BACKGROUND:Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines. METHODS:Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020-004123-16) enroled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster. RESULTS:The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083-244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5-241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954-74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53-0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9-9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8-4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17-7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules. CONCLUSIONS:A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.

As complex mental health traits and life histories are often poorly captured in hospital systems, the utility of using the Barratt Impulsivity Scale (BIS) and Adverse Childhood Experiences (ACEs) for assessing adult disease risks is unknown. Here, we use participants from the Healthy Nevada Project (HNP) to determine if two standard self-assessments could predict the incidence and onset of disease. We conducted a retrospective cohort study involving adult participants who completed the Behavioral and Mental Health Self-Assessment (HDSA) between September 2018 and March 2024. Impulsivity levels were measured using the BIS-15, and retrospective self-reports of ACEs were collected through a standardized questionnaire. In total, 17,482 HNP participants completed the HDSA. Our findings indicate that ACEs were significantly associated with impulsivity. Disease associations with impulsivity and ACEs were evaluated using a phenome-wide association study, identifying 230 significant associations with impulsivity. Among these, 44 were related to mental health diagnoses, including major depressive disorder (MDD). Kaplan-Meier survival estimates characterized the differences in the lifetime predicted probability between high and low impulsivity for major depressive disorder and essential hypertension. This analysis showed that having both high ACEs and high impulsivity confer substantial risk of MDD diagnosis (hazard ratios 2.81, 2.17, respectively). Additionally, lifetime predicted probability of MDD was approximately 40% higher for high ACEs and high impulsivity compared to no ACEs and low impulsivity. Essential hypertension demonstrated similar trends, with an approximate 20% increase in predicted lifetime probability of diagnosis. These results demonstrate that high ACES and elevated impulsivity scores are associated with a range of negative health outcomes and a simple self-assessment of complex traits and life history may significantly impact clinical risk assessments.

Background: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vac-cines from day (D) 28 to D242 following third doses in seven study arms. Methods: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) de-livered at three groups of six sites. Participants in each site group were randomised to three or four ex-perimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer-BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naive during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation.Results: Among the 817 participants included in this report, the median age was 72 years (IQR: 55-78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both popula-tions who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became sig-nificantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms.Conclusions: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns.& COPY; 2023 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: Artificial intelligence (AI), machine learning and deep learning (including generative AI) are increasingly being investigated in the context of research and management of human infection. Objectives: We summarise recent and potential future applications of AI and its relevance to clinical infection practice.Methods: 1617 PubMed results were screened, with priority given to clinical trials, systematic reviews and meta-analyses. This narrative review focusses on studies using prospectively collected real-world data with clinical validation, and on research with translational potential, such as novel drug discovery and micro-biome-based interventions. Results: There is some evidence of clinical utility of AI applied to laboratory diagnostics (e.g. digital culture plate reading, malaria diagnosis, antimicrobial resistance profiling), clinical imaging analysis (e.g. pul-monary tuberculosis diagnosis), clinical decision support tools (e.g. sepsis prediction, antimicrobial pre-scribing) and public health outbreak management (e.g. COVID-19). Most studies to date lack any real-world validation or clinical utility metrics. Significant heterogeneity in study design and reporting limits com-parability. Many practical and ethical issues exist, including algorithm transparency and risk of bias.Conclusions: Interest in and development of AI-based tools for infection research and management are undoubtedly gaining pace, although the real-world clinical utility to date appears much more modest.& COPY; 2023 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: Human challenge studies involve the deliberate exposure of healthy volunteers to an infectious micro-organism in a highly controlled and monitored way. They are used to understand infectious diseases and have contributed to the development of vaccines. In early 2020, the UK started exploring the feasibility of establishing a human challenge study with SARS-CoV-2. Given the significant public interest and the complexity of the potential risks and benefits, it is vital that public views are considered in the design and approval of any such study and that investigators and ethics boards remain accountable to the public. Methods: Mixed methods study comprising online surveys conducted with 2,441 UK adults and in-depth virtual focus groups with 57 UK adults during October 2020 to explore the public’s attitudes to a human challenge study with SARS-CoV-2 taking place in the UK. Results: There was overall agreement across the surveys and focus groups that a human challenge study with SARS-CoV-2 should take place in the UK. Transparency of information, trust and the necessity to provide clear information on potential risks to study human challenge study participants were important. The perceived risks of taking part included the risk of developing long-term effects from COVID, impact on personal commitments and mental health implications of isolation. There were a number of practical realities to taking part that would influence a volunteer’s ability to participate (e.g. Wi-Fi, access to exercise, outside space and work, family and pet commitments). Conclusions: The results identified practical considerations for teams designing human challenge studies. Recommendations were grouped: 1) messaging to potential study participants, 2) review of the protocol and organisation of the study, and 3) more broadly, making the study more inclusive and relevant. This study highlights the value of public consultation in research, particularly in fields attracting public interest and scrutiny.

