mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

 Zijun Wang, Fabian Schmidt, Yiska Weisblum, Frauke Muecksch, Christopher O. Barnes, Shlomo Finkin, Dennis Schaefer-Babajew, Melissa Cipolla, Christian Gaebler, Jenna A. Lieberman, Zhi Yang, Morgan E. Abernathy, Kathryn E. Huey-Tubman, Arlene Hurley, Martina Turroja, Kamille A. West, Kristie Gordon, Katrina G. Millard, Victor Ramos, Justin Da Silva, Jianliang Xu, Robert A. Colbert, Roshni Patel, Juan Dizon, Cecille Unson-O’Brien, Irina Shimeliovich, Anna Gazumyan, Marina Caskey, Pamela J. Bjorkman, Rafael Casellas, Theodora Hatziioannou, Paul D. Bieniasz, Michel C. Nussenzweig

doi: https://doi.org/10.1101/2021.01.15.426911

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.01.15.426911v1.full.pdf

ABSTRACT

To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected nearly 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease-2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3–5. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S), receptor binding domain (RBD) binding titers3,5. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection6,7. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

Competing Interest Statement

The Rockefeller University has filed a provisional patent application in connection with this work on which Z.W. and M.C.N. are inventors (US patent 63/021,387).

https://www.biorxiv.org/content/10.1101/2021.01.15.426911v1

Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera

 Alexander Muik, Ann-Kathrin Wallisch, Bianca Sänger, Kena A. Swanson, Julia Mühl, Wei Chen, Hui Cai, Ritu Sarkar, Özlem Türeci, Philip R. Dormitzer, Ugur Sahin

doi: https://doi.org/10.1101/2021.01.18.426984

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF: https://www.biorxiv.org/content/10.1101/2021.01.18.426984v1.full.pdf

Abstract

Recently, a new SARS-CoV-2 lineage called B.1.1.7 has emerged in the United Kingdom that was reported to spread more efficiently than other strains. This variant has an unusually large number of mutations with 10 amino acid changes in the spike protein, raising concerns that its recognition by neutralizing antibodies may be affected. Here, we investigated SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 16 participants in a previously reported trial with the mRNA-based COVID-19 vaccine BNT162b2. The immune sera had equivalent neutralizing titers to both variants. These data, together with the combined immunity involving humoral and cellular effectors induced by this vaccine, make it unlikely that the B.1.1.7 lineage will escape BNT162b2-mediated protection.

Competing Interest Statement

U.S. and O.T. are management board members and employees at BioNTech SE. A.M., A.W., J.M. and B.S. are employees at BioNTech SE. U.S., O.T. and A.M. are inventors on patents and patent applications related to RNA technology and COVID-19 vaccine. U.S., O.T., A.M., J.M. and B.S. have securities from BioNTech SE; K.A.S., W.C., H.C., R.S. and P.R.D. are employees at Pfizer and may have securities from Pfizer.

https://www.biorxiv.org/content/10.1101/2021.01.18.426984v1

Emergence of a novel SARS-CoV-2 strain in Southern California, USA

 Wenjuan Zhang, Brian D Davis, Stephanie S Chen, Jorge M Sincuir Martinez,  

View ORCID ProfileJasmine T Plummer, Eric Vail

doi: https://doi.org/10.1101/2021.01.18.21249786

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2021.01.18.21249786v1.full.pdf

Abstract

Since October 2020, novel strains of SARS-CoV-2 including B.1.1.7, have been identified to be of global significance from an infection and surveillance perspective. While this strain (B.1.1.7) may play an important role in increased COVID rates in the UK, there are still no reported strains to account for the spike of cases in Los Angeles (LA) and California as a whole, which currently has some of the highest absolute and per-capita COVID transmission rates in the country. From the early days of the pandemic when LA only had a single viral genome uploaded onto GISAID we have been at the forefront of generating and analyzing the SARS-CoV-2 sequencing data from the LA region. We report a novel strain emerging in Southern California. Most current cases in the catchment population in LA fall into two distinct subclades: 1) 20G (24% of total) is the predominant subclade currently in the United States 2) a relatively novel strain in clade 20C, CAL.20C strain (∼36% of total) is defined by five concurrent mutations. After an analysis of all of the publicly available data and a comparison to our recent sequences, we see a dramatic growth in the relative percentage of the CAL.20C strain beginning in November of 2020. The predominance of this strain coincides with the increased positivity rate seen in this region. Unlike 20G, this novel strain CAL.20C is defined by multiple mutations in the S protein, a characteristic it shares with both the UK and South African strains, both of which are of significant clinical and scientific interest

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Internal funding from the Department of Biomedical Sciences, Cedars Sinai Medical Center was awarded for the execution and completion of this work.

https://www.medrxiv.org/content/10.1101/2021.01.18.21249786v1

Memory B Cells, Infection, and Vaccination

 By Derek Lowe

This new article, I have to say, is rather reassuring about the human immune response to the coronavirus. It’s from a large team centered at Rockefeller University in New York, and it examines 87 people who have previously been infected. We’ve seen many studies of antibody titers and the like over time, but this is going to a deeper level and looking at the actual memory B cells. Those, you may well recall or already know, are the ones that persist and stay on guard should the same antigens reappear. They can go on for decades as an inbuilt surveillance system, ready to expand and start the antibody production process again if a similar immunologic threat shows up again.

