Publications by authors named "Shabir A Madhi"

411 Publications

Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant.

N Engl J Med 2021 Mar 16. Epub 2021 Mar 16.

From the South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit (S.A.M., V.B., A.L.K., G.K., S.B., J.P., A.J., M.L., S.M., A.M., C.T., A.T., A.I.), African Leadership in Vaccinology Expertise (C.L.C.), Wits Reproductive Health and HIV Institute (L.F., E.H., M. Masenya, F.P., S.E.), the Antibody Immunity Research Unit, School of Pathology (J.N.B., C.K.W., P.L.M.), and the Perinatal HIV Research Unit (C.B.), Faculty of Health Sciences, and the Department of Science and Innovation/National Research Foundation South African Research Chair Initiative in Vaccine Preventable Diseases Unit (S.A.M., V.B., A.L.K., G.K., S.B., A.I.), University of the Witwatersrand, and the National Institute for Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS) (J.N.B., C.K.W., P.L.M.), Johannesburg, Setshaba Research Centre, Tshwane (S.D.P., K.A., M. Malahleha, M. Masilela, K.M.), the Division of Pulmonology, Groote Schuur Hospital and the University of Cape Town (K.D., A.E., S.O.), and the Family Centre for Research with Ubuntu, Department of Paediatrics, University of Stellenbosch (S.L.B., M.G., L.R.), Cape Town, Soweto Clinical Trials Centre, Soweto (Q.E.B., A.E.B.), and the Africa Health Research Institute (S.-H.H., H.R., A.S.) and the KwaZulu-Natal Research and Innovation Sequencing Platform (KRISP), University of KwaZulu-Natal (S.P., H.T., T.O., A.S.), Durban - all in South Africa; the Oxford Vaccine Group, Department of Paediatrics (M.V., P.A., S.R., A.J.P.), and Jenner Institute, Nuffield Department of Medicine (T.L., S.G.), University of Oxford, Oxford, the Faculty of Infectious and Tropical Diseases, Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London (K.D., A.E.), Division of Infection and Immunity, University College London, London (K.D.), and AstraZeneca Biopharmaceuticals, Cambridge (N.M.D., E.J.K., T.L.V.) - all in the United Kingdom; and Max Planck Institute for Infection Biology, Berlin (S.-H.H., H.R.).

Background: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa.

Methods: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×10 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose.

Results: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (92.9%) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups.

Conclusions: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).
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http://dx.doi.org/10.1056/NEJMoa2102214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993410PMC
March 2021

Malaria is a cause of iron deficiency in African children.

Nat Med 2021 Feb 22. Epub 2021 Feb 22.

Kenya Medical Research Institute (KEMRI), Centre for Geographic Medicine Research, Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.
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http://dx.doi.org/10.1038/s41591-021-01238-4DOI Listing
February 2021

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

Lancet 2021 03 19;397(10277):881-891. Epub 2021 Feb 19.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address:

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.

Methods: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 10 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 10 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005).

Findings: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]).

Interpretation: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose.

Funding: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(21)00432-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894131PMC
March 2021

In utero human cytomegalovirus infection is associated with increased levels of putatively protective maternal antibodies in nonprimary infection: evidence for boosting but not protection.

Clin Infect Dis 2021 Feb 9. Epub 2021 Feb 9.

Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.

Background: Although primary maternal cytomegalovirus infections are associated with higher risk of in utero transmission, most fetal infections worldwide result from nonprimary maternal infections. Antibodies directed at glycoprotein B and the gH/gL/pUL128-130-131 pentamer can neutralize virus, and higher levels of antibody directed at several particular pentamer epitopes defined by monoclonal antibodies (mAbs) are associated with reduced risk of fetal cytomegalovirus transmission during primary maternal infection. This had not been explored in maternal nonprimary infection.

Methods: In a setting where most maternal cytomegalovirus infections are nonprimary, 42 mothers of infants with congenital CMV infections (transmitters) were compared to 75 cytomegalovirus-seropositive mothers whose infants were cytomegalovirus-uninfected (nontransmitters). Control infants were matched by sex, maternal HIV status and gestational age. We measured the ability of maternal antibodies to block three key pentameric epitopes: one in the gH subunit, another straddling UL130/UL131 and the third straddling gH/gL/UL128/UL130. We tested if levels of antibodies directed at these epitopes were higher in nontransmitters compared to transmitters.

Results: Levels of all three putatively protective pentamer-directed antibodies were significantly higher in transmitters compared to nontransmitters. In contrast, antibodies targeting an epitope on glycoprotein B were not different. Total antibody specific for pentamer and for gB were also higher in transmitters.

Conclusions: We found no evidence that higher levels of any CMV-specific antibodies were associated with reduced risk of congenital CMV infection in nonprimary maternal infection. Instead, we found higher maternal antibody targeting epitopes on CMV pentamer in transmitters than nontransmitters, providing evidence for antibody boosting but not protection.
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http://dx.doi.org/10.1093/cid/ciab099DOI Listing
February 2021

Approaches, achievements, challenges, and lessons learned in setting up an urban-based Health and Demographic Surveillance System in South Africa.

Glob Health Action 2021 Jan;14(1):1874138

Medical Research Council: Vaccine and Infectious Disease Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand , Johannesburg, South Africa.

Reliable civil registration and vital statistics (CRVSs) are essential for estimating mortality rates and population changes, and are critical for public health and socio-economic planning. CRVSs are largely incomplete in Africa, thus Health and Demographic Surveillance Systems (HDSSs) fill gaps in CRVSs, albeit existing HDSSs in South Africa are in rural areas. This limits the generalisability of such data in a country such as South Africa where over 60% live in urban areas, and where there are limitations to access health and social services. We describe the approaches, achievements, challenges and lessons learned in setting up a HDSS site in Soweto and Thembelihle (SaT-HDSS), Johannesburg; which is the first urban-based HDSS in Southern Africa. We also highlight a number of studies being implemented in the HDSS. In 2017-2020, the HDSS has enrolled 124,169 individuals and followed up 95% of this population through 3 rounds of data collection. Several challenges were encountered during the initiation of the HDSS, including difficulties in community mobilisation and entry, stakeholders' engagement and participation, inaccessibility problems and concerns about safety of fieldworkers, and difficulty in getting/recruiting technical staff with requisite experience. Nevertheless, the SaT-HDSS was successfully established through application of several strategies, including continuous community engagement and stakeholders' mobilisation; in-depth training and retraining of all study staff; technical support from well-established HDSS sites across Africa, and international academic collaborations. Despite the challenges of undertaking routine surveillance of a hard-to-reach and highly mobile population, the SaT-HDSS was successfully established with a high-retention rate. The HDSS offers an important lens on morbidity and mortality and serves as a platform for pilots of interventions and programmes aimed at improving health and well-being of an urban population.
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http://dx.doi.org/10.1080/16549716.2021.1874138DOI Listing
January 2021

An affordable pneumococcal conjugate vaccine after 20 years.

