Fun day with the family. Vaccine far from my thoughts. No news to report. Doing my reports regularly.
How good must you be doing to forget to update the blog?
That good. Dreams are better. Back to work as usual. Busy clinic day. Congratulated by patients for working towards making myself safer by getting vaccinated. Frustrated by peoples’ dogmatic fear of the unknown. Still, when my patients, the Veterans, signed up to fight, it was to die for the nation. This is such a tiny effort by comparison. I feel ashamed when people call me brave, because I take care of the truly brave, and I am no match for them. If there is a downfall to the idea of America, like there was Rome, it is because we, the people, have become way too comfortable. Who stands up for what is right? That which is uncomfortable? Like many things, Science matters. Next time you check your smartphone or device, get an antibiotic for an infection or a medical procedure, remember that it needed a scientific study to create and test. Now, if you are paid to do any of those things (as an engineer, scientist or physician), you are even more indebted to the research. Think about that, the next time you cringe at a vaccine.
Slower, but getting there…
First day back to exercising today. Times on the rower are longer but within acceptable ranges. 7:44 2K. Some photography with the SL. Usual caseload at work. Couple of meetings. Mentally back to firing on all cylinders. Met with friend at SLU who, it turns out is a vaccine skeptic. Sad.
It remains frustrating to see how people are willing to ask others for money for science, but not support science’s efforts to save lives. C’est la vie.
Have to keep the enthusiasm up. This blog helps with that.
What a relief to be back. After the fog I was living in over the last two days, today was a breath of fresh air. I completed by NIH progress report for my grant, did a 60mm CTO, organized experiments in the lab and still had enough energy to play with the dog.
Last night was awful. Tried to work last night. Could not even sit. Got dizzy. Had an awful headache. Needed an NSAID. Slept ok. Bad nightmares, very vivid. Very action movie. Really a comedy type, myself. Did not like the pace of the dream/nightmare. NOt sure if it was vaccine or just hypoglycemia from my loss of appetite.
Today, much brighter.
Definitely taking time off for the booster dose. Bit close to my R01 submission, but too late to change my mind now.
Did get a phone call from the vaccine research center after logging in the symptoms. No advice regarding my COVID19 NP swab. Which must mean that it was negative. Which is a good thing.
Was called by a colleague from Med School. Thought I was “brave”. Disabused him of that. Entering an NIH funded trial for a vaccine that has completed Phase 1 and 2 trials and is unlikely to be available in time for the winter is not “brave”. I would argue that even the 50% chance that I DID get the vaccine, is a sign that I am not brave enough to risk a COVID exposure and infection when the next surge happens. And it looks like with slow recruitment, it will be mid October before this trial stops recruiting. Which means that the second dose for a large number of patients will be in November. Which also means we won’t have results of anything till mid December. Which would, of course, be too late to vaccinate people against a predicted surge beginning in November.
This is so stupid of people to take this attitude. With a disease as dangerous as COVID19, which has a mortality of 0.5% in someone with my health status (156 lbs, 6′, BMI 21, Body Fat 7%, 7’26” 2K Row) as compared to close to ZERO if I don’t get it, this paranoid and implanted fear of a remarkable vaccine trial is as much as a rejection of “earth is round” or “wash your hands” concepts.
If people of science and education resort to such base nonsense, how on earth do we expect those without the requisite knowledge or education to follow science?
Or even wear a mask.
To all those people that cry “foul” at those that don’t wear a mask, but fear the vaccine trial, I would like to point out their delightful clay feet.
Full day of work today. Achiness in weird places besides my left arm. Somewhat foggy today. Luckily, doesn’t seem to impair my ability to function. Some NSAIDs last night to deal with pain. No fever. Seems to be like what was published in the Phase I data. Plan on taking time off for booster dose.
And so, it begins.
At St. Louis U at 8AM today to the vaccine center. Was not busy at all. Went right in. About 2 hours total – including screening examination, labs and consent. Received something (vaccine or placebo). 27Ga needle with about 0.7mL vaccine. Painless injection.
Noticed some achiness about two hours later. No fever. No chills yet. (3:21PM). Finished my E-diary for the trial.
Donating proceeds from trial to kids to pick their favorite charity. This has to be about the science, not the reimbursement. Tempting as it is.
Schedule of phone visits, every week for the first few weeks – then less frequently for 2 years.
