Antibodies to the Flu and COVID-19 Cross-React

Posted on by Jesse Santiano, M.D.

The journal International Pharmacology published a study about the cross-reactivity between antibodies to SARS-CoV-2 and the influenza virus. [1]

The cross-reactivity of antibodies between the virus that causes COVID-19 and influenza is particularly relevant now that we are entering the flu season. That’s because antibodies elicited by previous flu or the flu shot may affect the outcome of COVID-19. So far, evidence has shown that flu shots is associated with milder COVID-19.

Reports of Flu shots and Mild COVID-19

The British Medical Journal Evidence-Based-Medicine published, Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil. The study sampled 53,752 clinically confirmed COVID-19 patients. Results and conclusion are below.

Patients who received a recent influenza vaccine experienced on average 7% lower odds of needing intensive care treatment, 17% lower odds of requiring invasive respiratory support, and 16% lower odds of death.

Patients with COVID-19 with recent inactivated influenza vaccination experience significantly better health outcomes than non-vaccinated patients in Brazil.

The journal Internal and Emergency Medicine released Effect of influenza vaccine on COVID-19 mortality: a retrospective study in March 2021. It is a study of 635 patients who sought consultation at the Emergency Department of Fondazione Policlinico Gemelli.  They said:

 After correction for gender, age, and comorbidities, we found a lower risk of death at 60 days in patients with flu vaccination than in not vaccinated patients. Our study shows that flu vaccination could reduce the mortality of COVID-19.

Influenza Vaccination and COVID-19 Mortality in the USA: An Ecological Study was reported in the journal Vaccines on April 2021.  The study was among ≥65 years old from 2,482 counties in the US. [2] They concluded that flu shots are associated with lower COVID-19 mortality. They reported,

Our results show that, at the county level, there is a reduction in the COVID-19 mortality rate associated with higher influenza vaccination coverage in the elderly population.

With that background, researchers from Translational Health Science & Technology Institute and the Department of Biochemistry, All India Institute of Medical Sciences analyzed why influenza vaccination is associated with lower COVID-19 death rates.

The study is Non-neutralizing SARS CoV-2 directed polyclonal antibodies demonstrate cross-reactivity with the HA glycans of influenza virus.

Before we go to the results, here are some definitions.

The SARS-CoV-2 is the coronavirus that causes the COVID-19 pandemic.

SARS-CoV-2 Virus. from Wikipedia

The coronavirus has “spikes” sticking out from a central nucleus.  Spikes are made up of protein.

Below is an electron microscope of a spike protein of the SARS-CoV-2. The Receptor-Binding Domain (RBD) in magenta below is the part of the spike protein of the SARS-CoV-2. It binds to the ACE2 receptor of human cells.  Once the RBD is attached, the virus enters the cells and replicates, and then the COVID-19 disease starts.

The RBD is the magenta on top of the spike protein. Source: Wikipedia

Neutralizing antibodies attach to the RBD of the spike protein. Once they stick to the RBD, no entry to human cells happens. Thus, infection is prevented.

Non-neutralizing antibodies stick to other parts of the spike protein. They have a dual nature. They can protect against infection, or they can enhance the disease.  Infection enhancement is explained below.

Hemagglutinin is a protein on the surface of the influenza virus. The influenza virus uses hemaglutinin to stick to human cells. In flu vaccination, the objective is for the body to make antibodies against hemagglutinin.

Influenza virus attaching to the cell membrane via the surface protein hemagglutinin. Source: Wikipedia

The outcome of the study showed that

A. Non-neutralizing antibodies against the SARS-CoV-2 reacted with the hemagglutinin of the influenza virus.

B. The antibodies against influenza hemagglutinin also cross-react in a non-neutralizing manner with the spike protein of SARS-CoV-2.

This cross-reaction brings out a question. If the antibodies from influenza are non-neutralizing to the SARS-CoV-2, why is the flu shot protective against COVID-19 deaths?