Lancet Infect Dis 2021 Jan 28. Epub 2021 Jan 28.

Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/S1473-3099(21)00002-5DOI Listing
January 2021

Pneumococcal Conjugate Vaccine Protection against Coronavirus-Associated Pneumonia Hospitalization in Children Living with and without HIV.

mBio 2021 01 8;12(1). Epub 2021 Jan 8.

Medical Research Council: Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

In December 2019 a new coronavirus (CoV) emerged as a human pathogen, SARS-CoV-2. There are few data on human coronavirus infections among individuals living with HIV. In this study we probed the role of pneumococcal coinfections with seasonal CoVs among children living with and without HIV hospitalized for pneumonia. We also described the prevalence and clinical manifestations of these infections. A total of 39,836 children who participated in a randomized, double-blind, placebo-controlled clinical trial on the efficacy of a 9-valent pneumococcal conjugate vaccine (PCV9) were followed for lower respiratory tract infection hospitalizations until 2 years of age. Nasopharyngeal aspirates were collected at the time of hospitalization and were screened by PCR for four seasonal CoVs. The frequency of CoV-associated pneumonia was higher in children living with HIV (19.9%) than in those without HIV (7.6%,  < 0.001). Serial CoV infections were detected in children living with HIV. The case fatality risk among children with CoV-associated pneumonia was higher in those living with HIV (30.4%) than without HIV (2.9%,  = 0.001). C-reactive protein and procalcitonin levels were elevated in 36.8% (≥40 mg/liter) and 64.7% (≥0.5 ng/ml), respectively, of the fatal cases living with HIV. Among children without HIV, there was a 64.0% (95% CI: 22.9% to 83.2%) lower incidence of CoV-associated pneumonia hospitalizations among PCV9 recipients compared to placebo recipients. These data suggest that infections might have a role in the development of pneumonia associated with endemic CoVs, that PCV may prevent pediatric CoV-associated hospitalization, and that children living with HIV with CoV infections develop more severe outcomes. SARS-CoV-2 may cause severe hospitalization, but little is known about the role of secondary bacterial infection in these severe cases, beyond the observation of high levels of reported inflammatory markers, associated with bacterial infection, such as procalcitonin. We did a secondary analysis of a double-blind randomized trial of PCV to examine its impact on human CoV infections before the pandemic. We found that both children living with and without HIV randomized to receive PCV had evidence of less hospitalization due to seasonal CoV, suggesting that pneumococcal coinfection may play a role in severe hospitalized CoV infections.
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http://dx.doi.org/10.1128/mBio.02347-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845626PMC
January 2021

Single-dose nirsevimab prevents RSV infection.

J Pediatr 2021 01;228:310-313

University of Colorado School of Medicine and Center for Global Health, Aurora, Colorado.

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http://dx.doi.org/10.1016/j.jpeds.2020.10.066DOI Listing
January 2021

Association of Group B streptococcus serum serotype-specific anti-capsular IgG concentration and risk reduction for invasive Group B streptococcus disease in South African infants: an observational birth-cohort, matched case-control study.

Clin Infect Dis 2020 Dec 20. Epub 2020 Dec 20.

South African Medical Research Council: Vaccines and Infectious Diseases Analytical Research Unit (VIDA), University of the Witwatersrand, Faculty of Health Science Johannesburg, South Africa.

Background: Licensure of a Group B streptococcus (GBS) polysaccharide-protein conjugate vaccine for protecting infants against invasive GBS disease (IGbsD) will likely need to be based on demonstrating vaccine safety in pregnant women, and benchmarking immunogenicity against a serological threshold associated with risk reduction of IGbsD. We investigated the association between naturally-derived GBS serotype-Ia and III IgG and risk reduction of IGbsD in infants' ≤90 days of age.

Methods: In a matched case-control study (ClinicalTrials.gov NCT02215226), IGbsD cases were identified from a cohort of 38,233 mother-newborn dyads. Mothers colonized vaginally with serotype-Ia or III at birth, and their healthy infants were eligible as matched controls. GBS serotype-specific anti-capsular IgG was measured on maternal and cord blood/infant sera by multiplex Luminex assay; and the IgG threshold associated with 90% risk reduction of IGbsD derived by estimating absolute disease risk.

Results: In infants born ≥34 weeks gestational age, cord-blood IgG geometric mean concentrations (GMC) were lower in cases than controls for serotype-Ia (0.05 vs. 0.50µg/ml; p=0.004) and III (0.20 vs. 0.38µg/ml; p=0.078). Cord-blood IgG concentration ≥1.04 and ≥1.53µg/ml were associated with 90% risk reduction of serotype-Ia and III IGbsD, respectively. The maternal sera IgG threshold associated with 90% risk reduction was ≥2.31 and ≥3.41µg/ml for serotype-Ia and III, respectively.

Conclusions: The threshold associated with a reduced risk for serotype-Ia and III IGbsD identified on infant sera supports the case for licensure of a GBS polysaccharide-protein conjugate vaccine based on immunogenicity evaluation benchmarked against the defined thresholds.
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http://dx.doi.org/10.1093/cid/ciaa1873DOI Listing
December 2020

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

Lancet 2021 01 8;397(10269):99-111. Epub 2020 Dec 8.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address:

Background: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials.

Methods: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674.

Findings: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation.

Interpretation: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials.

Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(20)32661-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723445PMC
January 2021

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

Lancet Glob Health 2021 01 26;9(1):e33-e43. Epub 2020 Nov 26.

Centre for Global Health, Usher Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years.

Methods: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths.

Findings: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries.

Interpretation: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(20)30393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783516PMC
January 2021

Bacterial nasopharyngeal carriage following infant immunization with pneumococcal conjugate vaccines according to a 2+1 schedule in children in South Africa: an exploratory analysis of two clinical trials.

Expert Rev Vaccines 2020 12 21;19(12):1177-1189. Epub 2020 Dec 21.

Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand , Johannesburg, South Africa.

