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Multivalent diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine (DTaP/IPV) has been offered to pregnant women in the United Kingdom since 2012. To assess the impact of maternal DTaP/IPV immunisation on the infant immune response to IPV, we measured poliovirus-specific neutralising antibodies at 2, 5 and 13 months of age in a randomised, phase 4 study of Repevax or Boostrix/IPV in pregnancy and in a non-randomised group born to women not given DTaP/IPV in pregnancy. Infants whose mothers received DTaP/IPV were less likely to seroconvert after three IPV doses than those whose mothers did not receive DTaP/IPV. At 13 months of age, 63/110 (57.2 %), 46/108 (42.6 %) and 40/108 (37.0 %) were seropositive to types 1 to 3, compared with 20/22 (90.9 %), 20/22 (90.9 %) and 14/20 (70.0 %) (p-values 0.003

Summary Background Following the emergency use authorisation of the Pfizer–BioNTech mRNA COVID-19 vaccine BNT162b2 (international non-proprietary name tozinameran) in Israel, the Ministry of Health (MoH) launched a campaign to immunise the 6·5 million residents of Israel aged 16 years and older. We estimated the real-world effectiveness of two doses of BNT162b2 against a range of SARS-CoV-2 outcomes and to evaluate the nationwide public-health impact following the widespread introduction of the vaccine. Methods We used national surveillance data from the first 4 months of the nationwide vaccination campaign to ascertain incident cases of laboratory-confirmed SARS-CoV-2 infections and outcomes, as well as vaccine uptake in residents of Israel aged 16 years and older. Vaccine effectiveness against SARS-CoV-2 outcomes (asymptomatic infection, symptomatic infection, and COVID-19-related hospitalisation, severe or critical hospitalisation, and death) was calculated on the basis of incidence rates in fully vaccinated individuals (defined as those for whom 7 days had passed since receiving the second dose of vaccine) compared with rates in unvaccinated individuals (who had not received any doses of the vaccine), with use of a negative binomial regression model adjusted for age group (16–24, 25–34, 35–44, 45–54, 55–64, 65–74, 75–84, and ≥85 years), sex, and calendar week. The proportion of spike gene target failures on PCR test among a nationwide convenience-sample of SARS-CoV-2-positive specimens was used to estimate the prevelance of the B.1.1.7 variant. Findings During the analysis period (Jan 24 to April 3, 2021), there were 232 268 SARS-CoV-2 infections, 7694 COVID-19 hospitalisations, 4481 severe or critical COVID-19 hospitalisations, and 1113 COVID-19 deaths in people aged 16 years or older. By April 3, 2021, 4 714 932 (72·1%) of 6 538 911 people aged 16 years and older were fully vaccinated with two doses of BNT162b2. Adjusted estimates of vaccine effectiveness at 7 days or longer after the second dose were 95·3% (95% CI 94·9–95·7; incidence rate 91·5 per 100 000 person-days in unvaccinated vs 3·1 per 100 000 person-days in fully vaccinated individuals) against SARS-CoV-2 infection, 91·5% (90·7–92·2; 40·9 vs 1·8 per 100 000 person-days) against asymptomatic SARS-CoV-2 infection, 97·0% (96·7–97·2; 32·5 vs 0·8 per 100 000 person-days) against symptomatic COVID-19, 97·2% (96·8–97·5; 4·6 vs 0·3 per 100 000 person-days) against COVID-19-related hospitalisation, 97·5% (97·1–97·8; 2·7 vs 0·2 per 100 000 person-days) against severe or critical COVID-19-related hospitalisation, and 96·7% (96·0–97·3; 0·6 vs 0·1 per 100 000 person-days) against COVID-19-related death. In all age groups, as vaccine coverage increased, the incidence of SARS-CoV-2 outcomes declined. 8006 of 8472 samples tested showed a spike gene target failure, giving an estimated prevalence of the B.1.1.7 variant of 94·5% among SARS-CoV-2 infections. Interpretation Two doses of BNT162b2 are highly effective across all age groups (≥16 years, including older adults aged ≥85 years) in preventing symptomatic and asymptomatic SARS-CoV-2 infections and COVID-19-related hospitalisations, severe disease, and death, including those caused by the B.1.1.7 SARS-CoV-2 variant. There were marked and sustained declines in SARS-CoV-2 incidence corresponding to increasing vaccine coverage. These findings suggest that COVID-19 vaccination can help to control the pandemic. Funding None.

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.

