Every year I get a quadravalent flu shot made by recombinant DNA technology. This is not a subtle anti-vaxer piece. But for that nutcase movement,  I would have no qualms about what I am about to say, and has to be said. This is about vaccine safety culture.

In the 1950’s and 60’s. the first effective vaccine against polio, developed by Jonas Salk, was replaced by the Sabin live-virus, which was itself replaced by a series of improvements on Salk. The story of polio vaccines makes a tense read, marked by patient tragedies and accusations of murder, yet driven by desperation to chance  Hippocratic Oath #1: Do no harm.

I think the chance is worth taking.  But the front runners present a challenge, to both  safety culture and to the public eye, that hasn’t been seen since the days of polio.

The most dangerous vaccine in widespread use is 17D for yellow fever. An old number was 1 per 50,000 chance of death from the vaccine. The number has been revised downward,  but remains risky for age > 60, so pick your own. (Oxford) Immune Response during Adverse Events after 17D-Derived Yellow Fever Vaccination in Europe.

Yellow fever 17D is a live virus vaccine.  It contains a mutated, non-virulent strain of the yellow fever virus. In rare cases, the weakened virus can cause disease similar to the real thing. (CDC) Reactions to Yellow Fever Vaccine. Even with the old number, 1 in 50,000, regions affected by yellow fever preferred vaccination with 17D to the disease itself.  The choice is baked into these cultures through centuries of yellow fever tragedy.

Americans are still in the novelty phase with COVID, where suspicion rules over logic. Though not related in technology, yellow fever 17D may be the example of what is yet come, a vaccine that saves lives, yet rejected by the public as a dice roll they want to skip. (Reuters) Exclusive: A quarter of Americans are hesitant about a coronavirus vaccine – Reuters/Ipsos poll.

Though live-virus for COVID is not likely to be funded in the developed countries, new vaccine technology may hold surprise in the form of  risk unbounded  by experience. The risks will be reduced in a replacement cycle, with perhaps 6 iterations:

• First Response. Mediocre but fast.  High incidence of adverse events, compared to other approaches. May produce intolerance to re-vaccination. Immunity may be  short-lived.  Even with net public health benefit, may be rejected by the public.
  
• #2: Safer vaccines, with fewer adverse events.
• #3:  Seasonal administration, without restriction on the number of inoculations.
• #4: Effective against multiple strains with just one or two shots.
• #5: Produce immunity for decades with just one shot.  With the technology now available, in technical conflict with #4.
• #6: Require no refrigeration in storage or transport.

The   complexity of the immune system is unfathomable.. Yet the vaccine world can be (almost) neatly split in two, with a division into 2 kinds, classic and novel. The classic vaccine seeks no change in the body save a normal immune response to antigens in the shot. Many novel vaccines contain active principles that alter the machinery of cells.

The classic dead virus vaccine contains, among other things, antigens, which the immune system reacts to by making antibodies. The other things are dead viruses, pieces of viruses, stabilizers, adjuvants, or unavoidable contaminants. The second goal of the vaccine maker is to ensure that these other things, except for the adjuvant, do nothing.  The classic dead-virus vaccine is inert, playing no role other than to be destroyed by the aroused immune system.

The classic live-weakened virus vaccine adds one active principle, the virus-made-harmless.  As polio and yellow fever 17D show, ensuring harmlessness is a challenge. Test cohorts must be followed for many years.  But 150 years of experience has fostered live-virus vaccines of exemplary safety.

The novel vaccine arrived in several steps:

The recombinant vaccine behaves in the body like a superior classic vaccine. The injected antigen, or antigen particles, are almost completely inert, serving no purpose other than to present antigen to the immune system.

• Nucleic acid (DNA, RNA) vaccines  abandon inertness. Instead of supplying antigens, these vaccines modify the cell machinery at the injection site for varying periods of time.
• Virus vector vaccines use an adenovirus to carry nucleic acid into the cell.

The most novel-of-the-novel  include at least one bullet.  Some include both, each presenting novel risk. The risks may be more than additive.

This is not an indictment, or a guide to buying stocks. These are points to watch for. The novel vaccines are diverse; sharing an acronym does not imply  a shared hazard. Yet as Golda Meir used to say, even paranoids have real enemies.

