Mechanisms Behind Vaccine Side-Effects: The Science That Causes That Sore Arm

After receiving a vaccination shot, it’s likely that we’ll feel some side-effects. These can range from merely a sore arm to swollen lymph nodes and even a fever. Which side-effects to expect depend on the exact vaccine, with each type and variant coming with its own list of common side-effects. Each person’s immune system will also react differently, which makes it hard to say exactly what one can expect after receiving the vaccination.

What we can do is look closer at the underlying mechanisms that cause these side-effects, to try and understand why they occur and how to best deal with them. Most relevant here for the initial response is the body’s innate immune system, with dendritic cells generally being among the first to come into contact with the vaccine and to present the antigen to the body’s adaptive immune system.

Key to the redness, swelling, and fever are substances produced by the body which include various cytokines as well as prostaglandin, producing the symptoms seen with inflammation and injury.

Tackling the Intruder

Artistic rendering of a human dendritic cell. (Source: NIH)

The first difference between vaccines is found in how the antigen is introduced into the body. Traditional vaccines use either weakened whole viruses, or parts of viruses, which are thus the antigen or contain the intended antigen as part of their structure. Viral vector-based and mRNA (lipid-vector) vaccines use a vector that transfers RNA into the body’s cells, where the cell’s ribosomes then assemble copies of the antigen. As a foreign protein, this is then presented on the surface of the cell as an antigen to lymphocytes.

If antibodies exist already against this specific antigen, the lymphocytes (B and T cells) of the body’s adaptive immune system will immediately act upon this antigen, and thus the (presumed) intruder (virus, bacteria or toxin) that is attached to the antigen. If no antibodies exist, the process is similar, but takes a bit longer for the immune response to ramp up.

Meanwhile, as the adaptive immune system ramps up, the dendritic and other cells of the innate immune system which possess pattern recognition receptors (PRRs) for pathogen-associated molecular patterns (PAMPs) like macrophages and mast cells also release a number of cytokines, including inflammatory cytokines which cause vasodilation. The resulting influx of blood causes the reddening of the skin (rubor) and increased heat (calor) .

As the blood vessels dilate, other mediators act to make the walls of these vessels more permeable, causing the amount of fluid outside of the blood vessels (intracellular space) to increase. This exudation of fluid causes swelling (tumor) which decreases the likelihood of pathogens coming into contact with body tissues, while giving macrophages and other leukocytes (white blood cells) free roam so that they can hunt down pathogens.

In addition to the vasodilation process, some of the released cytokins cause hyperalgesia (dolor), essentially an increased sensitivity to pain. All of these form part of the acute inflammation process and are responsible for the ‘sore arm’ often experienced after getting a vaccination.

Fever From a Vaccine

Simplified diagram of human thermoregulation (Author: J. W. Dietrich)

Among the symptoms commonly experienced after getting certain types of vaccines, fever (along with a headache) is not nearly as common as a sore arm, but still frequently reported. If we look at the CDC study results for the Pfizer-BioNTech mRNA vaccine for COVID-19 where people self-reported their symptoms, we can see headaches as a frequently reported symptom, however due to the prevalence in the placebo group of this symptom a strong causal link appears to be absent.

A more clear connection between vaccines and fevers exist, as one of the substances released during the inflammation process is an eicosanoid called prostaglandin. This compound is involved in vasodilation, as well as the inhibiting of blood platelet aggregation (anti-clotting) and most importantly in this case strongly affecting the body’s thermoregulatory center in the hypothalamus.

Simply put, the inflammatory response from the body’s innate and adaptive immune system results in a positive input to the body’s thermoregulatory system. The result from this can differ from merely experiencing some thermal discomfort, to actual fever where one’s body temperature can exceed its normal levels by a significant amount.

None of this is anything to worry about so long as the fever does not exceed 40 °C (104 °F), which as the earlier linked CDC vaccine study results show is exceedingly rare. It is safe to use an NSAID like ibuprofen to help with any fever as well as pain symptoms that may occur after the vaccination. As there is no real pathogen present from the vaccine, the only important factor is that the adaptive immune system gets an opportunity to learn the new antigen, meaning that there is no immunological benefit from developing a fever, let alone pain around the injection site.

