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.

Orphanhood vulnerabilities for violence and HIV by education, sex, and orphan type among 18-24-year-old youth: findings from the 2018 Lesotho violence against children and youth survey.

HIV and violence among orphans are key measures of vulnerability in low-resource settings. Although Lesotho has the second highest HIV adult prevalence rate (21.1%) in the world, and the prevalence of orphanhood (44.2%) and violence exposure (67.0%) is high, little research exist on orphanhood vulnerabilities for violence and HIV in Lesotho. Using data from 4,408 youth (18-24 years old) from Lesotho's 2018 Violence Against Children and Youth survey, a nationally representative cross-sectional household survey, the study examined associations among orphan status, violence, and HIV and assessed how associations differed by education, sex, and orphan type, using logistic regression. Orphans had higher odds of violence (aOR, 1.21; 95% CI, 1.01-1.46) and HIV (aOR, 1.69; 95% CI, 1.24-2.29). Having primary education or less (aOR, 1.43; 95% CI, 1.02-2.02), male sex (aOR, 1.74; 95% CI, 1.27-2.36), and being a paternal orphan (aOR, 1.43; 95% CI, 1.14-1.80) were significant interaction terms for violence. Orphans who completed primary school or less (aOR, 1.61; 95% CI, 1.09-2.39), female (aOR, 3.08; 95% CI, 2.14-4.42) and double orphans (aOR, 2.54; 95% CI, 1.56-4.13) had higher odds of HIV. These relationships highlight the importance of comprehensive strategies to support education and family strengthening for orphans as core violence and HIV prevention efforts.

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.

Effect of 13-valent pneumococcal conjugate vaccine on experimental carriage of Streptococcus pneumoniae serotype 6B in Blantyre, Malawi: a randomised controlled trial and controlled human infection study.

BACKGROUND: The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage. METHODS: We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20 000 colony forming units (CFUs) per naris, 80 000 CFUs per naris, or 160 000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed. FINDINGS: Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20 000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80 000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160 000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7-80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci. INTERPRETATION: This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination. FUNDING: Wellcome Trust.

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).

Population Estimates of HIV Risk Factors to Inform HIV Prevention Programming for Adolescent Girls and Young Women.

Violence Against Children and Youth Survey (VACS) data from seven countries were analyzed to estimate population-level eligibility for the President's Emergency Plan for AIDS Relief (PEPFAR) Determined, Resilient, Empowered, AIDS-Free, Mentored, and Safe (DREAMS) HIV prevention program for adolescent girls and young women (AGYW). The prevalence of overall eligibility and individual risk factors, including experiences of violence, social, and behavioral risks differ across countries and age groups. A large proportion of AGYW across all countries and age groups examined have at least one risk factor making them eligible for DREAMS. Experiencing multiple risks is also common, suggesting that researchers and programs could work together to identify combinations of risk factors that put AGYW at greatest risk of HIV acquisition, or that explain most new HIV infections, to more precisely target the most vulnerable AGYW. The VACS provides important data for such analyses to refine DREAMS and other youth programming.

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.

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.

Streptococcus pneumoniae colonization associates with impaired adaptive immune responses against SARS-CoV-2.

BackgroundAlthough recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses.MethodsHere, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus.ResultsIn both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients.ConclusionOur findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection.Trial registrationISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study).

A comparison of two population-based household surveys in Uganda for assessment of violence against youth.

Violence is associated with health-risk behaviors, potentially contributing to gender-related HIV incidence disparities in sub-Saharan Africa. Previous research has demonstrated that violence, gender, and HIV are linked via complex mechanisms that may be direct, such as through forced sex, or indirect, such as an inability to negotiate safe sex. Accurately estimating violence prevalence and its association with HIV is critical in monitoring programmatic efforts to reduce both violence and HIV. We compared prevalence estimates of violence in youth aged 15-24 years from two Ugandan population-based cross-sectional household surveys (Uganda Violence Against Children Survey 2015 [VACS] and Uganda Population-based HIV Impact Assessment 2016-2017 [UPHIA]), stratified by gender. UPHIA violence estimates were consistently lower than VACS estimates, including lifetime physical violence, recent intimate partner physical violence, and lifetime sexual violence, likely reflecting underestimation of violence in UPHIA. Multiple factors likely contributed to these differences, including the survey objectives, interviewer training, and questionnaire structure. VACS may be better suited to estimate distal determinants of HIV acquisition for youth (including experience of violence) than UPHIA, which is crucial for monitoring progress toward HIV epidemic control.

