Safety and Immunogenicity of RNA-based Vaccines Against SARS-CoV-2 Variants in Healthy Participants

COVID-19 Clinical Trial

Official title:

A Phase II Trial to Evaluate the Safety and Immunogenicity of SARS-CoV-2 Monovalent and Multivalent RNA-based Vaccines in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05004181
• Other study ID #: BNT162-17
• Secondary ID: 2021-003458-22
• Status: Completed
• Phase: Phase 2
• Start date: August 25, 2021
• Est. completion date: October 4, 2023

Study information

• Verified date: November 2023
• Source: BioNTech SE
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial consists of three parts, Part A, Part B, and Part C, and will evaluate the safety and immunogenicity of a third booster injection of the multivalent vaccine BNT162b2 (B.1.1.7 + B.1.617.2), and the safety and immunogenicity of a third booster injection of the monovalent vaccine BNT162b2 (B.1.617.2) or BNT162b2 (B.1.1.7), in participants who have received two doses of the parent vaccine BNT162b2 at 30 µg, at least 6 months after the second dose of BNT162b2. It will also evaluate the safety and immunogenicity of a three-dose regimen of BNT162b2 (B.1.1.7 + B.1.617.2) in participants who have not received prior Coronavirus Disease 2019 (COVID-19) vaccination. In addition, the safety and immunogenicity of BNT162b2 (B.1.1.529.1) or BNT162b2 given as a third or fourth vaccine dose to RNA COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection will be evaluated and contrasted with the natural immune response reached after infection with the SARS-CoV-2 Omicron variant.

Description:

Trial participants in Part A will be assigned to one of 6 cohorts (Cohort 1-6). Trial participants in Part B will be assigned to one of 3 cohorts (Cohort 1, 4, and 6). Trial participants in Part C will be randomized in a 2:2:1 ratio into 3 cohorts (Cohort 7-9).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1383
• Est. completion date: October 4, 2023
• Est. primary completion date: August 16, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Have given informed consent by signing the informed consent form (ICF) before initiation of any trial-specific procedures.
• Volunteers who at the time of consent are:
• Part A: 18 to 55 years old.
• Part B and Part C: 18 to 85 years old (~60% should be 18 to 55 years old and ~40% 56 to 85 years old).
• For Cohorts 1 to 5: In Part A, who have received BNT162b2 vaccine (30 µg, two-dose regimen) in either a clinical trial or as part of the governmental vaccination programs at least 6 months before Visit 0. Participants who are currently enrolled in the Phase III BNT162-02 / C4591001 trial, have already been unblinded, and have previously received two doses of BNT162b2 at least 6 months earlier can be included (for Cohorts 1 and 4 in Part B, prior enrollment and dosing in the BNT162-02 / C4591001 trial is mandatory). At enrollment into Part B of this trial, their participation in the BNT162-02 / C4591001 trial will be terminated. Participants should have not experienced COVID-19 based on medical history.
• For Cohort 6: Are COVID-19 vaccine-naïve and have not experienced COVID-19 based on their medical history.
• Are willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other trial procedures.
• Are overall healthy at Visit 0 in the clinical judgment of the investigator based on the medical history, clinical assessment (including physical examination, vital signs, blood and urine clinical laboratory tests, 12-lead electrocardiogram (ECG), and oral swab for Nucleic Acid Amplification-based Test (NAAT)-based Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing).
• Note: Healthy volunteers with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 12 weeks before Visit 0, can be included.
• Note: Volunteers who had hepatitis C (HCV) infection, but have completed curative treatment based on the medical history can be included. Volunteers who had or have hepatitis B (HBV) or human immunodeficiency virus (HIV) based on the medical history cannot be included.
• Agree not to enroll in another trial of an Investigational Medicinal Product (IMP), starting after Visit 0 and continuously until the last planned visit in this trial.
• Women of childbearing potential (WOCBP) must test negative in a urine beta-human chorionic gonadotropin (ß-HCG) test at Visits 0 and 1.
• WOCBP must agree to practice a highly effective form of contraception starting at Visit 0 and continuously until 28 days after their last IMP administration in this trial.
• WOCBP must confirm that they practiced an acceptable form of contraception for the 14 days prior to Visit 0.
• WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction starting after Visit 0 and continuously until 28 days after their last IMP injection in this trial.
• Men who are sexually active with a WOCBP and have not had a vasectomy must agree to use a highly effective form of contraception with their female partner of childbearing potential starting after Visit 0 and continuously until 28 days after their last IMP injection in this trial.
• Men must be willing to refrain from sperm donation, starting after Visit 0 and continuously until 28 days after their last vaccination.
• For Part C, Cohorts 7, 8, and 9: have received two or three documented doses of any authorized COVID-19 RNA-based vaccine (e.g., BNT162b2 [Comirnaty] or the Moderna vaccine [Spikevax]) prior to being diagnosed with SARS-CoV-2 infection from January 2022 onwards (and limited to a period when there was a high prevalence of SARS-CoV-2 Omicron infections).
• Note: The interval between the last COVID-19 RNA-based vaccine administered and randomization should be >4 months. The latest prior diagnosed SARS-CoV-2 infection should be at least 2 months before randomization. The latest SARS-CoV-2 infection should be documented with a result from a NAAT (as a preferable option). In case no historic NAAT result is available proving prior SARS-CoV-2 infection, the local positive result of SARS-CoV-2 N-binding antibodies done at screening will be sufficient.

