Introduction
ModernaTX, Inc has submitted a Biologics License Application (BLA) STN BL 125752 for its COVID-19 vaccine, SPIKEVAX™, which is designed for active immunization against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in individuals aged 18 and older The vaccine is given intramuscularly in a two-dose series, with each dose measuring 0.5 mL and administered one month apart.
SPIKEVAX, also known as the mRNA-1273 vaccine or Moderna COVID-19 Vaccine under Emergency Use Authorization (EUA), utilizes nucleoside-modified messenger RNA (mRNA) to encode the pre-fusion stabilized spike (S) glycoprotein of SARS-CoV-2 This mRNA is encapsulated in a lipid nanoparticle (LNP) composed of four key lipids: SM-102, PEG 2000 DMG, cholesterol, and DSPC The vaccine's mechanism involves delivering these mRNA-LNPs into host cells, facilitating the expression of the SARS-CoV-2 S antigen and triggering an immune response that provides protection against the virus.
SPIKEVAX is a sterile, white to off-white suspension intended for intramuscular injection, with each 0.5 mL dose containing 0.1 mg of mRNA in buffered sucrose Notably, the vaccine is free from preservatives, antibiotics, adjuvants, and any human or animal-derived materials.
SPIKEVAX is available in two multiple-dose vial presentations: one with a 10 mL fill volume for up to 11 doses and another with a 15 mL fill volume for up to 15 doses The vaccine must be stored frozen between -50 to -15ºC but can be refrigerated at 2 to 8°C for up to 30 days before first use Prior to administration, SPIKEVAX should be thawed in the refrigerator for 2.5 hours (10 mL) or 3 hours (15 mL) and allowed to sit at room temperature for 15 minutes Alternatively, it can be thawed at room temperature for 1 hour (10 mL) or 1.5 hours (15 mL) After the first dose is withdrawn, the vial should be kept at 2 to 25ºC and used within 12 hours.
SPIKEVAX, supplied in multiple dose vials, has a shelf life of 9 months from the manufacturing date when stored at temperatures between -25°C and -15°C The manufacturing date refers to the final sterile filtration of the drug product, and any reprocessing or reworking after this stage requires prior FDA approval.
Background
SARS-CoV-2 is a zoonotic coronavirus that emerged in late 2019, initially identified in pneumonia patients of unknown cause Named for its similarity to the SARS-CoV virus, it is a positive-sense, single-stranded RNA virus that shares over 70% of its sequence with SARS-CoV and around 50% with MERS-CoV As the causative agent of COVID-19, it presents a range of symptoms, from asymptomatic or mild cases to severe respiratory illnesses like pneumonia and acute respiratory distress syndrome, which can lead to multiorgan failure and death.
The SARS-CoV-2 pandemic continues to present a challenge to global health and, as of
As of January 14, 2022, the COVID-19 pandemic has resulted in approximately 318 million cases and 5.58 million deaths globally, with the United States reporting over 65 million cases and 847,000 fatalities, according to the CDC The ongoing spread of SARS-CoV-2, along with emerging variants like Delta and the now-dominant Omicron variant, has posed significant challenges to healthcare systems, disrupted economies, and affected various aspects of daily life, including travel, employment, and education.
In December 2020, the FDA granted emergency use authorizations for two mRNA vaccines targeting the SARS-CoV-2 S glycoprotein: the Pfizer-BioNTech COVID-19 Vaccine, developed by Pfizer, Inc in collaboration with BioNTech Manufacturing GmbH, for individuals aged 16 and older, and the Moderna COVID-19 Vaccine.
In February 2021, the FDA granted an Emergency Use Authorization (EUA) for the Moderna COVID-19 vaccine, designed for individuals aged 18 and older Additionally, the FDA approved the Janssen COVID-19 Vaccine, a replication-incompetent adenovirus type 26 (Ad26)-vectored vaccine encoding a stabilized variant of the SARS-CoV-2 spike glycoprotein, also for adults 18 and older.