There is more to say, so it will be continued shortly.

This is not a continuation of COVID Vaccines. It’s a digression.

If I were to go political in a partisan way, I’d lose half my readership. And for nothing. You can get all the politics you want from the news sites. And yet there is an intersection of public health and politics that cannot be ignored. This intersection defines what kinds of public health responses are desirable, possible, and impossible; achievable, and unachievable.

A minority of insurrectionist mood is companion to the partisan split.  That minority has been with us since the passing of the Era of Good Feelings, circa 1817-1825. but it has found a voice. It is the hoarse, chaotic, and dissonant voice of an emerging underclass; the obsolete human being. Perhaps we’re lucky they don’t have Peter Finch to give them eloquence: I’m mad as hell and I’m not going to take this anymore! The discontent of the Insurrection is a mix of quiet desperation with incomprehension.

In 1976, obsolete human beings were a thing of the future. We’ve staved off the reckoning with PlayStations, but not everyone is pacified by first-person-shooter games. Some have to express their discontent in the real world. So with a cheap substitution of spitefulness for social consciousness, they refuse to wear masks. And they are every bit as sure of themselves as the 1968 draft protestors shouting, “Hell no, we won’t go!” The difference is that the mask refusniks haven’t got a moral leg to stand on.

In the 1918-1919 influenza epidemic, which killed 685,000 Americans, there was no equivalent. Some were cited for failing to wear masks, but there was no protest. Society demanded conformity  in dress, grooming, and social behavior, including masks. With high barriers of class distinction and prejudice,  social mobility was a thing of the future. But there were no obsolete human beings as long as toil with pick and shovel beckoned.

This is the America I see, traveling through time like Kurt Vonnegut’s Billy Pilgrim of Slaughterhouse Five, past, present, and future, simultaneously, like a child’s flip-book. I see politics as a process of conflict resolution, not of the totality-of-the-reality.  Politics is caught in the eternal moment, attempting to capture the past and future with simple slogans.

With authoritarian compulsion, social distancing in China has accomplished something we could not: saving  millions of lives, más o menos. In China, this is not a political issue, even to the degree that politics exists in that country. Here, it’s the hot button. Is there a way around this? Is a nonpartisan compromise possible?

I think not. Among the Insurrectionists and fellow travelers, Live free or die has been altered to Live free and die. There are a lot of fellow travelers, because they are going broke. The more stringent the science, the more the Insurrection will grow, perhaps to massive civil disobedience.

The approach advocated by Dr. Fauci is scientifically correct. The next nine months are going to look like California in fire season. Yet potential of Insurrection blocks a national approach. The Insurrectionists have made their choice for all of us: Learn by dying.  An interesting hypothetical: If you are the politician, and you have the votes to impose strict social distancing, would you do so in the face of powerful backlash that shakes society to the core?

After the dying has gone on for a while, the Insurrectionists will not recant, but their voice will weaken. Perhaps by then, herd immunity will have developed. If not, politics will turn the page. It won’t look back to examine the social forces that lead us to this pass.

You know what? I’m sick and tired of being trapped like a rat in my house in the burbs with central heat and A/C. I’m gonna open a window. And then I’m gonna shout:

I’m mad as hell and I’m not going to take this anymore!

Thank you, Paddy Chayefsky, Sidney Lumet, Peter Finch, and the rest. In Network, you shouted for all of us.

Let’s compare a very old disease to a very new one. You might be thinking this is in the line of “Oh, what a terrible scourge this could be” Not! This is about the immune system, and exploding some popular ideas about it.

Differences

• Tuberculosis (TB), which has existed for at least 17,000 years, was the leading bacterial cause of death in 2014. COVID-19 jumped species no more than six months ago.
• The infectious agent of tuberculosis is a bacteria, a kind of living cell. COVID-19 is caused by a coronavirus, a non-living package of malevolent instructions for the machinery of a cell, with a misleading label on the box.

Similarities

• Only 10% of persons exposed to TB get the disease. This corresponds to the huge preponderance of asymptomatic COVID-19.
• Both TB and coronavirus have tricky strategies to evade the immune system long enough to reproduce and infect more people. Unlike most bacteria, which live next to human cells, and in bodily fluids, mycobacterium tuberculosis must inhabit a human cell to survive.  Hidden within a cell, it is almost invisible to circulating antibodies. On the surface of the lung lining, COVID-19 is shielded from large antibodies.

