Advances in COVID-19 vaccine development, described for the lay person

I cannot find the source (and author) of this article — but it is an excellent lay summary of why these vaccines are being developed so rapidly and successfully, despite no vaccines to coronaviruses ever having been successful, prior to 2018. My lab was involved in the early 1980s with this concept of “adding unprotected mRNA to a cell or an organism, and having the encoded protein produced from that RNA.” It could not be done, or any effects were undetectable, because of the fragility of mRNA (VERY quickly destroyed by Rnases, enzymes breaking it down). The present snippet of mRNA, coding just for the ACE2 receptor spike protein, is delivered in a lipid particle that protects it from these RNases.

DwN

The Beginning of the End

Last email, I said the endgame for COVID would begin with the announcement that a vaccine works in a large randomized trial. Three days later, Pfizer reached that milestone. One week later, Moderna joined in. It’s queen to bishop 7 and checkmate for COVID-19.

The Pfizer vaccine, known as BNT162b2 among the cognoscenti, was initially developed by BioNTech, a German biotech company that has mostly focused on cancer vaccines. BioNTech needed the added expertise of a big pharma outfit like Pfizer to help get their COVID-19 vaccine through the necessary clinical trials and past the regulatory pathways. BioNTech is headquartered outside of Frankfurt but also has a footprint near Boston. Some folks are concerned about high unemployment right now, but I’d point out that BioNTech is hiring, and so if you’ve been laid off during COVID and happen to be a PhD immunologist with expertise in flow cytometry, well, we’re talking a matching 401(k), free parking, and pet insurance!

A New Sheriff is in Town

To understand why a German outfit that is developing cancer vaccines is first in line for ending the COVID pandemic, we’ll need an introduction to the newest and most exciting development in vaccine research in the past hundred years: vaccines made from genetic code.

Until recently, all vaccines were a dead or weakened version of the bug we want to protect against, or a piece of that bug, and manufactured in a big vat of viruses, bacteria, yeast, or chicken embryos. But what if we cut out the middleman? What if we just inject ourselves with the instructions on how to make our own vaccine? Such an approach could have some big advantages in speed and safety.

Our genetic code is DNA of course, and that DNA sits balled up in most every cell of our bodies. When a cell wants to make a protein, such as the enzyme alcohol dehydrogenase that our liver uses to break down all the booze we’re drinking right now, or for the collagen in the tendon needed to push the remote control on your TV, the master copy of DNA is unrolled and a working copy is produced, using a slightly different molecule, RNA, that looks mostly like DNA but is better suited as a template for manufacturing proteins. DNA is like the file stored on an architect’s computer, where RNA is a printed copy of blueprints sent to the construction site. It is going to get used, trashed, and thrown out, but while it lasts, it instructs the contractor on how to build the house. There are several different types of RNA that have different functions, but for our purposes, we’re interested in messenger RNA, abbreviated mRNA. That mRNA has the job of taking the instructions on DNA inside the nucleus of the cell, making copies in the nucleo-meister, and traveling out to little blobs in the cell called ribosomes where we make a protein.

Imagine that we just put a little snippet of custom-designed RNA directly into the cell. Instead of making the usual proteins that the cell produces, the cell will suddenly start making the protein specified in that strip of RNA. RNA is a very fragile molecule, and it won’t be long before enzymes called RNases chew it up, but for about 10 days, our own cell is going to be a miniature vaccine-producing factory. Most cells are not too picky and will readily make whatever protein we give it via RNA.

In the case of COVID, picking what protein to make is pretty easy. Those big spike proteins on the coronavirus are like having a “shoot here” sign on a video game. The Pfizer and Moderna vaccines are a strip of mRNA that produces a pile of the COVID spike protein, exactly as the protein looks when it is sitting on the virus floating around the body and before it has attached to a cell. This is where and when we want to attack the virus. In practice, there are challenges to getting these vaccines to work, but they offer many advantages, and some disadvantages, over current vaccine technology.

Advantages of mRNA Vaccines Over Those Clunky 1950s Models

One advantage is the speed at which an mRNA vaccine can be produced. Since these vaccines are made in a chemistry lab and require no living organisms to generate the product, we can manufacture vaccines in a rapid, standardized, and controlled fashion. It’s the difference between making vodka and wine. If you walked into a manufacturing facility for Pfizer’s BNT162b2 or Moderna’s mRNA-1273, you would not find big vats full of microorganisms making our pandemic-ending vaccine. Instead, you’d find an industrial chemistry lab and a team of managers working 90 hours/week having a nervous breakdown. Yeah, no pressure guys, but a hundred people did just die of COVID while you were on your coffee break.

Another advantage is safety. When you take a huge pile of polio virus and weaken it before injecting it into children, there is always the risk that your weakening process did not work right or that the virus mutated back to a more severe version. This can’t happen with an mRNA vaccine. Not only is RNA a fragile, easily-destroyed molecule, but it cannot make changes to our DNA. The copying is in one direction only. You can mark up your household Bible in Revelations 16:16 (that would be the part about Armageddon), but it won’t change the master copy at the printers, no matter how many exclamation points you’ve put in there since March. Similarly, mRNA vaccines cannot produce permanent changes in the body’s genes.

