The COVID-19 Textbook

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SECTION 3 • Immunology

first member of the cascade, C1q, to deposit on the surface of the pathogen. 56 C1q, a pentamer of C1 molecules, can interact with IgM (also a pentamer) or multimerized IgG3 and IgG1 antibodies via their Fc-domains, once they have bound to the surface of a pathogen. 57,58 C1q binding then leads to a cascade of enzymatic reactions and catalytic events, wherein additional members of the comple ment cascade deposit, forming the membrane attack complex (MAC) that ruptures the membrane of the pathogen and death. The deposition of complement components, midway in the formation of the MAC, such as C3b or C5b, can lead to rapid opsonophagocytosis by phagocytic cells. Thus, antibody-mediated complement may have an effect via direct destruction or a pathogen clearance. CDC is a protective mechanism in mAbs against influenza virus, 59,60 vaccinia virus, 61 cytomegalo virus, 62 and HIV. 50,51 However, complement activation may contribute to disease severity in both dengue virus (DV) 63,64 and HIV infection. 65,66 Antibody-mediated adaptive cell activation occurs when T cells and B cells, which both ex press complement receptors and FcRs, 67,68 are modulated by the presence of antibody-pathogen complexes. For example, IC interactions with Fc γ RIIB on B cells temper B-cell activation, helping to control inflammatory immune responses. 69,70 Complement receptors on T cells play a critical role in the initiation of the T-cell response, allowing ICs that may form immediately after infection to drive rapid activation and maturation of T cells. 71 These processes are known as antibody-mediated immunomodulation and have important therapeutic implications. Antibody-dependent enhancement (ADE) is the process by which antibodies either facilitate the uptake of pathogens into cells or contribute to the pathogenesis associated with the infection. ADE is principally mediated by IgG antibodies; it has also been shown to be mediated by IgM and complement or IgA antibodies. 72-75 For example, in the setting of DV infection, preexisting non-neutralizing or sub-neutralizing concentrations of DV-specific antibodies have been shown to facilitate DV uptake upon reinfection into monocytes/macrophages, providing the virus with a direct conduit to their target cells thereby promoting infection and disease. 76-78 Specifically, cross-reactive antibodies from the first infection form ICs upon reinfection with a different serotype of DV; these stabilize the virus and promote viral uptake by macrophages, leading to dengue hemorrhagic fever and shock syndrome. 79-82 ADE has been observed in other flaviviruses such as Zika virus, where in vitro studies show both convalescent plasmid therapy and mAbs enhance infection. 83 In an animal model, SARS-1 pox viral vector–based vaccination of nonhuman primates induced antibodies that enhanced inflammation and pathology in the lungs, rather than enhance infection, 84,85 pointing to a second mechanism by which antibodies could contribute to enhanced disease. Thus, understanding both the immune-protective and also potential pathologic activities of antibodies is key to harnessing their full vaccine and therapeutic potential. 86 IMPORTANCE OF ANTIBODIES IN CONTROL OF COVID-19 Following SARS-CoV-2 infection, SARS-CoV-2-specific antibody development occurs in a predict able pattern (Figure 8.3). First, IgM antibodies appear rapidly within the first weeks of infection, fol lowed closely by IgA antibodies in the mucosal membranes. Then, IgG antibodies appear, peaking at 3 to 7 weeks postsymptom onset. 87 Neutralizing Abs, 90% of which target the RBD, 88 appear within 7 to 15 days following symptom onset, increasing over time, then level off and decay, 89 similar to natural decay patterns observed for nAbs to other common coronaviruses. 90 This decay process ren ders previously infected individuals newly susceptible to infection every 2 to 4 years. 91 SARS-CoV 2-specific antibodies primarily target the immunogenic S and nucleocapsid (N) proteins, particularly the highly immunogenic RBD. Antibody production correlates with severity of disease, with the highest number of antibod ies observed in individuals with severe COVID-19 and the lowest levels detected in asymptomatic cases. 92,93 Thus, antibody levels are linked to the level of viral replication, or antigen levels, suggesting that individuals with more severe disease likely harbor higher levels of virus in their lungs, triggering stronger B-cell responses and thus eliciting higher levels of antibodies. 94,95 Individuals with milder disease also show enhanced FcR binding, Fc-effector function, and neutralization, along with an increased number of antibody subclasses present. 96-98 Individuals with mild disease also have lower viral loads and lower antibodies. This suggests that qualitative differences in the antiviral functions of

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