pfizer omicron vaccine trials pfizer omicron vaccine trials

[TimeFrame:At 1 week after study vaccination. Copyright 2023 Genetic Engineering & Biotechnology News. ], Cohorts 2+3 (18-55 yrs), Cohorts 2+3 (>55 yrs): GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 Substudy E). ], Cohorts 2+3 (18-55 yrs), Cohorts 2+3 (>55 yrs): GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 Substudy E). Pfizer expects to charge a private market price ranging from $110130 a dose (the same range as rival Modernas vaccine). Suburban campuses as well as downtown buildingsmany transformed from office or other commercial usehave helped the New York metro area grow into a vibrant regional cluster for biotech and other life sciences, said Nancy J. Kelley, a founding member of Builds Bio+, which recently expanded its focus beyond New York City. ], Cohort 2: Geometric Mean Titers (GMT) of SARS-CoV-2 Omicron (BA.4/BA.5), Omicron (BA.1), and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g or 60 g [TimeFrame:At 1 month after study vaccination. The U.S so far has secured 171 million doses of Pfizer's and Moderna's new boosters. All vaccines in this study are investigational but are very similar to BNT162b2 (Comirnaty), a COVID-19 RNA vaccine approved for use in the US and in many countries. hide caption. The lack of human data for the BA.5 shots has caused some controversy, but Dr. Peter Marks, a senior FDA official, said the agency followed the same process used for years with strain changes for flu vaccines. A Division of NBCUniversal. Prof Ugur Sahin, CEO and co-founder of BioNTech, said new data indicated that "vaccine-induced protection against infection and mild to moderate disease wanes more rapidly than was observed with prior strains". Then finally, Cohort 3 of the Pfizer study will include participants who have not received a COVID vaccine at all yet. On board the worlds last surviving turntable ferry. The European Union bloc is reportedly negotiating an amended deal with Pfizer Inc (NYSE: PFE) and BioNTech SE (NASDAQ: BNTX) for around 70 million Access unmatched financial data, news and content in a highly-customised workflow experience on desktop, web and mobile. The real Biden was executed for his crimes long ago along with Clinton.". Capable of giving signed informed consent. Some countries have already started offering additional booster doses, but a recent study from Israel showed that while a fourth dose of an mRNA vaccine boosted antibodies, the level was not high enough to prevent Omicron infection. Participation in other studies involving a study intervention within 28 days before randomization. The CDC and FDA used human data from clinical trials for shots targeting the original version of omicron, BA.1, which triggered a stronger immune response than the old vaccines. But once we do, we find that our attrition is lower, Bjornson observed. Moderna presented data showing that the BA.5 shots increased antibodies in mice more than fourfold compared with the old shots. I think the ability to retain talent is very good. Among individuals 12 to 17 years of age who had received only one dose of Pfizer-BioNTech COVID-19 Vaccine, those who had evidence of previous infection with Australia's flagship carrier, Qantas Airways Ltd , on Tuesday named its finance chief Vanessa Hudson to serve as its new chief executive starting in November, making her the first woman to lead the century-old airline. ], Cohorts 2+3 (18-55 yrs), Cohorts 2+3 (>55 yrs): GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 Substudy E). It is unrelated to safety. ], Cohort 1: Percentages of participants with seroresponse to BNT162b5 Bivalent (WT/OMI BA.2) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g in terms of GMTs of SARS-CoV-2 Omicron (BA.2), Omicron (BA.1), and reference strain neutralizing antibody levels. Pfizer acquired in 2009 for $68 billion, and based as many as 4,000 people in Pearl River before eliminating its consumer health production and later its vaccine production operations, shrinking its workforce to about 700 by 2016. ], Cohorts 2+3 (18-55 yrs), C2+3 (>55 yrs): % of participants with seroresponse to BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 SSE) for GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels. It gave confidence for the companynot just for those of us in R&D but the whole companythat this is an environment that we can invest in and be successful in.. 11 . Read about our approach to external linking. Millions of Americans could be eligible for new Covid booster, Alzheimers patients may wait years to get treated with new drugs, putting them at risk of more severe disease, Carl Icahn calls Illumina Q1 results very disappointing, slams cost-cutting plan, DOJ sues Tennessee, alleging it discriminates against transgender youth with new law, Abortion pill mifepristone is banned or restricted in some states despite Supreme Court ruling, Eli Lilly says obesity drug tirzepatide resulted in weight loss of up to 34 pounds, Eli Lilly misses on earnings but raises full-year