: We evaluated bacterial nasopharyngeal carriage (NPC) prevalence and cumulative acquisition following 7-valent pneumococcal conjugate vaccine (PCV7) or pneumococcal non-typeable protein D conjugate vaccine (PHiD-CV) administration. : Participants were children from two clinical trials in a South African center who received PCV7 (n = 250) or PHiD-CV (n = 100) at ~6 weeks, ~14 weeks, and ~9-10 months of age, and were enrolled between Dec2009-Apr2010 and Mar2009-May2010 in the PCV7 and PHiD-CV studies, respectively. Sample collection, most microbiological assessments, and data re-analysis methods were identical. : NPC prevalence of any pneumococcal serotype was 18.5% and 17.0% at pre-vaccination, and 63.1% and 67.3% in 24-27 month-old children among PCV7 and PHiD-CV recipients, respectively. In 24-27 month-old children, 96.1% and 99.0% of PCV7 and PHiD-CV recipients had acquired ≥1 pneumococcal serotype, 53.7% and 62.9% ≥1 PCV7 serotype, 1.5%, and 3.1% ≥1 of serotypes 1, 5 or 7F, 23.2% and 19.6% serotype 6A, 23.2% and 21.7% serotype 19A, 88.7%, and 91.0% , and 50.3% and 62.9% , respectively. : This analysis of two concurrent clinical trials did not reveal differences in bacterial NPC prevalence or acquisition in PCV7- and PHiD-CV-vaccinated children. : South African National Clinical Trial Register (NHREC DOH-27-0511-299); ClinicalTrials.gov (NCT00829010).
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http://dx.doi.org/10.1080/14760584.2020.1853533DOI Listing
December 2020

The role of National Immunization Technical Advisory Groups (NITAG) in strengthening health system governance: Lessons from three middle-income countries-Argentina, Jordan, and South Africa (2017-2018).

Vaccine 2020 10 16;38(45):7118-7128. Epub 2020 Sep 16.

Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Introduction: Toward the Global Vaccine Action Plan 2020 goal, almost 90% of countries have established a National Immunization Technical Advisory Group (NITAG). However, little is known about NITAG's contributions to governance.

Methods: In 2017-2018, a two-step, qualitative retrospective study was conducted. Jordan (JO), Argentina (AR), and South Africa (SA) were selected owing to government-financed NITAGs from middle-income countries (MICs), geographic diversity, and a vaccine introduction with NITAG support. Country case studies were developed, collecting data through desk review and face-to-face key informant interviews (KIIs) from Ministry of Health (MoH) and NITAG. Case studies were analyzed together, to assess governance applying the European Observatory on Health Systems and Policies framework focusing on transparency, accountability, participation, integrity, and policy capacity (TAPIC).

Results: Document review and 53 KII (22 AR, 20 SA, 11 JO) showed NITAGs played a pivotal role as advisors promoting a culture of evidence-informed policies. NITAGs strengthened governance, although practices varied among countries. Meetings were conducted behind-closed-doors, participation restricted to members, only in one country agendas, and recommendations were public (AR). To increase participation, policy capacity, and transparency, countries considered adding experts in communications, advocacy, and economics. AR and SA contemplated including community members. NITAGs functioned autonomously from the government, with no established internal or external monitoring or supervision. NITAG meeting minutes allowed the review of integrity, adherence to terms of reference, standard operating procedures, and conflict of interest (CoI). For the most part, NITAGs abided by their mandates. Significant issues were related to the level of MoH support and oversight of CoI declaration and documentation.

Conclusions: Systematically implementing governance approaches could improve processes, better tailor policies, and implementation. The long-term survival and resilience of NITAGs in these countries showed they play a significant role in strengthening governance. Lessons learned could be useful to those promoting country-driven evidence-informed decision-making.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.069DOI Listing
October 2020

Neurological and growth outcomes in South African children with congenital cytomegalovirus: A cohort study.

PLoS One 2020 17;15(9):e0238102. Epub 2020 Sep 17.

Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Objectives: To assess neurological sequelae and growth in the first 12 months of life in a cohort of congenital cytomegalovirus (cCMV) infected infants compared to cCMV uninfected infants.

Study Design: This was a prospective matched cohort study conducted in Soweto, South Africa where forty-six confirmed cCMV cases were matched on HIV-exposure, gender and gestational age (±two weeks) to 84 cCMV-uninfected controls in a 1:2 ratio. Cases and controls were followed up until 12 months of age to assess anthropometry, hearing and neurodevelopmental outcomes.

Results: Thirty-four (73.9%) cCMV cases and 74 (88.1%) controls, completed all assessments at 12 months age. At 12 months, one cCMV case had died, none of the children in either group had SNHL and neurodevelopmental delay was present in a similar percentage of cCMV cases (n = 2; 6%) and controls (n = 1, 4%; OR 1.09, 95% CI 0.04-27.84, p = 0.958). Anthropometry did not differ between cases and controls overall throughout the follow up period. HIV-exposed cases had smaller head circumference for age at 6 and 12 months when compared with HIV-exposed controls.

Conclusion: By 12 months of age, there was no evidence of a difference in neurological sequelae between cCMV infected South African children and cCMV uninfected children in this study. Further follow-up is warranted to detect late-onset hearing loss and neurodevelopmental delay beyond 12 months of age.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498063PMC
October 2020

Systematic review of Group B Streptococcal capsular types, sequence types and surface proteins as potential vaccine candidates.

Vaccine 2020 10 2;38(43):6682-6694. Epub 2020 Sep 2.

Maternal, Adolescent, Reproductive & Child Health (MARCH) Centre, London School of Hygiene & Tropical Medicine, London, UK; Dept of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Background: 21 million pregnant women worldwide (18%) are estimated to carry Group B Streptococcus (GBS), which is a risk for invasive disease in newborns, pregnant women, and stillbirths. Adults ≥ 60 years or with underlying health conditions are also vulnerable to invasive GBS disease. We undertook systematic reviews on GBS organism characteristics including: capsular polysaccharide (serotype), sequence type (multi-locus sequence types (MLST)), and virulence proteins. We synthesised data by at-risk populations, to inform vaccine development.

Methods: We conducted systematic reviews and meta-analyses to estimate proportions of GBS serotypes for at risk populations: maternal colonisation, invasive disease in pregnant women, stillbirths, infants 0-90 days age, and older adults (≥60 years). We considered regional variation and time trends (2001-2018). For these at-risk population groups, we summarised reported MLST and surface proteins.

