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How to design a new coronavirus vaccine to avoid the ADE effect?

Preliminary Study on the Mechanism of Coronavirus ADE Effect

Coronavirus has an ADE effect is a fact that many people know. Many studies in vivo and in vitro have confirmed this. This is also a major obstacle to the development of a vaccine against the new coronavirus. Understanding the ADE mechanism of the coronavirus will be the key to designing a vaccine that can avoid the production of ADE.


This article is very dry, onlookers can pull it down to read the conclusion and just like it.


This article will expand from the following three aspects:


Introduction to the ADE effect

  1. Introduction to the phenomenon of coronavirus species ADE
  2. The mechanism of coronavirus ADE

What is the ADE effect?

ADE is the abbreviation of antibody-dependent enhancement, Chinese "antibody-dependent enhancement".


ADE or "antibody-dependent enhancement" was first discovered during dengue virus infection.


The main disease caused by dengue virus infection is dengue fever. It is generally a self-limiting disease, that is, it is not harmful. 

This is a mosquito-borne infectious disease that is prevalent mainly in tropical and subtropical regions, which is transmitted by mosquitoes sucking blood. 

The vector is what we know as the "flower mosquito", which is the Aedes mosquito, including Aedes aegypti and Aedes albopictus.


As mentioned above, dengue fever caused by dengue virus infection is mainly a self-limiting disease, but there are four serotypes of dengue virus. Dengue virus-dengue virus, DENV. DENV-1, DENV-2, DENV-3, DENV-4. 

Serotype is a very important method used for classification before the great development of molecular biology, based on the reactivity of antibodies produced by the body to viruses.


As for the dengue virus, there are 4 serotypes, which means that if a person is infected with DENV-1 and recovers, the person will produce antibodies against DENV-1, so generally there will be almost no DENV-1 infection. What reaction is equivalent to having been vaccinated. 

But antibodies against DENV-1 cannot protect this person from DENV-2 infection, so they will get sick after being infected with DENV-2.


Moreover, this person may have more severe symptoms after being infected with DENV-1 and then infected with DENV-2. This is the ADE effect.


Two infections of a person with different serotypes of DENV may cause severe dengue infection (including dengue hemorrhagic fever/DHF and dengue shock syndrome/DSS). 

The traditional interpretation of textbooks is:

1.) Monocytes are the target cells of dengue virus. The antibodies (IgG) produced after the first infection cannot neutralize the second virus of another serotype, but can mediate the virus through the Fc of the antibody. It is easier to infect monocytes. Makes more progeny viruses produced.

2.) Over-activated monocytes and T lymphocytes secrete more cytokines, which increases the permeability of blood vessels, causing severe symptoms such as bleeding and even shock.

Therefore, the traditional ADE effect mainly believes that antibodies cannot neutralize the virus, but instead act as a "Trojan horse", making the virus more likely to infect monocytes.

This is the traditional explanation. In 2017, a report in Science magazine extended this theory. It is believed that the mechanism of the ADE effect of dengue virus is due to the high affinity of IgG1 subclass antibodies for the non-fucosylated Fc receptor FcγRIIIA, and non-neutralization. 

Antibodies induce the reduction of platelets in the body, which in turn leads to thrombocytopenia. There was science popularization at that time, so skip it.


Breakthrough progress, expansion of the explanation of the mechanism of dengue virus ADE effect

Summary: The "antibody-dependent enhancement effect" of the ADE effect means that the antibody cannot neutralize the virus. Instead, it acts as a "Trojan horse", making the virus more capable of infecting immune cells, producing more progeny viruses, and causing severe symptoms.


The ADE effect found in coronavirus research

At present, the ADE effect of coronavirus that I personally retrieved was published in 1981 (additions are welcome), and the research object is feline infectious peritonitis virus (FIPV).


In addition, pet owners may be aware of this cat-borne abdomen disease, or some people may know that the prodrug (GS-441524) of remdesivir (GS-5734) is a special medicine for the treatment of cat-borne abdomen.

There are two studies, one is adoptive immunization and the other is vaccine research.


Adoptive immunization means returning the antibodies in the recovered body to un-immunized individuals, and then evaluating the virus infection on these individuals.


Antibody-mediated enhancement of disease in feline infectious peritonitis: comparisons with dengue hemorrhagic fever.

Adoptively immunized kittens with cat serum with high titers of antibodies against FIPV, and then challenge with FIPV will make the immune kittens appear more disease symptoms (including fever/pyrexia, jaundice/icterus and thrombocytopenia/thrombocytopenia) than control kittens ), and death is faster (M±SEM: 10±0.6 days vs 28.8±8.3 days).


The earliest vaccine research is the viral vector vaccine, which used the famous vaccinia virus that eliminated smallpox. 

The modified vaccinia virus genome carries the S gene of FIPV, so it can induce the body to produce antibodies against the S protein.


Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virusimmunization.

Using vaccinia virus (smallpox vaccine) to recombine the S protein of FIPV, it can induce the production of neutralizing antibodies in mice. But when kittens are immunized with FIPV-S vaccinia virus and then immunized, they can only obtain very low titer neutralizing antibodies. 

After FIPV challenge, the kittens in the immunized group died earlier than the control group (wild-type vaccinia virus).

However, the results of these early studies suggest that vaccine research aimed at "cat transmission" is not optimistic. Pet owners may also know that after 8 weeks, the "master" should be given a "triple vaccine" to prevent cat plague, cat nasal branch, cat cup shape, and rabies vaccine. 