guidance, Merck results beat expectations despite a big drop in sales of Covid antiviral treatment, FDA grants accelerated approval for Biogen ALS drug that treats rare form of the disease, Mpox outbreak was wake-up call for smallpox preparation, vaccine maker Bavarian Nordic says, Johnson & Johnson to price shares of consumer spinoff Kenvue at $20 to $23 in IPO. A continued decline in COVID-19 vaccines and related products caused a 34% revenue decline. Chick-fil-A donates another $1.8 million to anti-LGBTQ groups, backtracking on its promise not to. 1. Pfizer also said it was developing a vaccine tailored to combat the omicron variant of the virus which has spread rapidly around the globe in recent weeks. Driving Pfizers planned expansion is a desire to deliver a proverbial shot in the arm to its vaccine development effort as the explosive revenue growth generated by the COVID-19 vaccines it has co-developed with BioNTech fades. [TimeFrame:From before study vaccination (Day 1) to 1 month after study vaccination. ], Cohort 2: Geometric Mean Titers (GMT) of SARS-CoV-2 Omicron (BA.4/BA.5), Omicron (BA.1), and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g or 60 g [TimeFrame:At 3 months after study vaccination. Were moving in a variety of ways to advance science in so many different fields. "This study is part of our science-based approach to develop a variant-based vaccine that achieves a similar level of protection against Omicron as it did with earlier variants, but with longer duration of protection," he added. [TimeFrame:At 6 months after study vaccination], Cohorts 2+3 (>55 yrs) Superiority analysis: Geometric Mean Ratio (GMR) of SARS-CoV-2 Omicron (BA.4/BA.5)-neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g to BNT162b2 30 g (C4591031 Substudy E). "The data are illustrating the impact of a booster and that our vaccine works best as a primary regimen of three doses," Pfizer's chief scientific officer, Mikael Dolsten, said on a conference call, according to Reuters. ], Cohort 2: Geometric Mean Titers (GMT) of SARS-CoV-2 Omicron (BA.4/BA.5), Omicron (BA.1), and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g or 60 g [TimeFrame:Before study vaccination (Day 1). The company turns over four to five percent of its Pearl River staff each year, adding to Pfizers challenge of attracting researchers and other employees to the site in suburban Rockland County, about an hours drive north of Times Square. have received 3 prior doses of 30 micrograms BNT162b2, with the last dose being 150 to 365 days before Visit 1 of this study. Pfizers vote of confidence, their thumbs up, their decision to expand on the campus is huge. You have reached the maximum number of saved studies (100). Screen for heightened risk individual and entities globally to help uncover hidden risks in business relationships and human networks. ], Cohort 1: Percentages of participants with seroresponse to BNT162b5 Bivalent (WT/OMI BA.2) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g in terms of GMTs of SARS-CoV-2 Omicron (BA.2), Omicron (BA.1), and reference strain neutralizing antibody levels. Participants 12-17 years old will receive 30 g of BNT162b2 Bivalent (WT/OMI BA.4/BA.5) at Visit 1. The space is going to allow us to catch up, accommodate many of the new staffers who are now in leased buildings and leased spaces, bringing more of them into our core campus, and also have the opportunity for us to grow over time.. [Pfizer]Pfizers expansion planwhich the company has dubbed Project Vitalitywould allow the pharma giant to expand the sites current workforce of more than 1,200 people (another 50 positions are open), by creating lab and office capacity for up to 370 additional staffers for future growth, and thus expand vaccine R&D operations that grew dramatically during the pandemic. "The study will now include evaluating a third dose of 3 [micrograms] at least two months after the second dose of the two-dose series to provide high levels of protection in this young age group," the companies said in a statement. Nam Y. Huh/AP Deaths and hospitalizations from Covid among people ages 65 and older have increased since April, according to Heather Scobie, a CDC epidemiologist who presented data during Thursday's meeting. BNT162b5 Wild Type and BNT162b5 OMICRON [B.1.1.529 sublineage BA.2]. May 01, 2023 - 03:23 PM. Individual Participant Data (IPD) Sharing Statement: Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: have received 1 booster dose of a US-authorized COVID-19 vaccine, with the last dose being 90 or more days before Visit 1 of this study. The bivalent doses were authorized for emergency use in August 2022.. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study vaccines. Los Angeles-based IRG operates over 150 industrial and other commercial properties in 31 states with over 100 million square feet of rentable space. For Cohort 3, this study is seeking participants who are: Choosing to participate in a study is an important personal decision. Pfizer has said that two doses of the original vaccine may not be sufficient to protect against infection from Omicron, and that protection against hospitalizations and deaths may be waning. 