Results: Based on 198 studies (29247isolates), 93-99% of GBS isolates were serotypes Ia, Ib, II, III, IV and V. Regional variation is likely, but data gaps are apparent, even for maternal colonisation which has most data. Serotype III dominates for infant invasive disease (60%) and GBS-associated stillbirths (41%). ST17 accounted for a high proportion of infant invasive disease (41%; 95%CI: 35-47) and was found almost exclusively in serotype III strains, less present in maternal colonisation (9%; 95%CI:6-13),(4%; 95%CI:0-11) infant colonisation, and adult invasive disease (4%, 95%CI:2-6). Percentages of strains with at least one of alp 1, alp2/3, alpha C or Rib surface protein targets were 87% of maternal colonisation, 97% infant colonisation, 93% infant disease and 99% adult invasive disease. At least one of three pilus islands proteins were reported in all strains.

Discussion: A hexavalent vaccine (serotypes Ia, Ib, II, III, IV and V) might provide comprehensive cover for all at-risk populations. Surveillance of circulating, disease-causing target proteins is useful to inform vaccines not targeting capsular polysaccharide. Addressing data gaps especially by world region and some at-risk populations (notably stillbirths) is fundamental to evidence-based decision-making during vaccine design.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526974PMC
October 2020

Immunogenicity of influenza vaccines administered to pregnant women in randomized clinical trials in Mali and South Africa.

Vaccine 2020 09 29;38(41):6478-6483. Epub 2020 Aug 29.

Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, USA; Hubert Department of Global Health, Emory University Rollins School of Public Health, Atlanta, USA; Emory Vaccine Center, Atlanta, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, USA.

Background: A key consideration for expanding recommendations for influenza vaccination is a robust assessment of immunogenicity and efficiency of transplacental antibody transfer after maternal vaccination.

Methods: We pooled data from two trials of maternal influenza vaccination to analyze vaccine immunogenicity with more power than either trial had alone. We compared hemagglutination-inhibition (HAI) titers and titer factor change for women and their infants between trial arms using t-tests; maternal and infant putative seroprotective titers (HAI ≥ 1:40) within each trial arm and maternal seroconversion between trial arms using exact tests; and transplacental antibody transfer between trial arms using t-tests. We used marginal linear models and generalized estimating equations to examine the impact of time between maternal vaccination and delivery on transplacental antibody transfer, infant titers, and infant seroprotection.

Results: For all vaccine components (A/H1N1, A/H3N2, and Type B), >80% of vaccinated women had seroprotective titers, >60% of them seroconverted, and >50% of their infants were born with seroprotective titers. These immunogenicity outcomes occurred more often in vaccine recipients and their infants than in controls. No difference in efficiency of transplacental antibody transfer was observed between vaccine recipients and controls.

Conclusions: Our results provide robust support for further expansion of maternal influenza vaccination recommendations.

Clinical Trials Registration: NCT01430689 and NCT01306669.
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http://dx.doi.org/10.1016/j.vaccine.2020.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505225PMC
September 2020

COVID-19 vaccines and neglected pregnancy.

Lancet 2020 09 27;396(10252):e22. Epub 2020 Aug 27.

Materno-fetal and Obstetrics Research Unit, Department Woman-Mother-Child, Lausanne University Hospital, 1011 Lausanne, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)31822-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723327PMC
September 2020

Immunogenicity of a single-dose compared with a two-dose primary series followed by a booster dose of ten-valent or 13-valent pneumococcal conjugate vaccine in South African children: an open-label, randomised, non-inferiority trial.

Lancet Infect Dis 2020 12 25;20(12):1426-1436. Epub 2020 Aug 25.

South African Medical Research Council Vaccines and Infectious Diseases Analytical Research Unit, University of the Witwatersrand, Faculty of Health Science, Johannesburg, South Africa; Department of Science, National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Faculty of Health Science, Johannesburg, South Africa.

Background: Routine childhood immunisation with pneumococcal conjugate vaccine (PCV) has changed the epidemiology of pneumococcal disease across age groups, providing an opportunity to reconsider PCV dosing schedules. We aimed to evaluate the post-booster dose immunogenicity of ten-valent (PCV10) and 13-valent (PCV13) PCVs between infants randomly assigned to receive a single-dose compared with a two-dose primary series.

Methods: We did an open-label, non-inferiority, randomised study in HIV-unexposed infants at a single centre in Soweto, South Africa. Infants were randomly assigned to receive one priming dose of PCV10 or PCV13 at ages 6 weeks (6w + 1 PCV10 and 6w + 1 PCV13 groups) or 14 weeks (14w + 1 PCV10 and 14w + 1 PCV13 groups) or two priming doses of PCV10 or PCV13, one each at ages 6 weeks and 14 weeks (2 + 1 PCV10 and 2 + 1 PCV13 groups); all participants then received a booster dose of PCV10 or PCV13 at 40 weeks of age. The primary endpoint was geometric mean concentrations (GMCs) of serotype-specific IgG 1 month after the booster dose, which was assessed in all participants who received PCV10 or PCV13 as per the assigned randomisation group and for whom laboratory results were available at that timepoint. The 1 + 1 vaccine schedule was considered non-inferior to the 2 + 1 vaccine schedule if the lower bound of the 96% CI for the GMC ratio was greater than 0·5 for at least ten PCV13 serotypes and eight PCV10 serotypes. Safety was a secondary endpoint. This trial is registered with ClinicalTrials.gov (NCT02943902) and is ongoing.

Findings: Of 1695 children assessed, 600 were enrolled and randomly assigned to one of the six groups between Jan 9 and Sept 20, 2017; 542 were included in the final analysis of the primary endpoint (86-93 per group). For both PCV13 and PCV10, a 1+1 dosing schedule (either beginning at 6 or 14 weeks) was non-inferior to a 2 + 1 schedule. For PCV13, the lower limit of the 96% CI for the ratio of GMCs between the 1 + 1 and 2 + 1 groups was higher than 0·5 for ten serotypes in the 6w+1 group (excluding 6B, 14, and 23F) and 11 serotypes in the 14w + 1 group (excluding 6B and 23F). For PCV10, the lower limit of the 96% CI for the ratio of GMCs was higher than 0·5 for all ten serotypes in the 6w+1 and 14w + 1 groups. 84 serious adverse events were reported in 72 (12%) of 600 participants. 15 occurred within 28 days of vaccination, but none were considered to be related to PCV injection. There were no cases of culture-confirmed invasive pneumococcal disease.

Interpretation: The non-inferiority in post-booster immune responses following a single-dose compared with a two-dose primary series of PCV13 or PCV10 indicates the potential for reducing PCV dosing schedules from a 2 + 1 to 1 + 1 series in low-income and middle-income settings with well established PCV immunisation programmes.

