Wide Range of Antibody Responses After ‘Mild’ COVID-19

Patients hospitalized with mild COVID-19 in China exhibited a wide range of SARS-CoV-2-specific neutralizing antibodies, with a minority of patients with levels below the detectable limit of the assay, researchers found.

Out of 175 patients, 30% developed SARS-CoV-2-specific neutralizing antibody titers of less than 500, and 10 patients with neutralizing antibody titers under the detectable limit, reported Jinghe Huang, PhD, of Fudan University in Shanghai, and colleagues.

These titers tended to be higher in men versus women, and in older and middle-age patients versus younger patients, and those with indicators of stronger immune response, the authors wrote in JAMA Internal Medicine.

An accompanying editor’s note from JAMA Internal Medicine deputy editor Mitchell Katz, MD, mused about this contradiction between the patients with higher antibody levels compared to patients hit hardest by the virus.

“Men, older patients, and those with stronger inflammatory response and older age have generally fared worse, suggesting that the higher titers of antibodies do not necessarily lead to higher recovery rate,” wrote Katz, of NYC Health + Hospitals in New York City.

He also highlighted the 10 patients with “undetectable antibody levels” despite having documented infections.

“Are these patients susceptible to future infection, or do they have protection based on their infection sensitizing killer T cells or memory B cells?” Katz said.

Huang and colleagues noted how neutralizing antibodies are not only considered the key to recovery and protection against viral diseases, but are often used to determine efficacy of vaccines.

Researchers examined data from patients in Shanghai who were diagnosed with laboratory-confirmed COVID-19 from January 24 to February 26. They were isolated and hospitalized, but were classified as having “mild symptoms” (defined as fever, respiratory symptoms, and radiologic evidence of pneumonia). Severe and critical patients were excluded from the study, as they received antibody treatment.

Patients were discharged after being afebrile for 3 days, with improved respiratory symptoms, imaging that showed lessening of inflammation, and two sequential negative nucleic acid tests in nasopharyngeal samples. Plasma was collected at 2 weeks post-discharge and neutralizing antibody titers were measured against measurements obtained at discharge.

Overall, patients were a median age of 50 and a little over half were women. Median hospital stay was 16 days, while median disease duration was 22 days. Two-thirds of the 175 patients were followed up until March 16.

SARS-CoV-2-specific neutralizing antibody titers ranged from below the limit of detection (50% inhibitory dose, or ID50, <40) to over 21,000 at the time of discharge, the authors said. The greatest proportion of patients (39%) had medium-high levels of neutralizing antibody titers (ID50, 1,000-2,500), while 17% had medium-low levels (ID50, 500-999), and 14% had high levels (ID500, >2,500). Only two patients had neutralizing antibody titers with ID50 levels over 15,000.

Interestingly, the patients who developed high levels of neutralizing antibody titers were older (median age 63) and 56% were men. While the 10 patients where neutralizing antibody titers were below the limit of detection were younger (median age 34) and eight were women.

Notably, at admission, neutralizing antibody titers were correlated with plasma C-reactive protein (CRP) levels, but not lymphocyte counts, and the authors offered up a hypothesis for the findings:

“[Neutralizing antibody] titers at discharge positively correlated with blood CRP levels but negatively correlated with lymphocyte counts at admission, suggesting that high levels of [neutralizing antibodies] may be a consequence of strong inflammation or innate immune response in these older patients in whom the lower lymphocyte count may reflect poorer T cell responses.”

Limitations to the data included that patients were only followed up to 2 weeks following discharge, only 117 patients were available for follow-up, and disease duration was calculated as disease onset to discharge, which is longer than symptom duration.

Ultimately, the authors concluded that due to the wide range of antibody titers from patients with mild COVID-19 infection, the clinical implications for vaccine development and future preventative measures are still “unknown.”