Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines.

BACKGROUND: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), have been used since December 2020 in the United Kingdom. Real-world data have shown the vaccines to be highly effective against Covid-19 and related severe disease and death. Vaccine effectiveness may wane over time since the receipt of the second dose of the ChAdOx1-S (ChAdOx1 nCoV-19) and BNT162b2 vaccines. METHODS: We used a test-negative case-control design to estimate vaccine effectiveness against symptomatic Covid-19 and related hospitalization and death in England. Effectiveness of the ChAdOx1-S and BNT162b2 vaccines was assessed according to participant age and status with regard to coexisting conditions and over time since receipt of the second vaccine dose to investigate waning of effectiveness separately for the B.1.1.7 (alpha) and B.1.617.2 (delta) variants. RESULTS: Vaccine effectiveness against symptomatic Covid-19 with the delta variant peaked in the early weeks after receipt of the second dose and then decreased by 20 weeks to 44.3% (95% confidence interval [CI], 43.2 to 45.4) with the ChAdOx1-S vaccine and to 66.3% (95% CI, 65.7 to 66.9) with the BNT162b2 vaccine. Waning of vaccine effectiveness was greater in persons 65 years of age or older than in those 40 to 64 years of age. At 20 weeks or more after vaccination, vaccine effectiveness decreased less against both hospitalization, to 80.0% (95% CI, 76.8 to 82.7) with the ChAdOx1-S vaccine and 91.7% (95% CI, 90.2 to 93.0) with the BNT162b2 vaccine, and death, to 84.8% (95% CI, 76.2 to 90.3) and 91.9% (95% CI, 88.5 to 94.3), respectively. Greater waning in vaccine effectiveness against hospitalization was observed in persons 65 years of age or older in a clinically extremely vulnerable group and in persons 40 to 64 years of age with underlying medical conditions than in healthy adults. CONCLUSIONS: We observed limited waning in vaccine effectiveness against Covid-19-related hospitalization and death at 20 weeks or more after vaccination with two doses of the ChAdOx1-S or BNT162b2 vaccine. Waning was greater in older adults and in those in a clinical risk group.

Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant.

BACKGROUND: A rapid increase in coronavirus disease 2019 (Covid-19) cases due to the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 in highly vaccinated populations has aroused concerns about the effectiveness of current vaccines. METHODS: We used a test-negative case-control design to estimate vaccine effectiveness against symptomatic disease caused by the omicron and delta (B.1.617.2) variants in England. Vaccine effectiveness was calculated after primary immunization with two doses of BNT162b2 (Pfizer-BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccine and after a booster dose of BNT162b2, ChAdOx1 nCoV-19, or mRNA-1273. RESULTS: Between November 27, 2021, and January 12, 2022, a total of 886,774 eligible persons infected with the omicron variant, 204,154 eligible persons infected with the delta variant, and 1,572,621 eligible test-negative controls were identified. At all time points investigated and for all combinations of primary course and booster vaccines, vaccine effectiveness against symptomatic disease was higher for the delta variant than for the omicron variant. No effect against the omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% confidence interval [CI], 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks. Among ChAdOx1 nCoV-19 primary course recipients, vaccine effectiveness increased to 62.4% (95% CI, 61.8 to 63.0) at 2 to 4 weeks after a BNT162b2 booster before decreasing to 39.6% (95% CI, 38.0 to 41.1) at 10 or more weeks. Among BNT162b2 primary course recipients, vaccine effectiveness increased to 67.2% (95% CI, 66.5 to 67.8) at 2 to 4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI, 44.7 to 46.7) at 10 or more weeks. Vaccine effectiveness after a ChAdOx1 nCoV-19 primary course increased to 70.1% (95% CI, 69.5 to 70.7) at 2 to 4 weeks after an mRNA-1273 booster and decreased to 60.9% (95% CI, 59.7 to 62.1) at 5 to 9 weeks. After a BNT162b2 primary course, the mRNA-1273 booster increased vaccine effectiveness to 73.9% (95% CI, 73.1 to 74.6) at 2 to 4 weeks; vaccine effectiveness fell to 64.4% (95% CI, 62.6 to 66.1) at 5 to 9 weeks. CONCLUSIONS: Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time. (Funded by the U.K. Health Security Agency.).

Type I interferons and MAVS signaling are necessary for tissue resident memory CD8+ T cell responses to RSV infection.