Another advantage is the strong immune response. If the body sees some dead hepatitis protein floating around, it might make antibodies, and it might not. Inert protein floating around is not highly motivating to the immune system. With an mRNA vaccine, a cell is now producing “viral” proteins, and to the immune system, it looks like the cell was infected with a virus. The better we can trick the body into thinking a vaccine is an actual viral infection, the stronger the immune response. In addition, just the presence of RNA outside of a cell causes the immune system to ramp up, and this increases the response to vaccination. RNA floating around is a signature of a viral infection.

Disadvantages of mRNA Vaccines

These mRNA vaccines do have some disadvantages. First, they have the same safety risks common to all vaccines. Rarely, a vaccine makes a patient worse if he or she gets the disease. Also, in order for the vaccine to work well, there is the chance of a sore arm, fever, or feeling unwell for a day or two. When people get sick with a virus, often the main cause of symptoms such as body aches, fever, or fatigue, is our own immune system’s response. The same is true for some vaccines that make us feel unwell. In research trials, vaccines for hepatitis and the flu don’t seem to make people any sicker than a placebo shot, but other vaccines, like the one for shingles, do sometimes make people sick.

Although the fragility of mRNA is a safety advantage, it is also a disadvantage, as we need mRNA vaccines to get inside cells in order to work. The body destroys RNA if it ever sees it outside a cell. The Pfizer and Moderna vaccines are enclosed in a very tiny ball of fat, called a lipid nanoparticle. This hides the mRNA and makes the vaccine look like a chocolate truffle to the cells in the body. In fact, it’s a chocolate truffle with sprinkles, because proteins stick to that ball of fat, what chemists call a protein corona, even though the nation collectively twitches a bit every time we hear the word “corona.” This ball of fat with proteins is as irresistible to many types of cells as a sprinkle-covered chocolate truffle is to most of us.

A third disadvantage is storage. Because mRNA is such a fragile molecule, the Pfizer vaccine is kept at -70 C, or for those of us still on the Fahrenheit scale, 94 degrees below zero. Brrrr. Moderna’s vaccine is stable in a standard medical freezer (-15 C or 5 F) for six months, giving it an advantage in logistics, but right now, we’ll take any vaccine we can get. It’s likely that the Pfizer vaccine will last at least a few days in a standard freezer so that frequent, smaller shipments will allow us to vaccinate patients with that product. In the long term, having a vaccine stable for a year in a standard refrigerator would be the ideal goal. That, or a freeze-dried powder we can mix up as needed. Some very smart chemists are working on the storage problem for us, and I don’t mean lightweight biochemists who watch The Big Bang Theory. I’m talking real, heavy duty chemists, the kind who work where chemistry becomes physics, the kind who wear T-shirts with math puns on them, the kind who obsessed on The Lord of the Rings when they were nine.

Other Uses for mRNA Vaccines

Currently, mRNA vaccines for influenza, Zika virus, HIV, and rabies are being tested in humans and animals, but the 60,000 or so subjects who have gotten mRNA vaccines specifically for COVID represent the largest group that has received this vaccine technology. Preventing infections is not the only reason to have an mRNA vaccine. BioNTech is actually developing most of its vaccines to treat cancer. The approach is to take the proteins that sit on top of cancer cells and make a snippet of RNA that will produce those proteins and inject it as a cancer vaccine. This stimulates our immune system to respond to the cancer. In a recent study of patients with very advanced melanoma, an mRNA vaccine was helpful, but not a cure.

Not only can you develop an mRNA vaccine against a type of cancer, but you can actually take a single patient and produce a customized vaccine for that person’s cancer cells. This approach is obviously expensive, but as the technology improves, we might see more personalized cancer vaccines in use. Research is underway for personalized mRNA cancer vaccines for brain tumors, leukemia, melanoma, and breast cancer. Just as NASA’s moon landing brought us huge advances in science that benefited everyday Americans with essential life-enhancing products like Tang, freeze-dried ice cream, and space blankets, the mRNA vaccines for COVID are going to accelerate the development of these vaccines in many areas of medicine.

More Vaccines are Coming

Novartis has an mRNA vaccine in development that cures baldness, produces 12-hour erections, and makes people thin no matter how much they eat. Ok, just kidding about that. But it is highly likely we’ll see reports on other vaccines made with other vaccine technology, such as the Oxford vaccine, generating positive results in the near future. The pharmaceutical industry takes a lot of heat in the press for high prices and aggressive marketing, but we should not forget that these large, for-profit, multinational corporations are about to save millions of people all over the planet, and that we’d be far worse off without them. Not to denigrate the frontline health care workers my staff and me who are risking our lives and the lives of our families to care-for patients, but the real heroes here are the scientists working in a mad frenzy to develop and push these COVID vaccines over the finish line. Sure, we’re the tip of the spear, but a tip is worthless without all those feathers at the back sending the arrow where it needs to go.

