Corona Virus
© NIAID/NIH
Science / March 31, 2021

How the vaccines fight the coronavirus

What side effects should I expect from the vaccines against the new SARS-CoV-2 coronavirus? Have they been developed too fast? To support a factual debate, our experts from the fields of immunology and RNA biology answered frequently asked questions.
How does a vaccine work?

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A vaccine prepares the body for a possible infection, doing so in such a way that our immune system can fight off the pathogen and one doesn’t get sick. A vaccine is usually injected for this purpose. Its components have characteristics of the virus, but cannot cause the disease. Since the 19th century, various vaccines have been developed that have been very successful; severe to fatal viral diseases such as measles have been nearly eradicated in large parts of America and Europe as a result.

Not all vaccines are created equal. Sometimes only part of the virus is used, sometimes the complete virus is used but has been killed by heat, for example, sometimes a harmless viral variant is used that seems similar enough to the body. These “traditional” vaccines are also under development worldwide against coronavirus. But their production often takes a long time.

During the SARS-CoV-2 pandemic, vaccines based on new platform technologies could be adapted and developed most quickly to the new virus. These include mRNA vaccines from BioNTech/Pfizer and Moderna, respectively, or the adenovirus vaccine from Oxford University and AstraZeneca. The mRNA vaccine from BioNTech/Pfizer has been used in Germany since late December, and the Moderna vaccine has been licensed in Europe since January 6, 2021. Another mRNA vaccine from the firm CureVac is still being clinically tested.

How do mRNA vaccines work?

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The mRNA vaccine consists of two parts: a messenger RNA (mRNA) molecule and “packaging material.” The packaging is necessary for this mRNA molecule to be able to enter the cells of the body.

mRNA molecules are important components of all cells in the human body for short-term storage of our genetic information. If you think of our genetic material, which consists of DNA molecules in the cell nucleus, as a cookbook, then mRNA molecules from it are transcribed notes, which are used in the cell plasma and then disposed of again.

The genetic material of the coronavirus consists of RNA, and the new vaccines use a section of it. Instead of the complete four-course menu (= the genetic material of the entire virus), the “note” only includes the recipe for the appetizer: small spikes of the virus.

When our body’s cells absorb the vaccine, they use it to “cook” a protein in the cytoplasm, which normally sits on the surface of viruses, and then present it on their mantle. The immune system can now produce antibodies and other immune cells to fight against the spikes. Once the right virus enters the body after an infection, it is recognized and attacked by the antibodies. This way, it can do much less damage.

The mRNA molecule in the vaccine is designed to be read as often as possible. It’s a very robust note, so to speak. That’s what makes the vaccine so efficient. Thanks to decades of basic research – long before the coronavirus – it was possible to camouflage this mRNA as a cell’s own, so that it is not immediately recognized as “coming from outside.” However, the camouflage is not perfect, and the reaction to it could be a reason for various side effects, including fever and pain. The note is read, but the format is somehow a bit inappropriate. After one or two days, the mRNA molecules are degraded in the cells.

Since the mRNA can hardly get into our cells on its own – it is too large and electrically charged – it is “packaged” into soap-like bubbles. These substances (lipids and polyethylene glycol) have been steadily refined over the past decade to ensure that they cause as little damage as possible to the body. They are now considered safe enough for widespread use.

How can it be proved whether a vaccine really does what it promises to do?

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As devastating as the pandemic is, because so many people become infected, it is also favorable for clinical vaccine trials. For example, to test efficacy, in the case of BioNTech/Pfizer, about 18,000 people received the vaccine, while an additional group of 18,000 people only received a saline shot (control group). Over the course of several months, there were nearly 200 incidental infections in the control group, but only about a dozen in the vaccinated group. This uneven distribution shows that the vaccine is highly effective.

In addition, researchers have demonstrated the inoculation protection in animal studies with rhesus monkeys. Rhesus monkeys are naturally susceptible to infection with SARS-CoV-2 and also develop symptoms such as pneumonia. Thus, they represent suitable animal models for the COVID-19 illness. After administration of the experimental vaccine, the animals were exposed to the virus – but they were inoculated and infection was not detectable.