Many COVID-19 cases, including those who recover, show weak antibody response. The coronavirus does not share anything of detail with tuberculosis, but the result is the same: stealth. COVID-19 may take advantage of barrier membranes in the lung to avoid circulating antibodies.

The antibody response to TB is also weak, wrong, or nonexistent. Quoting from (NCBI/PMC) Emerging Themes for the Role of Antibodies in Tuberculosis [brackets mine],

The best way to debunk a scientific dogma is to throw irrefutable evidence at it….the tide of the opinion has begun to turn in favour of Abs [antibodies] but we also caution against…

Thus, the strongest argument that Abs do not contribute to protection against TB comes from numerous preclinical vaccine studies showing strong Ab responses but minimal or no protection;

Both TB mycobacterium tuberculosis and coronavirus can persist in the body. The TB bacillus was isolated in 1882. By 1939, it was thought that eventually, all the bacteria left in the lung of a recovered patient eventually die. It’s 2020, and we’re back to “nobody knows.” For both COVID and TB, there is no skin, blood, or culture test that definitively proves the pathogen (germ) is gone from the body.

Antibodies are a question, not an answer. From (NCBI/PMC) Latently and uninfected healthcare workers exposed to TB make protective antibodies against Mycobacterium tuberculosis (brackets mine),

Our results indicate that certain individuals make protective antibodies against Mtb [TB] and challenge paradigms about the nature of an effective immune response to TB. …

Although it was known that both active TB patients and healthy subjects make detectable antibody responses to Mtb [TB](19–21), it was not known whether any of these antibodies afford direct protection against infection. … suggesting that protective antibodies isolated from our study are part of a complex interplay between the pathogen [germ] and host immune system and highlighting a protective role.

From (NCBI/PMC) Antibodies and tuberculosis,

The discovery of individuals in high-exposure settings that do not have a detectable T-cell response to M.tb antigens by tuberculin skin testing (TST) or ex vivo stimulation has triggered interest in the search for individuals with unusually effective immune responses against TB [42]

Takeaway #1: The expert picture is more confused than the popular, which grabs onto oversimplification.

Takeaway #2: Antibodies have been exaggerated in popular media, which view them as the body’s main defense from disease. In many cases, they are secondary to other processes by which the body fights disease. Any time we are looking at antibodies, they might be the:

• Wrong ones, created by error, attacking the body’s own tissue.
  
• Useless, diverting the body from effective response. The tuberculin skin test may be an example.
• Useful in moderating disease severity, by preventing spread from one tissue compartment of the body to another, such as the blood.
• Secondary means by which the body fights the disease.
• For some diseases, effective prevention and cure.

Takeaway #3: TB and COVID use different tricks to hide from antibodies. As with TB,  even a weakly effective COVID-19 vaccine may be useful in ways yet to be revealed. Nota bene: This cannot be predicted. It can only be observed.

Besides the famous movie-star antibody, what other defenses does the body have? A hint of the puzzle: A partially effective vaccine against TB exists, which appears to have beneficial effects other than antibody production. New vaccine technologies offer possible diverse benefits. The body has another immune system, which we will get into shortly.

Clusters of asymptomatic cases suggest that with COVID-19, the personal and local biomes (the germs we live with) may be crucial.

To be continued shortly.

(CNN) What happens if a coronavirus vaccine is never developed? It has happened before.

This is possible.  Before we get into it, urgency requires this up front:

Vaccines come in different quality grades. The quality depends on two main factors: the antigenic target, and the process by which the vaccine is made. For example, leafy green plants like tobacco can be used to make vaccines.  But a vaccine manufactured in  tobacco plants  cannot reach the  quality of a well designed animal-cell culture vaccine. It could still be good enough.