BackgroundThere is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity.MethodsA prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2>28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection.FindingsIndependent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2[Relative Risk (RR)=0·42 (95%CI: 0·34-0·52),P5 [RR=0·33 (95%CI: 0·21-0·50),P3 days [RR=0·84 (95%CI: 0·76-0·92),PInterpretationWe provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease.FundingAvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.RESEARCH IN CONTEXTEvidence before this studyThe burden of COVID-19 on hospital services is determined by the prevalence and severity of SARS-CoV-2 variants, and modified by individual factors such as age, frailty and vaccination status. Real world data suggest that vaccine effectiveness is lower and may wane faster over time against symptomatic disease with Omicron (B.1.1.529) than with Delta (B.1.617.2) SARS-CoV-2 variant. However, numbers of hospitalisations as a case proportion during the Omicron wave have been considerably lower than previous waves. Several reports have compared the risk of hospitalisation or severe disease based on SARS-CoV-2 variant, some suggesting that Omicron is probably less severe than Delta in vaccinated and unvaccinated individuals.Added value of this studyThis study provides robust data assessing the relative severity of Delta and Omicron SARS-CoV-2 variants in patients admitted to hospital, including the first analysis assessing risk for any positive pressure ventilatory support, as well as risk of supplementary oxygen requirement and extended hospital admission, that may guide resource planning in hospitals. We found evidence that infection with Omicron was associated with a milder clinical course following hospital admission than that caused by Delta and that vaccination was independently associated with lower in-hospital disease severity using these three separate severity measures. Specifically, compared to Delta, Omicron-related hospitalizations were 58%, 67%, and 16% less likely to require high flow oxygen >28% FiO2, positive pressure ventilatory support or more critical care, and to have a hospital stay lasting more than three days, respectively.This study reports the considerable morbidity resulting from Omicron infection, with 18% of Omicron admissions requiring oxygen supplementation FiO2>28%, 6% requiring positive pressure ventilation, 62% needing hospitalization ≥four days, and 4% in-hospital mortality. In determining the reduced requirement of increased oxygen requirement and total positive pressure requirement, including non-invasive ventilation, this analysis should contribute to future hospital care and service planning assessments.Implications of all the available evidenceThe risk of severe outcomes following SARS-CoV-2 infection is substantially lower for Omicron than for Delta, with greater reductions for more severe disease outcomes. Significant variation in risk occurs with age and vaccination status, with older and unvaccinated individuals remaining at particular risk of adverse outcome. These results highlight the importance of maintaining high levels of vaccine coverage in patient groups at risk of severe disease.The impact of lower severity Omicron-related hospitalization must be balanced against increased transmissibility and overall higher numbers of infections with this variant and there remains a substantial patient and public health burden. The increased admission rate of older patients with Omicron counteracts some of the benefit arising from less severe disease. Despite the risk reduction in high level oxygen supplementation requirement and high dependency care with Omicron compared to earlier variants at the individual level, healthcare systems could still be overwhelmed.

Human Papillomavirus (HPV) bivalent (Cervarix®) and quadrivalent (Gardasil®) vaccines demonstrate robust efficacy against vaccine types and cross-protection against related non-vaccine types. Here we evaluate the breadth, magnitude and durability of the vaccine-induced antibody response against vaccine (HPV6/11/16/18) and non-vaccine (HPV31/33/45/52/58) type antigens up to 7 years following vaccination of 12-15 year old girls in a three dose schedule and contrast these data with the levels of antibody typically seen in natural infection. Vaccine-type antibody levels waned over the 7-year follow up period but remained at least an order of magnitude above the typical antibody levels elicited by natural infection. Seropositivity to non-vaccine types remained high 7 years after initial vaccination, but antibody levels approached those typically generated following natural infection. Empirical data on the breadth, magnitude, specificity and durability of the immune response elicited by the HPV vaccines contribute to improving the evidence base supporting this important public health intervention.

Summary Different vaccine strains included in the live attenuated influenza vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a Phase IV open‐label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunization. There was a significant increase in nasal immunoglobulin (Ig)A to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting that the response is multi‐factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine; the reasons for this require further investigation., Different vaccine strains included in the Live Attenuated Influenza Vaccine (LAIV) have variable efficacy. We performed an immunogenicity study of quadrivalent LAIV in children during the 2015/16 season. There was a significant increase in nasal IgA to the H3N2, B/Victoria lineage (B/Brisbane), and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component.

Bivalent (Cervarix®) and quadrivalent (Gardasil®) Human Papillomavirus (HPV) vaccines demonstrate remarkable efficacy against the targeted genotypes, HPV16 and HPV18, but also a degree of cross-protection against non-vaccine incorporated genotypes, HPV31 and HPV45. These outcomes seem to be supported by observations that the HPV vaccines induce high titer neutralizing antibodies against vaccine types and lower responses against non-vaccine types. Few data are available on the robustness of the immune response against non-vaccine types. We examined the durability of vaccine and non-vaccine antibody responses in a follow up of a head-to-head study of 12–15 year old girls initially randomized to receive three doses of Cervarix® or Gardasil® vaccine. Neutralizing antibodies against both vaccine and non-vaccine types remained detectable up to 7 years following initial vaccination and a mixed effects model was used to predict the decline in antibody titers over a 15 year period. The decline in vaccine and non-vaccine type neutralizing antibody titers over the study period was estimated to be 30% every 5–7 years, with Cervarix® antibody titers expected to remain 3–4 fold higher than Gardasil® antibody titers over the long term. The antibody decline rates in those with an initial response to non-vaccine types were similar to that of vaccine types and are predicted to remain detectable for many years. Empirical data on the breadth, magnitude, specificity and durability of the immune response elicited by the HPV vaccines contribute to improving the evidence base supporting this important public health intervention. Original trial: ClinicalTrials.gov NCT00956553.