Also got an NP swab. Always pleasant. Feels like my memory is improved by the brain cleaning. 😦
All else is good. Will update tomorrow.
Shout out to Ali Javaheri for his support.
Also to family for dealing with this.
I signed up from a link on the CDC website to be a volunteer for the vaccine. As a physician, scientist and responsible citizen, I felt it to be my duty to support solid scientific method over the profusion of hokum cures that have spread like raging wildfires in the wake of this unheralded virus. It goes without saying that this vaccine (Moderna) is the world’s first RNA vaccine. In this first blog post, I am going to go over some basics for non-experts on how viruses and anti-virus vaccines work (in completely layman terms), what RNA is (and why it may be a revolution), the due diligence I did before choosing to participate as well as the reasons why scientific methods in US funded research is protected by incredible safeguards. (In the interest of full disclosure though, being a research fanboy may make me blind to people disguised as scientists or those who subvert the organizations that keep us safe, but if that occurs who is safe after all?) By means of this blog, I want to keep a running record of my experience with the build up to getting the vaccine, people’s reactions to my volunteering, as well as a real time account of both the trial as well as my own reactions to the vaccine. Whether successful or not, this vaccine will be a game-changer and a first person account of a recipient may be of value.
In the next few sections, I will start with defining what a virus is. But, to help you understand how they work or cause damage, I will review what a cell is and how it came to be (including a basic primer on genetics). I will keep it extremely easy (at the 10-year old level– which may have something to do with my own level of maturity) and it will be helpful if you could imagine it being read to you by Stephen Fry (as he did in the Hitchhiker’s Guide to the Galaxy). It is important to understand cells because that will make it easier to understand COVID-19 and thus why the vaccine and the reasons why it might be amazing…or a bust. It will also give you an idea of why I chose to sign up to be a volunteer in this effort.
Viruses, viruses everywhere….
SARS-Cov-2 (a.k.a novel coronavirus, the virus causing COVID-19) is a novel virus that affects small mammals and has made the jump to humans and other primates. It has killed a quarter of a million people worldwide via infection and a likely far larger number (both until now and in the future) by the economic fallout. This brings us to the question, what is a virus?
Viruses are extremely tiny quasi-living things, that take simple living to the limit. They vary greatly from tiny particles consisting of a small piece of genetic information protected by a shell of proteins to nearly visible complex structures consisting of multiple proteins, a lipid envelope and a large genetic storehouse. Unlike the concept of a “cell” seen from ancient bacteria to man, these simple beings make up for the lack of sophistication of structure with the elegant effectiveness of their ability to survive and propagate, their only purpose. Like all other life-forms, the virus’ genetic material is its identity, the protective shell is its body. Lacking in their own machinery to build anything, viruses commandeer the machinery of the cells they manage to get into, to generate new proteins (made from sources in their ‘host’), to make new copies of the their genetic identity, to assemble these into progeny virus particles and then leave the cell (either by activating cellular self destruct signals or by allowing the cell to survive and using export pathways to leave the cell).
That is all very nice, but what exactly is a cell??
We’ve talked about “cells”, but what exactly does that term mean? Each currently existing lifeform (viruses and prions excluded) consists of an organized compartmentalization into individual units called cells. In fact, the converse way of looking at it would be that an individual being is the result of billions of these units coming together. Each of these cells has an oil-lining (lipid bilayer to you technical folk) which holds a little water-based chamber containing protein, oil and sugar (carbohydrate) based structures. These are arranged in unique patterns and the manner of arrangement is determined by the type of function needed by the cells. Some cells are tiny and others are huge, some ephemeral lasting days or weeks while others span the lifetime of a being. Each of these cells have, during at least some portion of their lifespan, a complete storehouse of genetic information for the entire organism stored in a digital-esque format on an organic platform of a single chain of compounds known as nucleic acids. (Hmmm… or maybe computer memory is genetic-like, not sure.)
