The longevity of functional neutralizing antibodies against SARS-CoV-2 can vary greatly on an individual level

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Scientists from Duke-NUS Medical School, the National Center for Infectious Diseases (NCID) and the Agency for Science, Technology and Research (A*STAR) Infectious Diseases Labs found that antibodies against SARS-CoV-2 wane at different rates, lasting for mere days in some individuals, while remaining present in others for decades.

The study, published in The Lancet Microbe, shows that the severity of the infection could be a deciding factor in having longer-lasting antibodies. Individuals with low levels of neutralizing antibodies may still be protected from COVID-19 if they have a robust T-cell immunity.

The team followed 164 COVID-19 patients in Singapore for six to nine months, analyzing their blood for neutralizing antibodies against SARS-CoV-2, T cells and immune system signaling molecules.

They then used this data to establish a machine learning algorithm to predict the trajectories of peoples’ neutralizing antibodies over time.

“The key message from this study is that the longevity of functional neutralizing antibodies against SARS-CoV-2 can vary greatly and it is important to monitor this at an individual level.

This work may have implications for immunity longevity after vaccination, which will be part of our follow-up studies,” said Professor Wang Linfa, from Duke-NUS’ Emerging Infectious Diseases (EID) Program, a corresponding author of the study.

The team was able to categorize people into five groups depending on how long their antibodies lasted. The first group, who never developed detectable neutralizing antibodies also called the ‘negative’ group, comprised 11.6 percent of the patients in the study. The ‘rapid waning’ group (26.8 percent) had varying early levels of antibodies that waned quickly.

The ‘slow waning’ group (29 percent) tested mostly positive for antibodies at six months. The ‘persistent’ group (31.7 percent) showed little change in their antibody levels up to 180 days and, finally, the ‘delayed response’ group (1.8 percent) showed a marked rise in neutralizing antibodies during late convalescence.

While this study focused on determining the levels of neutralizing antibodies, which are part of the body’s comprehensive immune defense system, the other important aspect of an effective immune defense is T-cell immunity. The study found that the patients tested, including those from the ‘negative group’, displayed sustained T-cell immunity six months after initial infection.

This shows that individuals may still be protected if they have a robust T-cell immunity when the neutralizing antibody level is low.

“Our study examines neutralizing antibodies which are important in protection from COVID-19. We found that antibodies against SARS-CoV-2 wane in different people at different rates. This emphasizes the importance of public health and social measures in ongoing pandemic outbreak response.

However, the presence of T-cell immunity provides hope of longer-term protection which will require more studies and time for epidemiological and clinical evidence to confirm,” said Associate Professor David Lye, Director, Infectious Disease Research and Training Office, NCID, also a corresponding author of the study.

“This study reminds us that we all react differently to infection and that various people mount different protective immune responses. Understanding the basis of these differences will help build better vaccines,” added Professor Laurent Renia, Executive Director, A*STAR Infectious Diseases Labs.

The findings are important as policy makers design vaccination programs and pandemic exit strategies. The rate of antibody waning suggests re-infection may occur in subsequent waves of infection.

Also, if immunity provided via vaccinations wanes like naturally-produced antibodies, then annual vaccine administration could be necessary to prevent future outbreaks of COVID-19. Further research will be needed to clarify this as vaccine programs are rolled out.


Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 and has caused more than 102 million confirmed cases worldwide as of January 31, 2021.1 Despite intensive study throughout the scientific and medical communities, many clinical and biologic aspects of the disease, especially in the pediatric population, have not yet been elucidated.

As data emerged from the initial outbreaks in China, the number of COVID-19 cases in children appeared to be low, with reports indicating that less than 1% were patients younger than 10 years, 1.2% were aged between 10 and 19 years, and only 9 patients were infants with mild symptoms.2 In the United States, pediatric infection cases comprised only 7% of total cases as of August 2020.2,3 The US Centers for Disease Control and Prevention (CDC) reported that, as of September 19, 2020, only 4.1% of the nationally confirmed COVID-19 cases were in school-aged pediatric patients (aged 5-17 years).4

Although the causes of these differences remain unclear, most children with SARS-CoV-2 infection are either asymptomatic or exhibit mild symptoms5-7 and have a low risk of developing severe respiratory disease.8,9 The CDC reported that the average weekly incidence of COVID-19 cases among adolescents aged 12 to 17 years was approximately twice that of children aged 5 to 11 years.4

Only a relatively small number of pediatric patients have experienced severe disease during the acute phase of COVID-19. However, these patients are at risk of severe complications from multisystem inflammatory syndrome in children (MIS-C), an emerging entity thought to occur as sequelae to acute SARS-CoV-2 infection.10,11 Thus, there appears to be differences in pathophysiologic responses to SARS-CoV-2 based on age.

