Covid-19 hyperinflammation, post-Covid illness may start in mast cell activation syndrome

 

Lawrence B.Afrina, Leonard B.WeinstockbGerhard J.Molderingsc 

DOI: https://doi.org/10.1016/j.ijid.2020.09.016

PDF: https://www.sciencedirect.com/science/article/pii/S1201971220307323/pdfft?md5=7af57d7248552203969bd62f626d851c&pid=1-s2.0-S1201971220307323-main.pdf

Highlights

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Much of Covid-19 hyperinflammation is consistent with mast-cell-driven inflammation.

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Prevalence of severe Covid-19 is similar to that of mast cell activation syndrome (MCAS).

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Drugs inhibiting mast cells (MCs) and their mediators show promise in Covid-19.

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None of the authors currently treated MCAS patients with Covid-19 had severe forms or mortality.

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The dysfunctional MCs of MCAS may underlie severe acute and chronic Covid-19 illness.

Abstract

Objectives

One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses.

Methods

Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS.

Results

The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19’s hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors’ treated MCAS patients with Covid-19 suffered severe infection, let alone mortality.

Conclusions

Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.

https://www.sciencedirect.com/science/article/pii/S1201971220307323

CureVac Commences Global Pivotal Phase 2b/3 Trial for COVID-19 Vaccine Candidate

 CureVac N.V. (Nasdaq: CVAC), a clinical-stage biopharmaceutical company developing a new class of transformative medicines based on messenger ribonucleic acid (mRNA), announced today that it has enrolled the first participant in the pivotal Phase 2b/3 study of its mRNA vaccine candidate, CVnCoV, against COVID-19. The randomized, observer blind, placebo-controlled Phase 2b/3 trial called HERALD will assess the safety and efficacy of CVnCoV in adults at a dose of 12 µg. The study is expected to include more than 35,000 participants at sites in Europe and Latin America.

“With the start of the pivotal Phase 2b/3 study, we have reached another important milestone in the development of our vaccine candidate, CVnCoV,” said Dr. Franz-Werner Haas, CEO of CureVac. “The clinical safety and immunogenicity data achieved to date look promising and we are hopeful that this trial will continue to demonstrate the impact of mRNA technology and our vaccine to prevent COVID-19, and to help defeat this pandemic.”

The HERALD trial will start with an initial Phase 2b part, which is expected to seamlessly merge into a Phase 3 efficacy trial. Subjects 18 years of age or older will be enrolled at multiple sites and will receive a two-dose schedule of either CVnCoV or placebo.

Besides the primary safety objective, the study design includes two primary efficacy objectives: the demonstration of the efficacy of CVnCoV in preventing first episodes of confirmed cases of COVID-19 of any severity, as well as preventing moderate to severe confirmed cases of COVID-19 in participants who have never been infected with SARS-CoV-2.

Efficacy of CVnCoV will be assessed by an event-driven analysis based on a certain number of participants who present with laboratory confirmed symptomatic COVID-19 disease during the study. To ensure continued and close safety monitoring of the participants in the trial, data will be reviewed by an independent Data Safety Monitoring Board on a regular basis.

https://www.curevac.com/en/2020/12/14/curevac-commences-global-pivotal-phase-2b-3-trial-for-covid-19-vaccine-candidate-cvncov/

Autoantibody Problems

 By Derek Lowe 

Here’s a preprint from a large team at Yale with a close look at a less-studied aspect of coronavirus infection. It’s been well established by now that a feature of severe cases is a misfiring immune response (the “cytokine storm”, etc.), and one reason that fatality rates have been going down for hospitalized cases is better management of this problem. But the details are still being worked out – and since we’re talking immunology, there are a lot of details.

And it looks like one of those details, potentially a very important one, is a striking correlation with autoantibodies. Those are antibodies to a person’s own proteins – the sort of friendly fire that you see in autoimmune diseases of all sorts (acute and chronic). This work features a new assay (Rapid Extracellular Antigen Profiling, REAP) against a displayed library of 2,770 extracellular (secreted) human proteins displayed via yeast cells, providing a high-throughput method to check a patient’s own serum for antibodies to these. 194 subjects (Yale patients and healthcare workers) were screened, with a wide range of disease severity, as compared to 30 uninfected controls. The new assay showed good correlation with standard ELISA assays as a reality check.

It appears that the more severe a coronavirus infection a patient has, the better the chances that they show a wide variety of autoantibodies towards their own cell-surface and secreted proteins (see the figures above). I wrote here about a study that showed that patients with antibodies towards some of their own interferons have a harder clinical course of the disease, and this new paper confirms that work and extends it. A set of patients were examined over time, and it appears that at least 50% of these reactivities were observed early enough in the course of the disease that they may well have been pre-existing. Around 10% of them were seen to increase over time, though, suggesting that the coronavirus infection was bringing on such autoimmune problems. Interestingly, about 15% of the antibody titers seemed to decrease over time, and I’m not sure what to make of that.