Respiratory syncytial virus (RSV) can cause bronchiolitis and viral pneumonia in young children and the elderly. Lack of vaccines and recurrence of RSV infection indicate the difficulty in eliciting protective memory immune responses. Tissue resident memory T cells (TRM) can confer protection from pathogen re-infection and, in human experimental RSV infection, the presence of lung CD8+ TRM cells correlates with a better outcome. However, the requirements for generating and maintaining lung TRM cells during RSV infection are not fully understood. Here, we use mouse models to assess the impact of innate immune response determinants in the generation and subsequent expansion of the TRM cell pool during RSV infection. We show that CD8+ TRM cells expand independently from systemic CD8+ T cells after RSV re-infection. Re-infected MAVS and MyD88/TRIF deficient mice, lacking key components involved in innate immune recognition of RSV and induction of type I interferons (IFN-α/ß), display impaired expansion of CD8+ TRM cells and reduction in antigen specific production of granzyme B and IFN-γ. IFN-α treatment of MAVS deficient mice during primary RSV infection restored TRM cell expansion upon re-challenge but failed to recover TRM cell functionality. Our data reveal how innate immunity, including the axis controlling type I IFN induction, instructs and regulates CD8+ TRM cell responses to RSV infection, suggesting possible mechanisms for therapeutic intervention.

Effects of COVID-19 Pandemic Response on Service Provision for Sexually Transmitted Infections, HIV, and Viral Hepatitis, England.

Since the coronavirus disease pandemic response began in March 2020, tests, vaccinations, diagnoses, and treatment initiations for sexual health, HIV, and viral hepatitis in England have declined. The shift towards online and outreach services happened rapidly during 2020 and highlights the need to evaluate the effects of these strategies on health inequalities.

Effectiveness of BNT162b2 and ChAdOx-1 vaccines in residents of long-term care facilities in England using a time-varying proportional hazards model.

INTRODUCTION: residents of long-term care facilities (LTCFs) are at high risk of adverse outcomes from SARS-CoV-2. We aimed to estimate the vaccine effectiveness (VE) of one and two doses of BNT162b2 and ChAdOx-1 against SARS CoV-2 infection and COVID-19-related death in residents of LTCFs. METHODS: this observational study used testing, vaccination and mortality data for LTCF residents aged ≥ 65 years who were regularly tested regardless of symptoms from 8 December 2020 to 30 September 2021 in England. Adjusted VE, calculated as one minus adjusted hazard ratio, was estimated using time-varying Cox proportional hazards models for infection and death within 28 days of positive test result. Vaccine status was defined by receipt of one or two doses of vaccine and assessed over a range of intervals. RESULTS: of 197,885 LTCF residents, 47,087 (23.8%) had a positive test and 11,329 (5.8%) died within 28 days of a positive test during the study period. Relative to unvaccinated individuals, VE for infection was highest for ChAdOx-1 at 61% (40-74%) at 1-4 weeks and for BNT162b2 at 69% (52-80%) at 11-15 weeks following the second dose. Against death, VE was highest for ChAdOx-1 at 83% (58-94%) at 1-4 weeks and for BNT162b2 at 91% (75-97%) at 11-15 weeks following second dose. CONCLUSIONS: compared with unvaccinated residents, vaccination with one dose of BNT162b2 or ChAdOx-1 provided moderate protection against infection and death in residents of LTCFs. Protection against death improved after two doses. However, some waning of protection over time was noted.

High-throughput transposon sequencing highlights the cell wall as an important barrier for osmotic stress in methicillin resistant Staphylococcus aureus and underlines a tailored response to different osmotic stressors.

Staphylococcus aureus is an opportunistic pathogen that can cause soft tissue infections but is also a frequent cause of foodborne illnesses. One contributing factor for this food association is its high salt tolerance allowing this organism to survive commonly used food preservation methods. How this resistance is mediated is poorly understood, particularly during long-term exposure. In this study, we used transposon sequencing (TN-seq) to understand how the responses to osmotic stressors differ. Our results revealed distinctly different long-term responses to NaCl, KCl and sucrose stresses. In addition, we identified the DUF2538 domain containing gene SAUSA300_0957 (gene 957) as essential under salt stress. Interestingly, a 957 mutant was less susceptible to oxacillin and showed increased peptidoglycan crosslinking. The salt sensitivity phenotype could be suppressed by amino acid substitutions in the transglycosylase domain of the penicillin-binding protein Pbp2, and these changes restored the peptidoglycan crosslinking to WT levels. These results indicate that increased crosslinking of the peptidoglycan polymer can be detrimental and highlight a critical role of the bacterial cell wall for osmotic stress resistance. This study will serve as a starting point for future research on osmotic stress response and help develop better strategies to tackle foodborne staphylococcal infections.

