Bite Point

Covid-19 RNA Vaccines, Explained

Covid-19 RNA Vaccines, Explained

As we approach a time when effective Covid-19 vaccines become available, I wish to explain to you all one further twist on these potentially life-saving medicines. All the major vaccine contenders now are RNA vaccines. What is an RNA vaccine, and are they safe?

First of all, what is a virus, exactly? A couple of biologists back in the Seventies made the delightfully snarky comment, “A virus is bad news wrapped in protein.” And that’s about the truth of it. Although viruses can do some remarkably complex things, they are blindingly simple in structure. A virus consists of the genetic material that codes for what it will do when it enters its targeted host cell—this can be DNA or RNA, depending on the species. And then there’s a protective protein coat, which contains all the devious machinery that allows the virus to enter that host cell once it encounters it.

That’s it. RNA and a protein coat. In Covid-19’s case, around 30,000 base pairs of RNA wrapped up in an absolutely weaponized protein coat, dang it, so effective is it at invading human lung cells.

Now, recall that there are several broad categories of vaccine types against viruses. Attenuated Vaccines contain a weakened form of the virus in question. Inactivated Vaccines contained killed virus, meaning that its DNA or RNA has been inactivated in some manner. And then Subunit Vaccines contain only some piece or fragment of the viral external protein envelope. Something that our body can recognize and mount an immune response to, but that does not contain any viral DNA or RNA.

This is the part that I truly hope I can help you all feel comfortable with. A Subunit Vaccine does not contain the genetic blueprint for the virus! A piece of protein is all it is. Sometimes when we get a Subunit Vaccine we feel a little off for a couple of days, but that’s from our immune response, not from the vaccine itself.

But how does a piece of a virus protect us against the whole virus? Well, our immune system can “recognize,” by making antibodies that fit them like lock and key, various different parts of the surfaces of viruses and bacteria. One good marker molecule is all it takes to fight the invader effectively.

It’s only the Covid-19 RNA that can harm us, and yet, select just the right piece of its protein coat (I believe they chose the "spike glycoprotein"), and that’s enough for our immune system to mount an effective response to the whole virus.

To make a Subunit Vaccine, a virus of concern is injected into many, many hen’s eggs, often for multiple generations, egg after egg after egg after egg, and each time incubated for several days to make more copies of the virus. Finally the fluid containing the virus is harvested from the eggs, the viruses are killed, and the desired viral proteins are cleaved off and purified over several days. Somehow, scientists are able to isolate and separate a specific viral coat protein from this yellow yolky mess, to use in their vaccine. There are also newer, recombinant subunit techniques, in which yeast is induced to manufacture the protein of interest, by altering its genome. All of these processes take six months and more to accomplish.

Oy! Complicated stuff. But at least we finally have the answer to that age-old question that periodically vexes us.

Why did the chicken cross the road?
Apparently, to get away from the egg-obsessed biologist!

In contrast to these time-consuming and labor-intensive methods, RNA vaccines induce some muscle cells in our arm, at the site of the inoculation, to make the viral coat protein. What scientists do is to identify the exact section of Covid-19’s RNA that codes for the desired coat protein. Then they cut that section of RNA out and isolate it. It’s been a huge challenge to stabilize that small section of RNA for shipping, and also to protect it from being instantly destroyed by the human immune system once injected. But they’ve done all that now, so here’s what happens when we get one of these RNA Subunit Vaccines:

The scrap of viral RNA that codes for the desired Covid-19 coat protein is injected into, say, our left arm. The muscle cells there say, “Oh, ok, here’s some RNA, I have to make this protein now.” Their ribosomes, our cells' amazingly cool protein-producing factories, read this scrap of RNA and assemble the Covid-19 coat protein. This vaccine RNA strand does NOT become a permanent part of our genes in any way; it’s not DNA, and it degrades completely in a day or two. It’s gone.

Meantime, thousands upon thousands of copies of the Covid-19 coat protein have been manufactured by ribosomes and pumped into our bloodstream. Our immune cells mount their response to what they perceive as a big threat, antibodies are made by the tens of millions, and voila! We have immunity to Covid-19 at long last. Without ever having been exposed to the whole virus at all. How long the immunity will last is currently unknown. It may be necessary to have yearly Covid-19 vaccines in order to maintain immunity.

