Moderna COVID-19 vaccine

Extended version of the vaccine

Moderna COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure
Listed for emergency use on 30 April 2021 [WHO, 2021 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Individuals aged 18 years and above [WHO, 2021 ]

European Commission (based upon the recommendation of the European Medicines Agency)
Conditional Marketing Authorization
6 January 2021: In individuals 18 years of age and older [EMA , 2021 ]
23 July 2021: In individuals from 12 to 17 years of age [EMA, 2021 ]

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Not authorized

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Not authorized

Health Canada
Authorized for emergency use: 23 December 2020

Public Health Institute (ISP, Chile)
Not authorized

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use: 25 june 2021 [INVIMA, 2021 ]
20 September 2021: In individuals from 12 years of age and older [INVIMA, 2021 ]

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized

U.S. Food and Drug Administration (FDA)
Authorized for emergency use (Emergency Use Authorization)
18 December 2020
Emergency Use Authorization (EUA) in individuals 18 years of age and older [Moderna, Inc, 2020 ]

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use: 18 august 2021 [Gobierno de México, 2021 ]

Authorization in other jurisdictions in the Americas
Guatemala
Honduras
Saint Vincent and the Grenadines
Curaçao
Guyana
Haiti
Honduras
Paraguay
Puerto Rico
Saba
San Martin
Seychelles
Sint Eustatius

Authorization in other jurisdictions
Listed by alphabetical order
Andorra
Australia
Austria
Bangladesh
Belgium
Bhutan
Botswana
Brunei
Bulgaria
Congo
Croatia
Cyprus
Czechia
Denmark
Estonia
Faroe Islands
Fiji
Finland
France
Germany
Ghana
Greece
Greenland
Hungary
Iceland
India
Indonesia
Israel
Italy
Japan
Kenya
Kuwait
Latvia
Libya
Liechtenstein
Lithuania
Luxembourg
Malaysia
Maldives
Malta
Micronesia
Mongolia
Netherlands
Nigeria
Norway
Palestine
Pakistan
Philippines
Poland
Portugal
Qatar
Romania
Saudi Arabia
Seychelles
Singapore
Slovakia
Slovenia
South Korea
Spain
Sri Lanka
Sweden
Switzerland
Taiwan
Thailand
United Arab Emirates
UK
Vietnam
West Bank

Manufacturing

Drug substance [World Health Organization, 2020 ]
Moderna TX, Inc, an American company based in Cambridge and in the United States.


Lonza Group manufactures the vaccine at facilities in Portsmouth, New Hampshire in the United States and in Visp in Switzerland. It has been reported that four manufacturing facilities are planned, each capable of producing an estimated 100 million doses per year
[MODERNA TX INC. & LONZA SALES LTD, 2020 ].

Drug Product [World Health Organization, 2020 ]
Rovi Pharma Industrial Services, S.A company based in Spain are the main manufacturers of Moderna COVID-19 vaccine, they have several alliances for manufacturing contractors of the product
Catalent is a company headquartered in Somerset, New Jersey. It provides vial filling and packaging [Rick Mullin, 2021 ].

Baxter Pharmaceutical Solutions, is a company located in the United States, it produces the drug product of the vaccine.

General characteristics

Moderna is an RNA vaccine composed of nucleoside-modified mRNA (modRNA). The synthetic mRNA is a single-stranded, 5'-capped messenger RNA encoding the SARS-CoV-2 spike (S) glycoprotein of SARS-CoV-2 virus stabilized in its prefusion conformation (S-2P antigen). S-2P consists of the SARS-CoV-2 glycoprotein (S glycoprotein) with a transmembrane anchor and an intact S1-S2 cleavage site. S-2P is stabilized in its prefusion conformation by two consecutive proline substitutions at amino acid positions 986 and 987, at the top of the central helix in the S2 subunit [Wrapp D, 2020 ]. The S glycoprotein mediates host cell attachment and is required for viral entry [Corbett KS, 2020 ].

It is important for the immune system to respond to the virus at the prefusion stage, because it would probably be too late for the immune system to intervene at the postfusion stage when the virus is entering into the cell [Xia X, 2021 ]. Proline substitution is one of the main techniques reported to stabilize the SARS-CoV-2 spike at prefusion conformation. Spike protein variants can exhibit different levels of expression in comparison to the parental construct, and improved ability to withstand heat stress, storage temperature and resistance to freeze-thaw cycles [Hsieh CL, 2020 ]

The mRNA sequence encoding the protein was synthesized using an optimized T7 RNA polymerase-mediated transcription reaction with complete replacement of uridine by N1-methyl-pseudouridine [Corbett KS, 2020 ]. The reaction included a DNA template containing the immunogen open reading frame flanked by 5′untranslated region (UTR) and 3′UTR sequences and was terminated by an encoded polyA tail [Corbett KS, 2020 ].

Assembling mRNA using pseudouridine, a nucleoside variant naturally occurring in the body, reduces the response of dendritic cells, interferon-associated genes and other components of the immune system to trigger an inflammatory response. [Karikó K, 2008 ].

One way a vaccine mRNA molecule can be modified is by placing it between two RNA untranslated regions which stabilize the mRNA and optimize it for translation. The ends of the mRNA, known as 5‘ and 3‘ ends, can be modified by addition of a cap and a poly(A) tail. The cap serves as a recognition signal for the cellular ribosome to bind and translate the mRNA and the poly(A) tail stabilizes the protein and further enhances translation of the protein [Schlake T, 2012 ].

The mRNA is encapsulated in lipid nanoparticles through a modified ethanol-drop nanoprecipitation process [Hassett KJ, 2019 ].

The modification of the lipid nanoparticles improves the immune response and improves tolerability [Hassett KJ, 2019 ].

After injection, body cells take up the lipid nanoparticle, delivering the mRNA sequence into cells for translation into viral protein and then initiating the immune response against COVID-19 [Hassett KJ, 2019 ]. The membrane-bound spike protein of SARS-CoV-2 is expressed and then recognized by immune cells as a foreign antigen. This elicits both T-cell and B-cell responses to generate neutralizing antibodies, which may contribute to protection against COVID-19.

Dosage form and ingredients
The dosage form is a dispersion for intramuscular injection that is provided in a multidose vial (vial: 10 doses of 0.5 mL, total 5 mL per vial).

The vaccine contains the following ingredients:
Active ingredient:
One dose (0.5 mL) contains 100 micrograms of nucleoside-modified messenger RNA encoding the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion configuration.
Excipients:
Lipids
SM-102 (proprietary to Moderna)
Polyethylene glycol (PEG) 2000-dimyristoyl glycerol (DMG)
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
Cholesterol
Salts, sugars and buffers
Tromethamine (Synonyms: trometamol,tromethamin,Tris, tris(hydroxymethyl)aminomethane)
Tromethamine hydrochloride (Synonyms: Tris hydrochloride; Tris chloride; Tris(hydroxymethyl)aminomethane hydrochloride)
Acetic acid
Sodium acetate trihydrate
Sucrose
Water for injections
Moderna COVID-19 vaccine is preservative-free.

Risk considerations

Risk of insertional mutagenesis
Unlike DNA vaccines, which might carry a small risk of insertional mutagenesis and integration, mRNA does not have the potential to integrate into the host genome and is degraded naturally during the process of antigen expression [Stenler S, 2014 ]

Risk of infection
Moderna COVID-19 vaccine is a non-replicating platform. This means the delivered mRNA does not carry an intrinsic risk for infection [GAVI,2020 ]. Additionally, contaminating microorganisms in mRNA vaccines are unlikely because the manufacturer does not need bacterial cell culture [Pardi N, 2018 ].

Inflammatory reactions
mRNA vaccines have a more pronounced proinflammatory nature. This feature might provide a self-adjuvant property but also can result in local and systemic reactions
[Liu MA, 2019 ]. However, a proposed mechanism for possible autoimmune responses is via the induction of type I interferon, which has been observed in preclinical studies [Pepini T, 2017 ].

Allergic reactions
Most immediate allergic reactions associated with vaccines are related with excipients
[Stone CA, 2019 ]. Polyethylene glycols (PEG) are frequently used as excipients in many liquid and solid formulations of medications and are also used to stabilize the lipid nanoparticle containing the mRNA of Moderna COVID-19 vaccine. Therefore, PEG constitutes the main candidate for explaining the cause of allergic reactions to this vaccine [Stone CA, 2019 ].
PEG itself has not previously used in other vaccines but polysorbate, a closely related compound, has been implicated in allergic reactions to other vaccines [Stone CA, 2019 ]

Dosification and schedule

Countries that have not yet achieved high vaccine coverage rates in the high-priority groups who are experiencing a high incidence of COVID-19 cases combined with vaccine supply constraints, WHO recommends that such countries should focus on achieving a high first dose coverage in the high priority groups by extending the inter-dose interval up to 12 weeks [WHO, 2021 ].

Dose-finding studies
mRNA-1273-P201 was a dose-finding, randomized, phase 2 trial sponsored by ModernaTX, Inc. and conducted in The United States between 22 May 2020 and 08 July 2020. It was registered with the trial registry number NCT04405076.
The trial included healthy participants ≥18 years with a body mass index of 18 kg/m2-30 kg/m2.
The sample size was 600 (2 cohorts of 300). The mean age of the participants was 37.4 years in cohort 1 (≥18 - <55 years) and 64.3 years in cohort 2 (≥55 years) and the proportion of females was 61%.
Participants were randomly assigned in a 1:1:1 ratio to receive Moderna COVID-19 vaccine 50 µg, 100 µg or placebo.
The vaccine induced binding antibodies and neutralizing antibodies by 28 days post-vaccination one that were higher at the 100 µg dose relative to the 50 µg dose but the difference was less apparent post-vaccination two. Binding antibodies and neutralizing antibodies increased substantially by 14 days following the second vaccination (day 43) to levels exceeding those of convalescent sera and remained elevated through day 57. [Chu L, 2021 ]

There is no data available on the interchangeability of the Moderna COVID-19 vaccine with other COVID-19 vaccines to complete the vaccination series [WHO, 2021 ].
There is no evidence yet about the effects of the coadministration of Moderna COVID-19 vaccine with other vaccines included in routine vaccination programs [WHO, 2021 ].

Indications and contraindications

Indications
Moderna COVID-19 vaccine is indicated in adult individuals 18 years of age and older [WHO, 2021 ].

Contraindications
Moderna COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of Moderna COVID-19 vaccine [WHO, 2021 ].
The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose of Moderna COVID-19 vaccine [WHO, 2021 ].

