SARS-CoV-2 infection and immune responses

Abstract

The recent pandemic caused by the SARS-CoV-2 virus continues to be an enormous global challenge faced by the healthcare sector. Availability of new vaccines and drugs targeting SARS-CoV-2 and sequelae of COVID-19 has given the world hope in ending the pandemic. However, the emergence of mutations in the SARS-CoV-2 viral genome every couple of months in different parts of world is a persistent danger to public health. Currently there is no single treatment to eradicate the risk of COVID-19. The widespread transmission of SARS-CoV-2 due to the Omicron variant necessitates continued work on the development and implementation of effective vaccines. Moreover, there is evidence that mutations in the receptor domain of the SARS-CoV-2 spike glycoprotein led to the decrease in current vaccine efficacy by escaping antibody recognition. Therefore, it is essential to actively identify the mechanisms by which SARS-CoV-2 evades the host immune system, study the long-lasting effects of COVID-19 and develop therapeutics targeting SARS-CoV-2 infections in humans and preclinical models. In this review, we describe the pathogenic mechanisms of SARS-CoV-2 infection as well as the innate and adaptive host immune responses to infection. We address the ongoing need to develop effective vaccines that provide protection against different variants of SARS-CoV-2, as well as validated endpoint assays to evaluate the immunogenicity of vaccines in the pipeline, medications, anti-viral drug therapies and public health measures, that will be required to successfully end the COVID-19 pandemic.

Keywords: COVID-19; SARS-CoV-2; antibodies; immunopathology; inflammation; vaccines.

Figure 1.. Number of Clinical Trial studies occurring across the world depicting widespread research on COVID-19 therapeutics as posted on ClinicalTrials.gov (23^rd February 2023). Ongoing clinical trials related to COVID-19 vaccine development (A) and COVID-19 drug treatment (B) across regions. Search terms included COVID-19 vaccine and COVID-19 drug treatment respectively.

Figure 2.. Genomic surveillance of the proportions of circulating Omicron sub-variants in the United States (07/02/2022 to 10/01/2022). Lineages are VOC sub-variants of Omicron or Delta strain in USA and circulating above 1% nationally in at least one week period. *Other represents the aggregation of lineages which are circulating <1% nationally during all weeks displayed.

Figure 3.. Immune response of natural infection with SARS-CoV-2 and vaccine-induced response against infection. The innate response to SARS-CoV-2 (left) is initiated by infection of the host cell expressing the ACE2 receptor by SARS-CoV-2 and recognition by pattern recognition receptors including the RIG-I-like receptor (RLR), and melanoma differentiation-associated gene-5 (MDA5). Successful activation of MDA5 leads to the downstream production of type I interferons (IFN) and cytokines. The produced cytokines and chemokines can recruit and activate inflammatory cells including monocytes and macrophages. IFNs bind to IFNAR on its own cell and neighboring cells. SARS-CoV-2 proteins can evade the immune response by inhibiting the action of MDA5. Adaptive responses (middle) are characterized by activated T helper cells (CD4+ Th cells) assisting B cell activation resulting in antibody production. Neutralizing antibodies mainly work to block viral entry into host cells. Activated CD8 T cells (cytotoxic CD8+ T cells) recognize viral antigens presented by the host major histocompatibility complex I (MHC I) molecules in infected cells and kill the infected cell by releasing cytotoxins granzyme and perforin. Vaccine-induced responses are targeted to specific proteins from the virus which, if effective, leads to protective adaptive immunity. In the example of mRNA vaccines (Right), administered mRNA is taken up by a cell and translated to produce the Spike protein. Antigen presenting cells such as dendritic cells, uptake the protein and process it to prime T cells.

Figure 4.. The immune responses driven by different COVID-19 vaccine platforms. The mRNA platform by Moderna and Pfizer administer mRNA encoded for spike protein, for cellular uptake and translation of the mRNA to protein. The produced spike protein largely leads to activation of B cells to plasma cells for neutralizing antibody production. The viral vector platform used by AstraZeneca and Johnson & Johnson engineer adenovirus vectors carrying genomic material for the spike protein that transfects cells inserting the DNA for production of the protein. Similarly, this leads to B cell and plasma cell production. Inactivated virus platforms used by Sinovac and Sinopharm chemically degrade the genomic material of SARS-CoV-2. Once administered the inactivated virus acting as an immunogen can be taken by antigen presenting cells such as dendritic cells that can lead to the downstream activation of T cells and B cells, and the production of antibodies. The protein subunit vaccine by Novavax includes the nanoparticle composed of spike proteins and the saponin-based Matrix M adjuvant that can be detected and presented by the APC, dendritic cell, for T cell and B cell activation.