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Distinct Level of SARS-CoV-2 Antibodies May Be Necessary for Durable Protection

Key findings

  • This study analyzed functional humoral immune response over time in 120 people with COVID-19 (61% without symptoms) who were identified through a community-based prospective surveillance study
  • Significant heterogeneity in antibody titers was observed across the infected population, which positively correlated with the number of symptoms experienced by each individual
  • Limited antibody waning was noted over the study period, but an antibody titer threshold was observed that discriminated between individuals who did or did not exhibit neutralization, humoral immune responses and T-cell immunity
  • This threshold may be necessary for durable protection against SARS-CoV-2, which would explain why some people become re-infected

Once antibodies bind to an antigen, they can protect an individual by blocking infection (neutralization) or by recruiting the immune system to clear and control disease. In the case of SARS-CoV-2, elderly people and people who become severely ill develop higher antibody levels, and humoral immune responses have been observed to persist for at least several months.

However, cases of reinfection have begun to be reported, which calls into question the protective nature of humoral immunity.

Galit Alter, PhD, principal investigator at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, and colleagues have observed neutralization, humoral responses and T-cell responses only in individuals infected with SARS-CoV-2 whose antibody titers were above certain thresholds. In Nature Communications, they explain the implications of their findings for vaccination programs.

Study Methods

The researchers conducted a prospective seroprevalence surveillance study of 4,300 employees at Space Exploration Technologies Corporation (SpaceX). The volunteers started SARS-CoV-2 antibody testing in April 2020, which was repeated as often as they wanted (average interval 40 days). At each blood draw, the participants reported whether they had any of a list of COVID-19 symptoms.120 people (92% male, median age 31) tested positive for SARS-CoV-2 during the study and were analyzed further. 61% had no symptoms.

Antibody Levels and Symptoms

There was significant heterogeneity in antibody titers among people who tested positive. Antibodies were found in both symptomatic and asymptomatic participants, but as in previous research, titers were positively correlated with the number of symptoms.

Titer Kinetics

48 people who tested positive had at least two follow-up tests. The typical pattern was a rise in antibodies, early waning and then stability—for more than 60 days in some cases. Whether these persisting binding antibodies can drive the immune responses necessary for protection against subsequent infection is still unclear.

Functional Implications of Titer Heterogeneity

The researchers then explored why some individuals become reinfected despite the presence of antibodies. They divided the 120 seropositive individuals into two groups according to their maximum titers of antibodies to the SARS-CoV-2 receptor-binding domain (RBD): above or below the median of 0.45 mcg/mL. Remarkably, neutralization and two humoral immune activities (complement deposition and neutrophil phagocytosis) occurred solely in participants who had higher RBD-specific antibody titers. Furthermore, these immune functions remained stable over time.

SARS-CoV-2–specific T-cell responses occurred almost exclusively in individuals who had robust humoral immune responses. This suggests T- and B-cell responses evolve at the same time, driven by symptomatic infection.

Implications for Vaccination

A threshold for vigorous immune activity—which can be captured by measuring antibody titers—appears to exist in people infected with SARS-CoV-2. Attaining this threshold may be essential for durable protection. Studies of large numbers of people who become re-infected might determine the precise antibody levels needed for protection. Once those are known, people who are vulnerable to re-infection could be prioritized for vaccination. Unlike natural asymptomatic/mild infection, nearly all SARS-CoV-2 vaccines appear to elicit neutralization at levels observed in people recovering from symptomatic COVID-19, and some vaccines are also able to drive humoral immunity.

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