On May 27, 2021, Seattle Children’s researchers published a study that uncovered a deeper understanding of why people who have had mild cases of the novel coronavirus 2019 (COVID-19) lose functional antibodies within a few months.

The researchers observed that total anti-S trimer, anti-receptor-binding domain (RBD), and anti-nucleocapsid protein (NP) IgG are relatively stable over 6 months of follow-up, that anti-S and anti-RBD avidity increases over time, and that fever is associated with higher levels of antibodies. However, neutralizing antibody responses rapidly decay and are strongly associated with declines in IgM levels. Thus, while total antibody against SARS-CoV-2 may persist, functional antibody, particularly IgM, is rapidly lost. These observations have implications for the duration of protective immunity following mild SARS-CoV-2 infection.

The team found that IgG-binding titers to viral antigens remain durable over time, and avidity studies provide evidence of B cell maturation. Humoral responses were associated with fever, but not other clinical variables. However, neutralizing activity rapidly contracted 2–3 months following infection, despite the overall maintenance of IgG-binding antibody levels.

Notably, neutralization was most strongly correlated with anti S-trimer IgM, rather than IgG or IgA, offering a possible explanation for the apparent paradox between stable IgG and waning neutralization. Our findings indicate that despite the overall maintenance and durability of humoral immune responses after infection, neutralizing activity waned rapidly as IgM titers decayed. Overall, these findings imply that mild infections may not generate lasting protection and highlight the urgent need for the rapid deployment of effective vaccines to stem the spread of SARS-CoV-2.

Neutralizing antibodies are thought to be a critical component of the antiviral antibody response and are a correlate of protection for numerous licensed vaccines. Neutralization is the capacity of antibodies to bind the virus and prevent entry into target cells and are differentiated from non-neutralizing antibodies that bind the viral antigens but do not prevent infection. While the correlates of protective antibody immunity against SARS-CoV-2 are not clearly understood, it is likely that neutralizing antibodies will be a critical component of protective immunity after infection and vaccination.