Effectiveness of BNT162b2 mRNA vaccine third doses and previous infection in protecting against SARS-CoV-2 infections during the Delta and Omicron variant waves; the UK SIREN cohort study September 2021 to February 2022.

Third doses of COVID-19 vaccines were widely deployed following the primary vaccine course waning and the emergence of the Omicron-variant. We investigated protection from third-dose vaccines and previous infection against SARS-CoV-2 infection during Delta-variant and Omicron-variant (BA.1 & BA.2) waves in our frequently PCR-tested cohort of healthcare-workers. Relative effectiveness of BNT162b2 third doses and infection-acquired immunity was assessed by comparing the time to PCR-confirmed infection in boosted participants with those with waned dose-2 protection (≥254 days after dose-2), by primary series vaccination type. Follow-up time was divided by dominant circulating variant: Delta 07 September 2021 to 30 November 2021, Omicron 13 December 2021t o 28 February 2022. We used a Cox regression model with adjustment/stratification for demographic characteristics and staff-type. We explored protection associated with vaccination, infection and both. We included 19,614 participants, 29% previously infected. There were 278 primary infections (4 per 10,000 person-days of follow-up) and 85 reinfections (0.8/10,000 person-days) during the Delta period and 2467 primary infections (43/10,000 person-days) and 881 reinfections (33/10,000) during the Omicron period. Relative Vaccine Effectiveness (VE) 0-2 months post-3rd dose (3rd dose) (3-doses BNT162b2) in the previously uninfected cohort against Delta infections was 63% (95% Confidence Interval (CI) 40%-77%) and was lower (35%) against Omicron infection (95% CI 21%-47%). The relative VE of 3rd dose (heterologous BNT162b2) was greater for primary course ChAdOX1 recipients, with VE 0-2 months post-3rd dose over ≥68% higher for both variants. Third-dose protection waned rapidly against Omicron, with no significant difference between two and three BNT162b2 doses observed after 4-months. Previous infection continued to provide additional protection against Omicron (67% (CI 56%-75%) 3-6 months post-infection), but this waned to about 25% after 9-months, approximately three times lower than against Delta. Infection rates surged with Omicron emergence. Third doses of BNT162b2 vaccine provided short-term protection, with rapid waning against Omicron infections. Protection associated with infections incurred before Omicron was markedly diminished against the Omicron wave. Our findings demonstrate the complexity of an evolving pandemic with the potential emergence of immune-escape variants and the importance of continued monitoring.

Effect of second booster vaccinations and prior infection against SARS-CoV-2 in the UK SIREN healthcare worker cohort.

Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI -11.4 to 27.8) and 1.7% (95% CI -17.0 to 17.4) at 2-4 and 4-6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0-6, and 6-12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Electronic health records to capture primary outcome measures: two case studies in HIV prevention research.

BACKGROUND: There is increasing interest in the use of electronic health records (EHRs) to improve the efficiency and cost-effectiveness of clinical trials, including the capture of outcome measures. MAIN TEXT: We describe our experience of using EHRs to capture the primary outcome measure - HIV infection or the diagnosis of HIV infection - in two randomised HIV prevention trials conducted in the UK. PROUD was a clinic-based trial evaluating pre-exposure prophylaxis (PrEP), and SELPHI was an internet-based trial evaluating HIV self-testing kits. The EHR was the national database of HIV diagnoses in the UK, curated by the UK Health Security Agency (UKHSA). In PROUD, linkage to the UKHSA database was performed at the end of the trial and identified five primary outcomes in addition to the 30 outcomes diagnosed by the participating clinics. Linkage also produced an additional 345 person-years follow-up, an increase of 27% over clinic-based follow-up. In SELPHI, new HIV diagnoses were primarily identified via UKHSA linkage, complemented by participant self-report through internet surveys. Rates of survey completion were low, and only 14 of the 33 new diagnoses recorded in the UKHSA database were also self-reported. Thus UKHSA linkage was essential for capturing HIV diagnoses and the successful conduct of the trial. CONCLUSIONS: Our experience of using the UKHSA database of HIV diagnoses as a source of primary outcomes in two randomised trials in the field of HIV prevention was highly favourable and encourages the use of a similar approach in future trials in this disease area.

