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BackgroundMost studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. MethodsPlasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FindingsStrong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months. Nasal and plasma anti-S IgG remained elevated for at least 12 months with high plasma neutralising titres against all variants. Of 180 with complete data, 160 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal. Samples 12 months after admission showed no association between nasal IgA and plasma IgG responses, indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. InterpretationThe decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSWhile systemic immunity to SARS-CoV-2 is important in preventing severe disease, mucosal immunity prevents viral replication at the point of entry and reduces onward transmission. We searched PubMed with search terms "mucosal", "nasal", "antibody", "IgA", "COVID-19", "SARS-CoV-2", "convalescent" and "vaccination" for studies published in English before 20th July 2022, identifying three previous studies examining the durability of nasal responses that generally show nasal antibody to persist for 3 to 9 months. However, these studies were small or included individuals with mild COVID-19. One study of 107 care-home residents demonstrated increased salivary IgG (but not IgA) after two doses of mRNA vaccine, and another examined nasal antibody responses after infection and subsequent vaccination in 20 cases, demonstrating rises in both nasal IgA and IgG 7 to 10 days after vaccination. Added value of this studyStudying 446 people hospitalised for COVID-19, we show durable nasal and plasma IgG responses to ancestral (B.1 lineage) SARS-CoV-2, Delta and Omicron (BA.1) variants up to 12 months after infection. Nasal antibody induced by infection with pre-Omicron variants, bind Omicron virus in vitro better than plasma antibody. Although nasal and plasma IgG responses were enhanced by vaccination, Omicron binding responses did not reach levels equivalent to responses for ancestral SARS-CoV-2. Using paired plasma and nasal samples collected approximately 12 months after infection, we show that nasal IgA declines and shows a minimal response to vaccination whilst plasma antibody responses to S antigen are well maintained and boosted by vaccination. Implications of all the available evidenceAfter COVID-19 and subsequent vaccination, Omicron binding plasma and nasal antibody responses are only moderately enhanced, supporting the need for booster vaccinations to maintain immunity against SARS-CoV-2 variants. Notably, there is distinct compartmentalisation between nasal IgA and plasma IgA and IgG responses after vaccination. These findings highlight the need for vaccines that induce robust and durable mucosal immunity.
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Relationships between viral load, severity of illness, and transmissibility of virus, are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of viral load dynamics observed in the upper respiratory tract (URT), drawing upon 2172 serial measurements from 605 subjects, collected from 17 different studies. We developed a mechanistic model to describe viral load dynamics and host response, and contrast this with simpler mixed-effects regression analysis of peak viral load and its subsequent decline. We observed wide variation in URT viral load between individuals, over 5 orders of magnitude, at any given point in time since symptom onset. This variation was not explained by age, sex, or severity of illness, and these variables were not associated with the modelled early or late phases of immune-mediated control of viral load. We explored the application of the mechanistic model to identify measured immune responses associated with control of viral load. Neutralizing antibody correlated strongly with modelled immune-mediated control of viral load amongst subjects who produced neutralizing antibody. Our models can be used to identify host and viral factors which control URT viral load dynamics, informing future treatment and transmission blocking interventions.
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Introductory paragraphThe mechanisms that underpin COVID-19 disease severity, and determine the outcome of infection, are only beginning to be unraveled. The host inflammatory response contributes to lung injury, but circulating mediators levels fall below those in classical cytokine storms. We analyzed serial plasma samples from 619 patients hospitalized with COVID-19 recruited through the prospective multicenter ISARIC clinical characterization protocol U.K. study and 39 milder community cases not requiring hospitalization. Elevated levels of numerous mediators including angiopoietin-2, CXCL10, and GM-CSF were seen at recruitment in patients who later died. Markers of endothelial injury (angiopoietin-2 and von-Willebrand factor A2) were detected early in some patients, while inflammatory cytokines and markers of lung injury persisted for several weeks in fatal COVID-19 despite decreasing antiviral cytokine levels. Overall, markers of myeloid or endothelial cell activation were associated with severe, progressive, and fatal disease indicating a central role for innate immune activation and vascular inflammation in COVID-19.
