Superior immunity that allows neutralization of all SARS-CoV-2 variants of concern develops in COVID-19 convalescents and naïve individuals after three vaccinations

Infection-neutralizing antibody responses after SARS-CoV-2 infection or COVID-19 vaccination are an essential part of antiviral immunity. This immune protection is challenged by the occurrence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529) that is rapidly spreading worldwide. Here, we report neutralizing antibody dynamics in a longitudinal cohort of COVID-19 convalescent and naïve individuals vaccinated with mRNA BNT162b2 by quantifying anti-SARS-CoV-2-spike antibodies and determining their avidity and neutralization capacity. A superior infection-neutralizing capacity against all VoCs, including omicron, developed by either two vaccinations of convalescents, or a third vaccination or breakthrough infection of twice-vaccinated naïve individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. In conclusion, an infection/vaccination-induced hybrid immunity or a triple immunization induces high-quality antibodies resulting in superior neutralization capacity against VoCs, including omicron.

Durability of Antibody Responses to SARS-CoV-2 Infection and Its Relationship to Disease Severity Assessed Using a Commercially Available Assay

Background: Assessing the humoral immune response to SARS-CoV-2 is crucial for inferring protective immunity from reinfection and for assessing vaccine efficacy. Data regarding the durability and sustainability of SARS-CoV-2 antibodies are conflicting. In this study, we aimed to determine the seroconversion rate of SARS-CoV-2 infection in a cohort of reverse-transcriptase polymerase chain reaction (RT–PCR)-confirmed SARS-CoV-2 infections and the antibody dynamics, durability, and the correlation of antibody titers with disease severity using the commercially available SARS-CoV-2 anti-spike (S1/S2) protein.Methods: A total of 342 subjects with PCR-confirmed COVID-19 were enrolled. A total of 395 samples were collected at different time points (0–204) after the onset of symptoms or from the day of positive PCR in asymptomatic patients. Demographics, clinical presentation and the date of PCR were collected. All samples were tested using the automated commercial chemiluminescent system (DiaSorin SARS-CoV-2 S1/S2 IgG) on the LIAISONXL® platform (LIAISON).Results: The seroconversion rate for samples collected 14 days after the onset of infection was much higher than that for samples collected before 14 days (79.4% vs. 39.4%). The rate of seroconversion in symptomatic participants (62.1%) was similar to that of asymptomatic participants (56.1%) (p = 0.496). The IgG titer distribution was also similar across both groups (p = 0.142), with a median IgG level of 27.86 AU/ml (3.8–85.5) and 15 AU/ml (3.8–58.85) in symptomatic and asymptomatic participants, respectively. However, IgG titers were significantly higher in ICU patients, with a median of 104 AU/ml (3.8–179) compared to 34 AU/ml (3.8–70) in the non-ICU participants (p < 0.0001). Furthermore, the median time to seroconversion occurred significantly faster in ICU patients than in non-ICU participants (19 versus 47 days) (P < 0.0001). IgG titers were also higher in subjects ≥50 years compared to those <50 years (p < 0.009), male compared to female (p < 0.054) and non-Saudi compared to Saudi (p < 0.003). Approximately 74% of all samples tested beyond 120 days were positive.Conclusion: Antibodies can persist in circulation for longer than 4 months after COVID-19 infection. The majority of patients with COVID-19 mounted humoral immune responses to SARS-CoV-2 infection that strongly correlated with disease severity, older age and male gender. However, the population of individuals who tested negative should be further evaluated.

Reconstructing antibody dynamics to estimate the risk of influenza virus infection

