Safety and immunogenicity of a variant-adapted SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant as a booster in adults primed with authorized vaccines

BackgroundBooster vaccines providing protection against emergent SARS-CoV-2 variants are needed. In an international phase 3 study, we evaluated booster vaccines containing prototype (D614) and/or Beta (B.1.351) variant recombinant spike proteins and AS03 adjuvant (CoV2 preS dTM-AS03). MethodsAdults, primed 4-10 months earlier with mRNA (BNT162b2, mRNA-1273]), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or adjuvanted protein (CoV2 preS dTM-AS03 [D614]) vaccines and stratified by age (18-55 and [≥]56 years), were boosted with monovalent (MV) D614 (5g, n=1285), MV (B.1351) (5g, n=707) or bivalent (BiV) (2.5g D614 plus 2.5g B.1.351, n=625) CoV2 preS dTM-AS03. SARS-CoV-2-naive adults (controls, n=479) received a primary series (two injections, 21 days apart) of CoV2 preS dTM-AS03 containing 10g D614. Antibodies to D614G, B.1.351 and Omicron BA.2 and BA.1 variants were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay. D614G or B.1.351 PsVN titers 14 days (D15) post-booster were compared with pre-booster (D1) titers in BNT162b2-primed participants (18-55 years old) and controls (D36), for each booster formulation (co-primary objectives). Safety was evaluated throughout the trial. Results of a planned interim analysis are presented. ResultsAmong BNT162b2-primed adults (18-55 years old), PsVN titers against D614G or B.1.351 were significantly higher post-booster than anti-D614G titers post-primary vaccination in controls, for all booster formulations, with an anti-D614G GMT ratio (98.3% CI) of 2.16 (1.69; 2.75) for MV(D614), an anti-B.1.351 ratio of 1.96 (1.54; 2.50) for MV (B.1.351) and anti-D614G and anti-B.1.351 ratios of 2.34 (1.84; 2.96) and 1.39 (1.09; 1.77), respectively, for BiV. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 across vaccine priming subgroups and against Omicron BA.1 (evaluated in BNT162b2-primed participants). Similar patterns in antibody responses were observed for participants aged [≥]56 years. No safety concerns were identified. ConclusionCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. ClinicalTrials.govNCT04762680 FundingSanofi and federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under Contract # HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense under Contract # W15QKN-16-9-1002.

Prolonged T-cell activation and long COVID symptoms independently associate with severe disease at 3 months in a UK cohort of hospitalized COVID-19 patients

COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed the extent and nature of immune activation at 3 months post hospital admission in patients with mild, moderate or severe COVID-19 and investigated whether immune activation associates with disease severity and long COVID. Patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, but they lacked activation of other immune subsets. Elevated plasma levels of IL-4, IL-7, IL-17 and TNF- were present in patients with severe compared to mild and/or moderate disease. Plasma from severe patients caused T-cells from healthy donors to upregulate IL-15R, suggesting that factors in the plasma of severe patients may increase T-cell responsiveness to IL-15-driven bystander" activation, which may drive persistent T-cell activation after severe COVID-19. Patients with severe disease reported a higher number of long COVID symptoms which correlated with the frequency of two subsets of activated CD4+ and CD8+ T cells (CD4+ T-cell population 2 and CD8+ T-cell population 4; FDR p<0.05), however these associations were lost after adjusting for age, sex and disease severity. Our data suggests that persistent immune activation and long COVID correlate independently with severe disease.

Use of illness severity scores to predict mortality in interstitial lung disease patients hospitalised with acute respiratory deterioration

