The emergence and rapid transmission of COVID-19, an acute respiratory disease caused by the SARS-2 coronavirus as well as its mutated versions, results in global morbidity and mortality, in addition to causing a widespread social and economic catastrophe. Under such a situation, the developments of several vaccines worldwide offered some sort of relief, although a class of people is still confused about the efficiencies and side effects of the vaccines; However, the effect and adverse effects of a vaccine massively rely on antibody-dependent enhancement (ADE).
Herein, I shall discuss the basics of ADE and its relation with a virus/vaccine, in brief and possibly the simplest way. Meanwhile, you’ll be able to achieve a clear concept of the strategies of recently developed COVID-19 vaccines and their association with antibody-dependent enhancement (ADE).
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The Mission Process of SARS-CoV-2 in Human body
The structure and ethnicity of the earlier SARS-CoV-1, MERS-CoV, and newer SARS-CoV-2 coronaviruses show that all viruses belong to the beta-coronavirus class. SARS-CoV-2 represents 80% and 54% similarities in genetic sequence with SARS-CoV-1 and MERS-CoV, respectively, which were previously responsible for respiratory diseases in 2002 and 2012. SARS-CoV-2 is also genetically related to other human coronaviruses that cause mild infections, such as HCoV-HKU1 (52%), HCoV-OC43 (51%), HCoV-NL63 (49%), and HCoV-229E (48%). In several reports from reputed recent research articles, it is assumed that the new coronavirus responsible for COVID-19 has been transmitted from bats to humans through some of the intermediate animals, later, which spreads from person to person. However, research is going for further confirmation of this fact.
The SARS-CoV-2 virus unlocks the angiotensin-converting enzyme 2 (ACE2), a receptor protein in human cells, with the key to a spike-like protein located outside it; further it enters the human body and cells are infected by the coronavirus. Serine proteases, neuropilin-1, and TMPRSS2 help in spike proteins’ maturation. Subsequently, the RNA virus continues to replicate cells, releasing virions (active, infectious forms of the virus) into human cells through various complex processes, and coming out of the cell to infect the adjacent cells. The spike protein contains the S1 subunit, contains the Receptor Binding Domain (RBD), and the S2 subunit, which aids in the fusion of the virus with the cell membrane.
What is Antibody-dependent Enhancement (ADE)?
Antibody-dependent enhancement (ADE) occurs when the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies.
A major goal in the development of vaccines and therapeutics is to inhibit ACE2-RBD binding or to inhibit cell membrane and virus fusion by producing antibodies. One potential impediment to the development of antibody-based vaccines and therapies is the increase in antibody-dependent enhancement (ADE). ADE can increase the severity of multiple viral infections, including respiratory syncytial viruses (RSV) and measles (Measles).
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Definition of Neutralizing Antibodies
Immune management involves many cells and proteins that run our body’s immune system. In the early stages of infection, these reactions are not specific, indicating that although they are directed against the pathogens, they are not specific to it. This is called innate immunity. Within a few days, the adaptive immunity takes on this resistance and reacts specifically with the invading germ. Adaptive immune responses initiate the production of respective antibodies, and as the number of specific antibodies increase the Adaptive immunity also increases. One of the main goals of antibodies is to bind to the external pathogens and prevent them from infecting any cell. These antibodies that inhibit infections are called neutralizing antibodies.
Reasons behind Antibody-dependent Enhancement (ADE)
Many vaccines are capable of producing neutralizing antibodies. However, not all antibody responses act equally. Sometimes antibodies do not block the entry of germs or viruses into the cells and in some cases, through a mechanism called ADE (antibody-dependent enhancement) they can increase the ability of the viruses to enter the cells and cause an increasing severity of the disease.
Sometimes when antibodies detect and bind to a virus or pathogen, ADE is formed along with the body’s active immune system, making them unable to prevent infection. Instead, these antibodies act as the so-called “Trojan horse” in Greek mythology, allowing the virus to enter the cells and activating the immune system, which is harmful to the body’s healthy cells.
For instance, dengue virus infections can cause antibody-dependent enhancement (ADE). The dengue virus is one of the world’s leading infections, infecting millions of people each year and killing thousands. There is only one type of virus exists for measles or mumps, but there are four different forms of the dengue virus, called “serotypes”, DENV-1, DENV-2, DENV-3, and DENV-4. These serotypes are very similar, but slight differences between them can cause ADE. If a person gets infected with a serotype of the dengue virus, the severity of the disease remains mild and builds up a protective immune system with neutralizing antibodies. However, if the person is infected with the second serotype of the dengue virus, the neutralizing antibodies generated from the first infection may bind to the virus and increase its ability to enter the cell, resulting in ADE and a deadly form of the disease called dengue hemorrhagic fever.
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Antibody-dependent enhancement (ADE) caused by Vaccination: The Examples
Vaccination has caused ADE in a few cases, which are discussed here:
Respiratory syncytial virus (RSV)
RSV is a virus that usually causes pneumonia in children. A vaccine was created by artificially growing RSV, purifying it, and inactivating it with the chemical formaldehyde. In clinical trials, children who were vaccinated were more likely to develop pneumonia or die after RSV infection. As a result, vaccine testing was discontinued and the vaccine was never submitted for approval or released to the public.
