Background: Streptococcus pyogenes-related skin infections are increasingly implicated in the development of rheumatic heart disease (RHD) in lower-resourced settings, where they are often associated with scabies. The true prevalence of S. pyogenes-related pyoderma may be underestimated by bacterial culture. Methods: A multiplex qPCR for S. pyogenes, Staphylococcus aureus and Sarcoptes scabiei was applied to 250 pyoderma swabs from a cross-sectional study of children <5 years in The Gambia. Direct PCR-based emm-typing was used to supplement previous whole genome sequencing (WGS) of cultured isolates. Results: Pyoderma lesions with S. pyogenes increased from 51% (127/250) using culture to 80% (199/250) with qPCR. Compared to qPCR, the sensitivity of culture was 95.4% for S. pyogenes (95% CI 77.2-99.9) in samples with S. pyogenes alone (22/250, 9%), but 59.9% (95% CI 52.3-67.2) for samples with S. aureus co-infection (177/250, 71%). Direct PCR-based emm-typing was successful in 50% (46/92) of cases, identifying 27 emm-types, including six not identified by WGS (total 52 emm-types). Conclusions: Bacterial culture significantly underestimates the burden of S. pyogenes in pyoderma, particularly when co-infected with S. aureus. Molecular methods should be used to enhance the detection of S. pyogenes in surveillance studies and clinical trials of preventative measures in RHD-endemic settings.

OBJECTIVES:Accurate diagnosis of Streptococcus pyogenes (S. pyogenes) pharyngitis is imperative in high rheumatic heart disease-burden countries. We aimed to assess the diagnostic accuracy of two rapid diagnostic tests and five clinical decision rules (CDRs) in The Gambia. METHODS:Children under 16 years presenting with signs and symptoms of pharyngitis were recruited at Sukuta Health Centre, The Gambia. A rapid antigen detection test (SD Bioline; LFT) and a rapid gene-amplification test (ID NOW™ STREP A2) were assessed for diagnostic accuracy alongside five CDRs against culture and qPCR for S. pyogenes. Logistic regression was used to determine risk factors for S. pyogenes pharyngitis. RESULTS:Among 376 participants, S. pyogenes positivity was 9·8% (37/376) by culture, 32·4% (122/376) by PCR, 31·6% (119/376) by LFT, and 33·3% (122/366) by ID NOW. The ID NOW had sensitivities and specificities of 94·6% and 73·6% against culture, and 93·5% and 87·6% against PCR. The LFT had sensitivities and specificities of 83·8% and 74·0% against culture and 55·7% and 80·0% against PCR. The Smeesters CDR performed best with an area under the curve (AUC) of 0·694 against culture. S. pyogenes pharyngitis risk increased with age. Recent chest infection/cough (aOR 1·89, 1·08-3·28) and concurrent skin infection (aOR 2·11, 1·21-3·69) were associated with increased S. pyogenes pharyngitis. CONCLUSIONS:The LFT and the CDRs had poor performance in detecting S. pyogenes pharyngitis compared to PCR and culture. Molecular methods detected a higher proportion of S. pyogenes than culture. Affordable and sensitive diagnostics are urgently needed to improve S. pyogenes management in resource-limited settings.

Streptococcus pyogenes leads to 500,000 deaths annually, many due to rheumatic heart disease in low-income settings. Limited understanding of natural protective immunity to S. pyogenes hinders vaccine development. Here we describe the evolution of serological profiles to conserved vaccine antigens and serotype-specific M proteins from birth and throughout the life course in The Gambia. As placentally transferred IgG waned after birth, serological evidence of new exposure was seen in 23% of infants during the first year of life. After culture-confirmed S. pyogenes events, the highest IgG increases occurred in children younger than 2 years of age after both pharyngeal and skin disease and asymptomatic carriage at both sites. Higher IgG levels against conserved vaccine antigens correlated with functional activity and were associated with protection from culture-confirmed events after adjustment for age and anti-M protein IgG levels. To our knowledge, our data provide the first evidence of protection associated with humoral immunity to conserved vaccine candidate antigens in humans.

