RESUMEN
Age is a major risk factor for hospitalization and death after SARS-CoV-2 infection, even in vaccinees. Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here we show that individuals 70 or older who received a primary two dose schedule with AZD1222 and booster third dose with mRNA vaccine achieved significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared to those younger than 70. One month after the booster neither the concentration of serum binding anti spike IgG antibody, nor the frequency of spike-specific B cells showed differences by age grouping. However, the impaired neutralization potency and breadth post-third dose in the elderly was associated with enrichment of circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. Single cell RNA sequencing confirmed an expansion of TBX21-, ITGAX-expressing B cells in the elderly that enriched for B cell activation/receptor signalling pathway genes. Importantly we also observed impaired T cell responses to SARS-CoV-2 spike peptides in the elderly post-booster, both in terms of IFNgamma and IL2 secretion, as well as a decrease in T cell receptor signalling pathway genes. This expansion of atypical B cells and impaired T cell responses may contribute to the generation of less affinity-matured antibodies, with lower neutralizing capacity post-third dose in the elderly. Altogether, our data reveal the extent and potential mechanistic underpinning of the impaired vaccine responses present in the elderly after a booster dose, contributing to their increased susceptibility to COVID-19 infection.
RESUMEN
Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.
RESUMEN
Two dose mRNA vaccination provides excellent protection against SARS-CoV-2. However, there are few data on vaccine efficacy in elderly individuals above the age of 801. Additionally, new variants of concern (VOC) with reduced sensitivity to neutralising antibodies have raised fears for vulnerable groups. Here we assessed humoral and cellular immune responses following vaccination with mRNA vaccine BNT162b22 in elderly participants prospectively recruited from the community and younger health care workers. Median age was 72 years and 51% were females amongst 140 participants. Neutralising antibody responses after the first vaccine dose diminished with increasing age, with a marked drop in participants over 80 years old. Sera from participants below and above 80 showed significantly lower neutralisation potency against B.1.1.7, B.1.351 and P.1. variants of concern as compared to wild type. Those over 80 were more likely to lack any neutralisation against VOC compared to younger participants following first dose. The adjusted odds ratio for inadequate neutralisation activity against the B.1.1.7, P.1 and B.1.351 variant in the older versus younger age group was 4.3 (95% CI 2.0-9.3, p<0.001), 6.7 (95% CI 1.7-26.3, p=0.008) and 1.7 (95% CI 0.5-5.7, p=0.41). Binding IgG and IgA antibodies were lower in the elderly, as was the frequency of SARS-CoV-2 Spike specific B-memory cells. We observed a trend towards lower somatic hypermutation in participants with suboptimal neutralisation, and elderly participants demonstrated clear reduction in class switched somatic hypermutation, driven by the IgA1/2 isotype. SARS-CoV-2 Spike specific T-cell IFN{gamma} and IL-2 responses fell with increasing age, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high risk population that warrant specific measures in order to mitigate against vaccine failure, particularly where variants of concern are circulating.
RESUMEN
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
RESUMEN
SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and{Delta} H69/{Delta}V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing{Delta} H69/{Delta}V70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The{Delta} H69/{Delta}V70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against{Delta} H69/{Delta}V70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.