Precautions
A history of anaphylaxis to any other vaccine or injectable therapy (i.e. intramuscular, intravenous, or subcutaneous vaccines or therapies), is not a contraindication to vaccination. For such persons, a risk assessment should be conducted by a health professional. Such persons should be observed for 30 minutes after vaccination [WHO, 2021 ].
Individuals with an immediate non-anaphylactic allergic reaction to the first dose (such as urticaria, angioedema or respiratory symptoms, that occur within 4 hours of administration) should not receive additional doses, unless recommended after review by a health professional [WHO, 2021 ].
As a small number of anaphylactic reactions have also been reported in vaccines without a history of anaphylaxis, it is recommended that Moderna COVID-19 vaccine should be administered only in settings where anaphylaxis can be treated [WHO, 2021 ].

A possible causal association with very rare cases of myocarditis in young men (16−24 years of age) is currently being investigated [WHO, 2021 ].
Adverse events reports suggest an increased risk of myocarditis and pericarditis, particularly following the second dose and onset of symptoms within a few days after vaccination. Vaccinated individuals should be instructed to seek immediate medical attention if they develop the following symptoms: chest pain, shortness of breath, or feelings of having fluttering after vaccination [FDA, 2021 ].

Severe allergic reaction (e.g. anaphylaxis) to an injectable medication.
Moderna COVID-19 vaccine does not contain eggs or gelatine, there is no contraindication or precaution to vaccination for persons with allergies to any food substances.
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection [WHO, 2021 ].
Reactions related with stress or anxiety, such as syncope or hyperventilation may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting.
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [EMA, 2021 ].
The interaction of concomitant administration of Moderna COVID-19 vaccine with other vaccines has not been studied. [EMA, 2021 ]
WHO recommends the use of mRNA-1273 in pregnant women when the benefits of vaccination to the pregnant woman outweigh the potential risks. To help pregnant women make this assessment, they should be provided with information about the risks of COVID-19 in pregnancy, the likely benefits of vaccination, and the current limitations of safety data. WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2021 ].
Data are not available on the potential benefits or risks of the vaccine to breastfed children. However, as mRNA-1273 is not a live virus vaccine and the mRNA does not enter the nucleus of the cell and is degraded quickly, it is biologically and clinically unlikely to pose a risk to the breastfeeding child. On the basis of these considerations, WHO recommends the use of mRNA-1273 in lactating women as in other adults. WHO does not recommend discontinuing breastfeeding because of vaccination [WHO, 2021 ].
Age is not a precaution. Vaccination is generally recommended for older persons without an upper age limit since the benefits outweigh the potential risks.
The available data on Moderna COVID-19 vaccine vaccination of immunocompromised persons, including persons living with HIV, are insufficient to assess vaccine efficacy.
There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule, until data on co-administration with other vaccines are available [World Health Organization, 2021 ]
Vaccination may be offered regardless of a person‘s history of symptomatic or asymptomatic SARS-CoV-2 infection [World Health Organization, 2021 ]
Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].
Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].

Close observation for at least 30 minutes is recommended following vaccination.

Storage and logistics

Storage
Moderna COVID-19 vaccine is provided as a frozen dispersion stored at -20°C / -4°F (between -25° to -15°C [-13° to 5°F]).
For shipping and longer-term storage, keep the vaccine at -20°C (-4°F), equal to most home or medical freezer temperatures, for up to 7 months [WHO, 2021 ].
Vaccine vials can be stored refrigerated between 2°C to 8°C (36°F to 46°F) for up to 31 days prior to first use or, stored between 8°C to 25°C (46°F to 77°F) for up to 12 hours prior to first use [WHO, 2021 ].
After the first dose has been withdrawn, the vial should be held between 2°C to 25°C (36° to 77°F) and discarded after 6 hours.

Do not refreeze once thawed.
Do not store on dry ice or below -40°C (-40°F).
Keep vaccine vials in their box and place them in the storage unit.
Store in the original carton to protect from light.

After thawing, the vaccine remains stable at standard refrigerated conditions of 2°C to 8°C (36°F to 46°F) for up to 30 days (the change from previous estimate of 7 days was announced by Moderna in a press release issued in November, 2020 [World Health Organization, 2021 ]) within the 7-month shelf life.

Logistic at the time of administration
Remove the required number of the vial(s) from storage and thaw each vial before use.
Keep the vial for 2 hours and 30 minutes in the refrigerator from 2°C to 8°C (36°F and 46°F), after, let vial sits for 15 minutes before administering, or, maintained 1 hour at room temperature from 15°C to 25°C
[Moderna Inc., 2020 ].
The vaccine should be inspected visually for particulate matter and discoloration prior to administration.
The vial should be inspected visually for cracks or any abnormalities, such as evidence of tampering prior to administration. If any of these should exist, do not administer the vaccine.
Swirl the vial gently after thawing and before each withdrawal. Do not shake or dilute [WHO, 2021 ]
Use a sterile needle and syringe to extract a single dose of 0.5 mL from the multidose vial.
In the multi-dose vial in which each vial contains a maximum of 11 doses, a range of 10-11 doses can be extracted (0.5 mL each) [FDA, 2021 ].
In the multi-dose vial in which each vial contains a maximum of 15 doses, a range of 13-15 doses can be extracted (0.5 mL each) [FDA, 2021 ].


After the first dose has been withdrawn, the vial should be held between 2° to 25°C (36° to 77°F) and discarded after 6 hours. Do not refreeze once thawed.
Once thawed, withdraw each 0.5 mL dose of vaccine from the vial using a new sterile needle and syringe for each injection to prevent transmission of infectious agents from one person to another. Once the vial has been punctured, the vaccine should be used immediately and be discarded after 6-hours. The maximum time the vial must be open is up to 6 hours refrigerated or at room temperature (2°C to 25°C). Record the date and time of first use on the vial label.
Visually inspect each dose of the vaccine in the dosing syringe prior to administration. The white to off-white dispersion may contain white or translucent product-related particulates.
Do not administer if the vaccine is discolored or contains other particulate matter.
Storage after first puncture
After the first puncture of the vial, preferably use immediately [WHO, 2021 ].
After the first puncture of the vial, the vaccine can be held at 2°C to 8°C (36°F to 46°F) for up to 6 hours. [WHO, 2021 ]
Record the date and time the vial should be discarded.
To improve traceability, the name and batch number of the administered product should be clearly recorded [0e04f93435e4ce41f1835cd40750b2d1bdad0fb4
Administration
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 ml reuse prevention syringe (RUP) or a 5 ml RUP syringe, and a 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the 0.5 ml dose. If the amount of vaccine remaining in the vial cannot provide a full 0.5 ml dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.
Disposal
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

Randomized trials
COVE (an acronym for: Coronavirus Efficacy and Safety Study) or study P301 was a phase 3 randomized clinical trial sponsored by ModernaTX, Inc. and conducted The United States between July 27, 2020, and October 23, 2020. It was registered with trial registry number NCT04470427.
The trial included participants 18 years of age or older with no known history of SARS-CoV-2 infection and with circumstances that put them at an appreciable risk of SARS-CoV-2 infection, a high risk of severe COVID-19, or both. The sample size was 30420. The mean age of the participants was 51.4 years and the proportion of females was 47.3%.
Participants were randomly assigned in a 1:1 ratio to receive Moderna COVID-19 vaccine or placebo vaccine. The intervention was administered as a sterile liquid at a concentration of 0.2 mg per milliliter and administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 µg of mRNA-1273 or saline placebo. Vaccine mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration [Baden LR, 2021 ]

TeenCove was a phase 2-3, randomized, placebo-controlled trial sponsored by ModernaTX, Inc and conducted United States between December 2020 to June 2022. It was registered with trial registry number NCT04649151. The trial included healthy male and female adolescents between the ages of 12 and 17 years. The sample size was 3732. The mean age of the participants was 14.3 years and the proportion of women was 49%. Participants were randomly assigned in a 2:1 ratio to receive mRNA-1273 (2489 participants) or placebo (1243 participants). The intervention was administered as two injections of either mRNA-1273 vaccine (each injection containing 100 µg, for a total dose of 200 µg) or placebo (saline solution), 28 days apart [Ali K, 2021 ].

Hall VG et al was an ongoing phase 4, randomized, placebo-controlled trial sponsored by University Health Network, Toronto and conducted Canada May 2021 to August 2021. It was registered with trial registry number NCT04885907. The trial included organ-transplant recipients who had received two doses of mRNA-1273. The sample size was 120. The mean age of the participants was 66.6 years. The proportion of women in the mRNA-1273 group was 38.3% and in the placebo group was 30%. Participants were randomly assigned in a 1:1 ratio to receive a third dose of mRNA-1273 or a placebo. The intervention was administered as a third dose of mRNA-1273 vaccine or saline placebo 2 months after the second dose of mRNA-1273 (dosing schedule: 0, 1, and 3 months). [Hall VG, 2021 ]

Ongoing randomized trials
MOSAIC is an ongoing phase 2, randomized trial (registered with the number NCT04894435 [Canadian Immunization Research Network, 2021 ]) sponsored by Canadian Immunization Research Network that is being conducted in Canada. It was first registered in May 2021 and plans to enroll 1200 healthy adults with mild or moderate stable comorbidities of 18 years of age and older. Participants will receive two different vaccines (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) for first and second doses, as well as for differing intervals between the first and second dose of the vaccines. It is expected to run until March 2023.

ARNCOMBI is an ongoing multicenter, randomized, open-label trial (registered with the number NCT04900467 [Assistance Publique - Hôpitaux de Paris, 2021 ]) sponsored by Assistance Publique - Hôpitaux de Paris that is being conducted in France. It was first registered in May 2021 and plans to enroll 400 patients aged 18 years and older that will receive a regimen of vaccines combining Pfizer-BioNTech or Moderna. It is expected to run until January 2022.

VATICO is an ongoing open-label, randomized trial (phase 4) (registered with the number NCT04969250 [International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), 2021 ]) sponsored by International Network for Strategic Initiatives in Global HIV Trials that is being conducted in United States, Denmark, Greece, India, Nigeria, Poland, Singapore, Spain, Switzerland, Uganda, and United Kingdom. It was first registered in July 2021 and plans to enroll 640 participants of the ACTIV-3/TICO clinical trial (NCT04501978) that will receive Moderna mRNA-1273 or the Pfizer BNT162b2 vaccine. It is expected to run until July 2022

Guerrerio PA et al is an ongoing randomized, placebo-controlled crossover study (phase 2) (registered with the number NCT04977479 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in The United States. It was first registered in July 2021 and plans to enroll 100 people aged 18-69 that will receive Pfizer-BioNTech COVID-19 vaccine and one dose of placebo on different days. It is expected to run until December 2022.