BACKGROUND:Live attenuated influenza vaccines (LAIVs) alter nasopharyngeal microbiota in adults. It is poorly understood why LAIV immunogenicity varies across populations, but it could be linked to the microbiome. We aimed to investigate the interactions between intranasal immunisation with LAIV and nasopharyngeal microbiota composition in children from The Gambia. METHODS:We conducted a phase 4, open-label, randomised controlled trial in Sukuta, The Gambia. Children aged 24-59 months with no underlying illness or history of respiratory illness for at least 14 days before recruitment were eligible. Participants were randomly assigned (2:1) by use of a computer-generated sequence in permuted blocks of 15, stratified by sex, to receive trivalent LAIV either on day 0 (intervention group) or after active follow-up at day 21 (control group). The investigator team was initially masked to block size and randomisation sequence; however, group allocation was later revealed to the team. Microbiome profiles were characterised from nasopharyngeal samples collected from all participants on days 0, 7, and 21 by use of 16S rRNA sequencing. The primary outcomes were the effect of LAIV on nasopharyngeal microbiome profiles on day 7 and day 21, and the association between the nasopharyngeal microbiome at baseline and LAIV-induced mucosal IgA responses at day 21, assessed with permutational ANOVA tests. Asymptomatic respiratory viral co-infection at baseline and year of recruitment (2017 or 2018) were included as covariates. This trial is registered with ClinicalTrials.gov (NCT02972957) and is closed. FINDINGS:Between Feb 8 and April 12, 2017, and Jan 15 and March 28, 2018, 343 children were screened for eligibility, of whom 220 (64%) children were randomly assigned to the intervention group and 110 (32%) to the control group. 213 (97%) children in the intervention group and 108 (98%) in the control group completed the study and were included in the final analysis. Although we did not observe an independent effect of LAIV on microbial community composition at days 7 or 21, we found that LAIV had an effect dependent on the year of recruitment. LAIV affected microbial community composition in 2018 (R2 1·97% [95% CI 0·85-5·94]; p=0·037), but not in 2017 (1·23% [0·49-4·46]; p=0·091). We also found that viral co-infection at baseline had an effect on microbial composition at day 7, regardless of recruitment year (R2 1·01% [95% CI 0·28-3·01]; p=0·026). Nasopharyngeal microbial community composition at baseline had no effect on mucosal IgA responses to LAIV administration (R2 0·51% [95% CI 0·23-2·49]; p=0·46). INTERPRETATION:Our findings suggest that the effect of LAIVs on nasopharyngeal microbiota composition in children is modest and temporary; therefore, LAIVs could be used as an intervention to curb influenza in children from low-income and middle-income countries, without causing long-lasting perturbations in nasopharyngeal microbiota. However, nasopharyngeal microbiota at the time of vaccination might not explain the variability observed between individuals in LAIV-induced IgA responses. FUNDING:The Wellcome Trust, UK National Institute for Health Research, and Chief Scientist Office Scotland.

AbstractMultiple respiratory viruses lead to high morbidity and mortality, yet global surveillance platforms focus primarily on seasonal influenza viruses. The COVID-19 pandemic and new RSV vaccines highlight the importance of a broader approach. Upper respiratory tract swabs from children aged 24–59 months presenting with influenza-like illness in The Gambia were collected during follow-up of a live-attenuated influenza vaccine randomised controlled trial in 2017–18. A microfluidic quantitative polymerase chain reaction (qPCR) assay was established and used to detect 21 respiratory viruses. 76.6% of samples had one or more viruses detected (n = 121/158). The viruses detected most frequently were rhinovirus (n = 37/158, 23.4%) and adenovirus (n = 34/158, 21.5%), followed by parainfluenza virus 3, influenza B and human metapneumovirus B. A third of positive samples had multiple viruses detected (two n = 31/121, 25.6%; three n = 9/121, 7.4%). Our data demonstrates how microfluidic qPCR is a useful tool for high-throughput, comprehensive detection of multiple respiratory viruses in surveillance platforms. Rapidly changing epidemiology exemplifies the need for new, broader approaches to virus surveillance in low-resource settings to respond to future epidemics and to guide the need for and use of new prevention and therapeutic measures.

