4-2- Antibody-mediated responses
The antibody-mediated humoral response is crucial for preventing viral infections. A subset of these antibodies, which reduce viral infectivity via binding to the surface epitopes of viral particles and thereby blocking the entry of the virus to an infected cell, are defined as neutralizing antibodies (Klasse, 2014).
Virus neutralizing antibodies induced by vaccines or infected viruses play vital roles in controlling viral infections (Y. Zhou, Yang, Huang, Jiang, & Du, 2019). They target S1-RBD, S1-NTD, or the S2 region, blocking the binding of RBDs to their respective receptors and interfering with S2-mediated membrane fusion or entry into the host cell, thus inhibiting viral infections (Lanying Du et al., 2009; Jiang, Du, & Shi, 2020). Most of these antibodies target the RBD, while a few target regions in the S2 subunit or the S1/S2 proteolytic cleavage site. For example, in a previous research, the human neutralizing mAbs S230.15 and m396 were isolated from SARS-CoV-infected individuals. They neutralize human and palm civet SARS-CoV infection by interacting with the RBD, thus blocking binding between the viral RBD and the cellular ACE2 receptor (Zhu et al., 2007).
It has been reported that neutralizing antibodies are declined within 2–3 months in COVID-19 recovered patients. One mathematical model has suggested shortly durable immunity, as well (Long et al., 2020). The durability of neutralizing antibodies in other human coronaviruses may be relevant for comparison. Among the seven pathogenic coronaviruses of human beings, HCoV-229E, HCoV-NL63, HCoVOC43 and HCoV-HKU1 cause mild disease (common cold); whereas, SARS-CoV, MERS-CoV, and SARS-CoV-2 are highly pathogenic. Antibody titers lack longevity and wane substantially one-year post-infection in common cold coronaviruses; three years in SARS-CoV; and are persist for 2 years after recovery from severe MERS-CoV infection (Sariol & Perlman, 2020). As SARS-CoV-2 infection has a mostly asymptomatic or mild clinical presentation, like common cold coronaviruses, rapidly waning antibody responses following primary infection or immunization (compared to severe cases) may allow susceptibility to re-infection. The secretory IgA as a protective neutralizing antibody against SARS-CoV-2 should also be explored, as mucosal immunity provides protection by intranasal immunization against closely-related SARS-CoV and MERS-CoV (Priyanka, Choudhary, & Singh, 2020). In a study on 175 COVID-19 recovered patients with mild symptoms, SARS-CoV-2-specific neutralizing antibodies were detected at the convalescent phase of infection from day 10–15 after the onset of the disease and remained thereafter. The titers of neutralizing antibodies were variable in different patients. Plasma neutralizing antibody titers in elderly and middle-aged patients were significantly higher. Neutralizing antibody titers were positively correlated with CRP levels and negatively with the lymphocyte counts of patients. It could be suggested that other immune responses, including T cells or cytokines, may contribute to the recovery of these patients. One of important practical results of this study was the highly variable levels of neutralizing antibodies in the patients with COVID-19. It could be indicate that convalescent plasma from recovered donors should be titrated before use in a passive antibody therapy; an easy task that can be performed using the protocol of SARS-CoV-2 Pseudovirus (PSV) neutralization assay (Wu et al., 2020).
Patients with SARS-CoV infection had a strong humoral immune response to SARS-CoV-2 (A. T. Huang et al., 2020). Serum IgG, IgM, and IgA responses to SARS-CoV appeared in patients after primary SARS infection (Woo et al., 2004). Neutralizing IgGs against SARS-CoV reached a peak in serum during the convalescent phase and diminished after recovery (Cao, Liu, Zhang, Zhang, & Richardus, 2007).
A previous study showed that antibodies from some recovered SARS-CoV-2 patients might cross-react or neutralize SARS-CoV from other patients (L. Du, Ma, & Jiang, 2013). Like SARS-CoV-1 infection (Hsueh, Huang, Chen, Kao, & Yang, 2004), seroconversion occurs in most COVID-19 patients between 7 and 14 days after the onset of symptoms, and antibody titers persist in the weeks following virus clearance (Haveri et al., 2020; Okba et al., 2020).
It seems that antibodies binding the SARS-CoV-2 internal N protein and the external S glycoprotein are commonly detected (Amanat et al., 2020). The S protein is highly immunogenic, and specific antibodies against the receptor-binding domain (RBD) can neutralize and block virus interactions with ACE2 as the host entry receptor (Ju et al., 2020). SARS-CoV-2 S protein can bind ACE2 with a higher affinity than SARS-CoV S (Wrapp et al., 2020). The high affinity of the S protein for human ACE2 may lead to the great human-to-human transmission of SARS-CoV-2. Due to the key role of the S protein, it is the main target for antibody-mediated neutralization (G. Zhou & Zhao, 2020).
In a previous study, RBD-specific CD19+IgG+ memory B cells were single-cell sorted from COVID-19 donors between days 9 and 28 after the onset of symptoms. Many SARS-CoV-2-specific monoclonal antibodies were produced using their antibody gene sequences. The monoclonal antibodies had a diverse repertoire, relatively low or no somatic mutations, and variable binding reactivity, with dissociation constants reaching 10-8 to 10-9, like antibodies isolated during acute infections. Two potent neutralizing SARS-CoV-2 RBD-specific monoclonal antibodies were characterized that did not cross react with the RBD of SARS-CoV-1 or MERS-CoV (A. T. Huang et al., 2020). Together, these results demonstrate that antibody-mediated neutralization is virus-specific and propably driven by the binding of epitopes within the RBD.
It was demonstrated that the IgM response to SARS-CoV-2 occurred and peaked earlier than the IgG antibody response; the IgM antibody response began to decline at week 3 of the illness (Fig. 3), while the IgG antibody response persisted and maintained in patients with COVID-19; and severe cases of COVID-19 tended to have a more vigorous response in both IgG and IgM antibodies to COVID-19 illness. Importantly, the timings of IgM and IgG antibody occurrence in patients were considerably different, and this variation in timing may be associated with age as well as a comorbidity (To et al., 2020).