Could N protein-based COVID-19 vaccines hinder SARS-CoV-2's NK cell inhibition?

When a virus invades an individual, both innate and adaptive immunity play crucial roles. The successful viral pathogens can antagonize these immune pathways with genes that inhibit the key players in the immune system.

The coronavirus disease 2019 (COVID-19) pandemic is caused by the novel beta coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is known that the SARS-CoV-2 antagonizes interferon (signaling proteins released in response to viral infection) induction. However, understanding how SARS-CoV-2 antagonizes the cellular immune response is as yet unclear.

Upon SARS-CoV-2 infection, what are the changes occurring on the surface of the host cell? To address this, and a team of researchers undertook a study exploring the natural killer (NK) cells and their role during a SARS-CoV-2 infection. The team’s study was recently released on the bioRxiv* preprint server.

Using a proteomic approach, the researchers systematically analyzed the changes happening in the receptors on the cell surface. They found that the SARS-CoV-2 remodeled the plasma membrane by downregulating the multiple cell surface immune ligands.

The researchers found that the SARS-CoV-2 mediated down-regulation of NK-activating ligands (Nectin-1, B7-H6, ULBP2 and MICA) on the SARS-CoV-2-infected lung epithelial cell surface; with no effect on cell surface MHC-I. Surprisingly, they also observed robust antibody-dependent NK cell activation (ADNKA) to be independent of the spike antibodies, although spike-specific antibodies played a dominant role in the virus neutralization.

The researchers reported that the spike-specific antibodies played only a minor role in ADNKA compared to antibodies to other viral proteins, including ORF3a, Membrane, and Nucleocapsid. In this study, they reported that following natural infection, the ADNKA responses are dominated by non-spike antibodies (nucleocapsid, membrane and ORF3a). And the spike-specific antibodies following vaccination are found to be weak mediators of ADNKA.

The researchers reported that the ADNKA induced after vaccination was: 1) focused solely on the spike, 2) weaker than ADNKA following natural infection, and 3) not boosted by the second dose.

Despite high levels of antibody binding, and a substantial ability to activate ADCC when expressed in isolation, spike may be a relatively poor ADCC target in the context of natural infection. ”

Spike antibodies play a crucial role in the defense against the SARS-CoV-2 infection. The spike is a transmembrane glycoprotein present on the surface of the SAR-CoV-2; it binds to the human host angiotensin-converting enzyme 2 (ACE2) receptor, enabling viral entry. Most of the antivirals and vaccines are designed to target the spike structure and sequence.

When viruses interfere with the cellular immune response, they downregulate the MHC-I inhibiting CD8+ T-cell mediated cytotoxicity. When this happens, the NK cells take over. The NK cells are lymphocytes, with both cytotoxicity and cytokine-producing effector functions. They actively kill tumor cells or cells infected with microbes - discriminating ‘target cells’ from other self and healthy cells.

It is known that to limit the NK cell activation, some viruses have evolved to manipulate the levels of NK activating ligands, thus reducing the NK cell-mediated control of the immune system. These ligands (such as MICA, MICB and ULBP2) are expressed on the surface of target cells in response to stress, infection, or transformation. This calls for NK cell-mediated activation leading to the target cell’s death.

The NK cells can also operate via antibody-dependent NK activation (ADNKA), which leads to antibody-dependent cellular cytotoxicity (ADCC). ADCC is an important function in COVID-19 and is strongly induced following infection with SARS-CoV-2. Because lack of ADCC is linked strongly with severe COVID-19, the virus variants may therefore evolve to evade ADCC responses as well as neutralizing responses. This supports an important role for ADCC in the protection against COVID-19.

While viral entry glycoproteins are often found on the infected cell surface and can mediate ADCC when expressed alone, other viral proteins may be the principal mediators of ADCC during infection.”

Contrastingly, in this study, the researchers found that the virus cannot actively antagonize adaptive cellular immunity. The researchers demonstrated that this is evident from 1) the lack of significant MHC-I cell surface downregulation, 2) the emergence of ADNKA with humoral immunity, and 3) the inability of infected cells to bind human IgG from seronegative donors (i.e., the virus does not encode Fc receptors as ADNKA decoys).

Given the observations from this study, the researchers pointed out that it is significant that the spike-vaccine generated antibody responses were poor ADNKA inducers. They recommended the addition of other viral proteins (such as nucleocapsid) to vaccines, which would engage a wider range of immune effector pathways. This approach might improve efficacy against both viral transmission and disease, resulting in vaccines that are more resistant to viral variants containing mutations that diminish antibody neutralization, the researchers anticipate.

The researchers also recommended studying if the coronaviruses evade innate and adaptive immunity in their original bat host and whether this contributes to their persistence in that species.

In conclusion, the researchers have demonstrated in this study that the SARS-CoV-2 remodels the plasma membrane proteome, modulates multiple NK cell ligands, and inhibits NK cell activation. However, they reported that the NK-cell evasion is overcome by antibody-dependent activation (ADCC). Thus the researchers highlighted overcoming the viral immune evasion through the antibody-dependent mechanisms, suggesting that in addition to neutralizing the virus, SARS-CoV-2 antibodies may aid virus clearance through ADCC

The study brings out the multiple proteins other than spike that could be major contributors to the ADCC during the SARS-CoV-2 infection. Also, it is important to note that the monoclonal anti-spike antibodies only weakly mediate ADNKA despite binding strongly to infected cells.

Vaccines may be redesigned with the addition of antigens such as nucleocapsid, to recruit additional effector mechanisms. This may further reduce any reduction in the vaccine efficacy that may be caused due to mutation of the spike in novel variants. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design, the researchers write.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Ramya Dwivedi

Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.


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