RESUMEN
BackgroundThe COVID-19 pandemic continues to grow at an unprecedented rate. Healthcare workers (HCWs) are at higher risk of SARS-CoV-2 infection than the general population but risk factors for HCW infection are not well described. MethodsWe conducted a prospective sero-epidemiological study of HCWs at a UK teaching hospital using a SARS-CoV-2 immunoassay. Risk factors for seropositivity were analysed using multivariate logistic regression. Findings410/5,698 (7{middle dot}2%) staff tested positive for SARS-CoV-2 antibodies. Seroprevalence was higher in those working in designated COVID-19 areas compared with other areas (9{middle dot}47% versus 6{middle dot}16%) Healthcare assistants (aOR 2{middle dot}06 [95%CI 1{middle dot}14-3{middle dot}71]; p=0{middle dot}016) and domestic and portering staff (aOR 3{middle dot}45 [95% CI 1{middle dot}07-11{middle dot}42]; p=0{middle dot}039) had significantly higher seroprevalence than other staff groups after adjusting for age, sex, ethnicity and COVID-19 working location. Staff working in acute medicine and medical sub-specialities were also at higher risk (aOR 2{middle dot}07 [95% CI 1{middle dot}31-3{middle dot}25]; p<0{middle dot}002). Staff from Black, Asian and minority ethnic (BAME) backgrounds had an aOR of 1{middle dot}65 (95% CI 1{middle dot}32 - 2{middle dot}07; p<0{middle dot}001) compared to white staff; this increased risk was independent of COVID-19 area working. The only symptoms significantly associated with seropositivity in a multivariable model were loss of sense of taste or smell, fever and myalgia; 31% of staff testing positive reported no prior symptoms. InterpretationRisk of SARS-CoV-2 infection amongst HCWs is heterogeneous and influenced by COVID-19 working location, role, age and ethnicity. Increased risk amongst BAME staff cannot be accounted for solely by occupational factors. FundingWellcome Trust, Addenbrookes Charitable Trust, National Institute for Health Research, Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre. Research in context Evidence before this studySpecific risk factors for SARS-CoV-2 infection in healthcare workers (HCWs) are not well defined. Additionally, it is not clear how population level risk factors influence occupational risk in defined demographic groups. Only by identifying these factors can we mitigate and reduce the risk of occupational SARS-CoV-2 infection. We performed a review of the evidence for HCW-specific risk factors for SARS-CoV-2 infection. We searched PubMed with the terms "SARS-CoV-2" OR "COVID-19" AND "Healthcare worker" OR "Healthcare Personnel" AND "Risk factor" to identify any studies published in any language between December 2019 and September 2020. The search identified 266 studies and included a meta-analysis and two observational studies assessing HCW cohort seroprevalence data. Seroprevalence and risk factors for HCW infections varied between studies, with contradictory findings. In the two serological studies, one identified a significant increased risk of seroprevalence in those working with COVID-19 patients (Eyre et al 2020), as well as associations with job role and department. The other study (Dimcheff et al 2020) found no significant association between seropositivity and any identified demographic or occupational factor. A meta-analysis of HCW (Gomez-Ochoa et al 2020) assessed >230,000 participants as a pooled analysis, including diagnoses by both RT-PCR and seropositivity for SARS-CoV-2 antibodies and found great heterogeneity in study design and reported contradictory findings. Of note, they report a seropositivity rate of 7% across all studies reporting SARS-CoV-2 antibodies in HCWs. Nurses were the most frequently affected healthcare personnel and staff working in non-emergency inpatient settings were the most frequently affected group. Our search found no prospective studies systematically evaluating HCW specific risk factors based entirely on seroprevalence data. Added value of this studyOur prospective cohort study of almost 6,000 HCWs at a large UK teaching hospital strengthens previous findings from UK-based cohorts in identifying an increased risk of SARS-CoV-2 exposure amongst HCWs. Specifically, factors associated with SARS-CoV-2 exposure include caring for confirmed COVID-19 cases and identifying as being within specific ethnic groups (BAME staff). We further delineated the risk amongst BAME staff and demonstrate that occupational factors alone do not account for all of the increased risk amongst this group. We demonstrate for the first time that healthcare assistants represent a key at-risk occupational group, and challenge previous findings of significantly higher risk amongst nursing staff. Seroprevalence in staff not working in areas with confirmed COVID-19 patients was only marginally higher than that of the general population within the same geographical region. This observation could suggest the increased risk amongst HCWs arises through occupational exposure to confirmed cases and could account for the overall higher seroprevalence in HCWs, rather than purely the presence of staff in healthcare facilities. Over 30% of seropositive staff had not reported symptoms consistent with COVID-19, and in those who did report symptoms, differentiating COVID-19 from other causes based on symptom data alone was unreliable. Implications of all the available evidenceInternational efforts to reduce the risk of SARS-CoV-2 infection amongst HCWs need to be prioritised. The risk of SARS-CoV-2 infection amongst HCWs is heterogenous but also follows demonstrable patterns. Potential mechanisms to reduce the risk for staff working in areas with confirmed COVID-19 patients include improved training in hand hygiene and personal protective equipment (PPE), better access to high quality PPE, and frequent asymptomatic testing. Wider asymptomatic testing in healthcare facilities has the potential to reduce spread of SARS-CoV-2 within hospitals, thereby reducing patient and staff risk and limiting spread between hospitals and into the wider community. The increased risk of COVID-19 amongst BAME staff cannot be explained by purely occupational factors; however, the increased risk amongst minority ethnic groups identified here was stark and necessitates further evaluation.
