![]() , Key figure), which can exhibit a rather wide tissue/organ distribution (discussed later). In mRNA vaccines, which are characterized by relatively rapid prototyping and manufacturing on a large scale, the S protein-encoding mRNA is delivered via lipid nanoparticles (LNPs) to human cells that produce the mature viral protein or related antigens ( Figure 1 įollowing an unprecedented effort of biomedical research and mobilization of resources, two mRNA vaccines – namely BNT162b2 (Comirnaty TM) from Pfizer-BioNTech and the mRNA-1273 of Moderna (encoded antigen: SARS-CoV-2 S protein of the Wuhan-Hu-1 strain) – were the first to receive FDA emergency use authorization. These immune responses are age- and gender-dependent and may either mount poorly in a background of genetic causes and pre-existing morbidities, or become very intense and essentially uncontrolled in severe disease leading to ARDS and systemic failure. As SARS-CoV-2 initially infects the upper RS, defensive immune responses start to develop at respiratory mucosal surfaces, and this is followed by systemic immunity. SARS-CoV-2 infection in healthy individuals triggers innate as well as adaptive immune system responses, that is, CD4 + and CD8 + T cells and antibodies, including neutralizing antibodies (NAbs) produced by terminally differentiated B cells, which altogether suppress the extent of infection. In a recent trial, in which young people were intentionally exposed to a low dose of SARS-CoV-2, nearly half of the participants did not become infected, some were asymptomatic, and those who developed COVID-19 reported mild to moderate symptoms, including sore throats, runny noses, sneezing, and loss of sense of smell and taste fever was less common, and no one developed a persistent cough. It has been postulated that higher pediatric innate interferon responses restrict viral replication and disease progression. ![]() The risk for severe COVID-19 increases significantly with age or pre-existing comorbidities, and younger individuals have a substantially lower risk – even compared to influenza infection – for developing severe COVID-19. A minority will require hospitalization this is due to severe symptoms which develop due to extensive inflammation, a process often referred to as a ‘cytokine storm’, causing ARDS which may be accompanied by viremia and can lead to systemic multiorgan collapse. In most of SARS-CoV-2-infected carriers the virus is contained in the upper RS, resulting in either no symptoms or mild symptoms. SARS-CoV-2 infection of human cells proceeds via its binding to the cell surface protein ACE2 through the RBD of its protruding S glycoprotein which remains in a metastable prefusion state through the association of subunits 1 (S1) and 2 (S2) via noncovalent interactions the infection process is also facilitated by host proteases. If systemic collapse and death are avoided, the postulated direct virus ‘attack’ – or indirect effects due to cytokine storm or imbalance of the renin–angiotensin system (RAS) – causing multiorgan damage, possibly foster systemic defects which cause a chronic condition (referred to as long COVID-19) which is independently associated with the severity of the initial illness. This may be due to the broad expression of its receptor angiotensin-converting enzyme 2 (ACE2) in several cell types and tissues which results in an expanding tropism of SARS-CoV-2 for various critical organs (heart, pancreas, kidneys, etc.). ARDS may then lead to organ damage beyond the RS because of micro-/macro-thromboembolism, hyperinflammation, aberrant complement activation, or extended viremia. ![]() In patients with severe disease, infection of airway and lung tissues may cause pneumonia and excessive inflammation which can lead to acute respiratory distress syndrome (ARDS) (see Glossary) ( Box 1). Although SARS-CoV-2 may also circulate in the gastrointestinal tract, being a respiratory virus, the virus itself or its related antigens will not, in most cases, impact tissues and organs other than the respiratory system (RS) ( Box 1). Nevertheless, for the majority of SARS-CoV-2-infected individuals, COVID-19 will remain asymptomatic or only mildly symptomatic. ) and has resulted in millions of deaths worldwide. Fighting the COVID-19 pandemic with SARS-CoV-2 S protein-encoding mRNA vaccinesĬOVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ( Box 1 ![]()
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