MPNforum Magazine

 

 

 

 

Special Alert: April 18, 2021:  ASH warns, MPN patients may not be fully protected by covid vaccine. Bulletin here.

The Covid-19 variants:  the growing threat

 Interferon challenges MPN Covid-19 patients:  Greater risk, greater benefit.

 

Attack and Counter-attack…

You’re sick of …the restrictions….  Checking the fridge for leftovers. …Another day without restaurants….A year of binging through  Amazon Prime Movies and all the Netflix series you can stand.. You’re restless, bored, depressed, vaccinated. Time to bust out.   

 

The patient case was originally described Dec. 3, 2020, as a New England Journal of Medicine report by scientists at Brigham and Women’s Hospital  a few weeks before the variants initially detected in the U.K. and South Africa were first reported to the World Health Organization. Interestingly, the patient-derived virus contained a cluster of changes on its spike protein—the current target for vaccines and antibody-based treatments—and some of these changes were later detected in viral samples in the U.K. and South Africa,…

 

 

We are at war.  This is not a fanciful description of reality. It is reality.

This is the shape of World War III, There have been more Americans killed in one year of WW III than in the two preceding World Wars combined.   Populations uprooted, streets deserted, shops shuttered, schools closed. nations immobilized.  We can’t see its face.  We can’t hear its tanks.  But the enemy is among us, killing us.

 

It’s Spring, we’re getting outdoors again. Vaccination rates are soaring. Airports are once again crowded with travelers.  Things are looking up… but there’s a looming threat on the horizon.  

The pandemic has taken a nasty turn for the worse.  In order to defend ourselves against the emergence of more infection, more lethal versions of the SARs-CoV02 virus, we have a choice. We can hang in just a little longer with mask and social distance.  We can actively engage the enemy the best way we can. It’s a war. They have countless trillions of reinforcements on the way. And they don’t have to stop to eat. Or think. Or breathe.  Humans can think and feel. We have science and communicationsa and bodies. We have Covid pinned to the wall, genome, mutations all seqeucned down to the last base. And we’re counter-attacking  with upgraded vaccines and mitigating drugs. Meanwhile, Covid slips away into its coat of invisibility, shifts shape and silently puts on new armor.

 

Our  local little wars that blossomed into a planet wide conflagration have morphed into a war of survival. A war between Species, a war for domination between human mammals and the SARS-CoV-2 zombie virus. Vikings of the New  world, this warrior mob has come to pillage and kill. Don’t believe it? Just count the dead and dying. The escalation of conflict.:  The emergence of killer variants on their side, a hundred million jabs of spike-blocking vaccine on ours.

Do not be so sure of victory.

We’ve been here  before. Smallpox and Influenza. The plague, polio. Sometimes a bacteria someitmes a virus sometimes something else but so far we have alwalys been victorious…if by survival we claim victory.  Becauses we’re still food for the bugs and micro bugs and they keep getting smarter and  tougher.

But didn’t Jennifer Doudna and her Berkeley crew have a hand in discovering CRISPR? And haven’t we got drones and Rovers on Mars,  weather satellites, cell phone systems, chemicals and labs. This may end in prolonged guerrilla warfare but we’re not losing to Covid the Horrid. Still, the virus is a powerful enemy.  .

Covid has one will, one mission and is not burdened with hunger. memory or fear but loaded with coded defenses against our immune defense system. Their clones have been able to cloak, hide, and mislead our front lines, penetrate our cells, overwhelm our defenses and multiply their forces by turning our own biological machinery against us..

And humans are distracted, dealing with climate change and environmental disasters, unemployed millions, deeply divided populations,  melting glaciers and ships flying national flags bumping up against each other in open seas.

We’re distracted  while being attacked by an invisible shape shifting mindless murderer who  steals in under the radar on a breath, through mouth and trachea to lung their bristling corona spikes bobbing into potential  celllar hosts….They stab they fuse they reproduce.  They use the plaster from our cellular walls to adorn the envelope of their fat wrapped offspring, their seething little genome under its capsid.  They’re ready to reproduce. Always ready…..

They  melt into our cells and use our biological tools  In our cytoplasm they insert theri RNA directly into our cruisiing ribosomes, our protein factories,  cranking out tens of thousands of copies of themselves, . All ready to fold into wartime shape and bust out of the hollowed out cell and go a-Viking.

 

It might help to understand the shape shifting  power and limitations of this attacking virus.

As MPN patients we are uniquely poised to understand –and suffer from–the corona virus pandemic. After all the virus is parading around our neighborhood

At the very least we’re somewhat familiar with the world of mutations,  genetics, attacks on our autoimmune system, inflammation, and invisible molecular processes powering a weakening sometimes lethal disease. We are also at greater risk of SARs-2-CoV infection due to our therapies and compromised immune systems.

SARs-CoV2  is evolving rapidly, churning out much more infectious and deadly clones. Mutations developed within infected individuals have created whole new variations and challenges for existing vaccines.

The face of the enemy.