These “nucleic acids” are named for where they were first found, the nucleus. Early scientists noted that all cells had a ‘dot’ in the center, filled with organic material composed of sugars, and specific benzene-ring like circular acidic molecules containing a combination of carbon, hydrogen and nitrogen. Turns out that, in the interest of simplicity, the body selected four such molecules, Adenine (A), Thymine (T), Guanine (G) and Cytosine (C). When arranged in pairs, the molecules are peculiar in partnering with each other as A-T and G-C linkages. By arranging this alphabet on a chain formed by a backbone of a sugar (deoxyribose) and phosphates (from ATP – yes, from all those energy drink ads) gives rise to one of the single largest molecules in existence, deoxyribo-nucleic acid or your DNA. An that is exactly what it is, an entire library of all the information that it takes to be YOU. All written in the long-hand of a 4-letter alphabet, with 3-letter syllables. Despite small differences, this arrangement of genetic identification information is preserved through ancient times to the present. Every organism carries in its DNA all the information of all its ancestors and its history to try to deal with every eventuality. DNA allows a cell to pass on this information to the next generation. While life is so much larger than the DNA itself, life as we know it requires the DNA-based information to construct the cell, use historical information stored to react to the environment and ultimately, to pass it on to the next generation. But why did it have to be thus?
The origin of life
In the beginning (more than a billion years prior), when the primordial ocean soup existed on Earth, simple organic (i.e. carbon-based, not something to do hippies and Whole Foods) molecules formed. This likely occurred under the influence of solar and extrasolar radiation as well as local random factors leading to this happy happenstance. These carbon-based entities (likely primordial protein-like molecules) were the first form of life, and had the capacity to assemble and transform their environment. Unfortunately for them, they were continuously under attack from the same environment that brought them into existence. Over the next millions of years, some lucky molecules were enveloped in oils which formed a protective barrier around them. This had both advantages and disadvantages. The big plus, obviously, was that these early “living molecules” were now isolated from the harms of the environment. The big downside, equally obviously, was that being isolated from the environment limited their ability to modify it (a key feature of being ‘alive’). Somewhere in that ancient history, some water managed to creep into the protein containing oil droplets, creating a microcosm of the environment within the droplet and thus creating the first cell. The next step was to use the protein molecule to allow selective entry of water and solutes to maintain a unique environment inside this primordial cell. Somewhere along the course of history, the meeting of two different oil bubbles with different proteins resulted in the formation of a bigger bubble that had more proteins and thus greater functionality. In this next phase, an accretion of bubbles lead to growth to the point where the chaos ensuing from the size of the bubble resulted in the bubble breaking apart into “daughter” cells. In this phase, the daughter cells with the most symmetric distribution of resources had an advantage and survived. By “sticking” together ( a result of surface tension of the oil and water interface), they could now help or protect each other. The big problem in this was how to store the information they had to be able to pass it on to the next generation. To do so, would take another eon, when using the template of the “living” proteins, these primordial cells could put together simple codes to memorize them in a linear chain, the primordial “nucleic” acids (a misnomer because there was no nucleus at that time). To keep things simple our ancient ancestor had defined a code to signify individual protein constituents – one that has continued through every life-form since on this planet.
Which brings us to viruses. It is not clear if viruses represent a truly ancient form of life or are the product of later species. Although previously believed to be the former, modern biology seems to indicate that they are the latter. Each one, a product of the species that it gravitates to. This also explains the fact that they can be benign to some, yet amazing dangerous to others. Causing a common cold to a bat, while resulting in deaths of millions of humans. In fact, new data indicate that all beings generate protein-nucleic acid-lipid complexes (known as membrane-less organelles) that have critical in the stress-response mechanisms in cells. The similarity in organization and structure as well as appearance to viruses is remarkable.
In every cell, from the library book of DNA, the cell transcribes a copy onto a Post-it! (the RNA or Ribonucleic acid). Unlike the remarkably durable DNA, that is compactly stored in duplicate (the famous double helix), RNA is a linear strand that is relatively evanescent. With an extremely short span of existence, the RNA, once transcribed, is “translated” by the cells’ 3-d printers into the proteins that define their every single aspect. Unlike the stability required for the DNA (to endure across generations), the function of the RNA is to be a temporary copy of genetic message, that tells the cell machinery what needs to be made. Using a system of feedback loops (driven by so-called “transcription factors”), the passage of messages between the cellular machinery and its central library defines the normal functioning of all cells, be they bacterial, murine or human.
