Serotype 3 Experimental Human Pneumococcal Challenge (EHPC) study protocol: dose ranging and reproducibility in a healthy volunteer population (challenge 3).

INTRODUCTION: Since the introduction of pneumococcal conjugate vaccines, pneumococcal disease rates have declined for many vaccine-type serotypes. However, serotype 3 (SPN3) continues to cause significant disease and is identified in colonisation epidemiological studies as one of the top circulating serotypes in adults in the UK. Consequently, new vaccines that provide greater protection against SPN3 colonisation/carriage are urgently needed. The Experimental Human Pneumococcal Challenge (EHPC) model is a unique method of determining pneumococcal colonisation rates, understanding acquired immunity, and testing vaccines in a cost-effective manner. To enhance the development of effective pneumococcal vaccines against SPN3, we aim to develop a new relevant and safe SPN3 EHPC model with high attack rates which could be used to test vaccines using small sample size. METHODS AND ANALYSIS: This is a human challenge study to establish a new SPN3 EHPC model, consisting of two parts. In the dose-ranging/safety study, cohorts of 10 healthy participants will be challenged with escalating doses of SPN3. If first challenge does not lead into colonisation, participants will receive a second challenge 2 weeks after. Experimental nasopharyngeal (NP) colonisation will be determined using nasal wash sampling. Using the dose that results in ≥50% of participants being colonised, with a high safety profile, we will complete the cohort with another 33 participants to check for reproducibility of the colonisation rate. The primary outcome of this study is to determine the optimal SPN3 dose and inoculation regime to establish the highest rates of NP colonisation in healthy adults. Secondary outcomes include determining density and duration of experimental SPN3 NP colonisation and characterising mucosal and systemic immune responses to SPN3 challenge. ETHICS AND DISSEMINATION: This study is approved by the NHS Research and Ethics Committee (reference 22/NW/0051). Findings will be published in peer-reviewed journals and reports will be made available to participants.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh medium spiny neurons (MSN) in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males and were not estrous cycle dependent. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain from ethanol consumption. Furthermore, these findings also highlight a specific sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may underlie their more rapid advancement to alcohol use disorder and increased risk of alcohol related neurodegeneration compared to males.

Pain management in primary care: A review of the updated CDC guideline.

ABSTRACT: In 2022, the CDC released an updated clinical practice guideline for prescribing opioids and managing pain in the outpatient setting. This article synthesizes the guideline recommendations and implementation considerations for clinical NP practice.

Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants.

BACKGROUND: The safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)-associated lower respiratory tract infection when administered in healthy infants are unclear. METHODS: In a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen. RESULTS: A total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P = 0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P = 0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P = 0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group. CONCLUSIONS: Nirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510).

Participant perceptions and experiences of a novel community-based respiratory longitudinal sampling method in Liverpool, UK: A mixed methods feasibility study.

Longitudinal, community-based sampling is important for understanding prevalence and transmission of respiratory pathogens. Using a minimally invasive sampling method, the FAMILY Micro study monitored the oral, nasal and hand microbiota of families for 6 months. Here, we explore participant experiences and opinions. A mixed methods approach was utilised. A quantitative questionnaire was completed after every sampling timepoint to report levels of discomfort and pain, as well as time taken to collect samples. Participants were also invited to discuss their experiences in a qualitative structured exit interview. We received questionnaires from 36 families. Most adults and children >5y experienced no pain (94% and 70%) and little discomfort (73% and 47% no discomfort) regardless of sample type, whereas children ≤5y experienced variable levels of pain and discomfort (48% no pain but 14% hurts even more, whole lot or worst; 38% no discomfort but 33% moderate, severe, or extreme discomfort). The time taken for saliva and hand sampling decreased over the study. We conducted interviews with 24 families. Families found the sampling method straightforward, and adults and children >5y preferred nasal sampling using a synthetic absorptive matrix over nasopharyngeal swabs. It remained challenging for families to fit sampling into their busy schedules. Adequate fridge/freezer space and regular sample pick-ups were found to be important factors for feasibility. Messaging apps proved extremely effective for engaging with participants. Our findings provide key information to inform the design of future studies, specifically that self-sampling at home using minimally invasive procedures is feasible in a family context.