Background Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants’ antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens). Methods This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP5-IPV (n = 77) or TdaP3-IPV (n = 77) at 28–32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum. Results Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n = 67) or TdaP3-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV- and TdaP3-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 [0.56–0.90] and 0.78 [0.61–0.98], respectively); by 13 months of age, this difference was no longer observed. Conclusion Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy. Trial registration ClinicalTrials.gov, NCT02145624, registered 23 May 2014

Tuberculosis (TB) remains a major global threat and diagnosis of active TB ((ATB) both extra-pulmonary (EPTB), pulmonary (PTB)) and latent TB (LTBI) infection remains challenging, particularly in high-burden countries which still rely heavily on conventional methods. Although molecular diagnostic methods are available, e.g., Cepheid GeneXpert, they are not universally available in all high TB burden countries. There is intense focus on immune biomarkers for use in TB diagnosis, which could provide alternative low-cost, rapid diagnostic solutions. In our previous gene expression studies, we identified peripheral blood leukocyte (PBL) mRNA biomarkers in a non-human primate TB aerosol-challenge model. Here, we describe a study to further validate select mRNA biomarkers from this prior study in new cohorts of patients and controls, as a prerequisite for further development. Whole blood mRNA was purified from ATB patients recruited in the UK and India, LTBI and two groups of controls from the UK (i) a low TB incidence region (CNTRLA) and (ii) individuals variably-domiciled in the UK and Asia ((CNTRLB), the latter TB high incidence regions). Seventy-two mRNA biomarker gene targets were analyzed by qPCR using the Roche Lightcycler 480 qPCR platform and data analyzed using GeneSpring™ 14.9 bioinformatics software. Differential expression of fifty-three biomarkers was confirmed between MTB infected, LTBI groups and controls, seventeen of which were significant using analysis of variance (ANOVA): CALCOCO2, CD52, GBP1, GBP2, GBP5, HLA-B, IFIT3, IFITM3, IRF1, LOC400759 (GBP1P1), NCF1C, PF4V1, SAMD9L, S100A11, TAF10, TAPBP, and TRIM25. These were analyzed using receiver operating characteristic (ROC) curve analysis. Single biomarkers and biomarker combinations were further assessed using simple arithmetic algorithms. Minimal combination biomarker panels were delineated for primary diagnosis of ATB (both PTB and EPTB), LTBI and identifying LTBI individuals at high risk of progression which showed good performance characteristics. These were assessed for suitability for progression against the standards for new TB diagnostic tests delineated in the published World Health Organization (WHO) technology product profiles (TPPs).

Background: Israel recently initiated a rapid nationwide COVID-19 vaccination campaign to immunize persons ≥16 years of age and used exclusively Pfizer–BioNTech BNT162b2 mRNA COVID-19 vaccine according to schedule (two doses, 21 days apart). We provide the first estimates of the number of COVID-19 cases, hospitalizations, and deaths averted by a nationwide vaccination campaign. Methods: We used national surveillance data from the first 112 days (Dec 20, 2020 ‒ Apr 10, 2021) of Israel’s vaccination campaign to estimate averted burden of four outcomes: SARS-CoV-2 infections and COVID-19-related hospitalizations, severe or critical hospitalizations, and deaths. The direct effects of the immunization program were estimated for all susceptible individuals (i.e., no previous evidence of laboratory-confirmed SARS-CoV-2 infection) who were at least partially vaccinated (defined as receipt of at least one dose with ≥14 days after the first dose). Cases averted were estimated based on cumulative daily, age-specific rate differences comparing rates among unvaccinated to those who were at least partially vaccinated for each of the four outcomes and the (age-specific) size of the susceptible population and proportion that was at least partially vaccinated. Findings: Through Apr 10, 2021, we estimated that Israel’s vaccination campaign averted 158,665 (95% uncertainty range: 115,899‒201,431) SARS-CoV-2 infections, 24,597 (6,622‒42,571) hospitalizations, 17,432 (3,065‒31,799) severe and critical hospitalizations, and 5,533 (-1,146‒12,213) deaths. Of these, 66% of hospitalizations and 91% of deaths averted were among those ≥65 years of age. Seventy-three percent of SARS-CoV-2 infections and 79% of COVID-19-related hospitalizations and deaths averted stemmed from the protective effects in fully vaccinated persons. Interpretations: Without vaccination, Israel would have likely experienced triple the number of hospitalizations and deaths compared to what actually occurred during their largest wave of SARS-CoV-2 to date, which would have likely overwhelmed the healthcare system. Indirect effects and long-term benefits of the program, which could be substantial, were not included in these estimates and warrant future research. Funding: None. Declaration of Interest: John McLaughlin, Frederick Angulo, Farid Khan, Gabriel Mircus, Kaijie Pan, Jo Southern, David Swerdlow, and Luis Jodar hold stock and stock options in Pfizer Inc. Marc Lipsitch has provided advice on COVID-19 free of charge to Janssen, Astra-Zeneca, Pfizer, and COVAXX (United Biomedical), as well as to the nonprofit One Day Sooner and has received consulting income or honoraria from Merck, Bristol Meyers Squibb, and Sanofi, and institutional research support from Pfizer. All other authors report no conflicts.