Viruses, as we discussed before, come in various kinds. Some (like the virus causing Hepatitis B) use DNA as their source of genetic material (and thus can be very robust). The problem with this, is the limitations of how they get into the cell and the difficulties they encounter in starting the process of subverting the cell to their own agenda, as the transcription and translation machinery clearly prefers the host DNA to the viral one. To subvert this, some viruses, like our bete noire, SARS-Cov-2, use RNA. The advantage to this is that they are able to easily subvert the cell’s protein printing machinery to their own direction by bypassing the need for transcription. The obvious downside, is the fragility of RNA itself. Which is why SARS-Cov-2 has a strong protective protein coat (the N protein) AND a lipid envelope made from the cells own lipid membranes. Furthermore, by putting sticky anchors and stabilizers on the envelope (the Spike and Envelope proteins respectively), it is able to easily enter a variety of cells by binding to receptors on the surface of the cell that normally act as gatekeepers for blood borne messages. In the case of SARS-Cov-2, this receptor appears to be the ACE2 receptor that is important in the sensing of a polypeptide hormone – angiotensin II.
By coopting the cells’ tendency to internalize the activated receptor complex to repair and replenish it, the virus gains entry into the cells, where the breakdown of the outer structures – rather than damaging it – releases the viral RNA into the cell, thus unleashing its fury. In addition, to triggering its own replication, the upregulation of an immune respone paradoxically drives inflammation, coughing and thus viral shedding to new hosts. When exaggerated, the combination of viral injury and inflammation result in death of the human host, while the virus moves on to the next.
Immunity. Not just in a court-room…
While this paints a bleak picture, it is worthwhile to note that humans have a remarkable ability to counteract viruses. Except in the case of HIV, where the immune system is targeted, most viruses can trigger the formation of an immune response consisting of a combined cellular and antibody-mediated response. This activation results in rapid recognition of the virus as a foreign threat and a brisk elimination from the system. To put this immunity in perspective, it is worthwhile to note, that most people think nothing of measles and chicken-pox, in non-immune populations, these are often lethal. While generalized inflammation as well as specific immune responses can be triggered by the cells’ innate ability to sense foreign genetic materiel, the body’s virus specific systemic immune response requires priming to specific and easily found proteins and features on the surface of the viral particles.
A Brief History of Vaccines
Through their history, from the effects of Pasteur’s initial efforts, vaccines have used the presence of inactivated or non-lethal virus proteins to be sensed by the body’s immune system to develop a memory and resistance to future infection. By recognizing a milkmaid’s resistance to small-pox from a prior exposure to cowpox, humans have been able to train and marshal the immune system, to the detriment of polio, smallpox and a host of viral infections. In turn, naturally mischievous viruses like influenza, are able to survive this challenge by continuously changing their surface protein combinations (the H and N proteins) to stymie the antibody and cell response. This is why people need a new flu shot every year, while the vaccination course for polio, measles and hepatitis B is more durable. From the injection of digested tissue (animal or human) to the development of cell culture based vaccines to the development of synthetic viral proteins, it has been possible to dramatically augment the safety and cost and thus, the availability of safe “cures” for these scourges.
The whole point of a vaccine is to mimic a viral infection, without the risk of viral injury. The problem with using proteins to do so is manifold. Firstly, the proteins need to be stable enough and “clean” enough to avoid replacing one one infection with another. The second is to generate an immune response without an exaggerated inflammatory response that may result if the body senses a large amount of foreign protein. To avoid this, live attenuated viruses (like the oral polio (Sabin) vaccine) can be used that trigger an immune response. Often, these can be less effective, but are more protection than nothing.
The other big problem is the timeline. To develop an immune response is something that takes days or weeks. As we find out differently every year on the effectiveness of that year’s flu shot, testing the immune effect of a give vaccine is a slow and tedious process. Thus, developing a new vaccine, against a hitherto unknown pathogen, poses unique challenges. Firstly, traditional approaches of using subunit proteins alone is plagued by the issue of making enough it on the scale of billions of people. More importantly, to be sure that it works and can be stably delivered with an acceptable adverse effect profile.
RNA Vaccines. The Way of the Future?