Population genetic structure and adaptation of malaria parasites on the edge of endemic distribution.

To determine whether the major human malaria parasite Plasmodium falciparum exhibits fragmented population structure or local adaptation at the northern limit of its African distribution where the dry Sahel zone meets the Sahara, samples were collected from diverse locations within Mauritania over a range of ~1000 km. Microsatellite genotypes were obtained for 203 clinical infection samples from eight locations, and Illumina paired-end sequences were obtained to yield high coverage genomewide single nucleotide polymorphism (SNP) data for 65 clinical infection samples from four locations. Most infections contained single parasite genotypes, reflecting low rates of transmission and superinfection locally, in contrast to the situation seen in population samples from countries further south. A minority of infections shared related or identical genotypes locally, indicating some repeated transmission of parasite clones without recombination. This caused some multilocus linkage disequilibrium and local divergence, but aside from the effect of repeated genotypes there was minimal differentiation between locations. Several chromosomal regions had elevated integrated haplotype scores (|iHS|) indicating recent selection, including those containing drug resistance genes. A genomewide FST scan comparison with previous sequence data from an area in West Africa with higher infection endemicity indicates that regional gene flow prevents genetic isolation, but revealed allele frequency differentiation at three drug resistance loci and an erythrocyte invasion ligand gene. Contrast of extended haplotype signatures revealed none to be unique to Mauritania. Discrete foci of infection on the edge of the Sahara are genetically highly connected to the wider continental parasite population, and local elimination would be difficult to achieve without very substantial reduction in malaria throughout the region.

Effectiveness of autumn 2023 COVID-19 vaccination and residual protection of prior doses against hospitalisation in England, estimated using a test-negative case-control study.

INTRODUCTION: The last COVID-19 vaccine offered to all adults in England became available from November 2021. The most recent booster programme commenced in September 2023. Bivalent BA.4-5 or monovalent XBB.1.5 boosters were given. During the study period, the JN.1 variant became dominant in England. METHODS: Vaccine effectiveness against hospitalisation was estimated throughout using the test-negative case-control study design where positive PCR tests from hospitalised individuals are cases and comparable negative PCR tests are controls. Multivariable logistic regression was used to assess vaccine effectiveness against hospitalisation with the test result as the outcome, vaccination status as the primary exposure variable of interest and confounder adjustment. RESULTS: There was no evidence of residual protection for boosters given as part of previous campaigns. There were 28,916 eligible tests included to estimate the effectiveness of the autumn 2023 boosters in those aged 65 years and older. VE peaked at 50.6% (95% CI: 44.2-56.3%) after 2-4 weeks, followed by waning to 13.6% (95% CI: -11.7 to 33.2%). Estimates were generally higher for the XBB.1.5 booster than the BA.4-5 booster, but this difference was not statistically significant. Point estimates were highest against XBB sub-lineages. Effectiveness was lower against both JN.1 and EG.5.1 variants with confidence intervals non-overlapping with the effectiveness of the XBB sub-lineages at 2-4 weeks for EG.5.1 where VE was 44.5% (95% CI: 20.2-61.4%) and at 5-9 weeks for JN.1 where VE was 26.4% (95%CI: -3.4 to 47.6%). CONCLUSIONS: The recent monovalent XBB.1.5 and bivalent BA.4-5 boosters provided comparable and good protection against hospitalisation, however there was evidence of lower VE against hospitalisation of these boosters against JN.1.

Effectiveness of the Sanofi/GSK (VidPrevtyn Beta) and Pfizer-BioNTech (Comirnaty Original/Omicron BA.4-5) bivalent vaccines against hospitalisation in England.