Boost-TX is an ongoing phase 2, randomized, single blinded study (registered with the number 2021-002927-39 [Medical University of Vienna, 2021 ]) sponsored by Medical University of Vienna that is being conducted in Austria. It was first registered in May 2021 and plans to enroll 200 kidney transplant recipients that will receive BNT162b2 or mRNA-1273 (mRNA) vaccines. End of trial: Date not available.
mRNA-1283-P101 is an ongoing phase 1, randomized, observer-blind, dose-ranging study (registered with the number ClinicalTrials.gov number NCT04813796 [ModernaTX, Inc., 2021 ]) sponsored by ModernaTX, Inc that is being conducted in United States. It was first registered in March 2021 and plans to enroll 125 healthy adults aged 18-55 years that will receive mRNA-1283 and mRNA-1273 SARS-CoV-2 Vaccine. It is expected to run until April 2022.

mRNA-1273-D3-2021 is an ongoing phase 4, randomized controlled trial (registered with the number ClinicalTrials.gov number NCT04677660 [Mark Loeb, 2021 ]) sponsored by Mark Loeb that is being conducted in Canada. It was first registered in July 2021 and plans to enroll 414 vaccinated residents ≥65 years that will receive a third dose of mRNA-1273 (Moderna COVID-19) vaccine. It is expected to run until April 2022.

QHD00028 is an ongoing phase 2, open-label study (registered with the number NCT04969276 [Sanofi Pasteur, a Sanofi Company, 2021 ]) sponsored by Sanofi Pasteur, a Sanofi Company that is being conducted in United States. It was first registered in July 2021 and plans to enroll 300 fully vaccinated adults with mRNA-1273 65 years of age and older that will receive a dose of Fluzone High-Dose Quadrivalent vaccine and a booster dose of Moderna COVID-19 Vaccine, administered concomitantly or singly. It is expected to run until January 2022.

Deepali Kumar et al is an ongoing phase 4, randomized, double-blind, placebo-controlled trial (registered with the number NCT04885907 [University Health Network, Toronto, 2021 ]) sponsored by University Health Network, Toronto that is being conducted in Canada. It was first registered in May 2021 and plans to enroll 120 fully vaccinated adults with mRNA-1273 18 years of age and older that will receive a third dose of the mRNA-1273 vaccine or saline placebo. It is expected to run until August 2021.

COVERALL is an ongoing phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial (registered with the number NCT04805125 [University Hospital, Basel, Switzerland, 2021 ]) sponsored by University Hospital, Basel that is being conducted in Switzerland. It was first registered in March 2021 and plans to enroll 431 patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study that will receive mRNA vaccine Comirnaty (Pfizer / BioNTech) or the Covid-19 mRNA Vaccine Moderna. It is expected to run until July 2022.

SWITCH is an ongoing multicenter, randomized, single-blind, controlled trial (registered with the number ClinicalTrials.gov number NCT04927936 [Erasmus Medical Center, 2021 ]) sponsored by Erasmus Medical Center that is being conducted in Netherlands. It was first registered in June 2021 and plans to enroll 432 health care workers aged 18 to 65 years vaccinated once with Janssen vaccine that will receive Janssen vaccine (homologous boosting); Moderna vaccine (heterologous boosting);or Pfizer vaccine (heterologous boosting). It is expected to run until September 2022.

CoVPN 3006 is an ongoing phase 3, randomized clinical trial (registered with the number ClinicalTrials.gov number NCT04811664 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases that is being conducted in United States. It was first registered in March 2021 and plans to enroll 37500 adults aged 18-29 that will receive Moderna COVID-19 vaccine against SARS-CoV-2 infection. It is expected to run until December 2021.

21-0002 is an ongoing phase 1 trial, open-label, randomized (registered with the number ClinicalTrials.gov number NCT04785144 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases that is being conducted in United States. It was first registered in March 2021 and plans to enroll 135 naïve and previously vaccinated adults 18 years of age and older that will receive SARS-CoV-2 Variant Vaccine (mRNA-1273.351). It is expected to run until August 2022.

DAIT ACV01 is an ongoing randomized, multi-site, adaptive, open-label clinical trial (registered with the number ClinicalTrials.gov number NCT05000216 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in the United States. It was first registered in August 2021 and plans to enroll 600 participants with autoimmune diseases requiring immunosuppressive medications, that will receive different COVID-19 vaccines booster doses (Moderna, Pfizer-BioNTech or Janssen COVID-19 vaccine) to compare the immune response in the participants. It is expected to run until December 2022.

TAK-919-1501 is an ongoing phase 1 and 2, randomized, observer-blind, placebo-controlled trial (registered with the number ClinicalTrials.gov number NCT04677660 [Takeda, 2021 ]) sponsored by Takeda that is being conducted in Japan. It was first registered in December 2020 and plans to enroll 200 healthy adults aged 20 years and older that will receive TAK-919 vaccine. It is expected to run until March 2022.

IMCOVAS is a randomized ongoing trial (registered with the number EudraCT Number 2021-001993-52 [University of Antwerp, 2021 ]) sponsored by University of Antwerp that is being conducted in Belgium. It was first registered in May 2021 and plans to enroll 840 healthy volunteer adults, the study will assess the humoral immune response against SARS-Cov-2 infection of different vaccines and adapted vaccine schedules in comparison with the reference schedules. It is expected to run until a date not yet available.

The P204 trial (mRNA-1273-P204) (NCT04796896) is an ongoing RCTs that will assess efficacy of Moderna COVID-19 vaccine in children and adolescents (for more information see -Efficacy of the vaccine in subgroups-)

Other studies providing efficacy or safety data
20-0003 (expansion in older adults) was a phase 1, non-randomized study sponsored by National Institute of Allergy and Infectious Diseases (NIAID) and conducted in the United States of America at Kaiser Permanente Washington Health Research Institute in Seattle, the Emory University School of Medicine in Atlanta, and the National Institute of Allergy and Infectious Diseases Vaccine Research Center in Bethesda, Maryland between April 16 and May 12, 2020. It was registered with ClinicalTrials.gov number NCT04283461 [National Institute of Allergy and Infectious Diseases (NIAID), 2020 ].
This trial was expanded to include participants older than 56 years [Anderson EJ, 2020 ].
The sample size was 40. The mean age of the participants was 68.7 years and the proportion of females was 53%.
All the participants were assigned sequentially to receive two doses of either 25 µg or 100 µg of vaccine administered 28 days apart.

The ICARUS-IBD study, was a cohort study, that enroll individuals with inflammatory bowel disease receiving the vaccine (for more information see -Efficacy of the vaccine in subgroups-) [Serre-Yu Wong, 2021 ].

Gee et al. (CDC report) was a safety monitoring non-comparative study conducted in United states. The study enrolled 13,794,904 vaccine doses (Pfizer or Moderna) participants that received Moderna COVID-19 vaccine. Based on data from Vaccine Adverse Event Reporting System and the v-safe system between 14 December 2020 and 13 January 2021.

HEROES-RECOVER was a prospective cohort study conducted in United states. The study enrolled 5,716 (3,964 unvaccinated, 1,754 vaccinated) participants that received Moderna COVID-19 vaccine. Based on data from HEROES-RECOVER cohorts between December 14, 2020 to April 10 2021.

Flacco et al. was a retrospective cohort study conducted in Italy. The study enrolled 2,020 participants that received Moderna COVID-19 vaccine. Based on data from an interim analysis of COVID-19 vaccines effectiveness in the entire population of an Italian Province between 2 January to 21 May 2021.

Khan et al. was a retrospective cohort study conducted in United states. The study enrolled 3,380 older adults with inflammatory bowel disease participants that received Moderna COVID-19 vaccine. Based on data from the Veterans Health Administration (VHA) between December 18 2020 to April 20 2021.

Pawlowski C et al. was a retrospective cohort study conducted in United States. The study enrolled 16,471 participants that received Moderna COVID-19 vaccine. Based on data from the Mayo Clinic health system between December 1 2020 and April 20 2021.

Desai AP et al. (CDC report) was a safety monitoring non-comparative study conducted in United States. The study enrolled 3,203 participants that received Moderna COVID-19 vaccine. Based on data from Vaccine Adverse Event Reporting System and the v-safe system between December 14 2020 through February 5 2021.

Shimabukuro et al. (CDC report) was a safety monitoring non-comparative study conducted in United States. The study enrolled 16,439 (pregnant persons) pregnant persons that received Moderna or Pfizer COVID-19 vaccine. Based on data from Vaccine Adverse Event Reporting System and the v-safe system from December 14 2020 to February 28, 2021

Andrejko et al. was a case-control study conducted in United States. The study enrolled 1,023 participants that received Moderna COVID-19 vaccine. Based on data from California Department of Public Health via a web-based reporting system from 24 February to 29 April 2021.

Malinis et al. was a cross-sectional study conducted in United States. The study enrolled 557 (solid organ transplant recipients) participants that received Moderna COVID-19 vaccine. Based on data from Yale New Haven Hospital on May 18, 2021.
Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324 ,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test-negative design study among patients who had symptoms consistent with covid-19 between 14 December 2020 and 19 April 2021.

Pawlowski C et al. was a retrospective study conducted in United States. The study enrolled 266,094 participants (36,352 Moderna doses). Based on data from the Mayo Clinic health system between January 1 2017 and March 15, 2021

Tarke A et al. was an immunogenicity study conducted in United States. The study enrolled 30 general population that received Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) vaccines.

Alisa Fox et al. was a cohort conducted in United States. The study enrolled 50 Lactating females (Twenty-three participants had received Pfizer vaccine, 14 had received Moderna vaccine, and 13 had received J&J vaccine). Fifty pairs of milk samples were obtained from vaccine recipients within 1 week before vaccination and 14 days (Pfizer/Moderna) or 28 days (J&J) after completion of the vaccine regimen.

Omar M Albalawi et al. was a retrospective database analysis study conducted in United States. The study enrolled the General population that received Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S vaccines. This retrospective analysis was conducted using the publically available database of the U.S. Vaccine Adverse Event Reporting System (VAERS). VAERS is a critical component of the national passive surveillance (spontaneous reporting) system of the approved vaccines in the U.S

Vivek Naranbhai et al. was an observational conducted in united States. The study enrolled 1470 ambulatory adults vaccinated with mRNA-1273, BNT-162b2, or Ad26.COV2.S that received mRNA-1273, BNT-162b2, or Ad26.COV2.S. based on data taken between February and May 2021

Tré-Hardy M et al. was a cohort conducted in United Kingdom. The study enrolled 160 healthcare workers that received BNT162b2 or ARNm-1273. Based on data in the serological status of the healthcare workers during the national vaccination campaign

Tré-Hardy M et al. was a cohort conducted in United Kingdom. The study enrolled 206 healthcare workers that received BNT162b2 or ARNm-1273. Based on data in healthcare workers who reported adverse events the national vaccination campaign

Pushkar Aggarwal was a cross-sectional conducted in United States. The study enrolled 31459 participants that received Pfizer, Moderna, or Janssen vaccine. Based on data from Vaccine Adverse Event Reporting System (VAERS) between January 1, 1990, to April 10, 2021

Zhao H et al. was a cross-sectional conducted in United States. The study enrolled 15,785 adverse event reports (0.7% (113) urologic symptoms) from participants that received Pfizer-BioNTech and Moderna vaccines. Based on data from FDA Vaccine Adverse Event Reporting System (VAERS) between ) as of February 12th, 2021.