Group A Streptococcus (Strep A) bacteria causes a broad spectrum of diseases. The most common manifestations of Strep A infection are sore throat and pus-producing skin infections such as impetigo. Complications of Strep A infection can lead to inflammation in the bones, muscles, joints, and internal organs causing acute rheumatic fever and rheumatic heart disease (RHD). In The Gambia, the RHD burden is thought to be very high. However, epidemiological data is minimal, and Strep A control programmes do not exist. This study aimed to explore common beliefs and practices related to sore throats among primary caregivers of children, and healthcare providers in a community with a high Strep A disease burden. Four informal conversations with providers and fifteen semi-structured interviews with caregivers were conducted in the peri-urban area of Sukuta, The Gambia. Sampling was purposive and gradual, beginning from households identified to have recently experienced sore throat through a parallel cohort study. Themes explored in qualitative analysis included: sore throat causal attributions and diagnoses, care practises, health-seeking behaviour, and perceived barriers to using the biomedical sector. We found that sore throats were typically perceived to affect one child in a family, disproportionately or exclusively. Sore throats were rarely perceived as life-threatening, and awareness of links between sore throat and ARF or RHD was not reported among caregivers or providers in this study population. Most cases of sore throat were initially managed at home using traditional medicine which delayed resort to antibiotics, though in two instances of severe pain with the presence of exudate, fear that the child’s life was at risk prompted care-seeking through the formal health system. Our findings can inform the development of tailored strategies to increase community knowledge of the potential long-term consequences of sore throats and appropriate care-seeking, alongside improvements in the health system, to prevent Strep A sequelae effectively.

Background Streptococcus pyogenes (StrepA) causes a significant burden of disease globally from superficial infections to invasive disease. It is responsible for over 500,000 deaths each year, predominantly in low- and middle-income countries (LMIC). Superficial StrepA infections of the skin and pharynx can lead to rheumatic heart disease, the largest cause of StrepA-related deaths in LMIC. StrepA can also asymptomatically colonise normal skin and the pharynx (carriage), potentially increasing infection risk. Streptococcus dysgalactiae subsp. equisimilis (SDSE) carriage is also common in LMIC and may interact with StrepA. This study aims to investigate StrepA and SDSE carriage and infection epidemiology, transmission dynamics and naturally acquired immunity within households in The Gambia. Methods A longitudinal household observational cohort study will be conducted over one year. 45 households will be recruited from the urban area of Sukuta, The Gambia, resulting in approximately 450 participants. Households will be visited monthly, and available participants will undergo oropharyngeal and normal skin swabbing. Incident cases of pharyngitis and pyoderma will be captured via active case reporting, with swabs taken from disease sites. Swabs will be cultured for the presence of group A, C and G beta-haemolytic streptococci. Isolates will undergo whole genome sequencing. At each visit, clinical, socio-demographic and social mixing data will be collected. Blood serum will be collected at baseline and final visit. Oral fluid and dried blood spot samples will be collected at each visit. Mucosal and serum anti-StrepA antibody responses will be measured. Outcome This study will report StrepA and SDSE clinical epidemiology, risk factors, transmission dynamics, and serological responses to carriage and infection. Detailed social mixing behaviour will be combined with phylogenetic relatedness to model the extent of transmission occurring withing and between households. The study will provide data to help meet global strategic StrepA research goals.

Streptococcus pyogenes is a leading cause of human morbidity and mortality, especially in resource-limited settings. The development of a vaccine against S. pyogenes is a global health priority to reduce the burden of postinfection rheumatic heart disease. To support this, molecular characterization of circulating S. pyogenes isolates is needed. We performed whole-genome analyses of S. pyogenes isolates from skin and soft tissue infections in Sukuta, The Gambia, a low-income country (LIC) in West Africa where there is a high burden of such infections. To act as a comparator to these LIC isolates, skin infection isolates from Sheffield, United Kingdom (a high-income country [HIC]), were also sequenced. The LIC isolates from The Gambia were genetically more diverse (46 emm types in 107 isolates) than the HIC isolates from Sheffield (23 emm types in 142 isolates), with only 7 overlapping emm types. Other molecular markers were shared, including a high prevalence of the skin infection-associated emm pattern D and the variable fibronectin-collagen-T antigen (FCT) types FCT-3 and FCT-4. Fewer of the Gambian LIC isolates carried prophage-associated superantigens (64%) and DNases (26%) than did the Sheffield HIC isolates (99% and 95%, respectively). We also identified streptococcin genes unique to 36% of the Gambian LIC isolates and a higher prevalence (48%) of glucuronic acid utilization pathway genes in the Gambian LIC isolates than in the Sheffield HIC isolates (26%). Comparison to a wider collection of HIC and LIC isolate genomes supported our findings of differing emm diversity and prevalence of bacterial factors. Our study provides insight into the genetics of LIC isolates and how they compare to HIC isolates. IMPORTANCE The global burden of rheumatic heart disease (RHD) has triggered a World Health Organization response to drive forward development of a vaccine against the causative human pathogen Streptococcus pyogenes. This burden stems primarily from low- and middle-income settings where there are high levels of S. pyogenes skin and soft tissue infections, which can lead to RHD. Our study provides much needed whole-genome-based molecular characterization of isolates causing skin infections in Sukuta, The Gambia, a low-income country (LIC) in West Africa where infection and RHD rates are high. Although we identified a greater level of diversity in these LIC isolates than in isolates from Sheffield, United Kingdom (a high-income country), there were some shared features. There were also some features that differed by geographical region, warranting further investigation into their contribution to infection. Our study has also contributed data essential for the development of a vaccine that would target geographically relevant strains.