From December 2019 arising in China, Covid-19  swept across the globe. Covid the Horrid. the Son of Sars and its numberless hordes of invisible, shape-shifting, multiplying troops locked down Nations, crippled commerce and overwhelmed hospitals and morturaries. Covid occupied more territory in a few short months than  the combined armies of Alexander the Great, Ghengis Khan,  Caeser, the Mongol hordes and Attila the Hun in their several  lifetimes of campaigning..

Beaten back in some places, aggressively surging in others, the Pandemic – wearing a new face, with new armament and shield, is still far from defeated

When infected, a host cell is forced to rapidly produce thousands of identical copies of the original virus. When not inside an infected cell or in the process of infecting a cell, viruses exist in the form of independent particles, or virions, consisting of: (i) the genetic material, i.e., long molecules of DNA or RNA that encode the structure of the proteins by which the virus acts; (ii) a protein coat, the capsid, which surrounds and protects the genetic material; and in some cases (iii) an outside envelope of lipids

A mindless pirate

The coronavirus SARs-CoV-2 is a blood thirsty parasite driven by mindless programmed lust for plunder and expansion.  Definitely a Pirate but He is no swashbuckling, hardliving, rum swilling, peg legged, eye-patched thug with a parrot on his shoulder. In fact he is not a he at all, nor a she. And has no shoulder to speak of. In fact, strictly speaking, Covid is not alive at all.

Covid does not eat or breathe and relies entirely on its victim’s cellular machinery to breed and expand its mindless pillaging.

Despite not being able to see or hear, or live on its own,  Covid-19, in a blitzkrieg of just a few months, briefly but fully conquered the human population on all the continents of Planet Earth.

 

A close up look at COVID’s simple and powerful attack strategy.

The gory details:  (Unless you have a morbid interest in the mechanics of SARS-Co-V2 infection — which I do — you can skip over the next few paragraphs.)

Stealth is the key, Invisible, infinitesimally small to begin with, COVID arrives on a breath of air in a droplet of moisture, its hard packed RNA nucleic acid heart of 30000 bases wrapped in a gossamer envelope of delicate protein and fat from a which an array of spikes protrude.

Inhaled Covid latches on to a cellular docking point, the ACE (angiotensin-converting enzyme)  pathway that acts both as doorway to the cell  and its treasure house of biological machinery. Its glycoprotein covering of an outer envelope helps cloak to  the virus from the patrolling antibodies and Natural Killer Cells cruising the blood stream just outside the cell wall.    The COVIC Spike that then undergoes a radical transformation to fuse into the cell wall itself

The Sars2-CoV virus is essentially  25-30,000 bases of single strand mRNA (messenger ribonucleic acid) capable of generating working proteins, the spike, the uncovering of genome, the evasion of enemies. The whole vius is packaged within a flimsy envelope of lipids, easily washed off with soap and water. Surrounding the virus are appendages, peplomars or “spikes,” coded by the virus’ S protein.

These spikes have two functional units: S-I and S-2.  S-I hones in on the ACE2 host cell receptor and binds to the cell. Once attached SI refolds into a fusion form (S-2) melting into the cell itself incorporating Host cell material and evading antibodies.    Once within the cell the virus uses the cell’s multitudes of ribosomes —  miniature factories that translate (transcription, replication) messenger RNA into proteins  – and spew out legions of new virus.

This transcription stage is where mutations arise – deletions, insertions, transpositions.  The mutations that increase the virus’ ability to infect, transmit, evade immune systems etc.,  a survival advantage that will soon allow it to dominate the circulating mass of virus

In the end, the virus and its replicated clones bud out of the surface of the cell. In this process the virus borrows into the cell’s membrane to make its own envelope, essentially “eating” its victim from within to use its materials as a covering. The newly hatched budded-out viruses then swarm out to continue its massive attack on neighboring cells or new organisms.

 

How serious are these mutations?

Mutations are dangerous when the resulting virus is (1) more contagious, (2) Causes more serious disease or (3) blunts or evades the immune response.  The three currently peaking variations  — Britain, South Africa, Brazil — qualify on all three counts. Again, despite our frustration and fatigue, we need to respond with proven defenses –vaccine,  masks, social distance, handwashing…and at all costs avoid long exposure to groups indoors.

According to Sebastion Funk, professor of infectious disease at the Londosn School of Hygiene and Tropical Medicne “The best way to think about the British Variation ( B.1.1.7) and other variants is to treat them as separate epidemics….We’re really kind of obscuring the view by adding them all up to giva eus an overall number of cases.”   (New York Times,  Mandavil, A, April 3, 2011)

The survival advantage of mutated SARs-CoV2  virus has created a more transmissible, more deadly pathogen.   B.1.1.7 the British variant that floored England and much of Europe has arrived in the US .

According to the New York Times, “As of March 13 the British variant accounts for about 27% of new cases nationwide up from just 1 percent in early Febraury. “  Best estimate, reports the Times,  is “B.1.1.7.is about 60% more contagious and 67% more deadly than the original Sars-CoV-2 virus.”