Català A et al. was a cross-sectional conducted in Spain. The study enrolled 405 cutaneous reactions from participants that received BNT162b2 (Pfizer-BioNTech, 40.2%), mRNA-1273 (Moderna, 36.3%) and AZD1222 (AstraZeneca, 23.5%) vaccines. Based on data from an online professional survey and clinical photographs were sent by email between February 16 to May 15, 2021

So ACP et al. was a longitudinal conducted in United kingdom. The study enrolled 373 participants that received Pfizer-BioNTech, Moderna, and AstraZeneca vaccines. Based on data from the London cancer center from 8 December 2020 to 28 February 2021

Schulz, J. B et al. was a cross-sectional conducted in Germany. The study enrolled 45 Reports of cerebral sinus and venous thrombosis (CVT) participants that received Pfizer-BioNTech, Moderna, and AstraZeneca vaccines. Based on data from a web-based questionnaire sent to all Departments of Neurology during April 2021

Maxime Taquet et al. is a cohort conducted in United States. The study enrolled 537913 patients with a confirmed diagnosis of COVID-19. Based on data from ​a federated electronic health records network recording anonymized data from 59 healthcare organizations from January 2020, 2018 to March 25, 202

Other ongoing studies:
ANTICOV is an ongoing observational study (registered with the number ClinicalTrials.gov number NCT04878796 [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ]) sponsored by Azienda Socio Sanitaria Territoriale di Cremona that is being conducted in Italy. It was first registered in May 2021 and plans to enroll 300 cancer patients aged 18 years and older receiving active therapy or who have completed their oncologic treatment within 6 months, that will assess vaccine efficacy on patients who received BNT162b2 (Pfizer) and mRNA-1273 (Moderna). It is expected to run until May 2022.

Gurbel PA et al is an ongoing non-randomized study (registered with the number NCT04910971 [LifeBridge Health, 2021 ]) sponsored by LifeBridge Health that is being conducted in United States. It was first registered in June 2021 and plans to enroll 60 COVID-19 vaccinated health care workers that received Pfizer/BioNTech or Moderna vaccine. It is expected to run until July 2022.

Covid-19-Abs is an ongoing non-randomized study (registered with the number NCT04944095 [Dr. Sidney J. Stohs, 2021 ]) sponsored by Dr. Sidney J. Stohs that is being conducted in United States. It was first registered in June 2021 and plans to enroll 10000 residents and staff associated with nursing homes, extended care facilities, and over-55 communities that received Pfizer, Moderna, or J &J COVID-19 vaccines. It is expected to run until December 2022.

CoVEHPI is an ongoing cohort study (registered with the number NCT04709003 [Clalit Health Services, 2020 ]) sponsored by Clalit Health Services that is being conducted in Israel. It was first registered in January 2021 and plans to enroll 4504 healthcare workers aged 18 years and older that received Pfizer or Moderna COVID-19 vaccine. It is expected to run until June 2022.

McKelvey JL et al is an ongoing non-randomized study (registered with the number NCT04852289 [National Institute on Aging (NIA), 2021 ]) sponsored by National Institute on Aging that is being conducted in United States. It was first registered in April 2021 and plans to enroll 160 healthy individuals over 18 years of age that will receive Pfizer or Moderna COVID-19 vaccines. It is expected to run until March 2024.

Friis-Hansen L et al is an ongoing non-randomized study (registered with the number NCT04842305 [Lenanrt Friis-Hansen, 2021 ]) sponsored by Lenanrt Friis-Hansen that is being conducted in Denmark. It was first registered in April 2021 and plans to enroll 500 SARS-COV-2 Naïve persons, COVID-19 convalescents, and vaccinated with Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, or AstraZeneca ChAdOx1-S vaccine. It is expected to run until March 2024.

21-0012 is an ongoing phase 1/2, non-randomized study (registered with the number NCT04889209 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases that is being conducted in United States. It was first registered in May 2021 and plans to enroll 550 vaccinated healthy individuals 18 years of age and older that will receive a delayed booster dose of Ad26.COV2.S or mRNA-1273 vaccine. It is expected to run until May 2025.

IROC is an ongoing non-randomized study (registered with the number NCT04930055 [Indiana University, 2021 ]) sponsored by Indiana University that is being conducted in United States. It was first registered in June 2021 and plans to enroll 240 cancer patients 18 years of age and older receiving BTN162b2, mRNA-1273, or Ad26.COV2.S. It is expected to run until August 2023.

LymphVAX is an ongoing non-randomized study (registered with the number NCT04872738 [Massachusetts General Hospital, 2021 ]) sponsored by Massachusetts General Hospital that is being conducted in United States. It was first registered in May 2021 and plans to enroll 2000 women with a history of breast cancer that received Moderna or Pfizer COVID-19 vaccines. It is expected to run until December 2022.

VIOLA is an ongoing non-randomized study (registered with the number NCT04843774 [NYU Langone Health, 2021 ]) sponsored by NYU Langone Health that is being conducted in United States. It was first registered in April 2021 and plans to enroll 60 Multiple Sclerosis patients treated with Ocrelizumab that received Moderna or Pfizer COVID-19 vaccines. It is expected to run until October 2022.

Bahl A et al is an ongoing non-randomized study (registered with the number NCT04912700 [William Beaumont Hospitals, 2021 ]) sponsored by William Beaumont Hospitals that is being conducted in United States. It was first registered in June 2021 and plans to enroll 11834 patients with COVID-19 who presented to Beaumont Health emergency departments. It is expected to run until June 2021.

VAX4FRAIL is an ongoing non-randomized study (registered with the number NCT04848493 [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ]) sponsored by Azienda Unità Sanitaria Locale Reggio Emilia that is being conducted in Italy. It was first registered in April 2021 and plans to enroll 1300 frail subjects with impaired immuno-competence that received Pfizer-BioNTech or Moderna vaccines. It is expected to run until April 2022.

mRNA-1273-P903 is an ongoing non-randomized study (registered with the number NCT04958954 [ModernaTX, Inc., 2021 ]) sponsored by ModernaTX, Inc that is being conducted in United States. It was first registered in July 2021 and plans to enroll 50000000 adults 18 years of age and older that received SARS-CoV-2 mRNA-1273 vaccine. It is expected to run until June 2023.

CPAT is an ongoing non-randomized study (registered with the number NCT04969263 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in United States. It was first registered in July 2021 and plans to enroll 200 kidney transplant recipients that will receive a third dose of the same vaccine as the prior two doses (Moderna COVID-19 vaccine or Pfizer-BioNTech COVID-19 vaccine). It is expected to run until October 2022.

US-TYS-11909 is an ongoing cohort, non-randomized study (registered with the number NCT04834401 [St. Barnabas Medical Center, 2021 ]) sponsored by St. Barnabas Medical Center that is being conducted in United States. It was first registered in April 2021 and plans to enroll 120 people with multiple sclerosis aged 18 to 65 years that will receive Moderna COVID-19 vaccine. It is expected to run until April 2023.

COVIAAD is an ongoing non-randomized study (registered with the number NCT04806113 [McGill University Health Centre/Research Institute of the McGill University Health Centre, 2021 ]) sponsored by McGill University Health Centre/Research Institute of the McGill University Health Centre that is being conducted in Canada. It was first registered in March 2021 and plans to enroll 220 patients with rheumatic diseases that will receive mRNA-1273 vaccine. The time between dose 1 and dose 2 of the vaccine will be 28 days. It is expected to run until June 2022.

000115-C is an ongoing non-randomized study (registered with the number NCT04847050 [National Cancer Institute (NCI), 2021 ]) sponsored by National Cancer Institute (NCI) that is being conducted in United States. It was first registered in April 2021 and plans to enroll 120 adults 18 years of age and older with solid tumors or blood cancer that will receive a dose of mRNA-1273 on day 1 and day 29. It is expected to run until February 2023.

mRNA-1273-P205 is an ongoing phase 2/3, non-randomized study (registered with the number NCT04927065 [ModernaTX, Inc., 2021 ]) sponsored by ModernaTX, Inc that is being conducted in United States. It was first registered in June 2021 and plans to enroll 896 fully vaccinated adults with mRNA-1273 that will receive a single booster dose of mRNA-1273.211. It is expected to run until July 2022.

mRNA-1273-P304 is an ongoing phase 3b, open-label, non-randomized study (registered with the number NCT04860297 [ModernaTX, Inc., 2021 ]) sponsored by ModernaTX, Inc that is being conducted in United States. It was first registered in April 2021 and plans to enroll 240 adult solid organ transplant recipients and healthy controls that will receive mRNA-1273 vaccine. It is expected to run until March 2023.

NL73618.100.20 is an ongoing phase 4, non-randomized study (registered with the number 2021-001202-30 [Diakonessenhuis, 2021 ]) sponsored by Diakonessenhuis that is being conducted in Netherlands. It was first registered in April 2021 and plans to enroll 400 adults 18 years of age and older that received Pfizer, Moderna, AstraZeneca, or Janssen COVID-19 vaccine. End of study: Date not available.

R10933-10987-COV-2118 is an ongoing phase 2 randomized, open-label, parallel-group study (registered with the number NCT04852978 [Regeneron Pharmaceuticals, 2021 ]) sponsored by Regeneron Pharmaceuticals that is being conducted in United States. It was first registered in April 2021 and plans to enroll 180 healthy adult volunteers that will receive Moderna mRNA-1273 vaccine administered with Casirivimab+Imdevimab. It is expected to run until August 2022.

CoviCompareM is an ongoing phase 2, comparative, non-randomized study (registered with the number NCT04748471 [Assistance Publique - Hôpitaux de Paris, 2021 ]) sponsored by Assistance Publique - Hôpitaux de Paris that is being conducted in France. It was first registered in February 2021 and plans to enroll 180 volunteers 18-75 years of age that will receive Moderna vaccine. It is expected to run until January 2023.

PNR-1475 is an ongoing cohort study (registered with the number NCT04892888 [Takeda, 2021 ]) sponsored by Takeda that is being conducted in Japan. It was first registered in May 2021 and plans to enroll 1000 subjects with underlying disease considered to be at high risk for a severe illness that received mRNA-1273 vaccine. It is expected to run until February 2022.

COVATRANS is an ongoing cohort study (registered with the number NCT04828460 [University Hospital, Strasbourg, France, 2021 ]) sponsored by University Hospital, Strasbourg that is being conducted in France. It was first registered in April 2021 and plans to enroll 3500 kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna, and Astra-Zeneca vaccines. It is expected to run until February 2023.