At the six-month check-in, the patients in this study were all PCR-negative for the virus – they were no longer infected. Still, 38 of them reported some persistent long-term effects from it (you really, really do not want to catch this if you can avoid it – for more on long-term effects, see this new paper). The more severe the acute infection was, the more likely people were to experience long-term problems. Over a six-month period after recovery from SARS-CoV2, the patients in this work did indeed show lowered antibody levels. The drop in antibody titers was not evenly distributed over the different types (antibodies against the Spike receptor-binding domain (RBD) or the nucleoprotein (N), and IgM for these versus IgA), but overall neutralizing antibody activity was down about five-fold at the six month point as compared to the after-one-month check. But that’s what happens with any infection: the immune system does not crank out high levels of specific antibodies forever. It settles back down to its watch-and-wait mode, and that’s where the memory B cells come in.

And looking at those B cells showed some interesting patterns. There were a variety of them at both the 1-month and 6-month points, but they changed over time. Some of the clonal lines that were present earlier had disappeared, while new ones had continued to show up. The distribution was different as well: at the earlier point, the most common B cell clones were a greater percentage of the whole than at the 6-month point, for example. The authors say: “We conclude that while the magnitude of the RBD-specific memory B cell compartment is conserved between 1.3 and 6.2 months after SARS-CoV-2 infection, there is significant clonal turnover and antibody sequence evolution, consistent with prolonged germinal center reactions.“

What’s that antibody evolution look like, then? The good news is that the ones from the six-month check showed both increased potency and an increased range of responses against various protein mutations. That includes many of the ones that are in the news these days, things like R346S, Q493R, and E484K. (As an aside, did anyone ever imagine that amino acid variant notation would creep into major news stories? Strange days). But while the one-month antibody samples were unable to recognize these and bind to them, the six-month ones were.

How does the immune system do this? It comes down to follicular dendritic cells (FDCs), a specialized cohort that displays antigens on their cell surface for an extended time in the “germinal centers” where B cells replicate. You’ll find them in lymph nodes, spleen, bone marrow, and other tissues (here’s a review article on the subject). They’re quite odd, with unusual cellular structures (very few visible organelles in their cytoplasm and an overall large, spread-out net-like structure). They secrete chemokine signals that attract B cells, allowing them to be exposed repeatedly over the long term to the antigens that they present on the FDC surfaces (which are technically in the form of “immune complexes” there).

In severe autoimmune disease, it appears that this process can go wrong and lead to FDCs and B-cells assembling in other parts of the body entirely as part of a sustained (and completely inappropriate) immune response. But when things are working as they’re supposed to, the reservoir of antigen in the FDCs and its continued presentation to the B cells allows for the generation and selection of new and improved antibodies, as seen in this study. We got this system via evolution, too, of course: the viruses that have been attacking us and our phylogenetic ancestors for hundreds of millions of years have always been mutating in real time, so having a system that keeps pace with them after an initial infection is a clear survival advantage. As always, the immune system inspires awe and a bit of terror as well.

What does this mean for people who are vaccinated, instead of getting their immune response by being really infected by the virus? As that last link mentions, “an efficient vaccine should maximize the deposition of immune complexes on FDCs“. You would expect the Spike protein produced in the body via the mRNA or viral vector vaccines to be handled in just this way, as well as the directly-introduced antigen proteins in a vaccine like Novavax is developing. The new paper being discussed also looks into the possibility of persistence of viral antigens in intestinal tissue, which was seen in some (but not all) of the patients studied, and would be expected to drive the evolution of IgA-type antibodies in particular. But overall, the key would be to make sure that the FDCs are displaying the Spike antigen the way that they should be.

How about the variations on the coronavirus that are out there right now? This has a bearing on some very real-time data from Ravi Gupta’s lab at Cambridge. There’s a manuscript that’s on the way to MedrXiv, but this pre-preprint stuff can be found on Twitter here and here. They’re looking at antibodies from the blood of people who were vaccinated three weeks ago, and seeing how these perform against the B.1.1.7 variant. In short, they still have neutralizing activity, but it’s generally lower (at least, in ten of the fifteen patients studied). Now, this doesn’t mean that the vaccine is ineffective in those people – the antibodies still do their job. But it does mean that as mutations continue to pile up, that escape of such a new variant of the coronavirus is not impossible.