In 2021, the FDA expanded the EUAs for:
The Pfizer-BioNTech COVID-19 Vaccine consists of a two-dose primary series for individuals aged 5 and older, an additional third dose for those 5 and older with specific immunocompromising conditions, and a single booster dose for individuals aged 12 and older.
The Moderna COVID-19 Vaccine now offers a third primary series dose for individuals aged 18 and older who have specific immunocompromising conditions, along with a single booster dose for all individuals aged 18 and older.
• The Janssen COVID-19 Vaccine to include a single booster dose in individuals 18 years of age and older
All three vaccines were also authorized for use as a heterologous (or “mix and match”) booster dose following completion of primary vaccination with an another available COVID-19 vaccine
Several therapies, including antivirals, SARS-CoV-2 -targeting monoclonal antibodies, immune modulators and convalescent plasma, are available under emergency use
On August 23, 2021, the Pfizer-BioNTech COVID-19 Vaccine was approved for use in individuals 16 years of age and older under the trade name COMIRNATY
After the Emergency Use Authorization of COVID-19 vaccines in December 2020, the United States saw a significant decline in cases and deaths during the first half of 2021 However, the rise of the Delta variant, inconsistent public health measures, and ongoing transmission among unvaccinated individuals contributed to a resurgence of COVID-19, peaking in September 2021 The situation worsened with the detection of the first U.S case of the Omicron variant on December 1, 2021, leading to a staggering 540% increase in daily new cases over six weeks With the onset of winter and increased indoor activities, there are growing concerns that this upward trend in COVID-19 cases may persist.
The regulatory history of SPIKEVAX is summarized in Table 1
IND submission IND 19635 f or Phase 1 Study: February 20, 2020
IND 19745 f or Phase 2 Study: April 27, 2020 Fast Track designation granted May 11, 2020
Pre-BLA meeting April 28, 2021, Clinical
July 1, 2021, CMC/Regulatory BLA 125752/0 submission August 24, 2021
Mid-Cycle communication The Applicant cancelled
Late-Cycle meeting The Applicant cancelled
Chemistry Manufacturing and Controls
SPIKEVAX is an mRNA-based vaccine indicated for active immunization for prevention of
SPIKEVAX, a COVID-19 vaccine, utilizes mRNA-1273, which consists of 3819 nucleotides encoding the full-length S glycoprotein from the SARS-CoV-2 virus This mRNA is engineered with two proline residues to stabilize the S glycoprotein in its pre-fusion state It includes four regulatory elements: untranslated regions that enhance translation accuracy, a poly(A) tail for mRNA stability, and a 5’ cap for efficient translation To reduce immune reactions, N1-methyl-pseudouridine is used instead of uridine The mRNA is encapsulated in a lipid nanoparticle made of four lipids: SM-102, PEG2000-DMG, cholesterol, and DSPC SPIKEVAX is provided in multiple-dose vials as a preservative-free frozen suspension that requires thawing before use.
The manufacturing process for SPIKEVAX drug substance (DS) consists of
The SPIKEVAX DP is manufactured by filling of final containers, and labeling/packaging
The CX-024414 mRNA manufacturing process consists of
Manufacturing Process Development - CX-024414 mRNA
The manufacturing process for CX-024414 mRNA was developed progressively to support clinical development, emergency use authorization, and commercial supply The initial process was developed in the ModernaTX
To support increases in manufacturing capacity, the process underwent scale-related changes, denoted as Scale A initial Scale B and commercial Scale B
The defined increases in scale included
The major process changes implemented between the and Scale A include
Subsequent unit operations remained consistent from Scale A through commercial Scale B
The comparability of Scale A, initial Scale B, and commercial Scale B processes was established through analytical comparability assessments, including release, extended characterization, and stability testing, as well as process performance evaluations using in-process controls (IPCs) and critical process parameters (CPPs) measured against expected or proven acceptance ranges (PARs) All release results from process performance qualification (PPQ) batches produced with the commercial Scale B process met both specification and comparability criteria across various lots from ModernaTX and Lonza sites Additionally, extended analytical characterization results aligned with the expected comparability range, confirming that the manufacturing process parameters and quality attributes of Scale B were consistent across all manufacturing locations.