Background: SARS-CoV-2 variant Beta (B.1.351) was designated as a Variant of Concern (VoC) after becoming the dominant strain in South Africa and spreading internationally. BNT162b2 showed lower levels of neutralizing antibodies against Beta than against other strains raising concerns about effectiveness of vaccines against infections caused by Beta. We estimated BNT162b2 effectiveness against Beta infections in Israel, a country with high vaccine uptake. Methods: The Ministry of Health (MoH) identified Beta cases through mandatory reporting of SARS-CoV-2 cases and whole genome sequencing (WGS) of specimens from vaccination-breakthrough infections, reinfections, arriving international travelers, and a selection of other infected persons. A cohort analysis was conducted of exposure events of contacts of primary Beta cases. WGS was conducted on available PCR-positive specimens collected from contacts. VE estimates with 95% confidence intervals (CIs) against confirmed and probable Beta infections were determined by comparing infection risk between unvaccinated and fully-vaccinated ( > 7 days after the second dose) contacts, and between unvaccinated and partially-vaccinated ( 16 years, were identified. 343/552 (62%) contacts were interviewed and tested. 71/343 (21%) contacts were PCR-positive. WGS was performed on 7/71 (10%) PCR-positive specimens; all were Beta. Among SARS-CoV-2-infected contacts, 48/71 (68%) were symptomatic, 10/71 (14%) hospitalized, and 2/71 (3%) died. Fully-vaccinated VE against confirmed or probable Beta infections was 72% (95% CI -5 - 97%; p =0.04) and against symptomatic confirmed or probable Beta infections was 100% (95% CI 19 - 100%; p =0.01). There was no evidence of protection in partially-vaccinated contacts. Interpretation: Two doses of BNT162b2 conferred protection against Beta infections and disease. Introductions of Beta did not interrupt control of the pandemic in Israel. Funding: None to declare. Declaration of Interest: Frederick Angulo, David Swerdlow, John McLaughlin, Farid Khan, Gabriel Mircus, Kaijie Pan, Jo Southern, and Luis Jodar hold stock and stock options in Pfizer Inc. Marc Lipsitch has provided advice on COVID-19 free of charge to Janssen, Astra-Zeneca, Pfizer, and COVAXX (United Biomedical), as well as to the nonprofit One Day Sooner and has received consulting income or honoraria from Merck, Pfizer, Bristol Meyers Squibb, Janssen, and Sanofi, and institutional research support from Pfizer. He is on the Scientific Advisory Committee of the Coalition for Epidemic Preparedness and Innovations (CEPI). All other authors report no conflicts. Ethical Approval: This study was approved by MoH’s Institutional Review Board (CoR-MoH-080-2021).

Summary The United Kingdom has a national immunization programme which includes annual influenza vaccination in school-aged children, using live attenuated influenza vaccine (LAIV). LAIV is given annually, and it is unclear whether repeat administration can affect immunogenicity. Because LAIV is delivered intranasally, pre-existing local antibody might be important. In this study, we analysed banked samples from a study performed during the 2017/18 influenza season to investigate the role of pre-existing influenza-specific nasal immunoglobulin (Ig)A in children aged 6–14 years. Nasopharyngeal swabs were collected prior to LAIV immunization to measure pre-existing IgA levels and test for concurrent upper respiratory tract viral infections (URTI). Oral fluid samples were taken at baseline and 21–28 days after LAIV to measure IgG as a surrogate of immunogenicity. Antibody levels at baseline were compared with a pre-existing data set of LAIV shedding from the same individuals, measured by reverse transcription–polymerase chain reaction. There was detectable nasal IgA specific to all four strains in the vaccine at baseline. However, baseline nasal IgA did not correlate with the fold change in IgG response to the vaccine. Baseline nasal IgA also did not have an impact upon whether vaccine virus RNA was detectable after immunization. There was no difference in fold change of antibody between individuals with and without an URTI at the time of immunization. Overall, we observed no effect of pre-existing influenza-specific nasal antibody levels on immunogenicity, supporting annual immunization with LAIV in children.

ObjectiveTo investigate the relationship between social risk factors and latent tuberculosis infection (LTBI) among individuals who are eligible for LTBI screening in the United Kingdom (UK).MethodsThis cross-sectional study used data collected in the UK Prognostic Evaluation of Diagnostic Interferon-Gamma Release Assays (IGRAs) Consortium Study which enrolled 9176 recent tuberculosis (TB) contacts and migrants at National Health Service (NHS) facilities and community settings in the UK. The study outcome was LTBI (positive IGRA test (QuantiFERON-TB Gold In-Tube or T-SPOT.TB)). The main exposures were history of smoking, history of substance misuse, homelessness, prison stay and socioeconomic deprivation.Results4914 (56.2%) individuals resided in the most deprived areas and 2536 (27.6%) had LTBI. In the multivariable analysis (adjusting for age, gender, place of birth, ethnicity, HIV status, BCG vaccination and recent TB contact) living in the least deprived areas compared with living in the most deprived areas was associated with reduced odds of LTBI (odds ratio (OR)=0.68, 95% CI: 0.51 to 0.90) while ever been homeless (OR=1.50, 95% CI: 1.02 to 2.21) was associated with increased odds of LTBI. Smoking, homelessness and substance misuse were not associated with LTBI.ConclusionSocial deprivation could be an important risk factor for LTBI, highlighting the social inequality in the burden of TB infection in the UK. Migrants and TB contacts who were socially deprived or homeless were at a significantly higher risk for LTBI, thus tailored intense public health interventions to these groups may help to reduce the risk of future TB disease.Trial registration numberClinicalTrials.gov Registry (NCT01162265).