But so far, there is no vaccine available for "cat-to-belly". It also explains the difficulty of the coronavirus vaccine.


What is the research on human coronavirus?

We now turn to SARS-CoV and MERS-CoV.

Evaluation of Antibody-Dependent Enhancement of SARS-CoV Infection in Rhesus Macaques Immunized with an Inactivated SARS-CoV Vaccine. Evaluation of antibody-dependent enhancement of SARS-CoV infection in rhesus monkeys immunized with inactivated SARS-CoV vaccine.

Immunodominant SARSCoronavirusEpitopes in Humans Elicited both Enhancing and Neutralizing Effects on Infection in Non-human Primates.  The dominant epitope of SARS-CoV in the human population can cause both neutralizing antibody response and infection enhancement effects in non-human primates.

Antibody-dependent infection of human macrophages by severe acute respiratory syndromecoronavirus. Antibody-dependent SARS-CoV infects human macrophages.

Anti-spikeIgGcausessevereacutelunginjurybyskewingmacrophage responses during acute SARS-CoVinfection. IgG antibodies against S protein cause acute lung injury in acute SARS-CoV infection by shifting the macrophage response (2019 article, Hong Kong University Chen Zhiwei/Yuan Guoyong team)

ImmunizationwithinactivatedMiddleEastRespiratorySyndromecoronavirusvaccineleadstolungimmunopathologyonchallengewithlivevirus. The inactivated vaccine against MERS-CoV can cause lung pathological damage after virus attack.

Briefly introduce the JCI insight article summary of the 2019 Hong Kong University Chen Zhiwei/Yuan Guoyong team. The vaccine used in this article is a recombinant Ankara strain (MVA) of vaccinia virus. 

The characteristic of this viral vector is that it can only replicate once after entering the cell. The genome is incomplete, and a complete progeny virus cannot be produced. Therefore, the effect of inducing the body's immune response is better, but it is very safe. 

The previous replicating live attenuated smallpox vaccine (vaccinia vaccine) will cause serious side effects in many people, and there will be no small skin damage at the site of the vaccination.

MVA itself, as a smallpox prevention vaccine, has completed phase III clinical trials. The article was published on NEJM in November 2019 and was licensed in Bavaria, Germany.


The JCI insight article of Chen Zhiwei/Yuan Guoyong’s team first used the MVA control vaccine and the SARS-CoV-S protein-expressing vaccine to vaccinate 8 monkeys each. 

In the eighth week, the SARS-CoV nasal cavity was challenged, the ninth and thirteenth weeks Perform pathological examinations, and begin to take blood after immunization to test neutralizing antibody titer and viral load.


Infographics on designing a new coronavirus vaccine to avoid the ADE effect

It can be seen that the neutralizing antibody in the serum of the immune group reached a high titer in the second week and remained until after the challenge (5 lower left, blue line). 

The neutralizing antibody of the control group only started to rise after the challenge (5 lower left, black line).


Correspondingly, the viral load of the throat swab was also much lower in the vaccine group than in the control group (5 times, solid blue circles vs. hollow black circles). 

However, the pathology score of the lung organs is rather heavier in the vaccine group. 


What is adoptive immunization?

The procedure of adoptive immunization was that two complete control monkeys were injected intravenously with 200 mg of irrelevant antibody IgG control. 

The experimental group used two doses of antibodies against SARS-CoV-S, 5 mg and 200 mg respectively. 

Two days after the injection, SARS-CoV was challenged in the nasal cavity. Pathological examinations were performed 2 days and 21 days after the challenge.


It can be seen that the neutralizing antibodies of the three groups of serum are clearly distinguished.

The high-dose group (5 lower left, dark blue line) has high inhibition, and the low-dose group (5 lower left, light blue line) first low and then high, and The control group only started to rise a week after being exposed to the virus (5 lower left, black line).


But similar to the vaccine immunization group, the pathology scores of the lung organs in the S antibody group (regardless of the dose) are heavier than the control (5 lower right, solid dark or light blue column vs. hollow black column).


This part of the results shows that antibodies against S are the reason for the increase in the pathological indicators of animal lungs after vaccine immunization in monkeys.


What is the principle of the Coronavirus ADE effect?

Or introduce the JCI insight article of the 2019 Hong Kong University Chen Zhiwei/Yuan Guoyong team.


The previous results indicate that the antibodies against S are the cause of the increase in the pathological indicators of the animal lungs after the vaccine immunized monkeys, and then the exploration of the mechanism began:


Anti-S-IgG induced severe lung injury during acute SARS-CoV infection

Anti-S-IgG induced severe lung injury during acute SARS-CoV infection 

S-IgG failed to prevent SARS-CoV lower respiratory tract infection and amplified IMM infiltration and accumulation in the lungs.

S-IgG resistance does not prevent SARS-CoV from infecting the lower respiratory tract and amplifies the inflammatory mononucleus in the lungs. Infiltration and accumulation of macrophages (IMM).

Alveolar monocytes/macrophages assumed a wound-healing function as early as 2 dpi in macaques not treated with S-IgG. 

In monkeys not treated with S-IgG, alveolar monocytes/macrophages assumed a wound-healing function as early as 2 dpi Has wound healing function.

S-IgG treatment skewed wound-healing macrophage response in the lungs during acute SARS-CoV infection.

S-IgG treatment skewed wound-healing macrophage response in the lungs during acute SARS-CoV infection.

Onset of an antibody response prior to viral clearance is associated with abrogated wound healing.


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