ABSTRACT
Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.
ABSTRACT
The emergence of successive SARS-CoV-2 variants of concern (VOC) during 2020-22, each exhibiting increased epidemic growth relative to earlier circulating variants, has created a need to understand the drivers of such growth. However, both pathogen biology and changing host characteristics - such as varying levels of immunity - can combine to influence replication and transmission of SARS-CoV-2 within and between hosts. Disentangling the role of variant and host in individual-level viral shedding of VOCs is essential to inform COVID-19 planning and response, and interpret past epidemic trends. Using data from a prospective observational cohort study of healthy adult volunteers undergoing weekly occupational health PCR screening, we developed a Bayesian hierarchical model to reconstruct individual-level viral kinetics and estimate how different factors shaped viral dynamics, measured by PCR cycle threshold (Ct) values over time. Jointly accounting for both inter-individual variation in Ct values and complex host characteristics - such as vaccination status, exposure history and age - we found that age and number of prior exposures had a strong influence on peak viral replication. Older individuals and those who had at least five prior antigen exposures to vaccination and/or infection typically had much lower levels of shedding. Moreover, we found evidence of a correlation between the speed of early shedding and duration of incubation period when comparing different VOCs and age groups. Our findings illustrate the value of linking information on participant characteristics, symptom profile and infecting variant with prospective PCR sampling, and the importance of accounting for increasingly complex population exposure landscapes when analysing the viral kinetics of VOCs.
Subject(s)
COVID-19ABSTRACT
T cell correlates of protection against SARS-CoV-2 infection after vaccination ('vaccine breakthrough') are incompletely defined, especially the specific contributions of CD4+ and CD8+ T cells. We studied 279 volunteers in the Protective Immunity from T Cells in Healthcare Workers (PITCH) UK study, including 32 cases (with SARS-CoV-2 positive testing after two vaccine doses during the Delta-dominant era) and 247 controls (no positive test nor anti-nucleocapsid seroconversion during this period). 28 days after second vaccination, before all breakthroughs occurred, cases had lower ancestral S- and RBD-specific immunoglobulin G titres and S1- and S2-specific T cell interferon gamma (IFN{gamma}) responses compared with controls. In a subset of matched cases and controls, cases had lower CD4+ and CD8+ IFN{gamma} and tumour necrosis factor responses to Delta S peptides with reduced CD8+ responses to Delta versus ancestral peptides compared with controls. Our findings support a protective role for T cells against Delta breakthrough infection.
Subject(s)
Necrosis , Breakthrough Pain , COVID-19ABSTRACT
Background Patients on kidney replacement therapy (KRT; dialysis and kidney transplantation) are at the highest risk of severe outcomes from COVID-19. Due to limited inclusion of patients on KRT in clinical trials, information is limited on the effectiveness of sotrovimab (a neutralising monoclonal antibody). We sought to address this by comparing its effectiveness against molnupiravir (an antiviral) in preventing severe COVID-19 outcomes in non-hospitalised adults with symptomatic COVID-19. Methods With the approval of NHS England we used routine clinical data from 24 million patients in England linked to the UK Renal Registry (UKRR) to identify patients on KRT, and data on antiviral treatments, COVID-19 test results, hospitalisation events and death from the OpenSAFELY-TPP data resource. Cox proportional hazards models (stratified for region) were used to estimate hazard ratios of sotrovimab vs. molnupiravir with regards to COVID-19 related hospitalisation or deaths in the subsequent 28 days (as the primary outcome). Further analyses were conducted using propensity score weighting (adjusted for region) and to investigate robustness of results with regards to different time periods, missing data, and adjustment variables. We also conducted a complementary analysis using data from patients in the Scottish Renal Registry (SRR) treated with sotrovimab or molnupiravir, following similar analytical approaches. Results Among the 2367 renal patients treated with sotrovimab (n=1852) or molnupiravir (n=515) between December 16, 2021 and August 1, 2022 in England, 38 cases (1.6%) of COVID-19 related hospitalisations/deaths were observed during the 28 days of follow-up after treatment initiation, with 21 (1.1%) in the sotrovimab group and 17 (3.3%) in the molnupiravir group. In multiple-adjusted analysis sotrovimab was associated with substantially lower risk of 28-day COVID-19 related hospitalisation/death than treatment with molnupiravir (hazard ratio, HR=0.35, 95% CI: 0.17 to 0.71; P=0.004), with results remaining robust in sensitivity analyses. In the SRR cohort, there were 19 cases (1.9%) of COVID-19 related hospitalisations/deaths during the 28 days of follow-up after treatment initiation of sotrovimab (n=723) or molnupiravir (n=270). In multiple-adjusted analysis, sotrovimab showed a trend toward lower risk of 28-day COVID-19 related hospitalisation/death than treatment with molnupiravir (HR=0.40, 95% CI: 0.13 to 1.21; P=0.106). In both datasets, sotrovimab had no evidence of association with other hospitalisation/death compared with molnupiravir (HRs ranging from 0.73-1.20; P>0.05). Conclusions In routine care of non-hospitalised patients with COVID-19 on kidney replacement therapy, those who received sotrovimab had substantially lower risk of severe COVID-19 outcomes than those receiving molnupiravir.