The paper goes on to make connections between specific autoantibodies and immune function – for example, some of the ones that target specific proteins on the surfaces of immune cells are associated in patients with decreased numbers of those cells. The team also looked for correlations between antibodies to specific targets (or those associated with specific tissues) and clinical outcomes. It’s a complex thing to untangle, though. If you think about some specific circulating cytokine protein, antibodies to it could help to clear it from the bloodstream more quickly, or to bind to it in a way that keeps it from working (either partially or completely, which seems to be the case for the interferon autoantibodies), or at the other end of the scale, to bind to it in a way that doesn’t interfere so much with its function and could even stabilize its levels in the blood.

But overall, there was no well-defined set of “COVID-19” antibodies that showed up in infected patients but not in controls, and no obvious ways to match up antibody profiles to specific outcomes. Some of that difficulty, though, may be due to the wide variety of responses seen. Instead of broadly obvious trends, what shows up are a great number of individual responses that can add up to real outcomes, but which are very hard to untangle. Immunology!

One of the things that needs to be done, then, is more extensive profiling in the population. I would assume that ideally you’d want to get a good-sized sample of healthy people, profile them for autoantibodies, and then watch over time to see what happens. This isn’t just a coronavirus story at that point. Are there people who have greater susceptibility to various diseases, or to worse outcomes, if they have particular autoimmune fingerprints? Or will it still be a big tangled ball of yarn if you try to track these things down? At the least, I would expect that if there is indeed a population who have some sort of partial failure of immune tolerance and thus show existing high levels of auto-antibodies, then they would be at greater risk of severe coronavirus infection. How many such people are there, and how many of them are currently unrecognized?

Beyond that, there’s the possibility that some of the autoimmune effects are being actually brought on by the infection. We already know about some of the larger, more obvious examples of this sort of thing (such as Guillain-Barré and others), but profiling via an assay like REAP could help to shed more light. There are already several mechanisms known for such tolerance failures, but it’s for sure that there’s a lot more to learn, and I would think that a good-sized longitudinal study might have a lot to tell us. (Of course, I’m not the person who has to go out and get funding for it, so that’s easy for me to say!)

https://blogs.sciencemag.org/pipeline/archives/2020/12/15/autoantibody-problems

Pandemic Vaccines: How Are We Going to Be Better Prepared Next Time?

 

Florian Krammer

DOI: https://doi.org/10.1016/j.medj.2020.11.004

PDF: https://www.cell.com/action/showPdf?pii=S2666-6340%2820%2930027-1

In response to the SARS-CoV-2 pandemic, we are currently witnessing the fastest vaccine development in history. While these vaccines will now make a significant impact on ending the pandemic, they were needed much earlier. Here I discuss how to ensure that vaccines will become available within 3-4 months after a new outbreak.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 in Wuhan, China, and caused a global coronavirus disease 2019 (COVID-19) pandemic.

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 Since then more than one million people have died globally, millions have been infected, and in many countries we are seeing signs of societal disintegration. The global economy has taken a major hit and businesses in many areas including tourism, hospitality, and the airline industry are fighting for their survival or have already gone bankrupt. Daily life has become difficult, even for people who have not been infected or have lost loved ones. In addition, while countermeasures like social distancing, wearing face masks, and restrictions on large gatherings (especially indoors) can help to keep infections low if effectively implemented, the populations in many countries are getting tired and are often unwilling to comply to countermeasures, let alone complete lockdowns.

Vaccines against infectious diseases have been one of the greatest successes in human history, effectively reducing disease burden for many pathogens. They have even allowed us to eliminate a human virus (smallpox) and a livestock virus (Rinderpest virus) from the face of the earth. When the sequence of SARS-CoV-2 was made openly available by Chinese scientist on January 10, 2020, a race to develop a vaccine began.

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 This was not a race of vaccine candidates against each other, but a race against the virus. SARS-CoV-2 vaccine development is moving ahead at record speed. Based on important development work already done on other coronaviruses,

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 the first phase 1 trial was started on March 16, 2020,

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 the first individuals were enrolled in phase 3 trials in summer 2020, and results showing high effectiveness of two of these vaccines were recently reported. This speed of vaccine development is unprecedented, and the vaccines will likely be key in ultimately resolving this situation. They will also save millions of lives. However, vaccines were needed much earlier, as early as possible (Figure 1A). While it is unlikely that vaccines would have stopped the virus from going global, a well-prepared infrastructure capable of producing vaccines 3–4 months into the outbreak (in March or April) would have saved many lives and would likely have normalized the situation in many geographic areas by now (Figure 1B). Still, without vaccines, countries in the Northern hemisphere experience a strong increase in cases during the fall, even in countries that controlled the initial wave well. Here, I will try to provide a strategy that might allow us to be better prepared in the future from a vaccine perspective.

