Immune response in COVID-19: what is next?

Abstract

The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.

Fig. 1. The mutation landscape of the spike proteins of selected SARS-CoV-2 variants.

The top panel shows the mutation profiling and prevalence of spike proteins across 13 SARS-CoV-2 lineages that received a Greek designation and 7 recently emerged SARS-CoV-2 variants with public attention. The parent lineages of the new SARS-CoV-2 variants were depicted in the table. The bottom images show the side and top view of the 3-dimension structure for the Omicron spike protein with mutation amino acids mapped [170]. Note: the insertion mutations are not profiled.

Fig. 2. NETosis.

Immune fluorescence detects the NET components citrullinated Histone H3 and neutrophil elastase (both green) as well as extranuclear DNA (DAPI; red) in the vessels of a central human lung. Note, the intravascular DNA-enzyme-histone complexes fill the whole lumen of many vessels (some of the clogged vessels are marked with asterisks).

Fig. 3. Targeting type I IFN production by SARS-CoV-2.

a Schematic demonstration of the viral proteins. Those marked with asterisks were reported to regulate IFN production. b IFN production signaling pathways targeted by SARS-CoV-2 proteins. SARS-CoV-2 infection induces a delayed type-I IFN response, which is underlaid by the inhibited RIG-I/MDAS-MAVS signaling at the early stage and the cytoplasmic-micronuclei-activated cGAS-STING signaling at the late stage.

Fig. 4. The SARS-CoV-2 Omicron variant with high mutational burden exhibits increased antibody evasion.

In a typical SARS-CoV-2 infection, the virus presented in the lymphoid organs evokes T helper cells which facilitate the activation of both humoral and cellular immune responses. Antibodies and effector CD8⁺ T cells were then released into circulation. Antibodies neutralize virus and eliminate infected cells through ADCC. CD8⁺ T cells kill infected cells through cytotoxicity. However, as for SARS-CoV-2 Omicron, the effects of antibody-mediated protection were dramatically reduced, which is possibly brought about by over 30 mutations in the genes encoding spike proteins. There are 3 possibilities explaining the sudden appearance of Omicron: 1. Omicron may have been transmitted within a neglected population without sufficient medical surveillance; 2. It could be outcompeted in a patient with chronic COVID-19 infections; 3. It may be zoonotic and just spilled back into human.

Fig. 5. The figure shows the SARS-CoV-2 spike protein receptor-binding domain (RBD) bound by class 1/2 (blue), class 3 (orange) and class 4 (green) neutralizing antibodies.

The potency and breadth of neutralization across SARS-CoV-2 variants are denoted for each antibody class [–173].

Fig. 6. Heterologous prime-boost strategies with inactivated vaccine (1^st) and mRNA vaccine (2^nd) provide strong protections against SARS-CoV-2.

Inactivated SARS-CoV-2 vaccine reserves all viral proteins for immune recognition. Once immunized, these antigens could elicit a T helper pool broadly targeting SARS-CoV-2 proteins. mRNA vaccine, on the other hand, elicits strong humoral and cellular immune responses against the SARS-CoV-2 variants in individuals who previously received the inactivated vaccine. We hypothesized that the T helper pool primed by inactivated vaccine could be activated upon mRNA vaccination, which facilitates the building of stronger immune response and memory.