(Best in Show Ribosome image from https://www.thoughtco.com/ribosomes-meaning-373363 )

RNA Subunit Vaccines can be made fast and, once made, adjusted and adapted with great speed when a virus mutates. They’re safe, fast and flexible. The one real concern is, what if the viral protein closely resembles something else in our body, and we end up with an auto-immune illness? This is possible with any vaccine, yet it seems unlikely with Covid-19. Humanity has been assaulted with so many coronavirus species for so many thousands of years that it's highly unlikely that the protein chosen for these vaccines resembles any of our own protein structures.

I hope this all eases your mind about receiving such a vaccine in the near future when they become available.

 

Once again, I’ll end with a quote from my favorite poem, A. E. Houseman’s Terence.

“Therefore, since the world has still       

Much good, but much less good than ill,               

And while the sun and moon endure     

Luck’s a chance, but trouble’s sure.        

I’d face it as a wise man would,

And train for ill and not for good.”

Covid-19 Immunity Through Masking

Please allow me to share a rare piece of encouraging news in these challenging times we're in.

In a September 8th paper in the prestigious New England Journal of Medicine, Drs. Gandhi and Rutherford present to us a remarkable idea.

As we know, face masks help prevent the spread the of Covid-19 virus by blocking viral particles from entering our bodies via the nose and mouth. And yet masks also appear to do something else, something remarkable.

Often, tiny amounts of the Covid-19 virus get past masks and into our bodies, when we are in stores and such. The small "viral load" is too minimal to cause disease in most people. The number of virus particles is low and our immune system destroys them. And that's the thing: We mount an immune response to Covid-19. Repeated tiny viral loads are like vaccines! And thus the authors state:

"Universal facial masking might help reduce the severity of disease and ensure that a greater proportion of new infections are asymptomatic. If this hypothesis is borne out, universal masking could become a form of 'variolation' that would generate immunity and thereby slow the spread of the virus in the United States and elsewhere, as we await a vaccine."

This is the sought-after "herd immunity" we've all heard talked about.

And yes, I had to look up "variolation," even though I pride myself on knowing many medical terms. Again, from the authors: "Variolation was a process whereby people who were susceptible to smallpox were inoculated with material taken from a vesicle of a person with smallpox, with the intent of causing a mild infection and subsequent immunity. Variolation was practiced only until the introduction of the variola vaccine, which ultimately eradicated smallpox."

Here is the full article:

https://www.nejm.org/doi/full/10.1056/NEJMp2026913

For the science geeks in the audience, there's actually a third beneficial thing that mask-wearing does for us, which is to "tame" or "domesticate" the Covid-19 virus:

https://https://rickwilsondmd.typepad.com/rick_wilson_dmds_blog/2020/07/covid-19-may-very-well-be-with-us-permanently.html

We Philadelphians should be proud, as we wear masks in higher numbers than folks in many other areas of the U.S. And this concept of repeated tiny doses of the virus--tiny amounts of a poison, in effect--bestowing immunity puts me in mind of the ending of my favorite poem, Terence This is Stupid Stuff, by A.E. Houseman. Here it is. The madcap tale of an ancient king who avoided being poisoned by taking poisons--in small doses. Enjoy the relevance, stay safe, and hang in there on this mask thing. Someday, it will be over.

 

There was a king reigned in the East:
There, when kings will sit to feast,
They get their fill before they think
With poisoned meat and poisoned drink.
He gathered all that springs to birth
From the many-venomed earth;
First a little, thence to more,
He sampled all her killing store;
And easy, smiling, seasoned sound,
Sate the king when healths went round.
They put arsenic in his meat
And stared aghast to watch him eat;
They poured strychnine in his cup
And shook to see him drink it up:
They shook, they stared as white’s their shirt:
Them it was their poison hurt.
—I tell the tale that I heard told.
Mithridates, he died old.

SARS-CoV-2 Vaccines, Explained

 

We are coming up against a time when a vaccine against Covid-19, also called SARS-CoV-2, may become available.

Viruses mutate very rapidly, changing their surface proteins and such. The virus variants that are best at evading the human immune system are the ones that prosper, which makes our challenges in fighting them very difficult. Yet, effective vaccines againsts the Covid-19 virus are now being developed. It may be that, like influenza vaccines, new Covid-19 vaccines will need to be administered each year, in order to keep up our collective immunity.

There's one thing I am certain of regarding a Covid-19 vaccine in modern America, however, and that is that in all respects, it will be a politically and culturally charged issue.

Thus, I wish to explain the four types of anti-viral vaccines, so that you are all prepared for the time when we will face the personal and societal decision on being inoculated.