Background: Live attenuated influenza vaccine (LAIV) alters nasopharyngeal microbial community structures in adults. Additionally, LAIV immunogenicity varies across populations for reasons poorly understood, but may be linked to the microbiome. We investigated the impact of LAIV on nasopharyngeal microbiota, and the impact of nasopharyngeal microbiota on LAIV immunogenicity in an open label randomised controlled trial in Gambian children.Methods: We conducted a phase IV open label randomised controlled trial in clinically well children aged 24-59 months in The Gambia (NCT02972957). Participants (n=330) were randomised 2:1 to receive trivalent LAIV at recruitment (day 0 (D0), LAIV group) or after follow-up (day 21, control group) (NCT02972957). Primary outcomes were impact of LAIV on microbial communities as determined by 16S rRNA sequencing, and the impact of microbiota profiles on LAIV-induced mucosal IgA responses. Secondary outcomes were impact of microbiota on seroconversion, Influenza A Matrix and Nucleoprotein CD4+T-cell responses (MNP), and induction of ex vivo peripheral T follicular helper (Tfh)-like CD4+ cells. Respiratory viral co-infection (asymptomatic) at recruitment, and year of recruitment were included as covariates.Findings: Between February and April 2017, and January and March 2018, of 343 children were screened for eligibility. We analysed samples from 213 children receiving LAIV and 108 controls. Although we did not observe an independent impact of LAIV on microbial community structure at day 7 or day 21, we observed an effect of LAIV depending on year of recruitment. We observed that LAIV impacted microbiome structure significantly in 2018 (Effect size(R2)=1.97%, p=0.037) but not in 2017 (R2=1.23%, p=0.091). We also observed a significant impact of viral co-infection at baseline on day 7 microbiota regardless of year (R2=0.96%, p=0.026). D0 microbiota had no impact on mucosal IgA responses (R2=0.5% p=0.463), however, they did impact MNP-responses (R2=2.4%, p=0.003) and Tfh-responses (R2=4.0%, p=0.012).Interpretation: The impact of LAIV on nasopharyngeal microbiota in children is modest and temporary. Nasopharyngeal microbiota may play an important role in LAIV immunogenicity.Trial Registration: The study was a randomised controlled phase 4 clinical trial with registration number NCT02972957Funding: This study was funded by a Wellcome Trust Intermediate Clinical Fellowship award (to TIdS; 110058/Z/15/Z). Research at the MRC Unit The Gambia at LSHTM is jointly funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the European & Developing Countries Clinical Trials Partnership 2 programme supported by the EU. DHD is funded by the MRC SHIELD consortium (MR/N02995X/1). BK is supported by the UK MRC (MR/K007602/1). CP is funded by the UK National Institute for Health Research (reference 16/136/46). DB is funded by the Chief Scientist Office (CSO) Scotland (reference SCAF/16/03) and WdSP by a grant from the Netherlands Organisation for Scientific research (NWO-VIDI; grant 91715359 to DB).Declaration of Interests: The authors declare no competing interests.Ethics Approval: The study was approved by The Gambia Government and UK Medical Research Council joint ethics committee and the Medicines Control Agency of The Gambia. Parents provided written or thumb printed informed consent for their children to participate. For parents who were not English literate, an informed consent discussion was conducted in a local language in the presence of an impartial witness. The impartial witness signed to confirm completeness of the consent provided.