Objectives: To evaluate the persistence of immunogenicity three months after third dose boosters. Methods: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naive during the study. Results: Amongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naive participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 mu g) or BNT (30 mu g) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 mu g) versus BNT (30 mu g) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses. Conclusions: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association.

High quality health care research must involve patients and the public. This ensures research is important, relevant and acceptable to those it is designed to benefit. The world's first human challenge study with SARS-CoV-2 undertook detailed public involvement to inform study design despite the urgency to review and establish the study. The work was integral to the UK Research Ethics Committee review and approval of the study. Discussion with individuals from ethnic minorities within the UK population supported decision-making around the study exclusion criteria. Public review of study materials for consent processes led to the addition of new information, comparisons and visual aids to help volunteers consider the practicalities and risks involved in participating. A discussion exploring the acceptability of a human challenge study with SARS-CoV-2 taking place in the UK, given the current context of the pandemic, identified overall support for the study. Public concern for the wellbeing of trial participants, as a consequence of isolation, was identified. We outline our approach to public involvement and its impact on study design.

Background Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com- COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020-005085-33). Findings Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77-89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS- CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4- week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2-ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1 center dot 4 (95% CI 1 center dot 1-1 center dot 8) for homologous BNT162b2, 1 center dot 5 (1 center dot 2-1 center dot 9) for ChAdOx1 nCoV-19-BNT162b2, 1 center dot 6 (1 center dot 3-2 center dot 1) for BNT162b2-ChAdOx1 nCoV-19, and 2 center dot 4 (1 center dot 7-3 center dot 2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0 center dot 17- 0 center dot 24 of the 28-day postsecond dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19-BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.

The human nasopharynx contains a stable microbial ecosystem of commensal and potentially pathogenic bacteria, which can elicit protective primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica produced safe, sustained pharyngeal colonization. This has potential utility as a vehicle for sustained release of antigen to the human mucosa, but commensals in general are thought to be immunologically tolerated. Here, we show that engineered N. lactamica, chromosomally transformed to express a heterologous vaccine antigen, safely induces systemic, antigen-specific immune responses during carriage in humans. When the N. lactamica expressing the meningococcal antigen Neisseria Adhesin A (NadA) was inoculated intranasally into human volunteers, all colonized participants carried the bacteria asymptomatically for at least 28 days, with most (86%) still carrying the bacteria at 90 days. Compared to an otherwise isogenic but phenotypically wild-type strain, colonization with NadA-expressing N. lactamica generated NadA-specific immunoglobulin G (IgG)-and IgA-secreting plasma cells within 14 days of colonization and NadA-specific IgG memory B cells within 28 days of colonization. NadA-specific IgG memory B cells were detected in peripheral blood of colonized participants for at least 90 days. Over the same period, there was seroconversion against NadA and generation of serum bactericidal antibody activity against a NadA-expressing meningococcus. The controlled infection was safe, and there was no transmission to adult bedroom sharers during the 90-day period. Genetically modified N. lactamica could therefore be used to generate beneficial immune responses to heterologous antigens during sustained pharyngeal carriage.

Background Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELI SA) at 28 days after boost, when comparing ChAd/BNTwith ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97.5% CI of the GMR of these comparisons was greater than 0.63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57.8 years (SD 4.7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9.2 (one-sided 97.5% CI 7.5 to infinity). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0-51 (one-sided 97.5% CI 0.43 to infinity). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Copyright Crown Copyright (C) 2021 Published by Elsevier Ltd.

