Antibody-dependent enhancement (ADE) happens when antibodies intensify infection rather than prevent it.
ADE uses the immune system of the host to make the infection worse. Understanding what the immune system does to battle COVID-19 will make it easy to know ADE.
COVID-19
In COVID-19, the more virus, the worse the infection. The clinical course of COVID-19 can be divided into two parts. The first is when the SARS-CoV-2 multiplies. A person may be asymptomatic or have mild to moderate illness at this time. The majority of infected people survive this stage because of their natural immune response.
The second stage happens if viral replication persists unabatedly. The immune system mounts a greater immune response.
Severe COVID-19 is due to the inappropriate and overactive immune response that produces a lot of cytokines that attack several organs. A cytokine storm.
The lungs get flooded with fluid, both kidneys and the heart can fail, and mental status deteriorates. This stage has a high mortality.
To prevent cytokine storms, effective early treatment is necessary.
Neutralizing Antibodies
COVID-19 prevention is the goal of vaccination. Neutralizing antibodies generated from vaccines should block the viral entry to the cells. Viruses need to use the cells’ machinery to make copies of themselves.
The problem is that neutralizing antibodies after vaccination wane after six to eight months according to a study from Israel published in the New England Journal of Medicine. [11]
Six months after receipt of the second dose of the (Pfizer) BNT162b2 vaccine, humoral response was substantially decreased, especially among men, among persons 65 years of age or older, and among persons with immunosuppression.
In the same edition of NEJM, a Qatar study also said the same, [12]
Estimated BNT162b2 effectiveness against any SARS-CoV-2 infection was negligible in the first 2 weeks after the first dose. It increased to 36.8% in the third week after the first dose and reached its peak at 77.5% in the first month after the second dose.
Effectiveness declined gradually thereafter, with the decline accelerating after the fourth month to reach approximately 20% in months 5 through 7 after the second dose.
Effectiveness against symptomatic infection was higher than effectiveness against asymptomatic infection but waned similarly.
Variant-specific effectiveness waned in the same pattern. Effectiveness against any severe, critical, or fatal case of Covid-19 increased rapidly to 66.1% by the third week after the first dose and reached 96% or higher in the first 2 months after the second dose; effectiveness persisted at approximately this level for 6 months.
After that, the vaccinated individual becomes prone again to COVID-19. [5], That’s the reason why vaccine makers push for booster shots.
But that’s not all. As neutralizing antibodies go down, the non-neutralizing antibodies predominate. [3]
Non-neutralizing antibodies
Non-neutralizing antibodies do not prevent attachment to human cells. They can still provide protection. After attachment to the virus, non-neutralizing antibodies call forward the other parts of the immune system to destroy the foreign body. Similar to a soldier shining a laser on a target for the missiles. In the immune system, those missiles are the complement cascade and antibody-dependent cytotoxicity or ADCC.
The complement cascade is a series of molecules that get activated in sequences that results in viral destruction.
In antibody-dependent cytotoxicity or ADCC, the antibody bound to the virus draws another cell that comes in to lyse the target cell. Natural killer cells or NK cells are an example.
In the image below, NK cells attach to the antibody-antigen complex to destroy a tumor cell. NK cells will do the same thing to viruses. (Antigens are a part of foreign bodies that the antibodies stick to after recognition).
Now that we know that, we proceed to the main topic. Below, non-neutralizing antibodies will be referred to as antibodies for easier reading.
The titles below each mechanism link to an article that elaborates on that topic.
The ADE Mechanisms are the following:
I. Antibodies allow viral entry to macrophages, destroying the defense and promoting viral replication simultaneously.
Macrophages. Macrophages are a type of white blood cell and are front-line defense. They go around and eat germs like viruses. Some macrophages have a receptor on their surface called the FcγR. (FcγR means Fc gamma receptor). Antibodies with FcγR will attach to those macrophages.
The image below is an immune globulin or antibody. The top is the Fab that binds to an antigen like a virus, and the bottom is the Fc.
