ABSTRACT
Background: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between first and second dose extends. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose, the immunity after an extended interval between the first and second dose of ChAdOx1 nCoV-19(AZD1222), and the response to a third dose as a late booster. Methods: Volunteers aged 18-55 years who were enrolled in a Phase 1/2 or Phase 2/3 clinical trial of ChAdOx1 nCoV-19 and had received either a single dose or two doses of 5×10 10 viral particles were invited back for vaccination. Reactogenicity and immunogenicity of a delayed second dose or a third dose are reported here.Findings: Antibody titres after a single dose and measured on d362 remain higher than the titres measured on d0 (62.61 EU; 95% CI 47.43-82.64 vs 1 EU 95% CI 1-16). 30 participants received a late second dose of ChAdOx1 nCoV-19 (median 44 weeks after first dose), antibody titres were higher in those with a longer interval between first and second dose (median EU for 8-12, 15-25, and 44-46 weeks were 923 [IQR 525-1764], 1860 [IQR 917-4934] and 3738 [IQR 1824-6625] respectively). 90 participants received a third dose and antibody titres were significantly higher following a third dose (FRNT50 612 [IQR 351-920]) when compared with the response 28 days after a second dose (FRNT 50 319 [IQR 176-591]. T-cell responses were also boosted after a third dose. Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.Interpretation: A longer delay before the second dose of ChAdOx1 nCoV-19 leads to an increased antibody titre after the second dose. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlate with high efficacy after second dose and boosts T-cell responses.Funding: UK Research and Innovation (MC_PC_19055), Engineering and Physical Sciences Research Council (EP/R013756/1), National Institute for Health Research (COV19 OxfordVacc-01), Coalition for Epidemic Preparedness Innovations (Outbreak Response To Novel Coronavirus (COVID-19)), National Institute for Health Research Oxford Biomedical Research Centre (BRC4 Vaccines Theme), Thames Valley and South Midland’s NIHR Clinical Research Network, and AstraZeneca. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. SCG and AVSH are cofounders of and shareholders in Vaccitech (collaborators in the early development of this vaccine candidate) and named as inventors on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine (SCG only). TL is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and was a consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AJP is a NIHR Senior Investigator.Ethical Approval: In the UK, the COV001 and COV002 studies were approved by the South Central Berkshire Research Ethics Committee (COV001 reference 20/SC/0145, March 23, 2020; and COV002 reference 20/SC/0179; conditional approval April 8, full approval April 19, 2020).
Subject(s)
COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is normally controlled by effective host immunity including innate, humoral and cellular responses. However, the trajectories and correlates of acquired immunity, and the capacity of memory responses months after infection to neutralise variants of concern - which has important public health implications - is not fully understood. To address this, we studied a cohort of 78 UK healthcare workers who presented in April to June 2020 with symptomatic PCR-confirmed infection or who tested positive during an asymptomatic screening programme and tracked virus-specific B and T cell responses longitudinally at 5-6 time points each over 6 months, prior to vaccination. We observed a highly variable range of responses, some of which - T cell interferon-gamma (IFN-γ) ELISpot, N-specific antibody waned over time across the cohort, while others (spike-specific antibody, B cell memory ELISpot) were stable. In such cohorts, antiviral antibody has been linked to protection against re-infection. We used integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling Over Night) to explore this heterogeneity and to identify predictors of sustained immune responses. Hierarchical clustering defined a group of high and low antibody responders, which showed stability over time regardless of clinical presentation. These antibody responses correlated with IFN-γ ELISpot measures of T cell immunity and represent a subgroup of patients with a robust trajectory for longer term immunity. Importantly, this immune-phenotype associates with higher levels of neutralising antibodies not only against the infecting (Victoria) strain but also against variants B.1.1.7 (alpha) and B.1.351 (beta). Overall memory responses to SARS-CoV-2 show distinct trajectories following early priming, that may define subsequent protection against infection and severe disease from novel variants.
Subject(s)
COVID-19ABSTRACT
Background: The progress of the COVID-19 pandemic profoundly impacts the health of communities around the world, with unique impacts on colleges and universities. Transmission of SARS-CoV-2 by asymptomatic people is thought to be the underlying cause of a large proportion of new infections. However, the local prevalence of asymptomatic and pre-symptomatic carriers of SARS-CoV-2 is influenced by local public health restrictions and the community setting. Objectives: This study has three main objectives. First, we looked to establish the prevalence of asymptomatic SARS-CoV-2 infection on a university campus in California. Second, we sought to assess the changes in viral prevalence associated with the shifting community conditions related to non-pharmaceutical interventions (NPIs). Third, we aimed to compare the performance of CRISPR- and PCR-based assays for large-scale virus surveillance sampling in COVID-19 asymptomatic persons. Methods: We enrolled 1,808 asymptomatic persons for self-collection of oropharyngeal (OP) samples to undergo SARS-CoV-2 testing. We compared viral prevalence in samples obtained in two time periods: May 28th-June 11th; June 23rd-July 2nd. We detected viral genomes in these samples using two assays: CREST, a CRISPR-based method recently developed at UCSB, and the RT-qPCR test recommended by US Centers for Disease Control and Prevention (CDC). Results: Of the 1,808 participants, 1,805 were affiliates of the University of California, Santa Barbara, and 1,306 were students. None of the tests performed on the 732 samples collected between late May to early June were positive. In contrast, tests performed on the 1076 samples collected between late June to early July, revealed nine positive cases. This change in prevalence met statistical significance, p = 0.013. One sample was positive by RT-qPCR at the threshold of detection, but negative by both CREST and CLIA-confirmation testing. With this single exception, there was perfect concordance in both positive and negative results obtained by RT-qPCR and CREST. The estimated prevalence of the virus, calculated using the confirmed cases, was 0.74%. The average age of our sample population was 28.33 (18-75) years, and the average age of the positive cases was 21.7 years (19-30). Conclusions: Our study revealed that there were no COVID-19 cases in our study population in May/June. Using the same methods, we demonstrated a substantial shift in prevalence approximately one month later, which coincided with changes in community restrictions and public interactions. This increase in prevalence, in a young and asymptomatic population which would not have otherwise accessed COVID-19 testing, indicated the leading wave of a local outbreak, and coincided with rising case counts in the surrounding county and the state of California. Our results substantiate that large, population-level asymptomatic screening using self-collection may be a feasible and instructive aspect of the public health approach within large campus communities, and the almost perfect concordance between CRISPR- and PCR-based assays indicate expanded options for surveillance testing