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.

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 the plasma of convalescent patients that recovered from infection were also the most obvious tool to cure COVID-19. The first exploitation of antibodies in the COVID-19 pandemic was the transfusion of plasma with high titers of neutralizing antibodies from convalescent to hospitalized patients. Several trials have demonstrated some benefit and plasma therapy was the first treatment authorized by the FDA for emergency use [4]. However, due to the complexity and risks linked to the administration of hyperimmune plasma, a massive effort in dozens of labs around the world let to the isolation of human monoclonal antibodies (mAbs) from convalescent patients. Before the COVID-19 pandemic, little attention had been paid to the use of mAbs to treat infections despite more than 100 had been licensed as therapeutics for cancer, autoimmunity and inflammation. This was mostly because of their high cost, which did not make them suitable for a broader use. A game changer in the field of mAbs for infectious diseases was the cloning of potent neutralizing antibodies from memory B cells of convalescent subjects following SARS infection [5]. Since then, several technologies were developed for isolating and cloning mAbs from B cells. They were extensively used for instance in the HIV research, where mAbs helped the discovery of highly conserved epitopes, thus driving vaccine design and the development of passive treatments for prevention of infection and therapy [6]. This progress allows today the routine isolation of mAbs which are 1000 fold more potent than those identified two decades ago, and which require 1000 fold less doses to be effective, which translates into the possibility to apply the same approaches to develop affordable therapies also for other infectious diseases. When the COVID-19 pandemic started in January 2020, the field was mature. Several academic laboratories and pharmaceutical companies focused on the development of mAbs specific for the SARS-CoV-2 virus. Potent, ultrapotent and extremely potent mAbs targeting the SARS-CoV-2 spike protein RBD have been promptly described which targeted the RBD of the spike protein and neutralized the virus at concentrations of 100 ng/ml or below, with only very rare antibodies able to neutralize the virus at concentrations below 10 ng/ml [7] (Fig. 1B). These mAbs protected animals from infection when administered prior to virus challenge and allowed faster recovery when used as therapeutics [8]. Several mAbs entered clinical testing within the first six months of the pandemic and have already started to deliver preliminary results. When administered early after infection, accelerated viral clearance and reduced hospitalization by 75% was reported [9]. Based on preliminary clinical data, two of them received emergency use authorization by the FDA. At this point it is clear that mAbs are a good preventive and therapeutic tool for SARS-CoV-2. However, there are still many pending questions. We do not know yet whether the antibodies can be used to treat severely ill hospitalized patients. Indeed, it remains to be proved whether the antibody Fc portions may need to be engineered to remove their effector functions, which may worsen the disease outcome by promoting increased inflammation via ADE [10]. Moreover, little is known on whether mAbs can promote mutations that may select the so-called “escape mutants.” These mutants can be selected in vitro when the virus (or pseudovirus) is grown in the presence of antibodies, but it is not clear whether this will be relevant in the therapeutic setting, where the mAb will work together with the natural cocktail of antibodies produced by the patients. An obvious way to reduce the risk of selecting escape mutants is to use a cocktail of antibodies, which however has the downside to make the development of the treatments more complex and more expensive.

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