What's behind COVID-19 vaccine side effects?

A growing concern among coronavirus vaccines is the vaccine side effects. Fear or misinformation about side effects may fuel vaccine hesitancy, contributing to low vaccination rates. Australian researchers recently published an article in Science Immunology to discuss why people develop side effects and their benefits.

Study: COVID-19 vaccine side effects: The positives about feeling bad. Image Credit: ROCOTHERY / Shutterstock
Study: COVID-19 vaccine side effects: The positives about feeling bad. Image Credit: ROCOTHERY / Shutterstock

About 60% of people have experienced a range of side effects from muscle aches, headaches, and fever. There have also been reports of more serious, albeit rare heart problems and blood clotting disorders.

The article suggests that vaccine side effects are a byproduct of short bursts of type I interferon (IFN-I) production needed to mount an effective immune response.

“In light of the above, the prospect of fatigue and headache after vaccination for COVID-19 should be viewed positively: as a necessary prelude to an effective immune response. The side effects of vaccination will nearly always be mild and transient and indicate merely that the vaccine is doing its job of stimulating the production of interferon, the body’s in-built immune stimulator,” wrote the researchers.

IFN-I’s role in early immune response

Most symptoms result from overproducing a cytokine involved in the early immune response called type I interferon (IFN-I). Its activation of IFN-I and IFN-III in the respiratory system has antiviral effects that prevent the virus from spreading throughout the body.

The activation of IFN-I also increases activation of dendritic cells, which relays antigen information to naive CD4+ and CD8+ T cells. The CD4+ cells stimulate B cells to produce antibodies while CD8+ cells become cytolytic effector cells.

“IFN-I acts in part by improving the immunogenicity of DC, particularly by elevating the surface expression of molecules that costimulate T cell activation. In addition, IFN-I has a direct stimulatory effect on T cells, promoting the optimal expansion of these cells and formation of long-lived memory cells, both for CD4+ and CD8+ T cells,” explained the authors.

IFN-I during viral infection

For some infectious diseases, a virus may trigger an excessive IFN-I that leads to high inflammation, known as a cytokine storm. But, the researchers note that current evidence shows this is probably unlikely for SARS-CoV-2 because patients with severe COVID-19 infection have shown below-normal IFN-I levels in their blood.

Patients with COVID-19 infection may sustain damage because of cytokine storms from an overproduction of IL-6, but it’s likely not IFN-I mediated. Instead, severe COVID-19 infection might be linked with a break in IFN-I production during the early stage of infection. Some clinical evidence supports this notion as administering IFN-I to patients during the early stages of disease has been beneficial.

While there has been no direct evidence of IFN-I production after a COVID-19 vaccination, the researchers suggest this is likely happening because other mRNA vaccines stimulate IFN-I production.

IFN-I production may be correlated with COVID-19 vaccine side effects

Would this suggest IFN-I production is the cause behind the myriad of COVID-19 vaccines? The answer is still unclear. IFN-I therapy is currently used to treat hepatitis B and C and multiple sclerosis and shows similar side effects — headaches, fever, and fatigue — as the COVID-19 mRNA vaccines. Though, IFN-I stimulates a lot of downstream effects, including the release of different cytokines and chemokines. There is a possibility that one of these downstream effects is the true culprit behind the side effects.

Vaccines not only produce immunity by antigen recognition on dendritic cells but T cells also respond to costimulation or ‘second signal.’ The additional signal comes after contact with T cell CD28 molecules with CD80 and CD86 molecules on dendritic cells.

Because of the needed co-stimulation to induce immunity, a successful vaccine requires information on the virus or an adjuvant to increase costimulatory molecules on dendritic cells, and in turn, mount an immune response.

Similar to IFN-I, adjuvants binding to complementary pattern recognition receptors on dendritic cells. This then stimulates activation of cells and an upregulation of costimulatory molecules. The similarity in response has researchers suggesting that IFN-I is a potential adjuvant, and side-effects of COVID-19 vaccines result from a quick burst of IFN-I production after generating an immune response.

“The point to emphasize here is the striking correlation with IFN-I production. Thus, closely paralleling the intensity of typical immune responses, IFN–I generation is substantially stronger in females than males and in younger than older people.”

COVID-19 infection generates low IFN-I levels, while the flu stimulates high IFN-I levels. This may explain why some people reported more flu-like symptoms after vaccination, even when they were asymptomatic while sick with COVID.

Though more research on this topic is needed to be sure.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.


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