ADE: Concerns about covid vaccine

Undeniably the most reliable and effective ways to protect humanity from SARS-CoV-2 infection are the vaccines and treatment based on immunotherapy approaches like therapeutic antibodies. Almost all the vaccines currently in use, or development stage, target the Spike protein of SARS-CoV-2. The COVID-19 vaccine works by preparing the host immune system to combat the future re-infections of SARS-CoV-2. Once inside the body, the components in the vaccines are recognized by the host immune system and in turn, elicit the immune response, the most prominent being the generation of antibodies against the virus and memory T and B cells. The antibodies are the primary molecules responsible for the protection which work by binding and neutralizing the virus. Generally, the antibodies are Y shaped, with two arms responsible for antigen-binding (Ab) region and the tail for receptor binding region called fragment crystallizable (Fc). Generation of this antibody response is thus the first cardinal property of any vaccine to be efficacious. The other being that the antibodies generated should possess both robust binding and neutralization potential. History teaches us that even though some vaccines may elicit a robust antibody binding, some of these antibody responses may not be effective. The reason is that some of these antibodies, through binding to the target virus, may not neutralize them in the process and that is where the problem may arise. In the following sections, I will explain terms like antibody reactivity, antibody neutralization, antibody-dependent enhancement, and why SARS-CoV-2 vaccines may always be a good option irrespective of some of the limitations which may arise in future.

What are binding antibodies?

Binding antibodies are the antibodies which attach to the target antigen expressed by a pathogen like SARS-CoV-2. These antibodies may or may not be neutralizing. Depending upon the features present in the Fc region of the antibody, it can either neutralize the target antigen and remove the pathogen from the body or in some instances it can help the pathogen to enter into the cells, replicate and worsen the disease condition in a process called antibody dependent enhancement (ADE), discussed below. Thus, while developing the vaccines or antibody-based therapies, a rigorous process of assays is performed to ensure that the antibodies have sufficient neutralization potential. Many viruses like Dengue virus, Zika virus, and Respiratory Syncytial virus have been shown to generate non-neutralizing antibodies and so is the case for the vaccines which have been tried for these viruses. Thus, one major reason that many vaccines cannot make it to the clinic is that they may generate non-neutralizing antibodies.

What are neutralizing antibodies?

Only a small subset of antibodies that bind to the target pathogen are neutralizing antibodies (Nabs). Nabs are naturally produced by the body in response to infections or after vaccination. The Nabs are specialized in neutralizing the specific antigen expressed by the pathogens such as SARS-CoV-2. These Nabs thus prevent the binding and attachment of pathogens to target cells and subsequently prevent the pathogen entry into the cells. In simple terms, the antibody neutralization means that the antibody should (1) bind to the target pathogen, and (2) then neutralize the pathogen to render it ineffective.

Do SARS-CoV-2 vaccines generate neutralizing antibodies?

The clinically approved and currently in-use COVID-19 vaccines have been shown to develop a robust Nab response. These antibodies, besides binding to the SARS-CoV-2, also neutralizes the virus effectively. SARS-CoV-2 Nabs act against various regions of the spike protein, especially against the receptor binding domain (RBD). After they recognize and attach to the virus, these antibody-antigen complexes are subsequently cleared by white blood cells and eliminated from the body without eliciting any complications.

The potency of the vaccines is measured by looking at the neutralization potential of the antibodies generated. Almost all the approved vaccines for SARS-CoV-2 have been shown to generate robust antibody responses which besides binding to the target pathogen, exhibit potent neutralization potential. In addition to the vaccine generated Nabs, some of therapeutic antibodies currently being used for the treatment of COVID-19 exhibit potent neutralization potential, as per scientific studies. One recently approved antibody cocktail (Casirivimab and Imdevimab) developed by Regeneron, USA and distributed by Roche, USA and Cipla, India has been approved for the treatment of COVID-19. However, it has been shown that in some instances the therapeutic antibodies or antibodies generated by the vaccines may worsen the disease condition through a process called antibody dependent enhancement.

What is antibody dependent enhancement?

One potential limitation with vaccines is the ADE which may exacerbate the disease condition. Earlier experiences have shown that ADE is a concern with many respiratory viruses such as syncytial virus (RSV), SARS-CoV-1 and MERS, and is categorized in a broader term of enhanced respiratory disease (ERD). Under certain circumstances the binding antibodies attach to the virus, but cannot neutralize them. These non-neutralizing or sub-neutralizing antibodies may pose complications by two processes: (1) Instead of eliminating from the body, the non-Nabs may enhance the virus uptake by the cells. The virus is taken up by phagocytic cells like macrophages (these are specialized cells which engulf the pathogens) which express specific receptors that bind to the Fc part of the antibody. This will result in enhanced replication of virus inside these cells and then dissemination leading to an exacerbation of the disease condition. (2) The other way by which the non-Nabs may exacerbate the disease is by forming immune complexes. These antigen-antibody immune complexes activate robust proinflammatory response and thus worsen the disease condition. This pathway is yet to be comprehensively explored for antibodies against SARS-CoV-2 generated by vaccines or therapeutic antibodies.

ADE was one of the reasons for earlier failure of vaccines against Dengue virus, Zika virus, and SARS-CoV-1. The animals which were vaccinated showed robust ADE than those that were not and developed severe disease conditions. As of now, no such complications have been reported with the approved COVID-19 vaccines. Findings till date exclude the possibility of ADE of SARS-CoV-2 by macrophages. Notably, these cells have been shown to be replication deficient for SARS-CoV-2, that means even if the virus is taken up by these cells, the virus will not replicate in these cells.

As of now, there is no major concern of ADE associated with the approved COVID-19 vaccines but comprehensive studies are warranted to find the long-term impact. Especially since some of the vaccines against other diseases like dengue virus, Zika virus, and other respiratory viruses generate non-neutralizing antibodies, the concern regarding COVID-19 vaccines is valid. However, none of the studies have yet demonstrated any such concern with the approved COVID-19 vaccines. Further, in case of therapeutic antibodies, the Fc portion of the antibodies could be engineered with mutations that abrogate ADE. In future, some of these concerns like ADE may arise, but one has to remember that benefits of COVID-19 vaccine will always outweigh any complications.

Dr. Tanveer Ahmad is Assistant Professor, Jamia Millia Islamia