Funding: The Bill & Melinda Gates Foundation (OPP1 + 152352).
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http://dx.doi.org/10.1016/S1473-3099(20)30289-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689288PMC
December 2020

Digital auscultation in PERCH: Associations with chest radiography and pneumonia mortality in children.

Pediatr Pulmonol 2020 11 11;55(11):3197-3208. Epub 2020 Sep 11.

Department of International Health, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Background: Whether digitally recorded lung sounds are associated with radiographic pneumonia or clinical outcomes among children in low-income and middle-income countries is unknown. We sought to address these knowledge gaps.

Methods: We enrolled 1 to 59monthold children hospitalized with pneumonia at eight African and Asian Pneumonia Etiology Research for Child Health sites in six countries, recorded digital stethoscope lung sounds, obtained chest radiographs, and collected clinical outcomes. Recordings were processed and classified into binary categories positive or negative for adventitial lung sounds. Listening and reading panels classified recordings and radiographs. Recording classification associations with chest radiographs with World Health Organization (WHO)-defined primary endpoint pneumonia (radiographic pneumonia) or mortality were evaluated. We also examined case fatality among risk strata.

Results: Among children without WHO danger signs, wheezing (without crackles) had a lower adjusted odds ratio (aOR) for radiographic pneumonia (0.35, 95% confidence interval (CI): 0.15, 0.82), compared to children with normal recordings. Neither crackle only (no wheeze) (aOR: 2.13, 95% CI: 0.91, 4.96) or any wheeze (with or without crackle) (aOR: 0.63, 95% CI: 0.34, 1.15) were associated with radiographic pneumonia. Among children with WHO danger signs no lung recording classification was independently associated with radiographic pneumonia, although trends toward greater odds of radiographic pneumonia were observed among children classified with crackle only (no wheeze) or any wheeze (with or without crackle). Among children without WHO danger signs, those with recorded wheezing had a lower case fatality than those without wheezing (3.8% vs. 9.1%, p = .03).

Conclusions: Among lower risk children without WHO danger signs digitally recorded wheezing is associated with a lower odds for radiographic pneumonia and with lower mortality. Although further research is needed, these data indicate that with further development digital auscultation may eventually contribute to child pneumonia care.
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http://dx.doi.org/10.1002/ppul.25046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692889PMC
November 2020

Neurodevelopmental Impairment at 1 Year of Age in Infants With Previous Invasive Group B Streptococcal Sepsis and Meningitis.

Pediatr Infect Dis J 2020 09;39(9):794-798

From the Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Background: Invasive group B streptococcal (GBS) disease causes considerable morbidity and mortality in young infants, and 18% of GBS-meningitis survivors have moderate-to-severe neurodevelopmental impairment. However, there is a paucity of data regarding neurologic impairment following GBS sepsis.

Methods: A case-control study was undertaken in infants at 3 secondary-tertiary hospitals in Johannesburg, South Africa. Neurodevelopmental assessments were done at 1 year of age using the Denver II Developmental screening tool. A case was defined as isolation of GBS from blood or cerebrospinal fluid in infants less than 90  days of age. Three healthy controls (range: 1-6) were matched to maternal age, maternal HIV-infection status, gestational age and timing of enrollment.

Results: Of 122 invasive GBS cases, 78 (63.9%) had sepsis and 44 (36.1%) meningitis. Twenty-two (18%) invasive GBS cases (17 of 78; 21.8% with sepsis and 5 of 44; 11.4% with meningitis) died during the course of hospitalization, and a further 2 (1.6%; 1 sepsis and 1 meningitis case) died by 1 year of age. Five (1.1%) of 449 controls died by 1 year of age. Of the 45 GBS sepsis cases and 141 matched controls followed through to 1 year of age, 11 (24.4%) cases (3 with moderate-to-severe impairment) and 10 (7.1%) controls had an abnormal Denver score with an adjusted (for gender) odds ratio of 3.51; 95% confidence interval (CI): 1.23-10.04; P = 0.019. Four (20%) of the 20 GBS meningitis cases compared with 1 (1.5%) control had neurologic impairment at 1-year of age (aOR: 8.29; 95% CI: 0.88-78.3; P = 0.065) CONCLUSION:: In this setting, invasive GBS disease is associated with a high mortality. Infant survivors of invasive GBS sepsis compared with controls had 3.5-fold greater odds of neurologic impairment by 1 year of age. This corroborates the need for strategies to prevent invasive GBS disease.
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http://dx.doi.org/10.1097/INF.0000000000002695DOI Listing
September 2020

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

N Engl J Med 2020 07;383(5):426-439

From the Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, and the Department of Science and Technology-National Research Foundation, Vaccine Preventable Diseases, University of the Witwatersrand (S.A.M., C.L.C.), and Shandukani Research Centre, Wits Reproductive Health and HIV Institute (M.S.M.), Johannesburg, Setshaba Research Centre, Soshanguve (K.A., A.O.), and the Family Centre for Research with Ubuntu, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg Hospital (M.F.C.), and the Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, South African Medical Research Council Unit on Child and Adolescent Health, University of Cape Town (H.J.Z.), Cape Town - all in South Africa; Fundación INFANT (F.P.P., R.L.), Hospital Militar Central Dr. Cosme Argerich (G.P.M.), and the National Scientific and Technical Research Council (R.L.), Buenos Aires, and the Department of Pediatric Pulmonology, Hospital del Niño Jesús, Tucumán (C.J.L.) - both in Argentina; the Departments of Pediatrics and Molecular Virology and Microbiology, Baylor College of Medicine, Houston (P.A.P., F.M.M.); the University of Auckland, Middlemore Hospital, Auckland, New Zealand (A.A.T.); the Department of Pediatrics, University of Colorado School of Medicine, and the Children's Hospital Colorado, Center for Global Health, Colorado School of Public Health, Aurora (E.A.F.S.); the Department of Obstetrics and Gynecology, Duke University, Durham, NC (G.K.S.); Novavax (S.A., A.A., J.C., I.C., A.F., J.S.P., V.S., D.N.T., J.W., G.M.G., L.F.F.), Gaithersburg, and the Department of International Health, International Center for Maternal and Newborn Health (A.H.B.), and the Center for American Indian Health, Department of International Health (L.H.), Johns Hopkins Bloomberg School of Public Health, Baltimore - all in Maryland; the Vaccine Institute (A.C., P.T.H.) and the Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute (A.K.), St. George's, University of London, London, Paediatric Infectious Diseases, Clinical and Experimental Sciences, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton (C.E.J.), and the Oxford Vaccine Group, Department of Paediatrics, University of Oxford and National Institute for Health Research Oxford Biomedical Research Centre (M.D.S.), and the Nuffield Department of Women's and Reproductive Health, University of Oxford (M.V.), Oxford - all in the United Kingdom; the Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle (J.A.E.);the Department of Obstetrics and Gynecology, Wayne State University, Detroit (B.G.); the Research Institute for Tropical Medicine, Muntinlupa, Philippines (J.N.J., M.L.); the Department of Pediatrics (D.W.K.) and the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology and Center for Women's Reproductive Health (A.T.T.), University of Alabama, Birmingham; the Women's and Children's Hospital and Robinson Research Institute, University of Adelaide, Adelaide, SA (H.S.M.), the Melbourne School of Population and Global Health, University of Melbourne, and Murdoch Children's Research Institute, Parkville, VIC (T.M.N., K.P.P.), and Wesfarmers Center of Vaccines and Infectious Diseases, Telethon Kids Institute, Division of Paediatrics, School of Medicine, University of Western Australia, Perth Children's Hospital, Perth (P.C.R., T.S.) - all in Australia; Marshfield Clinic Research Institute, Marshfield, WI (J.K.M.); Pediatría Clínica, Infectología y Traslacional Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain (F.M.-T.); the Division of General Pediatrics, Department of Pediatrics, School of Medicine (J.H.S.), and the Department of Obstetrics and Gynecology (M.W.V.), University of Utah Health Sciences Center, Salt Lake City; Meridian Clinical Research, Norfolk, NE (K.V.); and the International Center for Diarrhoeal Disease Research Bangladesh, Dhaka (K.Z.).

