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What do we know about the mRNA vaccine and cytokine storm?

This article was published on
January 20, 2021

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There is no evidence to suggest that mRNA COVID-19 vaccines or non-mRNA COVID-19 vaccines would result in cytokine storms.  Cytokine storms happen when outside pathogens trigger an overproduction of proteins called cytokines. This overproduction can result in damaged lung tissue, acute respiratory distress syndrome, and death. While no single definition of cytokine storm is widely accepted, three features of cytokine storms are commonly shared: elevated levels of cytokines, acute systemic inflammatory symptoms, and either secondary organ dysfunction or any cytokine-driven organ dysfunction. Although the mechanisms of lung injury and organ failure in COVID-19 are still being studied, data suggest that cytokine storms contribute to the development and severity of COVID-19 in some patients.  One hypothesis about cytokine storms is that they are a consequence of a process through which antibodies bind to viruses and give them easier entry to cells instead of attacking them, which incites a harmful immune response. This is called antibody-dependent enhancement (ADE). Scientists are not yet completely sure if ADE actually promotes cytokine storms and are also considering other factors that may play a role.  ADE and cytokine storms can result naturally due to a range of underlying causes; however, there is no evidence that they would result from an mRNA COVID-19 vaccine, or any COVID-19 vaccine. In very rare cases, ADE has resulted from vaccines, such as the Respiratory syncytial virus (RSV) vaccine in the 1960s and the Dengue vaccine in 2016, due to Dengue's four strains. Today’s routinely recommended vaccines, however, do not cause ADE, and Phase 3 trials are designed to specifically detect such negative outcomes.  Neither Moderna nor Pfizer-BioNTech, the two leading biopharmaceutical companies that produced the mRNA COVID-19 vaccines being distributed, found any evidence of ADE or cytokine storm from any trial phase. In addition, rates of disease were significantly lower in the vaccinated group, and among those who did contract COVID-19 in the vaccinated group, rates of severe disease were lower than in the placebo group. Scientists and public health professionals will continue to closely monitor vaccinated individuals to ensure that ADE and cytokine storms can be entirely ruled out as a side effect of COVID-19 vaccines. For the moment, however, there is no evidence that shows the vaccines to have such effects.

There is no evidence to suggest that mRNA COVID-19 vaccines or non-mRNA COVID-19 vaccines would result in cytokine storms.  Cytokine storms happen when outside pathogens trigger an overproduction of proteins called cytokines. This overproduction can result in damaged lung tissue, acute respiratory distress syndrome, and death. While no single definition of cytokine storm is widely accepted, three features of cytokine storms are commonly shared: elevated levels of cytokines, acute systemic inflammatory symptoms, and either secondary organ dysfunction or any cytokine-driven organ dysfunction. Although the mechanisms of lung injury and organ failure in COVID-19 are still being studied, data suggest that cytokine storms contribute to the development and severity of COVID-19 in some patients.  One hypothesis about cytokine storms is that they are a consequence of a process through which antibodies bind to viruses and give them easier entry to cells instead of attacking them, which incites a harmful immune response. This is called antibody-dependent enhancement (ADE). Scientists are not yet completely sure if ADE actually promotes cytokine storms and are also considering other factors that may play a role.  ADE and cytokine storms can result naturally due to a range of underlying causes; however, there is no evidence that they would result from an mRNA COVID-19 vaccine, or any COVID-19 vaccine. In very rare cases, ADE has resulted from vaccines, such as the Respiratory syncytial virus (RSV) vaccine in the 1960s and the Dengue vaccine in 2016, due to Dengue's four strains. Today’s routinely recommended vaccines, however, do not cause ADE, and Phase 3 trials are designed to specifically detect such negative outcomes.  Neither Moderna nor Pfizer-BioNTech, the two leading biopharmaceutical companies that produced the mRNA COVID-19 vaccines being distributed, found any evidence of ADE or cytokine storm from any trial phase. In addition, rates of disease were significantly lower in the vaccinated group, and among those who did contract COVID-19 in the vaccinated group, rates of severe disease were lower than in the placebo group. Scientists and public health professionals will continue to closely monitor vaccinated individuals to ensure that ADE and cytokine storms can be entirely ruled out as a side effect of COVID-19 vaccines. For the moment, however, there is no evidence that shows the vaccines to have such effects.

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What our experts say

There is no evidence to suggest that mRNA COVID-19 vaccines or non-mRNA COVID-19 vaccines would result in cytokine storms. 