Respiratory mucosal immune memory to SARS-CoV-2 after infection and vaccination.

Respiratory mucosal immunity induced by vaccination is vital for protection from coronavirus infection in animal models. In humans, the capacity of peripheral vaccination to generate sustained immunity in the lung mucosa, and how this is influenced by prior SARS-CoV-2 infection, is unknown. Here we show using bronchoalveolar lavage samples that donors with history of both infection and vaccination have more airway mucosal SARS-CoV-2 antibodies and memory B cells than those only vaccinated. Infection also induces populations of airway spike-specific memory CD4+ and CD8+ T cells that are not expanded by vaccination alone. Airway mucosal T cells induced by infection have a distinct hierarchy of antigen specificity compared to the periphery. Spike-specific T cells persist in the lung mucosa for 7 months after the last immunising event. Thus, peripheral vaccination alone does not appear to induce durable lung mucosal immunity against SARS-CoV-2, supporting an argument for the need for vaccines targeting the airways.

A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge.

Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).

Surveillance towards preventing paediatric incidence of respiratory syncytial virus attributable respiratory tract infection in primary and secondary/tertiary healthcare settings in Merseyside, Cheshire and Bristol, UK.

INTRODUCTION: Respiratory syncytial virus (RSV) is a common respiratory virus, particularly affecting children, and can cause respiratory infections such as croup and bronchiolitis. The latter is a leading cause of paediatric hospitalisation within the UK. Children <3 years of age and/or with underlying health conditions are more vulnerable to severe RSV infection.There are currently limited data on the incidence of laboratory-confirmed RSV, particularly within primary care settings and outside the typical 'RSV season', which in the Northern hemisphere tends to coincide with winter months. There is also a lack of data on the health economic impact of RSV infection on families and healthcare systems.This observational surveillance study aims to collect data on the incidence of laboratory-confirmed RSV-attributable respiratory tract infection (RTI) in children aged <3 years presenting to primary, secondary or tertiary care; it also aims to estimate the health economic and quality of life impact of RSV-attributable infection in this cohort. Such data will contribute to informing public health strategies to prevent RSV-associated infection, including use of preventative medications. METHODS AND ANALYSIS: Parents/carers of children <3 years of age with RTI symptoms will consent for a respiratory sample (nasal swab) to be taken. Laboratory PCR testing will assess for the presence of RSV and/or other pathogens. Data will be obtained from medical records on demographics, comorbidities, severity of infection and hospitalisation outcomes. Parents will complete questionnaires on the impact of ongoing infection symptoms at day 14 and 28 following enrolment. The primary outcome is incidence of laboratory-confirmed RSV in children <3 years presenting to primary, secondary or tertiary care with RTI symptoms leading to health-seeking behaviours. Recruitment will be carried out from December 2021 to March 2023, encompassing two UK winter seasons and intervening months. ETHICS AND DISSEMINATION: Ethical approval has been granted (21/WS/0142), and study findings will be published as per International Committee of Medical Journal Editors' guidelines.

Comprehensive review of safety in Experimental Human Pneumococcal Challenge.