Background: The Sanofi/GSK AS03-adjuvanted (VidPrevtyn Beta) vaccine and the Pfizer-BioNTech mRNA (Comirnaty Original/Omicron BA.4-5) bivalent vaccine were offered to adults aged 75 years and over in England from 3rd April 2023. This is the first time an adjuvanted COVID-19 vaccine has been administered as part of a UK COVID-19 vaccination programme. In clinical trials, antibody levels generated were comparable with mRNA vaccines but there are no real-world data on the effectiveness or duration of protection. Methods: We used a test-negative case-control study design to estimate the incremental vaccine effectiveness of the Sanofi/GSK and Pfizer bivalent BA.4-5 boosters against hospitalisation amongst those aged 75 years and older in England. Cases (those testing positive) and controls (those testing negative) were identified from the national COVID-19 PCR testing data undertaken in hospital settings. The study period included tests from 3rd April 2023 to 27th August 2023. Tests were linked to the COVID-19 vaccination register and to the national hospital admission database, restricting to those with an acute respiratory infection coded in the primary diagnosis field. Vaccine effectiveness was estimated using multivariable logistic regression amongst those who had last received an autumn 2022 booster given at least 3 months prior. The test result was the outcome and vaccination status the exposure. Analyses were adjusted for week of test, gender, age, clinical risk group status, care home resident status, region, index of multiple deprivation, ethnicity, influenza vaccination status and recent COVID-19 positivity. Findings: There were 14,169 eligible tests from hospitalised individuals aged 75 years and older; 3005 cases (positive tests) and 11,164 controls (negative tests). Effectiveness was highest in the period 9-13 days post vaccination for both manufacturers at about 50%; 43.7% (95% CI, 20.1-60.3%) and 56.1% (95% CI, 25.2-74.2%) for Sanofi/GSK and Pfizer BA.4-5, respectively. There was evidence of waning with a reduction to about 30% for both manufacturers after 5-9 weeks. The longest time interval post vaccination for which we were able to estimate effectiveness was 10+ weeks post vaccination, at which point vaccine effectiveness was 17.6% (95% CI, -3.6 to 34.5%) and 37.9% (95% CI, 13.2-55.5%) for the Sanofi/GSK and Pfizer BA.4-5 boosters, respectively. Interpretation: Both boosters provided good protection against hospitalisation amongst older adults. The finding that the adjuvanted vaccine targeting the distant Beta strain had similar effectiveness to the bivalent mRNA vaccine targeting more closely matched Omicron sub-lineages is notable and highlights the need for further real-world studies into the effectiveness of vaccines from different vaccine platforms and formulations in the presence of matched and unmatched strains. Funding: No external funding.

The impact of vaccination and SARS-CoV-2 variants on the virological response to SARS-CoV-2 infections during the Alpha, Delta, and Omicron waves in England.

Vaccination status and the SARS-CoV-2 variant individuals are infected with are known to independently impact viral dynamics; however, little is known about the interaction of these two factors and how this impacts viral dynamics. Here we investigated how monovalent vaccination modified the time course and viral load of infections from different variants. Regression analyses were used to investigate the impact of vaccination on cycle threshold values and disease severity, and interval-censored survival analyses were used to investigate the impact of vaccination on duration of positivity. A range of covariates were adjusted for as potential confounders and investigated for their own effects in exploratory analyses. All analyses were done combining all variants and stratified by variant. For those infected with Alpha or Delta, vaccinated individuals were more likely to report mild disease than moderate/severe disease and had significantly shorter duration of positivity and lower viral loads compared to unvaccinated individuals. Vaccination had no impact on self-reported disease severity, viral load, or duration if positivity for those infected with Omicron. Overall, individuals who were immunosuppressed and clinically extremely vulnerable had longer duration of positivity and higher viral loads. This study adds to the evidence base on disease dynamics following COVID-19, demonstrating that vaccination mitigates severity of disease, the amount of detectable virus within infected individuals and reduces the time individuals are positive for. However, these effects have been significantly attenuated since the emergence of Omicron. Therefore, our findings strengthen the argument for using modified or multivalent vaccines that target emerging variants.

Association between COVID-19 Vaccination and SARS-CoV-2 Infection among Household Contacts of Infected Individuals: A Prospective Household Study in England.

BACKGROUND: We investigated whether COVID-19 vaccination reduced SARS-CoV-2 infection risk among adult household contacts of COVID-19 index cases during the Alpha, Delta, and Omicron waves in England. METHODS: Between February 2021 and February 2022, SARS-CoV-2 RT-PCR nasal swabs were collected from COVID-19-confirmed index cases aged ≥20 years and their household contacts at enrolment and three and seven days thereafter. Generalized Estimating Equations models were fitted with SARS-CoV-2 positivity as the outcome and household contacts' vaccination status as the main exposure while adjusting for confounders. RESULTS: SARS-CoV-2 infection was confirmed in 238/472 household contacts (50.4%) aged ≥20 years. The adjusted relative risk (95% confidence interval) of infection in vaccinated versus unvaccinated household contacts was 0.50 (0.35-0.72) and 0.69 (0.53-0.90) for receipt of two doses 8-90 and >90 days ago, respectively, and 0.34 (0.23-0.50) for vaccination with three doses 8-151 days ago. Primary vaccination protected household contacts against infection during the Alpha and Delta waves, but only three doses protected during the Omicron wave. Vaccination with three doses in the index case independently reduced contacts' infection risk: 0.45 (0.23-0.89). CONCLUSIONS: Vaccination of household contacts reduces their risk of infection under conditions of household exposure though, for Omicron, only after a booster dose.