Forced Sexual Initiation and Early Sexual Debut and Associated Risk Factors and Health Problems Among Adolescent Girls and Young Women - Violence Against Children and Youth Surveys, Nine PEPFAR Countries, 2007-2018.

Adolescent girls and young women aged 13-24 years are disproportionately affected by HIV in sub-Saharan Africa (1), resulting from biologic, behavioral, and structural* factors, including violence. Girls in sub-Saharan Africa also experience sexual violence at higher rates than do boys (2), and women who experience intimate partner violence have 1.3-2.0 times the odds of acquiring HIV infection, compared with those who do not (3). Violence Against Children and Youth Survey (VACS) data during 2007-2018 from nine countries funded by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) were analyzed to estimate prevalence and assess factors associated with early sexual debut and forced sexual initiation.† Among adolescent girls and young women aged 13-24 years who ever had sex, the prevalence of lifetime sexual violence ranged from 12.5% to 49.3%, and forced sexual initiation ranged from 14.7% to 38.9%; early sexual debut among adolescent girls and young women aged 16-24 years ranged from 14.4% to 40.1%. In multiple logistic regression models, forced sexual initiation was associated with being unmarried, violence victimization, risky sexual behaviors, sexually transmitted infections (STIs), and poor mental health. Early sexual debut was associated with lower education, marriage, ever witnessing parental intimate partner violence during childhood, risky sexual behaviors, poor mental health, and less HIV testing. Comprehensive violence and HIV prevention programming is needed to delay sexual debut and protect adolescent girls and young women from forced sex.

The nose is the best niche for detection of experimental pneumococcal colonisation in adults of all ages, using nasal wash.

Previous studies have suggested that the pneumococcal niche changes from the nasopharynx to the oral cavity with age. We use an Experimental Human Pneumococcal Challenge model to investigate pneumococcal colonisation in different anatomical niches with age. Healthy adults (n = 112) were intranasally inoculated with Streptococcus pneumoniae serotype 6B (Spn6B) and were categorised as young 18-55 years (n = 57) or older > 55 years (n = 55). Colonisation status (frequency and density) was determined by multiplex qPCR targeting the lytA and cpsA-6A/B genes in both raw and culture-enriched nasal wash and oropharyngeal swab samples collected at 2-, 7- and 14-days post-exposure. For older adults, raw and culture-enriched saliva samples were also assessed. 64% of NW samples and 54% of OPS samples were positive for Spn6B in young adults, compared to 35% of NW samples, 24% of OPS samples and 6% of saliva samples in older adults. Many colonisation events were only detected in culture-enriched samples. Experimental colonisation was detected in 72% of young adults by NW and 63% by OPS. In older adults, this was 51% by NW, 36% by OPS and 9% by saliva. The nose, as assessed by nasal wash, is the best niche for detection of experimental pneumococcal colonisation in both young and older adults.

Regional heterogeneity in violence and individual characteristics associated with recent transactional sex among Ugandan girls and young women: A national and regional analysis of data from the Violence Against Children and Youth Survey.

