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June 2020

A Simple Mutation Might Have Accelerated The Infection

70% of the sequences of ~50,000 CoV-2 genomes isolated from infected people around the world carry a simple mutation that might impart an increased ability of the virus to infect human cells. The mutation, first noticed by a researcher at Northwestern University Feinberg School of Medicine, designated D614G or "G" for short, has been found to affect the virus spike protein, which is the surface protein that gives the virus its distinctive “corona” and that binds to ACE-2 molecules on human cells in the lungs, GI tract and vascular endothelium. Lab studies suggest that the mutation in the spike protein enhances its binding to the ACE-2 receptor, thereby enhancing the virus infectability.

The mutation only changes one of about 1300 amino acid building blocks that make up the spike protein. It changes the spike protein amino acid #614 from “D” (aspartic acid) to “G” (glycine). The fact that 70% of viral isolates carry the mutation indicates that the mutation gives the virus variant an infectious advantage that has allowed it to dominate the original virus first identified in China.

The outer parts of the mutated viral spike protein are less likely to break off, which was a weakness of the original CoV-2 virus that originated in China. This weakness made the original virus harder to invade human cells. The “G” mutation makes the virus 10 times more infectious in lab experiments done at the Scripps Institute. Other researchers at the New York Genome Center and New York University, who were studying how the virus binds to and enters cells, but using the original strain isolated in January in China, had a very hard time getting the virus to infect human cells in tissue culture. When they switched to the “G” variant, they found a huge increase in infection, which agreed with what researchers at Scripps found. In human studies done at the Los Alamos National Laboratory, patients with the “G” virus variant typically carried a higher viral load, consistent with the greater infectious nature of the virus. A higher viral load would then make them more likely to spread the virus. In sum, a greater infectious ability and higher viral load, would likely accelerate the spread of the virus.

The mutation does not seem to affect the virulence of the virus. But, all of this points out that as mutations accumulate while the virus spreads, changes in its behavior due to changes in its genome are quite possible.

This is all very preliminary and the research has not been officially published, but it was made available as “preprint” research. The data have been submitted for publication. More research is needed to confirm the observations.

We will see.


Some People Say That A COVID-19 Vaccine Will Never Happen

It is amazing how many new “expert” virologists, immunologists and vaccinologists have popped up since the COVID-19 pandemic began. Over the last few weeks I have repeatedly seen claims from such “experts” that since we don’t have a vaccine for the coronavirus that causes the common cold, we will never have one for the coronavirus that causes COVID-19. Therefore, they conclude that the current efforts and expense to make such a vaccine simply waste time and resources. That syllogism assumes that someone has tried and failed to make a vaccine to prevent the common cold.

These are the facts: Only ~30% of colds are caused by a coronavirus; rhinoviruses and adenoviruses also cause what we call a cold. Therefore, we would have to develop several vaccines against several different viruses in order to prevent colds. Since colds do not cause serious morbidity or mortality, there has been little interest in developing several different cold vaccines. Thus, the first point in the “expert” syllogism falls apart.

Second, coronavirus vaccines that effectively prevent certain diseases in animals do, in fact, exist. Therefore, it is quite possible to develop a vaccine to a novel coronavirus. This defeats the second point in the “expert” syllogism.

I am pretty certain that in a couple of years, there will be several successful CoV-2 vaccines. In fact, there is a very good chance that by the end of this year, we might very well have one or two effective vaccines. This humble blogger predicts that the biggest problem we face is not in developing an effective vaccine, but getting enough people quickly vaccinated.

On May 18, this blog reported that 133 vaccine candidates were under development around the world. Today, the Milken Institute reports that 172 vaccines are under development.


120,000 Deaths And Counting....

The US just passed 120,000 deaths due to COVID-19. That happened in just five months and WITH quarantine measures in place. That is 3-4 times the number of deaths we see in an entire typical 18 month flu season WITHOUT quarantine measures. So, to those who try to brush this off as just another flu, I wish a pox on you (pun intended).

It is true, as many COVID-19 skeptics point out, that >97% of infected people survive the virus. But that was also true of the Spanish flu in 1918, which, in just 24 weeks, killed more people than were killed in the 10 total years of WWI and WWII combined. It is wise to view all the statistics rather than just cherry pick the ones you like.