Today, demonstrating the power of Natural Selection and the speed of this transmission, B.1.1.7 , starting from ground zero just a couple of weeks ago, is now the dominant United States’ variant .

 

And our vaccines?

The vaccines authorized in the United States are very effective against the B.1.1.7 variant and will significantly slow virus spread once a large share of the population is vaccinated. Some experts estimate 70 to 90 percent of the population would need to acquire resistance before transmission would substantially slow. As of April 5, less than 20 percent of the U.S. population has been fully vaccinated against the virus. –– Source: New York Times analysis of data from U.S. Department of Health and Human Service April 9, 2021

Vaccines that target the S protein, the spike that initiates infection and fuses into the cell, are believed to be somewhat effective against the new variations.  A long list of scientists and Covid spokepeople point “We don’t yet know how long the antibodies will circulate nor how effective they will be against emerging, more virulent versions of this corona virus.”

We do know however that we can shut down the virus by following the routines that brought us through the first year of pandemic, retreat to our Bubble.  Isolate   But looking at the numbers, retreat seems a little premature at this stage now that we have tools to retaliate. Or maybe just the need to get back to our lives..

MPN patients are prime targets:   The mutation of  SARsCoV-2 is greatly enhanced by  “ protracted infections because of immune impairment from therapy for hematologic malignancies or autoimmunity.”  . (SCIENCE, Mellors, J.,  March 25, 2021)

Our first line of defense..

What we have known from the beginning will continue to work.  Maintain social distance.  Wear a mask in public.  Wash hands frequently.  Prolonged group contact in closed spaces should be avoided.

Get vaccinated!  Once a substantial majority of the population is vaccinated or recovered from infection, the virus will lose its ability to mutate and spread.

Note  Our immunity starts a couple of weeks after our second shot and though it may imperfectly protect us against the newer variants, the resultant flood of antibodies should be adequate to mitigate any serious viral effects. Dr. Anthony Fauci suggests a third shot might be more valuable than waiting for the development of a new booster shot aimed at a specific variant, the so-called Whack-a-Mole approach.

 

MPN patients are prime targets:   The mutation of  SARsCoV-2 is greatly enhanced by  “ protracted infections because of immune impairment from therapy for hematologic malignancies or autoimmunity.” (5) Mellors, J. SCIENCE March 25, 2021)

 

Interferon… There’s both good and bad news on the MPN treatment front..

The bad news…specially for the men.   Interferon — The single drug that has produced structural changes in our hematopoietic system and long-term minimal residual disease– has been implicated in contributing to severe Covid-19 cases.    ( “Flawed interferon response spurs severe illness,” SCIENCE, Vol 369, 25, Wadman, M, Sept 2020 )

Type I interferon, Interferon, the front line virus fighter has been missing in action in some severe Covid-19 cases. The enemy:  ” Rogue antibodies underlie Covid-19 in 10% of gravely ill patients,” reports  Dr. Isabelle Meyes, a pediatric immunologist at the University Hospitals., Leuven.   94% of the patients with interferon-attacking antibodies were male. (The current hypothesis is this interferon response is an x-linked recessive trait.  Women with two X chromosomes are protected.)

The findings challenge the use of plasma donations from recovered patients which may be rich in antibodies to the virus since some donations could harbor the interferon-neutralizing antibodies, says Dr. Elina Zuniga, a UC San Diego immunologist specializing in the interferons..

“Type I interferons are made by every cell in the body and are vital leaders of the anti-viral battle early in infection. They launch an immeidatem intense local response when a virus invades a cell, triggeirng infected to cells to produce proteins that  the attack  the virus. They also summon immune cells to the site…”

“This suggests that we are more reliant on type I interferons to protect ourselves agaisnt SARS-CoV-2 versus other viral infections,” say Zuniga. “That makes it important to try therapies aimed at boosting type I interfeorn responses.”But synthetic interferons won’t help patients who harbor mutations that prevent interferons from working or those with antibodies that attack them.

When it comes to polycythemia vera, Interferon works!   The Good News will come as no surprise to most MPN patients...,  In a Preprint  of a Leukemia paper, “Interferon-alpha for treating polycythemia vera yieds improved myelofibroisis-free and overall survival,” interferon has been decisively demonstrated to outperform both hydroxyurea and phlebotomy-only treatment.

‘Dr. Richard T. Silver and his team reported the results of their single center 470 PV patient retrospective study comparing both myelofibrosis free suvival and overall survival  with interferon therapy versus two other primary treatments, hydroxyurea and phlebotomy-only, In High- risk patients, 20 year MF-free survival for interferon treated patients. was 89% versus 41% for hydroxyurea and 36% for phlebotomy only. 20-year Overall suvival was equally impressive: 66% vs. 40% (HU) and 14% (phebotomy-only).

“The study,” concludes the authors,: “supports treatment of PV with rIFNa to prevent myelofibrosis and potentially prolong survival.”

Ghaith Abu-einah et al., Leukemia, 2021, Preprint)

 

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