Light at the end of a dark, dark tunnel

From a lineup of worthy competitors, Covid-19 won first place in making 2020 a garbage year. With almost 100 million cases worldwide, with almost 2 million deaths so far, Covid has caused so much suffering. Thanks to tireless work by dedicated scientists, it appears there might be light at the end of the tunnel. In November 2020, pharmaceutical companies Pfizer-BioNTech and Moderna reported that they had highly efficacious vaccines for SARS-CoV-2, the virus responsible for Covid-191. After emergency use authorization by multiple countries, the Covid-19 vaccine became the front-and-center story. With these stories came confusion, misinformation, and worry. In this piece, I address the science of mRNA vaccines, safety considerations, and answer some of your questions.

Types of vaccines and mRNA vaccines

The main goal of a vaccine for a pathogen such as SARS-CoV-2 is to teach the immune system what that virus looks like. Once taught, the immune system will mount a vigorous attack on the virus if it enters the body again.

Vaccines used previously have been either weakened/inactivated pathogens (e.g. polio vaccine2) or proteins from the pathogen. Once immunity is achieved, our immune system recognizes these intruders and neutralizes them.

Unlike these two types, the currently-approved Covid-19 vaccines are mRNA vaccines. This is the first time in history that mRNA vaccines have been used to treat disease. It’s an exciting milestone but let’s start by understanding what mRNA is:

In biology, genetic information is stored in DNA* (long strings of A, C, G and T letters in the nucleus of your cells). Your genome has genes that determine everything from eye color to lactose tolerance. The genes, however, are not themselves the actors. The genes code for proteins that carry out all the biology and chemistry (Fig. 1, below).
* except some viruses like SARS-CoV-2 that have RNA genomes

Fig. 1: Central dogma of biology. Source: Khan Academy

In the above image, we see that the DNA is used as a template to make messenger RNA (mRNA), and this RNA is then “translated” into protein. mRNA gets its name because it acts as a messenger, carrying information from your DNA to the ribosome where proteins are made.

The mRNA Covid vaccine is similar to mRNA that your body makes. The “message” carried by this mRNA is used to make a part of the SARS-CoV-2 spike protein (Fig 2, below).

Fig. 2: Cartoon structure of the SARS-CoV-2 virus particle. Spike glycoprotein (red box) is highlighted. Adapted from: Encyclopedia Britannica

Understanding our immune response

The full predicted immune response to SARS-CoV-2 is complex, and I’m not an immunologist so I won’t pretend to understand it:

Source: InvivoGen

Instead, I’ll summarize the above schematic: The vaccine’s mRNA is coated in a lipid layer that resembles the membranes of your cells. This similarity allows for the mRNA to be taken up by cells near the vaccination site3 for the immune response to start. Once the mRNA enters your cells, the cells start producing the encoded spike protein. After the partial spike protein is made, the cell actively degrades the mRNA and disposes of it. Importantly, the mRNA never enters the cell’s nucleus or affects genetic material.

Like all proteins in your cells, the spike protein is chewed up, and small fragments (called antigens) are displayed on the cell surface for your surveillance immune system to evaluate. In the lymph nodes, the antigens are ‘presented’ to other immune cells, and this induces a larger, more specific response in the form of antibody production.

The process of developing antibodies for the spike protein takes a few weeks. Once antibodies are made, they circulate throughout your immune system. If you get infected with the virus again, the circulating antibodies will bind to the spike protein and tag them for immune cells to neutralize the threat. Our immune system stores the “memory” (in the form of memory B cells) of encountering the virus, which lasts months or even years. Current estimates suggest that these mRNA vaccines keep us immune for 8 months4.

Fun fact: Our bodies use a feature called immune tolerance by which we can differentiate self from non-self. People with autoimmune diseases (e.g. Celiac’s, Type I Diabetes) have faulty immune tolerance systems.

If you want to learn more about vaccines and if they are truly effective (spoiler: they are), visit my other article on vaccines here.

So if traditional vaccines work, why risk an mRNA vaccine?

This is the first time in human history that we have successfully used an mRNA vaccine. For an urgent operation at this scale, is it worth the risk of trying something new?
Two words: Warp Speed.
The traditional vaccine development process involves growing up a large amount of a pathogen, weakening/inactivating it or extracting a single protein from it. These processes are complex, with safety and yield being the biggest factors.

By contrast, working with mRNA is easier on three fronts:
– mRNA is 100% non-toxic
– mRNA can be made without relying on the virus or any other microorganism (RNA can be made by chemical synthesis or in vitro transcription)
– Different vaccine candidates can be tested quickly. In fact, when the SARS-CoV-2 genome sequence was published in January 20205, researchers around the world started formulating and testing hundreds/thousands of vaccine candidates immediately.