At this time, COVID-19 is increasing in several Southern US states, so we are not out of the woods. It also is exploding in Central and South America, and India. Your humble blogger believes that Africa is not far behind.

Recent reports indicate that large cities in India, such as its modern financial capital of Mumbai, have been hammered by the virus. News reports talk of overwhelmed hospitals in Mumbai where the ICU beds stretch into hallways and new patients sleep on the floor while waiting a bed. It also appears that new hotspots are emerging in rural areas across India as people leave the big cities and head to their homes in the hinterland where there is less access to basic health care, let alone ICU beds and ventilators.

Brazil has passed the US in the disease rate and Peru and Mexico are not far behind. So much for hoping that the warm summer would retard the virus spread. Below is an aerial image of mass graves recently dug in Brazil to deal with COVID-19 fatalities.

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And as the virus hammers these countries, its victims are younger than those in the US and Europe where ~70% of the people who die from the virus are over 75 years old. In contrast, just 12% of COVID-19 deaths in India, and 17% in Mexico have been people over 75.  In these countries, it is mostly people in their 40s and 50s who are dying from the disease.

There are many possible reasons for the change in these mortality statistics, including different demographics and health care availability. But, it also raises the scary specter that the virulence of the virus could be changing. The bottom line is that younger people cannot be complacent about it.

The virus is an opportunist. It will have its will with whoever is most available.


Genetics and COVID-19: Why Do Some Get Sick And Others Do Not?

Why do some people who are infected with CoV-2 experience no, or mild, symptoms, while others become gravely ill? Age and underlying chronic conditions like heart disease, diabetes, obesity, etc. all seem to play a very significant role. But, since the pandemic began, stories of some healthy, young people without these risk factors becoming very sick have persisted as reported here and here and here. Why?

In this regard, this virus is very unusual and it becomes important to understand why some people just get a digestive or respiratory problem, other people suffer strokes, some get “COVID toes” (purplish toes), some lose their sense of taste and smell, some have systemic coagulopathies (clotting throughout their bodies), and others experience none of these symptoms. Are there different strains of the virus with different virulent properties, as was the case during the 1918-20 Spanish flu, or are there human genetic variables that cause these very different responses?

Popular genomics companies like 23andMe, Inc., and Ancestry, Inc., along with University investigators have been mining genomic databases to see if they can find human genetic links to help explain the disparate responses of individuals to the virus. Genome-wide association study (GWAS) that searched more than 750,000 genomes have found a genetic sequence on chromosome 9  in a region that determines blood type that correlates with disease severity. People with type O blood seem to be significantly protected from serious illness caused by CoV-2, while people with type A blood face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected.

Another genetic association with disease severity was found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. This stretch of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the cell surface molecule that allows the novel coronavirus to infect human cells. The region also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.

These statistically significant studies were reported by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway.

How these genetic regions affect our response to the virus is not yet clear. More research needs to be done.

We will see.


FDA Revokes Emergency Use Approval Of Hydroxychloroquine

The Food and Drug Administration has revoked its emergency use authorization for the drugs hydroxychloroquine and chloroquine for treatment of Covid-19.

“FDA has concluded that...it is no longer reasonable to believe that oral formulations of HCQ and CQ may be effective in treating COVID-19, nor is it reasonable to believe that the known and potential benefits of these products outweigh their known and potential risks," FDA chief scientist Denise Hinton wrote in a letter to Gary Disbrow of the Biomedical Advanced Research and Development Authority (BARDA) on Monday.

Doctors can continue to legally prescribe the drugs off-label, as they can with any drug that's approved for other conditions. The FDA's emergency use authorization for hydroxychloroquine and chloroquine was narrow in scope, applying only to hospitalized Covid-19 patients and only to drugs donated to the Strategic National Stockpile.

The World Health Organization and other laboratories around the world are still testing hydroxychloroquine for Covid-19 treatment. The WHO had temporarily paused the trial in May due to concerns surrounding the drug's safety and in order to review its own data, but resumed the program earlier this month after an interim data analysis determined that they had not seen significant safety concerns.

We will see.

 


Fish: An Unexpected Problem From The Pandemic

Excerpted from the Wall Street Journal, June 14.