VAX-TRES is an ongoing phase 2, non-randomized study (registered with the number NCT04930770 [Maria Joyera Rodríguez, 2021 ]) sponsored by Maria Joyera Rodríguez that is being conducted in Spain. It was first registered in June 2021 and plans to enroll 80 patients with renal transplants that will receive a third dose of mRNA-1273 vaccine. It is expected to run until March 2022

Deepak Sahasrabudhe et al is an ongoing non-randomized study (registered with the number NCT04854980 [University of Rochester, 2021 ]) sponsored by University of Rochester that is being conducted in United States. It was first registered in April 2021 and plans to enroll 55 cancer patients 50 to 75 years of age that received both doses of mRNA-1273 vaccine. It is expected to run until July 2022.

PNR-1474 is an ongoing cohort study (registered with the number NCT04941144 [Takeda, 2021 ]) sponsored by Takeda that is being conducted in Japan. It was first registered in June 2021 and plans to enroll 20000 individuals who have participated in the preceding cohort study that received Moderna COVID-19 vaccine. It is expected to run until December 2022.

mRNA-1273-P902 is an ongoing cohort study (registered with the number NCT04958304 [ModernaTX, Inc., 2021 ]) sponsored by ModernaTX, Inc that is being conducted in United States. It was first registered in July 2021 and plans to enroll 1000 pregnancies in females exposed to the Moderna COVID-19 vaccine (mRNA-1273) during pregnancy. It is expected to run until January 2024.

CVG01 is an ongoing non-randomized study (registered with the number 2021-001769-19 [GUVAX (Gothenburg University Vaccine Research Institute), 2021 ]) sponsored by GUVAX that is being conducted in Sweden. It was first registered in March 2021 and plans to enroll 1200 immune-competent subjects and patients with primary or secondary immune deficiency aged 18 years and older that received Moderna vaccine. End of study: Date not available.

COVID-19-004 (NCT04796896) is an ongoing phase 2, randomized trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). It was first registered in February 21, 2021 and plans to enroll 3400 participants with one population including individuals with a history of allergic reactions or Mast Cell Disorder (HA/MCD) and one non-atopic population, finalizing in June 2021.
Participants will be randomized to receive Moderna COVID-19 Vaccine, Pfizer-BioNTech COVID-19 Vaccine or placebo [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

COVAC-IC is an ongoing prospective observational study (registered with the number NCT04805216 [University Hospitals of North Midlands NHS Trust, 2021 ]) sponsored by University Hospitals of North Midlands NHS Trust that is being conducted in the United Kingdom. It was first registered in March 18, 2021 and plans to enroll 80 immunosuppressed participants with hematological conditions that will receive several COVID-19 vaccines including Moderna COVID-19 Vaccine. It is expected to run until November 15, 2021.

Methods used to assess efficacy and effectiveness

In the COVE trial [Baden LR, 2021 ], the primary endpoint was specified as efficacy against symptomatic Covid-19 at least 14 days after the second dose among participants who were seronegative at trial entry. End points were judged by an independent adjudication committee that was unaware of group assignment.

COVID-19 cases were defined as occurring in participants who had at least two of the following symptoms: fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for SARS-CoV-2 by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of SARS-CoV-2-binding antibodies specific to the SARS-CoV-2 nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for SARS-CoV-2 RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. SARS-CoV-2-infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of SARS-CoV-2 infection were collected from participants with symptoms of COVID-19.

Methods used to assess safety

Safety assessments included: Solicited local adverse events; solicited systemic adverse events; unsolicited adverse reactions; adverse events leading to discontinuation from a dose; adverse events leading to discontinuation from participation in the trial; medically attended adverse events; serious adverse events.
End points were judged by an independent adjudication committee that was unaware of group assignment.

Efficacy and effectiveness of the vaccine

Efficacy of the vaccine in preclinical studies

The capacity to induce protective immune responses against an infectious pathogen by a directly injected, non-replicating mRNA had been previously demonstrated for other pathogens [Petsch B, 2012 ]

Direct preclinical evidence of immune response induced by Moderna COVID-19 Vaccine came from one study in nonhuman primates that received 10 or 100 µg of the vaccine or no vaccine [Corbett KS, 2020 ]. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2 and active viral replication and viral genomes in bronchoalveolar-lavage fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. The vaccination induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung.

Mutations of mRNA sequence of SARS-CoV-2, such as E484K, N501Y or K417N, can potentially reduce vaccine-elicited response. The evidence on these and other variants is still evolving but mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy [Wang Z, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

mRNA-1273-P201 (NCT04405076) was a phase 2 trial sponsored by ModernaTX, Inc. and conducted in the United States. The trial included healthy participants ≥18 years of age. The sample size was 600 (2 cohorts of 300). Participants were randomized 1: 1 to receive Moderna COVID-19 vaccine in doses of 50 µg, 100 µg or placebo. The results showed that in both vaccination schemes of mRNA-1273 vaccine, the geometric mean titers increased 28 days after the first dose. Furthermore, 14 days after the second dose (day 43), the geometric mean titers improved significantly, 1733 (1611-1865) µg/ml in the 50 µg group and 1909 (1849-1971) µg/ml in 100 µg group in young adults, while in older adults, mean titers were 1827 (1722 -1938) µg/ml in the 50 µg group and 1686 [1521-1869] µg/ml in the 100 µg group of mRNA-1273 vaccine [Chu L, 2021 ].

In the preliminary report of the phase 1 study [Jackson LA, 2020 ], it was reported that the vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. In this dose-escalation trial, in 45 adults 18 to 55 years of age antibody responses were higher with higher doses after a first vaccination, and serum neutralizing activity was detected after second vaccination.

Key messages

Moderna COVID-19 vaccine reduces the risk of contracting COVID-19

Moderna COVID-19 vaccine reduces the risk of contracting severe COVID-19


Main efficacy outcomes of Moderna COVID-19 vaccine

Contracting COVID-19 (measured at least 14 days after the second injection, with a median follow-up of 7 weeks post completion of 2nd dose)

The relative risk of contracting COVID-19 in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0.03 to 0.11). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 185 people not receiving Moderna COVID-19 vaccine out of 14073 presented this outcome (13 per 1000) versus 11 out of 14134 in the group that did receive it (1 per 1000). In other words, 12 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.2%, or that the intervention reduced the risk of contracting COVID-19 by 1.2 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 83. Which means that 83 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting severe COVID-19 (measured at least 14 days after the second injection, with a median follow-up of 7 weeks post completion of 2nd dose)

The relative risk of contracting severe COVID-19 in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.02 (95% CI 0 to 0.27). This means Moderna COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 98%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 30 people not receiving Moderna COVID-19 vaccine out of 14073 presented this outcome (2 per 1000) versus 0 out of 14134 in the group that did receive it (0 per 1000). In other words, 2 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.2%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.2 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 500. Which means that 500 people need to receive the vaccine for one of them to not contract severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting COVID-19 after the first dose (measured <14 days after first dose)

The relative risk of contracting COVID-19 among the people who only received 1 dose (<14 days) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.49 (95% CI 0.17 to 1.41). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 after the first dose (<14 days) by 51%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 after the first dose (<14 days). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 11 people not receiving Moderna COVID-19 vaccine out of 1079 presented this outcome (10 per 1000) versus 5 out of 996 in the group that did receive it (5 per 1000). In other words, 5 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.5%, or that the intervention reduced the risk of contracting COVID-19 after the first dose (<14 days) by 0.5 percentage points.
Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 200. Which means that 200 people need to receive the vaccine for one of them to not contract COVID-19 after first dose.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 after the first dose (measured at least 14  days after the first injection)

The relative risk of contracting COVID-19 after the first dose (>14 days) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.05 (95% CI 0.03 to 0.09). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 after the first dose (>14 days) by 95%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 after the first dose (>14 days). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 225 people not receiving Moderna COVID-19 vaccine out of 14073 presented this outcome (16 per 1000) versus 11 out of 14134 in the group that did receive it (1 per 1000). In other words, 15 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.5%, or that the intervention reduced the risk of contracting COVID-19 after the first dose (>14 days) by 1.5 percentage points.
Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 67. Which means that 67 people need to receive the vaccine for one of them to not contract COVID-19 after first dose (>14 days).


Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Efficacy of the vaccine in subgroups

Contracting COVID-19 after second dose (12-17y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 after second dose (12-17y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.05 (95% CI 0 to 1). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 after second dose (12-17y) by 95%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: Contracting COVID-19 after second dose (12-17y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, people not receiving Moderna COVID-19 vaccine out of presented this outcome (4 per 1000) versus out of in the group that did receive it (0 per 1000). In other words, 4 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.4%, or that the intervention reduced the risk of Contracting COVID-19 after second dose (12-17y) by 0.4 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 250. Which means that 83 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting COVID-19 (>65y) (measured at least 14 days after the second injection, with a median follow-up of 9 weeks post completion of 2nd dose)

The relative risk of Contracting COVID-19 (>65y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.14 (95% CI 0.05 to 0.39). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>65y) by 86%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: Contracting COVID-19 (>65y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 29 people not receiving Moderna COVID-19 vaccine out of 3552 presented this outcome (8 per 1000) versus 4 out of 3583 in the group that did receive it (1 per 1000). In other words, 7 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.7%, or that the intervention reduced the risk of Contracting COVID-19 (>65y) by 0.7 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 143. Which means that 83 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Summary of findings (iSoF) Table

Efficacy and effectiveness of the vaccine on subgroups

Subgroup analyses of the primary efficacy endpoint in the COVE trial showed similar efficacy point estimates across different age groups, gender, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19 [Baden LR, 2021 ].

Sex

Randomized trials
The proportion of females in the COVE trial was 47.3% (14366 out of 30351 participants) [Baden LR, 2021 ].
The relative risk of contracting COVID-19 in men that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.05 (95% CI 0.02 to 0.13), or a 95% reduction, compared with the placebo vaccine.
The relative risk of contracting COVID-19 in females that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.07 (95% CI 0.03 to 0.15), or a 93% reduction, compared with the placebo vaccine.
The magnitude of the effect was similar between the subgroups, and there was no statistical evidence of a subgroup effect by sex

Age

Randomized trials
The proportion of patients ≥65 years of age in the COVE trial was 25% (7512 out of 30351 participants) [Baden LR, 2021 ].
The relative risk of contracting COVID-19 in participants of 18 to <65 years of age that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.06 (95% CI 0.01 to 0.23), or a 94% reduction, compared with the placebo vaccine.
The relative risk of contracting COVID-19 in ≥65 years of age participants that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.14 (95% CI 0.05 to 0.39), or a 86% reduction, compared with the placebo vaccine.
The observed differences in efficacy of the vaccine between patients ≥65 years of age and participants of 18 to <65 were not statistically significant.