Side effects

Some vaccines have almost no side effects, while others are more unpleasant. Where does the new vaccine rank? Will one feel sick after being vaccinated?

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Side effects often occur with vaccinations, and they can arise in two different ways. On the one hand, a vaccination can be a “small infection”. So the body reacts in a similar way to what one might experience with a viral infection, e.g., with fever, headache or fatigue. On the other hand, there can be also a reaction at the injection site, as well as to parts of the vaccine.

In the study of the effectiveness of the BioNTech/Pfizer vaccine, such side effects were examined in detail. In the vaccinated group, about 80 percent experienced pain at the injection site (of which about two-thirds of the cases were “mild”, one-third were “moderate” and a few were “severe”), compared with 14 percent in the control group. In general, side effects were more severe after the second dose than after the first. Among those vaccinated, 59 percent then reported fatigue (control group 23 percent), 52 percent a headache (control group 24 percent), and 37 percent muscle pain (control group 8 percent). In each case, just over half felt the side effects were moderate, and some severe. Fever above 38 degrees was experienced by 16 percent of those vaccinated after the second dose, with a few experiencing fever above 39 degrees. Swollen lymph nodes were noted in three out of 1,000 vaccinated; other, more severe side effects did not occur, according to the phase 3 trial study.

So overall, many of those vaccinated can expect noticeable, sometimes unpleasant side effects for one to three days. But these are a good sign – showing that the immune system is doing what it should. Rarer or long-term consequences are not known. However, participants in the vaccine trials will continue to be monitored.

The “packaging material” can produce other unintended side effects. These have been closely followed in the case of polyethylene glycol (PEG). There are people who have antibodies against this substance. When vaccinated, this can lead to an allergic reaction, so it is being considered whether people with many allergies should be vaccinated later. Those vaccinated should also stay in the respective vaccination center for 15–30 minutes. This is because adrenaline shots, for example, are kept on hand there to treat allergic shock, which would occur 5–30 minutes after vaccination. This has been documented in 1 out of 100,000 vaccinated people so far.

At the second vaccination appointment, questions are asked about how the person tolerated the first dose. Vaccinated individuals can report to their general practitioner if they experience further complications. General practitioners and health offices pass on information about unusual physical reactions to the Paul-Ehrlich-Institut (PEI), Federal Institute for Vaccines and Biomedicines. This information is then systematically recorded in a database and evaluated as to whether a connection with the vaccination is possible. PEI also informs the European regulatory authority EMA, which collects these reports in a central database. If there is a statistically significant connection between health complaints and the vaccination, these side effects would be quickly registered.

What is our experience with lipid nanoparticles? How do they break down in the body?

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Lipid nanoparticles (LNPs) are similar to liposomes (fat droplets), which have been used as drug carriers in medicine for over 20 years. In another approved drug (Patisiran, Onpattro®), therapeutic RNA molecules are “packaged” in very similar fat globules. With these drugs, however, the patients receive significantly higher quantities of the lipids as an infusion compared with a vaccination.

Vaccines with a similar structure already exist: virosomal vaccines like Epaxal that protects against hepatitis A, or Inflexal against influenza. Virosomes are also phospholipid vesicles that carry envelope proteins of the viruses on their surface. These vaccines have been used in medicine for many years, and they have a good safety profile.

The structure of the lipid nanoparticles is formed – like in our bodies’ biological membranes – by phospholipids with cholesterol embedded in them. The various LNPs also contain other lipid components that impart special properties. Since all lipids are identical or very similar to the body’s own lipids, these nanoparticles are considered “biodegradable.” It can therefore be assumed that they are degraded by enzymes in the body, in a similar way to dietary lipids, and are largely absorbed into the body’s own fat metabolism. The potential toxicity of each of these novel vaccine preparations was assessed in preclinical tests prior to approval.

What side effects can lipid nanoparticles cause?

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The general rule is that “only the dose makes the poison.” This is the case even with everyday substances that we consume all the time. Toxicology tests are therefore mandatory before a drug or vaccine is approved for use in humans.