When a restaurant serves a fish whole, there is a reason it fits the plate perfectly. It’s because Boris Musa grew it that way. His indoor fish farm in Australia supplies restaurants with plate-size barramundi grown to 1.8 pounds. The coronavirus put the restaurant industry on ice for months, but Mr. Musa’s fish kept growing. That led to a big fish problem—as in, his fish were getting too big.

If Mr. Musa’s barramundi, a white fish popular in Australia, grow too much, the water-filtration system that is keeping them alive won’t be able to keep up. Once they tip the scales at about 3 pounds, he said, they’re too large for a restaurant dinner plate. To save his fish, and his future profits, Mr. Musa is turning to science. He is betting that by lowering the water temperature in his tanks, he can slow down the metabolism of his fish, reduce their appetites and stall their growth.

Fish farmers all over the world are trying to slow the growth of their fish as the pandemic wreaks havoc on supply chains and consumer demand. Others are trying different strategies: freezing their fish using liquid nitrogen, smoking them so they can be stored until demand returns, and skipping the restaurants and selling their fish online. Restaurants around the world are reopening, but the lockdown created a fish-farm backlog.

Fish farming now accounts for almost half of the world’s seafood production. But unlike traditional fishermen, who can stay in port if demand falls, fish farmers who have put time and money into growing their fish can’t just shut down.

“We’ve got to look at it as if we have a 16-month crystal ball,” said John Ng, president of Hudson Valley Fisheries, an indoor fish farm about 100 miles north of New York City. That is how long it takes to grow Mr. Ng’s steelhead trout to its target size of nearly 7 pounds.  

Fish tank

Seven pounds is the target size for steelhead trout grown at Hudson Valley Fisheries in New York.

Unlike weekend anglers looking for bragging rights, fish farmers frequently don’t want monster fish in their tanks. They often judge a fish ready for sale when it grows to the size of a dinner plate—perfect for serving whole in restaurants.

Clean Seas Seafood Ltd., which farms kingfish off the coast of South Australia, has reduced the amount of food it is giving some fish that already have reached their target weight. But it can’t adjust its water temperature because its fish, often used for high-end sashimi, are farmed in pens in the ocean. Instead, the company is harvesting its fish mostly as usual and using liquid nitrogen to freeze them, which should give them a shelf life of at least two years. Clean Seas began using the technique before the pandemic, but has since increased its cold-storage capacity, Mr. Head said.


Face Masks: A Substitute For Herd Immunity?

Since this coronavirus pandemic hit, the phrase “herd immunity” has become common in our lexicon. It refers to a situation when a sufficient number of people have developed immunity to the virus that they cease being viral reservoirs who can spread it to others. The point is that sufficient herd immunity will provide a significant block to further viral spread in the community. It is too dangerous to develop natural herd immunity by natural exposure to the virus; therefore, a vaccine is the best way to ensure herd immunity, but that is a year, probably longer into the future as reported earlier in these pages.

The virus has proven to be highly contagious, more so than your typical seasonal flu. An infected person can be expected to pass the virus to up to four other individuals, whereas the flu is typically spread to only two or fewer others. This, plus lack of immunity is a perfect storm for continued viral spread, and continued morbidity and mortality due to COVID-19, hence the necessity for lockdowns and social isolation to prevent viral spread as much as possible. So, what if there was another way to significantly retard spread of the virus while we wait for a vaccine and herd immunity?

A study just published by University of Cambridge researchers in the Proceedings of the Royal Society A found that widespread mask-wearing can help prevent a resurgence of the virus with less reliance on lockdowns that have proven economically devastating. The study found that if 50 percent or more of the population routinely wore masks, each infected person would on average spread the virus to less than one additional person, reducing the transmission rate by about 75%. That is exactly what herd immunity would hopefully accomplish.

It is important to understand the true value of facemasks. Your typical mask does NOT protect the wearer. Very little of the air a mask wearer breaths is filtered through the fabric. It almost all comes from the sides of the mask and is no different from the air you would breath without a mask. Also, virus in the air can infect through your eyes, which are not protected by a mask. However, masks do a very good job preventing viral laden exhalations, especially from talking and from droplets produced by sneezes and coughs. Thus, the value of masks is in inhibiting spread of virus from infected people, especially from those who do not know they are infected.