A reference human induced pluripotent stem cell line for large-scale collaborative studies.

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between lines makes it challenging to replicate key findings and integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC lines and deeply characterized their genetic properties using whole genome sequencing, their genomic stability upon CRISPR-Cas9-based gene editing, and their phenotypic properties including differentiation to commonly used cell types. These studies identified KOLF2.1J as an all-around well-performing iPSC line. We then shared KOLF2.1J with groups around the world who tested its performance in head-to-head comparisons with their own preferred iPSC lines across a diverse range of differentiation protocols and functional assays. On the strength of these findings, we have made KOLF2.1J and its gene-edited derivative clones readily accessible to promote the standardization required for large-scale collaborative science in the stem cell field.

Free HIV self-test for identification and linkage to care of previously undetected HIV infection in men who have sex with men in England and Wales (SELPHI): an open-label, internet-based, randomised controlled trial.

BACKGROUND: High levels of HIV testing in men who have sex with men remain key to reducing the incidence of HIV. We aimed to assess whether the offer of a single, free HIV self-testing kit led to increased HIV diagnoses with linkage to care. METHODS: SELPHI was an internet-based, open-label, randomised controlled trial that recruited participants via sexual and social networking sites. Eligibility criteria included being a man or trans woman (although trans women are reported separately); being resident in England or Wales, UK; being aged 16 years or older; having had anal intercourse with a man; not having a positive HIV diagnosis; and being willing to provide name, email address, date of birth, and consent to link to national HIV databases. Participants were randomly allocated (3:2) by computer-generated number sequence to receive a free HIV self-test kit (BT group) or to not receive this free kit (nBT group). Online surveys collected data at baseline, 2 weeks after enrolment (BT group only), 3 months after enrolment, and at the end of the study. The primary outcome was confirmed (linked to care) new HIV diagnosis within 3 months of enrolment, analysed by intention to treat. Those assessing the primary outcome were masked to allocation. This study is registered with the ISRCTN Clinical Trials Register, number ISRCTN20312003. FINDINGS: 10 111 participants (6049 in BT group and 4062 in nBT group) enrolled between Feb 16, 2017, and March 1, 2018. The median age of participants was 33 years (IQR 26-44 years); 9000 (89%) participants were White; 8118 (80%) participants were born in the UK; 81 (1%) participants were transgender men; 4706 (47%) participants were university educated; 1537 (15%) participants had never been tested for HIV; and 389 (4%) participants were taking pre-exposure prophylaxis. At enrolment, 7282 (72%) participants reported condomless anal sex with at least one male partner in the previous 3 months. In the BT group, of the 4511 participants for whom HIV testing information was available, 4263 (95%) reported having used the free HIV self-test kit within 3 months.Within 3 months of enrolment there were 19 confirmed new HIV diagnoses (0·31%) in 6049 participants in the BT group and 15 (0·37%) of 4062 in the nBT group (p=0·64). INTERPRETATION: The offer of a single, free HIV self-test did not lead to increased rates of new HIV diagnoses, which could reflect decreasing HIV incidence rates in the UK. Nonetheless, the offer of a free HIV self-testing kit resulted in high HIV testing rates, indicating that self-testing is an attractive testing option for a large group of men who have sex with men. FUNDING: UK National Institute for Health and Care Research.

Re-assessing the late HIV diagnosis surveillance definition in the era of increased and frequent testing.