For >70 years, a 4-fold or greater rise in antibody titer has been used to confirm influenza virus infections in paired sera, despite recognition that this heuristic can lack sensitivity. Here we analyze with a novel Bayesian model a large cohort of 2,353 individuals followed for up to 5 years in Hong Kong to characterize influenza antibody dynamics and develop an algorithm to improve the identification of influenza virus infections. After infection, we estimate that hemagglutination-inhibiting (HAI) titers were boosted by 16-fold on average and subsequently decrease by 14% per year. Greater boosting in HAI titer is observed in epidemics with a circulating strain that is different from the previous epidemic. In six epidemics, the infection risks for adults were 3%-19% while the infection risks for children were 1.6-4.4 times higher than that of younger adults. Every two-fold increase in pre-epidemic HAI titer was associated with 19%-58% protection against infection. Among the 1731 infections inferred by our model, around half were missed by the 4-fold rise criteria, suggesting that this criteria underestimates infection risks by 23-70%. The sensitivity and specificity of identifying infections for our approach are 87% (95% CrI: 85%, 89%) and 98% (95% CrI: 97%, 98%) respectively, which are higher than 82% (95% CrI: 80%, 84%) and 96% (95% CrI: 96%, 97%) for using 4-fold rise criteria. Our inferential framework clarifies the contributions of age and pre-epidemic HAI titers to characterize individual infection risk and offers an improved algorithm to identify influenza virus infections.

Prediction of long-term kinetics of vaccine-elicited neutralizing antibody and time-varying vaccine-specific efficacy against the SARS-CoV-2 Delta variant by clinical endpoint

Evidence on vaccine-specific protection over time and boosting impact against the Delta variant across different clinical endpoints and age groups is urgently needed. To address this, we used a previously published model, combined with neutralization data for four vaccines - mRNA-1273, BNT162b2, NVX-CoV2373, and CoronaVac - to evaluate long-term dynamics of neutralizing antibody and to predict time-varying efficacy against the Delta variant by specific vaccine, age group, and clinical severity. We found that booster vaccination produces higher neutralization titers compared with titers observed following primary-series vaccination for all vaccines studied. We estimate the efficacies of mRNA-1273 and BNT162b2 against Delta variant infection to be 63.5% (95%CI: 51.4-67.3%) and 78.4% (95%CI: 72.2-83.5%), respectively, 14-30 days after the second dose, and that efficacies decreased to 36.0% (95%CI: 24.1-58.0%) and 38.5% (95%CI: 28.7-49.1%) 6-8 months later. After administration of booster doses, efficacies against the Delta variant would be 97.0% (95%CI: 96.4-98.5%) and 97.2% (95.7-98.1%). All four vaccines are predicted to provide good protection against severe illness from the Delta variant after both primary and booster vaccination. Long-term monitoring and surveillance of antibody dynamics and vaccine protection, as well as further validation of neutralizing antibody or other markers that can serve as correlates of protection against SARS-CoV-2 and its variants are needed to inform COVID-19 pandemic preparedness.

Evaluation of Antibody Response in Sows after Vaccination with Senecavirus A Vaccine and the Effect of Maternal Antibody Transfer on Antibody Dynamics in Offspring

Senecavirus A (SVA) is a newly porcine virus that has been detected in many countries since its first detection in pigs in Canada in 2007, and it remains endemic in many countries in Asia and America, which has become a substantial problem for the pig industry. Vaccination is a potentially effective strategy for the prevention and control of SVA infection. Our lab has developed a SVA vaccine candidate previously. In this study, the antibody response to the prepared vaccine in sows and their offspring was evaluated. Vaccination of sows with inactivated SVA vaccines during pregnancy elicited SVA-specific virus-neutralizing antibodies. Vaccination with a high dose of SVA vaccine followed a booster immunization contributed to a long-term duration of the persistence of maternally derived neutralizing antibodies (MDAs) in the milk of the sows (>14 days). In contrast, vaccination with a single low dose of SVA vaccine resulted in a short-term persistence of MDAs in the milk (2–7 days). The MDAs could be efficiently transferred from the sows to their offspring through the colostrum/milk but not the umbilical cord blood. The antibody titers and the duration of the persistence of MDAs in the offspring are highly associated with the antibody levels in the milk from the sows. Vaccination of sows with a booster dose of SVA vaccine resulted in a longer-lasting MDAs in their offspring (persisted for at least 90 days). However, vaccination with the single low dose of vaccine only brought about 42 days of MDAs persistence in their offspring. The effect of MDAs on active immunization with SVA vaccine in offspring was further evaluated, which showed that vaccination of the SVA vaccine in the presence of MDAs at the titer of ≈1:64 or less could overcome the MDAs’ interference and give rise to effective antibody response. This will help for establishing the optimal times and schedules for SVA vaccination in pigs.