IntroductionHospitalisations relating to acute respiratory deteriorations (ARD) in Interstitial Lung Disease (ILD) have poor outcomes. Factors predicting adverse outcomes are not fully understood and data addressing the use of illness severity scores in prognostication are limited. ObjectiveTo validate the use of CURB-65 and NEWS-2 severity scores to predict mortality following ARD-ILD hospitalisation. MethodsA dual-centre prospective observational cohort study of all adults ([≥]18y) hospitalised with ARD-ILD in Bristol, UK (n=179). Gender-Age-Physiology (GAP), CURB-65 and NEWS-2 scores were calculated for each eligible admission. Receiver operating characteristics (ROC) curve analysis was used to quantify the strength of discrimination for NEWS-2 and CURB-65 scores. Univariable and multivariable logistic regression analyses were performed to explore the relationship between baseline severity scores and mortality. ResultsGAP showed some merit at predicting 30-day mortality (AUC=0.64, P=0.015); whereas CURB-65 showed modest predictive value for in-hospital (AUC=0.72, P<0.001) and 90-day mortality (AUC=0.67, P<0.001). NEWS-2 showed higher predictive value for in-hospital (AUC=0.80, P<0.001) and 90-day mortality (AUC=0.75, P<0.001), with an optimal derived cut-off [≥]6.5 found to be sensitive and specific for predicting in-hospital (83% and 63%) and 90-day (73% and 72%) mortality. In exploratory analyses, GAP score addition improved the predictive ability of NEWS-2 against 30-day mortality and CURB-65 across all time-periods. ConclusionNEWS-2 has good discriminatory value for predicting in-hospital mortality and moderate discriminatory value for predicting 90-day mortality. The optimal NEWS-2 cut-off value determined was the same as in a previous retrospective cohort, confirming the NEWS-2 score shows promise in predicting mortality following ARD-ILD hospitalisation. KEY MESSAGESO_ST_ABSWhat is the key question?C_ST_ABS- Can NEWS-2 and CURB-65 be used to predict inpatient mortality in a cohort of patients with acute respiratory deterioration on a background of known interstitial lung disease? What is the bottom line?- The NEWS-2 score shows high sensitivity and specificity in predicting both 90-day and in-hospital mortality in patients hospitalised with ARD-ILD - Whilst the CURB-65 score showed high sensitivity for predicting mortality, there was a low specificity, and did not add value to the predictive ability of the NEWS-2 score. Why read on?- This analysis included 179 patients from two study sites and provides, for the first time, prospective evidence for utilising NEWS-2 and CURB-65 as tools to predict in-hospital and post hospitalisation morbidity.

Severity of Omicron (B.1.1.529) and Delta (B.1.1.617.2) SARS-CoV-2 infection among hospitalised adults: a prospective cohort study

Limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 variant infections, and to what extent patient-factors, including vaccination and pre-existing disease, affect variant-dependent disease severity. This prospective cohort study of all adults ([≥]18 years of age) hospitalised at acute care hospitals in Bristol, UK assessed disease severity using 3 different measures: FiO2 >28%, World Health Organization (WHO) outcome score >5, and hospital length of stay (LOS) >3 days following admission for Omicron or Delta variant infection. Independent of other variables, including vaccination, Omicron variant infection was associated with a statistically lower severity compared to Delta; risk reductions were 58%, 67%, and 16% for FiO2, WHO score, and LOS, respectively. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden following admission.

Development and evaluation of low-volume tests to detect and characterise antibodies to SARS-CoV-2

Low-volume antibody assays can be used to track SARS-CoV-2 infection rates in settings where active testing for virus is limited and remote sampling is optimal. We developed 12 ELISAs detecting total or antibody isotypes to SARS-CoV-2 nucleocapsid, spike protein or its receptor binding domain (RBD), 3 anti-RBD isotype specific luciferase immunoprecipitation system (LIPS) assays and a novel Spike-RBD bridging LIPS total-antibody assay. We utilised pre-pandemic (n=984) and confirmed/suspected recent COVID-19 sera taken pre-vaccination rollout in 2020 (n=269). Assays measuring total antibody discriminated best between pre-pandemic and COVID-19 sera and were selected for diagnostic evaluation. In the blind evaluation, two of these assays (Spike Pan ELISA and Spike-RBD Bridging LIPS assay) demonstrated >97% specificity and >92% sensitivity for samples from COVID- 19 patients taken >21 days post symptom onset or PCR test. These assays offered better sensitivity for the detection of COVID-19 cases than a commercial assay which requires 100-fold larger serum volumes. This study demonstrates that low-volume in- house antibody assays can provide good diagnostic performance, and highlights the importance of using well-characterised samples and controls for all stages of assay development and evaluation. These cost-effective assays may be particularly useful for seroprevalence studies in low and middle-income countries.