OBJECTIVES: Late HIV diagnosis (CD4 <350 cells/mm3 ) is a key public health metric. In an era of more frequent testing, the likelihood of HIV diagnosis occurring during seroconversion, when CD4 counts may dip below 350, is greater. We applied a correction, considering markers of recent infection, and re-assessed 1-year mortality following late diagnosis. METHODS: We used national epidemiological and laboratory surveillance data from all people diagnosed with HIV in England, Wales, and Northern Ireland (EW&NI). Those with a baseline CD4 <350 were reclassified as 'not late' if they had evidence of recent infection (recency test and/or negative test within 24 months). A correction factor (CF) was the number reclassified divided by the number with a CD4 <350. RESULTS: Of the 32 227 people diagnosed with HIV in EW&NI between 2011 and 2019 with a baseline CD4 (81% of total), 46% had a CD4 <350 (uncorrected late diagnosis rate): 34% of gay and bisexual men (GBM), 65% of heterosexual men, and 56% of heterosexual women. Accounting for recency test and/or prior negative tests gave a 'corrected' late diagnosis rate of 39% and corresponding CF of 14%. The CF increased from 10% to 18% during 2011-2015, then plateaued, and was larger among GBM (25%) than heterosexual men and women (6% and 7%, respectively). One-year mortality among people diagnosed late was 329 per 10 000 after reclassification (an increase from 288/10 000). CONCLUSIONS: The case-surveillance definition of late diagnosis increasingly overestimates late presentation, the extent of which differs by key populations. Adjustment of late diagnosis is recommended, particularly for frequent testers such as GBM.

Trends in COVID-19 hospital outcomes in England before and after vaccine introduction, a cohort study.

Widespread vaccination campaigns have changed the landscape for COVID-19, vastly altering symptoms and reducing morbidity and mortality. We estimate trends in mortality by month of admission and vaccination status among those hospitalised with COVID-19 in England between March 2020 to September 2021, controlling for demographic factors and hospital load. Among 259,727 hospitalised COVID-19 cases, 51,948 (20.0%) experienced mortality in hospital. Hospitalised fatality risk ranged from 40.3% (95% confidence interval 39.4-41.3%) in March 2020 to 8.1% (7.2-9.0%) in June 2021. Older individuals and those with multiple co-morbidities were more likely to die or else experienced longer stays prior to discharge. Compared to unvaccinated people, the hazard of hospitalised mortality was 0.71 (0.67-0.77) with a first vaccine dose, and 0.56 (0.52-0.61) with a second vaccine dose. Compared to hospital load at 0-20% of the busiest week, the hazard of hospitalised mortality during periods of peak load (90-100%), was 1.23 (1.12-1.34). The prognosis for people hospitalised with COVID-19 in England has varied substantially throughout the pandemic and according to case-mix, vaccination, and hospital load. Our estimates provide an indication for demands on hospital resources, and the relationship between hospital burden and outcomes.

A comparison of two frameworks for multi-state modelling, applied to outcomes after hospital admissions with COVID-19.

We compare two multi-state modelling frameworks that can be used to represent dates of events following hospital admission for people infected during an epidemic. The methods are applied to data from people admitted to hospital with COVID-19, to estimate the probability of admission to intensive care unit, the probability of death in hospital for patients before and after intensive care unit admission, the lengths of stay in hospital, and how all these vary with age and gender. One modelling framework is based on defining transition-specific hazard functions for competing risks. A less commonly used framework defines partially-latent subpopulations who will experience each subsequent event, and uses a mixture model to estimate the probability that an individual will experience each event, and the distribution of the time to the event given that it occurs. We compare the advantages and disadvantages of these two frameworks, in the context of the COVID-19 example. The issues include the interpretation of the model parameters, the computational efficiency of estimating the quantities of interest, implementation in software and assessing goodness of fit. In the example, we find that some groups appear to be at very low risk of some events, in particular intensive care unit admission, and these are best represented by using 'cure-rate' models to define transition-specific hazards. We provide general-purpose software to implement all the models we describe in the flexsurv R package, which allows arbitrarily flexible distributions to be used to represent the cause-specific hazards or times to events.

Impact of prior SARS-CoV-2 infection and COVID-19 vaccination on the subsequent incidence of COVID-19: a multicentre prospective cohort study among UK healthcare workers - the SIREN (Sarscov2 Immunity & REinfection EvaluatioN) study protocol.

