Antibodies, epicenter of SARS-CoV-2 immunology

Abstract

Antibodies against SARS-CoV-2 are the epicenter of the efforts to understand and fight the COVID-19 pandemic. They play a central role in clearing the virus from infected patients, they are key reagents of rapid diagnostics, they are first line treatments for hospitalized COVID-19 patients and they are the main objective of COVID-19 vaccine development. However, antibodies are also blamed for worsening the disease through antibody-dependent disease enhancement (ADE), thereby putting them under the spotlight of many COVID-19 immunological studies. Here we propose a short overview of the natural antibody response induced by the infection, the efforts to isolate and produce human monoclonal antibodies for therapy and prevention, and the attempts to induce potently neutralizing antibodies by vaccination. To prevent and cure the SARS-CoV-2 infection, a great deal of studies has been conducted to understand the capacity of the natural antibody response to neutralize this virus. Such capacity was measured by testing in vitro the ability of the antibodies to engage the S1 subunit of SARSCoV-2 spike protein, which contains the receptor biding domain (RBD) to the human angiotensin-converting enzyme 2, and their ability to neutralize the real or pseudotyped virus. Numerous studies have reported that, while in asymptomatic subjects the antibody response is usually quite low, the intensity of the response correlates with the severity of the disease, with the highest levels being observed in hospitalized patients. It was also noticed that the quantity of circulating neutralizing antibodies rapidly declines in time, which led to the hypothesis that long term immunity to SARS-CoV-2 might be difficult to achieve. These observations are supported by studies that investigated the DNA sequences of the genes encoding the circulating antibodies and showed that neutralizing antibodies are only few mutations distant from their respective germline sequence, suggesting absence of affinity maturation in germinal centers and low capacity to induce long-lived plasma cells [1]. A report showing that COVID-19 patients have a reduced number of Bcl-6 expressing follicular helper T cells in germinal centers proposed that one of the pathogenetic mechanisms of the virus might involve avoidance of a proper affinity maturation process of the host antibodies [2]. It is important to notice that most of the reported studies followed the antibody response very early after infection, which might lead to the hypothesis that the rapid waning of the antibodies is explained by the natural decline of the peak immune response. Indeed, after an initial phase of high antibody levels, and following the normal antibody half-life of 21 days, their titer typically drops to a lower level of persistent immunity which is maintained by long-lived plasma cells (Fig. 1A). To support this hypothesis, recent longitudinal studies, where the immune response was followed over time, have reported a sustained response in some individuals and a decline in others [3]. However, the majority of subjects had detectable neutralizing responses lasting for several months. In conclusion, we believe that most of the studies published so far reported observations that we will not be able to fully understand until it is demonstrated which is the level of neutralizing antibodies that confers protection. Once the correlate of protection is identified, it will be easier to establish whether SARS-CoV-2 infection induces protective antibody levels and how long they last. Modern medicine was born with passive immunization when Emil von Behring discovered that immune serum was able to prevent and cure diphtheria. In the absence of specific drugs and vaccines, SARS-CoV-2 antibodies present in * Rino Rappuoli [email protected]