A Gut-Check Safety Moment

A patient asked me if I was nervous about such a new vaccine. The fact is, for shots against tetanus, hepatitis, polio, and measles, we’ve given more than a billion doses. For COVID, the Pfizer and Moderna products will have been tested in less than 100,000 people before being unleashed on the public. I’m sure after 20 million doses are administered, it’s quite possible we’re going to find uncommon, but nasty side effects. However, the odds of having a life-threatening illness or dying from COVID, at any age, are far higher than the risk of the vaccine. I will be getting this vaccine if it is approved, as will everyone in my family, as soon as we are permitted to receive it.

Monoclonal Antibodies for COVID

The two key pillars for control of COVID are public health (getting people to wear masks and quit having parties) and vaccination. However, treatments for patients with COVID are still important, especially over the next six months as vaccination gets underway. We do have medications for sick, hospitalized patients with COVID, but what about relatively healthy people seen in a doctor’s office? For folks not sick enough to be hospitalized, but at risk for serious illness, the most promising approach is the infusion of antibodies against the SARS-CoV-2 spike protein. The FDA has recently approved an antibody treatment called bamlanivimab (Bam’la-niv”-a-mab to rhyme with Pam-la give a gab) from Eli Lilly. This drug makes sick, hospitalized patients worse, but it appears to be effective for not-so-sick people who are not in the hospital but have COVID.

The FDA is allowing the drug to be used in these settings:

Age 65 or older.

Age 55 or older with high blood pressure, heart disease, or lung disease.

Age 12 or older with BMI over 35 (severe obesity), diabetes, kidney disease, or immunosuppressed.

Age 12-17 with certain other chronic medical problems.

The research trial, called BLAZE-1, showed that in people 65 or older, or those with a BMI of 35 or greater, the risk of hospitalization was 14.6% in the placebo group, and 4.2% in those who got the antibody infusion. If we treat 10 people, we’ll save one person a hospitalization. Good news, but not perfect, and this strategy has a few drawbacks.

The first problem is unleashing this complex medicine on millions of people based on a clinical trial involving only a few hundred folks. As we commonly see with new treatments, a second, larger trial with thousands of patients might reveal a host of issues that were not apparent here. Another problem is that of the 600,000 people getting COVID every day worldwide right now, probably 200,000 would be eligible for this drug, which has to be given as a one-hour intravenous infusion. We would exhaust the total supply in 36 hours. Lilly hopes to have a million doses by the end of the year, but again, not nearly enough to treat all eligible patients. In addition, the hospital infrastructure to give all these intravenous infusions would overwhelm many healthcare systems that now can barely keep up with the hospitalized COVID cases. It is not optimal to launch this undertaking full tilt for millions of patients without a bigger study. In the meantime, the best use for this drug is probably for the highest-risk (age 80 or 85 and older) patients. In the future, after vaccination, there will be a few patients who still get COVID anyway, and then, with much lower numbers of cases, bamlanivimab will be a potential option. In the meantime, if you’re in a higher-risk group, lordy, don’t rely on this treatment. DON’T GET COVID.

Antidepressants for COVID?

Another approach for mildly ill patients with COVID is to put them on the antidepressant fluvoxamine, sold under the brand name Luvox. In theory, one could also use Prozac, Zoloft, or Lexapro. All these drugs raise serotonin, of course, but they also stimulate a receptor called sigma-1 that is involved in many cellular functions, including damping down the immune system. A study out of Washington University in St. Louis randomized 152 adult patients with mild to moderate COVID to get fluvoxamine, which they quickly dialed up to the maximum dose, or placebo, and found a possible benefit to the drug. This approach would need to be tested in a larger trial to know if it works. It is extremely challenging to run studies like this in the middle of a pandemic, but it is even worse to not run them. Early, small studies of hydroxychloroquine suggested a benefit, later, bigger studies showed it was worthless, if not harmful. Remdesivir appeared to speed recovery by a few days in a 1000 patient study published in The New England Journal of Medicine, but a larger study of remdesivir, with almost triple the number of patients, did not really show much benefit. That study, sponsored by the World Health Organization, tested four different treatments for COVID and found all were worthless. Once again, the best treatment is not to get COVID in the first place.

The Tsunami Has Arrived

We’re right in the midst of what is likely the final wave of COVID. As the vaccines are being mass produced and distribution plans are underway, now it is more important than ever not to get this disease. I urge my higher-risk patients to be extra careful. It will be extremely embarrassing to die of COVID in December, only to have vaccine available in January. Now is the time to postpone holiday plans until next year. Christmas in July and Thanksgiving in June are great ideas. I urge everyone to be extra careful during this peak in cases. We’re not dragging folks in for a routine annual exam right now, but of course, if you need care or if you’re way overdue, then a visit might be in order.

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