INTRODUCTION: Understanding the effectiveness and durability of protection against SARS-CoV-2 infection conferred by previous infection and COVID-19 is essential to inform ongoing management of the pandemic. This study aims to determine whether prior SARS-CoV-2 infection or COVID-19 vaccination in healthcare workers protects against future infection. METHODS AND ANALYSIS: This is a prospective cohort study design in staff members working in hospitals in the UK. At enrolment, participants are allocated into cohorts, positive or naïve, dependent on their prior SARS-CoV-2 infection status, as measured by standardised SARS-CoV-2 antibody testing on all baseline serum samples and previous SARS-CoV-2 test results. Participants undergo monthly antibody testing and fortnightly viral RNA testing during follow-up and based on these results may move between cohorts. Any results from testing undertaken for other reasons (eg, symptoms, contact tracing) or prior to study entry will also be captured. Individuals complete enrolment and fortnightly questionnaires on exposures, symptoms and vaccination. Follow-up is 12 months from study entry, with an option to extend follow-up to 24 months.The primary outcome of interest is infection with SARS-CoV-2 after previous SARS-CoV-2 infection or COVID-19 vaccination during the study period. Secondary outcomes include incidence and prevalence (both RNA and antibody) of SARS-CoV-2, viral genomics, viral culture, symptom history and antibody/neutralising antibody titres. ETHICS AND DISSEMINATION: The study was approved by the Berkshire Research Ethics Committee, Health Research Authority (IRAS ID 284460, REC reference 20/SC/0230) on 22 May 2020; the vaccine amendment was approved on 12 January 2021. Participants gave informed consent before taking part in the study.Regular reports to national and international expert advisory groups and peer-reviewed publications ensure timely dissemination of findings to inform decision making. TRIAL REGISTRATION NUMBER: ISRCTN11041050.

Protection against SARS-CoV-2 after Covid-19 Vaccination and Previous Infection.

BACKGROUND: The duration and effectiveness of immunity from infection with and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are relevant to pandemic policy interventions, including the timing of vaccine boosters. METHODS: We investigated the duration and effectiveness of immunity in a prospective cohort of asymptomatic health care workers in the United Kingdom who underwent routine polymerase-chain-reaction (PCR) testing. Vaccine effectiveness (≤10 months after the first dose of vaccine) and infection-acquired immunity were assessed by comparing the time to PCR-confirmed infection in vaccinated persons with that in unvaccinated persons, stratified according to previous infection status. We used a Cox regression model with adjustment for previous SARS-CoV-2 infection status, vaccine type and dosing interval, demographic characteristics, and workplace exposure to SARS-CoV-2. RESULTS: Of 35,768 participants, 27% (9488) had a previous SARS-CoV-2 infection. Vaccine coverage was high: 95% of the participants had received two doses (78% had received BNT162b2 vaccine [Pfizer-BioNTech] with a long interval between doses, 9% BNT162b2 vaccine with a short interval between doses, and 8% ChAdOx1 nCoV-19 vaccine [AstraZeneca]). Between December 7, 2020, and September 21, 2021, a total of 2747 primary infections and 210 reinfections were observed. Among previously uninfected participants who received long-interval BNT162b2 vaccine, adjusted vaccine effectiveness decreased from 85% (95% confidence interval [CI], 72 to 92) 14 to 73 days after the second dose to 51% (95% CI, 22 to 69) at a median of 201 days (interquartile range, 197 to 205) after the second dose; this effectiveness did not differ significantly between the long-interval and short-interval BNT162b2 vaccine recipients. At 14 to 73 days after the second dose, adjusted vaccine effectiveness among ChAdOx1 nCoV-19 vaccine recipients was 58% (95% CI, 23 to 77) - considerably lower than that among BNT162b2 vaccine recipients. Infection-acquired immunity waned after 1 year in unvaccinated participants but remained consistently higher than 90% in those who were subsequently vaccinated, even in persons infected more than 18 months previously. CONCLUSIONS: Two doses of BNT162b2 vaccine were associated with high short-term protection against SARS-CoV-2 infection; this protection waned considerably after 6 months. Infection-acquired immunity boosted with vaccination remained high more than 1 year after infection. (Funded by the U.K. Health Security Agency and others; ISRCTN Registry number, ISRCTN11041050.).