Background Immunity to Streptococcus pyogenes in high burden settings is poorly understood. We explored S. pyogenes nasopharyngeal colonization after intranasal live attenuated influenza vaccine (LAIV) among Gambian children aged 24-59 months, and resulting serological response to 7 antigens. Methods A post-hoc analysis was performed in 320 children randomized to receive LAIV at baseline (LAIV group) or not (control). S. pyogenes colonization was determined by quantitative Polymerase Chain Reaction (qPCR) on nasopharyngeal swabs from baseline (D0), day 7 (D7) and day 21 (D21). Anti-streptococcal IgG was quantified, including a subset with paired serum pre/post S. pyogenes acquisition. Results The point prevalence of S. pyogenes colonization ranged from 7-13%. In children negative at D0, S. pyogenes was detected at D7 or D21 in 18% of LAIV group and 11% of control group participants (p=0.12). The odds ratio (OR) for colonization over time was significantly increased in the LAIV group (D21 vs D0 OR 3.18, p=0.003) but not in the control group (OR 0.86, p=0.79). The highest IgG increases following asymptomatic colonization were seen for M1 and SpyCEP proteins. Conclusions Asymptomatic S. pyogenes colonization appears modestly increased by LAIV, and may be immunologically significant. LAIV could be used to study influenza- S. pyogenes interactions.

The infections of urogenital tract caused by candida glabrata or candidemia are particularly prevalent in immunocompromised but can happen in immunocompetent patients.In this case report, diabetes, use of SGLT-2 inhibitor, and azoles are main risk factors.

[This corrects the article DOI: 10.1016/j.xcrm.2021.100465.].

Streptococcus pyogenes is a leading cause of human morbidity and mortality, especially in resource limited settings. The World Health Organisation has recently made a vaccine for S. pyogenes a global health priority to reduce the burden of the post-infection rheumatic heart disease. For a vaccine to be active against all relevant strains in each region, molecular characterisation of circulating S. pyogenes isolates is needed. We performed extensive comparative whole genome analyses of S. pyogenes isolates from skin and soft tissue infections in The Gambia, West Africa, where there is a high burden of such infections. To act as a comparator to this low-income country (LIC) collection of isolates, we performed genome sequencing of isolates from skin infections in Sheffield, UK, as representative high-income country (HIC) isolates. LIC isolates from The Gambia were genetically more diverse (46 emm -types in 107 isolates) compared to HIC isolates from Sheffield (23 emm -types in 142 isolates), with only 7 overlapping emm -types and with diverse genetic backgrounds. Characterisation of other molecular markers indicated some shared features, including a high prevalence of the skin infection-associated emm -pattern D and the variable fibronectin-collagen-T antigen (FCT) types FCT-3 and FCT-4. A previously unidentified FCT (FCT-10) was identified in the LIC isolates, belonging to two different emm -types. A high proportion (79/107; 73.8%) of LIC isolates carried genes for tetracycline resistance, compared to 53/142 (37.3%) HIC isolates. There was also evidence of different circulating prophages, as very few prophage-associated DNases and lower numbers of superantigens were detected in LIC isolates. Our study provides much needed insight into the genetics of circulating isolates in a LIC (The Gambia), and how they differ from those circulating in HICs (Sheffield, UK). Common molecular features may act as bacterial drivers for specific infection types, regardless of the diverse genetic background.