Evaluation of isotype specific salivary antibody assays for detecting previous SARS-CoV-2 infection in children and adults

Saliva is easily obtainable non-invasively and potentially suitable for detecting both current and previous SARS-CoV-2 infection. We established 6 standardised enzyme linked immunosorbent assays (ELISA) capable of detecting IgA and IgG antibodies to whole SARS-CoV-2 spike protein, to its receptor binding domain region and to nucleocapsid protein in saliva. In test accuracy (n=320), we found that spike IgG performed best (ROC AUC: 95.0%, 92.8-97.3%), followed by spike IgA (ROC AUC: 89.9%, 86.5-93.2%) for discriminating between pre-pandemic and post COVID-19 saliva samples. Using machine learning, diagnostic performance was improved when a combination of tests was used. As expected, salivary IgA was poorly correlated with serum, indicating an oral mucosal response whereas salivary IgG responses were predictive of those in serum. When deployed to 20 household outbreaks undergoing Delta and Omicron infection, antibody responses were heterogeneous but remained a reliable indicator of recent infection. Intriguingly, unvaccinated children showed evidence of exposure almost exclusively through specific IgA responses in the absence of evidence of viral infection. We have provided robust standardisation, evaluation, and field-testing of salivary antibody assays as tools for monitoring SARS-CoV-2 immune responses. Future work should focus on investigating salivary antibody responses following infection and vaccination to understand patterns of SARS-CoV-2 transmission and inform ongoing vaccination strategies.

Neutrophils in severe COVID-19 are characterized by a hyperactive immature state and maintained CXCR2 expression

Neutrophils are vital in defence against pathogens but excessive neutrophil activity can lead to tissue damage and promote acute respiratory distress syndrome (ARDS). COVID-19 is associated with systemic expansion of immature neutrophils but the functional consequences of this shift to immaturity are not understood. We used flow cytometry to investigate activity and phenotypic diversity of circulating neutrophils in acute and convalescent COVID-19 patients. First, we demonstrate hyperactivation of immature CD10- subpopulations in severe disease, with elevated markers of secondary granule release. Partially activated immature neutrophils were detectable three months post symptom onset, indication long term myeloid dysregulation in convalescent COVID-19 patients. Second, we demonstrate that neutrophils from moderately ill patients downregulate the chemokine receptor CXCR2, while neutrophils from severely ill individuals failed to do so, suggesting altered ability for organ trafficking and a potential mechanism for induction of disease tolerance. CD10-and CXCR2hi neutrophil subpopulations were enriched in severe disease and may represent prognostic biomarkers for identification of individuals at high risk of progressing to severe COVID-19.

The Dynamics of SARS-CoV-2 Infectivity with Changes in Aerosol Microenvironment

Understanding the factors that influence the airborne survival of viruses such as SARS-CoV-2 in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets ([~]5-10{micro}m equilibrated radius) over timescales spanning from 5 seconds to 20 minutes using a novel instrument to probe survival in a small population of droplets (typically 5-10) containing [~]1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to [~]10 % of the starting value was observable for SARS-CoV-2 over 20 minutes, with a large proportion of the loss occurring within the first 5 minutes after aerosolisation. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallise at RHs below 50% leading to a near instant loss of infectivity in 50-60% of the virus. However, at 90% RH the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 minutes, beyond which it decays to only 10% remaining infectious after 10 minutes. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilisation of CO2 from bicarbonate buffer within the droplet. Three different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH. SignificanceThe aerosol microenvironment is highly dynamic exposing pathogens, such as the SARS-CoV-2 virus when exhaled in respiratory aerosol, to extreme conditions of solute concentration, pH and evaporative cooling. Yet surviving this environment is a key step in the transmission of such pathogens. Understanding the impact that airborne transport has on pathogens and the influence of environmental conditions on pathogen survival can inform the implementation of strategies to mitigate the spread of diseases such as COVID-19. We report changes in the infectivity of the airborne virus over timescales spanning from 5 s to 20 minutes and demonstrate the role of two microphysical processes in this infectivity loss: particle crystallisation and aerosol droplet pH change.