Objectives This natural experiment was designed to assess the impact of exposure to an active case of tuberculosis (TB) on a group of immunosuppressed individuals, with end-stage renal disease over an extended follow-up. Study design Close contacts of people with sputum smear–positive Mycobacterium tuberculosis are at high risk of infection, particularly immunosuppressed individuals. An infectious TB healthcare worker worked in a renal dialysis unit for a month before diagnosis, with 104 renal dialysis patients, was exposed for ≥8 h. Methods Patients were informed and invited for screening 8–10 weeks postexposure. They either underwent standard two-step assessment with tuberculin skin test (TST) and QuantiFERON®-TB Gold (Cellestis GmbH; QFN) interferon-gamma release assay (IGRA) or after consent, enrolled in a study where these two tests were performed simultaneously with T-SPOT®-TB (Oxford Immunotec Ltd; TSPOT). Patients within the study were followed up for 2 years from exposure, with QFN and TSPOT repeated at months 3 and 6 from the first testing. Results Of 104 exposed individuals, 75 enrolled in the study. There was a high degree of discordance among QFN, TSPOT and TST. This was seen at both the first time point and also over time in subjects who were retested. No patients had active TB at the baseline testing. None received treatment for latent TB infection. Over the following 2 years, no one developed TB disease. Conclusion This study suggests that there is a low risk of progression to active TB in low-incidence countries even in high-risk groups. This plus the degree of the test result discordance emphasises the complexities of managing TB in such settings as it is unclear which of these tests, if any, provides the best diagnostic accuracy.

Background We report a phase III/IV open-label study on the immunogenicity of a single dose of a Live Attenuated Influenza Vaccine (LAIV) (Fluenz™) in children naive to, or in previous receipt of, AS03B adjuvanted A/H1N1pdm09 influenza vaccine (Pandemrix™), to investigate whether early exposure to an adjuvanted subunit influenza vaccine impacts on subsequent response to quadrivalent LAIV (qLAIV). Method and findings Eligible children were enrolled to receive qLAIV and stratified according to previous Pandemrix™ vaccination. Functional antibody for the vaccine strains were analysed using Haemagglutination Inhibition (HAI); in addition antibodies to the A/H1N1pdm09 strain were measured by Neuraminidase Antibody Inhibition (NAI) and neutralisation assays. Fourfold titre increases by HAI were observed for 39% (95% confidence interval 33–46%) and 43% (37–51%) of subjects for the two influenza B vaccine strains and 8% (5–13%) for the A/H3N2 strain with no significant differences between the Pandemrix™ naive or previously vaccinated groups in antibody tites pre- or post-vaccination or seroconversion rates. In both groups, the response to the qLAIV A/H1N1pdm09 component was barely detectable, overall HAI seroconversion rate 1.8% (0.5–4.7%). Previous receipt of Pandemrix™ was associated with significantly higher levels of A/H1N1pdm09 neutralising antibody, but decreased NAI titres pre-vaccination, with the differences maintained post-vaccination. Conclusion Previous receipt of Pandemrix™ has had a significant impact on the influenza immune status of children several years later. Higher levels of neutralising antibody to A/H1N1pdm09 pre- and post-vaccination, but significantly lower levels of antibody to NA, were observed compared with Pandemrix™-naive children, while responses to influenza B and A/H3N2 and antibody levels prior to vaccination were similar in both groups. This suggests that early vaccination with a powerful adjuvant maintains functional immunity for several years, which prevents natural infection. Alternatively, the AS03B adjuvant may have re-directed the immune response, with focus towards viral HA and away from viral NA.

BackgroundTackling tuberculosis requires testing and treatment of latent tuberculosis in high-risk groups. The aim of this study was to estimate the predictive values of the tuberculin skin test (TST) and two interferon-γ release assays (IGRAs) for the development of active tuberculosis in high-risk groups—ie, people in recent contact with active tuberculosis cases and from high-burden countries.MethodIn this prospective cohort study, we recruited participants from 54 centres (eg, clinics, community settings) in London, Birmingham, and Leicester in the UK. Participants were eligible if they were aged 16 years or older and at high risk for latent tuberculosis infection (ie, recent contact with someone with active tuberculosis [contacts] or a migrant who had arrived in the UK in the past 5 years from—or who frequently travelled to—a country with a high burden of tuberculosis [migrants]). Exclusion criteria included prevalent cases of tuberculosis, and participants who were treated for latent tuberculosis after a positive test result in this study. Each participant received three tests (QuantiFERON-TB Gold-In Tube, T-SPOT.TB, and a Mantoux TST). A positive TST result was reported using three thresholds: 5 mm (TST-5), 10 mm (TST-10), and greater than 5 mm in BCG-naive or 15 mm in BCG-vaccinated (TST-15) participants. Participants were followed up from recruitment to development of tuberculosis or censoring. Incident tuberculosis cases were identified by national tuberculosis databases, telephone interview, and review of medical notes. Our primary objective was to estimate the prognostic value of IGRAs compared with TST, assessed by the ratio of incidence rate ratios and predictive values for tuberculosis development. The study was registered with ClinicalTrials.gov, NCT01162265, and is now complete.FindingsBetween May 4, 2010, and June 1, 2015, 10 045 people were recruited, of whom 9610 were eligible for inclusion. Of this cohort, 4861 (50·6%) were contacts and 4749 (49·4%) were migrants. Participants were followed up for a median of 2·9 years (range 21 days to 5·9 years). 97 (1·0%) of 9610 participants developed active tuberculosis (77 [1·2%] of 6380 with results for all three tests). In all tests, annual incidence of tuberculosis was very low in those who tested negatively (ranging from 1·2 per 1000 person-years, 95% CI 0·6–2·0 for TST-5 to 1·9 per 1000 person-years, 95% CI 1·3–2·7, for QuantiFERON-TB Gold In-Tube). Annual incidence in participants who tested positively were highest for T-SPOT.TB (13·2 per 1000 person-years, 95% CI 9·9–17·4), TST-15 (11·1 per 1000 person-years, 8·3–14·6), and QuantiFERON-TB Gold In-Tube (10·1 per 1000 person-years, 7·4–13·4). Positive results for these tests were significantly better predictors of progression than TST-10 and TST-5 (eg, ratio of test positivity rates in those progressing to tuberculosis compared with those not progressing T-SPOT.TB vs TST-5: 1·99, 95% CI 1·68–2·34; pInterpretationIGRA-based or BCG-stratified TST strategies appear most suited to screening for potential disease progression among high-risk groups. Further work will be needed to assess country-specific cost-effectiveness of each screening test, and in the absence of highly specific diagnostic tests, cheap non-toxic treatments need to be developed that could be given to larger groups of people at potential risk.FundingNational Institute for Health Research Health Technology Assessment Programme 08-68-01.

