) to permit undiluted frozen vials of the vaccine to be transported and stored at between -25 and -15 C for up to two weeks before use.

In November 2020, Nature reported that "While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences [between Moderna and BioNtech], many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions."

History
In January 2020, Moderna announced development of an RNA vaccine, codenamed mRNA-1273, to induce immunity to SARS-CoV-2.

Moderna received US$955million from BARDA, an office of the U.S. Department of Health and Human Services. BARDA funded 100% of the cost of bringing the vaccine to FDA licensure.

The United States government provided US$2.5billion in total funding for the Moderna COVID‑19 vaccine (mRNA-1273). Private donors also made contributions to the vaccine's development.

Phase I–II
In April 2020, the PhaseI human trial of mRNA-1273 began in partnership with the US National Institute of Allergy and Infectious Diseases. In April, the US Biomedical Advanced Research and Development Authority (BARDA) allocated up to $483million for Moderna's vaccine development. Plans for a PhaseII dosing and efficacy trial to begin in May were approved by the US Food and Drug Administration (FDA). Moderna signed a partnership with Swiss vaccine manufacturer Lonza Group, to supply 300million doses per annum.

On 25 May 2020, Moderna began a PhaseIIa clinical trial recruiting six hundred adult participants to assess safety and differences in antibody response to two doses of its candidate vaccine, mRNA-1273, a study expected to complete in 2021.

On 14 July 2020, Moderna scientists published preliminary results of the PhaseI dose escalation clinical trial of mRNA-1273, showing dose-dependent induction of neutralizing antibodies against S1/S2 as early as 15 days post-injection. Mild to moderate adverse reactions, such as fever, fatigue, headache, muscle ache, and pain at the injection site were observed in all dose groups, but were common with increased dosage. The vaccine in low doses was deemed safe and effective in order to advance a PhaseIII clinical trial using two 100-μg doses administered 29 days apart.

In July 2020, Moderna announced in a preliminary report that its Operation Warp Speed candidate had led to production of neutralizing antibodies in healthy adults in PhaseI clinical testing. "At the 100-microgram dose, the one Moderna is advancing into larger trials, all 15 patients experienced side effects, including fatigue, chills, headache, muscle pain, and pain at the site of injection." The troublesome higher doses were discarded in July from future studies.

Phase III
Moderna and the National Institute of Allergy and Infectious Diseases began a PhaseIII trial in the United States on 27 July, with a plan to enroll and assign thirty-thousand volunteers to two groups – one group receiving two 100-μg doses of mRNA-1273 vaccine and the other receiving a placebo of 0.9% sodium chloride. As of 7August, more than 4,500 volunteers had enrolled.

In September 2020, Moderna published the detailed study plan for the clinical trial. On 30 September, CEO Stéphane Bancel said that, if the trial is successful, the vaccine might be available to the public as early as late March or early April 2021. As of October 2020, Moderna had completed the enrollment of 30,000 participants needed for its PhaseIII trial. The US National Institutes of Health announced on 15 November 2020, that overall trial results were positive.

, an interim analysis from the PhaseIII clinical trial, indicates 94% efficacy in preventing COVID‑19 infection. Side effects included flu-like symptoms, such as pain at the injection site, fatigue, muscle pain, and headache. The clinical trial is ongoing and is set to conclude in late 2022.

Since September 2020, Moderna has used Roche Diagnostics' Elecsys Anti-SARS-CoV-2 S test, authorized by the US Food and Drug Administration (FDA) under an Emergency Use Authorization (EUA) on 25 November 2020. According to an independent supplier of clinical assays in microbiology, "this will facilitate the quantitative measurement of SARS-CoV-2 antibodies and help to establish a correlation between vaccine-induced protection and levels of anti-receptor binding domain (RBD) antibodies." The partnership was announced by Roche on 9December 2020.

A review by the FDA in December 2020, of interim results of the PhaseIII clinical trial on mRNA-1273 showed it to be safe and effective against COVID‑19 infection resulting in the issuance of an EUA by the FDA.

Expedited
As of December 2020, mRNA-1273 was under evaluation for emergency use authorization (EUA) by multiple countries which would enable rapid rollout of the vaccine in the United Kingdom, the European Union, Canada, and the United States.

On 18 December 2020, mRNA-1273 was authorized by the United States Food and Drug Administration (FDA) under an EUA. This is the first product from Moderna that has been authorized by the FDA.

On 23 December 2020, mRNA-1273 SARS-CoV-2 was authorized by Health Canada.

On 5 January 2021, mRNA-1273 was authorized for use in Israel by its Ministry of Health.

On 3 February 2021, mRNA-1273 was authorized for use in Singapore by its Health Sciences Authority.

