Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection (preprint)

The rapid emergence of new SARS-CoV-2 variants challenges vaccination strategies. Here, we measured antigenic diversity among variants and interpreted neutralizing antibody responses following single and multiple exposures in longitudinal infection and vaccine cohorts. Antigenic cartography using primary infection antisera showed that BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and closer to the Beta cluster. Three doses of an mRNA COVID-19 vaccine increased breadth to BA.1 more than to BA.4/BA.5 or BA.2.12.1. Omicron BA.1 post-vaccination infection elicited antibody landscapes characterized by broader immunity across antigenic space than three doses alone, although with less breadth than expected to BA.2.12.1 and BA.4/BA.5. Those with Omicron BA.1 infection after two or three vaccinations had similar neutralizing titer magnitude and antigenic breadth. Accounting for antigenic differences among variants of concern when interpreting neutralizing antibody titers aids understanding of complex patterns in humoral immunity and informs selection of future COVID-19 vaccine strains.

Topological data analysis identifies distinct biomarker phenotypes during the inflammatory phase of COVID-19 (preprint)

OBJECTIVES: The relationships between baseline clinical phenotypes and the cytokine milieu of the peak inflammatory phase of coronavirus 2019 (COVID-19) are not yet well understood. We used Topological Data Analysis (TDA), a dimensionality reduction technique to identify patterns of inflammation associated with COVID-19 severity and clinical characteristics. DESIGN: Exploratory analysis from a multi-center prospective cohort study. SETTING: Eight military hospitals across the United States between April 2020 and January 2021. PATIENTS: Adult ([≥]18 years of age) SARS-CoV-2 positive inpatient and outpatient participants were enrolled with plasma samples selected from the putative inflammatory phase of COVID-19, defined as 15-28 days post symptom onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Concentrations of 12 inflammatory protein biomarkers were measured using a broad dynamic range immunoassay. TDA identified 3 distinct inflammatory protein expression clusters. Peak severity (outpatient, hospitalized, ICU admission or death), Charlson Comorbidity Index (CCI), and body mass index (BMI) were evaluated with logistic regression for associations with each cluster. The study population (n=129, 33.3% female, median 41.3 years of age) included 77 outpatient, 31 inpatient, 16 ICU-level, and 5 fatal cases. Three distinct clusters were found that differed by peak disease severity (p <0.001), age (p <0.001), BMI (p<0.001), and CCI (p=0.001). CONCLUSIONS: Exploratory clustering methods can stratify heterogeneous patient populations and identify distinct inflammation patterns associated with comorbid disease, obesity, and severe illness due to COVID-19.

SARS-CoV-2 Omicron neutralization by therapeutic antibodies, convalescent sera, and post-mRNA vaccine booster (preprint)

The rapid spread of the highly contagious Omicron variant of SARS-CoV-2 along with its high number of mutations in the spike gene has raised alarm about the effectiveness of current medical countermeasures. To address this concern, we measured neutralizing antibodies against Omicron in three important settings: (1) post-vaccination sera after two and three immunizations with the Pfizer/BNT162b2 vaccine, (2) convalescent sera from unvaccinated individuals infected by different variants, and (3) clinical-stage therapeutic antibodies. Using a pseudovirus neutralization assay, we found that titers against Omicron were low or undetectable after two immunizations and in most convalescent sera. A booster vaccination significantly increased titers against Omicron to levels comparable to those seen against the ancestral (D614G) variant after two immunizations. Neither age nor sex were associated with differences in post-vaccination antibody responses. Only three of 24 therapeutic antibodies tested retained their full potency against Omicron and high-level resistance was seen against fifteen. These findings underscore the potential benefit of booster mRNA vaccines for protection against Omicron and the need for additional therapeutic antibodies that are more robust to highly mutated variants. One Sentence Summary Third dose of Pfizer/BioNTech COVID-19 vaccine significantly boosts neutralizing antibodies to the Omicron variant compared to a second dose, while neutralization of Omicron by convalescent sera, two-dose vaccine-elicited sera, or therapeutic antibodies is variable and often low.

SARS-CoV-2 antibodies remain detectable 12 months after infection and antibody magnitude is associated with age and COVID-19 severity (preprint)

Importance: The persistence of SARS-CoV-2 antibodies may be a predictive correlate of protection for both natural infections and vaccinations. Identifying predictors of robust antibody responses is important to evaluate the risk of re-infection / vaccine failure and may be translatable to vaccine effectiveness. Objective: To 1) determine the durability of anti-SARS-CoV-2 IgG and neutralizing antibodies in subjects who experienced mild and moderate to severe COVID-19, and 2) to evaluate the correlation of age and IgG responses to both endemic human seasonal coronaviruses (HCoVs) and SARS-CoV-2 according to infection outcome. Design: Longitudinal serum samples were collected from PCR-confirmed SARS-CoV-2 positive participants (U.S. active duty service members, dependents and military retirees, including a range of ages and demographics) who sought medical treatment at seven U.S. military hospitals from March 2020 to March 2021 and enrolled in a prospective observational cohort study. Results: We observed SARS-CoV-2 seropositivity in 100% of inpatients followed for six months (58/58) to one year (8/8), while we observed seroreversion in 5% (9/192) of outpatients six to ten months after symptom onset, and 18% (2/11) of outpatients followed for one year. Both outpatient and inpatient anti-SARS-CoV-2 binding-IgG responses had a half-life (T1/2) of >1000 days post-symptom onset. The magnitude of neutralizing antibodies (geometric mean titer, inpatients: 378 [246-580, 95% CI] versus outpatients: 83 [59-116, 95% CI]) and durability (inpatients: 65 [43-98, 95% CI] versus outpatients: 33 [26-40, 95% CI]) were associated with COVID-19 severity. Older age was a positive correlate with both higher IgG binding and neutralizing antibody levels when controlling for COVID-19 hospitalization status. We found no significant relationships between HCoV antibody responses and COVID-19 clinical outcomes, or the development of SARS-CoV-2 neutralizing antibodies. Conclusions and Relevance: This study demonstrates that humoral responses to SARS-CoV-2 infection are robust on longer time-scales, including those arising from milder infections.