Background Disease incidence is a key indicator for the assessment of population health and to guide public health policies. Defining accurate population denominators is challenging for incidence studies of hospital-based events, for which hospital catchment areas depend on patient choice and geographic proximity and often do not match established town or city boundaries. We describe a new method to accurately define a hospital's population denominator, which we developed for a study designed to estimate the incidence of hospitalisation for adult acute lower respiratory tract disease in Bristol, UK. Methods We examined hospital data for adult acute lower respiratory tract disease to identify general practitioner (GP) practices (n=82) whose patients were treated for adult acute lower respiratory tract disease at study hospitals and confirmed that nearly all patients (9230 [94·5%] of 9764) were registered with practices within the National Health Service's Bristol, North Somerset, and South Gloucestershire Clinical Commissioning Group (CCG). Hospital admission data were linked to aggregated GP practice patient registration data within this CCG for April 1, 2017, to March 31, 2020. The proportion of GP practices' patients who were hospitalised for adult acute lower respiratory tract disease that occurred at a specific study hospital was multiplied by their patient registration count for six age groups to obtain the practices' contribution to that hospital's denominator (eg, if 50% of GP practice admissions were at a specific study hospital among patients aged 50–64 years, the practice contributed half of their patients aged 50–64 years to the denominator). Alternate denominators were calculated using population census data matched to 20-minute drivetime estimates for study hospitals (the method used to define hospital catchment for local health service purposes). Findings The percentage of admissions at study hospitals varied substantially by GP practice (0–100%). 231 342 (86·3%) of 268 093 of the CCG's GP practice registrants aged 18–34 years received treatment at study hospitals (compared with 19 229 [80%] of 23 938 registrants aged or older than 85 years); some received treatment at another local hospital to the south. With 20-minute drivetime as an estimate measure, hospital catchment would be 550 155 (66·5%) of 827 304 individuals in the CCG population. Interpretation Using health-care data stratified by local CCG enables the estimation of local population denominators to support accurate incidence ascertainment within hospital-based surveillance studies. Funding This work was funded by Pfizer.

Background The UK introduced quadrivalent live attenuated influenza vaccine (qLAIV) for children in 2013/2014. The impact of annual vaccination on effectiveness and immunogenicity is being assessed. Method A phase III/IV open-label study of the immunogenicity of annual vaccination with qLAIV (Fluenz™) was conducted over three consecutive years (2014/15–2016/17) in 254, 249 and 162 children respectively. Serum responses to vaccine components were measured by Haemagglutination Inhibition (HAI) and anti-A(H1N1)pdm09 Neuraminidase (NAI) assays, stratified according to previous receipt of AS03B-adjuvanted A(H1N1)pdm09 pandemic vaccine in 2009/10. Antibody levels to the A(H1N1)pdm09 and H3N2 vaccine components in oral fluids (OF) were explored using an ELISA. Findings More paired pre- and post-vaccination oral fluids (96%) than paired sera (87%) were obtained. Geometric mean titre rises using HAI assays were limited, with maximum rises seen in year one for both influenza B strains when 39% and 43% of subjects seroconverted (95% confidence interval 33–46% and 36–50%, respectively) and year two for influenza H3N2, when 40% (33–46%) individuals seroconverted. Prior pandemic vaccine receipt resulted in higher pre- and post-vaccination A(H1N1)pdm09 HAI titres and lower pre-and post-vaccination NAI (N1 neuraminidase) titres in all three years. OF results were congruent with HAI results; assay specificity compared to HAI was 88.1 and 71.6 percent, and sensitivity was 86.4 and 74.8 percent respectively for A(H1N1)pdm09 and H3N2. Conclusion In all three study years, vaccination with qLAIV resulted in poor antibody responses. However, OFs are an alternative specimen type that allows self sampling, can easily be obtained from children, and their analysis leads to similar conclusions as classic serology by HAI. Their suitability for seroprevalence studies should be investigated. We demonstrated a sustained effect from prior receipt of the AS03B-adjuvanted A(H1N1)pdm09 vaccine, even after repeat vaccination with qLAIV indicating that early exposure to influenza antigens has a significant long lasting effect.