33701 Washington, DC The companies said two doses did not produce a robust immune response in kids 2 to 5 years old. They study is about 6 months long for each participant. The FDA authorizes COVID booster shots for all U.S. adults. [TimeFrame:At 1 month after study vaccination. But Oliver noted that the risk of myocarditis following a BA.5 booster shot is unknown. The Center for Disease Control and Prevention cleared the reformulated omicron boosters Thursday. On April 18, the agency said it was revoking the emergency use authorization for the original Moderna and Pfizer-BioNTech monovalent vaccines to focus on newer, bivalent vaccines. Although there's no data on the real-world effectiveness of the new boosters, the U.S. is moving rapidly to roll them out in the hope that they will protect people this fall. ], Cohort 1: Percentages of participants with seroresponse to BNT162b5 Bivalent (WT/OMI BA.2) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g in terms of GMTs of SARS-CoV-2 Omicron (BA.2), Omicron (BA.1), and reference strain neutralizing antibody levels. Pfizer is planning a $470 million expansion of its Vaccine Research and Development facilities in Pearl River, NY, that it hopes to start work on next year. Dr. Pablo Sanchez, the only committee member who voted against the shots, called the recommendation premature and said the U.S. should have waited for human data before proceeding with the boosters. The shots were developed against the first strain that emerged in China, so they are no longer matched to target the omicron subvariants that are spreading. Pfizer aims to build 260,000 new square feet of space, including 55,000 square feet of new labs. Pfizer also said 30 million of a planned 80 million treatment courses of its Paxlovid antiviral pill will be available in the first six months of 2022. ], Cohort 2: GMFR (change between 2 timepoints) of SARS-CoV-2 Omicron (BA.4/BA.5), Omicron (BA.1), and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g or 60 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g or 60 g.. [TimeFrame:From before study vaccination (Day 1) to 1 month after study vaccination. Walensky said her decision followed "a comprehensive scientific evaluation and robust scientific discussion.". WebPfizer Inc. and BioNTech SE have started a trial evaluating an adapted version of their Covid-19 vaccine that targets the Omicron variant of the coronavirus.. "While current research and real-world data show that boosters continue to provide a high level of protection against severe disease and hospitalization with Omicron, we recognize the need to be prepared in the event this protection wanes over time and to potentially help address Omicron and new variants in the future," Pfizer's head of vaccine research and development, Kathrin Jansen, said in a statement. The bivalent vaccines protect against multiple variants, including the more recent omicron strain. The Centers for Disease Control and Prevention cleared reformulated Covid shots that target the latest omicron subvariants for the fall, making it possible for many people to get an extra booster within days. Participation in other studies involving receipt of a study intervention within 28 days before randomization. But protection against infection and mild symptoms is much lower and could decline more quickly. The eligible age groups can receive the boosters at least two months after completing their primary series or their most recent booster with the old shots. Vaccine makers Pfizer and BioNTech announced plans early Tuesday to test an omicron-specific COVID-19 vaccine in people. Pfizer and Moderna are continuing with clinical trials to see how their Omicron-specific whole-spike vaccines fare in people. Deaths have risen in particular among people ages 75 and older, Scobie said. Reuters, the news and media division of Thomson Reuters, is the worlds largest multimedia news provider, reaching billions of people worldwide every day. The FDA said it was authorizing the use of the current bivalent vaccines (that combat the original and omicron BA.4/BA.5 strains) for all people 6 months of age and older. "There's a lot of vaccine hesitancy already we need the human data," said Sanchez, a professor of pediatrics at Ohio State University. An independent committee recommended shots, which target the dominant omicron BA.5 subvariant. ], Cohorts 2+3 (18-55 yrs), C2+3 (>55 yrs): GMFR (change between 2 timepoints) of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 Substudy E). [TimeFrame:At 3 months after study vaccination. [TimeFrame:From before study vaccination (Day 1) to 1 month after study vaccination. Pfizer's omicron boosters are for people ages 12 and older, while Moderna's updated shots are for adults ages 18 and older. Pfizer expected to report diluted EPS declined about 41% to 80 cents from $1.37. Pfizer's clinical trial is also ongoing, though company hasn't said when it expects results. Hochul wants quarantine camps and imprisonment if youre suspected of having a disease. 