Background: Influenza and other respiratory viruses promote Streptococcus pneumoniae proliferation in the upper respiratory tract. We investigated the effect of intranasal live attenuated influenza vaccine (LAIV) on nasopharyngeal S. pneumoniae density in Gambian children, to study LAIV-pneumococcal interactions for the first time in a low and middle-income country (LMIC) with high pneumococcal carriage rates.Methods: In an open-label, randomised controlled trial (NCT02972957) in The Gambia, 330 healthy children aged 24-59 months were randomised 2:1 to receive one trivalent LAIV dose at enrolment (day 0, intervention) or at the end of active follow up (day 21, control). The primary outcome was PCR-quantified day 7 and 21 pneumococcal density. Generalised mixed-effects models were used to assess the impact of LAIV and other co-variates on pneumococcal densities.Findings: Between Feb-April, 2017, and Jan-March, 2018, 213 intervention and 108 control group children completed the study protocol. The baseline S. pneumoniae carriage rate was high (74.9%) and did not increase significantly following LAIV. LAIV administration at enrolment was associated with higher pneumococcal density during the study period (p=0.0097), with a small increase in mean density observed from day 0 (18197 copies/ml) to day 7 (28840 copies/ml) and day 21 (32359 copies/ml). Younger age (p=0.0030), baseline asymptomatic respiratory viral infection (p=0.017), and greater LAIV shedding at day 7 (p=0.024) were associated with higher pneumococcal density.Interpretation: LAIV led to an increased nasopharyngeal pneumococcal density in the 21 days following vaccination, but at a lower magnitude (1.78-fold) than in the only previous study, conducted in children from the UK (6-fold); providing reassurance for LAIV use in LMIC with high pneumococcal carriage. This increase was accelerated when LAIV was administered in the presence of pre-existing asymptomatic respiratory viruses, suggesting that nasopharyngeal S. pneumoniae proliferation is driven by the integration of net viral interactions.Clinical Trial Registration Details: NCT02972957.Funding Information: This study was funded by a Wellcome Trust 514 Intermediate Clinical Fellowship award (to TIdS; 110058/Z/15/Z).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The study was approved by The Gambia Government and UK Medical Research Council joint ethics committee and the Medicines Control Agency of The Gambia. Parents provided written or thumbprinted informed consent for their children to participate. If parents were not English literate, an impartial witness was present during the informed consent discussion performed in a local language, who signed to confirm completeness of the consent provided.

BackgroundInfluenza and other respiratory viruses promote Streptococcus pneumoniae proliferation in the upper respiratory tract. We sought to investigate for what we believe is the first time, the effect of intranasal live attenuated influenza vaccine (LAIV) on nasopharyngeal S pneumoniae density in a low-income to middle-income country population with high pneumococcal carriage rates.MethodsIn an open-label, randomised, controlled trial in The Gambia, 330 healthy children aged 24–59 months were randomly assigned 2:1 to receive one trivalent LAIV dose at enrolment (day 0, intervention) or at the end of active follow-up (day 21, control). The investigator team were initially masked to block size and randomisation sequence to avoid allocation bias. Group allocation was later revealed to the investigator team. The primary outcome was PCR-quantified day 7 and 21 pneumococcal density. Asymptomatic respiratory viral infection at baseline and LAIV strain shedding were included as covariates in generalised mixed-effects models, to assess the effect of LAIV and other variables on pneumococcal densities. The study is registered at ClinicalTrials.gov, NCT02972957, and is closed to recruitment.FindingsBetween Feb 8 and April 12, 2017, and Jan 15 and March 28, 2018, of 343 children assessed for eligibility, 213 in the intervention group and 108 in the control group completed the study and were included in the final analysis. Although no significant differences were seen in pneumococcal carriage or density at each timepoint when comparing groups, changes from baseline were observed in the LAIV group. The baseline S pneumoniae carriage prevalence was high in both LAIV and control groups (75%) and increased by day 21 in the LAIV group (85%, p=0·0037), but not in the control group (79%, p=0·44). An increase in pneumococcal density from day 0 amounts was seen in the LAIV group at day 7 (+0·207 log10 copies per μL, SE 0·105, p=0·050) and day 21 (+0·280 log10 copies per μL, SE 0·105, p=0·0082), but not in the control group. Older age was associated with lower pneumococcal density (−0·015 log10 copies per μL, SE 0·005, p=0·0030), with the presence of asymptomatic respiratory viruses at baseline (+0·259 log10 copies per μL, SE 0·097, p=0·017), and greater LAIV shedding at day 7 (+0·380 log10 copies per μL, SE 0·167, p=0·024) associated with higher pneumococcal density. A significant increase in rhinorrhoea was reported in the LAIV group compared with the control group children during the first 7 days of the study (103 [48%] of 213, compared with 25 [23%] of 108, p<0·0001), and between day 7 and 21 (108 [51%] of 213, compared with 28 [26%] of 108, p<0·0001).InterpretationLAIV was associated with a modest increase in nasopharyngeal pneumococcal carriage and density in the 21 days following vaccination, with the increase in density lower in magnitude than previously described in the UK. This increase was accelerated when LAIV was administered in the presence of pre-existing asymptomatic respiratory viruses, suggesting that nasopharyngeal S pneumoniae proliferation is driven by cumulative mixed-viral co-infections. The effect of LAIV on pneumococcal density is probably similar to other respiratory viral infections in children. Our findings provide reassurance for the use of LAIV to expand influenza vaccine programmes in low-income to middle-income country populations with high pneumococcal carriage.FundingWellcome Trust.

