5 patterns of SARS-CoV-2 neutralizing antibody dynamics: What they mean

Neutralizing antibody response against SARS-CoV-2 can be categorized into five patterns of response, with persistent neutralizing antibodies being correlated with severe COVID-19 disease and higher pro-inflammatory cytokine levels, according to a Singapore study.

“[One key unanswered question concerning the pandemic] is the nature and longevity of protective immunity, which is highly important in the context of risk assessment for reinfection and vaccine development,” said the researchers co-led by Professor Wang Lin-Fa from Duke-NUS Medical School, and Dr David Chien Lye from the National Centre for Infectious Diseases, Singapore.

In this longitudinal study, the researchers followed 164 patients who had recovered from COVID-19. The researchers collected 546 serum samples up to 180 days after symptom onset to monitor the changes in neutralizing antibody response using a validated operator-friendly surrogate virus neutralization test. [Lancet Microbe 2021;doi:10.1016/S2666-5247(21)00025-2]

The five patterns of neutralizing antibody response identified were: negative, rapid waning, slow waning, persistent, and delayed response.

In the negative category were participants (12 percent of 164 patients) who did not develop neutralizing antibodies at the prespecified 30 percent inhibition level. While neutralizing antibody levels varied greatly between individuals and within the same individual across time, those who seroreverted in <180 days were classified as rapid waning (27 percent) while those who remained positive for neutralizing antibodies at 180 days after symptom onset were classified as slow waning (29 percent).

The persistent category included individuals with minimal decay of neutralizing antibodies over time (observed in 32 percent of 164 patients). On the other hand, a small group of individuals (2 percent) with unexpected rise in neutralizing antibody levels during late convalescence period (at 90 or 180 days following symptom onset) were considered as having a delayed response.

“Some patients in the persistent and delayed response groups had increasing antibody levels many months after they recovered from acute disease … so it is important to monitor this at an individual level,” pointed out Wang and co-authors.

Patients in the persistent category had poorer clinical outcomes and more severe disease, with significantly more patients having pneumonia, requiring supplemental oxygen, mechanical ventilation, or intensive care unit admission.

“Greater disease severity was independently associated with persistent neutralizing antibody level, and patients with milder disease appeared to have more rapid neutralizing antibody waning,” noted the researchers.

Accordingly, persistent neutralizing antibodies were associated with sustained inflammatory cytokine levels, even 6 months after symptom onset in patients who had recovered.

In addition, patients with persistent antibody levels tended to be older with more comorbidities such as hypertension and diabetes.

In contrast, T-cell responses were similar across the five groups, regardless of the different dynamics of neutralising antibodies.

“[These findings] have implications for longevity of immunity after vaccination,” said Wang and co-authors. “Although we are not at a stage to conclusively correlate the level of antibody responses with protective immunity, we are in a much better position to assess the dynamics of antibody responses with data from a cohort who have been in convalescence for more than 6 months.”

“The rate of waning suggests reinfection during second and later waves of infection is likely to occur, limiting the viability of a herd immunity strategy before an effective vaccine,” they added. “Assuming similar rates of waning after vaccination, annual administration is likely to be necessary to prevent large outbreaks as population immunity declines.”