OBJECTIVES: This study assessed associations between recent transactional sex (TS) and potential determinants and variations in patterns across two geographic regions with high HIV burden compared to the rest of Uganda, among adolescent girls and young women (AGYW). METHODS: In 2015, a nationally representative cross-sectional household survey was conducted in Uganda. A stratified multi-stage cluster sample design produced nationally representative estimates and sub-national estimates for AGYW in two high HIV burden regions, DREAMS Central 1 (Bukomansimbi, Ssembabule, and Rakai districts) and DREAMS Central 2 (Mubende, Mityana, Gomba, and Mukono districts), and the rest of Uganda. To identify associations between recent TS (defined as sex in the past 12 months in exchange for material support or help) and risk factors, multivariable logistic regressions were conducted. Interaction terms assessed the associations between violence and recent TS across geographic regions. RESULTS: Nationally, 14.2% of sexually active AGYW engaged in recent TS. Region-specific significant associations emerged between recent TS and marriage, family wealth, friendship, orphanhood, and sexual debut. In DREAMS Central 1 and 2, AGYW who witnessed violence in the home or community, or experienced sexual, physical, or emotional violence had higher odds of recent TS than AGYW who did not experience that form of violence (adjusted odds ratio ranged between 2.10 (95% CI, 1.07, 4.13) and 8.25 (95% CI, 3.40, 20.06)). The magnitude of association between recent TS and types of violence varied by region. CONCLUSIONS: Violence is strongly and consistently associated with recent TS, and patterns in prevalence and risk factors vary across regions in Uganda. Given the high risk of HIV association with recent TS, HIV epidemic control efforts may benefit from focus on comprehensive violence prevention and target persons who engage in TS. Comprehensive HIV prevention programming aimed at keeping AGYW HIV-negative should incorporate prevention of violence and TS as key components to facilitate HIV epidemic control in this vulnerable population.

Sexual risk behaviors, mental health outcomes and attitudes supportive of wife-beating associated with childhood transactional sex among adolescent girls and young women: Findings from the Uganda Violence Against Children Survey.

Compared to young men, Ugandan young women are disproportionately impacted by HIV. Childhood transactional sex may contribute to this disparity. Using data from the 2015 Uganda Violence Against Children Survey, we used logistic regression models to assess the association between childhood transactional sex and negative outcomes. Among 18-24-year-old young women who had sex prior to 18 (n = 982), those who ever engaged in transactional sex had 5.9 times [adjusted odds ratio (AOR); confidence interval (CI): 1.6-22.2] higher odds of having multiple sexual partners in the past year; 5.2 times (AOR; CI: 2.1-12.9) higher odds of infrequent condom use in the past year; 3.0 times (AOR; CI: 1.2-7.9) higher odds of hurting themselves intentionally; and 3.2 times (AOR; CI: 1.3-7.7) higher odds of having attitudes justifying spousal abuse than young women who never engaged in transactional sex. Interventions for transactional sex and HIV in Uganda should consider prioritizing prevention, harm-reduction and continued investment in adolescent girls' and young women's futures.

Cycle of violence among young Kenyan women: The link between childhood violence and adult physical intimate partner violence in a population-based survey.

The aim of the current analysis is to elucidate the link between childhood experiences of violence and physical intimate partner violence in young adulthood in a national survey of young Kenyan women. In 2010, we conducted the Violence against Children Survey in Kenya, collecting retrospective reports from 13 to 24 year old males and females (N = 2928). The analysis presented here focused on females aged 18-24 who ever had an intimate partner (n = 566). Young Kenyan women had statistically higher odds of experiencing physical intimate partner violence (IPV) in young adulthood if they had experienced any childhood violence (including sexual, emotional, or physical) [adjusted odds ratio (AOR) = 3.1 CI: 1.2-7.9, p = 0.02)], any childhood sexual violence (AOR = 2.5, CI 1.3-4.9, p = 0.006), or unwanted completed sex (including pressured or forced sex prior to age 18) (AOR = 4.3, CI: 2.3-8.3, p < 0.0001). Exposure to two (AOR = 3.9, CI: 1.2-12.2, p = 0.02) or three (AOR = 5.0, CI: 1.4-18.1, p = 0.01) types of violence in childhood was also associated with a significantly higher odds of experiencing adult physical IPV. Childhood violence is associated with increased odds of adult physical IPV among young women; efforts to prevent violence against children and provide appropriate care and support to adult survivors are critical to interrupt this cycle of violence.