Similar-Species Vaccines are not common today, but were very important historically. The world-changing smallpox vaccine used cowpox, a poxvirus that was similar enough to smallpox to protect us against it, but not cause disease in humans. The Covid-19 vaccines currently being developed are not of this type.

The next category is Live-Attenuated (weakened) Vaccines. Attenuated vaccines can be made in several different ways, but they all involve passing a virus through a non-human host in the lab. Sometimes, for up to 200 cycles. The goal is to produce a version of the virus that can still be recognized by the human immune system, but cannot replicate (make copies of itself) well inside our bodies. Examples of attenuated vaccines include MMR (Measles, Mumps, Rubella), Chickenpox, Influenza, and Rotavirus.

There is one concern with attenuated viruses: that they may, through random mutations, regain the ability to replicate within the human body and cause illness again. The most significant example of this in the U.S. was the oral polio vaccine, which was an attenuated virus. In extremely rare cases, it mutated fast enough to cause polio again, so we switched the polio vaccine to the next category of vaccine types in order to 100% avoid this complication.

The next category is Inactivated Vaccines, which are produced by "killing" the pathogen with chemicals, heat and/or radiation.

(Sometimes, to be as certain as possible of total kill, researchers even expose the virus in question to repeated recordings of the rants of modern American Members of Congress and other politicians ...)

Note, I placed the word "killing" in quotations marks above. This is because a virus, in a philosophical sense, isn't really alive at all, at least in some ways of looking at it. Viruses are inert outside of their host, and don't really "do" anything at all until they make their way in and start causing trouble. It's a very weird concept to grapple with.

Any event. I imagine the technical trick with making inactivated vaccines is to wreck the virus DNA or RNA, so that it can't do anything to harm us, and yet leave the outer protein coat relatively intact. In this way, our immune system can still recognize the protein shapes it has to in order to fight the virus. It's a clever balance!

The fourth category of vaccines against viruses is the newest one, in use since the 1980s, and it's really clever: Subunit Vaccines.

What if we could take just parts of the protein shell, that our immune system can recognize, and not have any viral DNA or RNA at all? Without its DNA or RNA, a virus isn't a virus. Its genetic code is what enables it to harm us by telling the cells it enters to do something that the virus "wants" instead of going about their normal business. Robbed of its genetic material, such a mere shell of a virus makes the iconic country singer who's lost his gal, tore his best jeans and crashed his pickup truck look like the luckiest guy in the world.

To make a subunit vaccine, just one viral gene coding for one vaccine protein is inserted into producer cells in culture; often, yeast. The yeast (bless the little beasties, who also make us bread and beer) pump out this one protein, a vaccine is made with it, and even though our immune system doesn't get to "see" the whole virus, often times, one piece of it is enough to stimulate an effective immune reaction. Those red spikes on Covid-19 look like mighty fine targets, don't they?

The Hepatitis B and HPV (human papillomavirus) vaccines are examples of subunit vaccines.

What does this all mean for us as we go forward? The Covid-19 vaccines that reach commercial development are not going to be similar-species vaccines, so we can forgo that category.

For me, if a Covid-19 vaccine is a subunit vaccine or an inactivated vaccine, I have no worries at all about receiving it. Sign me up to go first, give me twenty boosters, I'm not worried about a thing.

If the vaccine is an attenuated one, I'll still get it, but even as a health care worker, I'm inclined to hold back for just a little while, to ensure that no Covid-19 infections result from it. Especially considering that this whole enterprise is a rush job. Probably just a month or so would be enough to make the call.

In my view, though, the rigid anti-vaxxer stance is foolish, misinformed and just a staggering example of human confirmation bias, in which no amount of real-world facts can change emotionally charged beliefs.

We get to have our own opinions, yes. But we don't get to have our own facts.

I sincerely hope that this post helps you all understand anti-viral vaccines better than you did before, and gives you the confidence to receive them, should Covid-19 vaccines become available.

Oh, and this year of all years, please get your flu vaccines.

And floss.