Background: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants.

Methods: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%).

Results: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups.

Conclusions: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).
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http://dx.doi.org/10.1056/NEJMoa1908380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299433PMC
July 2020

Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants.

N Engl J Med 2020 07;383(5):415-425

From AstraZeneca, Gaithersburg, MD (M.P.G., Y.Y., T.T., M.T.E., A.A.K., F.D., T.V.); SUNY Upstate Medical University, Syracuse, NY (J.B.D.); Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, and Department of Science and Technology/National Research Foundation South African Research Chair, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg (S.A.M.); the Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, and Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Turin - both in Italy (P.M.); the University of Colorado School of Medicine, Aurora (E.A.F.S.); and the Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN (J.P.D.V.).

Background: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose.

Methods: In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose.

Results: From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P<0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions.

Conclusions: A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).
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http://dx.doi.org/10.1056/NEJMoa1913556DOI Listing
July 2020

The Aetiology of pneumonia from analysis of Lung aspirate and Pleural fluid samples: Findings from the PERCH study.

Clin Infect Dis 2020 Jul 25. Epub 2020 Jul 25.

Medical Research Council Unit, Basse, The Gambia.

Background: An improved understanding of childhood pneumonia aetiology is required to inform prevention and treatment strategies. Lung aspiration is the gold standard specimen for pneumonia diagnostics. We report findings from analyses of lung and pleural aspirates collected in the Pneumonia Etiology Research for Child Health (PERCH) study.

Methods: The PERCH study enrolled children aged 1-59 months hospitalized with World Health Organization defined severe or very severe pneumonia in 7 countries in Africa and Asia. Percutaneous trans-thoracic lung (LA) and pleural fluid (PF) aspiration was performed on a sample of pneumonia cases with radiological consolidation and/or pleural fluid in 4 countries. Venous blood and nasopharyngeal/oropharyngeal swabs were collected from all cases. Multiplex quantitative PCR and routine microbiologic culture were applied to clinical specimens.

Results: Of 44 LAs performed within 3 days of admission on 622 eligible cases, 13 (30%) had a pathogen identified by either culture (5/44) or by PCR (11/29). A pathogen was identified in 12/14 (86%) PF specimens tested by either culture (9/14) or PCR (9/11). Bacterial pathogens were identified more frequently than viruses. All but one of the cases with a virus identified were co-infected with bacterial pathogens. Streptococcus pneumoniae (9/44 [20%]) and Staphylococcus aureus (7/14 [50%]) were the predominant pathogen identified in LA and PF, respectively.

Conclusions: Bacterial pathogens predominated in this selected subgroup of PERCH participants drawn from those with radiological consolidation or pleural fluid, with S. pneumoniae and S. aureus the leading pathogens identified.
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http://dx.doi.org/10.1093/cid/ciaa1032DOI Listing
July 2020

Global Perspectives on Immunization During Pregnancy and Priorities for Future Research and Development: An International Consensus Statement.

Front Immunol 2020 24;11:1282. Epub 2020 Jun 24.

Department of Medicine and Surgery, Pediatric Clinic, Pietro Barilla Children's Hospital, University of Parma, Parma, Italy.

Immunization during pregnancy has been recommended in an increasing number of countries. The aim of this strategy is to protect pregnant women and infants from severe infectious disease, morbidity and mortality and is currently limited to tetanus, inactivated influenza, and pertussis-containing vaccines. There have been recent advancements in the development of vaccines designed primarily for use in pregnant women (respiratory syncytial virus and group B vaccines). Although there is increasing evidence to support vaccination in pregnancy, important gaps in knowledge still exist and need to be addressed by future studies. This collaborative consensus paper provides a review of the current literature on immunization during pregnancy and highlights the gaps in knowledge and a consensus of priorities for future research initiatives, in order to optimize protection for both the mother and the infant.
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http://dx.doi.org/10.3389/fimmu.2020.01282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326941PMC
April 2021

Upper airways colonisation of Streptococcus pneumoniae in adults aged 60 years and older: A systematic review of prevalence and individual participant data meta-analysis of risk factors.

J Infect 2020 10 17;81(4):540-548. Epub 2020 Jun 17.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom. Electronic address:

Background: Colonisation with Streptococcus pneumoniae can lead to invasive pneumococcal disease and pneumonia. Pneumococcal acquisition and prevalence of colonisation are high in children. In older adults, a population susceptible to pneumococcal disease, colonisation prevalence is reported to be lower, but studies are heterogeneous.

Methods: This is a systematic review and meta-analysis of prevalence of, and risk factors for, pneumococcal colonisation in adults ≥ 60 years of age (PROSPERO #42016036891). We identified peer-reviewed studies reporting the prevalence of S. pneumoniae colonisation using MEDLINE and EMBASE (until April 2016), excluding studies of acute disease. Participant-level data on risk factors were sought from each study.