The phase 2, open-label study QHD00028 is currently evaluating the efficacy/safety of the vaccine in fully vaccinated adults with mRNA-1273 65 years of age and older [Sanofi Pasteur, a Sanofi Company, 2021 ].
The phase 4, randomized controlled trial mRNA-1273-D3-2021 is currently evaluating the efficacy/safety of the vaccine in vaccinated residents ≥65 years that received [Mark Loeb, 2021 ].


Non-comparative studies
The phase 1 study 20-0003 [Anderson EJ, 2020 ], NCT04283461 number, was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). This study showed that binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients. A follow up of this study at 119 days after the first vaccination [Widge AT, 2021 ] showed that despite a slight expected decline in titers of binding and neutralizing antibodies, the vaccine provided durable humoral immunity and elicited primary CD4 type 1 helper T responses.
There is no evidence that indicates a lower efficacy in older adults. It is important to notice that there were very few patients >80 years old included.

Children and adolescents

Randomized trials
The TeenCove or study P203 (NCT04649151) was a phase 2/3 trial sponsored by Moderna evaluating vaccine efficacy in adolescents from 12 to 17 years of age. Results of the study showed an efficacy of the vaccine of 95% after the second dose [Ali K, 2021 ].
P204 study (mRNA-1273-P204) is an ongoing phase 2/3, randomized trial sponsored by ModernaTX, Inc. It was first registered in March 15, 2021 and plans to enroll 6750 participants with children between 6 months of age and less than 12 years of age, finalizing in June 10, 2023.
Participants will be randomized to receive intramuscular injections of the vaccine at different doses (defined in the different states of the study), 28 days apart, on Day 1 and Day 29. [ModernaTX, Inc., 2021 ].

Race and ethnic group

Randomized trials
The proportion of white participants in the COVE trial was 79% (24024 out of 30351 participants) [Baden LR, 2021 ].
The relative risk of contracting COVID-19 in white race participants that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.07 (95% CI 0.04 to 0.13), or a 93% reduction, compared with the placebo vaccine.
The relative risk of contracting COVID-19 in communities of color that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.02 (95% CI 0 to 0.18), or a 98% reduction, compared with the placebo vaccine.
The observed differences in the efficacy of the vaccine between patients of different race and ethnic groups were not statistically significant.

Obesity

Randomized trials
The proportion of participants with severe obesity (Body Mass Index >30) in the COVE trial was 7% (2046 out of 30351 participants) [Baden LR, 2021 ].

A post-hoc analysis similarly demonstrated comparable efficacy in participants with obesity (95.8%, CI 95% 82.6- to 99.0%) versus no high-risk comorbidity (94.0%, CI 95% 83.5- to 97.8%) [FDA, 2020 ].

Some researchers have hypothesized, drawing on evidence of immune cell dysregulation and alterations in inflammatory signaling pathways, that these vaccines would offer reduced protection in obesity due to a weakened immune response, [Popkin BM, 2020 ]. Even though the COVE trial was not powered to detect differences between subgroups, the magnitude of the effect was similar between the subgroups, and there was no statistical evidence of a subgroup effect by race and ethnic group.

Pregnancy

Randomized trials
The available data are insufficient to assess vaccine efficacy since no clinical trial has included this group.

Non-comparative studies
The cohort study mRNA-1273-P902 is currently evaluating the efficacy/safety of the vaccine in pregnancy in females exposed to the Moderna COVID-19 vaccine (mRNA-1273) during pregnancy [ModernaTX, Inc., 2021 ].

Breast-feeding

Randomized trials
The available data are insufficient to assess vaccine efficacy since no clinical trial has included this group.
Non-comparative studies
Golan et al. was a prospective cohort study that enrolled 50 lactating women who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM increased significantly in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation [Golan Y et al., 2021 ].

Alisa Fox et al. was a cohort study that enrolled 50 lactating womans (23 participants had received Pfizer vaccine, 14 had received Moderna vaccine, and 13 had received Janssen Vaccine). 50 pairs of milk samples were obtained from vaccine recipients within 1 week before vaccination and that 14 days (Pfizer/Moderna) or 28 days (Janssen) after completion of the vaccine regimen. Results showed that Moderna milk samples exhibited significantly greater relative IgA compared to both Pfizer and Janssen recipients. It was found that 100% and 87% of Moderna and Pfizer recipient post-vaccine milk samples contained positive levels of Spike-specific IgG [Alisa Fox, 2021 ].
Immunocompromised persons

Randomized trials
Available data are currently insufficient to assess efficacy in persons with conditions compromising immunity since no clinical trial has included this group.

The Hall VG et al was a phase 4, randomized, placebo-controlled trial evaluating vaccine efficacy in organ-transplant recipients. Results showed that at month 4 post-vaccination, an anti-RBD antibody level of at least 100 U per milliliter was present in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group (relative risk, 3.1; 95% CI: 1.7 to 5.8; P<0.001) [Hall VG, 2021 ].

The randomized, multi-site, adaptive, open-label clinical trial DAIT ACV01 is currently evaluating the efficacy/safety of the vaccine in participants with autoimmune disease requiring immunosuppressive medications [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

The phase 3b, open-label, non-randomized study mRNA-1273-P304 is currently evaluating the efficacy/safety of the vaccine in adult solid organ transplant recipients and healthy controls [ModernaTX, Inc., 2021 ].
The phase 2, randomized, single blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].

Non-comparative studies
ICARUS-IBD was a cohort study conducted in the United States (sample size=48, including 25 receiving Moderna COVID-19 Vaccine). The study evaluated individuals with inflammatory bowel disease receiving biologics who completed two-dose vaccine schedules and found high levels of seroconversion. [Serre-Yu Wong, 2021 ]

The prospective observational study COVAC-IC is currently evaluating the immune response to Covid-19 vaccines in immunosuppressed participants with hematological conditions [University Hospitals of North Midlands NHS Trust, 2021 ].

The observational study ANTICOV is currently evaluating the effectiveness of COVID-19 mRNA vaccines Pfizer and Moderna in cancer patients aged 18 years and older receiving active therapy or who have completed their oncologic treatment within 6 months [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ].

The non-randomized study IROC is currently evaluating the efficacy/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].

The non-randomized study VIOLA is currently evaluating the immune response of the Pfizer-BioNTech and Moderna messenger RNA (mRNA)-platform vaccines in Multiple Sclerosis patients treated with Ocrelizumab [NYU Langone Health, 2021 ].

The non-randomized study VAX4FRAIL is currently evaluating the efficacy/safety of the vaccine in frail subjects with impaired immuno-competence [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].
The non-randomized study CPAT is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

The cohort, non-randomized study US-TYS-11909 is currently evaluating the efficacy/safety of the vaccine in people with multiple sclerosis aged 18 to 65 years [St. Barnabas Medical Center, 2021 ].

The non-randomized study COVIAAD is currently evaluating the efficacy/safety of the vaccine in patients with rheumatic diseases [McGill University Health Centre/Research Institute of the McGill University Health Centre, 2021 ].

The non-randomized study 000115-C is currently evaluating the efficacy/safety of the vaccine in adults 18 years of age and older with solid tumors or blood cancer [National Cancer Institute (NCI), 2021 ].

The phase 2, non-randomized study VAX-TRES is currently evaluating the efficacy/safety of the vaccine in patient with renal transplants [Maria Joyera Rodríguez, 2021 ].

The non-randomized study Deepak Sahasrabudhe et al is currently evaluating the efficacy/safety of the vaccine in cancer patients 50 to 75 years of age [University of Rochester, 2021 ].

The non-randomized study CVG01 is currently evaluating the efficacy/safety of the vaccine in immune competent subjects and patients with primary or secondary immune deficiency aged 18 years and older [GUVAX (Gothenburg University Vaccine Research Institute), 2021 ].

Persons living with HIV

Randomized trials
The proportion of participants with HIV in the COVE trial was 0.6% (179 out of 30351 participants) [Baden LR, 2021 ].
There were no reported differences in efficacy among the clinical trial participants with well controlled HIV. Available data are currently insufficient to evaluate efficacy for persons living with HIV who are not well controlled on therapy.

In a post hoc analysis, the relative risk of contracting COVID-19 in participants living with HIV that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.32 (95% CI 0.01 to 7.67) [FDA, 2020 ].

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].


Persons with recent COVID-19

Most guidelines recommend that individuals who have had COVID-19 should receive an identical vaccine regimen as those who have not had the infection.
Randomized trials
Participants with a known history of COVID-19 were excluded from the COVE trial [Baden LR, 2021 ],[FDA, 2020 ] and there was only one case of COVID-19 among study participants with positive SARS-COV-2 infection status at baseline. Thus, this trial does not offer information to assess the benefit in individuals with recent infection.

Comparative studies
Saadat S et al [Saman Saadat, 2021 ] assessed 59 health care workers with and without history of SARS-CoV-2 infection prior to vaccine. After a single dose of the SARS-CoV-2 vaccine (30/59 vaccinated with Moderna vaccine and the other half received Pfizer vaccine), individuals that had prior SARS-CoV-2 infection had higher titers of binding and functional antibodies than individuals that had no history of infection.

According to the researchers, these findings open the discussion about changing vaccination policy to deliver only a single dose to individuals with recent SARS-CoV-2 infection that may free up additional doses for individuals that have no preexisting immunity to the virus. However, no country is using previous infection as a criteria to decide who should receive the vaccine and how.

Other data from vaccine efficacy and effectiveness

Duration of protection

Randomized trials
The exact duration of protection afforded by the vaccine is unknown as it is still being determined by ongoing clinical trials.

Non-comparative studies
A follow up of the phase 1 study 20-0003 at 119 days after the first vaccination [Widge AT, 2021 ] showed that despite a slight expected decline in titers of binding and neutralizing antibodies, the vaccine provided durable humoral immunity and elicited primary CD4 type 1 helper T responses.

Limitations of vaccine effectiveness

Randomized trials
Individuals may not be fully protected until 14 days after their second dose. As with all vaccines, vaccination with Moderna COVID-19 vaccine may not protect all vaccine recipients.
SARS-CoV-2 variants

Comparative studies
Preliminary data show some reduction in neutralization activity of mRNA-1273 against the Beta (B.1.351) variant, and less marked reduction against the other variants of concern (Gamma (P1), Alpha (B.1.1.7), and Epsilon (B.1.429) [Kai Wu, 2021 ]. The impact of variants of concern on vaccine effectiveness remains unknown to date, especially for the recently emerged Delta (B.1.617.2) variant [WHO, 2021 ].
Puranik A et al was a cohort study that compared the effectiveness of two mRNA vaccines, Moderna (mRNA-1273) and Pfizer / BioNTech (BNT162b2) in vaccinated and unvaccinated individuals (n = 25,589 each) during a period in the which the Alpha or Delta variant was very prevalent. When comparing infection rates between individuals fully vaccinated with mRNA-1273 versus BNT162b2, mRNA-1273 conferred a two-fold risk reduction against breakthrough infection compared to BNT162b2 (IRR = 0.50, 95% CI: 0 , 39-0.64). The risk of infection in July after full 1273 mRNA vaccination was approximately 60% lower than after full BNT162-2 vaccination (IRR 0.39, 95% CI 0.24-0.62). The observational study highlights that while both COVID-19 mRNA vaccines protect strongly against infections and serious diseases, further evaluation is needed to analyze their effectiveness against new variants [Arjun Puranik, 2021 ].