Directly measuring evidence of influenza infections is difficult, especially in low-surveillance settings such as sub-Saharan Africa. Using a Bayesian model, we estimated unobserved infection times and underlying antibody responses to influenza A/H3N2, using cross-sectional serum antibody responses to 4 strains in children aged 24-60 months. Among the 242 individuals, we estimated a variable seasonal attack rate and found that most children had ≥1 infection before 2 years of age. Our results are consistent with previously published high attack rates in children. The modeling approach highlights how cross-sectional serological data can be used to estimate epidemiological dynamics.

Background The efficacy and effectiveness of the pandemic H1N1 (pH1N1) component in live attenuated influenza vaccine (LAIV) is poor. The reasons for this paucity are unclear but could be due to impaired replicative fitness of pH1N1 A/California/07/2009-like (Cal09) strains. We assessed whether an updated pH1N1 strain in the Russian-backbone trivalent LAIV resulted in greater shedding and immunogenicity compared with LAIV with Cal09. Methods We did an open-label, prospective, observational, phase 4 study in Sukuta, a periurban area in The Gambia. We enrolled children aged 24-59 months who were clinically well. Children received one dose of the WHO pre-qualified Russian-backbone trivalent LAIV containing either A/17/California/2009/38 (Cal09) or A/17/New York/15/5364 (NY15) based on their year of enrolment. Primary outcomes were the percentage of children with LAIV strain shedding at day 2 and day 7, haemagglutinin inhibition seroconversion, and an increase in influenza haemagglutinin-specific IgA and T-cell responses at day 21 after LAIV. This study is nested within a randomised controlled trial investigating LAIV-microbiome interactions (NCT02972957). Findings Between Feb 8, 2017, and April 12, 2017, 118 children were enrolled and received one dose of the Cal09 LAIV from 2016-17. Between Jan 15, 2018, and March 28, 2018, a separate cohort of 135 children were enrolled and received one dose of the NY15 LAIV from 2017-18, of whom 126 children completed the study. Cal09 showed impaired pH1N1 nasopharyngeal shedding (16 of 118 children [14%, 95% CI 8.0-21.1] with shedding at day 2 after administration of LAIV) compared with H3N2 (54 of 118 [46%, 36.6-55.2]; p<0.0001) and influenza B (95 of 118 [81%, 72.2-87.2]; p<0.0001), along with suboptimal serum antibody (seroconversion in six of 118 [5%, 1.9-10.7]) and T-cell responses (CD4+ interferon.-positive and/or CD4+ interleukin 2-positive responses in 45 of 111 [41%, 31.3-50.3]). After the switch to NY15, a significant increase in pH1N1 shedding was seen (80 of 126 children [63%, 95% CI 54.4-71.9]; p<0.0001 compared with Cal09), along with improvements in seroconversion (24 of 126 [19%, 13.2-26.8]; p=0.011) and influenza-specific CD4+ T-cell responses (73 of 111 [66%, 60.0-75.6; p=0.00028]). The improvement in pH1N1 seroconversion with NY15 was even greater in children who were seronegative at baseline (24 of 64 children [38%, 95% CI 26.7-49.8] vs six of 79 children with Cal09 [8%, 2.8-15.8]; p<0.0001). Persistent shedding to day 7 was independently associated with both seroconversion (odds ratio 12.69, 95% CI 4.1-43.6; p<0.0001) and CD4+ T-cell responses (odds ratio 7.83, 95% CI 2.99-23.5; p<0.0001) by multivariable logistic regression. Interpretation The pH1N1 component switch that took place between 2016 and 2018 might have overcome the poor efficacy and effectiveness reported with previous LAIV formulations. LAIV effectiveness against pH1N1 should, therefore, improve in upcoming influenza seasons. Our data highlight the importance of assessing replicative fitness, in addition to antigenicity, when selecting annual LAIV components. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.

