Nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination.

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.

Clinical characteristics with inflammation profiling of Long-COVID and association with one-year recovery following hospitalisation in the UK: a prospective observational study

BackgroundThere are currently no effective pharmacological or non-pharmacological interventions for Long-COVID. To identify potential therapeutic targets, we focussed on previously described four recovery clusters five months after hospital discharge, their underlying inflammatory profiles and relationship with clinical outcomes at one year. MethodsPHOSP-COVID is a prospective longitudinal cohort study, recruiting adults hospitalised with COVID-19 across the UK. Recovery was assessed using patient reported outcomes measures (PROMs), physical performance, and organ function at five-months and one-year after hospital discharge. Hierarchical logistic regression modelling was performed for patient-perceived recovery at one-year. Cluster analysis was performed using clustering large applications (CLARA) k-medoids approach using clinical outcomes at five-months. Inflammatory protein profiling from plasma at the five-month visit was performed. Findings2320 participants have been assessed at five months after discharge and 807 participants have completed both five-month and one-year visits. Of these, 35{middle dot}6% were female, mean age 58{middle dot}7 (SD 12{middle dot}5) years, and 27{middle dot}8% received invasive mechanical ventilation (IMV). The proportion of patients reporting full recovery was unchanged between five months 501/1965 (25{middle dot}5%) and one year 232/804 (28{middle dot}9%). Factors associated with being less likely to report full recovery at one year were: female sex OR 0{middle dot}68 (95% CI 0{middle dot}46-0{middle dot}99), obesity OR 0{middle dot}50 (95%CI 0{middle dot}34-0{middle dot}74) and IMV OR 0{middle dot}42 (95%CI 0{middle dot}23-0{middle dot}76). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate/cognitive, mild relating to the severity of physical, mental health and cognitive impairments at five months in a larger sample. There was elevation of inflammatory mediators of tissue damage and repair in both the very severe and the moderate/cognitive clusters compared to the mild cluster including interleukin-6 which was elevated in both comparisons. Overall, there was a substantial deficit in median (IQR) EQ5D-5L utility index from pre-COVID (retrospective assessment) 0{middle dot}88 (0{middle dot}74-1{middle dot}00), five months 0{middle dot}74 (0{middle dot}60-0{middle dot}88) to one year: 0{middle dot}74 (0{middle dot}59-0{middle dot}88), with minimal improvements across all outcome measures at one-year after discharge in the whole cohort and within each of the four clusters. InterpretationThe sequelae of a hospital admission with COVID-19 remain substantial one year after discharge across a range of health domains with the minority in our cohort feeling fully recovered. Patient perceived health-related quality of life remains reduced at one year compared to pre-hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. FundingUKRI & NIHR Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Embase databases for large studies reporting one-year follow-up data for hospitalised COVID-19 patients published between January 1, 2021 and November 7, 2021, without language restrictions. Search terms related to COVID-19, hospitalisation and long-term follow-up were used. A large prospective cohort study from Wuhan, China (n = 1276) showed that 49% of patients reported at least one persistent symptom during a follow-up clinic visit at 12 months post COVID-19; no significant improvement in exercise capacity was observed between six- and 12-month visits. Another two large cohort studies in China (n = 2433) and Spain (n = 1950) with one-year follow-up data from telephone interviews showed that 45% and 81% of patients reported at least one residual COVID-19 symptom, respectively. However, no previous studies have compared the trajectories of COVID-19 recovery in patients classified by different clinical phenotypes, and there are no large studies investigating the relationship between systemic inflammation and ongoing health impairments post COVID-19. Added value of this studyIn a diverse population of adults post-hospital admission with COVID-19, our large UK prospective multi-centre study reports several novel findings: the minority felt fully recovered at one year with minimal recovery from five months across any health domain; female sex and obesity are associated with being less likely to feel fully recovered at one year; several inflammatory mediators were increased in individuals with the most severe physical, mental health, and cognitive impairments compared to individuals with milder ongoing impairments. Implications of all the available evidenceBoth pharmacological and non-pharmacological interventions are urgently needed to improve the ongoing burden following hospitalisation for COVID-19 both for individuals and healthcare systems; our findings support the use of a precision medicine approach with potential treatable traits of systemic inflammation and obesity.