Enter the concept of the RNA vaccine. Never previously tried in humans on any large scale in the past, this is a novel approach, borne of the need for a speedy response to COVID19. The Moderna mRNA1273 vaccine is the RNA sequence coding for the Spike and associated proteins covered in an oil globule (called a liposome). The science behind this approach is that RNA enters the cells (using the liposome) and results in triggering the body to produce just the viral protein without the viral RNA or the protective coat (N-protein). When produced by the cell, particularly macrophages (specialized cells responsible for local cleanup in tissues), pieces of these proteins (a.ka. antigens) are displayed on the surface to trigger an immune response in B- and T- immune lymphocyte cells. Unlike in the real infection, where in addition to producing these proteins, the virus itself is replicating and up to additional damaging activities, the vaccine is only limited to these proteins. In contrast to protein based vaccines, where the bacterial origin of recombinant proteins carries the risk of non-specific inflammation, the RNA vaccine uses protein made by the host itself. Unlike attenuated live or killed viruses, there is no full length genetic materiel that could integrate itself into the host’s gene structure – possibly resulting in undesirable issues at a later time. Finally and most significantly, it is easy, quick and relatively cheap to produce as well as package the RNA fragment, completely synthetically. This has allowed development of a vaccine candidate within 3 months of the onset of the pandemic.
Clinical Trials, and the evidence so far
The data that has been published thus far is promising. In the initial Phase 1 study on human volunteers to look at doses and toxicity, all three doses tested resulted in an immune response after a second booster dose in 28days. The best profile of effectiveness as compared to the inflammatory side effects of an acute fever and muscle pain was found at the 100 microgram dose given in an intramuscular manner. Phase II trials are currently ongoing and I am signing up the NIAID sponsored (https://clinicaltrials.gov/ct2/show/NCT04470427) Phase III trials where at-risk individuals receive either vaccine or placebo and are studied to see if they develop an immune response and/or if they develop COVID19 despite the use of standard preventive measures.
At this point, I would like to talk briefly (not my forte, i.e. being brief) about clinical trials. As the quintessence of modern therapeutic testing, double blinded randomized control trials when properly conducted in the appropriate population have resulted in the elimination of biased assessment as well as ratification of therapies that have durably stood the test of time. In this approach, each entrant is randomly distributed into either a test group (drug) or a ‘control’ group (placebo). The best trials are conducted in a blinded fashion, where the person administering it as well as the patient and the person analysing the results are blinded to the treatment. In addition, all clinical trials must follow principles of beneficence, justice, and a respect for persons as well as to allow for the autonomy of choice of the participants. These failsafes and essential values are what stand between ethical research that I ascribe to, and the human experimentation with scant regard for ethics that have tainted clinical studies through history.
In each of these tainted events, the driving force for the taint is frequently the sponsor of the study and a drive for secondary gain, even at the cost of the subjects. I am proud to say, that the epitome of ethical standards in this regard, worldwide, has been the US research community that I am proud to be part of. Nowhere else in the world, has the focus of adhering to essential values been more firm that here. Within the US medical research community, the pinnacles of ethical research remain the Universities and the NIH. Despite the values demanded of all clinical studies in the US, the commercial biases often cloud the role of industry in clinical trials. In this instance, partnership between industry at building the vaccine and the NIH-based mechanism in conducting the trial provides the essential failsafe to deem the trial safe in my assessment.
When my family and friends heard that I was taking part in the trial, I was greeted by a puzzling cacophony of responses that varied from support (a minority), to shock-fear-trepidation-panic, as well as humor and derision. As a physician and scientist, this method of developing a cure to a clinical problem remains key to my own approach to my patients. If people like me don’t show our trust in the approach, how do I justify using it? After all, if it is too risky for me, by what basis do I prescribe this to my patients? As schools reopen and the virus surges again, I am hearing of more and more acquaintances that are either testing positive for the virus or suffering from COVID19. In my mind, the off-chance (50%) that I get the vaccine, and develop an immunity to the virus, I stand to benefit far more. Furthermore, with frequent checks for the antibody as well as the virus by PCR (built into the study itself), I will be more likely to be forewarned of an unanticipated exposure to the virus, allowing me to respond early. Finally, as a relatively young, and healthy man, if there is anyone who would withstand an untoward vaccine effect, it has to be someone like me. This information will help further improve the care delivery that I count on everyday as a physician.
It is up to all of us to stand with good science. To support efforts to fight this modern scourge. To avoid giving in to the cynicism and resistance to change. To face the unknown, not with blind faith but with armed with the calculated risk-taking borne of thinking and knowledge. May God be with us all and I pray that we prevail.