Findings: Of 2202 studies screened, 29 were analysable: 18 provided participant-level data (representing 6290 participants). Prevalence of detected pneumococcal colonisation was 0-39% by conventional culture methods and 3-23% by molecular methods. In a multivariate analysis, colonisation was higher in persons from nursing facilities compared with the community (odds ratio (OR) 2•30, 95% CI 1•26-4•21 and OR 7•72, 95% CI 1•15-51•85, respectively), in those who were currently smoking (OR 1•69, 95% CI 1•12-2•53) or those who had regular contact with children (OR 1•93, 95%CI 1•27-2•93). Persons living in urban areas had significantly lower carriage prevalence (OR 0•43, 95%CI 0•27-0•70).

Interpretation: Overall prevalence of pneumococcal colonisation in older adults was higher than expected but varied by risk factors. Future studies should further explore risk factors for colonisation, to highlight targets for focussed intervention such as pneumococcal vaccination of high-risk groups.

Funding: No funding was required.
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http://dx.doi.org/10.1016/j.jinf.2020.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532703PMC
October 2020

Initial findings from a novel population-based child mortality surveillance approach: a descriptive study.

Lancet Glob Health 2020 07;8(7):e909-e919

Emory Global Health Institute, Emory University, Atlanta, GA, USA. Electronic address:

Background: Sub-Saharan Africa and south Asia contributed 81% of 5·9 million under-5 deaths and 77% of 2·6 million stillbirths worldwide in 2015. Vital registration and verbal autopsy data are mainstays for the estimation of leading causes of death, but both are non-specific and focus on a single underlying cause. We aimed to provide granular data on the contributory causes of death in stillborn fetuses and in deceased neonates and children younger than 5 years, to inform child mortality prevention efforts.

Methods: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network was established at sites in seven countries (Baliakandi, Bangladesh; Harar and Kersa, Ethiopia; Siaya and Kisumu, Kenya; Bamako, Mali; Manhiça, Mozambique; Bombali, Sierra Leone; and Soweto, South Africa) to collect standardised, population-based, longitudinal data on under-5 mortality and stillbirths in sub-Saharan Africa and south Asia, to improve the accuracy of determining causes of death. Here, we analysed data obtained in the first 2 years after the implementation of CHAMPS at the first five operational sites, during which surveillance and post-mortem diagnostics, including minimally invasive tissue sampling (MITS), were used. Data were abstracted from all available clinical records of deceased children, and relevant maternal health records were also extracted for stillbirths and neonatal deaths, to incorporate reported pregnancy or delivery complications. Expert panels followed standardised procedures to characterise causal chains leading to death, including underlying, intermediate (comorbid or antecedent causes), and immediate causes of death for stillbirths, neonatal deaths, and child (age 1-59 months) deaths.

Findings: Between Dec 10, 2016, and Dec 31, 2018, MITS procedures were implemented at five sites in Mozambique, South Africa, Kenya, Mali, and Bangladesh. We screened 2385 death notifications for inclusion eligibility, following which 1295 families were approached for consent; consent was provided for MITS by 963 (74%) of 1295 eligible cases approached. At least one cause of death was identified in 912 (98%) of 933 cases (180 stillbirths, 449 neonatal deaths, and 304 child deaths); two or more conditions were identified in the causal chain for 585 (63%) of 933 cases. The most common underlying causes of stillbirth were perinatal asphyxia or hypoxia (130 [72%] of 180 stillbirths) and congenital infection or sepsis (27 [15%]). The most common underlying causes of neonatal death were preterm birth complications (187 [42%] of 449 neonatal deaths), perinatal asphyxia or hypoxia (98 [22%]), and neonatal sepsis (50 [11%]). The most common underlying causes of child deaths were congenital birth defects (39 [13%] of 304 deaths), lower respiratory infection (37 [12%]), and HIV (35 [12%]). In 503 (54%) of 933 cases, at least one contributory pathogen was identified. Cytomegalovirus, Escherichia coli, group B Streptococcus, and other infections contributed to 30 (17%) of 180 stillbirths. Among neonatal deaths with underlying prematurity, 60% were precipitated by other infectious causes. Of the 275 child deaths with infectious causes, the most common contributory pathogens were Klebsiella pneumoniae (86 [31%]), Streptococcus pneumoniae (54 [20%]), HIV (40 [15%]), and cytomegalovirus (34 [12%]), and multiple infections were common. Lower respiratory tract infection contributed to 174 (57%) of 304 child deaths.

Interpretation: Cause of death determination using MITS enabled detailed characterisation of contributing conditions. Global estimates of child mortality aetiologies, which are currently based on a single syndromic cause for each death, will be strengthened by findings from CHAMPS. This approach adds specificity and provides a more complete overview of the chain of events leading to death, highlighting multiple potential interventions to prevent under-5 mortality and stillbirths.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2214-109X(20)30205-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303945PMC
July 2020

Efficacy, duration of protection, birth outcomes, and infant growth associated with influenza vaccination in pregnancy: a pooled analysis of three randomised controlled trials.

Lancet Respir Med 2020 06;8(6):597-608

Bill & Melinda Gates Foundation, Seattle, WA, USA; Vaccines For All, Pune, India.

Background: Maternal influenza immunisation can reduce morbidity and mortality associated with influenza infection in pregnant women and young infants. We aimed to determine the vaccine efficacy of maternal influenza immunisation against maternal and infant PCR-confirmed influenza, duration of protection, and the effect of gestational age at vaccination on vaccine efficacy, birth outcomes, and infant growth up to 6 months of age.

Methods: We did a pooled analysis of three randomised controlled trials done in Nepal (2011-2014), Mali (2011-2014), and South Africa (2011-2013). Pregnant women, gestational age 17-34 weeks in Nepal, 28 weeks or more in Mali, and 20-36 weeks in South Africa, were enrolled. Women were randomly assigned 1:1 to a study group, in which they received trivalent inactivated influenza vaccine (IIV) in all three trials, or a control group, in which they received saline placebo in Nepal and South Africa or quadrivalent meningococcal conjugate vaccine in Mali. Enrolment at all sites was complete by April 24, 2013. Infants and women were assessed for respiratory illness, and samples from those that met the case definition were tested for influenza by PCR testing. Growth measurements, including length and weight, were obtained at birth at all sites, at 24 weeks in South Africa, and at 6 months in Nepal and Mali. The three trials are registered with ClinicalTrials.gov, numbers NCT01430689, NCT01034254, and NCT02465190.