Manufacture of mRNA-1273 LNP DS
The mRNA-1273 LNP DS manufacturing process consists of
Manufacturing Process Development - mRNA-1273 LNP DS
The mRNA-1273 LNP DS manufacturing process
To support increases in manufacturing capacity at ModernaTX,
To support the commercial supply,
The analytical methods for the mRNA-1273 LNP
DS release and stability testing were changed concurrently with process development
Comparability Assessment - mRNA-1273 LNP DS
The comparability studies for mRNA-1273 LNP DS were performed
Analytical comparability of commercial Scale B process was demonstrated through
ModernaTX and Lonza have confirmed that all release results for the PPQ lots tested met the specified comparability acceptance criteria The extended characterization data fell within the expected ranges for all tested attributes Additionally, all CPP, CIPC, and IPC values from the process comparability lots across both manufacturing sites achieved their PARs and anticipated outcomes, demonstrating consistent performance for the commercial production of mRNA-1273 LNP DS.
SPIKEVAX DP is a sterile, preservative-free mRNA-lipid complex suspension, featuring 0.20 mg/mL of CX-024414 mRNA encapsulated in lipid nanoparticles (LNPs) This formulation includes 3.87 mg/mL of SM-102 LNPs, all within a buffer solution of 20 mM Tris and 87 g/L.
SPIKEVAX DP is a ready-to-use suspension for intramuscular injection, provided in 10-mL vials sealed with a rubber stopper and aluminum crimp flip-off seal Each vial contains sucrose and mM acetate, formulated at a pH of 7.5.
Table 2 SPIKEVAX Drug Product Composition
Unit Formula (mg/vial) ( -mL fill)
Unit Formula (mg/vial) ( -mL fill)
Unit Formula (mg/dose) (0.5 mL dose)
CX-024414 mRNA mRNA that encodes for the pre-f usion stabilized Spike glycoprotein of 2019-novel Coronavirus (SARS-CoV-2)
SM-102 Lipid Nanoparticles (The individual lipids make up the Lipid Components of the SM-102 LNP)
Acetic acid Buf fer components for
Sodium Acetate buffer in LNP
Water f or injection Diluent q.s 1.0 mL q.s 0.5 mL
Abbreviations: DSPC = 1,2-distearoyl-sn-glycero-3-phosphocholine; q.s = quantum sufficit
The SPIKEVAX DP manufacturing processes at Catalent and Baxter facilities are very similar and consist of the same unit operations, i.e.,
Manufacturing process development for SPIKEVAX DP
Scale A process, at ModernaTX and then scaled at Catalent (Bloomington, IN) To support emergency use authorization and commercial supply, the commercial Scale B process at
The analytical methods were developed alongside the process development, ensuring that no changes were made that would affect the comparability of data generated from tests This approach maintains the integrity of the comparison between clinical development and commercial lots.
For comparison between manufacturing scales, the SPIKEVAX DP analytical comparability was assessed using relevant release, stability, and extended characterization testing against pre-
The acceptance criteria were clearly defined, and the results from the CPP and IPC were assessed against anticipated ranges to demonstrate the comparability of process performance To determine the expected analytical ranges, initial baseline comparability studies (Phase 1) were conducted utilizing development, clinical, GMP, and PPQ batches.
The post-change comparability of the commercial Scale B process was assessed in Phase 2 and Phase 3 studies that were performed at Catalent and Baxter manufacturing sites All CPP,
CIPCs and IPCs for the commercial process successfully met their PARs and expected ranges, showcasing reliable performance in the commercial production of SPIKEVAX DP across all filling lines at both manufacturing sites Release testing of PPQ lots was conducted according to the established specifications for each fill presentation The results from the Scale B -mL fill presentation DP batches produced at Catalent and Baxter indicate that the manufacturing processes and quality attributes remain consistent before and after changes.