Background Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). Methods COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26. COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. Findings Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46.7%) participants were female and 1380 (95.4%) were White, and in the BNT/BNT-primed group 770 (53.6%) participants were female and 1321 (91.9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1.8 (99% CI 1.5-2.3) in the half VLA group to 32.3 (24.8-42.0) in the m1273 group. GMRs for wildtype cellular responses compared with controls ranged from 1.1 (95% CI 0.7-1.6) for ChAd to 3.6 (2.4-5.5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1.3 (99% CI 1.0-1.5) in the half VLA group to 11.5 (9.4-14.1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1.0 (95% CI 0.7-1.6) for half VLA to 4.7 (3.1-7.1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. Interpretation All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

BACKGROUND:Antibiotic resistance is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infections (LRTIs), but there is little evidence from randomised controlled trials of the effectiveness of antibiotics, both overall or among key clinical subgroups. In ARTIC PC, we assessed whether amoxicillin reduces the duration of moderately bad symptoms in children presenting with uncomplicated (non-pneumonic) LRTI in primary care, overall and in key clinical subgroups.METHODS:ARTIC PC was a double-blind, randomised, placebo-controlled trial done at 56 general practices in England. Eligible children were those aged 6 months to 12 years presenting in primary care with acute uncomplicated LRTI judged to be infective in origin, where pneumonia was not suspected clinically, with symptoms for less than 21 days. Patients were randomly assigned in a 1:1 ratio to receive amoxicillin 50 mg/kg per day or placebo oral suspension, in three divided doses orally for 7 days. Patients and investigators were masked to treatment assignment. The primary outcome was the duration of symptoms rated moderately bad or worse (measured using a validated diary) for up to 28 days or until symptoms resolved. The primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with the ISRCTN Registry (ISRCTN79914298).FINDINGS:Between Nov 9, 2016, and March 17, 2020, 432 children (not including six who withdrew permission for use of their data after randomisation) were randomly assigned to the antibiotics group (n=221) or the placebo group (n=211). Complete data for symptom duration were available for 317 (73%) patients; missing data were imputed for the primary analysis. Median durations of moderately bad or worse symptoms were similar between the groups (5 days [IQR 4-11] in the antibiotics group vs 6 days [4-15] in the placebo group; hazard ratio [HR] 1·13 [95% CI 0·90-1·42]). No differences were seen for the primary outcome between the treatment groups in the five prespecified clinical subgroups (patients with chest signs, fever, physician rating of unwell, sputum or chest rattle, and short of breath). Estimates from complete-case analysis and a per-protocol analysis were similar to the imputed data analysis.INTERPRETATION:Amoxicillin for uncomplicated chest infections in children is unlikely to be clinically effective either overall or for key subgroups in whom antibiotics are commonly prescribed. Unless pneumonia is suspected, clinicians should provide safety-netting advice but not prescribe antibiotics for most children presenting with chest infections.FUNDING:National Institute for Health Research.

ABSTRACT The human nasopharynx is colonized by commensal bacteria and pathobionts, which comprise a complex microbial ecosystem capable of generating primary and secondary immune responses. Experimental intranasal infection of human adults with the commensal Neisseria lactamica results in safe, sustained colonization. Herein is described a novel technology to chromosomally transform N. lactamica with heterologous antigen, for the purpose of safe delivery to the mucosal surface and the generation of an antigen-specific immune response. N. lactamica was transformed to express the meningococcal vaccine antigen Neisseria Adhesin A (NadA) and was inoculated intranasally into humans at a dose of 10 5 colony-forming units. NadA-expressing N. lactamica colonized these individuals and was carried asymptomatically for 3 months. Colonization with NadA-expressing N. lactamica generated NadA-specific IgG-secreting plasma cells within 14 days of colonization and both NadA-specific IgG and NadA-specific IgG memory B cells within 28 days of colonization. NadA-specific IgG memory B cells circulate in the bloodstream of colonized participants for at least 90 days. Genetically transformed N. lactamica has the potential to be a safe bacterial vehicle to generate beneficial immune responses to a wide range of heterologous antigens during sustained pharyngeal carriage.

Rapid development of an effective vaccine for SARSCoV2 is a global priority. A controlled human infection model (CHIM) would accelerate the efficacy assessment of candidate vaccines. This strategy would require deliberate exposure of volunteers to SARSCoV2 with no currently available treatment and a small but definite risk of serious illness or death. This raises complex questions about the social and ethical acceptability of risk to individuals, given the potential benefit to the wider population, and as such, a study cannot be done without public involvement. We conducted a structured public consultation with 57 individuals aged 20–40 years to understand public attitudes to a CHIM, and pre-requisites for enrolment. The overall response to this strategy was positive, and many would volunteer altruistically. Carefully controlled infection is viewed as safer than natural exposure to wild virus. The prolonged social isolation required for the proposed CHIM is considered an obstacle but not insurmountable, with reasonable compensation and supportive care. Given the significant level of public interest, a CHIM should be done as open science with regular, controlled dissemination of information into the public domain. Importantly, there was a strong view that the final decision whether to conduct a CHIM should be in the hands of qualified and experienced clinician-scientists and the authorities.