Now you might be wondering, if it’s so easy, why haven’t we been using mRNA vaccines all along?

mRNA vaccines – decades in the making

The research responsible for the mRNA vaccine didn’t start in Jan 2020 – it began decades ago with fundamental research by university researchers on genome sequencing, DNA and RNA synthesis, virus biology, infection mechanisms, protein-protein interactions, mRNA stability, mRNA delivery into cells (called transfection), mRNA engineering, etc. By itself, each individual piece of this research might have seemed insignificant. Together, scientists were able to move mountains. We should all be proud of this effort. And always support increased funding for science research in national budgets – it could literally save your life.

mRNA vaccines – a new frontier against disease
It’s quite stunning that we have the first successful mRNA vaccine. Vaccinologists around the world are abuzz. Today, we’re using it for Covid-19. Tomorrow, we might use it for cancer or tuberculosis or malaria or HIV. There are a lot of reasons for this enthusiasm6:
– mRNA vaccines can be easily tested in animal models
– they can be rapidly designed, engineered, and tested for emerging infectious diseases
– mRNA is non-infectious, production can be easily and safely scaled up
– mRNA vaccines induce strong immune responses because our own cells are producing the antigens

You might be concerned about:

Can I get Covid-19 if I take the vaccine?
No. The mRNA vaccine only codes for a portion of one of the proteins (the spike glycoprotein) that make up the virus. As an analogy – you can’t say you read a book if you only skimmed a few pages. But it takes time for your immunity to develop, which means you could still get exposed from an infected person and get sick. Wear a mask, wash your hands, practice social distancing.

Is this gene therapy?
Absolutely not! Gene therapy is a technique by which your DNA is modified, typically to repair a mutated gene. The mRNA in the vaccine never enters the nucleus of your cells (where your DNA is stored) and doesn’t have any mechanism to alter your genome. Further, RNA is highly unstable (that’s why the vaccine needs to be stored at extremely cold temperatures). After producing the spike protein, the “garbage disposal” of the cell rapidly degrades the mRNA. In fact, it is estimated that the half-life (i.e. time taken for x amount of something to fall to half its original amount) is only 3-5 minutes7.

Is this genetic modification?
Still no. The mRNA sequence itself has been engineered to optimize for maximum immunity. That said, there is no modification of your own genetic information happening whatsoever.

Will I become autoimmune to my own proteins?
No. Our bodies use a nifty trick called immune tolerance to discriminate self from non-self. There is no evidence of developing autoimmunity from vaccines.

Isn’t herd immunity an option even without a vaccine?
Technically, yes. Realistically, no. Herd immunity is where most of a population is immune, thereby providing indirect protection to those who are not immune to the disease. Here’s the math: estimates suggest 70% of the US population would need to recover from Covid-19 for herd immunity to work8, or roughly 200 million people. Not only would this overwhelm our healthcare system, but with a current case fatality rate of 1.67% in the US9 (based on median age of US population of 37.6 years), that would mean roughly 3.3 million people would die in the US alone. That is an unconscionable death toll. Isn’t it so much simpler to take the vaccine?

So many people had anaphylaxis after taking the vaccine. Is it actually safe?
A few people, especially those that need to carry EpiPens with them, had severe allergic reactions within 15 minutes of taking the vaccine. If you have a history of serious allergic reactions, tell your doctor before getting the vaccine. That said, severe allergic reactions are rare. Covid-19 vaccination data from Dec 14-23 2020 shows 21 cases of anaphylaxis after administration of 1.9 million first doses of the Pfizer-BioNTech vaccine10.
That is 11.1 cases per million (or 0.001%), an astonishingly low number. By contrast, your probability of contracting the virus is 40 times higher (0.04%).

If the vaccine was developed so quickly, they surely cut corners somewhere?
For all practical purposes, no. Modern scientific tools (such as mRNA vaccines) sped up the research and development process greatly. Further, this might be one of the best funded research endeavors to date. Often, the fastest alternative is prohibitively expensive – cost wasn’t a concern this time. Further, it was easy and quick to recruit willing participants for clinical trials. The vaccines still went through Phase I-III of clinical trials that underwent independent assessment. Finally, production at the required scale is another challenge – in this case, Operation Warp Speed ensured billions of dollars had already been invested in production facilities. Pharma companies were ready for massive scale production.

Why did they pick the spike protein for the mRNA vaccine and not something else?
This was a smart choice by the scientists – the spike protein is crucial for the virus to attach to cells and cause infection. Blocking this crucial function is sure to neutralize the virus. Further, once immunity is established, our immune systems will be able to detect exposure quickly given that the spike protein is displayed on the outer surface of the virus particle.

Variants and a note on virus evolution

A lot of people are wondering if the mRNA vaccines will work against the different strains we’re hearing about. First, rest easy. The mRNA vaccines are effective against the two variants discovered so far11, at least in the laboratory. The variants were discovered too recently for tests on human participants.

Will SARS-CoV-2 become less deadly?
This trend in the last few weeks of highly-infectious variants appearing around the world is not surprising. This phenomenon has been extensively studied in other viruses (like the Flu Virus) for decades. A virus is at its deadliest when it makes the jump from one organism to another. It soon realizes that there is a fine equilibrium between virus (aka parasite) and host. A virus doesn’t benefit from killing its host – that’s bad for business. If the host dies, the virus no longer propagates in that host.
Over time (multiple years), the “fittest” virus is one that is highly infectious and not typically lethal. Take the 1918 Flu Pandemic for example – it killed tens of millions of people around the globe but almost disappeared a few years later. A strain of the original 1918 Flu is supposedly still around today somewhere, but it isn’t nearly as deadly as it once was.