1800 I Street NW Information provided by (Responsible Party): Participants will receive 30 g of BNT162b5 Bivalent (WT/OMI BA.2) at Visit 1. CDC Director Dr. Rochelle Walensky signed off on the shots a few hours later, clearing the way for pharmacies to soon start administering the shots. The companies say they expect to produce four billion doses of their Covid-19 vaccine this year, and this number will include doses of the updated vaccine if trials suggest it is needed. ], Cohort 1: Percentages of participants with seroresponse to BNT162b5 Bivalent (WT/OMI BA.2) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g in terms of GMTs of SARS-CoV-2 Omicron (BA.2), Omicron (BA.1), and reference strain neutralizing antibody levels. The CDC has shifted to a more targeted public health response with an emphasis on protecting the most vulnerable the elderly, people with serious medical conditions and those who have weak immune systems. ], Cohorts 2+3 (18-55 yrs), C2+3 (>55 yrs): % of participants with seroresponse to BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 SSE) for GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels. Well that vaccine is no longer authorized for use by the FDA," read one April 18 tweet that shared a screenshot of the FDAs announcement., But these posts dontdetail what changed or why., The FDA granted emergency use authorization to the monovalent COVID-19 vaccines in late 2020, and full approval in August 2021 and January 2022. While those revenues rose about three percent from $36.78 billion in 2021, the company has guided investors to expect only about ~$13.5 billion this year64% less than 2022as government contracts give way to commercial sales. 20006, Florida [TimeFrame:At 1 month after study vaccination. All Cohorts: Percentage of participants reporting local reactions [TimeFrame:For 7 days following the study vaccination], All Cohorts: Percentage of participants reporting systemic events [TimeFrame:For 7 days following the study vaccination], All Cohorts: Percentage of participants reporting adverse events [TimeFrame:For 1 month following the study vaccination], All Cohorts: Percentage of participants reporting serious adverse events [TimeFrame:For 6 months following the study vaccination], Cohort 1: Geometric Mean Titers (GMT) of SARS-CoV-2 Omicron (BA.2), Omicron (BA.1), and reference strain neutralizing antibody levels for BNT162b5 Bivalent (WT/OMI BA.2) 30 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g [TimeFrame:Before study vaccination (Day 1). It hopes to show the antibodies neutralise a spectrum of variants. "The goal of this vaccine is to protect against serious illness," said Dr. Paul Offit, an infectious disease expert at the University of Pennsylvania. The purpose of this clinical trial is to learn about the safety, extent of the side effects, and immune responses of the study vaccine (called bivalent BNT162b2 Omicron containing vaccine) in healthy children. Autocracies have grown weaker, not stronger.. [TimeFrame:At 1 month after study vaccination], Cohort 2: % of participants with seroresponse to BNT162b2 Bivalent(WT/OMI BA.4/BA.5) 30g or 60g and BNT162b2 Bivalent(WT/OMI BA.1) 30g or 60g for GMTs of SARS-CoV-2 Omicron(BA.4/BA.5), Omicron(BA.1), and reference strain neutralizing antibody levels. So, cost was definitely a factor, Bjornson explained. Pfizer and BioNTech have begun a clinical trial for their Omicron-specific Covid-19 vaccine candidate, they announced in a news release on Tuesday. [TimeFrame:At 1 month after study vaccination. "Today, FDA amended the (Emergency Use Authorizations) of the Pfizer-BioNTech and Moderna COVID-19 bivalent mRNA vaccines to simplify the vaccination schedule for most individuals," the FDA wrote on Twitter.. Both Moderna and Pfizer and its German partner BioNTech created boosters that contain instructions for making the BA.4 and BA.5 omicron subvariants spike The industry leader for online information for tax, accounting and finance professionals. [TimeFrame:From before study vaccination (Day 1) to 6 months after study vaccination. This is a 2-part study to evaluate the immunogenicity, safety, and reactogenicity of mRNA-1273.529 and mRNA-1273.214 administered as a booster dose. In the trial of the new vaccine, 615 adults will receive two doses of the current Pfizer-BioNTech vaccine, followed by one or two doses of the Omicron-targeted jab. Attracting talent is where we put a lot of our effort.. 