ANTIBODY DEPENDENT ENHANCEMENT – WILL IT HAMPER THE COVID – 19 VACCINE DEVELOPMENTS?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged as a zoonotic the virus in the late 2019 and is the causative agent of COVID-19. Exposure to SARS-CoV-2 can result in a range of clinical outcomes, varying from asymptomatic infection to severe acute respiratory distress and death. SARS-CoV-2 has spread globally and was declared as a pandemic on March 11, 2020, by WHO. As of July 23, 2020, more than 15 million people globally have been infected with more than 6,23,66 deaths. No vaccines have been approved for the prevention of COVID-19. There are currently more than 137 candidates undergoing preclinical development and 23 in early clinical development, according to the WHO. Coronaviruses are enveloped; positive-sense single-stranded RNA viruses with a glycoprotein spike on the surface, which mediates receptor binding and cell entry during infection. The roles of the spike protein in receptor binding and membrane fusion make it an attractive vaccine antigen.

How the coronavirus the
vaccine will work?

Background on Antibody-Dependent Enhancement (ADE)

ADE is also known as immune enhancement or disease enhancement. It involves in the cascade of events whereby viruses may infect susceptible cells via interaction between virions complexed with the antibodies (complement component) and Fc (complement receptors) respectively which leads to the amplification of their replication and increases the infectivity and the virulence.

In the case of ADE, the normal mechanisms of antigen-antibody complex clearance fail and instead it provides an alternative route for host cell infection. ADE has been reported in – vitro in Ebola virus, Zika virus, HIV, SARS and MERS. ADE has been linked to the development of cytokine storm syndrome, which occurs in the most severe cases in the SARS, MERS and the current COVID-19 infections. ADE assays are used as a valuable tool to assess the capacity of antibodies to enhance the secondary infection related to SARS-COV-2 and provide valuable insights into the pathogenesis of the covid-19 infections as well as the vaccine against the coronaviruses.

Viruses can acquire mutations that change the surface proteins, leading to distinct viral serotypes. After getting infected with one viral serotype, the host will produce antibodies to that particular serotype and this protects from the reinfections. The development of antibodies to one serotype doesn’t protect from the second serotype, even if the antibodies produced to the second serotype has the non-neutralizing capacity of the antibodies. Antibodies produced against one viral serotype not only fail to protect against the second viral serotype but actually do harm. These antibodies drive uptake of a newly infecting serotype into immune cells, promoting viral replication and similarly exacerbate the immune response.

ADE and Dengue Virus (DENV)

Dengue is one of the examples of an ADE seen in communities with multiple viral strains circulating. Antibodies developed against the first viral serotype only binds to the next serotype without neutralizing it. DENV can use Fc receptor to infect cells. Immune cells like macrophages dock onto tail ends of the antibodies using the Fc receptor. The antibodies that simply bind to the pathogens will actually end up helping the virus to enter the macrophages to detect the cells.

It was not just the non – neutralizing characteristic of the antibodies but also the neutralizing antibodies which were not numerous enough to block all the key proteins across the virus surface can cause ADE.

ADE and coronavirus           

Coronaviruses mainly infect humans that cause the common cold, so anti–coronavirus antibodies are likely to be present in many people. Several groups have suggested that prior infection with non – SARS coronaviruses promoted severe SARS in 2002–2004. Now the ADE is speculated to be responsible for severe COVID–19. Prior to the infection resulted in a sub–neutralizing level of coronavirus antibodies that enhances SARS–COV–2 replication and promotes the inflammation. It is theoretically possible, but there is little evidence for this so far and in principle, some COVID–19 patients could develop antibodies that don’t neutralize or produce neutralizing ones at insufficient concentrations and then develop severe symptoms if they get re-infected for the second time. But a handful of reported COVID–19 re-infections has found due to flawed tests. In the U.S, patients who received an antibody-containing blood plasma transfusion from COVID-19 survivors, the treatments did not make the situations worse, which is against the ADE.

ADE’s role in vaccine development

Even though it is a theoretical concept, ADE is a possibility that vaccine tested against flu-like infections, peritonitis, and coronavirus disease in cats. The vaccinated kittens died much sooner than the unvaccinated ones. One explanation for this was the proposed ADE; this could have produced antibodies that target parts of the virus without blocking the specific site on its spike proteins which it uses to infect cells – the Receptor Binding Domain (RBD).

The cellular entry of SARS-COV-2 occurs by the interaction between the receptor-binding protein in the spike region (RBD) and the angiotensin-converting enzyme₂ (ACE₂) binding cell receptor. If the immune system gives with the only choice of making an antibody to the RBD, it can drastically limit the possibility of ADE.

ADE is a concern for the monoclonal antibodies (m Abs) too, because the antibodies that fail to neutralize the virus also facilitate the virus entry into the cells. An antibody lacking Fc receptor can’t bind the macrophage and thus can’t cause ADE. That is why some companies are advancing monoclonal antibodies which lack the Fc region. A successful vaccine for prevention of SARS-CoV-2 infection probably needs to incorporate T-cell epitopes to induce a long term memory T-cell immune response to the virus.

The recent Oxford vaccine was found to be safe, tolerated and it produced a humoral immune response to both the spike and the RBD by day 28 of the post-prime and cellular immune response (T-cell) were induced by day 14. Neutralizing antibodies were induced in all participants after the second dose of the vaccine. However, a boost in the cellular responses was not observed following the second dose.

The degree of ADE in coronavirus vaccine is unknown. There are several ongoing clinical trials to check the safety, tolerability and immunogenicity of the coronavirus vaccines. These developing vaccines may give a temporary wave against the SARS-COV-2 as till now there is no study pointing out how long these neutralizing antibodies will be present in our body once we are vaccinated. Neutralizing antibodies from the coronavirus the vaccine will help the host body to develop memory T-cell immune responses which protects from the viral attack of the primary serotype. If in case of an entry of the second viral serotype, the neutralizing antibodies from the vaccine will not be able to produce antibodies against the new antigen from the second viral serotype and hence results in the exacerbated immune responses from the second viral serotype as well as from the neutralizing antibodies of the primary viral serotype. Once the effect of the coronavirus vaccine decreases with the time, the amount of these neutralizing antibodies also gets depleted which point outs the risk for an ADE as well as the re-infection from the second serotype and thus further studies are mandatory to avoid ADE and re-infections. Frequent booster doses of the vaccine can reduce the risk for the re-infections and the ADE as it can boost up the level of the neutralizing antibodies, if so the dose of the booster vaccines and the frequency of administration should be taken into consideration, if not in future if the ADE as well as the re-infection from the coronavirus vaccine can lead to an exacerbated immune response for the vaccinated population than the non-vaccinated ones.

Ms. Helan Kurian, Pharm.D Intern