Non-comparative studies
Da Silva et al [Wu K, 2021 ] assessed the neutralizing capacity of sera from human subjects or non-human primates that received for the United Kingdom (B.1.1.7) and Republic of South Africa (B.1.351) SARS-CoV-2 variants. No significant impact on neutralization against the B.1.1.7 variant was detected. Reduced but still significant neutralization against the B.1.351 variant was identified.
Cheng et al [Shen X, 2021 ] employed a lentivirus-based pseudovirus assay to show that variant B.1.1.7 remains sensitive to neutralization, albeit at moderately reduced levels (~2-fold), by serum samples from convalescent individuals and recipients of COVID-19 Vaccine Moderna. Some monoclonal antibodies to the receptor binding domain (RBD) of Spike were less effective against the variant while others were largely unaffected. The authors concluded that these findings indicate that B.1.1.7 is not a neutralization escape variant that would be a major concern for Moderna Vaccine, or for an increased risk of reinfection.
Several studies have assessed the neutralizing capacity of sera from human subjects that received mRNA-1273 against SARS-CoV-2 variants: [Xiaoying Shen, 2021 ], [Wang P et al., 2021 ], [Venkata Viswanadh Edara, 2021 ], [Wu K, 2021 ], [Wang P, 2021 ], [Xianding Deng, 2021 ] , [Venkata Viswanadh Edara, 2021 ], [Collier AY, 2021 ].

Safety of the vaccine

Safety of the vaccine in preclinical studies

Risk of DNA modification or infection
The mRNA platform is by definition a non-infectious, non-integrating platform. So, there is no potential risk of infection or insertional mutagenesis. The mRNA component from the vaccine does not enter the nucleus of the cell and does not affect or interact with a person‘s DNA. The mRNA is quickly degraded by normal cellular processes [Pardi N, 2018 ].

mRNA vaccine pharmacology
Naked mRNA is quickly degraded by extracellular RNase and is not internalized efficiently [Tsui NB, 2002 ].
Several modifications of the mRNA and delivery method [ Kauffman KJ, 2016 ],[Guan S, 2017 ] have been introduced to regulate degradation of mRNA by normal cellular processes, facilitate integration and promote translation, including:
The mRNA is assembled using pseudouridine, a nucleoside variant naturally occurring in the body that reduces the response of dendritic cells, interferon-associated genes and other components of the immune system to trigger an inflammatory response. [Karikó K, 2008 ].
The use of sequence-engineered mRNA avoids using chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system [Thess A, 2015 ].
The purification of the mRNA component with high performance liquid chromatography results in mRNA that does not induce an inflammatory response and is translated at 10- to 1000-fold greater levels in primary cells [Karikó K, 2011 ]
Mutations of mRNA sequence of SARS-CoV-2, such as E484K, N501Y or K417N, can potentially reduce vaccine-elicited response. The evidence on these and other variants is still evolving but mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy [Wang Z, 2021 ].
Reproductive toxicity
A study performed in rats assessing postnatal reproductive toxicity of Moderna COVID-19 vaccine was submitted to FDA on December 4, 2020. FDA review concluded that a dose of 100 µg given prior gestation periods did not have any adverse effects on female reproduction, fetal/embryonal development, or postnatal developmental [FDA, 2020 ]
Developmental and reproductive toxicology (DART) studies in rats concluded that the vaccine at a dose of 100 µg, given prior to mating and during gestation periods, did not have any adverse effects (including on female reproduction, fetal/embryonic development, or postnatal developmental).

Safety of the vaccine in clinical trials

Local adverse events after the 1st dose

The relative risk of local adverse events after the 1st dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 4.26 (95% CI 4.12 to 4.4). This means Moderna COVID-19 vaccine increased the risk of local adverse events after the 1st dose by 326%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 1st dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 2997 people not receiving Moderna COVID-19 vaccine out of 15155 presented this outcome (198 per 1000) versus 12765 out of 15168 in the group that did receive it (843 per 1000). In other words, 645 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 64.5%, or that the intervention increased the risk of local adverse events after the 1st dose by 64.5 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 2. Which means that 2 people need to receive the vaccine for one of them to experience a local adverse event after the first dose.




Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Local adverse events after the 2nd dose

The relative risk of local adverse events after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 4.76 (95% CI 4.6 to 4.92). This means Moderna COVID-19 vaccine increased the risk of local adverse events after the 2nd dose by 376%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 2735 people not receiving Moderna COVID-19 vaccine out of 14677 presented this outcome (186 per 1000) versus 13006 out of 14677 in the group that did receive it (885 per 1000). In other words, 699 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 69.9%, or that the intervention increased the risk of local adverse events after the 2nd dose by 69.9 percentage points. Another way of presenting the same information about the absolute effects is the number needed to harm (NNH), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 1. Which means that 1 person need to receive the vaccine for one of them to experience a local adverse event after the second dose.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Systemic adverse events after the 1st dose

The relative risk of systemic adverse events after the 1st dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.3 (95% CI 1.27 to 1.33). This means Moderna COVID-19 vaccine increased the risk of systemic adverse events after the 1st dose by 30%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 1st dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 6399 people not receiving Moderna COVID-19 vaccine out of 15155 presented this outcome (422 per 1000) versus 8320 out of 15168 in the group that did receive it (548 per 1000). In other words, 126 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 12.6%, or that the intervention increased the risk of systemic adverse events after the 1st dose by 12.6 percentage points. Another way of presenting the same information about the absolute effects is the number needed to harm (NNH), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 8.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Systemic adverse events after the 2nd dose

The relative risk of systemic adverse events after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.19 (95% CI 2.14 to 2.24). This means Moderna COVID-19 vaccine increased the risk of systemic adverse events after the 2nd dose by 119%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 5323 people not receiving Moderna COVID-19 vaccine out of 14677 presented this outcome (363 per 1000) versus 11652 out of 14677 in the group that did receive it (795 per 1000). In other words, 432 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 43.2%, or that the intervention increased the risk of systemic adverse events after the 2nd dose by 43.2 percentage points. Another way of presenting the same information about the absolute effects is the number needed to harm (NNH), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 2.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Any adverse event after the 1st dose

The relative risk of any adverse event after the 1st dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.83 (95% CI 1.8 to 1.86). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 1st dose by 83%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 1st dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 7284 people not receiving Moderna COVID-19 vaccine out of 15155 presented this outcome (481 per 1000) versus 13319 out of 15168 in the group that did receive it (879 per 1000). In other words, 398 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 39.8%, or that the intervention increased the risk of any adverse event after the 1st dose by 39.8 percentage points. Another way of presenting the same information about the absolute effects is the number needed to harm (NNH), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 3.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Any adverse event after the 2nd dose

The relative risk of any adverse event after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.16 (95% CI 2.11 to 2.2). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose by 116%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 6232 people not receiving Moderna COVID-19 vaccine out of 14566 presented this outcome (428 per 1000) versus 13534 out of 14677 in the group that did receive it (922 per 1000). In other words, 494 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 49.4%, or that the intervention increased the risk of any adverse event after the 2nd dose by 49.4 percentage points. Another way of presenting the same information about the absolute effects is the number needed to harm (NNH), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 2.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Non-serious adverse events

The total number of non-serious adverse events was not reported as a group, so it was not possible to estimate the effect for this outcome.

The most common non-serious adverse reactions associated with Moderna COVID-19 vaccine were pain at the injection site (91.6%), followed by fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%); local adverse reactions occurred more frequently after second dose, and were generally less frequent in younger participants (≥65 years of age).

Serious adverse events

The relative risk of serious adverse events in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.93 (95% CI 0.74 to 1.16). No statistically significant differences between groups were found for serious adverse events.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review 153 people not receiving Moderna COVID-19 vaccine out of 14566 presented this outcome (11 per 1000) versus 147 out of 153 in the group that did receive it (10 per 1000). In other words, 1 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.1%, or that the intervention reduced the risk of serious adverse events by 0.1 percentage points. Another way of presenting the same information about the absolute effects is the number needed to harm (NNH), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNH is 1000.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials
The proportion of females in the COVE trial was 47.3% (14366 out of 30351 participants) [Baden LR, 2021 ].
Safety profile of Moderna COVID-19 vaccine was similar across sex groups.

Older patients

Randomized trials
25% (7512/30351) of the participants in the COVE trial were aged 65 years or over (mean age: 70.6 years; range: 40-95 years) [Baden LR, 2021 ].

Severe adverse reactions were generally less frequent in participants ≥65 years of age as compared to younger participants [FDA, 2020 ].
Lymphadenopathy (axillary swelling and tenderness of the vaccination arm) was observed in 12.4% of vaccine recipients ≥65 years of age, as compared with 5.8% of placebo recipients [FDA, 2020 ].

The phase 2, open-label study QHD00028 is currently evaluating the efficacy/safety of the vaccine in fully vaccinated adults with mRNA-1273 65 years of age and older [Sanofi Pasteur, a Sanofi Company, 2021 ].

The phase 4, randomized controlled trial mRNA-1273-D3-2021 is currently evaluating the efficacy/safety of the vaccine in vaccinated residents ≥65 years that received [Mark Loeb, 2021 ].

Children and adolescents

Randomized trials
The TeenCove or study P203 (NCT04649151) was a phase 2/3 trial sponsored by Moderna evaluating vaccine efficacy in adolescents from 12 to 17 years of age. Results of the study showed that in the mRNA-1273 group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 93.1% and 92.4%, respectively), headache (in 44.6% and 70.2%, respectively), and fatigue (in 47.9% and 67.8%, respectively); in the placebo group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 34.8% or 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). No serious adverse events related to mRNA-1273 or placebo were noted [Ali K, 2021 ].

P204 study (mRNA-1273-P204) is an ongoing phase 2/3, randomized trial sponsored by ModernaTX, Inc. It was first registered in March 15, 2021 and plans to enroll 6750 participants with children between 6 months of age and less than 12 years of age, finalizing in June 10, 2023.
Participants will be randomized to receive intramuscular injections of the vaccine at different doses (defined in the different states of the study), 28 days apart, on Day 1 and Day 29. [ModernaTX, Inc., 2021 ].