The earliest version of the measles vaccine was made using formaldehyde to neutralize the measles virus. The children who were vaccinated, they got contracted to measles and developed fever, abnormal skin rash, and rare pneumonia. Observing these results, the vaccine was discontinued, and those who received this version of the vaccine were advised to be re-vaccinated using the live, milder measles vaccine, which did not cause ADE and is still used today.
Both the RSV and measles vaccines, developed in the 1960s, and were tested further to uncover the cause of ADE. Since then, other vaccines such as hepatitis A, rabies, and inactivated polio vaccines have been successfully developed by purifying and inactivating them chemically with formaldehyde. These latest vaccines do not cause ADE.
Recently, a vaccine of dengue virus has been reported to cause ADE:
A dengue virus vaccine was developed in 2016 to protect against four serotypes of the virus. It was expected to eradicate the virus by transmitting four serotype resistance responses at once, but in reality, the vaccine was found to cause ADE-related problems. The vaccine was administered to 800,000 children in the Philippines, fourteen of whom died after being exposed to the dengue virus. It is speculated that the children developed antibody responses that were not able to neutralize the natural virus. As such, the vaccine is only recommended for children over the age of 9 who have already been exposed to the virus.
A vaccine to prevent dengue (Dengvaxia®) is licensed and available in some countries for people ages 9-45 years old. The World Health Organization recommends that the vaccine only be given to persons with confirmed prior dengue virus infection.
In May 2019, Dengvaxia® was approved by the U.S. Food and Drug Administration (FDA) in the United States for use in children 9-16 years old living in an area where dengue is common.
Multiple vaccines are used against multiple types of viruses that are safe, such as polio (3 types), rotavirus (5 types), and vaccines against human papillomavirus (9 types).
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Does SARS-CoV-2 promote ADE?
Some viruses in the coronavirus family cause similar events to dengue fever. For example, a virus called Feline Infectious Peritonitis Virus (FIPV) of the coronavirus family attacks the phagocytes called macrophages. In this case, the first route of enhanced infection using antibodies was used. However, despite its association with FIPV, the current coronavirus, SARS-CoV-2 does not attack the same cells. Studies have shown that the current coronavirus can attack macrophages but cannot replicate between them. In fact, the phagocytosing cells play a positive role in fighting against the virus when antibodies are around, and they help to reduce the viral load.
Therefore, it can be said that the ADE pathway based on the invading cell of the immune system is not relevant to the current coronavirus. Like the former SARS-CoV-1 or MERS, SARS-CoV-2 attacks epithelial cells, mainly the epithelial cells of the lungs, and therefore causes respiratory diseases. Therefore, the concern about the current coronavirus was from the second pathway of ADE̶-it causes an inflammation that uncontrollably activates the immune system, which can greatly increase respiratory distress.
All about The Present Vaccines for COVID-19
The Oxford-AstraZeneca, Sputnik V, and Johnson and Johnson/Jansen vaccines use adenoviruses that are not harmful; they carry the genetic code of viral spike proteins in our cells and translate them into spike proteins in our own cellular processes, resulting in spike proteins in the body, triggering the anti-spike immunity.
On the other hand, mRNA vaccine technology has been applied to vaccines developed by Pfizer/ BioNTech and Moderna. In both cases, the RNA code of the virus spike protein is bound to the phospholipid membrane called liposomes. It helps our body cells to synthesize spike proteins and make specific antibodies. These antibodies and T cells fight the virus later on.
In the early stages of the development of vaccines against SARS-CoV-2, researchers found that neutralizing antibodies produced after vaccination were comprising a much lower risk of ADE. The COVID-19 vaccines that are developed by Pfizer and Moderna, work to eliminate the virus by producing antibodies against the spike proteins of virus. Here, they have used RNA technology, which further reduces the chances of ADE after the application of SARS vaccines in general. In the early stages of the development of the current vaccine, rats and monkeys have been tested for ADE potential, and no ADE has been observed.
The incidence of ADE has not been observed in those who have been vaccinated so far, not in those who have been re-infected, and also, not even in the plasma treatment. ADE has not been observed in the three-phase trials of vaccines given to thousands of people and despite the widespread provision of vaccines worldwide, no ADE has yet been reported in humans. However, there is still a need for regular testing in infected, vaccinated, and vaccinated populations. Further, tests and trials are being conducted on animals in order to follow up the process of ADE.
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It is important to remember that COVID-19 is a new disease with multiple variants. Although ADE has not yet reported any of the three variants affected by the recent B.1.1.7 (United Kingdom variant), B.1.351 (South Africa variant), B.1.617.2 (Indian variant), new mutants or variants of the coronavirus are evolving and spreading over; so continuous testing is needed to see if ADE occurs when people are re-infected with different forms of the virus. Due to the danger of the disease itself and the damage it can cause, it is necessary to be aware of regular clinical statistics and the nature of the disease.
- W. S. Lee, A. K. Wheatley, S. J. Kent, B. J. DeKosky, Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nat Microbiol., 2020, 5, 1185-1191. DOI: 10.1038/s41564-020-00789-5.
- J. Wen, Y. Cheng, R. Ling, Y. Dai, B. Huang, W. Huang, S. Zhang, Y. Jiang, Antibody-dependent enhancement of coronavirus. Int J Infect Dis., 2020, 100, 483-489. DOI: 10.1016/j.ijid.2020.09.015.