Exclusion Criteria:

• Any existing condition which may affect vaccine injection and/or assessment of local reactions assessment, e.g., tattoos, severe scars, etc.
• Any bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
• Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that, in the investigator's judgment, make the participant inappropriate for the trial.
• Any current febrile illness (body temperature =38.0°C/=100.4°F) or other acute illness within 48 h prior to Day 1/IMP injection in this trial.
• Any current or history of cardiovascular diseases, e.g., myocarditis, pericarditis, myocardial infarction, congestive heart failure, cardiomyopathy or clinically significant arrhythmias, unless such disease is not considered relevant for participation in this trial in the investigator's judgment.
• History of COVID-19 and/or clinical (based on COVID-19 symptoms/signs alone, if a SARS CoV 2 NAAT result was not available) or microbiological (based on COVID-19 symptoms/signs and a positive SARS CoV 2 NAAT result) evidence of prior infection with SARS CoV 2 at screening (Visit 0).
• Note: not applicable for Part C.
• History of Guillain-Barré syndrome.
• Known or suspected immunodeficiency.
• History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g., anaphylaxis) to any component of the trial IMPs.
• History or known allergy, hypersensitivity, or intolerance to the trial IMP including any excipients of the IMPs in this trial.
• Have received any SARS CoV 2 vaccination other than BNT162b2 (30 µg BNT162b2 given as a course of two doses approximately 21 days apart).
• Note: not applicable for Part C.
• Have received a live or live attenuated vaccine within 28 days prior to Day 1/IMP injection.
• Have received any other vaccines within 14 days before or after any IMP injection, e.g., influenza, tetanus, pneumococcal, hepatitis A or B. When possible standard or care vaccinations should be planned with the trial IMP administrations in mind.
• Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are administered for =14 days at a dose of =20 mg/day of prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned receipt throughout this trial. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.
• Receipt of blood/plasma products or immunoglobulin, from 60 days before IMP administration or planned receipt throughout this trial.
• Participation in other trials involving IMP within 28 days or 5 half-lives (whichever is longer) prior to Visit 1 and/or during trial participation, besides participation in trials with BNT162b2.
• Are pregnant or breastfeeding or are planning pregnancy within 28 days after last IMP treatment.
• Are vulnerable individuals as per International Conference on Harmonisation (ICH) E6 definition, i.e., are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.
• For Part C, Cohorts 7, 8, and 9: Vaccination with other non-RNA or unauthorized COVID-19 vaccines.
• For Part C, Cohorts 7, 8, and 9: Vaccination with any COVID-19 vaccine after SARS-CoV-2 infection from January 2022 onwards (and limited to a period when there was a high prevalence of SARS-CoV-2 Omicron infections).

Related Conditions & MeSH terms

• COVID-19
• Respiration Disorders
• Respiratory Tract Diseases
• SARS (Disease)
• SARS-CoV-2 Acute Respiratory Disease
• SARS-CoV2 Infection

Intervention

Biological:
• BNT162b2
Intramuscular (IM)
• BNT162b2 (B.1.1.7 + B.1.617.2)
Intramuscular (IM)
• BNT162b2 (B.1.1.7)
Intramuscular (IM)
• BNT162b2 (B.1.617.2)
Intramuscular (IM)
• BNT162b2 (B.1.1.529.1)
Intramuscular (IM)

Other:
• Observational
No vaccination within 3 months after Visit 1.