Stability Summary and Conclusion and Stability Data
The SPIKEVAX DP lots have an initial proposed shelf life of 9 months when stored in commercial container-closure systems at recommended long-term conditions of -25 to -15°C (-20°C) This shelf life accommodates up to 30 days of storage at 2 to 8°C (5°C) and allows for up to 24 hours at room temperature (25°C) to facilitate vaccine administration at point-of-care sites.
The tests and specifications applied for routine release of SPIKEVAX are shown in Table 3
Table 3 Testing Specifications for SPIKEVAX
Appearance Visual White to off-white dispersion May contain visible, white or translucent product-related particulates Identity
Container Content a Maximum 11 Dose (0.5 mL per dose) Presentation
Option A: 11 doses of 0.5 mL from 1 vial Option B: 10 doses of 0.5 mL from 1 vial Maximum 15 Dose (0.5 mL per dose) Presentation Syringe/Needle:
Option A: 15 doses of 0.5 mL from 1 vial Option B: 13 doses of 0.5 mL from 1 vial Bacterial Endotoxins
No growth Container-Closure Integrity
End of Shelf Life Pass a Container content is measured based on SOP-1229
The analytical methods and their validation and/or qualification for the SPIKEVAX DS and DP were found to be adequate for release testing and stability monitoring c CBER Lot Release
The revised lot release protocol template has been deemed acceptable, and a lot release testing plan developed by CBER will be implemented for routine lot release Additionally, a thorough facilities review and inspection process has been established.
The facility information and data presented in the Biologics License Application (BLA) for the Moderna COVID-19 Vaccine were deemed sufficient and acceptable A detailed list of the facilities involved in the vaccine's manufacturing is provided in Table 4, which also outlines the performed activities and inspection histories associated with each facility.
Table 4 Manufacturing Facilities Table for SPIKEVAX (COVID-19 Vaccine, mRNA)
Drug Substance mRNA and LNP manufacture
Drug Substance mRNA and LNP manufacture
Catalent Indiana, LLC (subsidiary of
Fill/f inish, labeling, packaging and release testing (sterility)
Fill/f inish, labeling, packaging and release testing (sterility)
The Data Universal Numbering System (DUNS) and FDA Establishment Identifier (FEI) are crucial for regulatory compliance in the pharmaceutical industry Lipid nanoparticles (LNP) play a significant role in drug delivery systems, while the Office of Regulatory Affairs (ORA) assesses compliance, indicating "no action indicated" (NAI) or "voluntary action indicated" (VAI) as necessary Additionally, the Office of Biological Products Operations (OBPO) oversees the regulation of biological products, ensuring safety and efficacy in the market.
CBER conducted a Pre-License Inspection (PLI) of Aldevron, LLC in November 2021 No Form FDA 483 was issued, and the inspection was classified as no action indicated (NAI)
CBER performed a PLI of ModernaTX, Inc in October 2021 No Form FDA 483 was issued, and the inspection was classified NAI
In October 2021, CBER conducted a Pre-License Inspection (PLI) of Lonza Biologics, Inc., resulting in the issuance of a Form FDA 483 at the conclusion of the inspection The company addressed the observations made, and their corrective actions were deemed satisfactory upon review All inspectional concerns were effectively resolved, leading to the classification of the inspection as voluntary action indicated (VAI).
CDER inspected the Catalent facility in Bloomington, IN for a different drug product This PLI was conducted in August/September 2020 Catalent is one of two Contract Manufacturing
The organizations overseeing the fill/finish operations, release, and stability testing of SPIKEVAX have successfully addressed all inspectional issues, resulting in the classification of the inspection as Voluntary Action Indicated (VAI) Following the inspection, a Form FDA 483 was issued, but all concerns were resolved promptly.