Tuberculosis incidence in country of origin is a key determinant of the risk of active tuberculosis in people living with HIV: Data from a 30-year observational cohort study.

INTRODUCTION: People living with HIV (PLWH) are at high risk of active tuberculosis (TB) but this risk in the era of antiretroviral treatment (ART) remains unclear. It is critical to identify the groups who should be prioritised for latent TB (LTBI) screening. In this study we identified the risk factors associated with developing incident TB disease, by analysing a 30-year observational cohort. METHODS: We evaluated PLWH in Leicester, UK, between 1983 and 2017 to ascertain those who developed active TB and the timing of this in relation to HIV diagnosis; whether before, concurrently with, or more than 3 months after the diagnosis of HIV (incident TB). Predictors of incident TB were ascertained using Cox proportional hazards models. RESULTS: In all, 325 out of 2158 (15.1%) PLWH under care had had active TB; 64/325 (19.7%) prior to HIV diagnosis, 161/325 (49.5%) concurrently with/within 3 months of HIV diagnosis and 100/325 (30.8%) had incident TB. Incident TB risk was 4.57/1000 person-years. Increased TB incidence in the country of birth was associated with an increased risk of developing incident TB [50-149/100 000 population, adjusted hazard ratio (AHR) = 3.10, 95% CI: 0.94-10.20; 150-249/100 000 population, AHR = 7.14, 95% CI: 3.46-14.74; 250-349/100 000 population, AHR = 5.90, 95% CI: 2.32-14.99; ≥ 350/100 000 population, AHR = 3.96, 95% CI: 1.39-11.26]. CONCLUSIONS: Tuberculosis risk remains high among PLWH and is related to TB incidence in the country of birth. Further work is required to determine whether specific groups of PLWH should be targeted for programmatic LTBI screening, and whether it will result in high uptake and completion of chemoprophylaxis and is cost-effective for widespread implementation.

COVID-19 mortality among people with diagnosed HIV compared to those without during the first wave of the COVID-19 pandemic in England.

OBJECTIVES: We describe COVID-19 mortality among people with and without HIV during the first wave of the pandemic in England. METHODS: National surveillance data on adults (aged ≥ 15 years) with diagnosed HIV resident in England were linked to national COVID-19 mortality surveillance data (2 March 2020-16 June 2020); HIV clinicians verified linked cases and provided information on the circumstances of death. We present COVID-19 mortality rates by HIV status, using negative binomial regression to assess the association between HIV and mortality, adjusting for gender, age and ethnicity. RESULTS: Overall, 99 people with HIV, including 61 of black ethnicity, died of/with COVID-19 (107/100 000) compared with 49 483 people without HIV (109/100 000). Compared to people without HIV, higher COVID-19 mortality rates were observed in people with HIV of black (188 vs. 122/100 000) and Asian (131 vs. 77.0/100 000) ethnicity, and in both younger (15-59 years: 58.3 vs. 10.2/100 000) and older (≥ 60 years: 434 vs. 355/100 000) people. After adjustment for demographic factors, people with HIV had a higher COVID-19 mortality risk than those without (2.18; 95% CI: 1.76-2.70). Most people with HIV who died of/with COVID-19 had suppressed HIV viraemia (91%) and at least one comorbidity reported to be associated with poor COVID-19 outcomes (87%). CONCLUSIONS: In the first wave of the pandemic in England, COVID-19 mortality among people with HIV was low, but was higher than in those without HIV, after controlling for demographic factors. This supports the strategy of prioritizing COVID-19 vaccination for people with HIV and strongly encouraging its uptake, especially in those of black and Asian ethnicity.

Linkage of Whole Genome Sequencing, Epidemiological, and Clinical Data to Understand the Genetic Diversity and Clinical Outcomes of Shigella flexneri among Men Who Have Sex with Men in England.