INTRODUCTION: Experimental Human Pneumococcal Challenge (EHPC) involves the controlled exposure of adults to a specific antibiotic-sensitive Streptococcus pneumoniae serotype, to induce nasopharyngeal colonisation for the purpose of vaccine research. The aims are to review comprehensively the safety profile of EHPC, explore the association between pneumococcal colonisation and frequency of safety review and describe the medical intervention required to undertake such studies. METHODS: A single-centre review of all EHPC studies performed 2011-2021. All recorded serious adverse events (SAE) in eligible studies are reported. An unblinded meta-analysis of collated anonymised individual patient data from eligible EHPC studies was undertaken to assess the association between experimental pneumococcal colonisation and the frequency of safety events following inoculation. RESULTS: In 1416 individuals (median age 21, IQR 20-25), 1663 experimental pneumococcal inoculations were performed. No pneumococcal-related SAE have occurred. 214 safety review events were identified with 182 (12.85%) participants presenting with symptoms potentially in keeping with pneumococcal infection, predominantly in pneumococcal colonised individuals (colonised = 96/658, non-colonised = 86/1005, OR 1.81 (95% CI 1.28-2.56, P = <0.001). The majority were mild (pneumococcal group = 72.7% [120/165 reported symptoms], non-pneumococcal = 86.7% [124/143 reported symptoms]). 1.6% (23/1416) required antibiotics for safety. DISCUSSION: No SAEs were identified directly relating to pneumococcal inoculation. Safety review for symptoms was infrequent but occurred more in experimentally colonised participants. Most symptoms were mild and resolved with conservative management. A small minority required antibiotics, notably those serotype 3 inoculated. CONCLUSION: Outpatient human pneumococcal challenge can be conducted safely with appropriate levels of safety monitoring procedures in place.

Persistence of immune response in heterologous COVID vaccination schedules in the Com-COV2 study - A single-blind, randomised trial incorporating mRNA, viral-vector and protein-adjuvant vaccines.

BACKGROUND: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development. METHODS: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration. FINDINGS: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies. INTERPRETATION: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics. ISRCTN: 27841311 EudraCT:2021-001275-16.

Ethanol Metabolite, Acetate, Increases Excitability of the Central Nucleus of Amygdala Neurons through Activation of NMDA Receptors.

The central nucleus of the amygdala (CeA) is a key brain region involved in emotional and stressor responses due to its many projections to autonomic regulatory centers. It is also a primary site of action from ethanol consumption. However, the influence of active metabolites of ethanol such as acetate on the CeA neural circuitry has yet to be elucidated. Here, we investigated the effect of acetate on CeA neurons with the axon projecting to the rostral ventrolateral medulla (CeA-RVLM), as well as quantified cytosolic calcium responses in primary neuronal cultures. Whole-cell patch-clamp recordings in brain slices containing autonomic CeA-RVLM neurons revealed a dose-dependent increase in neuronal excitability in response to acetate. N-Methyl-d-aspartate receptor (NMDAR) antagonists suppressed the acetate-induced increase in CeA-RVLM neuronal excitability and memantine suppressed the direct activation of NMDAR-dependent inward currents by acetate in brain slices. We observed that acetate increased cytosolic Ca2+ in a time-dependent manner in primary neuronal cell cultures. The acetate enhancement of calcium signaling was abolished by memantine. Computational modeling of acetic acid at NMDAR/NR1 glutamatergic and glycinergic sites suggests potential active site interactions. These findings suggest that within the CeA, acetate is excitatory at least partially through activation of NMDAR, which may underlie the impact of ethanol consumption on autonomic circuitry.

Detection of SARS-CoV-2 infection by saliva and nasopharyngeal sampling in frontline healthcare workers: An observational cohort study.

