Several S1-sACE2 complexes, free S1 fragments or sACE2 are likely released in bloodstream of COVID-19 infected patients by spike and ACE2 receptor cleavages. As already mentioned, circulating sACE2 protein shedding independent on virus contact has been also described either spontaneously when ACE2 transcription is upregulated or upon cytokine activation; it is therefore likely that in the bloodstreams ACE2 proteins are available to bind to both free S1 fragments and SARS-CoV-2 particles, finally leading to more and more S1-sACE2 and SARS-CoV-2-sACE2 complexes bearing enzymatic active sACE2 (see Figure later in the Section 4). Of note, SARS-CoV-2-sACE2 complexes, sequestrating sACE2, can drive part of the sACE2 systemic activity and concentrate it locally where the organs possess cells expressing ACE2 on their surface membrane, i.e., following the viral tropism (see Figure later in the Section 4). Indeed, although the viral load in sputum of adult SARS-CoV patients was usually higher than 104 copies/mL, reports indicate that plasma viral RNA concentrations are low, usually lower than 190 copies/mL and lymphocytes have much higher RNA-copy concentrations of SARS-CoV RNA than plasma [30]. Very low RNA concentrations with no difference between patients with mild or severe symptoms were detected in plasma from COVID-19 patients [30]. The viral load in nasal swabs of asymptomatic and symptomatic COVID-19-positive subjects was also not significantly different [31]. Of interest, SARS-CoV infected pediatric patients have more than double the amount of plasma RNA copies/mL when compared to adult patients [30], suggesting a different viral tropism between adults and children (different cellular ACE2 expression possibly leading to Kawasaki disease). Notably, free S1 fragments may have a decoy function for autologous/exogenous anti-S1-receptor binding domain (RBD) antibodies. On the other hand, sACE2-S1 complexes masking S1-RBD might also impair either generation of autologous high affinity antibodies against S1-RBD or recognition/inactivation of S1-RBD on SARS-CoV-2 by autologous/exogenous antibodies. Therefore, antibodies that do not compete with ACE2 for the binding to S1-RBD might be more effective in neutralizing SARS-CoV-2 [32,33], knowing that the number of spike proteins per virion is estimated to be around 70 and that every spike protein bears three S1 receptor binding domains, which are masked to autologous antibody recognition when in a “down” conformation. These highly organized molecular features clearly demonstrate that the coronaviruses are armed with sophisticated infection machinery able to evade immune responses induced or not by vaccination. Nevertheless, passive immunotherapy by means of convalescent plasma from COVID-19 recovered donors is a promising option for prevention and treatment of COVID-19 [32,33,34,35,36,37].