If an antibody with FcγR attaches to a macrophage and the other end of the antibody combines with the SARS-CoV-2, the antibody will allow the SARS-CoV-2 to enter the macrophage. The viruses then replicate and rapidly spread to other cells. That is putting an infection on fast-track[1]
What is Antibody-Dependent Enhancement, and why should you care.
II. Antibodies work with lipid rafts to facilitate entry to the host cells. Lipid rafts exist on the cell surface. Like a raft on the water, it has passengers. Lipid rafts contain proteins that work together. That makes for an efficient process.
Normally, lipid rafts near the ACE2 receptor carry proteins that bring in the angiotensin-converting enzyme 2 or ACE2. ACE2 is needed for several body processes.
In COVID-19 ADE, antibodies connect the lipid rafts and the spike protein of the virus. The antibodies change the conformation of the spike protein to an open position. This open position facilitates viral entry. This type of ADE has been demonstrated in the Delta variant. [8], [4]
Antibody-dependent enhancement can happen to Delta Variant COVID-19
III. Antibodies put the spike protein in a ready-to-infect open conformation.
The coronavirus spike protein is part of the coronavirus that attaches to the host cells. Spike proteins are like umbrellas. They are closed if not needed but are opened when used. Once the spike protein opens, they are ready to attach to the ACE2 and enter the cell.
A study from Osaka University found that antibodies keep the spike protein in an open conformation making it more infectious.
Here, we screened a series of anti-spike monoclonal antibodies from coronavirus disease 2019 (COVID-19) patients and found that some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2.
Delta Variant: Poised to be Resistant to the Current COVID Vaccines
IV. Antibodies for the Influenza virus cross-reacts with the SARS-CoV-2
An Indian study showed that antibodies against influenza cross-reacts with the SARS-CoV-2 virus. In the laboratory, the investigators found that antibodies elicited by influenza vaccination reacted with the COVID-19 virus.
The authors suggested that the complement cascade or ADCC can be activated and lead to serious illness.
Overall, our findings address the cross-reactive responses, although non-neutralizing, elicited (antibodies) against RNA viruses and warrant further studies to investigate whether such non-neutralizing antibody responses can contribute to effector functions such as antibody-dependent cellular cytotoxicity (ADCC) or ADE.
So far, no studies have definitely shown that this happens. In contrast, research has shown that people who had flu shots develop milder COVID-19.
Antibodies to the Flu and COVID-19 Cross-React
V. Antibodies to SARS-CoV-2 from breast milk can cause ADE in infants.
Mothers who had COVID-19 or have been injected with the COVID-19 vaccine develop antibodies that can be secreted in breast milk. An infant can also have COVID-19 although they are usually asymptomatic or mild. Once the antibodies from the breast milk attach to the SARS-CoV-2, the other end of the antibody can link and activate a mast cell.
Mast cells are naturally occurring cells that are involved in allergies and immunity. They contain histamine and heparin among others. Once activated, histamine can be released slowly and manifest as mild allergy symptoms like hives and diarrhea, or fussiness in a baby.
Rapid and systemic release leads to anaphylactic shock, including cardiovascular collapse and deaths. The condition has been likened to Kawasaki Disease and may explain Multisystem Inflammatory Syndrome in Children or MIS-C.
The article below has multiple real-life examples of mast cell ADE.
Antibody-Dependent Enhancement in Breastfed Infants
Concluding thoughts
With all the different mechanisms presented, ADE may be happening more than we know. Papers have suggested before that severe COVID-19 may be a manifestation of ADE from previous coronavirus exposures [10].
During the cold season, people tend to gather and stay indoors. That is when viral transmission gets higher. If you add the waning of neutralizing antibodies from booster shots, more people may develop ADE. I’m not a big fan of booster shots due to the risk of adverse effects but that’s just my opinion.
Early treatment is essential to prevent ADE from happening.
Knowledge about Covid-19 is rapidly evolving. Stay current by subscribing. Feel free to share and like.
Don’t Get Sick!
