Keating, R. | bioRxiv Science

bioRxiv2023

Mucosal and systemic immune dynamics associated with COVID-19 outcomes: a longitudinal prospective clinical study

RationaleCOVID-19 severity varies widely; children and African Americans have low and high risk, respectively. Mechanistic data from these groups and the mucosa is lacking. ObjectivesTo quantify mucosal and systemic viral and immune dynamics in a diverse cohort to identify mechanisms underpinning COVID-19 severity and outcome predictors. MethodsIn this prospective study of unvaccinated children and adults COVID-19 outcome was based on an ordinal clinical severity scale. We quantified viral RNA, antigens, antibodies, and cytokines by PCR, ELISA, and Luminex from 579 longitudinally collected blood and nasal specimens from 78 subjects including 45 women and used modeling to determine functional relationships between these data. Measurements and Main ResultsCOVID-19 induced unique immune responses in African Americans (n=26) and children (n=20). Mild outcome was associated with more effective coordinated responses whereas moderate and severe outcomes had rapid seroconversion, significantly higher antigen, mucosal sCD40L, MCP-3, MCP-1, MIP-1, and MIP-1{beta}, and systemic IgA, IgM, IL-6, IL-8, IL-10, IL-15, IL-1RA, and IP-10, and uncoordinated early immune responses that went unresolved. Mucosal IL-8, IL-1{beta}, and IFN-{gamma} with systemic IL-1RA and IgA predicted COVID-19 outcomes. ConclusionsWe present novel mucosal data, biomarkers, and therapeutic targets from a diverse cohort. Based on our findings, children and African Americans with COVID-19 have significantly lower IL-6 and IL-17 levels which may reduce responsiveness to drugs targeting IL-6 and IL-17. Unregulated immune responses persisted indicating moderate to severe COVID-19 cases may require prolonged treatments. Reliance on slower acting adaptive responses may cause immune crisis for some adults who encounter a novel virus. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSDespite the disparate outcomes for African Americans and children with COVID-19 and the vital role of mucosal immunity, the majority of mechanistic clinical studies lack these groups and mucosal assessments. To date, mucosal immune responses to SARS-CoV-2 has not been adequately described and we lack data from these understudied groups. What This Study Adds to the FieldThis was a prospective cohort study of children and adults with confirmed COVID-19. Mortality was low (2.5%). Severity outcomes were associated with African American Race, shortness of breath, fever, respiratory disease, high blood pressure, and diabetes. We systematically characterized viral and immune factors in the mucosa and periphery and observed that moderate and severe COVID-19 were associated with longer duration, impaired clearance, early overexuberant antibody and cytokine production that was sustained. This study demonstrates that African Americans are at high risk of severe COVID-19 and display unique mucosal and peripheral immune responses. Children with COVID-19 also had distinct immune responses. This illustrates the importance of vaccination and careful clinical oversight of these populations (e.g., lower IL-6 and IL-17 levels may diminish tocilizumab, siltuximab, secukinumab, and brodalumab efficacy). This study identified generalizable outcomes predictors, systemic IL-1RA with mucosal IL-1{beta} and IL-8, and demonstrated the utility of mucosal sampling from diverse cohorts.

immunology↗

bioRxiv2020

Broadly reactive influenza antibodies are not limited by germinal center competition with high affinity antibodies

Enhancing the generation of broadly reactive influenza antibodies is a pertinent goal towards developing a universal influenza vaccine. While antibodies that bind conserved influenza epitopes have been identified in humans, the frequency of these antibodies is typically very low. The predominant theory is that antibodies specific for conserved influenza epitopes are limited in germinal centers by competition with high affinity antibodies specific for the variable region of the virus. Here, we show that reducing germinal center formation and removing competition with high affinity antibodies was not sufficient to increase broadly reactive influenza antibodies or enhance protection against distinct influenza subtypes. These data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to competition in germinal centers. Additionally, levels of IgM antibodies specific for the variable region of HA persisted in mice in the absence of germinal centers, further demonstrating that immunodominance can be established independent of germinal centers. Our data also highlight the protective capacity of germinal center-independent IgM antibodies, which are not typically considered when testing correlates of protection, and offer an alternate target for delivering a universal influenza vaccine. IMPORTANCEIt is estimated that 250,000 - 650,000 individuals worldwide die each year from seasonal influenza infections. Current vaccines provide little protection against newly emerging strains. Thus, considerable effort is focused on enhancing the generation of broadly reactive influenza antibodies in order to develop a universal influenza vaccine. However, broadly reactive antibodies are rare and the factors that limit their generation are not completely understood. Our data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to completion in the germinal centers with antibodies to the variable HA head. Understanding the factors limiting antibodies specific for conserved regions of the influenza virus is imperative for developing a universal vaccine, which could potentially circumvent a global pandemic

immunology↗