801 3rd St. S read more. Pfizer wanted a way that all our colleagues can enter the site and feel like theyre walking into a place theyre proud to work in, Bjornson said. The agency's independent committee on vaccines voted 13 to 1 earlier Thursday in favor of the shots after reviewing the available safety and effectiveness data over an almost seven-hour-long meeting. The bivalent vaccines protect against multiple variants, including the more recent omicron strain. iCampus selling points include the ability to accommodate life sciences as well as vivarium, manufacturing, distribution, warehouse, data center, and office uses; about 30 acres of available land for development; a central utility plant serving all its buildings; as well as proximity to Interstates 87 (New York State Thruway) and 287, the Garden State and Palisades Interstate parkways, Routes 303/304 and 59, and the Nanuet and Pearl River commuter rail stations serving Metro-North Railroad and New Jersey Transit trains on the Pascack Valley Line. Bjornson said Pfizers decision to stay in Pearl River came down to people and money. The companies plan to study the safety and tolerability of the shots in the more than 1,400 people who will be enrolled in the trial. ], Cohorts 2+3 (18-55 yrs), C2+3 (>55 yrs): % of participants with seroresponse to BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 SSE) for GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels. Video shows Russian President Vladimir Putin talking in English about U.S. democracy. The most common side effects from the human trials of the BA.1 shots was pain, redness, swelling at the injection site, fatigue, headaches, muscle pain, joint pain, chills, nausea, vomiting and fever, according to the FDA. Browse an unrivalled portfolio of real-time and historical market data and insights from worldwide sources and experts. Depending on the amount of clinical trial data required by regulators, it may not be possible to realize a current plan to launch an Omicron-targeting vaccine by the end of March, BioNTech said. For all cohorts (groups of participants), this study is seeking participants who are healthy (who may have preexisting disease if it is stable); All participants will receive a single dose of the study vaccine at the first study clinic and will return to the study clinic at least 4 more times. A third dose was 77% effective at prevention hospitalization four months after receiving the shot, but protection declined after 120 day to as low as 34%, according to CDC data. Sign up for free newsletters and get more CNBC delivered to your inbox, Get this delivered to your inbox, and more info about our products and services., 2023 CNBC LLC. ], Cohorts 2+3 (18-55 yrs), C2+3 (>55 yrs): % of participants with seroresponse to BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g and BNT162b2 30 g (C4591031 SSE) for GMTs of SARS-CoV-2 Omicron (BA.4/BA.5) and reference strain neutralizing antibody levels. ], Cohort 2: GMFR (change between 2 timepoints) of SARS-CoV-2 Omicron (BA.4/BA.5), Omicron (BA.1), and reference strain neutralizing antibody levels for BNT162b2 Bivalent (WT/OMI BA.4/BA.5) 30 g or 60 g and BNT162b2 Bivalent (WT/OMI BA.1) 30 g or 60 g. Best Debt Consolidation Loans for Bad Credit, Personal Loans for 580 Credit Score or Lower, Personal Loans for 670 Credit Score or Lower. The decision to focus on BA.5 did not leave enough time to wait for data from human trials ahead of a fall vaccine rollout. iCampus consists of about two million square feet that is 43% occupied by 23 tenants including Pfizer, with more than 20 of the buildings vacant and available for lease. [TimeFrame:At 1 week after study vaccination], Cohort 2: % of participants with seroresponse to BNT162b2 Bivalent(WT/OMI BA.4/BA.5) 30g or 60g and BNT162b2 Bivalent(WT/OMI BA.1) 30g or 60g for GMTs of SARS-CoV-2 Omicron(BA.4/BA.5), Omicron(BA.1), and reference strain neutralizing antibody levels. [TimeFrame:At 3 months after study vaccination. If anything, the pandemic showed us what an amazing crown jewel we had in Pearl River, and we dont need to go anywhere else to be successful, Bjornson told an audience of biopharma executives, business professionals and others at a recent event held by Builds Bio+, which advances life sciences development in the New York and Philadelphia regions, at Innolabs in Long Island City, NY. "We know that the myocarditis risk is unknown but anticipate a similar risk to that seen after the monovalent vaccines," Oliver said. Moderna is also trialling a "bivalent" version that combines the original vaccine, as well as the new Omicron-specific spike mRNA. [TimeFrame:At 6 months after study vaccination. But Dr. Sarah Long, also a committee member, said there's no reason to expect the BA.5 boosters will be inferior to the old shots since they also include the original Covid strain, and they have potential to reduce hospitalizations and deaths heading into the fall and winter. Newest Booster Vaccines May Help You. - Received 3 prior doses of 30 micrograms BNT162b2, with last dose being 150 to 365 days before first study visit. Pfizers vaccines are designed to protect against childhood, adolescent, and adult infectionsincludingmeningococcal disease,influenza, Lyme disease, respiratory syncytial virus (RSV), and Clostridioides (C) difficile. We might not have to wait too long to find out how well they work. Data is a real-time snapshot *Data is delayed at least 15 minutes. BNT162b2 Wild Type and BNT162b2 OMICRON [B.1.1.529 sublineage BA.1].