Background Scabies is a WHO neglected tropical disease common in children in low- and middle-income countries. Excoriation of scabies lesions can lead to secondary pyoderma infection, most commonly by Staphyloccocus aureus and Streptococcus pyogenes (group A streptococcus, GAS), with the latter linked to acute post-streptococcal glomerulonephritis (APSGN) and potentially rheumatic heart disease (RHD). There is a paucity of data on the prevalence of these skin infections and their bacterial aetiology from Africa. Methodology/Principal findings A cross-sectional study, conducted over a four-month period that included the dry and rainy season, was conducted to determine the prevalence of common skin infections in Sukuta, a peri-urban settlement in western Gambia, in children <5 years. Swabs from pyoderma lesions were cultured for S. aureus and GAS. Of 1441 children examined, 15.9% had scabies (95% CI 12.2-20.4), 17.4% had pyoderma (95% CI 10.4-27.7) and 9.7% had fungal infections (95% CI 6.6-14.0). Scabies was significantly associated with pyoderma (aOR 2.74, 95% CI 1.61-4.67). Of 250 pyoderma swabs, 80.8% were culture-positive for S. aureus, and 50.8% for GAS. Participants examined after the first rains were significantly more likely to have pyoderma than those examined before (aRR 2.42, 95% CI 1.38-4.23), whereas no difference in scabies prevalence was seen (aRR 1.08, 95% CI 0.70-1.67). Swab positivity was not affected by the season. Conclusions/Significance High prevalence of scabies and pyoderma were observed. Pyoderma increased significantly during the rainy season. Given the high prevalence of GAS pyoderma among children, further research on the association with RHD in West Africa is warranted.

Background Poor efficacy and effectiveness of the pandemic H1N1 (pH1N1) component in intranasal live attenuated influenza vaccine (LAIV) has been demonstrated in several studies. The reasons for this are unclear, but may be due to impaired replicative fitness of pH1N1 A/California/07/2009-like (Cal09) LAIV strains. Methods In an open-label, prospective, observational, phase 4 study, we evaluated the impact of updating the pH1N1 component in the Russian-backbone trivalent LAIV from Cal09 in 2016-17 (n=118) to an A/Michigan/45/2015-like strain (A/17/New York/15/5364, NY15) in 2017-18 (n=126), on shedding and immunogenicity in Gambian children aged 2-4 years old. The study was nested within a larger randomised controlled trial investigating LAIV-microbiome interactions (ClinicalTrials.gov [NCT02972957][1]). Findings Cal09 showed impaired nasopharyngeal shedding compared to H3N2 and influenza B, along with sub-optimal serum antibody and T-cell responses. Following the switch to NY15, a significant increase in pH1N1 shedding was seen, along with improvements in seroconversion and influenza-specific CD4+ T-cell responses. Viral kinetics in vitro mirrored these findings, with NY15 showing greater replicative ability than Cal09 in human nasal epithelial cells. Persistent shedding to day 7 was independently associated with both seroconversion and CD4+ T cell response in multivariable logistic regression. Interpretation Our results suggest that the pH1N1 component switch in LAIV may have overcome problems in prior formulations. LAIV effectiveness against pH1N1 should therefore improve in upcoming influenza seasons. Our data also highlight the importance of evaluating replicative fitness, in addition to antigenicity, when selecting annual LAIV components and design of potentially more effective vaccines. Funding The Wellcome Trust. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02972957&atom=%2Fbiorxiv%2Fearly%2F2019%2F01%2F18%2F519256.atom

The burden of influenza in Africa is substantial and underappreciated. Although surveillance has increased, the medical community's understanding of seasonal influenza vaccine performance remains limited. We did a systematic review, using PRISMA guidelines (PROSPERO CRD42017058107), on the efficacy, effectiveness, and immunogenicity of influenza vaccines in populations within Africa with the aim of identifying key data gaps to help direct future research. We searched Embase, MEDLINE, Global Health database, and Web of Science for published studies from database inception to May 9, 2018. Unpublished studies were identified by searching ClinicalTrials.gov and the Pan-African Clinical Trial Registry, and by contacting experts within the field. Human studies that reported influenza vaccine immunogenicity, effectiveness, and efficacy were included. 1746 articles were assessed and 23 articles were included. Only three of the 23 studies were of high quality and many studies were underpowered. All 23 studies came from only six African countries (16 from South Africa), highlighting the need for data from a broader range of African populations. The majority of studies focused on effectiveness or efficacy against laboratory supported influenza with limited data for severe outcomes. Several factors known to interfere with influenza immunisation, such as malaria, HIV, and malnutrition were under-represented in this Review and require further study. Substantial gaps exist in our understanding of influenza vaccine performance across all WHO high-risk groups in Africa. Filling these knowledge gaps is vital to guide future influenza vaccine policies.