Although the physiologic mechanisms remain unclear, evidence suggests that SARS-CoV-2–specific antibody responses may be different in children and adolescents compared with those in adults,12 potentially modulating different clinical manifestations. Controversy exists as to whether children have an attenuated adaptive immune response, leading to tolerance of the SARS-CoV-2 infection,8 or if the innate immune response in children plays a more active role against SARS-CoV-2 than in adults.13 Additionally, the binding avidity of SARS-CoV-2 viral–specific antibodies, which represents the quality of the antibody response, has not been fully characterized in pediatric patients.

Given that the 2020-2021 school year has resumed, with approximately 56 million school-aged children and adolescents in the United States participating in in-person and/or remote classes, it is imperative to better understand the SARS-CoV-2 viral–specific immune responses in pediatric patients.

In this study, the magnitude of total antibody levels, immunoglobin (Ig) G levels, and surrogate neutralizing antibody (SNAb) activities as well as the antibody binding avidity in children, adolescents, and young adults were evaluated. In contrast to other studies, which focused mainly on hospitalized pediatric patients, this study investigated the antibody responses during the convalescent stage of previously asymptomatic or mildly ill nonhospitalized patients, which is more representative of the overall pediatric population of patients with COVID-19.

Results
SARS-CoV-2 Antibody Positivity Rates From April 9 to August 31, 2020

A total of 31 426 SARS-CoV-2 antibody tests were performed (19 797 [63.0%] female patients), including 1194 tests in pediatric patients (mean [SD] age, 11.0 [5.3] years) and 30 232 in adult patients (mean [SD] age, 49.2 [17.1] years). The testing volume as well as the number of positive results in each age group is shown in Figure 1A. Overall, 197 (16.5%; 95% CI, 14.4%-18.7%) and 5630 (18.6%; 95% CI, 18.2%-19.1%) results were positive in pediatric and adult patients, respectively.

The positivity rates for pediatric and adult individuals were not significantly different (P = .06). The positivity rates were then evaluated for different age groups (Figure 1B). Young adults, aged 19 to 24 years of age (242 of 990 [24.4%; 95% CI, 21.8%-27.3%]) and those aged 25 to 30 years (816 of 3468 [23.5%, 95% CI, 22.1%-25.0%]) had the highest positivity rates compared with other age groups. Children aged 1 to 10 years (76 of 500 [15.2%; 95% CI, 12.2%-18.6%]), patients aged 61 to 70 years (714 of 4494 [15.9%; 95% CI, 14.8%-17.0%]), patients aged 71 to 80 (365 of 2824 [12.9%; 95% CI, 11.7%-14.2%]), and patients older than 80 years (161 of 1208 [13.3%; 95% CI, 11.5%-15.4%]) had lower positivity rates.

Comparison of SARS-CoV-2 IgG Levels in Each Age Group

We compared the SARS-CoV-2 IgG levels from 85 positive pediatric and 3648 positive adult patient samples measured using a single platform (Pylon 3D), accounting for 43.1% (95% CI, 36.1%-50.4%) and 64.8% (95% CI, 63.5%-66.0%) of the positive pediatric and adult results, respectively. The IgG level in the pediatric population exhibited a moderate but significant negative correlation with age (r = −0.45; P < .001), and the adult population exhibited a weakly positive correlation with age (r = 0.24; P < .001) (Figure 2A).

Notably, the 32 children aged 1 to 10 years showed significantly higher median (IQR) SARS-CoV-2 IgG levels than the 127 young adults aged 19 to 24 years (443 [188-851] RFU vs 95 [47-180] RFU; P < .001), the 611 adults aged 25 to 30 years (99 [44-180] RFU; P < .001), the 956 adults aged 31 to 40 year (104 [48-224] RFU; P < .001), the 688 adults aged 41 to 50 years (137 [50-319] RFU; P = .001), and the 69 patients older than 80 years (165 [24-518] RFU; P = .01).

Young adults aged 19 to 24 years and 25 to 30 years exhibited the lowest median (IQR) SARS-CoV-2 IgG levels (95 [47-180] RFU and 99 [44-180] RFU, respectively), without any significant difference between these 2 age groups (Figure 2B). Patients aged 19 to 24 years showed significantly lower IgG levels than the 612 adults aged 51 to 60 years (95 [47-180] RFU vs 195 [65-585]; P < .001), the 415 aged 61 to 70 years (225 [65-660] RFU; P < .001), and the 170 aged 71 to 80 years (233 [62-675] RFU; P < .001), and patients aged 25 to 30 years old showed significantly lower median (IQR) IgG levels than adults older than 41 years (eg, vs patients aged 41-50: 99 [44-180] RFU vs 137 [50-319] RFU; P < .001) but not those 81 years or older (165 [24-518] RFU; P > .99).

