Having a pre-established public-private relationship and a high level of trust and confidence between partners was an important factor for making quick decisions needed to achieve rapid vaccine development in the midst of a pandemic.
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I’m going to introduce you to some of the students who helped do some of the lab work as we started making protein and developing assays to measure antibody responses. This is Olu Abiona, headed to an MD, PhD program.pic.twitter.com/p8IJNoTaMk
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This is Cynthia Ziwawo who is now a medical student. Her specialty was the ELISA that we used to measure antibody responses.pic.twitter.com/6Tdo5qngcm
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Geoffrey Hutchinson is now a graduate student continuing his work on vaccine design. He was a big part of the team in those early days.pic.twitter.com/eOeZCbpguX
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One year ago today I was in Barcelona giving a talk at the childhood pneumonia meeting while the team I introduced was making our first batch of nCoV spike protein. The virus was called novel coronavirus before it was called SARS-CoV-2.pic.twitter.com/tiDezkjbxD
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A few days earlier we were scrambling to find enough media to do the transfections. One part of the VRC had to borrow from another as supplies were backordered, but no days were lost. All hands on deck.pic.twitter.com/xtFoRsejTx
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The result of all the effort to advance the project without wasting any days resulted in eluting our first batch of nCoV spike protein on Jan. 30, 2020. We immediately sent protein and plasmids to CDC and to other collaborators. Dr. Fauci mentioned our work at ASM Biothreats mtg.pic.twitter.com/yj326e9z2e
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On Jan 31st, 2020 I was headed back to the airport after the childhood pneumonia meeting and checked in with Jason McLellan
@McLellan_Lab He and Daniel Wrapp had already obtained preliminary data on the nCoV spike structure in just 20 days from the time of sequence posting.pic.twitter.com/qzUYbrt9A0
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The first atomic level crystal structure of a virus glycoprotein (influenza hemagglutinin) was published by Ian Wison, John Skehel, and Don Wiley in Nature Jan 29, 1981. We are just passing the 40th anniversary of that event. HA is another class 1 fusion protein like CoV spike.
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On Feb 2, 2021 I got an email from Ugur Sahin from BioNtech who wanted to talk about vaccine antigen designs. I called and told him about our work on spike structure and stabilization and expression of trimeric antigens by gene-based delivery.
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I meant to add that on Feb 1 we used the protein first made on Jan 31 to test an ELISA. This is a method for measuring antibody. The protein is put on the bottom of each well then serum dilutions are added. More yellow means more antibody. You can see color changes with dilutions
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Feb 3,2020 Jason and Daniel Wrapp
@McLellan_Lab had refined the structure and we started writing the paper. Knowing protein is in the right conformation is what gives the confidence to construct diagnostics, make reagents for mAb discovery, and make vaccines.Show this thread -
Feb 4, 2020 was a big day. Several hundred mice were immunized with nCoV spike protein and the first research grade batch of mRNA-1273 expressing stabilized spike. Multiple dose levels & mouse strains used. Starting multiple groups gave flexibility for later experimental choices.
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I’m out of practice. Here are the ELISA plates that go with Feb 1, 2020 comment. Also, since I can’t edit, the year for the Feb 2 comment was written 2021 and should have been 2020.pic.twitter.com/mOT3EoBtQ0
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I’m going to review the connections between respiratory syncytial virus work over last few decades and current coronavirus vaccines. To put into context, RSV was discovered in 1956 and there are <20K scientific papers in the entire field. There are ~100K COVID papers in 1 yr.
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RSV is in Pneumovirus family. Used to be a paramyxovirus. Both are enveloped RNA viruses. They have a fusion (F) protein that is analogous to Spike protein on CoV. F rearranges to pull cell membrane into virus and fuse so virus genome can get in cell to start replicating.
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This was a big day one year ago. We immunized mice with mRNA-1273 on Feb 4th and collected serum 14 days later. You often don’t see much antibody response this soon after single dose and that’s why you typically need a second dose. This would be first indication of immunogenicity
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In this case, the ELISA plates turned bright yellow almost instantly meaning there was a strong antibody response to single 1 ug mRNA injection. We were still building virus to measure neutralizing activity, but seeing this was an indication we were making spike-binding antibody.
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March 11 was one year anniversary of the WHO declaration that COVID-19 was a pandemic disease and beginning of lockdown in the US. We were just a few days away from starting phase 1 study, which began as a demonstration project but now became an advanced development program.
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We had reached several milestones by this point last year. The paper describing the structure of the nCoV (I.e. SARS-CoV-2) spike went online 2/19/20. This was critical, because we had no mAb reagents yet other than what we had made from SARS-1 survivor PBMCs apheresed in 2018.
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Knowing the spike protein was in the right conformation gave us confidence to develop ELISA and NT assays, make probes for mAb discovery, and proceed with vaccine development despite not having the usual reagents to characterize the authenticity of the structure.
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I’m breaking my daughters 3 tweet per day rule because I got behind on the story over the last 3 weeks. Another milestone was Abcellera starting sorting survivor PBMCs on 2/27/21 with the spike probes we sent with the cells. A bonus or byproduct of the new vaccine technologies.
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By this week last year we had a working version of pseudovirus NT assay and obtained mouse sera from 2w post 2nd dose. At the time, what seemed like striking levels of neutralizing activity had been induced by mRNA-1273 which was important for me to see before starting phase 1.
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In the days prior to the start of the mRNA-1273 phase 1 last year we were frantically trying to keep up with requests for spike protein and plasmids and were shipping reagents all over the world. We were also trying to connect people with adjuvants to other groups with proteins.
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We were setting up shipments to have immunized mice challenged with Ralph Baric’s mouse-adapted virus and beginning NHP studies. Calls from collaborators & journalists flooding in and we were trying to cope with limited access of personnel to bench space because of lockdown.
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Importantly, we had already shipped spike probes and PBMCs to Abcellera and they had sequenced sorted B cells and selected antibodies that we had screened and already identified potent neutralizing mAbs. When Lilly got involved, manufacturing and clinical development sped up.
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One year ago (3/16/20) that Moderna Phase 1 started at the Kaiser Permanente Clinic in Seattle. COVID-19 had just begun spreading in US especially in Seattle. This created an unexpected complication for conducting trials while keeping staff and subjects safe and out of quarantine
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1 year ago today is when I first knew the vaccine was likely to work. Those first 8 subjects were boosted with 2nd dose on April 13th and on 4/27/20 serum was obtained. We had shown antibody responses occurred even after 1st dose, but still had not measured neutralizing activity.
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On May 9, 2020 I got a call from Jim Chappel and Mark Denison at Vanderbilt. They had been measuring neutralizing activity of vaccinee serum against live SARS-CoV-2 in their BL3 lab. They described the results and then showed me the curves. The potency was better than expected.
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Neutralization means that something can prevent virus infection of cells. This usually is based on serum antibodies that block attachment or interfere with protein rearrangement required for membrane fusion. The measurement is done by exposing virus to a range of serum dilutions.
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The neutralizing curve created by plotting serum dilutions against reduction of virus infection has several important features. It makes a sigmoid, S-shaped curve. It is usually reported as the dilution that caused 50% or 80% reduction. Having a steep slope in the curve is good.
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