Duration of protection of ancestral-strain monovalent vaccines and effectiveness of bivalent BA.1 boosters against COVID-19 hospitalisation in England: a test-negative case-control study.

BACKGROUND: Bivalent BA.1 booster vaccines were offered to adults aged 50 years or older and clinically vulnerable people as part of the 2022 autumn COVID-19 booster vaccination programme in England. Previously, all adults in England had been offered a primary course consisting of two doses of either ChAdOx1-S or monovalent mRNA vaccine and an mRNA monovalent booster vaccine. We aimed to estimate the long-term duration of protection provided by monovalent COVID-19 vaccines, and the incremental vaccine effectiveness of bivalent BA.1 boosters. METHODS: In this test-negative case-control study, cases of COVID-19 and controls aged 18 years or older were identified from national data for PCR tests done in hospital settings in England. Our analysis was restricted to people with acute respiratory infections coded in the primary diagnosis field. Data for vaccination status were extracted from the English national vaccine register and linked to COVID-19 testing data. Between June 13 and Dec 25, 2022, we estimated the vaccine effectiveness against hospitalisation of two or three or more doses of monovalent COVID-19 vaccines compared with being unvaccinated, stratified by age (18-64 years vs ≥65 years). Between Sept 5, 2022, and Feb 5, 2023, we estimated the incremental vaccine effectiveness (ie, in addition to the protection from earlier vaccines) of receiving a bivalent BA.1 booster vaccine in addition to at least two doses of a monovalent vaccine (when the last dose was at least 6 months ago) among people aged 50 years or older. Analyses were adjusted for week of test, gender, age, COVID-19 risk group, residing in a care home, being a health or social care worker, Index of Multiple Deprivation quintile, ethnicity, and recent COVID-19 positivity. FINDINGS: Our analysis of monovalent COVID-19 vaccines included 19 841 cases and 43 410 controls. Absolute vaccine effectiveness against hospitalisation among people who had received at least three doses plateaued from 6 months after the last dose at around 50% in those aged 65 years or older and at around 30% in those aged 18-64 years. Our analyses of the effectiveness of bivalent BA.1 boosters included data for 9954 cases and 39 108 controls aged 50 years or older. Incremental vaccine effectiveness peaked at 53·0% (95% CI 47·9-57·5) 2-4 weeks after administration, before waning to 35·9% (31·4-40·1) after 10 or more weeks. INTERPRETATION: Our study provides evidence that monovalent COVID-19 vaccines offer moderate long-term protection against hospitalisation in people aged 65 years or older and that the bivalent BA.1 booster vaccines were effective in preventing hospitalisation among people aged 50 years or older at a time when omicron lineages were circulating in England. FUNDING: None.

Protection against symptomatic infection with delta (B.1.617.2) and omicron (B.1.1.529) BA.1 and BA.2 SARS-CoV-2 variants after previous infection and vaccination in adolescents in England, August, 2021-March, 2022: a national, observational, test-negative, case-control study.