• The ASAP is for a vaccine with some benefit in the shortest possible time.
• A mediocre, but not harmful, vaccine satisfies this immediate requirement better than a high quality vaccine on the standard development time scale.
• Messenger RNA, used by Moderna and a few others, is a new addition to vaccine manufacture. The big advantage of RNA is that it can be produced by purely chemical means from a DNA template. It doesn’t have to grow.
• The original spotlight  on RNA was for therapeutics, for sick people. The bar is lower for sick people than for well people. Since  no RNA vaccine exists that has passed clinical trials, the risk of adverse reactions cannot be estimated from precedent. Speculation is the only guide.
• Moderna’s vacccine could be good, mediocre, or worthless. For the immediate need, mediocre satisfies. But it could also be evil.

Be warned: the immune system is possibly the most complex system that has come under the eye of man. The big picture is mostly darkness, with illumination of great detail.The sales pitch of the gambler should be taken with a grain of salt. No one, big talker or little voice, knows more than that.

An Urgent Note to The Powers That Be: The award to Moderna is justified. But it is extremely important to spread the money around.

Next: An old disease compared with COVID-19.

(CNN) Pentagon officially releases UFO videos.

Previous discussion:

• UFOs: Let’s Get Serious; Why a Program Goes “Black” Part 1
• UFOs: Let’s Get Serious; Why a Program Goes “Black” Part 2
• UFOs: Let’s Get Serious; Why a Program Goes “Black” Part 3
• (CNN, NYT) Navy pilots speak out on UFO sightings

Official release of the tapes does nothing to enhance their value. The tapes have been available for years. So what is the significance of release? This is a more tractable problem for enterprise journalism than the existence of UFOs.

The possible reasons include the mundane, and the curious. UFOs have never been more than a peripheral interest of DoD. Possibilities:

• Pure sloth. Sign-off forms to declassify sat on multiple desks for years, with the occupants worrying that sign-off would come back to bite them.
• A low priority technical investigation determined that the images do not represent a vulnerability of the weapon imaging systems  that made these recordings. These systems are very complex. Light scattering inside the optics could interact with data reduction software to create artifacts.
• A really thorough investigation would have isolated the optics, the raw sensor, and the software, challenging these parts with extreme imagery generated in the lab. This is a job for one of the national labs, probably Lawrence Livermore. With low priority, it took years to complete.
• An invitation to dialog with other pockets of interest.

UFOs: Let’s Get Serious; Why a Program Goes “Black” Part 3 offers UFO explanations that a good percentage of readers need an acid trip to feel comfortable with.  We grew up thinking that the mysteries of the Universe truth would eventually be reduced to simple truth. What if this is wrong?

The hydrogen atom seems to be a dividing point between things larger and smaller. The major features of hydrogen have notable simplicity. Every physics student learns the simple quantum mechanics  of hydrogen by separation of variables. At scales both smaller and larger than hydrogen, problems get way too complicated way too fast. Instead of simple truth, truth may have infinite complexity.

People who understand the scientific method know that physics is not a complete system, and that nothing is unconditionally true. Concrete thinkers don’t get this. They go for the extremes, absolute truth or absolute nonsense. For example, the Laws of Gravity are not laws; they are observations that seem to hold. So how do you explain the possibilities outside the box to someone who lives inside it?

We can pry the box lid off  with intelligent discussion. We can redirect interest away from sheet metal curios and religious revelations, to more important questions about the Universe, and our place in it. With a future that in some ways seems rather dim, UFOs beckon with a bright (and sometimes flashing) light.

(CNN) North Korean state media reports Kim Jong Un made first public appearance in weeks. (CNN) Will Ripley’s video is cautious. We can go further than that. Kim is likely incapacitated in a way that interferes with his ability to project personal power. Possibilities:

• Slightly drooping lip of partial paralysis, motor impairment and other factors of cosmetic significance.
• Brain fog.
• Major stroke, with aphasia (loss of speech), and altered level of consciousness.
• Coma.
• Persistent vegetative state.
• Brain death.

The nature of the regime naturally includes the body double. This was highly effective before the advent of biometric image processing that can use as input any photo or video. Totality of control prevents detection of the double by excluding all cameras, with separation of the audience by large distance. A body double that passes casual inspection at a distance risks exposure with image processing. The official photo does not count.

So there is more to this than the simple question of whether the event occurred.  While North Korea could have simply reported an event that did not occur, it has resources to do much more.