The public health value of whole genome sequencing (WGS) for Shigella spp. in England has been limited by a lack of information on sexual identity and behavior. We combined WGS data with other data sources to better understand Shigella flexneri transmission in men who have sex with men (MSM). WGS data for all S. flexneri isolates referred to the national reference laboratory were linked to i) clinical and behavioral data collected in seven of 21 health regions in England using a standardized exposure questionnaire and, ii) national HIV surveillance data. We included 926 S. flexneri isolates, of which 43.0% (n = 398) fell phylogenetically within two domestically circulating clades associated with genotypic markers of azithromycin resistance. Approximately one third of isolates in these clades were from people living with HIV, primarily acquired through sex between men. 182 (19.7%) isolates had linked questionnaire data; 88% (84/95) of MSM isolates fell phylogenetically within the domestically circulating clades, while 92% (72/78) of isolates from other cases fell within lineages linked with travel to high-risk regions. There was no evidence of sustained transmission between networks of MSM and the wider community. MSM were more likely to be admitted to hospital and receive antimicrobials. Our study emphasizes the importance of sex between men as a major route of transmission for S. flexneri. Combined WGS, epidemiological and clinical data provide unique insights that can inform contact tracing, clinical management and the delivery of targeted prevention activities. Future studies should investigate why MSM experience more severe clinical outcomes. IMPORTANCE Within the last 2 decades there have been an increasing number of Shigella spp. outbreaks among men who have sex with men (MSM) worldwide. In 2015, Public Health England (PHE) introduced routine whole genome sequencing (WGS) for the national surveillance of Shigella spp. However, the lack of information on sexual identity and behavior has hindered interpretation. Our study illustrates the power of linking WGS data with epidemiological, behavioral, and clinical data. We provide unique population-level insights into different transmission networks that can inform the delivery of appropriate public health interventions and patient management. Furthermore, we describe and compare clinical characteristics and outcomes of S. flexneri infection in MSM and other exposure groups. We found that MSM were more likely to be admitted to hospital and receive antimicrobials, indicating that their infections were potentially more severe. The exact reasons for this are unclear and require further exploration.

Trends in undiagnosed HIV prevalence in England and implications for eliminating HIV transmission by 2030: an evidence synthesis model.

BACKGROUND: A target to eliminate HIV transmission in England by 2030 was set in early 2019. This study aimed to estimate trends from 2013 to 2019 in HIV prevalence, particularly the number of people living with undiagnosed HIV, by exposure group, ethnicity, gender, age group, and region. These estimates are essential to monitor progress towards elimination. METHODS: A Bayesian synthesis of evidence from multiple surveillance, demographic, and survey datasets relevant to HIV in England was used to estimate trends in the number of people living with HIV, the proportion of people unaware of their HIV infection, and the corresponding prevalence of undiagnosed HIV. All estimates were stratified by exposure group, ethnicity, gender, age group (15-34, 35-44, 45-59, or 60-74 years), region (London, or outside of London) and year (2013-19). FINDINGS: The total number of people living with HIV aged 15-74 years in England increased from 83 500 (95% credible interval 80 200-89 600) in 2013 to 92 800 (91 000-95 600) in 2019. The proportion diagnosed steadily increased from 86% (80-90%) to 94% (91-95%) during the same time period, corresponding to a halving in the number of undiagnosed infections from 11 600 (8300-17 700) to 5900 (4400-8700) and in undiagnosed prevalence from 0·29 (0·21-0·44) to 0·14 (0·11-0·21) per 1000 population. Similar steep declines were estimated in all subgroups of gay, bisexual, and other men who have sex with men and in most subgroups of Black African heterosexuals. The pace of reduction was less pronounced for heterosexuals in other ethnic groups and people who inject drugs, particularly outside London; however, undiagnosed prevalence in these groups has remained very low. INTERPRETATION: The UNAIDS target of diagnosing 90% of people living with HIV by 2020 was reached by 2016 in England, with the country on track to achieve the new target of 95% diagnosed by 2025. Reductions in transmission and undiagnosed prevalence have corresponded to large scale-up of testing in key populations and early diagnosis and treatment. Additional and intensified prevention measures are required to eliminate transmission of HIV among the communities that have experienced slower declines than other subgroups, despite having very low prevalences of HIV. FUNDING: UK Medical Research Council and Public Health England.