ORA/OBPO performed a surveillance inspection of the Baxter facility in Bloomington, IN in
November 2021 A Form FDA 483 was issued at the end of the inspection All inspectional issues were resolved, and the inspection was classified VAI
ORA performed a surveillance inspection of
A Form FDA 483 was issued at the end of the inspection All inspectional issues were resolved, and the inspection was classified as VAI e Container/Closure System
The commercial multiple-dose SPIKEVAX DP lots are packaged in a primary container closure system that includes a vial, stopper, and seal Each vial is filled with bulk DP and sealed with a 20-mm stopper and aluminum seal These vials are packaged in secondary cartons, with each carton containing 10 vials Finally, 12 cartons are grouped together in a case for distribution.
Table 5 Container Closure Configurations for Multiple Dose mRNA-1273 DP Vials
Vial 10R clear Type 1 borosilicate glass vials
Vial 10-mL vial, RTU, sterile
Vial 10R clear Type 1 equivalent alkali aluminosilicate glass vial Vial 10R clear Type 1 borosilicate glass vial
Seal 20 aluminum seal with f lip-off plastic cap
20 mm aluminum seal f Environmental Assessment
The BLA included a request for categorical exclusion from an Environmental Assessment under
21 CFR 25.31 The FDA concluded that this request is justified, and no extraordinary circumstances exist that would require an environmental assessment
Nonclinical Pharmacology/Toxicology
Developmental Assessment and Reproductive Toxicology (DART) Study
In a developmental toxicity study, female rats were administered 0.2 mL of a nucleoside-modified mRNA vaccine formulation (100 mcg) on four occasions: 28 and 14 days before mating, and on gestation days 1 and 13 The study found no vaccine-related fetal malformations or adverse effects on postnatal development Additionally, Immunoglobulin G (IgG) responses to the pre-fusion stabilized spike protein antigen were detected in both maternal samples and F1 generation rats, indicating successful antibody transfer from mother to fetus and nursing pups.
Non-GLP Repeat Dose Toxicity and Immunogenicity Study
A report detailing a non-good laboratory practice (GLP) repeat-dose toxicity and immunogenicity study of the mRNA-1273 vaccine administered via IM injection in rats has been submitted and reviewed under the Biologics License Application (BLA) The study involved four groups of rats, with five males and five females per group, receiving two doses tri-weekly.
In a study involving intramuscular administrations of a Tris/sucrose buffer containing 30, 60, or 100 mcg of the mRNA-1273 vaccine, all treated animals exhibited dose-dependent edema at the injection site, with or without hindlimb impairment, beginning 24 hours post-administration and resolving by the end of the week Additionally, dose-independent hematological changes indicative of inflammation were observed, including significant increases in neutrophil and eosinophil counts across all treatment groups Slight, non-dose-dependent increases in triglycerides and cholesterol were also recorded in male rats.
Antibodies targeting the spike protein were detected in serum samples collected on day 13 after the second dose The study did not assess organ weight, gross pathology, or histological examinations Additionally, results from the intramuscular repeat dose rat toxicity study indicated that vaccine doses were tolerated at levels up to a specified threshold.
100 mcg (two doses given three weeks apart) were well-tolerated
The safety of SPIKEVAX is reinforced by comprehensive toxicity evaluations, including six GLP studies on various vaccines formulated with SM-102 lipid particles containing mRNAs for viral glycoprotein antigens, which showed no adverse effects from repeat doses Additional toxicology assessments, such as an in vitro rat micronucleus assay, indicated no genotoxic potential of mRNA in SM-102 LNP Furthermore, studies on PEG2000-DMG, including a bacterial reverse mutation test and an in vitro mammalian cell micronucleus test, also confirmed the absence of genotoxic effects.
A biodistribution study specifically for the mRNA-1273 vaccine was not conducted; however, data from a biodistribution study of a different vaccine, produced using the same methodology as SPIKEVAX and containing 100 µg mRNA in SM-102-based lipid nanoparticles (LNPs), were provided to support SPIKEVAX's approval Since biodistribution and retention are characteristics of the LNP rather than the mRNA itself, the findings from this study were deemed supportive for the approval of the SPIKEVAX Biologics License Application (BLA).