Findings: 10 002 women and 9800 liveborn infants were included. Pooled efficacy of maternal vaccination to prevent infant PCR-confirmed influenza up to 6 months of age was 35% (95% CI 19 to 47). The pooled estimate was 56% (28 to 73) within the first 2 months of life, 39% (11 to 58) between 2 and 4 months, and 19% (-9 to 40) between 4 and 6 months. In women, from enrolment during pregnancy to the end of follow-up at 6 months postpartum, the vaccine was 50% (95% CI 32-63) efficacious against PCR-confirmed influenza. Efficacy was 42% (12 to 61) during pregnancy and 60% (36 to 75) postpartum. In women vaccinated before 29 weeks gestational age, the estimated efficacy was 30% (-2 to 52), and in women vaccinated at or after 29 weeks, efficacy was 71% (50 to 83). Efficacy was similar in infants born to mothers vaccinated before or after 29 weeks gestation (34% [95% CI 12 to 51] vs 35% [11 to 52]). There was no overall association between maternal vaccination and low birthweight, stillbirth, preterm birth, and small for gestational age. At 6 months of age, the intervention and control groups were similar in terms of underweight (weight-for-age), stunted (length-for-age), and wasted (weight-for-length). Median centile change from birth to 6 months of age was similar between the intervention and the control groups for both weight and length.

Interpretation: The assessment of efficacy for women vaccinated before 29 weeks gestational age might have been underpowered, because the point estimate suggests that there might be efficacy despite wide CIs. Estimates of efficacy against PCR-confirmed influenza and safety in terms of adverse birth outcomes should be incorporated into any further consideration of maternal influenza immunisation recommendations.

Funding: Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2213-2600(19)30479-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284303PMC
June 2020

Influenza or Meningococcal Immunization During Pregnancy and Mortality in Women and Infants: A Pooled Analysis of Randomized Controlled Trials.

Pediatr Infect Dis J 2020 07;39(7):641-644

Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

This analysis includes pooled data from 2 placebo-controlled maternal influenza immunization trials, with a separate analysis on a meningococcal conjugate vaccine-controlled maternal influenza immunization trial. Maternal influenza immunization was not associated with infant or maternal all-cause mortality in placebo-controlled trials. In the meningococcal conjugate vaccine-controlled trial, there were fewer deaths during low or any influenza circulation weeks among infants whose mothers received meningococcal conjugate vaccine. ClinicalTrials.gov identifiers: NCT01430689, NCT01034254 and NCT02465190.
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http://dx.doi.org/10.1097/INF.0000000000002629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279057PMC
July 2020

Visualizing variation within Global Pneumococcal Sequence Clusters (GPSCs) and country population snapshots to contextualize pneumococcal isolates.

Microb Genom 2020 05 29;6(5). Epub 2020 Apr 29.

Parasites and microbes, Wellcome Sanger InstituteHinxton, UK.

Knowledge of pneumococcal lineages, their geographic distribution and antibiotic resistance patterns, can give insights into global pneumococcal disease. We provide interactive bioinformatic outputs to explore such topics, aiming to increase dissemination of genomic insights to the wider community, without the need for specialist training. We prepared 12 country-specific phylogenetic snapshots, and international phylogenetic snapshots of 73 common Global Pneumococcal Sequence Clusters (GPSCs) previously defined using PopPUNK, and present them in Microreact. Gene presence and absence defined using Roary, and recombination profiles derived from Gubbins are presented in Phandango for each GPSC. Temporal phylogenetic signal was assessed for each GPSC using BactDating. We provide examples of how such resources can be used. In our example use of a country-specific phylogenetic snapshot we determined that serotype 14 was observed in nine unrelated genetic backgrounds in South Africa. The international phylogenetic snapshot of GPSC9, in which most serotype 14 isolates from South Africa were observed, highlights that there were three independent sub-clusters represented by South African serotype 14 isolates. We estimated from the GPSC9-dated tree that the sub-clusters were each established in South Africa during the 1980s. We show how recombination plots allowed the identification of a 20 kb recombination spanning the capsular polysaccharide locus within GPSC97. This was consistent with a switch from serotype 6A to 19A estimated to have occured in the 1990s from the GPSC97-dated tree. Plots of gene presence/absence of resistance genes (, , ) across the GPSC23 phylogeny were consistent with acquisition of a composite transposon. We estimated from the GPSC23-dated tree that the acquisition occurred between 1953 and 1975. Finally, we demonstrate the assignment of GPSC31 to 17 externally generated pneumococcal serotype 1 assemblies from Utah via Pathogenwatch. Most of the Utah isolates clustered within GPSC31 in a USA-specific clade with the most recent common ancestor estimated between 1958 and 1981. The resources we have provided can be used to explore to data, test hypothesis and generate new hypotheses. The accessible assignment of GPSCs allows others to contextualize their own collections beyond the data presented here.
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http://dx.doi.org/10.1099/mgen.0.000357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371119PMC
May 2020

Pulmonary function sequelae after respiratory syncytial virus lower respiratory tract infection in children: A systematic review.

Pediatr Pulmonol 2020 07 4;55(7):1567-1583. Epub 2020 May 4.

Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) during early childhood may be associated with subsequent pulmonary sequelae, including recurrent wheezing and asthma. We undertook a systematic review to investigate the pulmonary function sequelae following RSV LRTI in the first 3 years of life. The systematic review protocol was registered on PROSPERO (CRD42018087168). PubMed, Scopus, Cochrane Library, and World Health Organization Global Index Medicus, as well as ClinicalTrials.gov and Cochrane Central Register of Controlled Trials, were searched up until 15 June 2019 for published and unpublished interventional and observational studies with the end-point outcome of pulmonary function testing (PFT) after a proven RSV LRTI in the first 3 years of life. Two independent reviewers screened all the titles, abstracts and full texts. Data were extracted using a standardized data extraction form. Corresponding authors were contacted for additional information if required. All studies were assessed for risk of bias using the Newcastle-Ottawa quality assessment scale. The final analysis included 31 studies. Thirteen studies using spirometry reported no association between RSV LRTI and pulmonary function sequelae. The remaining 16 reported abnormal spirometry; 12 obstructive airways disease, three restrictive lung disease, and one mixed lung disease. The heterogeneity in PFT techniques, different ages at testing, and methods used for reporting outcomes made direct comparisons or pooled effect estimates impossible. Children with confirmed RSV LRTI during the first 3 years of life often have abnormal PFTs, favoring obstructive airways disease. The evidence, however, is not overwhelming with conflicting results between studies.
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http://dx.doi.org/10.1002/ppul.24804DOI Listing
July 2020