Subject(s)
COVID-19 , DeathABSTRACT
Background: Kidney disease is a key risk factor for COVID-19-related mortality and suboptimal vaccine response. Optimising vaccination strategies is essential to reduce the disease burden in this vulnerable population. Methods: With the approval of NHS England, we performed a retrospective cohort study to estimate the comparative effectiveness of schedules involving AZD1222 (AZ; ChAdOx1-S) and BNT162b2 (BNT) among people with kidney disease. Using linked primary care and UK Renal Registry records in the OpenSAFELY-TPP platform, we identified adults with stage 3-5 chronic kidney disease, dialysis recipients, and kidney transplant recipients. We used Cox proportional hazards models to compare COVID-19-related outcomes and non-COVID-19 death after two-dose (AZ-AZ vs BNT-BNT) and three-dose (AZ-AZ-BNT vs BNT-BNT-BNT) schedules. Findings: After two doses, incidence during the Delta wave was higher in AZ-AZ (n=257,580) than BNT-BNT recipients (n=169,205; adjusted hazard ratios [95% CIs] 1.43 [1.37-1.50], 1.59 [1.43-1.77], 1.44 [1.12-1.85], and 1.09 [1.02-1.17] for SARS-CoV-2 infection, COVID-19-related hospitalisation, COVID-19-related death, and non-COVID-19 death, respectively). Findings were consistent across disease subgroups, including dialysis and transplant recipients. After three doses, there was little evidence of differences between AZ-AZ-BNT (n=220,330) and BNT-BNT-BNT recipients (n=157,065) for any outcome during a period of Omicron dominance. Interpretation: Among individuals with moderate-to-severe kidney disease, two doses of BNT conferred stronger protection than AZ against SARS-CoV-2 infection and severe disease. A subsequent BNT dose levelled the playing field, emphasising the value of heterologous RNA doses in vulnerable populations.
Subject(s)
COVID-19 , Renal Insufficiency, Chronic , Kidney Diseases , DeathABSTRACT
Introduction The impact of COVID-19 vaccination on disease in the community has been limited, as a result of both SARS-CoV-2 Variants of Concern that partially escape vaccine-induced immunity. We sought to characterise symptoms and viral loads over the course of COVID-19 infection in otherwise-healthy vaccinated adults, representative of the general population, to assess whether current self-isolation guidance remains justified. Methods In a prospective, observational cohort study, healthy vaccinated UK adults who reported a positive PCR or lateral flow test, self-swabbed on alternate days until day 10. We compared symptoms and viral kinetics between infections caused by VOCs Delta and Omicron (sub-variants BA.1 and BA.2) and investigated applicability of UK NHS isolation guidelines to these newer VOCs. Results 373 infection episodes were reported among 349 participants. Across VOCs, symptom duration was similar, however symptom profiles differed significantly among infections caused by Delta, Omicron BA.1 and BA.2. Anosmia was reported in <10% of participants with BA.1 and BA.2, compared to 42% with Delta infection, coryza fatigue and myalgia predominated. Most notably, viral load trajectories and peaks did not differ between Delta, BA.1 and BA.2, irrespective of symptom severity, VOC or vaccination status. Conclusion COVID-19 isolation guidance should not differ based on symptom severity or febrile illness and must remain under review as new SARS-CoV-2 VOCs emerge and population immunity changes. Our study emphasises the ongoing transmission risk of Omicron sub-variants in vaccinated adults with mild symptoms that may extend beyond current isolation periods.
Subject(s)
Hepatitis D , Fever , Olfaction Disorders , Common Cold , Myalgia , COVID-19ABSTRACT
BackgroundKidney disease is a significant risk factor for COVID-19-related mortality. Achieving high COVID-19 vaccine coverage among people with kidney disease is therefore a public health priority. MethodsWith the approval of NHS England, we performed a retrospective cohort study using the OpenSAFELY-TPP platform. Individual-level routine clinical data from 24 million people in England were included. A cohort of individuals with stage 3-5 chronic kidney disease (CKD) or receiving renal replacement therapy (RRT) at the start of the COVID-19 vaccine roll-out was identified based on evidence of reduced estimated glomerular filtration rate or inclusion in the UK Renal Registry. Individual-level factors associated with vaccine uptake were explored via Cox proportional hazards models. Results948,845 people with stage 3-5 CKD or receiving RRT were included. Cumulative vaccine coverage as of 11th May 2022 was 97.5%, 97.0%, and 93.5% for doses 1, 2, and 3, respectively, and 61.1% among individuals with one or more indications for receipt of a fourth dose. Delayed 3-dose vaccine uptake was associated with non-White ethnicity, social deprivation, and severe mental illness - associations that were consistent across CKD stages and in RRT recipients. Similar associations were observed for 4-dose uptake, which was also delayed among care home residents. ConclusionAlthough high primary and booster dose coverage has been achieved among people with kidney disease in England, key disparities in vaccine uptake remain across demographic groups. Identifying how to address these disparities remains a priority to reduce the risk of severe disease in this vulnerable patient group.