Figure 1Overview of the Current Situation with SARS-CoV-2 and an Ideal Scenario from the Vaccinology Point of View

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 Overall Strategy

Many different viruses may cause a pandemic in the future, but we know which virus families have the most potential. And it is viruses that spread from human to human via the respiratory tract that we worry about the most, since this is a transmission route that is hard to stop. Viruses that use other transmission routes can be highly problematic as well but might be impacted much more by non-pharmaceutical interventions. From each of the identified virus families, which should certainly include the Paramyxoviridae, Orthomyxoviridae, and Coronaviridae families, a handful of representative strains with the highest pandemic potential should be selected for vaccine production. Up to 50–100 different viruses could be selected and this would broadly cover all phylogenies that may give rise to pandemic strains. Importantly, the more we know about viruses circulating in animals and their pathogenicity, the easier it will be to choose relevant strains (Figure 2). If this sounds farfetched, we should consider that the number “2” in SARS-CoV-2 indicates that this virus is genetically related to SARS-CoV-1, the virus responsible for the SARS outbreak in 2003.

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 We have experienced SARS-CoV-1 and in the past researchers have warned us of the possible emergence of similar viruses very explicitly.

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,

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 It should be possible to choose candidates that are close to viruses that might emerge in the human population. The idea is that once viruses are selected, vaccines can be produced in different platforms and tested in phase 1 and phase 2 trials with some of the produced vaccine being stockpiled. This would likely cost 20–30 million US dollars per vaccine candidate resulting in a cost of 1–3 billion US dollars. In parallel, correlates of protection for related human viruses can be investigated (e.g., for human coronaviruses in the case of Coronaviridae). Production capacity can be built to allow rapid production of at least 2 billion doses per year using different vaccine platforms. If a new virus hits, the vaccine closest to the new strain is selected, a strain change is performed, vaccine production starts immediately, and phase 3 trials are initiated within a month. First readouts from the phase 3 trials would be expected likely post-second vaccination, and the vaccine could receive an emergency use authorization based on a correlate of protection 2 months after initiation of the trial. While initial trials continue, vaccine rollout is initiated, and production is ramped up.

...

https://www.cell.com/med/fulltext/S2666-6340(20)30027-1

Controversy over Smoking in COVID‐19 – Real World Experience

 

Kam Sing Ho M.D. 

 

Bharat Narasimhan M.D. 

 

Jacqueline Sheehan M.D. 

 

LingLing Wu M.D. 

 

Jennifer Y Fung M.D.

doi: 

 https://doi.org/10.1002/jmv.26738

PDF: https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.26738

Abstract

Background

Data is conflicting regarding the impact of tobacco smoking in people with pneumonia due to SARS‐CoV‐2 infection (COVID‐19).

Methods

We performed a retrospective multicentre cohort study of 9,991 consecutive patients hospitalized in a major New York academic centre between March 7th and June 5th, 2020 with laboratory confirmed COVID‐19. The clinical outcomes assessed included risk of hospitalization, in‐hospital mortality, risk of intensive care unit (ICU) admission, and need for mechanical ventilation among smokers (current and former). Multivariable logistic regression and propensity score models were built to adjust for potential confounders.

Findings

Among 9,991 consecutive patients diagnosed with COVID‐19, 2,212 (22.1%) patients were self‐reported smokers (406 current and 1806 former). Current smoking was not associated with an increased risk of hospitalization (propensity score [PS]‐adjusted OR 0.91; p=0.46), in‐hospital mortality (PS‐OR 0.77; p=0.12), ICU admission (PS‐OR 1.18; p=0.37), or intubation (PS‐OR 1.04; p=0.85). Similarly, former smoking was not associated with an increased risk of hospitalization (PS‐OR 0.88; p=0.11), in‐hospital mortality (PS‐OR 1.03; p=0.78), ICU admission (PS‐OR 1.03; p=0.95), or intubation (PS‐OR 0.93; p=0.57). Furthermore, smoking (current or former) was not associated with an increased risk of hospitalization (PS‐OR 0.85; p=0.05), in‐hospital mortality (PS‐OR 0.94; p=0.49), ICU admission (PS‐OR 0.86; p=0.17), or intubation (PS‐OR 0.79; p=0.06).

Interpretation

Smoking is a well‐known risk factor associated with greater susceptibility and subsequent increased severity of respiratory infections. In the current COVID‐19 pandemic, smokers may have increased risk and severe pneumonia. In the current COVID‐19 pandemic, smokers are believed to have an increased risk of mortality as well as severe pneumonia. However, in our analysis of real‐world clinical data, smoking was not associated with increased in‐patient mortality in COVID‐19 pneumonia, in accordance with prior reports.