Immunogenicity and safety of inactivated whole virion Coronavirus vaccine with CpG (VLA2001) in healthy adults aged 18 to 55: a randomised phase 1 /2 clinical trial

BackgroundWe assessed the safety, tolerability and immunogenicity of VLA2001 is a whole-virion inactivated SARS-CoV-2 vaccine adsorbed to alum with a toll-like receptor 9 agonist adjuvant in healthy volunteers aged 18-55. MethodsThe first 15 participants were enrolled, in groups of 5, to receive two doses, separated by 21 days, of one of three dose concentrations, administered intramuscularly. 138 further participants were randomised 1:1:1 to receive the same 3 dose concentrations, in a double blinded manner. Primary outcomes were solicited adverse reactions 7 days after each vaccination and neutralising antibody geometric mean titres (GMT) against SARS-CoV-2, 2 weeks after the second vaccination (day 36), measured by live microneutralisation assay against wild-type virus (MNA50). Secondary outcomes included unsolicited adverse events, and humoral and cellular responses at day 36, measured by IgG ELISA against Spike protein and interferon-{gamma} secreting T-cells by ELISpot stimulated with multiple SARS-CoV-2 antigens. (ClinicalTrials.gov NCT04671017, ISRCTN 82411169) FindingsBetween December 16, 2020 and January 21, 2021, 153 participants were enrolled and randomised evenly between the dose groups. The rates of solicited reactions were similar after the first and second doses and between the three dose groups. The most frequent local reactions were tenderness (58{middle dot}2%) and pain (41{middle dot}8%) and systemic reactions were headache (46%) and fatigue (39{middle dot}2%). In the high dose group, two weeks following the second dose, the geometric mean titres were 530.4 (95% CI: 421{middle dot}49, 667{middle dot}52) for neutralizing antibodies and 2147{middle dot}9 (95% CI: 1705{middle dot}98, 2704{middle dot}22) for S-binding antibodies. There was a dose dependent response with 90{middle dot}0% (95% CI:78{middle dot}0%.,97{middle dot}0%) seroconversion (4-fold rise) at day 36 in the high dose group, which was significantly higher than rates in both the medium (73.5%; 95% CI: 59%,85%), CIs) and low dose (51%; 95%CI: 37%,65%) rate, CIs) groups (both p < 0.001). Antigen-specific interferon-{gamma} T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49% of high dose recipients, respectively. InterpretationVLA2001-201 was well tolerated and produced both humoral and cellular immune responses, with a clear dose-response effect. FundingThis study was funded by the Department of Health and Social Care, UK The funder had no role in the study design, implementation or analysis.

Limits of lockdown: characterising essential contacts during strict physical distancing

COVID-19 has exposed health inequalities within countries and globally. The fundamental determining factor behind an individuals risk of infection is the number of social contacts they make. In many countries, physical distancing measures have been implemented to control transmission of SARS-CoV-2, reducing social contacts to a minimum. Characterising unavoidable social contacts is key for understanding the inequalities behind differential risks and planning vaccination programmes. We utilised an existing English longitudinal birth cohort, which is broadly representative of the wider population (n=6807), to explore social contact patterns and behaviours when strict physical distancing measures were in place during the UKs first lockdown in March-May 2020. Essential workers, specifically those in healthcare, had 4.5 times as many contacts as non-essential workers [incident rate ratio = 4.42 (CI95%: 3.88-5.04)], whilst essential workers in other sectors, mainly teaching and the police force had three times as many contacts [IRR = 2.84 (2.58-3.13)]. The number of individuals in a household, which is conflated by number of children, increases essential social contacts by 40%. Self-isolation effectively reduces numbers of contacts outside of the home, but not entirely. Together, these findings will aid the interpretation of epidemiological data and impact the design of effective SARS-CoV-2 control strategies, such as vaccination, testing and contact tracing.