BACKGROUND: Little is known about protection against SARS-CoV-2 infection following previous infection with specific individual SARS-CoV-2 variants, COVID-19 vaccination, and a combination of previous infection and vaccination (hybrid immunity) in adolescents. We aimed to estimate protection against symptomatic PCR-confirmed infection with the delta (B.1.617.2) and omicron (B.1.1.529) variants in adolescents with previous infection, mRNA vaccination, and hybrid immunity. METHODS: We conducted an observational, test-negative, case-control study using national SARS-CoV-2 testing and COVID-19 mRNA vaccination data in England. Symptomatic adolescents aged 12-17 years who were unvaccinated or had received primary BNT162b2 immunisation at symptom onset and had a community SARS-CoV-2 PCR test were included. Vaccination and previous SARS-CoV-2 infection status in adolescents with PCR-confirmed COVID-19 (cases) were compared with vaccination and previous infection status in adolescents who had a negative SARS-CoV-2 PCR test (controls). Vaccination data were collected from the National Immunisation Management System, and were linked to PCR testing data. The primary outcome was protection against SARS-CoV-2 delta and omicron infection (defined as 1 - odds of vaccination or previous infection in cases divided by odds of vaccination or previous infection in controls). FINDINGS: Between Aug 9, 2021, and March 31, 2022, 1 161 704 SARS-CoV-2 PCR tests were linked to COVID-19 vaccination status, including 390 467 positive tests with the delta variant and 212 433 positive tests with the omicron variants BA.1 and BA.2. In unvaccinated adolescents, previous SARS-CoV-2 infection with wildtype, alpha (B.1.1.7), or delta strains provided greater protection against subsequent delta infection (>86·1%) than against subsequent omicron infection (<52·4%); previous delta or omicron infection provided similar protection against omicron reinfection (52·4% [95% CI 50·9-53·8] vs 59·3% [46·7-69·0]). In adolescents with no previous infection, vaccination provided lower protection against omicron infection than against delta infection, with omicron protection peaking at 64·5% (95% CI 63·6-65·4) at 2-14 weeks after dose two and 62·9% (60·5-65·1) at 2-14 weeks after dose three, with waning protection after each dose. Adolescents with hybrid immunity from previous infection and vaccination had the highest protection, irrespective of the SARS-CoV-2 strain in the primary infection. The highest protection against omicron infection was observed in adolescents with vaccination and previous omicron infection, reaching 96·4% (95% CI 84·4-99·1) at 15-24 weeks after vaccine dose two. INTERPRETATION: Previous infection with any SARS-CoV-2 variant provided some protection against symptomatic reinfection, and vaccination added to this protection. Vaccination provides low-to-moderate protection against symptomatic omicron infection, with waning protection after each dose, while hybrid immunity provided the most robust protection. Although more data are needed to investigate longer-term protection and protection against infection with new variants, these data question the need for additional booster vaccine doses for adolescents in populations with already high protection against SARS-CoV-2 infection. FUNDING: None.

Monitoring the COVID-19 immunisation programme through a national immunisation Management system - England's experience.

BACKGROUND: In England routine vaccinations are recorded in either the patients General Practice record or in series of sub-national vaccine registers that are not interoperable. During the COVID-19 pandemic it was established that COVID vaccines would need to be delivered in multiple settings where current vaccine registers do not exist. We describe how a national vaccine register was created to collect data on COVID-19 vaccines. METHODS: The National Immunisation Management System (NIMS) was developed by a range of health and digital government agencies. Vaccinations delivered are entered on an application which is verified by individual National Health Service number in a centralised system. UKHSA receive a feed of this data to use for monitoring vaccine coverage, effectiveness, and safety. To validate the vaccination data, we compared vaccine records to self-reported vaccination dose, manufacturer, and vaccination date from the enhanced surveillance system from 11 February 2021 to 24 August 2021. RESULTS: With the Implementation of NIMS, we have been able to successfully record COVID-19 vaccinations delivered in multiple settings. Of 1,129 individuals, 97.8% were recorded in NIMS as unvaccinated compared to those who self-reported as unvaccinated. One hundred percent and 99.3% of individuals recorded in NIMS as having at least one dose and two doses of the COVID-19 vaccine were also self-reported as having at least one and two doses, respectively. Of the 100% reporting at least one dose, 98.3% self-reported the same vaccination date as NIMS. A total of 98.8% and 99.3% had the same manufacturer information for their first dose and second dose as that which was self-reported, respectively. DISCUSSION: Daily access to individual-level vaccine data from NIMS has allowed UKHSA to estimate vaccine coverage and provide some of the world's first vaccine effectiveness estimates rapidly and accurately.

Effectiveness of BNT162b2 and ChAdOx1 against SARS-CoV-2 household transmission: a prospective cohort study in England.

Background: The ability of SARS-CoV-2 vaccines to protect against infection and onward transmission determines whether immunisation can control global circulation. We estimated the effectiveness of Pfizer-BioNTech mRNA vaccine (BNT162b2) and Oxford AstraZeneca adenovirus vector vaccine (ChAdOx1) vaccines against acquisition and transmission of the Alpha and Delta variants in a prospective household study in England. Methods: Households were recruited based on adult purported index cases testing positive after reverse transcription-quantitative (RT-q)PCR testing of oral-nasal swabs. Purported index cases and their household contacts took oral-nasal swabs on days 1, 3 and 7 after enrolment and a subset of the PCR-positive swabs underwent genomic sequencing conducted on a subset. We used Bayesian logistic regression to infer vaccine effectiveness against acquisition and transmission, adjusted for age, vaccination history and variant. Results: Between 2 February 2021 and 10 September 2021, 213 index cases and 312 contacts were followed up. After excluding households lacking genomic proximity (N=2) or with unlikely serial intervals (N=16), 195 households with 278 contacts remained, of whom 113 (41%) became PCR positive. Delta lineages had 1.53 times the risk (95% Credible Interval: 1.04 - 2.20) of transmission than Alpha; contacts older than 18 years old were 1.48 (1.20 - 1.91) and 1.02 (0.93 - 1.16) times more likely to acquire an Alpha or Delta infection than children. Effectiveness of two doses of BNT162b2 against transmission of Delta was 36% (-1%, 66%) and 49% (18%, 73%) for ChAdOx1, similar to their effectiveness for Alpha. Protection against infection with Alpha was higher than for Delta, 69% (9%, 95%) vs. 18% (-11%, 59%), respectively, for BNT162b2 and 24% (-41%, 72%) vs. 9% (-15%, 42%), respectively, for ChAdOx1. Conclusions: BNT162b2 and ChAdOx1 reduce transmission of the Delta variant from breakthrough infections in the household setting, although their protection against infection within this setting is low.

