T Cells Recognize Recent SARS-CoV-2 Variants

 When variants of SARS-CoV-2 (the virus that causes COVID-19) emerged in late 2020, concern arose that they might elude protective immune responses generated by prior infection or vaccination, potentially making re-infection more likely or vaccination less effective. To investigate this possibility, researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and colleagues analyzed blood cell samples from 30 people who had contracted and recovered from COVID-19 prior to the emergence of virus variants. They found that one key player in the immune response to SARS-CoV-2—the CD8+ T cell—remained active against the virus.

The research team was led by NIAID’s Andrew Redd, Ph.D., and included scientists from Johns Hopkins University School of Medicine, Johns Hopkins Bloomberg School of Public Health and the immunomics-focused company, ImmunoScape.

The investigators asked whether CD8+ T cells in the blood of recovered COVID-19 patients, infected with the initial virus, could still recognize three SARS-CoV-2 variants: B.1.1.7, which was first detected in the United Kingdom; B.1.351, originally found in the Republic of South Africa; and B.1.1.248, first seen in Brazil. Each variant has mutations throughout the virus, and, in particular, in the region of the virus’ spike protein that it uses to attach to and enter cells. Mutations in this spike protein region could make it less recognizable to T cells and neutralizing antibodies, which are made by the immune system’s B cells following infection or vaccination. 

Although details about the exact levels and composition of antibody and T-cell responses needed to achieve immunity to SARS-CoV-2 are still unknown, scientists assume that strong and broad responses from both antibodies and T cells are required to mount an effective immune response.  CD8+ T cells limit infection by recognizing parts of the virus protein presented on the surface of infected cells and killing those cells. 

In their study of recovered COVID-19 patients, the researchers determined that SARS-CoV-2-specific CD8+ T-cell responses remained largely intact and could recognize virtually all mutations in the variants studied. While larger studies are needed, the researchers note that their findings suggest that the T cell response in convalescent individuals, and most likely in vaccinees, are largely not affected by the mutations found in these three variants, and should offer protection against emerging variants.    

Optimal immunity to SARS-Cov-2 likely requires strong multivalent T-cell responses in addition to neutralizing antibodies and other responses to protect against current SARS-CoV-2 strains and emerging variants, the authors indicate. They stress the importance of monitoring the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine if booster vaccinations are needed.  

ARTICLE:
AD Redd et al. CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. Open Forum Infectious Diseases DOI: 10.1093/ofid/ofab143 (2021).

WHO:
Anthony S. Fauci, M.D., NIAID Director and Chief, Laboratory of Immunoregulation, is available to comment on this research. Dr. Andrew Redd, staff scientist in the Laboratory of Immunoregulation, is also available.

This work was supported in part by NIAID grants R01AI120938, R01AI120938S1 and R01AI128779 and by National Heart Lung and Blood Institute grant 1K23HL151826-01.

https://www.niaid.nih.gov/news-events/t-cells-recognize-recent-sars-cov-2-variants

J&J Covid Vax Distribution Delayed by U.S. Factory Mix-up: NYT

 --A mix-up at a U.S. factory will delay distribution of the Johnson & Johnson Covid-19 vaccine, the New York Times reported.

--The NYT said that workers at the Baltimore plant had accidentally conflated the vaccine's ingredients weeks ago and ruined about 15 million doses of Johnson & Johnson's vaccine.

--The plant is run by Emergent BioSolutions, a manufacturing partner to Johnson & Johnson and AstraZeneca PLC, the NYT said.

--Johnson & Johnson vaccine doses currently being delivered and used nationwide were produced in the Netherlands and are not affected, the NYT reported, adding that all further shipments of the Johnson & Johnson vaccine were supposed to have come from the Baltimore plant and are now in question while the quality control issues are sorted out.

In after-hours trading, Johnson & Johnson shares were down 0.33% at $163.81, while Emergent Solutions' stock was down 4.85% at $88.40.

https://www.marketscreener.com/quote/stock/JOHNSON-JOHNSON-4832/news/Johnson-Johnson-Covid-19-Vaccine-Distribution-Delayed-by-U-S-Factory-Mix-up-NYT-Reports-32856355/

Experimental antibodies for Parkinson's, Alzheimer's may cause harmful inflammation

 A team led by scientists at Scripps Research has made a discovery suggesting that experimental antibody therapies for Parkinson's and Alzheimer's have an unintended adverse effect--brain inflammation--that may have to be countered if these treatments are to work as intended.

Experimental antibody treatments for Parkinson's target abnormal clumps of the protein alpha-synuclein, while experimental antibody treatments for Alzheimer's target abnormal clumps of amyloid beta protein. Despite promising results in mice, these potential treatments so far have not seen much success in clinical trials.

"Our findings provide a possible explanation for why antibody treatments have not yet succeeded against neurodegenerative diseases," says study co-senior author Stuart Lipton, MD, PhD, Step Family Foundation Endowed Chair in the Department of Molecular Medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research.

Lipton, also a clinical neurologist, says the study marks the first time that researchers have examined antibody-induced brain inflammation in a human context. Prior research was conducted in mouse brains, whereas the current study used human brain cells.