Californium

Warning: anything and everything made up of any combination of the any of the following elements is known to the State of California to cause cancer:

H - Hydrogen
He - Helium
Li - Lithium
Be - Beryllium
B - Boron
C - Carbon
N - Nitrogen
O - Oxygen
F - Fluorine
Ne - Neon
Na - Sodium
Mg - Magnesium
Al - Aluminum, Aluminium
Si - Silicon
P - Phosphorus
S - Sulfur
Cl - Chlorine
Ar - Argon
K - Potassium
Ca - Calcium
Sc - Scandium
Ti - Titanium
V - Vanadium
Cr - Chromium
Mn - Manganese
Fe - Iron
Co - Cobalt
Ni - Nickel
Cu - Copper
Zn - Zinc
Ga - Gallium
Ge - Germanium
As - Arsenic
Se - Selenium
Br - Bromine
Kr - Krypton
Rb - Rubidium
Sr - Strontium
Y - Yttrium
Zr - Zirconium
Nb - Niobium
Mo - Molybdenum
Tc - Technetium
Ru - Ruthenium
Rh - Rhodium
Pd - Palladium
Ag - Silver
Cd - Cadmium
In - Indium
Sn - Tin
Sb - Antimony
Te - Tellurium
I - Iodine
Xe - Xenon
Cs - Cesium
Ba - Barium
La - Lanthanum
Ce - Cerium
Pr - Praseodymium
Nd - Neodymium
Pm - Promethium
Sm - Samarium
Eu - Europium
Gd - Gadolinium
Tb - Terbium
Dy - Dysprosium
Ho - Holmium
Er - Erbium
Tm - Thulium
Yb - Ytterbium
Lu - Lutetium
Hf - Hafnium
Ta - Tantalum
W - Tungsten
Re - Rhenium
Os - Osmium
Ir - Iridium
Pt - Platinum
Au - Gold
Hg - Mercury
Tl - Thallium
Pb - Lead
Bi - Bismuth
Po - Polonium
At - Astatine
Rn - Radon
Fr - Francium
Ra - Radium
Ac - Actinium
Th - Thorium
Pa - Protactinium
U - Uranium
Np - Neptunium
Pu - Plutonium
Am - Americium
Cm - Curium
Bk - Berkelium
Cf - Californium
Es - Einsteinium
Fm - Fermium
Md - Mendelevium
No - Nobelium
Lr - Lawrencium
Rf - Rutherfordium
Db - Dubnium
Sg - Seaborgium
Bh - Bohrium
Hs - Hassium
Mt - Meitnerium
Ds - Darmstadtium
Rg - Roentgenium
Cn - Copernicium
Nh - Nihonium
Fl - Flerovium
Mc - Moscovium
Lv - Livermorium
Ts - Tennessine
Og - Oganesson

What’s that?
Oh, yes.
Even Californium.

Enamel Bonding, Dentin Bonding

"My name is Bond. Dentin Bond."

 

Ahhh, might-have-beens.  But I suppose "James" was a pretty good choice for 007's given name too...

The best dental restorations today are adhesive restorations; they're bonded onto or into the teeth that they help repair and maintain.  Like all technologies, dental adhesion is in a constant state of change and improvements are being made all the time.  Let's look at this vital aspect of modern dentistry and share a little insight into how the best restorations are currently achieved.

There are two fundamental parts of a tooth that we have to consider when we set out to bond to them: the enamel, and the dentin.

 

When we bond to enamel, we apply and then rinse away a 37% phosphoric acid solution.  No worries, your stomach is more acidic than this.  The solution etches the surface of the enamel, which is a substance made up of crystals.  Highly magnified, it looks like this afterwards:

 

The surface becomes rough on a very small scale.  We then apply a resin (the first part of these composite resin fillings of ours) that becomes micromechanically interlocked into the roughened surface.  The strength of this bond is incredible.  We can bond composite resin onto teeth in very functional areas and it often stays on for years without breaking or staining.  We measure bond strengths in MegaPascals or MPa, and 30 is a very good number to achieve.  (Don't worry about exactly what a MegaPascal is; all we need to do for the purposes of this discussion is to look at relative numbers.)  We need to hit at least 17 MPa to keep restorations sealed and on the tooth.

The first person to achieve this breakthrough was Michael Buonocore D.D.S., in 1955.