Heart Inflammation

Microscope image of heart tissue that suffered viral myocarditis.

Myocarditis (inflammatory cardiomyopathy) is an inflammation of the heart muscle which is most often caused by a viral infection. In an average year well over a million people world-wide will develop myocarditis, with over 300,000 patients dying from this condition. The cause of myocarditis is generally the infiltration of the heart muscle by pro-inflammatory white blood cells as a response to an infection. In the case of the SARS-CoV-2 virus, this pathogen directly binds to the ACE2 receptors on the heart tissue’s surface, allowing it to infect these cells.

In the case of the SARS-CoV-2 vaccines, myocarditis is a known, if rare, side-effect. An article by Biykem et al. speculates that its cause is molecular mimicry between the spike protein of SARS-CoV-2 viruses and self-antigens, including α-myosin. This is a protein also known as MYH6, and which is expressed significantly in both the cardiac atria and the cardiac ventricles.

In case of a mistaken identity by the adaptive immune system, this could lead to the heart muscle being targeted by leukocytes. Whether or not this is the actual mechanism responsible, David K. Shay et al. report that compared to natural occurrence of myocarditis, its occurrence in cases linked to COVID-19 immunization is exceedingly rare. Even so, without understanding the exact mechanism involved, any linking of specific myocarditis cases to a SARS-CoV-2 vaccination remains based on circumstantial evidence.

Placebo Side-Effects

As noted in the context of the CDC-published Pfizer-BioNTech study results, there were many side-effects reported in the placebo group as well, including significant symptoms like fever, diarrhea, and vomiting. This highlights a big problem not only with placebos during medical trials, but also as a corollary when people are administered the real medicine.

Fueled partially by media reports and things one may have read on social media or heard from friends and colleagues, the mere fact that one has been vaccinated can lead to symptoms such as nausea and pain. When you’re already looking for something to happen, you’re much more likely to find that thing. Exaggerated negative effects to a treatment or vaccine are generally referred to as ‘nocebo effect’, where the expectation of negative effects from the treatment (even if it is a placebo) can result in the patient suffering those effects.

The nocebo effect (or phenomenon) is becoming more the subject of studies, due to its effects on medical treatments and patient care, as reported by Winfried Häuser et al. in 2012. Especially noted here is the importance of communication with a patient about the expectations they have, and to adjust these accordingly. In the context of a world-wide vaccination campaign as is currently ongoing with the SARS-CoV-2 pandemic, one may also consider the impact that the (social) media has in terms of mass psychogenic illness (‘mass hysteria’).

Although clear communication to set expectations is attempted by medical health professionals and others, there exists enough disinformation via other channels that some individuals may have become convinced of the purported negative effects of these vaccines. Here the risk is that even in those who are not necessarily against getting vaccinated, they may still subconsciously project a subset of the negative effects they have heard about onto their own body, effecting a nocebo phenomenon.

Take a Chill (Sugar) Pill

As vaccines have become more refined and we understand better the effects and symptoms (desired and undesired) that they provoke in the body, they have become routine enough that generally we are barely aware of how they protect us. After our childhood vaccines the most we tend to deal with vaccines is when we need a booster for tetanus, or when we go to some foreign country that demands proof of certain vaccinations, or just to protect ourselves against specific diseases that are endemic there.

What the world is currently experiencing as a result of the SARS-CoV-2 pandemic is (so far) truly unique, in the sense that this is the first pandemic that we’re vaccinating against on a world-wide scale. Compared to the leisurely pace of the smallpox eradication program that took decades, the current goal is to get the entire world vaccinated in a matter of years. As a result of vaccinating so many individuals simultaneously on such a massive scale, even rare side-effects will occur more often on a pure cases basis.

Even so, for the overwhelming majority of people being vaccinated today, tomorrow, and in the coming months and years, a sore arm and possibly jittery sensations will be the most they will ever experience of this mass-vaccination campaign. All of which are merely natural signs of your body’s immune system doing exactly what it’s supposed to do.