Relevant to the topic to prevent ADE:
- Update to FLCCC Treatment Protocol for the Delta Variant
- The I-MASK+ for the Prophylaxis and Early Treatment Protocol of COVID-19
- The MATH+ Protocol Results in Greater Survival in Hospitalized COVID-19 Patients
- Adequate Vitamin D Prevents Severe COVID-19
- What should the household do if someone has an Early COVID-19?
- Update to the I-MASK+ Prevention & Early Outpatient Treatment Protocol for COVID-19
- Melatonin’s Multiple Actions Against COVID-19
- IVMMETA.COM: A website of studies on Ivermectin’s efficacy
- News that ivermectin overdose is clogging up hospitals is not true
- What makes Ivermectin a kick-ass antiviral?
- The anti-COVID-19 properties of Quercetin
References:
- Maemura T, Kuroda M, Armbrust T, Yamayoshi S, Halfmann PJ, Kawaoka Y. Antibody-Dependent Enhancement of SARS-CoV-2 Infection Is Mediated by the IgG Receptors FcγRIIA and FcγRIIIA but Does Not Contribute to Aberrant Cytokine Production by Macrophages. mBio. 2021 Sep 28:e0198721. doi: 10.1128/mBio.01987-21. Epub ahead of print. PMID: 34579572.
- Yu Y, Wang M, Zhang X, Li S, Lu Q, Zeng H, Hou H, Li H, Zhang M, Jiang F, Wu J, Ding R, Zhou Z, Liu M, Si W, Zhu T, Li H, Ma J, Gu Y, She G, Li X, Zhang Y, Peng K, Huang W, Liu W, Wang Y. Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients. Signal Transduct Target Ther. 2021 Sep 24;6(1):346. doi: 10.1038/s41392-021-00759-1. PMID: 34561414; PMCID: PMC8463587.
- Cloutier M, Nandi M, Ihsan AU, Chamard HA, Ilangumaran S, Ramanathan S. ADE and hyperinflammation in SARS-CoV2 infection- comparison with dengue hemorrhagic fever and feline infectious peritonitis. Cytokine. 2020;136:155256. doi:10.1016/j.cyto.2020.155256
- Sviridov D, Miller YI, Ballout RA, Remaley AT, Bukrinsky M. Targeting Lipid Rafts-A Potential Therapy for COVID-19. Front Immunol. 2020 Sep 29;11:574508. doi: 10.3389/fimmu.2020.574508. PMID: 33133090; PMCID: PMC7550455.
- , , , , , , , , , , , , , , COVID-19 Neutralizing Antibody Surveillance Testing for Fully Vaccinated Individuals During Delta Variant Spread.
- Liu Y, Soh WT, Kishikawa JI, et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell. 2021;184(13):3452-3466.e18. doi:10.1016/j.cell.2021.05.032
- Murugavelu P, Perween R, Shrivastava T, et al. Non-neutralizing SARS CoV-2 directed polyclonal antibodies demonstrate cross-reactivity with the HA glycans of influenza virus. Int Immunopharmacol. 2021;99:108020. doi:10.1016/j.intimp.2021.108020
- Yahi N, Chahinian H, Fantini J. Infection-enhancing anti-SARS-CoV-2 antibodies recognize both the original Wuhan/D614G strain and Delta variants. A potential risk for mass vaccination? J Infect. 2021 Aug 9:S0163-4453(21)00392-3. doi: 10.1016/j.jinf.2021.08.010. PMID: 34384810; PMCID: PMC8351274.
- The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines.
- Cloutier M, Nandi M, Ihsan AU, Chamard HA, Ilangumaran S, Ramanathan S. ADE and hyperinflammation in SARS-CoV2 infection- comparison with dengue hemorrhagic fever and feline infectious peritonitis. Cytokine. 2020 Dec;136:155256. doi: 10.1016/j.cyto.2020.155256. Epub 2020 Aug 20. PMID: 32866898; PMCID: PMC7439999.
- Levin et al. Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months. October 6, 2021. DOI: 10.1056/NEJMoa2114583
- Abu-Raddad et al., Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar. October 6, 2021. DOI: 10.1056/NEJMoa2114114