The study will appear in the Proceedings of the National Academy of Sciences of the United States of America during the week of March 29.

An approach that may need tweaking

Neurodegenerative diseases such as Alzheimer's and Parkinson's afflict more than 6 million Americans. These diseases generally feature the spread of abnormal protein clusters in the brain, with different mixes of proteins predominating in different disorders.

An obvious treatment strategy, which pharmaceutical companies began to pursue in the 1990s, is to inject patients with antibodies that specifically target and clear these protein clusters, also called aggregates.

The aggregates have included not only the large clusters that pathologists observe in patients' brains at autopsy, but also the much smaller and harder-to-detect clusters called oligomers that are now widely considered the most harmful to the brain.

Exactly how these protein clusters damage brain cells is an area of active investigation, but inflammation is a likely contributing factor. In Alzheimer's, for example, amyloid beta oligomers are known to shift brain immune cells called microglia to an inflammatory state in which they can damage or kill healthy neurons nearby.

Surprise finding

Lipton and colleagues were studying alpha synuclein oligomers' ability to trigger this inflammatory state when they encountered a surprise finding: While the oligomers on their own triggered inflammation in microglia derived from human stem cells, adding therapeutic antibodies made this inflammation worse, not better. The team traced this effect not to the antibodies per se but to the complexes formed with antibodies and their alpha synuclein targets.

Amyloid beta aggregates often co-exist with the alpha synuclein aggregates seen in Parkinson's brains, just as alpha synuclein often co-exists with amyloid beta in Alzheimer's brains.

In the study, the researchers added amyloid beta oligomers to their mix, mimicking what would happen in a clinical case, and found that it worsened inflammation. Adding anti-amyloid beta antibodies worsened it even further. They found that both alpha synuclein antibodies and amyloid beta antibodies made inflammation worse when they successfully hit their oligomer targets.

Lipton notes that virtually all prior studies of the effects of experimental antibody treatments were done with mouse microglia, whereas the key experiments in this study were done with human-derived microglia--either in cell cultures or transplanted into the brains of mice whose immune system had been engineered to accommodate the human microglia.

"We see this inflammation in human microglia, but not in mouse microglia, and thus this massive inflammatory effect may have been overlooked in the past," Lipton says.

Microglial inflammation of the kind observed in the study, he adds, could conceivably reverse any benefit of antibody treatment in a patient without being clinically obvious.

Lipton says that he and his colleagues have recently developed an experimental drug that may be able to counter this inflammation and thereby restore any benefit of antibody treatment in the human brain. They are actively working on this now.

###

The lead author of the study was Dorit Truder, PhD, a postdoctoral fellow in the Lipton laboratory. Other senior authors were Rajesh Ambasudhan, PhD, an adjunct assistant professor at Scripps Research; Michael Karin, PhD, a professor at the UC San Diego School of Medicine; and Nicholas Schork, PhD, a professor at the Translational Genomics Institute in Phoenix and adjunct professor at UC San Diego and Scripps Research.

"Soluble α-synuclein/antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia" was co-authored by Dorit Trudler, Kristopher Nazor, Yvonne Eisele, Titas Grabauskas, Nima Dolatabadi, James Parker, Abdullah Sultan, Zhenyu Zhong, Marshal Goodwin, Yona Levites, Todd Golde, Jeffery Kelly, Michael Sierks, Nicholas Schork, Michael Karin, Rajesh Ambasudhan and Stuart Lipton.

The work was supported by the National Institutes of Health (R01 NS086890, RF1 AG057409, R01 AG056259, R01 DA048882, DP1 DA041722, R01 AI043477).

https://www.eurekalert.org/pub_releases/2021-03/sri-eaf032621.php

Aptevo Reports 2020 Results, Business Update

 Advances Phase 1/1b Study of APVO436 for Treatment of Acute Myeloid Leukemia and High-Grade Myelodysplastic Syndrome; Enrollment in Cohort 10 Ongoing

Completes Sale of RUXIENCE Royalty Payments for Up Front Plus Milestone Payments of up to $67.5 million; Amends Non-Dilutive Term Loan Agreement

https://www.biospace.com/article/releases/aptevo-therapeutics-reports-2020-financial-results-and-provides-business-update/

FDA OKs Sanofi Sarclisa combo for relapsed or refractory multiple myeloma

 

• Sarclisa regimen reduced risk of disease progression or death by 45% compared to standard of care in patients who had relapsed after one to three prior therapies

• While the median progression free survival (PFS) for Sarclisa combination therapy is not yet reached, consistent improvement in PFS is seen across patient subgroups

• This is the second FDA approval for Sarclisa in combination with standard of care backbone therapies

https://finance.yahoo.com/news/fda-approves-sarclisa-isatuximab-combination-211500039.html

Mixed Results in Phase 1/2 of BioXcel Treatment for Opioid Withdrawal Symptoms

 BioXcel Therapeutics, Inc. (“BioXcel” or the “Company”) (NASDAQ: BTAI), a clinical-stage biopharmaceutical company utilizing artificial intelligence approaches to develop transformative medicines in neuroscience and immuno-oncology, today announced topline results from its Phase 1b/2 proof-of-concept RELEASE study of BXCL501, the Company’s proprietary, orally dissolving thin film formulation of dexmedetomidine, for the treatment of opioid withdrawal symptoms.