It is the nature of the press to report South Korea ‘s representations that Kim is well at face value, even though Administration sources hint at the opposite.  This site is about open source intelligence, so we must note that South Korean statements have no informative value. Their statements could be

• Mandated by source protection, the first obligation of all intelligence agencies.
• Due to faulty intelligence, as is sometimes provided by a double agent.
• Result from faulty analysis.

Hence S. Korean statements to present have no weight in the estimate of this problem. What does?

• Cautious U.S. statements, which, saying less, inform more.
• The non-appearance of Kim in any format accepted as record outside of North Korea.
• Kim’s health history. His smoking, obesity, and metabolic syndrome make him a sitting duck.
• A risk factor of the moment: If Kim contracted COVID-19, he is the picture of a patient with large blood vessel clot disorder. (NPR) Doctors Link COVID-19 To Potentially Deadly Blood Clots And Strokes
• (CNBC) China sent team including medical experts to advise on North Korea’s Kim, sources say.

Long time readers of this blog are familiar with the technique first described by Benjamin Franklin, of counting the pros and cons, with equal weight to each. For an application, see U.S. Strike on North Korea? Prediction Update. Depending upon how you count, there are between 5 and 9 independent pros, favoring Kim’s severe incapacitation.

In spite of the obvious desire of North Korea to contradict this with a “con”, their count is zero. The official photo does not count.

Media have been worrying about the terrible things that could happen without Kim. There hasn’t been any mention of the upside. Who are they kidding? This would be great news for North Korean Munchkins.  I’ve got the song ready:

Ding Dong, the Witch is Dead

Not long ago, augury, the divination of the future, was the preoccupation of the marginalized or foolish.  Though it now has a stronger attraction, it’s best to keep it as wish, not action. It can also inspire painters and poets, who don’t paint or write to be understood.

Divinations. 24×24″, oil on canvas. Click to enlarge.

We continue from (CNN) … is Wrong in so Many Ways About Hydroxychloroquine…the Facts Part 2 with this brief note.

The study of the moment is (medRxiv) Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19.

The popular maelstrom picks up on something like this with proclamations of worthlessness and political finger pointing. The value of this study is too small to become part of that. It usefully warns and reminds the clinician that:

• Hydroxychloroquine is a dangerous drug.
• If it does work, there is likely to be a tight regime, with the narrow therapeutic index characteristic of drugs of the pre-antibiotic era. With some of these drugs, the range between the effective dose and the lethal dose was exceedingly small.
• No one has any idea how to dose. Experimental dosage is based on toxicity to the malaria parasite, entirely different from the job of chaperoning zinc ions into an epithelial cell.

Quoting,

In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19.

The words are correct, but should not be confused with “found evidence that [the combinations] did not reduce the risk of mechanical ventilation in patients .”  The study found nothing. either pro or con.

The link contains reader comments, which are well thought out. One factoid draws attention. Quoting,

Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively.

This is a red flag. The ventilation rate for HC+AZ recipients was half that of the others. There are two ways to take this:

• The HC+AZ recipients did not enjoy a statistically meaningful reduction in mortality, so, so what?
• Something is wrong with the data.

Whenever we analyze statistical data, we look for “outliers”, data points are not coherent with the trend. The 6.9% could be the result of outliers in a too-small, invalid trial, or it could represent a unidentified cohort with salient characteristics.

Three choices are available:

• Continue the study until it is large enough that the salient characteristics of the cohort can be identified.
• Decide that no cohort exists. Exclude messy data as outliers.
• Decide that the data does not reach the threshold at which statistics can be applied.

This study does not reach the threshold of statistical validity, and should not become part of public policy debate. It has value only as a caution to the clinician.

(CNN US monitoring intelligence that North Korean leader is in grave danger after surgery. Quoting,

The US is monitoring intelligence that North Korea’s leader, Kim Jong Un, is in grave danger after a surgery, according to a US official with direct knowledge…Kim received the cardiovascular system procedure because of “excessive smoking, obesity, and overwork,” according to the news site, and is now receiving treatment in a villa in Hyangsan County following his procedure.

This is contradicted by (Reuters) South Korea says North Korean leader Kim not gravely ill.