Non-neutralizing antibodies can trigger other parts of the immune system like antibody-dependent cellular cytotoxicity (ADCC) and complement activation after attaching to an immune cell. Both can be protective or harmful.

Antibody-dependent cellular cytotoxicity is when an antibody binds to a microbe like a virus, and another immune cell comes in and destroys both. The figure below shows a CD16 natural killer cell or NK cell attaching to the other end of the antibody while the antibody is attached to a cancer cell. The result is the tumor cell dies.

Antibody-dependent cellular cytotoxicity. The purple Y figures are antibodies. NK- natural killer cells. Fc is a part of the antibody.  Apoptosis is orderly cell death. Wikipedia

The complement system or complement cascade works with the antibodies by causing inflammation and attacking the cell membranes of the microbes bound to antibodies. It involves several proteins that work sequentially. One process leading to another and ending with the death of a cell and the virus.

ADCC and complement cascade elicited by non-neuralzing antibodies can be double edged. It can protect against COVID-19 or worsen it. [3], [4] causing antibody-dependent enhancement ADE. No studies have demonstrated that flu shots can cause ADE.

There are other ways non-neutralizing antibodies can cause ADE. You can read about them at

The best strategy is to keep the immune system strong. That way, severe influenza and COVID-19 can be prevented.

Knowledge about Covid-19 is rapidly evolving. Information may update as new studies are made. Stay current by subscribing. Feel free to share and like.

Don’t Get Sick!

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References:

  1. Kumar et al. Non-neutralizing SARS CoV-2 directed polyclonal antibodies demonstrate cross-reactivity with the HA glycans of influenza virus. Int Immunopharmacol. 2021 Oct;99:108020. doi: 10.1016/j.intimp.2021.108020. Epub 2021 Jul 29. PMID: 34426117; PMCID: PMC8318684.
  2. Zanettini C, Omar M, Dinalankara W, Imada EL, Colantuoni E, Parmigiani G, Marchionni L. Influenza Vaccination and COVID-19 Mortality in the USA: An Ecological Study. Vaccines (Basel). 2021 Apr 24;9(5):427. doi: 10.3390/vaccines9050427. PMID: 33923159; PMCID: PMC8145634.
  3. Yu Y, Wang M, Zhang X, et al. Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients. Signal Transduct Target Ther. 2021;6(1):346. Published 2021 Sep 24. doi:10.1038/s41392-021-00759-1
  4. Chouaki Benmansour N, Carvelli J, Vivier E. Complement cascade in severe forms of COVID-19: Recent advances in therapy. Eur J Immunol. 2021 Jul;51(7):1652-1659. doi: 10.1002/eji.202048959. Epub 2021 Apr 10. PMID: 33738806; PMCID: PMC8250085.
  5. Candelli M, Pignataro G, Torelli E, Gullì A, Nista EC, Petrucci M, Saviano A, Marchesini D, Covino M, Ojetti V, Antonelli M, Gasbarrini A, Franceschi F. Effect of influenza vaccine on COVID-19 mortality: a retrospective study. Intern Emerg Med. 2021 Mar 20:1–7. doi: 10.1007/s11739-021-02702-2. Epub ahead of print. PMID: 33743150; PMCID: PMC7980752.
  6. Fink G, Orlova-Fink N, Schindler T, et al. Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil [published online ahead of print, 2020 Dec 11]. BMJ Evid Based Med. 2020;bmjebm-2020-111549. doi:10.1136/bmjebm-2020-111549

Image credits:

  1. SARS-CoV-2: By Alexey Solodovnikov (Idea, Producer, CG, Editor), Valeria Arkhipova (Scientific Сonsultant) – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=104914011
  2. RBD: By 5-HT2AR – Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=88638800
  3. Influenza hemaglutinin: By CSIRO, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=35437407
  4. ADCC By Satchmo2000 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15768505
  5. Complement cascade: by Perhelion – Own work based on: http://www.niaid.nih.gov/publications/immune/the_immune_system.pdf, Public Domain, https://commons.wikimedia.org/w/index.php?curid=45352985

 

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