Antibodies appear too late in severe cases

Although the majority of COVID-19 cases are asymptomatic or benign, some patients develop respiratory, vascular or neurological complications. Several recent studies have linked recovery from the illness with the effectiveness of the immune response. Despite antibody reaction being in general effective following SARS-CoV-2 infection, those factors leading to severe or fatal cases are still poorly understood.

To investigate these issues further, researchers at the University of Yale studied the production of antibodies in 229 patients (of whom 44 were not hospitalised) having contracted COVID-19 between March and May 2020. The cohort was completed by 16 vaccinated patients and 105 samples taken from negative patients.

From more than 300 samples taken in total, the team measured the following elements over time: the viral RNA (RT-PCR); the level of inflammatory cytokines (outsourced); the populations of immune cells (flow cytometry); and the antibodies (ELISA). The majority of patients (>95%) developed anti-spike or anti-RBD (Receptor Binding Domain) antibodies, with a peak at 15 days on average after the appearance of symptoms. The viral RNA peak occurred after between 11 and 13 days.

Over a given period, severely ill patients, that is, those who were intubated and characterised by high levels of ferretin and D-Dimers, etc, showed higher levels of IgG anti-spike antibodies, but not specifically anti-RBD antibodies. Levels observed in deceased patients were markedly inferior, but superior to those in moderately ill patients. These elevated levels were, on the other hand, linked to a longer period of hospitalisation, to reduced levels of T cells and to raised levels of monocytes and eosinophils (but not of B or Natural Killer cells). The researchers concluded that anti-spike antibodies do not determine the clinical outcome of natural infection with SARS-CoV-2.

Observation of longitudinal profiling shows that the peak level of anti-spike IgG anti-bodies (but not specifically anti-RBD antibodies) occurs later in deceased patients (up to 20 days later). In patients who are on the road to recovery, the peak is earlier and is linked to lower levels of pro-inflammatory cytokines, higher levels of chemokines (and other growth and reparative factors) and higher levels of T helper cells (not B cells). All of these elements could constitute a “protection signature”, giving an increased capacity for virus elimination. Using in vitro neutralisation tests, the researchers established that 89% of patients had developed neutralising antibodies. However, only 6 to 21% of them had raised levels, comparable to those of vaccinated patients, and superior to the rest of the cohort. In patients who recovered, the peak level of neutralising antibodies was also higher and occurred 9 days after the appearance of symptoms, but almost 2 weeks later in the case of deceased patients.

Other studies have shown that protection against SARS-CoV-2 is correlated with high levels of neutralising antibodies as well as with the different domains of the virus they target. This study complements existing data by showing that an interval of about 2 weeks exists after the appearance of symptoms, during which time neutralising antibodies must develop to provide adequate protection against the virus. In deceased patients, this development takes place too late and is not correlated with other factors of protection. The antibodies that develop after this period are incapable of eliminating the virus, perhaps because it manages to establish itself within vital tissues, or because these antibodies promote pathological progression via their Fc domain (see letter…). By extension, this study also suggests that, in order to be effective, antibody therapies need to be administered in the 2 weeks following the appearance of symptoms.