How Do Anti-SARS-CoV-2 mRNA Vaccines Protect from Severe Disease?

Abstract

COVID-19 pathogenesis develops in two phases. First, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 spreads within the epithelial cells of the mucosa of upper and, possibly, lower respiratory tracts. While the virus dissemination can be controlled by an emerging adaptive host immune response, if the virus diffuses to the pulmonary alveoli, a potentially lethal mechanism can arise in the second phase. It consists of an uncontrolled burst of cytokines/inflammatory factors (i.e., cytokine storm), leading to the insurgence of respiratory symptoms and, consequently, multi-organ failures. Messenger (m)RNA-based vaccines represent the most innovative approach in terms of prophylaxis against SARS-CoV-2-induced disease. The cumulating data indicate that the response to mRNA vaccines is basically ineffective to counteract the viral replication in the upper respiratory tracts, while showing efficacy in containing the development of severe disease. Considering that the antiviral immunity elicited by intramuscularly delivered mRNA vaccines is expected to show similar quantitative and qualitative features in upper and lower respiratory tracts, the different outcomes appear surprising and deserve accurate consideration. In this review, a still unexplored mechanism accounting for the mRNA vaccine effect against severe disease is proposed. Based on well-established experimental evidence, a possible inhibitory effect on alveolar macrophages as a consequence of the diffusion of the extracellular and/or cell-associated Spike protein can be envisioned as a key event counteracting the cytokine storm. This benefit, however, may be associated with defects in the immune functions of macrophages in other tissues whose possible consequences deserve careful evaluation.

Induction of SARS-CoV-2 N-specific CD8+T cell immunity in lungs by engineered extracellular vesicles associates with strongly impaired viral replication

“…The efficacy of anti-SARS-CoV-2 vaccines would be the result of promptness, potency, and durability of the immune response evoked in both upper and lower respiratory tracts. In humans, current mRNA-based vaccine have been shown to induce immune responses quantitatively limited and qualitatively incomplete in both tracts [28]. Second-generation vaccines are expected to overcome such limitations by focusing their immunogenic activity at pulmonary level.…”

Inclusion of deuterated glycopeptides provides increased sequence coverage in hydrogen/deuterium exchange mass spectrometry analysis of SARS‐CoV‐2 spike glycoprotein

“…Spike's binding to human angiotensin‐converting enzyme 2 (ACE2) is critical for SARS‐CoV‐2 penetration of a host cell and initiation of infection 3–5 . Spike is the surface antigen and target of all currently available COVID‐19 vaccines, 6 and improved understanding of spike's structures and functions is likely to result in more effective SARS‐CoV‐2 vaccines 7 …”

“…1,2 Spike's binding to human angiotensin-converting enzyme 2 (ACE2) is critical for SARS-CoV-2 penetration of a host cell and initiation of infection. [3][4][5] Spike is the surface antigen and target of all currently available COVID-19 vaccines, 6 and improved understanding of spike's structures and functions is likely to result in more effective SARS-CoV-2 vaccines. 7 Spike trimers engage in several dynamic structural changes related to binding ACE2, cleavage by protease TMPRSS2, unfolding their S2 domains, and finally refolding to pull viral and target cell membranes into juxtaposition.…”

Impact of Treatment with Anti-CD20 Monoclonal Antibody on the Production of Neutralizing Antibody Against Anti–SARS-CoV-2 Vaccination in Mature B-Cell Neoplasms

“… 1 , 2 Once the mRNA vaccine encapsulated in lipid nanoparticles is taken up by human cells, such as dendritic cells or myocytes, it is translated into a viral spike protein antigen that stimulates B cells to produce a neutralizing antibody (nAb) against the spike protein, which prevents viral infection and also induces cytotoxic T cells that acquire the ability of cellular immune responses against infected cells. 3 , 4 Therefore, immunocompromised patients and patients receiving treatment with an immunosuppressive moiety are generally at high risk for impaired antibody response against anti–SARS-CoV-2 vaccination. 5 , 6 Among the various settings of immunosuppressive treatment, therapeutic approaches that deplete B cells or impair B-cell function, such as an anti-CD20 monoclonal antibody (MoAb) or inhibitors for B-cell receptor signaling, have especially attracted attention as risk factors for severe COVID-19 in patients with B-cell malignancies, including B-cell lymphomas (BCLs) and chronic lymphocytic leukemia.…”