Cytokine storms happen when outside pathogens trigger an overproduction of proteins called cytokines. This overproduction can result in damaged lung tissue, acute respiratory distress syndrome, and death. While no single definition of cytokine storm is widely accepted, three features of cytokine storms are commonly shared: elevated levels of cytokines, acute systemic inflammatory symptoms, and either secondary organ dysfunction or any cytokine-driven organ dysfunction. Although the mechanisms of lung injury and organ failure in COVID-19 are still being studied, data suggest that cytokine storms contribute to the development and severity of COVID-19 in some patients. 

One hypothesis about cytokine storms is that they are a consequence of a process through which antibodies bind to viruses and give them easier entry to cells instead of attacking them, which incites a harmful immune response. This is called antibody-dependent enhancement (ADE). Scientists are not yet completely sure if ADE actually promotes cytokine storms and are also considering other factors that may play a role. 

ADE and cytokine storms can result naturally due to a range of underlying causes; however, there is no evidence that they would result from an mRNA COVID-19 vaccine, or any COVID-19 vaccine. In very rare cases, ADE has resulted from vaccines, such as the Respiratory syncytial virus (RSV) vaccine in the 1960s and the Dengue vaccine in 2016, due to Dengue's four strains. Today’s routinely recommended vaccines, however, do not cause ADE, and Phase 3 trials are designed to specifically detect such negative outcomes. 

Neither Moderna nor Pfizer-BioNTech, the two leading biopharmaceutical companies that produced the mRNA COVID-19 vaccines being distributed, found any evidence of ADE or cytokine storm from any trial phase. In addition, rates of disease were significantly lower in the vaccinated group, and among those who did contract COVID-19 in the vaccinated group, rates of severe disease were lower than in the placebo group.

Scientists and public health professionals will continue to closely monitor vaccinated individuals to ensure that ADE and cytokine storms can be entirely ruled out as a side effect of COVID-19 vaccines. For the moment, however, there is no evidence that shows the vaccines to have such effects.

Context and background

There are three main data points that suggest that cytokine storm may contribute to the development and severity of COVID-19 in patients: 1) reports of hemophagocytosis in affected patients (when immune cells that aren’t working properly “eat” other cells) 2) elevated cytokine levels in affected patients (especially those with severe COVID-19), and 3) beneficial effects of immunosuppressants in affected patients. 

In addition to the activated immune cells and elevated cytokine levels in patients that have a COVID-19–associated cytokine storm, several clinical and laboratory irregularities, such as renal dysfunction and elevated CRP (a measure in the blood that marks inflammation) are also observed with COVID-19 as they are with cytokine storm. Lab results reflecting hyperinflammation and tissue damage were also found to predict worse outcomes of COVID-19. 

Scientists are still researching to understand the complex number of causes that can cause a cytokine storm. In addition to the hypothesis of antibody-dependent enhancement, these storms can likely be caused by several different types of underlying health issues, including infection, genetic syndrome, and autoimmune disease. 

ADE is hypothesized to be a potential cause because it is a process through which the immune system essentially backfires. Early response to an infection is known as innate immunity. During the phase of innate immunity (0 - 96 hours of infection), immune response is non-specific, meaning that responses are directed at the outside pathogen (in this case the COVID-19 virus), but not specific to it. Within a few days, adaptive immunity takes over, which is specific to the invading pathogen and includes antibodies. 

One primary goal of antibodies is to bind to outside pathogens and prevent them from entering and infecting cells (neutralizing antibodies). However, if some of the antibodies produced do not bind to the pathogens well enough to carry out this prevention or are not present in the right concentration levels, they can latch onto the pathogens and actually worsen disease severity through the ADE process. In this process, these antibodies, instead of neutralizing the viruses, can help the viruses gain easier entry into cells and can incite a harmful immune response.

Resources

  1. Cytokine Storm (NEJM)
  2. Antibody-dependent Enhancement (ADE) and Vaccines (Children's Hospital of Philadelphia)
  3. COVID-19 Vaccine Developers Search for Antibodies That ‘First Do No Harm’ (Scientific American)
  4. The COVID-19 Cytokine Storm; What We Know So Far (Frontiers in Immunology)
  5. Change of Antigenic Determinants of SARS-CoV-2 Virus S-Protein as a Possible Cause of Antibody-Dependent Enhancement of Virus Infection and Cytokine Storm (Nature Public Health Emergency)
  6. COVID-19: consider cytokine storm syndromes and immunosuppression (The Lancet)
  7. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults (NEJM)
  8. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine (NEJM)

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