Discriminating Between Premigration and Postmigration HIV Acquisition Using Surveillance Data.

BACKGROUND: Migrant populations are overrepresented among persons diagnosed with HIV in the European Union and the European Economic Area. Understanding the timing of HIV acquisition (premigration or postmigration) is crucial for developing public health interventions and for producing reliable estimates of HIV incidence and the number of people living with undiagnosed HIV infection. We summarize a recently proposed method for determining the timing of HIV acquisition and apply it to both real and simulated data. METHODS: The considered method combines estimates from a mixed model, applied to data from a large seroconverters' cohort, with biomarker measurements and individual characteristics to derive probabilities of premigration HIV acquisition within a Bayesian framework. The method is applied to a subset of data from the European Surveillance System (TESSy) and simulated data. FINDINGS: Simulation study results showed good performance with the probabilities of correctly classifying a premigration case or a postmigration case being 87.4% and 80.4%, respectively. Applying the method to TESSy data, we estimated the proportions of migrants who acquired HIV in the destination country were 31.9%, 37.1%, 45.3%, and 45.2% for those originating from Africa, Europe, Asia, and other regions, respectively. CONCLUSIONS: Although the considered method was initially developed for cases with multiple biomarkers' measurements, its performance, when applied to data where only one CD4 count per individual is available, remains satisfactory. Application of the method to TESSy data, estimated that a substantial proportion of HIV acquisition among migrants occurs in destination countries, having important implications for public health policy and programs.

Tracking elimination of HIV transmission in men who have sex with men in England: a modelling study.

BACKGROUND: To manage the HIV epidemic among men who have sex with men (MSM) in England, treatment as prevention strategies based on test and treat were strengthened between 2011 and 2015, and supplemented from 2015 by scale-up of pre-exposure prophylaxis (PrEP). We examined the effect of these interventions on HIV incidence and investigated whether internationally agreed targets for HIV control and elimination of HIV transmission by 2030 might be within reach among MSM in England. METHODS: We used a novel, age-stratified, CD4-staged Bayesian back-calculation model to estimate HIV incidence and undiagnosed infections among adult MSM (age ≥15 years) during the 10-year period between 2009 and 2018. The model used data on HIV and AIDS diagnoses routinely collected via the national HIV and AIDS Reporting System in England, and knowledge on the progression of HIV through CD4-defined disease stages. Estimated incidence trends were extrapolated, assuming a constant MSM population from 2018 onwards, to quantify the likelihood of achieving elimination of HIV transmission, defined as less than one newly aquired infection per 10 000 MSM per year, by 2030. FINDINGS: The peak in HIV incidence in MSM in England was estimated with 80% certainty to have occurred in 2012 or 2013, at least 1 year before the observed peak in new diagnoses in 2014. Results indicated a steep decrease in the annual number of new infections among MSM, from 2770 (95% credible interval 2490-3040) in 2013 to 1740 (1500-2010) in 2015, followed by a steadier decrease from 2016, down to 854 (441-1540) infections in 2018. A decline in new infections was consistently estimated in all age groups, and was particularly marked in MSM aged 25-34 years, and slowest in those aged 45 years or older. Similar trends were estimated in the number of undiagnosed infections, with the greatest decrease after 2013 in the 25-34 years age group. Under extrapolation assumptions, we calculated a 40% probability of achieving the defined target elimination threshold by 2030. INTERPRETATION: The sharp decrease in HIV incidence, estimated to have begun before the scale up of PrEP, indicates the success of strengthening treatment as prevention measures among MSM in England. To achieve the 2030 elimination threshold, targeted policies might be required to reach those aged 45 years or older, in whom incidence is decreasing at the slowest rate. FUNDING: UK Medical Research Council, UK National Institute of Health Research Health Protection Unit in Behavioural Science and Evaluation, and Public Health England.

Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK.

BACKGROUND: Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital. METHODS: In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260. FINDINGS: Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8-32·7) in March 9 to April 26, 2020, to 16·4% (15·0-17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65-0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94-0·95) of the reduction in in-hospital mortality. INTERPRETATION: The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain. FUNDING: National Institute for Health Research and the Medical Research Council.

SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN).

BACKGROUND: Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. METHODS: A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. FINDINGS: From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13-0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. INTERPRETATION: A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. FUNDING: Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Association between self-reported signs and symptoms and SARS-CoV-2 antibody detection in UK key workers.

BACKGROUND: Screening for SARS-CoV-2 antibodies is under way in some key worker groups; how this adds to self-reported COVID-19 illness is unclear. In this study, we investigate the association between self-reported belief of COVID-19 illness and seropositivity. METHODS: Cross-sectional study of three key worker streams comprising (A) Police and Fire & Rescue (2 sites) (B) healthcare workers (1 site) and (C) healthcare workers with previously positive PCR result (5 sites). We collected self-reported signs and symptoms of COVID-19 and compared this with serology results from two SARS-CoV-2 immunoassays (Roche Elecsys® and EUROIMMUN). RESULTS: Between 01 and 26 June, we recruited 2847 individuals (Stream A: 1,247, Stream B: 1,546 and Stream C: 154). Amongst those without previous positive PCR tests, 687/2,579 (26%) reported belief they had COVID-19, having experienced compatible symptoms; however, only 208 (30.3%) of these were seropositive on both immunoassays. Both immunoassays had high sensitivities relative to previous PCR positivity (>93%); there was also limited decline in antibody titres up to 110 days post symptom onset. Symptomatic but seronegative individuals had differing symptom profiles and shorter illnesses than seropositive individuals. CONCLUSION: Non-COVID-19 respiratory illness may have been mistaken for COVID-19 during the outbreak; laboratory testing is more specific than self-reported key worker beliefs in ascertaining past COVID-19 disease.

Invasive Pneumococcal Disease in People With Human Immunodeficiency Virus in England, 1999-2017.

BACKGROUND: The 7-valent and 13-valent pneumococcal conjugate vaccines (PCVs) were introduced into the UK childhood immunization program in 2006 and 2010, respectively, with high effectiveness and resulting in both direct and indirect protection. We describe the epidemiology of invasive pneumococcal disease (IPD) in adults with human immunodeficiency virus (HIV) in England following the introduction of both PCVs. METHODS: Data on a national cohort of people with HIV were linked to confirmed IPD cases in adults aged ≥ 15 years during 1999-2017. Date of HIV infection was estimated using a CD4 slope decline algorithm. RESULTS: Among 133 994 adults with HIV, 1453 developed IPD during 1999-2017, with 70% (1016/1453) developing IPD ≥ 3 months after their HIV diagnosis. IPD and HIV were codiagnosed within 90 days in 345 (24%) individuals. A missed opportunity for earlier HIV diagnosis was identified in 6% (89/1453), mostly in earlier years. IPD incidence in people with HIV increased from 147/100 000 in 1999 to 284/100 000 in 2007 before declining and stabilizing between 92 and 113/100 000 during 2014-2017. Mean annual IPD incidence was lower among those receiving antiretroviral therapy during 2014-17 (68 vs 720/100 000; incidence rate ratio [IRR] 9.3; 95% confidence interval [CI], 7.3-11.8; P < .001) and was markedly lower in those with a suppressed viral load (50 vs 523/100 000; IRR 10.4; 95% CI, 7.6-14.1; P < .001). The latter group still had 4.5-fold higher (95% CI, 3.8-5.3; P < .001) IPD incidence compared to the general population (11.2/100 000). CONCLUSIONS: IPD incidence among people with HIV reduced after PCV13 introduction and has remained stable. Adults presenting with IPD should continue to be tested for HIV infection.