Locations

Country	Name	City	State
Germany	CRS Clinical Research Services Berlin	Berlin
Germany	IKF Institut fuer klinische Forschung Frankfurt	Frankfurt am Main
Germany	CRS Clinical Research Services Mannheim GmbH	Mannheim
Germany	Studienzentrum Brinkum Dr. Lars Pohlmeier und Torsten Drescher	Stuhr
South Africa	Worthwhile Clinical Trials	Benoni
South Africa	JOSHA Research	Bloemfontein	Free State
South Africa	Tiervlei Trial Centre	Cape Town
South Africa	Midrand Medical Centre	Halfway House
South Africa	Newtown Clinical Research	Johannesburg
South Africa	Langeberg Medicross Medical Centre	Kraaifontein	Western Cape
South Africa	Paarl Research Centre	Paarl	Western Cape
South Africa	Botho ke Bontle Health Service	Pretoria
South Africa	Global Clinical Trials	Pretoria
South Africa	Jongaie Research, Medicross Pretoria West	Pretoria
South Africa	Synexus SA Stanza Clinical Research Centre	Pretoria
South Africa	Synexus Helderberg Clinical Trial Centre	Somerset West	Western Cape
Turkey	Ankara University Faculty of Medicine, Avicenna Hospital	Ankara
Turkey	Hacettepe University Hospital	Ankara
Turkey	Bagcilar Medipol Mega University Hospital	Istanbul
Turkey	Istanbul University Medical Faculty	Istanbul
Turkey	Kocaeli Universitesi Tip Fakultesi	Kocaeli
United States	Atlanta Center for Medical Research	Atlanta	Georgia
United States	ARC Clinical Research	Austin	Texas
United States	Aventiv Research Inc.	Columbus	Ohio
United States	North Texas Infectious Diseases Consultants	Dallas	Texas
United States	Medpharmics, LLC	Gulfport	Mississippi
United States	Collaborative Neuroscience Network LLC	Long Beach	California
United States	Clinical Research Consulting, Llc	Milford	Connecticut
United States	Rochester Clinical Research	Rochester	New York
United States	Clinical Trials of Texas Inc.	San Antonio	Texas
United States	Diagnostics Research Group	San Antonio	Texas
United States	California Research Foundation	San Diego	California
United States	Meridian Clinical Research	Savannah	Georgia
United States	Stamford Therapeutics Consortium	Stamford	Connecticut
United States	Amici Clinical Research	Warren	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
BioNTech SE