BACKGROUND: The SARS-CoV-2 pandemic has caused an unprecedented strain on healthcare systems worldwide, including the United Kingdom National Health Service (NHS). We conducted an observational cohort study of SARS-CoV-2 infection in frontline healthcare workers (HCW) working in an acute NHS Trust during the first wave of the pandemic, to answer emerging questions surrounding SARS-CoV-2 infection, diagnosis, transmission and control. METHODS: Using self-collected weekly saliva and twice weekly combined oropharyngeal/nasopharyngeal (OP/NP) samples, in addition to self-assessed symptom profiles and isolation behaviours, we retrospectively compared SARS-CoV-2 detection by RT-qPCR of saliva and OP/NP samples. We report the association with contemporaneous symptoms and isolation behaviour. RESULTS: Over a 12-week period from 30th March 2020, 40·0% (n = 34/85, 95% confidence interval 31·3-51·8%) HCW had evidence of SARS-CoV-2 infection by surveillance OP/NP swab and/or saliva sample. Symptoms were reported by 47·1% (n = 40) and self-isolation by 25·9% (n = 22) participants. Only 44.1% (n = 15/34) participants with SARS-CoV-2 infection reported any symptoms within 14 days of a positive result and only 29·4% (n = 10/34) reported self-isolation periods. Overall agreement between paired saliva and OP/NP swabs was 93·4% (n = 211/226 pairs) but rates of positive concordance were low. In paired samples with at least one positive result, 35·0% (n = 7/20) were positive exclusively by OP/NP swab, 40·0% (n = 8/20) exclusively by saliva and in only 25·0% (n = 5/20) were the OP/NP and saliva result both positive. CONCLUSIONS: HCW are a potential source of SARS-CoV-2 transmission in hospitals and symptom screening will identify the minority of infections. Without routine asymptomatic SARS-CoV-2 screening, it is likely that HCW with SARS-CoV-2 infection would continue to attend work. Saliva, in addition to OP/NP swab testing, facilitated ascertainment of symptomatic and asymptomatic SARS-CoV-2 infections. Combined saliva and OP/NP swab sampling would improve detection of SARS-CoV-2 for surveillance and is recommended for a high sensitivity strategy.

Quality of antibody responses by adults and young children to 13-valent pneumococcal conjugate vaccination and Streptococcus pneumoniae colonisation.

Childhood pneumococcal conjugate vaccine (PCV) protects against invasive pneumococcal disease caused by vaccine-serotype (VT) Streptococcus pneumoniae by generating opsonophagocytic anti-capsular antibodies, but how vaccination protects against and reduces VT carriage is less well understood. Using serological samples from PCV-vaccinated Malawian individuals and a UK human challenge model, we explored whether antibody quality (IgG subclass, opsonophagocytic killing, and avidity) is associated with protection from carriage. Following experimental challenge of adults with S. pneumoniae serotype 6B, 3/21 PCV13-vaccinees were colonised with pneumococcus compared to 12/24 hepatitis A-vaccinated controls; PCV13-vaccination induced serotype-specific IgG, IgG1, and IgG2, and strong opsonophagocytic responses. However, there was no clear relationship between antibody quality and protection from carriage or carriage intensity after vaccination. Similarly, among PCV13-vaccinated Malawian infants there was no relationship between serotype-specific antibody titre or quality and carriage through exposure to circulating serotypes. Although opsonophagocytic responses were low in infants, antibody titre and avidity to circulating serotypes 19F and 6A were maintained or increased with age. These data suggest a complex relationship between antibody-mediated immunity and pneumococcal carriage, and that PCV13-driven antibody quality may mature with age and exposure.

Obesity, leptin and host defence of Streptococcus pneumoniae: the case for more human research.

Pneumococcal pneumonia is the leading cause of community-acquired pneumonia. Obesity is a risk factor for pneumonia. Host factors play a critical role in susceptibility to pulmonary pathogens and outcome from pulmonary infections. Obesity impairs innate and adaptive immune responses, important in the host defence against pneumococcal disease. One area of emerging interest in understanding the complex relationship between obesity and pulmonary infections is the role of the hormone leptin. There is a substantive evidence base supporting the associations between obesity, leptin, pulmonary infections and host defence mechanisms. Despite this, there is a paucity of research that specifically focuses on Streptococcus pneumoniae (pneumococcal) infections, which are the leading cause of community-acquired pneumonia hospitalisations and mortality worldwide. Much of the evidence examining the role of leptin in relation to S. pneumoniae infections has used genetically mutated mice. The purpose of this mini review is to explore the role leptin plays in the host defence of S. pneumoniae in subjects with obesity and posit an argument for the need for more human research.