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I hope you enjoyed this evaluation of mRNA vaccines for the SARS-CoV-2 virus. If you have any questions, please leave a comment. Other ideas for articles I should write? Let me know!

Thanks, and see you at the next one. Wear your mask, wash hands + social distancing.

A link to reliable, factual information on the Covid-19 vaccines: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/facts.html

References:
1. University of Minnesota Center for Infectious Disease Research and Policy. (https://www.cidrap.umn.edu/news-perspective/2020/11/pfizer-biontech-note-95-covid-vaccine-efficacy-will-apply-eua) Accessed Jan 11, 2021.
2. Centers for Disease Control and Prevention. Polio Vaccination: What Everyone Should Know. (https://www.cdc.gov/vaccines/vpd/polio/public/index.html)
3. Centers for Disease Control and Prevention. Pfizer-BioNTech COVID-19 Vaccine Questions. (https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/pfizer-bioNTech-faqs.html) Accessed Jan 11, 2021.
4. University of Minnesota Center for Infectious Disease Research and Policy. (https://www.cidrap.umn.edu/news-perspective/2020/12/two-studies-find-covid-19-antibodies-last-8-months) Accessed Jan 11, 2021.
5. Zhu et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine. January 2020
6. Pardi et al. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. January 2018
7. Chan et al. Non-invasive measurement of mRNA decay reveals translation initiation as the major determinant of mRNA stability. eLife. September 2018
8. Johns Hopkins Bloomberg School of Public Affairs. (https://www.jhsph.edu/covid-19/articles/achieving-herd-immunity-with-covid19.html) Accessed Jan 11, 2021
9. Our World In Data. Case fatality rate of COVID-19 vs. Median age of the population. (https://ourworldindata.org/grapher/case-fatality-rate-of-covid-19-vs-median-age?tab=chart&stackMode=absolute&time=latest&country=&region=World) Accessed Jan 11, 2021.
10. Centers for Disease Control and Prevention. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020 (https://www.cdc.gov/mmwr/volumes/70/wr/mm7002e1.htm#:~:text=During%20December%2014%E2%80%9323%2C%202020,within%2015%20minutes%20of%20vaccination.) Accessed Jan 11, 2021
11. Pfizer vaccine appears effective against rapidly spreading coronavirus variants. (https://www.cnet.com/news/pfizer-vaccine-appears-effective-against-rapidly-spreading-coronavirus-variants/) Accessed Jan 11, 2021

5 Comments

  1. I’m worried it will affect fertility. I understand there’s no proof this is the case but medicine often causes birth defects so it seems like something scientists should at least check?

    Like

    1. Hi there, thanks for your question! It’s a fair concern because it’s way too early to test this hypothesis. In fact, for a lot of drugs, it’s really tough to predict with certainty if it will have adverse consequences like birth defects. That’s why we do pre-clinical testing and clinical trials! Phase I of clinical trials only looks at safety in humans. When investigating a difficult question without clear answers, scientists look at the entire body of knowledge on drug-related infertility and birth defects, dissect the causes, and not repeat history’s mistakes. Using exactly that approach, I’m confident that the Covid vaccine will not affect fertility or cause birth defects. There are multiple reasons:
      (1) The approach of the mRNA vaccine is for cells near the vaccination site (your shoulder) to make a small part of the spike protein so the immune system can recognize it as “non-self” and produce antibodies. The process of making the spike protein is identical to how each cell in your body makes millions of proteins each day. This small bit of the spike protein made has no activity by itself. In fact, the protein is rapidly chewed up by the cell (like almost all other proteins in cells after a few seconds/minutes). None of this protein is freely traveling around your body to cause unintended consequences. The other parts of the vaccine (lipid coating, etc.) have been extensively tested for decades (refer to “decades in the making” section of the post) with no aberrant behavior. You can rest assured those are safe.
      (2) I would also correct your assertion that medicine “often” causes birth defects. The only confirmed case of birth defects happened in the 1950s – 60s with the teratogen (aka drugs that can cause birth defects) thalidomide. That was a huge learning moment for scientists. That drug molecule exists in 2 conformations (called isomers) – one of those treated disease, while the other (unintentionally produced in the manufacturing process) caused birth defects. Since then, the FDA has ruled that all drugs have to be “pure isomers” of the clinically-approved molecule to avoid situations like this. Today, companies are required to provide clear guidelines on whether there might be a risk for pregnant women. There is even a pregnancy risk classification for drugs that pregnant women should avoid. Finally, there is about a 4% chance of birth defects even if a pregnant mother refrains from drugs and chemicals.

      Thanks for your question again. I hope I eased some of your concerns. If you have follow-up questions, don’t hesitate to reply here!
      And for more information, check out this link: https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/drugs-medication-and-birth-defects

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