The last few weeks, we’ve been discussing some of the complicated history and science surrounding vaccination and immunity. The strategic and targeted defensive strategies employed by the immune system are by no means perfectly impregnable, but they represent several millennia of evolution under fire. Pathogens have always had a leg up on multicellular organisms—evolving more quickly and chaotically, unburdened by the constraints of form and function. They aren’t very sophisticated, but in terms of sheer brute force, there are already more viruses on earth than there are stars in the entire universe. We are besieged on all sides by these crafty pathogens, so it is an astounding feat of evolution and ingenuity that humanity continues to thrive. For much of history, deadly infections were the number one cause of death—smallpox, bubonic plague, polio—but the discovery of vaccines has already won many of these contentious battles. These days, heart disease is the leading cause of death—far above any pathogen-borne disease. People are living long, healthy lives. Child mortality has become a tragedy rather than an expectation (for most of history, roughly half of children could be expected to die before age 15, but by 2017 that number had dropped to less than 5%). Vaccines have played a significant role in these developments, providing necessary aid to the overwhelmed forces of the immune system. Now, in the midst of a seemingly endless battle against SARS-CoV-2, the newly approved Moderna and Pfizer/BioNTech Covid-19 vaccines might just be able to provide us with the fighting chance we need to win the war.
Back in April, I briefly introduced the Moderna vaccine, which was, at the time, in the early stages of clinical trials. Moderna began working on their mRNA-based Covid-19 vaccine in January 2020, and by early March, they were able to move it into human trials. At practically the same time, BioNTech, in collaboration with Pfizer, began working on their own Covid-19 vaccine using mRNA. By early December, after months of carefully coordinated trials, the FDA granted emergency approval for both the Moderna and Pfizer/BioNTech vaccines. These vaccines are unprecedented in terms of the speed and efficiency of their development. This speed is in part due to the inherent versatility of the technology and existing experience with it. While these are the first mRNA vaccines to be approved for clinical use, the technology has been under development for several years. The success of these vaccines and the versatility of mRNA will no doubt revolutionize the way vaccines are developed—giving us the tools to quickly squash future pathogen uprisings.
The Moderna and Pfizer/BioNTech vaccines are actually rather simple in terms of composition. Both vaccines contain mRNA from the viral spike protein wrapped up in a lipid shell. These lipid nanoparticles are suspended in a solution of salts and sugars that preserve and stabilize the vaccine for storage and transport. These salts and sugars are pretty standard for vaccines, so we won’t spend time looking at the subtle differences. Both vaccines use salts and sugars that appear in several other vaccines that have been approved as safe. Neither vaccine contains mercury or mercury salt (though it’s worth noting that the mercury salt preservative thimerosal is perfectly safe and not linked to any major health risks, but it is not used in most vaccines these days primarily due to negative public perception).
Because mRNA is so vulnerable to degradation by our body’s enzymes, it needs to be packaged until it can be released into a specific cell. Both the vaccines utilize small lipid shells to protect the mRNA and deliver it to the cells surrounding the injection site. Lipids are fat molecules that tend to be hydrophobic, meaning they avoid water (this is why oil and water separate into two layers after you mix them). These lipids create a solid barrier between the solution of mRNA inside the nanoparticle and the water-based fluids of the vaccine and your body.
In addition to their role as long-term energy storage (in our body’s fat cells), lipids also provide containment and protection for our cells. The cell membrane of every cell in the body is composed of a bilayer of phospholipids—a special type of lipid with a salty head and a fatty tail. The phospholipid head is hydrophilic—attracted to water—so when it is put in a water-based solution, it spontaneously forms a bilayer, keeping the hydrophobic tails away from the surrounding solution. The lipid composition of the cell membrane allows the cell to control what comes in and out of the cell. Molecules that are too big or too charged can’t move through the cell membrane without the help of embedded protein channels or pumps.
The Moderna and Pfizer/BioNTech vaccines use different specific lipid vehicles, which is part of the reason they have different storage requirements, but the mechanism is essentially the same. When either vaccine is injected into a patient’s arm, the lipid nanoparticles bump into cells around the injection site. When they find a body cell, the nanoparticles fuse to the phospholipid membrane, allowing them to dump their payload into the cell interior. Some of these particles will hopefully bump into dendritic cells, innate immunity guards that are crucial in triggering an active immune response. Once inside the cell, the normal cellular machinery does all the work.
In human cells, genetic information is stored within DNA inside the nucleus. But in order for the information to be understood and utilized outside the nucleus, individual genes have to be copied and processed using the single-stranded mRNA. This mRNA exits the nucleus into the cytoplasm of the cell, where ribosomes translate those instructions into functional proteins. This system is how all the necessary proteins of your body get made. It’s also the mechanism that viruses hijack to make copies of themselves. As long as the mRNA molecule is properly marked and processed, it will get picked up by a ribosome and translated. The mRNA is released after translation, but it is vulnerable to quick degradation—the individual amino acids get recycled for later use. There is absolutely no mechanism by which this mRNA can be integrated into the genome, so there is no risk for genetic mutation.
The Moderna and Pfizer/BioNTech vaccines also differ slightly in terms of the exact sequence of mRNA used, but they both essentially encode for the protein spike that SARS-CoV-2 uses to get inside our cells. Once the mRNA is translated by the machinery in the cell, the spike is moved to protrude from the membrane. Some spike proteins get chopped up and attached to the Major Histocompatibility Complex (MHC) molecules on the outside of the cell. On normal body cells, these MHC-spike complexes signal nearby cytotoxic T cells to kill the cell, which releases the spikes into the body. If the cell is one of the special dendritic cells, then the MHC-spike complex recruits helper T cells to coordinate a full immune response. These T cells stimulate the B cells—who have likely already found the spike proteins on cells or floating around in the body—to start producing antibodies. The antibodies find and destroy all the free-floating spikes.
Since there is no actual virus in the vaccine, the immune system has no problem eliminating all the foreign material. The Covid-19 vaccines are highly reactogenic—meaning they stimulate a robust immune response that can lead to soreness, inflammation, and even a low-grade fever. But this immune system overreaction is good for long-lasting immunity. After just two spaced out vaccinations, the immune system has created enough memory-B and -T cells to stop a Covid-19 infection in its tracks. Long-term testing will be needed to know exactly how long immunity lasts and whether boosters will be needed, but the results so far are promising.
Not only does vaccination help the body stop a potentially deadly infection, but it also helps to curb the spread. If enough people are vaccinated, there will be enough herd immunity to stop spread entirely. Highly transmissible viruses like measles require vaccination of at least 95% of the population to prevent spread. The exact requirement for Covid-19 herd immunity isn’t known yet, but it may be impossible to achieve if a significant portion of Americans chooses to refuse vaccination.
We’ll be taking a break next week, but in the meantime, check out last month’s series on influential women in science! Comment on this post or email me at contact@anyonecanscience.com to let me know what you think about this week’s blog post and tell me what sorts of topics you want me to cover in the future. And subscribe below for weekly science posts sent straight to your email!