Contact patterns before and during the UK's Autumn 2020 COVID-19 lockdown among university students and staff

IntroductionUK universities re-opened in September 2020, despite the on-going coronavirus epidemic. During the first term, various national social distancing measures were introduced, including banning groups of >6 people and the second lockdown in November. COVID-19 can spread rapidly in university-settings, and students adherence to social distancing measures is critical for controlling transmission. MethodsWe measured university staff and student contact patterns via an online, longitudinal survey capturing self-reported contacts on the previous day. We investigated the change in contacts associated with COVID-19 guidance periods: post-first lockdown (23/06/2020-03/07/2020), relaxed guidance period (04/07/2020-13/09/2020), "rule-of-six" period (14/09/2020-04/11/2020), and the second lockdown (05/11/2020-25/11/2020). Results722 staff (4199 responses) (mean household size: 2.6) and 738 students (1906 responses) (mean household size: 4.5) were included in the study. Contact number decreased with age. Staff in single-person households reported fewer contacts than individuals in 2-and 3-person households, and individuals in 4-and 5-person households reported more contacts. For staff, daily contacts were higher in the relaxed guidance and "rule-of-six" periods (means: 3.2 and 3.5, respectively; medians: 3) than the post-first lockdown and second lockdown periods (means: 4.5 and 5.4, respectively; medians: 2). Few students responded until 05/10/2020, after which the median student contacts was 2 and the mean was 5.7, until the second lockdown when it dropped to 3.1. DiscussionUniversity staff and students responded to national guidance by altering their social contacts. The response in staff and students was similar, suggesting that students are able to adhere to social distancing guidance while at university.

Blood group A Secretors are associated with a higher risk of COVID-19 cardiovascular disease complications

The SARS-CoV-2 virus causes COVID-19, an infection capable of causing severe disease and death but which may also be asymptomatic or oligosymptomatic in many individuals. While several risk factors, including age, have been described, the mechanisms of this variation are poorly understood. Several studies have described associations between blood group and COVID-19 severity, while others do not. Expression of ABO glycans on secreted proteins and non-erythroid cells is controlled by a fucosyltransferase (FUT2). Inactivating mutations result in a non-secretor phenotype which is known to protect against some viral infections. We investigated whether ABO or secretor status was associated with COVID-19 severity. Data combined from healthcare records and laboratory tests (n=275) of SARS-CoV-2 PCR positive patients hospitalised with COVID-19, confirmed higher than expected numbers of blood group A individuals compared to O (RR=1.24, CI 95% [1.05,1.47], P=0.0111). There was also a significant association between group A and COVID-19-related cardiovascular complications (RR=2.56, CI 95% [1.43,4.55], P=0.0011) which is independent of gender. Molecular analysis of phenotype revealed that group A patients who are non-secretors are significantly less likely to be hospitalised than secretors. In a larger cohort of 1000 convalescent plasma donors, among whom the majority displayed COVID-19 symptoms and only a small minority required hospitalisation, group A non-secretors were slightly over-represented. Our findings indicate that group A non-secretors are not resistant to infection by SARS-CoV-2, but they are likely to experience a less severe form of its associated disease. Key PointsO_LIBlood group type A is associated with an increased risk of cardiovascular complications in COVID-19 patients. C_LIO_LIFUT2 "non-secretor" status reduces the risk of severe COVID-19 outcomes in patients with blood group A. C_LI

Contacts and behaviours of university students during the COVID-19 pandemic at the start of the 2020/21 academic year

CONQUEST (COroNavirus QUESTionnaire) is an online survey of contacts, behaviour, and COVID-19 symptoms for University of Bristol (UoB) staff/students. We analysed survey results from the start of the 2020/2021 academic year, prior to the second national lockdown (14/09/2020-01/11/2020), where COVID-19 outbreaks led to lockdown of some student halls of residence. The aim of these analyses was to enhance knowledge of student contact patterns to inform infection disease mathematical modelling approaches. Responses captured information on demographics, contacts on the previous day, symptoms and self-isolation during the prior week, and COVID-19 status. 740 students provided 1261 unique records. Of 42 (3%) students testing positive in the prior fortnight, 99% had been self-isolating. The median number of contacts on the previous day was 2 (interquartile range: 1-5), mode: 1, mean: 6.1; 8% had [≥]20 contacts. 57% of student contacts were other UoB students/staff. Most students reported few daily contacts but there was heterogeneity, and some reported many. Around 40% of student contacts were with individuals not affiliated with UoB, indicating potential for transmission to non-students/staff.