Funding

There is no financial support for this work.

https://onlinelibrary.wiley.com/doi/10.1002/jmv.26738

Sarepta, Amicus Top B of A Biotech Picks Ahead Of Key Binary Events

 Biopharma stocks are risky investment bets that sway wildly in reaction to catalytic events. Binary events scheduled for Amicus Therapeutics, Inc. 

FOLD 0.42% and Sarepta Therapeutics Inc SRPT 2.54% render their stocks as top picks for the first half of 2021, according to an analyst at BofA Securities.

The Analyst: Tazeen Ahmad maintained a Buy rating and $194 price target for Sarepta. The analyst reiterated a Buy rating on Amicus and increased the price target from $24 to $30.

Sarepta's DMD Gene Therapy Main Valuation Driver: Of the two data readouts scheduled for Sarepta's microdystrophin gene therapy candidate SRP-9001 in Duchenne muscular dystrophy, topline functional results from Study 102 very early in 2021 is more important, Ahmad said. Results from Study 103 is due in the second quarter.

The results from Study 102, which are the first placebo-controlled data set in a significant number of patients, will likely show robust motor benefits, the analyst said. There is high excitement for a therapy such as SRP-9001.

SRP-9001, the analyst said, has the potential to be the first approved DMD gene therapy. Risk-adjusted peak sales for the asset are estimated at $2.4 billion in 2024, Ahmad said. SRP-9001 accounts for about $58 of BofA's price target for Sarepta.

"Statistically significant data with no safety concerns would add 20% upside to our NPV without changing other estimates," the analyst wrote in the note.

The stock could move even higher if investors read through to other programs. If the company can file for approval by year-end, there could be more than 50% valuation upside, BofA said.

Amicus Has Favorable Risk/reward Profile: Despite the recent run-up in Amicus shares, the risk/reward is favorable ahead of the pivotal PROPEL readout of AT-GAA - its next-generation enzyme replacement therapy, or ERT, for Pompe's disease due in the first quarter, Ahmad said.

The study is well powered to position AT-GAA as the only next-gen ERT to have shown superiority in its primary endpoint over the current standard-of-care Lumizyme, which is currently fetching annualized revenues in excess of $1 billion.

"AT-GAA would add to a stable and growing revenue base established by Galafold for Fabry disease," the analyst wrote in the note.

Positive PROPEL data could provide about 60% valuation upside, BofA estimates.

https://www.benzinga.com/analyst-ratings/analyst-color/20/12/18854451/sarepta-amicus-top-biotech-picks-ahead-of-key-binary-events-analyst

COVID-19 vaccines on sale for $250 on dark net

 As vaccination programmes against COVID-19 get underway around the world, criminals are stepping up efforts to offer them for sale on the dark net, according to cybersecurity specialists.

Check Point Software Technologies (CPST) says it has found “a stream of posts on the dark net from sources claiming to have a range of ‘coronavirus vaccines’  or ‘coronavirus remedies’ for sale,” typically asking for payments in Bitcoin of around $250 to $300.

There’s no way to determine what the vaccines being offered are – or whether they exist at all – but it’s certain that they have nothing to do with the candidates from the likes of Pfizer/BioNTech, Moderna, Johnson & Johnson and AstraZeneca that are closest to being widely-available.

That means users would be injecting unknown substances with a risk of infections as well as other side effects.

“Unfortunately, while most of us are watching with hope, there are some watching with greed and malice in their minds, with the intent of capitalising [on] people´s concerns about COVID-19 and desire to be protected against the risk of catching it,” according to CPST.

Coronavirus treatments are also on offer, including those such as chloroquine which have no evidence to back up their benefits.

In one example cited by CPST, the seller claims to have stock from a “leading” pharmaceutical company for a “newly-approved vaccine” that is supposedly available for sale and delivery to the UK, the US and Spain and is “just one WhatsApp or Telegram chat away!”

The finding comes shortly after Interpol has warned that organised criminals are preparing to cash in on the roll out of COVID-19 vaccines via “falsification, theft and illegal advertising of unlicensed shots” – as well as flu vaccines.

The US federal government has also taken action on this issue, launching Operation Stolen Promise 2.0 late last month in an attempt to identify and prevent the production, sale and distribution of illicit COVID-19 treatments and vaccines.

CPST also said it had seen a surge in COVID-19 vaccine related web domains in November, which serves as a surrogate marker for illicit activity, as well as a spike in vaccine-related phishing email campaigns.

“Our data shows that since the beginning of November there were 1,062 new domains which contain the word “vaccine” that were registered, out of which 400 also contain ‘covid’ or ‘corona’, it says.

For comparison, that is the same number of new domains with those characteristics for the three-month period from August through October.

https://www.securingindustry.com/pharmaceuticals/covid-19-vaccines-on-sale-for-250-on-dark-net/s40/a12683/#.X95XM9hKjIV