 

Bonding to dentin, though- that was a lot more difficult.  After removing decay with a drill there is a smear layer (yes, that's really its scientific name) of microscopic debris left all over the inside of the cavity prep.  This is removed with the etchant.  There are also tubules which are normal channels that run through the dentin:

 

According to the brilliant David Pashley:

"The success of bonding resins to acid-etched enamel is because of the fact that enamel contains little protein, and it can be dried without causing any collapse of the roughened surface. When Buonocore et al tried those same procedures on dentin, they were disappointed to find that the resin-dentin bond strengths to acid-etched dentin were very low (5 to 10 MPa) and were about the same as resin-dentin bonds made to smear layer-covered dentin. They did not know that acid-etching dentin transformed the surface from a hard, mineralized surface to a very soft, mineral-free, collagen-rich surface that collapses when air-dried. Although it is now known that acid-etching removes the smear layer and smear plugs, thereby making the tubules available for resin tag formation, drying the surface collapses the spaghetti-like collagen fibrils, making resin infiltration difficult.^"

Spaghetti.  Spaghetti is the key to understanding all of this.  Because once we've etched and rinsed the dentin, it looks like this:

 

 

The problem is, we can't leave the dentin soaked, or worse yet, underwater.  We have to dry it.  (And dentists, being as a class a somewhat compulsive lot, really tend to dry the teeth we work on, with a blast of air that the wind tunnel at NASA's Langley Research Center would be jealous of.)  Un-etched dentin has a compressive strength of 20,000 MegaPascals.  Etched dentin has a compressive strength of one MegaPascal.  Just one.  So here we create this wonderful substance to bond to- the dentin has this spaghetti-like mass of collagen which is highly chemically reactive and has a vast surface area- and what do we do to it?  We blast it down into a flat lifeless mass, like pizza dough that's been flattened and pulverized and all dried out.  The bond fails every time.  The stress in the filling material as it cures (usually with a light activation procedure) is higher than the bond to the dentin, and so gaps form.  Bond strength is terribly low.  Teeth are sensitive.  Painful to chew on because they're not bonded, the fillings actually move about when we bite.  Cavities recur more easily.  The left in this picture is collapsed, the right is properly expanded; in reality it can be far worse than the image indicates:

 

It's a disaster, and all because the pasta wasn't respected.

What, then, can we do?  Well, in 1985 or so, two independent researchers solved this technical problem of dentin bonding with an innovation called self-etching primers.  These researchers were Takeo Fusayama and John Gwinnett:

 

These researchers developed the class of dental bonding agents called self-etching primers.  These primers etch and bond all in the first application of liquid, and they take a novel approach- they enlist the smear layer into the bond itself.  They churn it up and make a hybrid layer out of it, a layer that is composed of the resin from the filling and also the debris from the smear layer, all activated and mixed into the spaghetti-like mass of etched dentin.  This technique can now get into the 32MPa range on dentin, and also treats the enamel properly to get an enamel bond as well.  It looks like this:

 

This technique is so excellent that, since adopting it some 12 or 14 years ago, I can say that I have never had a restoration fail from leakage and lack of bonding in its own right- they may fail from fracture, or decay around the restoration, but I do not see recurrent decay under the restoration primarily; it has to start externally, due to the patient overdoing the sugar and underdoing the flossing.

We still use etch-and-bond separately for front teeth and situations where the enamel bond is the most important factor, like chipped front teeth.  This method still gives higher enamel bonds.  We bias the relative bond strength between enamel and dentin to the clinical situation.  There are also one-bottle self-etch primers now which I suppose are being made to "simplify" the procedure; however for various technical reasons, in late 2010 these products do not get good results at all.  In fact there are only two existing self-etch products (both two-bottle) that I'd even consider using to restore a back tooth with a bonded composite resin restoration- Kuraray's SE Bond and Danville Engineering's Prelude SE.  They are so superior to any others that they are the only choice in 2010, and there's a lot of science to back it up.

The longevity of these restorations is quite good as well.  Silver amalgam restorations seal against the tooth by corroding, a process that reaches its peak at the two year point.  After that it's all downhill.  Composite resins bonded with self-etch primers seem to hold their bond strength to both enamel and dentin for at least 8-12 years, after a small initial decrease.  Their longevity may be quite longer.

For the technically minded in the audience- ok, for geeks like me- here are two of my source articles; they are excellent reviews of the literature and the progress in this vital aspect of dentistry:

 http://www.dentistrytoday.com/materials/1483.html

http://www.compendiumlive.com/article.php?id=2451

The reason for this rather technical review?  If you have a composite resin restoration placed and it's very sensitive, especially to cold and to chewing on it, there are three main possible causes:

-The bite is "high" and needs to be adjusted;

-The decay was deep and a root canal issue is brewing; or

-Total etch was employed and the bond is not good.  I'm sticking my neck out when I say this, but the science tells us that total etch is too technique sensitive to rely upon, and thus self-etch is the only rational way to restore a back tooth with composite resin at the present time.