Detecting SARS-CoV-2 variants with SNP genotyping

Tracking genetic variations from positive SARS-CoV-2 samples yields crucial information about the number of variants circulating in an outbreak and the possible lines of transmission but sequencing every positive SARS-CoV-2 sample would be prohibitively costly for population-scale test and trace operations. Genotyping is a rapid, high-throughput and low-cost alternative for screening positive SARS-CoV-2 samples in many settings. We have designed a SNP identification pipeline to identify genetic variation using sequenced SARS-CoV-2 samples. Our pipeline identifies a minimal marker panel that can define distinct genotypes. To evaluate the system we developed a genotyping panel to detect variants-identified from SARS-CoV-2 sequences surveyed between March and May 2020- and tested this on 50 stored qRT-PCR positive SARS-CoV-2 clinical samples that had been collected across the South West of the UK in April 2020. The 50 samples split into 15 distinct genotypes and there was a 76% probability that any two randomly chosen samples from our set of 50 would have a distinct genotype. In a high throughput laboratory, qRT-PCR positive samples pooled into 384-well plates could be screened with our marker panel at a cost of < {pound}1.50 per sample. Our results demonstrate the usefulness of a SNP genotyping panel to provide a rapid, cost-effective, and reliable way to monitor SARS-CoV-2 variants circulating in an outbreak. Our analysis pipeline is publicly available and will allow for marker panels to be updated periodically as viral genotypes arise or disappear from circulation.

Case Report: Concomitant Diagnosis of Plasma Cell Leukemia in Patient With JAK2 Positive Myeloproliferative Neoplasm.

Plasma cell dyscrasias and myeloproliferative neoplasms (MPN) are hematologic malignancies arising from two distinct hematopoietic cell lineages. They rarely occur concomitantly. Here, we report a case of a patient with a recent diagnosis of a JAK2 V617F positive MPN who presented with a new diagnosis of plasma cell leukemia. The patient had presented to the hospital with a leukocytosis predominantly comprised of plasma cells, followed by work-up involving peripheral blood flow cytometry, FISH analysis, and bone-marrow biopsy. FISH analysis was suggestive of a common progenitor cell for these distinct hematologic malignancies. To our knowledge, this case represents the second reported instance of a concomitant JAK2 positive MPN with primary plasma cell leukemia.

High COVID-19 transmission potential associated with re-opening universities can be mitigated with layered interventions

Background: Re-opening universities while controlling COVID-19 transmission poses unique challenges. UK universities typically host 20,000 to 40,000 undergraduate students, with the majority moving away from home to attend. In the absence of realistic mixing patterns, previous models suggest that outbreaks associated with universities re-opening are an eventuality. Methods: We developed a stochastic transmission model based on realistic mixing patterns between students. We evaluated alternative mitigation interventions for a representative university. Results: Our model predicts, for a set of plausible parameter values, that if asymptomatic cases are half as infectious as symptomatic cases then 5,760 (3,940 - 7,430) out of 28,000 students, 20% (14% - 26%), could be infected during the first term, with 950 (656 - 1,209) cases infectious on the last day of term. If asymptomatic cases are as infectious as symptomatic cases then three times as many cases could occur, with 94% (93% - 94%) of the student population getting infected during the first term. We predict that one third of infected students are likely to be in their first year, and first year students are the main drivers of transmission due to high numbers of contacts in communal residences. We find that reducing face-to-face teaching is likely to be the single most effective intervention, and this conclusion is robust to varying assumptions about asymptomatic transmission. Supplementing reduced face-to-face testing with COVID-secure interactions and reduced living circles could reduce the percentage of infected students by 75%. Mass testing of students would need to occur at least fortnightly, is not the most effective option considered, and comes at a cost of high numbers of students requiring self-isolation. When transmission is controlled in the student population, limiting imported infection from the community is important. Conclusions: Priority should be given to understanding the role of asymptomatic transmission in the spread of COVID-19. Irrespective of assumptions about asymptomatic transmission, our findings suggest that additional outbreak control measures should be considered for the university setting. These might include reduced face-to-face teaching, management of student mixing and enhanced testing. Onward transmission to family members at the end of term is likely without interventions.