Kim Jong Un is age 37, unusually youthful for a bypass. The procedure is, with high probability, balloon angioplasty, perhaps combined with stent placement.  Although these are very popular procedures, whether they improve long term survival over purely medical treatment has been questioned by some studies.

A common complication of these procedures occurs when small pieces of arterial plaque break free, lodging in small blood vessels of the brain. The resulting ischemia causes brain damage, from slight “brain fog”, to apparent, to severe.

This scenario would explain the divergences of the CNN and Reuters sources:

• It may have originally appeared critical, with danger to life receding after treatment with clot busters.
• Mild cognitive impairment, or motor problems would be hidden as long as possible by those who derive power from Kim.
• Cognitive impairment risks the crumbling of Kim’s personal power structure. Those who derive power from Kim are motivated to extreme measures of concealment, even a  body double.

In some cases, rulers with mild cognitive impairment remain in office because of the lack of a consensus replacement.  King Salman of Saudi Arabia is said to have Alzheimer’s.  From (Wikipedia) Salman of Saudi Arabia:

In August 2010, Salman underwent spinal surgery in the United States and remained out of the kingdom for recovery.^[103] He has had one stroke and despite receiving physiotherapy; his left arm does not work as well as his right.^{[104][105][106]} Salman also suffers from mild dementia,^[107] specifically Alzheimer’s.^[108]…

US intelligence officials believe that King Salman has been kept apart from his wife Princess Fahda bint Falah Al Hathleen for several years, on the orders of their son Prince Mohammad bin Salman.^[109] …

Yet up to the recent, Salman is credited in the media with command authority. With little or no open source contradiction, this indicates a system of ruling legitimacy that “splints” the incompetent.

António de Oliveira Salazar, dictator of Portugal from 1932 to 1968, had an incapacitating stroke that resulted in his immediate removal from office. He lived until 1970. He became lucid during this interval.  Out of popular respect,  he was never told he had been removed from office. He died in this illusion.

Fate has smiled on Salman and Salazar. But the power of neither was based on Mao’s claim, that Political power grows out of the barrel of a gun. As the authentic heir to a Stalinist state, Kim Jong un believes this.  If Mao was right, then so was Matthew: Those who live by the sword, die by the sword.

The estimate now follows:

• If Kim has sustained even mild cognitive impairment, his power structure will crumble, and he will be disposed of.
• U.S. policy towards North Korea should take into account Kim’s short life expectancy. The waiting game can win.

Some regard COVID-19 as a warning to prepare for the eventuality of a far more lethal plague.  I wondered whether dramatization of this threat would serve a good purpose.  I think it will, provided the drama is tempered with science.

(YouTube) The Satan Bug is a 1965 movie that anticipates an artificial virus that can end all life on earth. In the real world, natural selection prevents this from happening. A virus that has no person or creature  to infect dies out.  A virus needs hosts. There is a natural balance to such things.

In the natural world, in exceptional cases, the cap on virulence loosens temporarily, until the natural balance resumes. In the laboratory of bio-warfare, where hosts can be guaranteed, there is no equivalent cap. A virus is not alive; it is a machine. The only limitation to virulence is the complexity of viral machinery that can be devised to fit in the mechanism that opens the host cell. Some refer to modifications of added capability as gain of function.

What is the limit of virulence? Without the need to preserve some hosts for future infection,  is there a limitation to all viral machinery? Is it Ebola or a rabies virus, packaged for airborne delivery? Can stealth aspects be added, as observed with COVID-19 ? What of a constellation of virusoids that co-infect and extend the virulence of the engineered virus?

As a universal killer of all life, the Satan bug is almost impossible. Fiction takes dramatic license.  Life fights back with genetic diversity. But the border of reality is unknown. Vaccine technology has made great strides. The methods of trialing a vaccine have not; they do not reflect knowledge at molecular level that was unknown in the whole-virus live-or-killed vaccine era.

This time, the cost in lives of the prolonged vaccine trials will be in the low millions, or tens of millions. It could have been much worse.  (Atlantic) Hic sunt dracones. There be dragons.

It’s a good movie. Get the popcorn out. Directed by John Sturges. (  Bad Day at Black Rock, Gunfight at the O.K. Corral, The Magnificent Seven , The Great Escape , Ice Station Zebra)

The Satan Bug

Hic sunt dracones