Assessment of SARS-CoV-2 Antibody Quantity and Quality in Children, Adolescents, and Young Adult Patients
We further focused on pediatric patients (aged 1-18 years) and young adults (aged 19-24 years) to understand their characteristic profiles of SARS-CoV-2 antibody responses. More extensive SARS-CoV-2 serologic testing was performed in 126 outpatients aged 1 to 24 years. None of the 126 patients were admitted to the hospital due to COVID-19 prior to serum sample collection, and they were asymptomatic at the time of antibody testing (Table).

Of 118 patients with documentation in the EMR, 56 patients (47.5%) were previously symptomatic whereas 62 (52.5%) never had COVID-like symptoms. Nine patients (19.1%) had positive SARS-CoV-2 reverse transcription–polymerase chain reaction testing. Most patients (87 [69.0%]) underwent antibody testing due to previous exposure or previous COVID-19–like symptoms.

Other reasons for antibody testing included preprocedural testing (4 [3.2%]), annual checkup (3 [2.4%]), request for attending school or camp (11 [8.7%]), or to confirm prior positive SARS-CoV-2 antibody testing in another hospital (4 [3.2%]). Among patients who had self-reported dates of symptom onset, there was no correlation between age and the days between serology testing and symptom onset (mean (SD) time, 108 [48] days; r = 0.16; P = .27) (Figure 3E). Characterization of the symptoms and comorbidities in children, adolescents, and young adults are shown in the Table.

Similar to what was seen in the overall patient population (Figure 2), the level of SARS-CoV-2 IgG in this subset patient cohort showed a moderate but significantly negative correlation with age (r = −0.51; P < .001) (Figure 3A). Children aged 1 to 10 years had significantly higher median (IQR) SARS-CoV-2 IgG levels than adolescents aged 11 to 18 years (473 [233-656] RFU vs. 191 [82-349] RFU; P = .01) and young adults aged 19 to 24 years (85 [38-150] RFU; P < .001).

Adolescents also exhibited a significantly higher IgG level than young adults (191 [82-349] vs 85 [35-150]; P = .003) (Figure 4A). Similarly, the SARS-CoV-2 TAb levels in this subset patient cohort showed a negative correlation with age (r = −0.52; P < .001) (Figure 3B). Pediatric patients, both children aged 1 to 10 years and adolescents aged 11 to 18 years, showed higher median [IQR] SARS-CoV-2 TAb levels than young adults aged 19 to 24 years (children vs young adults: 2393 [1362-4346] RFU vs 370 [125-697] RFU; P < .001; adolescents vs young adults: 961 [290-2074] RFU vs 370 [125-697]; P = .006).

The SARS-CoV-2 SNAb activity and the binding avidity assays were used to assess the quality of the SARS-CoV-2 antibody. The %B/B0 was positively correlated with age (r = 0.50; P < .001) (Figure 3C), indicating an inverse correlation between SNAb activity and age. Similar to IgG and TAb, median (IQR) SNAb activities were higher in children (aged 1 to 10 years ) than adolescents (aged 11 to 18 years) (%B/B0: 21.5% [10.3% to 30.0%] vs 44.0% [25.0% to 65.3%]; P = .002) and young adults (aged 19 to 24 years) (%B/B0: 66.0% [37.5% to 79.5%]; P < .001).

Adolescents also exhibited higher median (IQR) SNAb activity than young adults (%B/B0: 44.0% [25.0% to 65.3%] vs 66.0% [37.5% to 79.5%]; P = .04) (Figure 4C). The relative dissociation rate between SARS-CoV-2 antibodies and the RBD exhibited a weak but significantly positive correlation with age (r = 0.29; P < .001) (Figure 3C), indicating a negative correlation between binding avidity and age.

While there was no significant difference between each age group, children aged 1 to 10 years old tended to exhibit lower median (IQR) relative dissociation rates and thus higher antibody binding avidity than young adults (5.7 × 10−4 [5.2 × 10−4 to 6.5 × 10−4] vs 6.3 × 10−4 [5.5 × 10−4 to 7.8 × 10−4]; P = .07) (Figure 4D).

reference link: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777743


More information: Wan Ni Chia, et al. Multifaceted dynamics of SARS-CoV-2 neutralising antibody responses predicts a wide range of immunity longevity from days to decades. The Lancet Microbe. doi.org/10.1016/S2666-5247(21)00025-2

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