The study met its primary safety endpoint across multiple doses given twice-daily over seven days. BXCL501 was generally well tolerated, with no severe or serious adverse events reported, and dose dependent exposures were observed across all doses evaluated (30 mcg, 60 mcg, 90 mcg, 120 mcg, 180 mcg and 240 mcg).

With respect to retention, a secondary endpoint, the study showed that patients in multiple dose cohorts treated with BXCL501 had numerical improvements in retention rates, a key goal of opioid withdrawal treatment. The 120 mcg and 180 mcg dose groups showed 42% and 52% rates of retention at Day 6 of BXCL501 treatment, respectively, versus 24% for placebo, though observations were not statistically significant. The results also showed that of the 87% of patients who had fentanyl in their systems upon entry, greater than 50% remained fentanyl positive following the morphine stabilization phase of 5 days. Consequently, withdrawal symptoms were not equivalent across various dose cohorts indicating morphine did not normalize withdrawal symptoms. Improvements were not observed in the severity of opiate withdrawal as measured by the Short Opiate Withdrawal Scale of Gossop (“SOWS-Gossop”) or the Clinical Opiate Withdrawal Scale (“COWS”). The Company believes that the high fentanyl prevalence and lack of normalization observed in study subjects could have confounded these results and made them difficult to interpret.

“We’re encouraged that the RELEASE study helped us to identify a dose range that was generally well tolerated and resulted in numerical improvements in retention in this patient population," commented Reina Benabou, M.D., Ph.D., Senior Vice President & Chief Development Officer.  "We’ll continue to analyze these results in collaboration with our advisors regarding potential next steps for this important indication.”

https://finance.yahoo.com/news/bioxcel-therapeutics-announces-results-phase-200100981.html

Akebia tries for FDA approval of anemia drug after mixed data

 

• Akebia Therapeutics is taking a chance on its closely watched pill for anemia, announcing Tuesday the submission of an application for approval to the Food and Drug Administration despite mixed study data disclosed last fall that lowered expectations for the drug. 
• In two Phase 3 studies, Akebia's experimental drug matched the approved injection Aranesp in raising and sustaining hemoglobin levels among trial participants with anemia due to their chronic kidney disease. But the pill, called vadadustat, appeared worse than Aranesp on a measure of heart safety, with a greater risk of major adverse cardiovascular events. 
• Akebia said then the company still intended to ask the FDA for approval, citing the totality of the data from those and other studies. But analysts who follow the company were more skeptical the drug could obtain a clearance for a broad patient population that includes both dialysis and non-dialysis patients. 

For several years now, Akebia has been chasing rival anemia drug developer Fibrogen, which appeared to be ahead in its development of a similar acting treatment and would-be competitor to vadadustat. 

Fibrogen applied for FDA approval last year, only to have a potential December decision delayed until March. Then, at the beginning of the month, the company and its investors were taken by surprise when the agency indicated it would call an advisory committee meeting to review Fibrogen's drug. 

At least twice before, Fibrogen claimed, the FDA had indicated it wouldn't convene a panel, making the last-minute communication an unexpected and potentially costly twist. No date has yet been set, and the FDA has now missed its March 20 goal. The company has not issued any update.

Now that Akebia has submitted its application, the FDA may seek to convene an advisory committee meeting covering both drugs, wrote Christopher Raymond, an analyst at Piper Sandler, in a note to clients. 

Both drugs are designed to replace current injectable therapies with a more convenient pill option. They are known as HIF-PH inhibitors and work by promoting red blood cell production in a way that mimics the body's response to low-oxygen environments.

Studies have shown both pills can match the efficacy of injectable drugs. But their safety, particularly for the heart, has become a key concern, especially following Akebia's results last year. Those findings could make the approval case for both drugs harder to regulators, given both are meant to be at least as safe, if not safer, than the injectable medicines like Aranesp that are already tied to potential heart problems. 

Akebia's submission came one to two months ahead of expectations, and the company indicated it did not include in its filing a priority review voucher. Such vouchers are a kind of a regulatory fast-pass and can be used to shorten FDA review times by four months. 

In early 2020, Akebia had struck a deal with partner Vifor Pharma to hold onto a voucher Vifor bought for about $100 million. The agreement specified the companies would either use it on vadadustat or resell it and share the proceeds. 

But the delay facing rival Fibrogen, and resulting uncertainty on the FDA's view of HIF-PH blockers, may have weakened the case for seeking a speedier review. Once a rare commodity, vouchers are now more common but can still fetch around $100 million in a sale. 

The FDA now has 60 days to determine whether Akebia's application is complete and ready for an official review. 

https://www.biopharmadive.com/news/akebia-fda-application-vadadustat-anemia-ckd/597556/