Vaccine effectiveness against hospitalisation estimated using a test-negative case-control study design, and comparative odds of hospital admission and severe outcomes with COVID-19 sub-lineages BQ.1, CH.1.1. and XBB.1.5 in England.

Background: Since the first emergence of Omicron BA.1 in England in November 2021, numerous sub-lineages have evolved. In September 2022, BA.5 dominated. The prevalence of BQ.1 increased from October, while the prevalence of CH.1.1 and XBB.1.5 increased from December 2022 and January 2023, respectively. Little is known about the effectiveness of the vaccines against hospitalisation with these sub-lineages, nor the relative severity, so we here used national-level electronic health records from England to estimate vaccine effectiveness and variant severity. Methods: The study period for tests contributing to all analyses was from 5th December 2022 to 2nd April 2023, when the variants of interest were co-circulating. A test-negative case-control study was used to estimate the incremental effectiveness of the bivalent BA.1 booster vaccines against hospitalisation, relative to those with waned immunity where the last dose was at least 6 months prior. The odds of hospital admission for those testing PCR positive on the day of an attendance to accident and emergency departments and the odds of intensive care unit admission or death amongst COVID-19 admissions were compared between variants. Additionally, a Cox proportional hazards survival regression was used to investigate length of stay amongst hospitalised cases by variant. Findings: Our vaccine effectiveness study included 191,229 eligible tests with 1647 BQ.1 cases, 877 CH.1.1 cases, 1357 XBB.1.5 cases and 187,348 test negative controls. There was no difference in incremental vaccine effectiveness against hospitalisation with BQ.1, CH.1.1 or XBB.1.5, nor was there a difference in the severity of these variants. Effectiveness against hospitalisation was 48.0% (95% C.I.; 38.5-56.0%), 29.7% (95% C.I.; 7.5-46.6%) and 52.7% (95% C.I.; 24.6-70.4%) against BQ.1, CH.1.1 and XBB.1.5, respectively, at 5-9 weeks post booster vaccination. Compared to BQ.1, the odds of hospital admission were 0.87 (95% C.I.; 0.77-0.99) and 0.88 (95% C.I.; 0.75-1.02) for CH.1.1 and XBB.1.5 cases attending accident and emergency departments, respectively. There was no significant difference in the odds of admission to intensive care units or death for those with CH.1.1 (OR 0.96, 95% C.I.; 0.71-1.30) or XBB.1.5 (OR 0.67, 95% C.I.; 0.44-1.02) compared to BQ.1. There was also no significant difference in the length of hospital stay by variant. Interpretation: Together, these results provide reassuring evidence that the bivalent BA.1 booster vaccines provide similar protection against hospitalisation with BQ.1, CH.1.1 and XBB.1.5, and that the emergent CH.1.1 and XBB.1.5 sub-lineages do not cause more severe disease than BQ.1. Funding: None.

Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation, a test negative case-control study.

The Omicron variant has been associated with reduced vaccine effectiveness (VE) against mild disease with rapid waning. Meanwhile Omicron has also been associated with milder disease. Protection against severe disease has been substantially higher than protection against infection with previous variants. We used a test-negative case-control design to estimate VE against hospitalisation with the Omicron and Delta variants using PCR testing linked to hospital records. We investigated the impact of increasing the specificity and severity of hospitalisation definitions on VE. Among 18-64-year-olds using cases admitted via emergency care, VE after a 3rd dose peaked at 82.4% and dropped to 53.6% by 15+ weeks after the 3rd dose; using all admissions for > = 2 days stay with a respiratory code in the primary diagnostic field VE ranged from 90.9% to 67.4%; further restricting to those on oxygen/ventilated/intensive care VE ranged from 97.1% to 75.9%. Among 65+ year olds the equivalent VE estimates were 92.4% to 76.9%; 91.3% to 85.3% and 95.8% to 86.8%. Here we show that with milder Omicron disease contamination of hospitalisations with incidental cases is likely to reduce VE estimates. VE estimates increase, and waning is reduced, when specific hospitalisation definitions are used.