BACKGROUND Better understanding of vaccine reactogenicity is crucial given its potential impact upon vaccine safety and acceptance. Here we report a comparison between conventional and novel (continuous) methods of monitoring temperature and evaluate any association between reactogenicity and the monocyte activation test (MAT) employed for testing four-component capsular group B meningococcal vaccine (4CMenB) batches prior to release for clinical use in Europe. METHODS Healthy 7-12-week-old infants were randomised in two groups: group PCV13 2 + 1 (received pneumococcal conjugate vaccine 13 valent (PCV13) at 2, 4 and 12 months) and group PCV13 1 + 1 (received reduced schedule at 3 and 12 months). In both, infants received the remaining immunisations as per UK national schedule (including 4CMenB at 2, 4 and 12 months of age). Fever was measured for the first 24 h after immunisations using an axillary thermometer and with a wireless continuous temperature monitoring device (iButton®). To measure the relative pyrogenicity of individual 4CMenB batches, MAT was performed according to Ph. Eu. chapter 2.6.30 method C using PBMCs with IL-6 readout. RESULTS Fever rates detected by the iButton® ranged from 28.7% to 76.5% and from 46.6% to 71.1% in group PCV13 2 + 1 and PCV13 1 + 1 respectively, across all study visits. The iButton® recorded a higher number of fever episodes when compared with axillary measurements in both groups (range of axillary temperature fevers; group PCV13 2 + 1: 6.7%-38%; group PCV13 1 + 1: 11.4%-37.1%). An agreement between the two methods was between 0.39 and 0.36 (p

RATIONALE: Development of diagnostic tools with improved predictive value for tuberculosis (TB) is a global research priority. OBJECTIVES: We evaluated whether implementing higher diagnostic thresholds than currently recommended for QuantiFERON Gold-in-Tube (QFT-GIT), T-SPOT.TB and the tuberculin skin test (TST) might improve prediction of incident TB. METHODS: Follow-up of a UK cohort of 9,610 adult TB contacts and recent migrants was extended by re-linkage to national TB surveillance records (median follow-up 4.7 years). Incidence rates and rate ratios, sensitivities, specificities and predictive values for incident TB were calculated according to ordinal strata for quantitative results of QFT-GIT, T-SPOT.TB and TST (with adjustment for prior BCG). MEASUREMENTS AND MAIN RESULTS: For all tests, incidence rates and rate ratios increased with the magnitude of the test result (p

Background:Live attenuated influenza vaccine (LAIV) is recommended for annual influenza vaccination in children from age 2 years. However, some guidelines recommend against its use in children with asthma or recurrent wheeze due to concerns over its potential to induce wheezing. Objective: To assess the safety of LAIV in children with moderate-severe asthma, and in preschool children with recurrent wheeze. Methods: Prospective, multi-center, open label, phase IV intervention studyin 14 specialist UK clinics.LAIV was administered under medical supervision, with follow-up of asthma symptoms 72 hours and 4 weeks late, using validated questionnaires.Clinical Trials.gov registration NCT02866942, EU Clinical Trials registration 2016-002352-24. Results: 478 young people (median 9.3, range 2–18 years) with physician-diagnosed asthma or recurrent wheeze were recruited, including 208 (44%) prescribed high-dose inhaled corticosteroids and 122 (31%) with severe asthma.There was no significant change in asthma symptoms in the 4 weeks following administration (median change 0, P=.26, McNemar’s test), with no impact of level of baseline asthma control/symptoms in predicting either a worsening of asthma or exacerbation following LAIV using a regression model. 47 subjects (14.7%, 95%CI 11% to 19.1%) reported a severe asthma exacerbation in the four weeks following immunization, requiring short course of systemic corticosteroids; in four cases, this occurred within 72 hours of vaccine. No association with asthma severity, baseline lung function or asthma control was identified.Conclusions: LAIV appears to be well-tolerated in the vast majority of children with asthma or recurrent wheeze, includingthosewhose asthma is categorized as severe or poorly controlled

We used whole genome sequencing (WGS) analysis to investigate the population structure of 877 Streptococcus pneumoniae isolates from five carriage studies from 2002 (N = 346), 2010 (N = 127), 2013 (N = 153), 2016 (N = 187) and 2018 (N = 64) in UK households which covers the period pre-PCV7 to post-PCV13 implementation. The genomic lineages seen in the population were determined using multi-locus sequence typing (MLST) and PopPUNK (Population Partitioning Using Nucleotide K-mers) which was used for local and global comparisons. A Roary core genome alignment of all the carriage genomes was used to investigate phylogenetic relationships between the lineages. The results showed an influx of previously undetected sequence types after vaccination associated with non-vaccine serotypes. A small number of lineages persisted throughout, associated with both non-vaccine and vaccine types (such as ST199), or that could be an example of serotype switching from vaccine to non-vaccine types (ST177). Serotype 3 persisted throughout the study years, represented by ST180 and Global Pneumococcal Sequencing Cluster (GPSC) 12, the local PopPUNK analysis and core genome maximum likelihood phylogeny separated them into two clades, one of which is only seen in later study years. The genomic data showed that serotype replacement in the carriage studies was mostly due to a change in genotype as well as serotype, but that some important genetic lineages, previously associated with vaccine types, persisted.