Pregnancy

Randomized trials
One study is collecting outcomes for all reported pregnancies that occur after vaccination or were undetected prior to the trial. Through December 2, 2020, 13 pregnancies were reported (6 vaccine group and 7 in the placebo). Unsolicited AEs related to pregnancy included a case of spontaneous abortion and a case of elective abortion, both in the placebo group. However, pregnancy outcomes are still unknown at this time [FDA, 2020 ]

Non-comparative studies
An analysis of the CDC v-safe COVID-19 Pregnancy Registry in 19,252 pregnant persons who received the vaccine did not show obvious safety signals [Shimabukuro TT, 2021 ].

Evidence suggests that pregnant women with COVID-19 (second and third trimester) are at higher risk of developing severe disease compared to non-pregnant women of reproductive age. COVID-19 in pregnancy has also been associated with an increased risk of preterm birth and of neonates requiring neonatal intensive care. Pregnant women who are older (age 35 years and above), or have a high body mass index, or have existing comorbidities such as diabetes or hypertension are at particular risk of serious outcomes from COVID-19. Completed developmental and reproductive toxicology (DART) studies in animals have not shown harmful effects of the vaccine in pregnancy. Clinical trial data on safety and immunogenicity in pregnancy are not currently available but are being collected [WHO, 2021 ].

Shimabukuro et al. (CDC report) was a safety monitoring non-comparative study that enrolled 16,439 pregnant women that received Moderna or Pfizer COVID-19 vaccine. Results showed that the most frequent local and systemic reactions wer: 95.6% injection-site pain, 80.6% fatigue, 65.0% headache, 46.0% fever or felt feverish. Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported (Data based on 827 participants in the v-safe pregnancy registry who received an mRNA Covid-19 vaccine, BNT162b2 or mRNA-1273). Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases) [Shimabukuro TT, 2021 ].
The cohort study mRNA-1273-P902 is currently evaluating the efficacy/safety of the vaccine in pregnancy in females exposed to the Moderna COVID-19 vaccine (mRNA-1273) during pregnancy [ModernaTX, Inc., 2021 ].

Breast-feeding

Randomized trials
No clinical trial evaluating vaccines to prevent COVID-19 has included breast-feeding females.

Persons/ individuals with comorbidities

Randomized trials
The comorbidities studied in clinical trials include hypertension, diabetes, asthma, pulmonary disease, liver disease, kidney disease, infection with human immunodeficiency virus (HIV), hepatitis C virus and hepatitis B virus.

Non-comparative studies
The cohort, non-randomized study US-TYS-11909 is currently evaluating the efficacy/safety of the vaccine in people with multiple sclerosis aged 18 to 65 years [St. Barnabas Medical Center, 2021 ].

Immunocompromised persons

Randomized trials
Available data are currently insufficient to assess safety in severely immunocompromised persons.

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

The randomized, multi-site, adaptive, open-label clinical trial DAIT ACV01 is currently evaluating the efficacy/safety of the vaccine in participants with autoimmune disease requiring immunosuppressive medications [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].
The phase 2, randomized, single blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].

Non-comparative studies
COVAC-IC is an ongoing prospective observational study (registered with the number NCT04805216 [University Hospitals of North Midlands NHS Trust, 2021 ]) sponsored by University Hospitals of North Midlands NHS Trust that is being conducted in the United Kingdom. It was first registered in March 18, 2021 and plans to enroll 80 immunosuppressed participants with hematological conditions that will receive several COVID-19 vaccines including Moderna COVID-19 Vaccine. It is expected to run until November 15, 2021.

The non-randomized study IROC is currently evaluating the efficacy/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].

The non-randomized study LymphVAX is currently eliciting patient experiences, choices, and side effects associated with the COVID-19 vaccine after breast cancer surgery in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].

The non-randomized study VAX4FRAIL is currently evaluating the efficacy/safety of the vaccine in frail subjects with impaired immuno-competence [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].

The non-randomized study CPAT is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

The non-randomized study COVIAAD is currently evaluating the efficacy/safety of the vaccine in patients with rheumatic diseases [McGill University Health Centre/Research Institute of the McGill University Health Centre, 2021 ].

The non-randomized study 000115-C is currently evaluating the efficacy/safety of the vaccine in adults 18 years of age and older with solid tumors or blood cancer [National Cancer Institute (NCI), 2021 ].

The phase 3b, open-label, non-randomized study mRNA-1273-P304 is currently evaluating the efficacy/safety of the vaccine in adult solid organ transplant recipients and healthy controls [ModernaTX, Inc., 2021 ].

The phase 2, non-randomized study VAX-TRES is currently evaluating the efficacy/safety of the vaccine in patient with renal transplants [Maria Joyera Rodríguez, 2021 ].

The non-randomized study Deepak Sahasrabudhe et al is currently evaluating the efficacy/safety of the vaccine in cancer patients 50 to 75 years of age [University of Rochester, 2021 ].

The non-randomized study CVG01 is currently evaluating the efficacy/safety of the vaccine in immune competent subjects and patients with primary or secondary immune deficiency aged 18 years and older [GUVAX (Gothenburg University Vaccine Research Institute), 2021 ].

Persons living with HIV

Randomized trials
There were no reported differences in safety among the clinical trial participants with well-controlled HIV. Available data are currently insufficient to evaluate safety for persons living with HIV who are not well controlled on therapy.

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

Safety of the vaccine post-authorization

Post-authorization studies


Comparative studies
None available

Non-comparative studies
Gee et al. (CDC report) was a safety monitoring non-comparative study that enrolled 13,794,904 vaccine doses (Pfizer or Moderna) participants that received Moderna COVID-19 vaccine. The symptoms most frequently reported were headache, fatigue and dizziness. Sixteen reports of anaphylaxis have been confirmed after receipt of the Moderna vaccine [Gee J, 2021 ].

Desai AP et al. (CDC report) was a safety monitoring non-comparative study that enrolled 3,203 participants that received Moderna COVID-19 vaccine. Results showed that there were 39 (1.22% [95% CI: 0.83%-1.61%]) reported cases of anaphylaxis in the study [Desai AP, 2021 ].

Pawlowski C et al. was a retrospective study that enrolled 266,094 participants (36,352 Moderna doses) that received Moderna COVID-19 vaccine. Comparing the incidence rates of Cerebral venous sinus thrombosis in a 30-day time windows before and after vaccination, the study found no statistically significant differences for the COVID-19 vaccines or any other vaccines studied in this population. No cases of Cerebral venous sinus thrombosis within the 30 days following Moderna vaccine was observed (n = 36,352 Moderna doses) [Colin Pawlowski, 2021 ].

Case reports and case series
Toom et al reported a flare-up in a 36-year-old female with a past medical history of thrombocytopenia, previously classified as immune thrombocytopenic purpura, following the first dose of Moderna COVID-19 vaccine [Toom S, 2021 ]
Mehta et al reported 4 cases of unilateral axillary adenopathy after vaccination and raises the importance of considering this finding in females under evaluation of breast cancer or other malignancy [Mehta N, 2021 ].
Cirillo et al summarized orofacial adverse events from documents available in the website of regulatory agencies. They found the vaccine was associated with potential orofacial adverse effects but they were rare (up to 1 in 1000 people), including facial paralysis and facial swelling, particularly in patients who have had facial cosmetic injections [Cirillo N, 2021 ].
Munavalli GG et al reported a case series in the United States (sample size=4). The study describes cases of delayed inflammatory reactions to hyaluronic acid dermal fillers after exposure to COVID-19 vaccines. Two cases occurred after Moderna COVID-19 vaccine [Munavalli GG, 2021 ]

Spontaneous report data

Disclaimer: Reporting suspected adverse reactions after authorization of the medicinal product is important because it allows continuous monitoring of the benefit/risk balance of the vaccines. However, they do not indicate a causal association between the vaccine and the observed effects. Furthermore, this information should not be used to estimate the frequency of adverse events in people receiving the vaccine or to make comparisons between different vaccines. The information emerging about possible adverse effects needs to be carefully evaluated in order to first establish if the adverse effect might have been caused by the vaccine.

CDC COVID-19 Response Team determined a rate of 2.5 anaphylaxis cases per million Moderna COVID-19 vaccine doses administered, based on the review of reports submitted to the Vaccine Adverse Event Reporting System (VAERS). The analysis considers information entered as of January 10, 2021, when 4,041,396 first doses of Moderna COVID-19 vaccine had been administered in the United States [CDC COVID-19 Response Team, 2021 ]
Severe allergic reactions (anaphylaxis) cases were reported directly from lot 041L20A of the vaccine. Quality assessment of the lot was provided by the marketing authorization holder and by the EU regulatory organization, as being consistent with the quality specifications of previous Moderna COVID-19 vaccine lots [European Medicine Agency, 2021 ]

An analysis of the CDC v-safe COVID-19 Pregnancy Registry including data from December 2020 to February 2021 from the “v-safe after vaccination health checker” surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) was published in April 2021 [Shimabukuro TT, 2021 ]. In a sample of 16,439 pregnant persons 16 to 54 years of age who received the vaccine no obvious safety signals were observed.
Post-introduction vaccine pharmacovigilance data thus far have not identified any acute safety problems, with a reactogenicity and adverse events profile similar to that reported in the absence of pregnancy. Based on previous experience with other vaccine use during pregnancy, the effectiveness of the mRNA-1273 in pregnant women is expected to be comparable to that observed for non-pregnant women in similar age groups. Data from small studies have demonstrated that COVID-19 mRNA vaccines are immunogenic in pregnant women and that vaccine-elicited antibodies are transported to infant cord blood and breast milk, suggesting possible neonatal as well as maternal protection [Kathryn J Gray, 2021 ], [Collier AY, 2021 ]. As data from additional studies become available, recommendations will be updated accordingly [World Health Organization, 2021 ].

Monitoring

WHO recommends the following research and post-authorization monitoring activities [World Health Organization, 2021 ]:

Safety surveillance and monitoring
• Serious adverse events including myocarditis, thromboembolic events, thrombosis with thrombocytopenia syndrome (TTS), anaphylaxis and other serious allergic reactions, Bell`s palsy, and transverse myelitis
• Cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death
• Background rates of AESIs (including myocarditis, thromboembolic events, and TTS), maternal and neonatal outcomes, and mortality in groups prioritized for vaccination.

Vaccine effectiveness
− vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding;
− assessment and reporting of vaccination failures and virus sequence information.

Subgroups
− prospective studies on the safety of Moderna COVID-19 vaccine in pregnant and lactating female.
− randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− safety data on vaccination in immunocompromised persons, including persons living with HIV and persons with autoimmune disease.

Vaccination logistics
− immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− stability of the vaccine under alternative cold-chain distribution and storage conditions.
− effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− interchangeability studies within and across COVID-19 vaccine platforms.

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