Single-Dose SARS-CoV-2 Vaccination With BNT162b2 and AZD1222 Induce Disparate Th1 Responses and IgA Production

While vaccination programs against SARS-CoV-2 are globally ongoing, disparate strategies for the deployment of spike antigen show varying effectiveness. In order to explore this phenomenon, we sought to compare the early immune responses against AZD1222 and BNT162b2. SARS-CoV-2 seronegative participants received a single dose of either vaccine and were analyzed for immune cell, effector T cell and antibody dynamics. AZD1222 induced transient leukopenia and major changes among innate and adaptive subpopulations. Both vaccines induced spike protein specific effector T cells which were dominated by Th1 responses following AZD1222 vaccination. A significant reduction of anti-inflammatory T cells upon re-stimulation was also restricted to AZD1222 vaccinees. While IgM and IgG were the dominant isotypes elicited by AZD1222, BNT162b2 led to a significant production of IgG and IgA. Our results suggest that the strategy for spike antigen delivery impacts on how and to what extent immune priming against the main SARS-CoV-2 antigen proceeds.

Differential antibody dynamics to SARS-CoV-2 infection and vaccination

ABSTRACTOptimal immune responses furnish long-lasting (durable) antibodies protective across dynamically mutating viral variants (broad). To assess robustness of mRNA vaccine-induced immunity, we compared antibody durability and breadth after SARS-CoV-2 infection and vaccination. While vaccination delivered robust initial virus-specific antibodies with some cross-variant coverage, pre-variant SARS-CoV-2 infection-induced antibodies, while modest in magnitude, showed highly stable long-term antibody dynamics. Vaccination after infection induced maximal antibody magnitudes with enhanced longitudinal stability while infection-naïve vaccinee antibodies fell with time to post-infection-alone levels. The composition of antibody neutralizing activity to variant relative to original virus also differed between groups, with infection-induced antibodies demonstrating greater relative breadth. Differential antibody durability trajectories favored COVID-19-recovered subjects with dual memory B cell features of greater early antibody somatic mutation and cross-coronavirus reactivity. By illuminating an infection-mediated antibody breadth advantage and an anti-SARS-CoV-2 antibody durability-enhancing function conferred by recalled immunity, these findings may serve as guides for ongoing vaccine strategy improvement.

Subacute Cognitive Impairment in Individuals With Mild and Moderate COVID-19: A Case Series

Background: Previous reported neurologic sequelae associated with SARS-CoV-2 infection have mainly been confined to hospital-based patients in which viral detection was restricted to nasal/throat swabs or to IgM/IgG peripheral blood serology. Here we describe seven cases from Brazil of outpatients with previous mild or moderate COVID-19 who developed subacute cognitive disturbances.Methods: From June 1 to August 15, 2020, seven individuals 18 to 60 years old, with confirmed mild/moderate COVID-19 and findings consistent with encephalopathy who were observed >7 days after respiratory symptom initiation, were screened for cognitive dysfunction. Paired sera and CSF were tested for SARS-CoV-2 (IgA, IgG ELISA, and RT-PCR). Serum and intrathecal antibody dynamics were evaluated with oligoclonal bands and IgG index. Cognitive dysfunction was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Clock Drawing Test (CDT).Results: All but one of our patients were female, and the mean age was 42.6 years. Neurologic symptoms were first reported a median of 16 days (IQR 15–33) after initial COVID-19 symptoms. All patients had headache and altered behavior. Cognitive dysfunction was observed mainly in phonemic verbal fluency (MoCA) with a median of six words/min (IQR 5.25–10.75) and altered visuospatial construction with a median of four points (IQR 4–9) (CDT). CSF pleocytosis was not detected, and only one patient was positive for SARS-CoConclusions: A subacute cognitive syndrome suggestive of SARS-CoV-2-initiated damage to cortico-subcortical associative pathways that could not be attributed solely to inflammation and hypoxia was present in seven individuals with mild/moderate COVID-19.