On 30 April 2021, the World Health Organization (WHO) granted emergency use listing.

On 5 May 2021, mRNA-1273 was authorized for emergency use in the Philippines by the Philippines Food and Drug Administration.

On 21 May 2021, COVID-19 Vaccine Moderna Intramuscular Injection (formerly TAK-919) was authorized for emergency use in Japan.

On 29 June 2021, mRNA-1273 was authorized for use in India by the Drugs Controller General of India. The same day, the vaccine was also approved by the Ministry of Health of Vietnam for emergency use in the country.

Standard
On 6 January 2021, the European Medicines Agency (EMA) recommended granting conditional marketing authorization and the recommendation was accepted by the European Commission the same day. On 6 June 2021, the EMA started evaluating an application to extend the use of the COVID‑19 Vaccine Moderna to include people aged 12 to 17.

On 12 January 2021, Swissmedic granted temporary authorization for the Moderna COVID-19 mRNA Vaccine in Switzerland.

On 1 April 2021, the Medicines and Healthcare products Regulatory Agency granted full marketing authorization in the United Kingdom.

Further development


It remains unknown whether the Moderna COVID-19 vaccine provides life-long immunity or if periodic booster shots are required. Pregnant and breastfeeding women were also excluded from the initial trials used to obtain Emergency Use Authorization, though trials in those populations are expected to be performed in 2021.

In January 2021, Moderna announced that it would offer a third dose of its vaccine to people who were vaccinated twice in its PhaseI trial. The booster would be made available to participants six to twelve months after they got their second dose. The company said it may also study a third shot in participants from its PhaseIII trial, if antibody persistence data warranted it.

In 2020, Moderna partnered with Takeda Pharmaceutical Company, and the Japan Ministry of Health, Labour and Welfare (MHLW). The vaccine is known as "COVID-19 Vaccine Moderna Intramuscular Injection".

On 25 January 2021, Moderna started development of a new form of its vaccine, called mRNA-1273.351, that could be used as a booster shot against the Beta variant (lineage B.1.351). It also started testing to see if a third shot of the existing vaccine could be used to fend off the virus variants. On 24 February, Moderna announced that it had manufactured and shipped sufficient amounts of mRNA-1273.351 to the National Institutes of Health to run PhaseI clinical trials. On March 16, 2021, in order to increase the span of vaccination beyond adults, Moderna started the clinical trials of vaccines on children age 6-months to 11-years-old in the US and in Canada (KidCove), in addition to the existing and fully-enrolled study on 12-17 year-olds (TeenCOVE).

Economics


In June 2020, Singapore signed a pre-purchase agreement for Moderna, reportedly paying a price premium in order to secure early stock of vaccines, although the government declined to provide the actual price and quantity, citing commercial sensitivities and confidentiality clauses.

On 11 August 2020, the US government signed an agreement to buy 100million doses of Moderna's anticipated vaccine, which the Financial Times said Moderna planned to price at US$50–60 per course. On November 2020, Moderna said it will charge governments who purchase its vaccine between US$25 and US$37 per dose while the E.U. is seeking a price of under US$25 per dose for the 160million doses it plans to purchase from Moderna.

In 2020, Moderna also obtained purchase agreements for mRNA-1273 with the European Union for 160million doses and with Canada for up to 56million doses. On 17 December, a tweet by the Belgium Budget State Secretary revealed the E.U. would pay US$18 per dose, while The New York Times reported that the US would pay US$15 per dose.

As of the authorization in Canada on 23 December 2020, Prime Minister of Canada Justin Trudeau had previously said deliveries would begin within 48 hours of approval and that 168,000 doses would be delivered by the end of December.

On 17 February 2021, the first shipment arrived in Singapore.

In February 2021, Moderna said it was expecting US$18.4billion in sales of its COVID-19 vaccine.

Controversies
In May 2020, after releasing partial and non-peer reviewed results for only eight of 45 candidates in a preliminary pre-PhaseI stage human trial directly to financial markets, the CEO announced on CNBC an immediate $1.25billion rights issue to raise funds for the company, at a $30billion valuation, while Stat said, "Vaccine experts say Moderna didn't produce data critical to assessing COVID-19 vaccine."

On 7 July 2020, disputes between Moderna and government scientists over the company's unwillingness to share data from the clinical trials were revealed.

Moderna also faced criticism for failing to recruit people of color in clinical trials.

Patent litigation
The PEGylated lipid nanoparticle (LNP) drug delivery system of mRNA-1273 has been the subject of ongoing patent litigation with Arbutus Biopharma, from whom Moderna had previously licensed LNP technology. On 4September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case.