A key message from this study to aid the widespread adoption of facemasks would be: ‘my mask protects you, your mask protects me’.


Mixed News About Hydroxychloroquine And The Coronavirus

A couple of weeks ago, headlines screamed that the WHO was stopping a large clinical trial testing the efficacy and safety of treating hospitalized COVID-19 patients with the anti-malaria drug, hydroxychloroquine (HCL). The WHO did this in response to a study published in the May 22 edition of the journal, Lancet, that reported that the drug provided no therapeutic benefit while increasing the risk of heart problems and death in treated patients. The flurry of headlines that resulted was misleading as reported in these pages on May 25. The WHO did not cancel its study; rather they made a mid-study pause so that a team of independent scientists could review the interim data that had been collected to see if it also showed increased risk to study patients as reported in the Lancet study. That interim data analysis is complete and the WHO just announced that the study was re-started. That means that the partial data they have collected did not reveal concerns about study subject safety.

The Lancet study was not a “gold-standard” blinded and controlled clinical trial, but a prospective “chart review” of medical records of 96,000 COVID-19 patients hospitalized in 671 hospitals across six continents. The study claimed to find a 30% increase in mortality in patients treated with the drug and based on this, the World Health Organization paused its global clinical trial of HCL, and many countries banned the drug as a COVID-19 treatment.

Since the Lancet study was published, more than 100 scientists around the world raised serious questions about the reported data and about Surgisphere, the organization that provided the data. They spotted glaring data errors. For example: Obesity and smoking rates in the study patients surprisingly were the same across the six continents. Well established population health data indicates that this is not true. Also, in a letter to Lancet’s editors last week, 120 scientists criticized the study’s sloppiness and aggregation of data from patients who were different in many respects including in the dose of hydroxychloroquine they received, and in the severity of their illness. The complaining scientists also pointed out that in the study Lancet failed to share all patient data. Surgisphere’s CEO, Sapan Desai, one of the study’s authors, claimed his hospital contracts did not allow these data to be shared. This raised more red flags since the reliability and accuracy of the chart data could not be independently confirmed, which is a serious breach of scientific standards.

It now looks like the study may have been based on questionable data from a dubious source. In vitro studies have indicated that hydroxychloroquine can block the virus’s replication, and the drug has been safely used to prevent and treat malaria in millions of people worldwide for 60 years. It is also used to safely treat rheumatoid arthritis and lupus. The Food and Drug Administration has approved it for emergency use for COVID-19 patients. Therefore, the study’s conclusions run counter to decades of experience with the drug.

Wednesday, June 3, Lancet published an “Expression of Concern” about the study and said it would undergo “an independent data audit.” That’s good, but the study's publication may have already done public-health harm. Study doctors are complaining that the negative press has made it difficult to recruit patients in the U.S. for ongoing clinical trials to study the drug’s effectiveness as a prophylactic or for early-stage treatment against Covid-19.

As a result of this brouhaha, the authors of the study recently retracted it. They decided to issue the retraction after Surgisphere Corp. refused to share the full, detailed data set as part of a review after outside researchers raised concerns.  “Based on this development, we can no longer vouch for the veracity of the primary data sources,” said the authors, Mandeep Mehra, Frank Ruschitzka and Amit Patel.

So, the WHO and other studies, including several in the US, such as at New York University, the University of Washington, and elsewhere, continue to study whether hydroxychloroquine can treat people exposed to the virus.

Can HCL treat people with COVID-19? The jury remains out despite this interruption. We will see.

Meanwhile, a different gold-standard, double-blind randomized clinical trial involving 821 subjects was also published last Wednesday in the New England Journal of Medicine and it concluded that the drug is ineffective at preventing infection. Study subjects took the drug or a placebo for 5 days and were followed for 2 more weeks. About 12% of those taking hydroxychloroquine came down with COVID-19 compared to 14% of the placebo group. The difference was not significant. Also, 40% of the subjects taking hydroxychloroquine reported mild side effects while only 17% of the placebo controls did. Nausea, upset stomach and diarrhea were the most common side effects, but none were considered serious.

The bottom line is that the news on HCL and COVID-19 is mixed and confusing. The research continues.

We will see.