Neutralizing antibodies mediate virus-immune pathology of COVID-19.

SARS-CoV-2 is a novel beta-coronavirus causing over 200.000 lethal cases within six months of first infecting humans. SARS-CoV-2 causes COVID-19, a form of severe acute respiratory syndrome (SARS). COVID-19 is characterized by two phases: the first resembles the flu with pneumonia, but after about seven or eight days the disease suddenly worsens to a sepsis-like syndrome. It is difficult to explain this virus-immune-pathology sequence from virology or immunology only. This paper hypothesizes that host-produced anti-spike protein antibodies are responsible for immune-induced viral dissemination. Subsequently, systemic distribution of virus-antibodies complexes activates the immune pathology observed in severe COVID-19. This hypothesis may be counterintuitive to immunologist that consider many anti-spike antibodies to be virus-neutralizing antibodies. Although anti-spike antibodies may hinder infection of epithelial cells, antibody binding to the spike protein may facilitate virus infection of myeloid leukocytes. If myeloid leukocytes reenter the circulation, they could spread the virus from a locoregional infection to a systemic disease. Disseminated virus in combination with antibodies results in dispersed virus-antibody complexes that overstimulate the immune system. The hypothesis aligns with the sequences of virus, immune and pathological events in COVID-19. The delay in onset from both syndromes results from an immune system still naïve to the non-cross-reactive spike protein. Details of this hypothesis are in concordance with many clinical characteristics of COVID-19, including its predominant lethality for the elderly, and the mostly asymptomatic course of disease in children. It predicts putative detrimental effects of vaccines that induce virus-neutralizing antibodies against the spike protein, as has been shown for other coronaviruses. This hypothesis has consequences for treatment of patients, evaluation of personal and herd immunity and vaccine development. In patients, cellular immunity should be stimulated. Neutralizing antibodies might not be indicative for immunity. Vaccines should aim to stimulate cellular immunity COVID-19 and/or stimulate humoral immunity against viral proteins except for the immunodominant spike protein.