Non-Clinical Effectiveness Pharmacology Studies
Non-clinical pharmacology studies conducted in mice, rats, hamsters, and non-human primates showed that the mRNA-1273 vaccine effectively generated binding and neutralizing antibodies against the Wuhan-Hu1 strain of SARS-CoV-2 These studies indicated a Th1-biased immune response and demonstrated that the vaccine protected the animals from viral replication and weight loss when challenged with SARS-CoV-2.
(b) (4) (b) (4) virus, while no enhanced respiratory disease was observed In addition, no other safety concerns were raised by these studies.
Clinical Pharmacology
Clinical studies have shown that SPIKEVAX elicits a humoral immune response targeting the SARS-CoV-2 spike protein However, the specific immunologic mechanisms that provide protection against SARS-CoV-2 remain unclear.
Clinical/Statistical
Clinical Diagnostic Assays Used to Support Primary Clinical Efficacy Endpoints
RT-qPCR Assay by Eurofins-Viracor for the Quantification of SARS-CoV-2 RNA
In 2020, the FDA granted Emergency Use Authorization (EUA) for a reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay developed by Eurofins Genomics and validated by Eurofins-Viracor to quantify SARS-CoV-2 RNA, specifically targeting the viral nucleocapsid (N) protein This assay effectively detects SARS-CoV-2 RNA in upper respiratory samples, including nasal swabs and bronchoalveolar lavage The comprehensive validation report detailed extraction and RT-qPCR methods, assessing analytical sensitivity, accuracy, precision, and stability This assay is instrumental in determining baseline SARS-CoV-2 status, identifying asymptomatic and symptomatic infections, and quantifying viral load over time to evaluate the mRNA-1273 vaccine's impact on infection kinetics, demonstrating its robust validation for diagnostic and viral load assessments.
Two anti-SARS-CoV-2 N protein immunoassays were used to assess baseline infection status by detecting anti-N protein IgG antibodies present in human serum and plasma
• enzyme-linked immunosorbent assay (ELISA) anti-N protein (quantitative method)
Both assays were performed and validated at In addition, the anti-N ELISA was used to quantify anti-N titers as exploratory endpoints in studies P201 and P301
Two anti-S immunoassays were used to quantify primary (study P201) or secondary (study P301) IgG S-protein binding antibody (bAb) immunogenicity endpoints in human sera:
• ELISA anti-S-2P (SARS-CoV-2 spike protein modified with 2 proline substitutions) to assess IgG antibodies against S-2P within the
• was developed to measure spike, receptor binding domain, and nucleocapsid proteins but the assay was only validated to measure binding IgG antibodies against the spike protein
The ELISA was validated at and the assay was validated at the
Two neutralizing antibody assays were used to quantify neutralizing antibodies in serum or plasma samples:
• Live-Virus Microneutralization (MN) assay was validated at
• Pseudovirus Neutralization Assay was initially developed at the but was transferred and validated at the
The validation reports for all assays were deemed acceptable, but only the Pseudovirus Neutralization Assay was utilized to evaluate neutralizing antibodies in clinical study P301.
The BLA submissions include several key studies summarized in Table 6, with a primary focus on the mRNA-1273-P301 study This multi-center, Phase 3, randomized, blinded, placebo-controlled study evaluates the safety, immunogenicity, and efficacy of the mRNA-1273 vaccine Additionally, the mRNA-1273-P201 Phase 2 dose-confirmation study investigated two different dose levels of the vaccine Furthermore, Phase 1 Study 20-0003 represents an open-label, dose-ranging, first-in-human trial of the mRNA-1273 vaccine.