Lipid nanoparticle technology, which involves the packaging of messenger RNA (mRNA), includes new ingredients, such as ALC-315 and ALC-159 (at BioNTech/Pfizer) and SM-102 and PEG2000-DMG (at Moderna). Some of the preclinical toxicology testing submitted for conditional approval was not extensive. Manufacturers are expected to submit additional studies and information to the European Medicines Agency (EMA).

To determine the “therapeutic window,” toxicology studies increase the dose until adverse effects are clearly detected in animals. In such tests, BioNTech/Pfizer researchers observed reversible liver changes in rodents after injecting them three times at weekly intervals with a dose of the vaccine 300 to 1000 times higher than that used in humans. This resulted in an accumulation of ALC-315 in the liver of the rats. From these findings it was possible to deduce that the administration of a low dose to humans can be considered toxicologically safe.

This is because humans are injected twice with a very small dose (0.05 to 1 milligram, depending on the substance) into the muscle. It is hardly to be expected that lipid nanoparticle technology will cause liver damage. By comparison, over-the-counter paracetamol is available in dosages of 500 and even 1000 milligrams per tablet. There are documented cases of liver damage following paracetamol administration in amounts as low as seven grams a day.

The results from the animal studies have generally not led the EMA to change its risk-benefit assessments. After all, one thing is absolutely certain: The SARS-CoV-2 coronavirus can cause considerable damage throughout the human body.

Does the vaccine contain adjuvants?

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The BioNTech/Pfizer vaccine contains no adjuvants or preservatives.

The excipients listed are as follows:

  • ALC-0315 = [(4-hydroxybutyl)azanediyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate)
  • ALC-0159 = 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
  • 1,2-Distearoyl-sn-glycero(3)phosphocholine
  • Cholesterol
  • Potassium chloride
  • Potassium dihydrogen phosphate
  • Sodium chloride
  • Disodium hydrogen phosphate dihydrate
  • Sucrose
  • Water for injections

Here we can see that the lipid nanoparticles of the BioNTech/Pfizer vaccine in which the mRNA is embedded contain, among other things, polyethylene glycol (PEG) to make them more soluble. PEG is also used in many other medicines and cosmetics. In rare cases, PEG can trigger an allergic reaction. PEG is therefore currently considered the main suspect for possible allergic reaction to COVID-19 vaccines. 

Can the mRNA change our genome?

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Every cell in the body contains an average of 360,000 messenger RNA (mRNA) molecules in its cytoplasm. And with every viral infection, including a mild cold, foreign RNA enters our cells. But it does not penetrate even the cell nucleus, where our genetic material is stored.

The integration of RNA into DNA is extremely unlikely due to, among other things, their different chemical structure. The two biomolecules do not fit together and cannot form chains. The most important differences are: DNA is double-stranded, whereas RNA is single-stranded; they use different sugar molecules as “building blocks”; and they also differ in one of their four nitrogenous bases, which form the “rungs” of the ladder-like biomolecules.

Is it possible to say after such a short time whether a vaccine is safe enough to be injected into large sectors of the population – and into risk groups first? Especially when it is completely new technology?

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There is never absolute certainty, not even with a novel vaccine like this one. However, it is important to weigh up what endangers one’s life more: the risk of a potentially severe coronavirus infection, which is associated with long-term consequences, or the mild side-effects of the vaccination that have been reported so far, which are only more severe in extremely rare cases. Particularly the elderly and the very elderly are at risk of dying from a SARS-CoV-2 infection.

A good example where such risks are weighed up is with the measles vaccination. Following infection with the measles virus, 98 percent of the unvaccinated go on to contract measles. One in 1,000 to 2,000 people who fall ill develop encephalitis during the course of the disease. With a measles vaccination, on the other hand, the risk of contracting encephalitis is less than one in a million. And even this connection is considered uncertain. Vaccination with the live attenuated vaccine therefore has a much lower complication rate than the disease itself.

Additional sources of credible scientific information on the SARS-CoV-2 vaccines:

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