Introduction Human challenge studies are becoming increasingly common as a method for investigating vaccines and the relationships between commensal microbes and humans. To date, these studies have been conducted exclusively in healthy adult populations. There is a significant burden from infectious diseases in the pregnant and neonatal population. Human challenge studies in pregnancy may help us elucidate the mechanisms underpinning risk from microbial transfer from mother to infant and help with vaccine development. However, it is unclear whether these studies would be acceptable to pregnant women. Therefore, we undertook an interview study to investigate whether human challenge studies would be acceptable to a pregnant population. Methods We recruited healthy pregnant women from a maternity hospital until data saturation was reached. We invited them to take part in an interview study that explored perception of risk and acceptability of a hypothetical human challenge study in pregnancy. We conducted qualitative analysis of interview transcripts to identify themes and patterns present. Results A significant proportion of the participants interviewed found a human challenge study in pregnancy to be acceptable. They reported that their participation in such a study could be encouraged by detailed explanations of risk and how study design would mitigate these. They reported that a degree of uncertainty would not dissuade them from participating. We found that participants were polarised in their opinions of this hypothetical study and early in the interview formed opinions about acceptability. Finally, once these opinions were formed reassurance did not change participants initial impressions of acceptability. Conclusion Conducting a human challenge study in pregnancy would be acceptable to some pregnant women and may offer a means to investigate the specific environment that surrounds commensalisation of neonates. Furthermore, this may offer new avenues to explore vaccine development for the prevention of neonatal infection. While participants would want the maximum amount of information available before considering whether to participate, initial aversion to this methodology it is unlikely to be changed.

Purpose of review There has been an exponential increase in research into infant microbiome evolution, and it appears that pharyngeal microbiota are associated with clinical phenotypes (e.g. infection and asthma). Although broad consensus views are emerging, significant challenges and uncertainties remain. Recent findings Infant pharyngeal microbiome research is limited by low biomass, high temporal diversity and lack of agreed standards for sampling, DNA sequencing and taxonomic reporting. Analysis of amplicon sequence variants and improved cost and availability of whole-genome sequencing are promising options for improving taxonomic resolution of such studies. Infant respiratory microbiomes arise, at least in part, from maternal flora (e.g. the respiratory tract and breastmilk), and are associated with environmental and clinical factors (e.g. mode of feeding and delivery, siblings, daycare attendance, birth season and antibiotic usage). Interventional research to modify the infant pharyngeal microbiota has recently been reported, using dietary supplements. Summary Further work is needed to improve characterization of the infant pharyngeal microbiomes, including routes of bacterial acquisition, role of environmental factors and associations with disease phenotypes. Methodological standards are desirable to facilitate more reproducible, comparable research. Improved understanding may enable manipulation of infant pharyngeal microbiota to improve clinical outcomes.

Despite high vaccine coverage in many parts of the world, pertussis is resurging in a number of areas in which acellular vaccines are the primary vaccine administered to infants and young children. This is attributed in part to the suboptimal and short-lived immunity elicited by acellular pertussis vaccines and to their inability to prevent nasal colonization and transmission of the etiologic agent Bordetella pertussis In response to this escalating public health concern, the National Institute of Allergy and Infectious Diseases held the workshop "Overcoming Waning Immunity in Pertussis Vaccines" in September 2019 to identify issues and possible solutions for the defects in immunity stimulated by acellular pertussis vaccines. Discussions covered aspects of the current problem, gaps in knowledge and possible paths forward. This review summarizes presentations and discussions of some of the key points that were raised by the workshop.

Purpose of review Nonpathogenic commensal Neisseria are rarely considered in the clinical setting despite evidence that they can cause invasive opportunistic infections. In contrast, they may offer protection against pathogenic Neisseria, and such relationships are being actively explored in experimental studies. Recent findings Recent case reports are presented of invasive infection caused by nonpathogenic Neisseria in patients on novel biologic therapies. On the other hand, Neisseria lactamica, a nonpathogenic commensal, has been shown in human challenge studies to inhibit colonization by Neisseria meningitidis. Experimental mouse models have also explored the inhibitory effects of nonpathogenic Neisseria on Neisseria gonnhoreae infection. Cutting-edge advances in metagenomics and microbiomics are being used to understand the mechanisms underpinning these effects. Summary Clinicians should have increased awareness of nonpathogenic Neisseria. First, as new immunomodulating therapies become licenced, the interactions that maintain balance between commensals and their human hosts may be altered. Second, these bacteria are showing promise in their capacity to exclude pathogenic Neisseria species from their anatomical niches.