Countries where clinical trial is conducted

United States,  Germany,  South Africa,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All parts - Percentage of participants reporting local reactions at the injection site	Local reactions (pain, tenderness, erythema/redness, induration/swelling).	up to 7 days after each dose
Primary	All parts - Percentage of participants reporting systemic events	Systemic events (fever, fatigue, headache, chills, vomiting, nausea, diarrhea, new or worsened muscle pain, and new or worsened joint pain).	up to 7 days after each dose
Primary	All parts - Percentage of participants reporting adverse events (AEs)		Part A and B: Dose 1 up to 1 month after each dose; Part C: Dose 1 up to 1 month after the last dose
Primary	All parts - Percentage of participants reporting serious adverse events (SAEs)		Dose 1 up to 6 months after the last dose
Primary	Part B - GMR of B.1.1.7 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III C4591001 trial.	GMR = Geometric mean ratio; NT = neutralizing titers	1 month
Primary	Part B - GMR of B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial		1 month
Primary	Part B - GMR of B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial		1 month
Primary	Part B - The difference in Seroresponse (SR) to B.1.1.7	The difference in SR to B.1.1.7 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial.	1 month
Primary	Part B - The difference in SR to B.1.617.2	The difference in SR to B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial.	1 month
Primary	Part B - The difference in SR to B.1.617.2 NT 1 month after 1 dose of BNT162b2 (B.1.617.2) on BNT162b2-experienced participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial		1 month
Primary	Part B - GMR of B.1.1.7 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial		1 month
Primary	Part B - GMR of B.1.617.2 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III BNT162-02 / C4591001 trial		1 month
Primary	Part B - The difference in SR to B.1.1.7 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III C4591001 trial		1 month
Primary	Part B - The difference in SR to B.1.617.2 NT 1 month after 2 doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants to the reference strain NT 1 month after 2 doses of BNT162b2 in participants from the Phase III C4591001 trial		1 month
Primary	Part B - GMR of reference strain NT in participants with evidence of prior infection to the reference strain NT in participants without evidence of infection (COVID-19 vaccine-naïve participants)	GMR of reference strain NT 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection to the reference strain NT 1 month after two doses of BNT162b2 in participants without evidence of infection from the Phase III trial BNT162-02 / C4591001.	1 month
Primary	Part B - The difference in SRs to the reference strain NT in subjects with evidence of prior infection and to the reference strain NT in participants without evidence of infection (COVID-19 vaccine-naïve participants)	The difference in SRs to the reference strain NT 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and to the reference strain NT 1 month after two doses of BNT162b2 in participants without evidence of infection from the Phase III trial BNT162-02 / C4591001.	1 month
Primary	Part C - GMR of B.1.1.529.1 NT 1 month after one dose of BNT162b2 (B.1.1.529.1) in RNA-based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection to those at 1 month after one dose of BNT162b2 for Cohorts 7 and 8.		1 month
Primary	Part C - The difference in SR of B.1.1.529.1 NT 1 month after one dose of BNT162b2 (B.1.1.529.1) in RNA-based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection to those at 1 month after one dose of BNT162b2 for Cohorts 7 & 8.		1 month
Secondary	Part A - Geometric mean titer (GMT) at each timepoint	For BNT162b2-experienced participants (defined as participants who have previously received two injections of 30 µg BNT162b2). Reference and variant(s) of concern (VOC) specific NT.	Day 1 up to Day 421
Secondary	Part A - Geometric mean fold rises (GMFR) from before vaccination to each subsequent time point after vaccination	For BNT162b2-experienced participants (defined as participants who have previously received two injections of 30 µg BNT162b2). Reference and VOC specific NT.	Day 1 to Day 421
Secondary	Part A - SR in terms of NT at each post vaccination time point	For BNT162b2-experienced participants (defined as participants who have previously received two injections of 30 µg BNT162b2). Reference and VOC specific NT.	Day 1 to Day 421
Secondary	Part B Cohort B1 - GMT - B.1.1.7 + B.1.617.2 vs BNT162b2	VOC and reference strain-specific NTs in participants from the BNT162-17 trial (BNT162b2-experienced participants) and reference strain NTs in participants from the Phase III BNT162-02 / C4591001 trial.; GMTs and SRs of VOCs and reference strain NT 1 month after 1 dose of BNT162b2 (B.1.1.7 + B.1.617.2) and dose 2 of BNT162b2.	Day 1 to Day 360
Secondary	Part B Cohort B4 - GMT - B.1.617.2 vs BNT162b2	VOC and reference strain-specific NTs in participants from the BNT162-17 trial (BNT162b2-experienced participants) and reference strain NTs in participants from the Phase III BNT162-02 / C4591001 trial (BNT162b2-experienced participants).; GMTs and SRs of VOCs and reference strain NT 1 month after 1 dose of BNT162b2 (B.1.617.2) and dose 2 of BNT162b2.	Day 1 to Day 360
Secondary	Part B Cohort B6 - GMT - B.1.1.7 + B.1.617.2 to the reference strain	VOC and reference strain NTs in participants from the BNT162-17 trial and reference strain NTs in participants from the Phase III BNT162-02 / C4591001 trial (COVID-19 vaccine-naïve participants).; GMTs and SRs of VOCs and reference strain NT 1 month after dose 2 and dose 3 of BNT162b2 (B.1.1.7 + B.1.617.2).	Day 1 to Day 386
Secondary	Part B - GMTs - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) and in BNT162b2- experienced participants without evidence of infection (one booster dose)	GMTs and SRs of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and 1 month after one booster dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants without evidence of infection.	Day 1 to Day 29
Secondary	Part B - GMR - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to in BNT162b2- experienced participants without evidence of infection (one booster dose)	GMR of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection to the VOCs NT 1 month after one booster dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2-experienced participants without evidence of infection.	Day 1 to Day 29
Secondary	Part B - Difference in SRs to VOCs in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to VOCs in BNT162b2- experienced participants without evidence of infection (one booster dose)	The difference in SRs to VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and to the VOCs NT 1 month after one booster dose of BNT162b2 (B.1.1.7 + B.1.617.2) in BNT162b2- experienced participants without evidence of infection.	Day 1 to Day 29
Secondary	Part B - GMTs - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) and in COVID-19 vaccine-naïve participants without evidence of infection (two primary doses)	GMTs and SRs of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection and 1 month after two doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants without evidence of infection.	Day 1 to Day 50
Secondary	Part B - GMR - VOC in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to in COVID-19 vaccine-naïve participants without evidence of infection (two primary doses)	GMR of VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in participants with evidence of prior infection to the VOCs NT 1 month after two doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants without evidence of infection.	Day 1 to Day 50
Secondary	Part B - Difference in SRs to VOCs in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) to in COVID-19 vaccine-naïve participants without evidence of infection (two primary doses)	The difference in SRs to VOC specific NTs (B.1.1.7, B.1.617.2, B.1.1.529.5 [Omicron BA.5]) 3 weeks after one dose of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants with evidence of prior infection (one primary dose) and to the VOCs NT 1 month after two doses of BNT162b2 (B.1.1.7 + B.1.617.2) in COVID-19 vaccine-naïve participants without evidence of infection.	Day 1 to Day 50
Secondary	Part C - GMT - B.1.1.529.1 in RNA based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection	VOC NT in RNA-based COVID-19 vaccine-experienced participants with history of SARS-CoV-2 infection at baseline and 7 days, 1 month, and 3 months after the trial start for Cohorts 7, 8, and 9, and 6 and 12 months after the trial start for Cohorts 7 and 8.	Day 1 to Day 360