Table 6 Clinical Trials Submitted in Support of Efficacy and Safety Determinations of the Moderna COVID-19 Vaccine mRNA-1273
Study Design, Type of Control
Dose Levels Assessed (amount of mRNA per dose) Study Status
30415 Phase 3, randomized, stratif ied, observer-blind, placebo-controlled study
600 Phase 2a randomized, observer-blind, placebo- controlled, dose- conf irmation study
120 Phase 1 open- label dose-ranging study
Ongoing a Sponsor: Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
The ongoing mRNA-1273-P301 study is a randomized, observer-blind, placebo-controlled trial assessing the efficacy, safety, and immunogenicity of the mRNA-1273 vaccine, administered in two doses 28 days apart to adults aged 18 and older Conducted at 99 sites across the United States, the study involves 415 participants who are randomly assigned in a 1:1 ratio to receive either the mRNA-1273 vaccine (100 mcg) or a placebo on Days 1 and 29 Participants are categorized into three groups based on age and health risk: those aged 18 to 64 without risk for severe COVID-19, those aged 18 to 64 with risk for severe COVID-19, and individuals aged 65 and older.
In a study comprising 41.4% of the participants at risk for severe COVID-19, individuals with underlying comorbidities such as diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease, or HIV infection were identified Notably, around 25% of the participants were healthcare workers, and the anticipated duration of participation in the study is approximately 25 months.
Primary efficacy objective: To demonstrate the efficacy of mRNA-1273 vaccine to prevent
COVID-19 starting 14 days after the second dose
Primary safety objective: To evaluate the safety and reactogenicity of 2 doses of the mRNA-1273 vaccine given 28 days apart
Secondary efficacy objectives: To demonstrate the efficacy of mRNA-1273 vaccine to prevent:
• Severe COVID-19 starting 14 days after the second dose.
• Serologically confirmed SARS-CoV-2 infection or COVID-19 regardless of symptomatology or severity.
• COVID-19 as defined by a secondary definition.
• COVID-19 starting 14 days after the first dose.
• COVID-19 regardless of evidence of prior SARS-CoV-2 infection.
Secondary immunogenicity objective: To evaluate the immunogenicity of 2 doses of mRNA-1273 vaccine given 28 days apart
The primary efficacy endpoint of the study was to assess the vaccine's effectiveness in preventing protocol-defined COVID-19 cases occurring at least 14 days after the second dose in participants who tested negative for SARS-CoV-2 at baseline This was determined through negative reverse transcription polymerase chain reaction (RT-PCR) and serology against SARS-CoV-2 nucleocapsid on Day 1 A confirmed COVID-19 case was defined as a positive RT-PCR result from a nasopharyngeal swab, nasal swab, saliva sample, or respiratory sample if the individual was hospitalized.
• At least TWO of the following systemic symptoms: Fever (≥38ºC), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR
• At least ONE of the following respiratory signs/ symptoms: cough, shortness of breath or difficulty breathing, or clinical or radiographical evidence of pneumonia
Participants who experienced COVID-19 symptoms during post-vaccination follow-up were prompted to schedule an unscheduled illness visit and undergo an NP swab If any symptom persisted for at least 48 hours—excluding fever and respiratory symptoms, which could last for any duration—the site organized an illness visit to collect an NP swab sample within 72 hours of the onset of symptoms.
• Fever (temperature ≥ 38ºC) or chills (of any duration, including ≤48 hours)
• Shortness of breath or difficulty breathing (of any duration, including ≤48 hours)
• Cough (of any duration, including ≤48 hours)
• New loss of taste or smell
The secondary efficacy endpoint evaluated COVID-19 using a broader definition from the CDC, which includes a positive NP swab, nasal swab, saliva sample, or respiratory sample for SARS-CoV-2 confirmed by RT-PCR, along with the presence of any systemic symptoms.
• shortness of breath or difficulty breathing,
• muscle aches or body aches,
• new loss of taste or smell,
• nausea or vomiting, or diarrhea
Another secondary endpoint assessed cases of severe COVID-19, defined as a case of confirmed COVID-19 plus at least one of the following:
• Clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths per minute, heart rate ≥125 beats per minute, SpO 2 ≤93% on room air at sea level, or
• Respiratory failure or acute respiratory distress syndrome (defined as needing high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation);
• Evidence of shock (systolic blood pressure