But. . .note that Gupta’s lab is (necessarily!) looking at the antibody profile of people who have been recently vaccinated. The paper I’m discussing today raises the strong possibility of continued B-cell and antibody evolution over a period of months, leading to a different set of antibodies that appears to be able to better deal with some of these mutations. It will be very interesting indeed to combine these two studies – clonal B cell changes and antibody evolution with activity against variants like B.1.1.7 – to see if this is indeed the case. It should be, but we’ll want to check!

https://blogs.sciencemag.org/pipeline/archives/2021/01/19/memory-b-cells-infection-and-vaccination

Full-dose blood thinners cut need for life support, improved outcomes in COVID-19

 Full dose anti-coagulation (blood thinner) treatments given to patients hospitalized for COVID-19 reduced the requirement of vital organ support in a large clinical trial conducted worldwide.  With large numbers of COVID-19 patients requiring hospitalization, this treatment is expected to reduce the pressure in intensive care units around the world.

Three clinical trial platforms spanning five continents in over 300 hospitals, have been working together since May 2020 to urgently test whether there is a greater benefit of full doses of heparin (blood thinners) to treat adults hospitalized for non-critical COVID-19 illness compared to the lower dose typically administered to prevent blood clots in hospitalized patients.

Based on the interim results of more than 1300 moderately ill patients admitted to hospital, findings showed that full doses of blood thinners were not only safe, but superior to the doses normally given to prevent blood clots in hospitalized patients. Moderately ill patients are those not in ICU and who did not receive organ support such as mechanical ventilation at trial enrollment. The trial investigators are now working as fast as possible to make the full results of the study available so clinicians can make informed decisions about treating their COVID-19 patients.

These trial results reported today complement the group’s findings announced in December that routine use of full-dose anti-coagulation when started in the ICU in critically ill COVID-19 patients was not beneficial and appeared to be harmful. 

“In a disease with a limited number of effective therapies, our results have the potential  to define a new standard of care for moderately ill hospitalized COVID-19 patients around the world,” said Ryan Zarychanski, MD, M.Sc., associate professor, hematologist and critical care physician at the University of Manitoba and CancerCare Manitoba, Canada, and chair of the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC) platform and of the therapeutic anticoagulation domain of the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP).

Early in the pandemic, physicians around the world observed increased rates of blood clots and inflammation among COVID-19 patients which affected multiple organs and led to complications such as lung failure, heart attack and stroke. Whether providing increased doses of blood thinners routinely administered to hospitalized patients would be safe and effective was unknown at that time.

“These results are very exciting and lead us to better understand the impact of applying the right therapies at the right time in the course of this challenging disease,” said Dr. Judith Hochman, chair of Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) platform, Harold Snyder Family Professor & Associate Director of Cardiology, Senior Associate Dean for Clinical Sciences and Co-Director, NYU-HHC Clinical and Translational Science Institute, NYU Grossman School of Medicine.

Knowing the effect of full dose blood thinners in hospitalized patients with non-critical disease was a key outstanding question that has now been answered.  Most COVID-19 patients hospitalized are non-critical and this study will impact their care and outcomes. The multiplatform trial further paves the way for future collaborations on a global scale.

“These are the first multi-platform international clinical trials ever undertaken and given the rapid discovery of Heparin’s positive impact on  patient outcomes during the middle of the deadly COVID-19 pandemic, I don’t think it will be the last time researchers, clinicians and patients join forces across continents to test potential treatments against any number of diseases,” said Patrick Lawler, MD, MPH cardiologist at the University of Toronto and Peter Munk Cardiac Centre at University Health Network, who was co-principal investigator of ATTACC and a member of the international trial steering committee for REMAP-CAP.

“Having cared for so many severely ill Covid-19 patients and witnessed the suffering involved for patients and their loved ones, it is profoundly gratifying that together we have discovered a treatment that can prevent patients from becoming severely ill and improve their recovery,” said critical care physician Ewan Goligher, MD, PhD, and co-chair of the therapeutic anticoagulation domain in REMAP-CAP, and assistant professor of medicine, University of Toronto and scientist, University Health Network

Clinical trials, overseen by independent boards, routinely review data. The positive conclusions drawn from results to date at these trial sites have now led to enrollment being stopped. However, an adaptive approach in response to scientific data enables this study, like others, to conduct safe, rapid testing of additional agents and evolve accordingly.

The trials are supported by multiple international funding organizations including Canadian Institutes of Health Research (CAN), the LifeArc Foundation, the NIH National Heart, Lung & Blood Institute, Translational Breast Cancer Research Consortium and the UPMC Learning While Doing Program  (US), National Institute for Health Research (UK), National Health and Medical Research Council (AUS), Health Research Council of New Zealand,  and the PREPARE and RECOVER consortia (EU).

https://news.umanitoba.ca/blood-thinners-decreased-need-for-life-support-and-improved-outcomes-in-hospitalized-covid-19-patients/