Background The roll-out of anti-retroviral therapy (ART) has changed contexts of human immunodeficiency virus (HIV) risk. Here, we summarise direct estimates of HIV incidence among adolescent girls and young women (AGYW) since ART and before large investments in targeted prevention for AGYW in sub-Saharan Africa. Methods Database searches identified studies reporting HIV incident data from serological samples collected among 15-24 year-old females in 10 countries selected for PEPFAR investment in 2015. Estimates collected between 2005-2015, published or received from authors, were summarised by age and sex, and pooled by region. Findings Fifty-one analyses were identified from nine of the eligible countries (save Lesotho). Directly-observed incidence rates were lowest among AGYW in Kumi, Uganda (0.38%) and highest in KwaZulu-Natal, South Africa (7.8% among 15-19y; 8.6% in 20-24y); fishing communities in Uganda (12.4% and 4.7% among 15-19y and 20-24y females); and among sex workers aged 18-24y in South Africa (13.2%) and Zimbabwe (10.8%). In pooled rates from general population studies, the greatest sex differentials were in the youngest age groups, i.e., 15-19y females compared to males in both Southern African (relative risk=5.94; 95% CI:3.39-10.44) and Eastern African countries (3.22; 95% CI:1.51-6.87), and not significantly different among the oldest (25-29y) in either region. Incidence often peaked earlier (during teenage years) among high-risk compared to general populations. Since 2005, AGYW incidence declined in Rakai (Uganda), Manicaland (Zimbabwe), and among sex workers in Kenya, but not in the highest-risk communities in South Africa. Interpretation Few sources of direct estimates of HIV incidence exist in high-burden countries and trend analyses with age/sex disaggregated data are rare but indicate recent declines among AGYW. In some of the highest-risk settings, however, little evidence exists to suggest ART availability and other efforts slowed transmission by 2016. Despite wide geographic diversity in absolute levels of AGYW incidence, risk relative to males persisted in all settings, with the greatest sex differentials in the youngest age groups. To end new infections among the growing population of adolescents in sub-Saharan Africa, prevention programs must address gender inequalities driving excessive risk among adolescent girls.

We used whole genome sequencing (WGS) analysis to investigate the population structure of 877 Streptococcus pneumoniae isolates from five carriage studies from 2002 (N = 346), 2010 (N = 127), 2013 (N = 153), 2016 (N = 187) and 2018 (N = 64) in UK households which covers the period pre-PCV7 to post-PCV13 implementation. The genomic lineages seen in the population were determined using multi-locus sequence typing (MLST) and PopPUNK (Population Partitioning Using Nucleotide K-mers) which was used for local and global comparisons. A Roary core genome alignment of all the carriage genomes was used to investigate phylogenetic relationships between the lineages. The results showed an influx of previously undetected sequence types after vaccination associated with non-vaccine serotypes. A small number of lineages persisted throughout, associated with both non-vaccine and vaccine types (such as ST199), or that could be an example of serotype switching from vaccine to non-vaccine types (ST177). Serotype 3 persisted throughout the study years, represented by ST180 and Global Pneumococcal Sequencing Cluster (GPSC) 12; the local PopPUNK analysis and core genome maximum likelihood phylogeny separated them into two clades, one of which is only seen in later study years. The genomic data showed that serotype replacement in the carriage studies was mostly due to a change in genotype as well as serotype, but that some important genetic lineages, previously associated with vaccine types, persisted.

Summary Background The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate. Methods In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov , NCT02482636 , and is complete. Findings Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5–98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2–97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0–92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5–94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions. Interpretation These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important. Funding Bill & Melinda Gates Foundation and the National Institute for Health Research.

Extensive limb swelling (ESL) after a booster dose of acellular pertussis (aP) containing vaccine can cause concern and has the potential to be confused with cellulitis. In the United Kingdom aP-containing vaccine was introduced for primary immunisation at 2, 3 and 4months of age in 2004, with the first cohorts eligible to receive a fourth dose in 2007 at school entry. We assessed the frequency of ESL (here defined as swelling >100mms diameter) in 973 children receiving a fourth dose of one of four aP vaccines given combined with inactivated polio, tetanus and either low dose diphtheria (TdaP/IPV) or high dose diphtheria (DTaP/IPV) vaccine; 2 of the 3 DTaP/IPV vaccines also contained Haemophilus influenza b conjugate vaccine (Hib). Post-vaccination symptoms and local reactions were recorded in 7-day diaries or by a telephone follow up if no diary was returned. Local swellings >50mm diameter were reported by 2.2% TdaP/IPV recipients compared with 6.6-11.1% of DTaP/IPV recipients; the corresponding proportions for redness >50mms was 7.0% for TdaP/IPV and 13.3-17.7% for DTaP/IPV recipients. Among the latter, the addition of Hib did not affect the frequency or size of local reactions. Pain at the injection site and systemic symptoms did not differ between the four vaccine groups. A history of atopy was not associated with development of local swelling or redness. A total of 13 children (1.3%) experienced an ESL, three after TdaP/IPV. ESLs resolved without systemic upset within a few days and were usually painless; medical advice was only sought for two children. Parents should be informed about the possible occurrence of an ESL with the pre-school aP-containing booster vaccine but can be reassured that it is a benign and transient condition.