Effectiveness of ChAdOx1-S COVID-19 booster vaccination against the Omicron and Delta variants in England.

Despite the availability of the ChAdOx1-S booster vaccine, little is known about the real-world effectiveness although clinical trials have demonstrated enhanced immunity following a ChAdOx1-S booster. In England 43,171 individuals received a ChAdOx1-S booster whilst 13,038,908 individuals received BNT162b2 in the same period. ChAdOx1-S booster recipients were more likely to be female (adjusted odds ratio (OR) 1.67 (1.64-1.71)), in a clinical risk group (adjusted OR 1.58 (1.54-1.63)), in the clinically extremely vulnerable group (adjusted OR 1.84 (1.79-1.89)) or severely immunosuppressed (adjusted OR 2.05 (1.96-2.13)). The effectiveness of the ChAdOx1-S and BNT162b2 boosters is estimated here using a test-negative case-control study. Protection against symptomatic disease with the Omicron variant peaks at 66.1% (16.6 to 86.3%) and 68.5% (65.7 to 71.2%) for the ChAdOx1-S and BNT162b2 boosters in older adults. Protection against hospitalisation peaks at 82.3% (64.2 to 91.3%) and 90.9% (88.7 to 92.7%). For Delta, effectiveness against hospitalisation is 80.9% (15.6% to 95.7%) and 93.9% (92.8% to 94.9%) after ChAdOx1-S and BNT162b2 booster vaccination. This study supports the consideration of ChAdOx1-S booster vaccination for protection against severe COVID-19 in settings yet to offer boosters and suggests that individuals who received a ChAdOx1-S booster do not require re-vaccination ahead of others.

Effectiveness of COVID-19 booster vaccines against COVID-19-related symptoms, hospitalization and death in England.

Booster vaccination with messenger RNA (mRNA) vaccines has been offered to adults in England starting on 14 September 2021. We used a test-negative case-control design to estimate the relative effectiveness of a booster dose of BNT162b2 (Pfizer-BioNTech) compared to only a two-dose primary course (at least 175 days after the second dose) or unvaccinated individuals from 13 September 2021 to 5 December 2021, when Delta variant was dominant in circulation. Outcomes were symptomatic coronavirus disease 2019 (COVID-19) and hospitalization. The relative effectiveness against symptomatic disease 14-34 days after a BNT162b2 or mRNA-1273 (Moderna) booster after a ChAdOx1-S (AstraZeneca) and BNT162b2 as a primary course ranged from around 85% to 95%. Absolute vaccine effectiveness ranged from 94% to 97% and was similar in all age groups. Limited waning was seen 10 or more weeks after the booster. Against hospitalization or death, absolute effectiveness of a BNT162b2 booster ranged from around 97% to 99% in all age groups irrespective of the primary course, with no evidence of waning up to 10 weeks. This study provides real-world evidence of substantially increased protection from the booster vaccine dose against mild and severe disease irrespective of the primary course.

Neutrophils in respiratory viral infections.

Viral respiratory infections are a common cause of severe disease, especially in infants, people who are immunocompromised, and in the elderly. Neutrophils, an important innate immune cell, infiltrate the lungs rapidly after an inflammatory insult. The most well-characterized effector mechanisms by which neutrophils contribute to host defense are largely extracellular and the involvement of neutrophils in protection from numerous bacterial and fungal infections is well established. However, the role of neutrophils in responses to viruses, which replicate intracellularly, has been less studied. It remains unclear whether and, by which underlying immunological mechanisms, neutrophils contribute to viral control or confer protection against an intracellular pathogen. Furthermore, neutrophils need to be tightly regulated to avoid bystander damage to host tissues. This is especially relevant in the lung where damage to delicate alveolar structures can compromise gas exchange with life-threatening consequences. It is inherently less clear how neutrophils can contribute to host immunity to viruses without causing immunopathology and/or exacerbating disease severity. In this review, we summarize and discuss the current understanding of how neutrophils in the lung direct immune responses to viruses, control viral replication and spread, and cause pathology during respiratory viral infections.