DNP Team Projects: A Reflection of Team Science.

BACKGROUND: Concern has been raised related to the rigor of DNP team projects due to the potential lack of individual opportunity for growth. However, team science, the scientific collaboration conducted by more than one individual in an interdependent fashion, is becoming standard practice for scientific inquiry and dissemination. DNP team projects provide an opportunity to demonstrate competencies related to collaboration, communication, organization, planning, reliability, accountability and acknowledgement of other opinions, expertise, and contributions. Faculty working with student teams may encounter challenges related to team dynamics and individual student evaluation. Thoughtful application of team science principles can assist in minimizing these challenges. METHOD: The purpose of this paper is to describe two school's combined experiences and lessons learned in application of team science to DNP team projects. CONCLUSION: When undertaken with an informed and organized approach, DNP team projects are an ideal strategy to enhance collaborative skills and position nurse leaders to positively impact health outcomes.

Protocol for a phase IV double-blind randomised controlled trial to investigate the effect of the 13-valent pneumococcal conjugate vaccine and the 23-valent pneumococcal polysaccharide vaccine on pneumococcal colonisation using the experimental human pneumococcal challenge model in healthy adults (PREVENTING PNEUMO 2).

INTRODUCTION: Despite widely available vaccinations, Streptococcus pneumoniae (SPN) remains a major cause of morbidity and mortality worldwide, causing community-acquired pneumonia, meningitis, otitis media, sinusitis and bacteraemia. Here, we summarise an ethically approved protocol for a double-blind, randomised controlled trial investigating the effect of the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23) on pneumococcal nasopharyngeal colonisation acquisition, density and duration using experimental human pneumococcal challenge (EHPC). METHODS AND ANALYSIS: Healthy adult participants aged 18-50 years will be randomised to receive PCV13, PPV23 or placebo and then undergo one or two EHPCs involving intranasal administration of SPN at 1-month post-vaccination with serotype 3 (SPN3) and 6 months with serotype 6B (SPN6B). Participants randomised to PCV13 and placebo will also be randomised to one of two clinically relevant SPN3 strains from distinct lineages within clonal complex 180, clades Ia and II, creating five study groups. Following inoculation, participants will be seen on days 2, 7, 14 and 23. During the follow-up period, we will monitor safety, colonisation status, density and duration, immune responses and antigenuria. The primary outcome of the study is comparing the rate of SPN3 acquisition between the vaccinated (PCV13 or PPV23) and unvaccinated (placebo) groups as defined by classical culture. Density and duration of colonisation, comparison of acquisition rates using molecular methods and evaluation of the above measurements for individual SPN3 clades and SPN6B form the secondary objectives. Furthermore, we will explore the immune responses associated with these vaccines, their effect on colonisation and the relationship between colonisation and urinary pneumococcal antigen detection. ETHICS AND DISSEMINATION: The study is approved by the NHS Research and Ethics Committee (Reference: 20/NW/0097) and by the Medicines and Healthcare products Regulatory Agency (Reference: CTA 25753/0001/001-0001). Findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN15728847, NCT04974294.

Human Infection Challenge with Serotype 3 Pneumococcus.

Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 µl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated (n = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.

Effect of priming interval on reactogenicity, peak immunological response, and waning after homologous and heterologous COVID-19 vaccine schedules: exploratory analyses of Com-COV, a randomised control trial.

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 1·4 (95% CI 1·1-1·8) for homologous BNT162b2, 1·5 (1·2-1·9) for ChAdOx1 nCoV-19-BNT162b2, 1·6 (1·3-2·1) for BNT162b2-ChAdOx1 nCoV-19, and 2·4 (1·7-3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17-0·24 of the 28-day post-second 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. FUNDING: UK Vaccine Taskforce and National Institute for Health and Care Research.