Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.

High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300-1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Antibiotic point prevalence survey and antimicrobial resistance in hospitalized patients across Peruvian reference hospitals.

BACKGROUND: Peru reports higher levels than other countries in Latin America of resistance to antimicrobials among Gram-positive and Gram-negative bacteria, however data on antibiotic use in Peru are scarce. This study aims to estimate the prevalence and quality of antibiotic prescription in hospitalized patients and to determine the antibiotic susceptibility rates of bacteria causing key bacterial infections. METHODS: We carried out a point prevalence survey of antibiotic prescription at ten public hospitals in nine regions of Peru. Data was collected from patients hospitalized during a 3-week period, with details about antibiotic use, patient information, and antimicrobial susceptibility. RESULTS: 1620 patient charts were reviewed; in 924 cases antibiotics were prescribed (57.0 %, range 45.9-78.9 %). Most of the antibiotics (74.2 %) were prescribed as empirical treatment, only 4.4 % as targeted treatment. For 9.5 % of cases the reason for antibiotic use was unknown. Cephalosporins were the most prescribed (30.0 %), followed by carbapenems (11.3 %). Ninety-four blood cultures were positive for bacterial growth, 48.8 % of the Staphylococcus aureus were methicillin-resistant, among Escherichia coli and Klebsiella pneumoniae, 51.7 % and 72.7 % were resistant to third-generation cephalosporins (3GC), 3.4 % and 18.2 % were resistant to carbapenems, respectively. Among bacteria isolated from urine cultures (n = 639), 43.9 % of E. coli and 49.2 % of K. pneumoniae were resistant to 3GC, and 0.9 % of E. coli and 3.2 % of K. pneumoniae were resistant to meropenem. CONCLUSIONS: The overall proportion of hospitalized patients receiving antibiotics in hospitals from different regions in Peru was high, with only a small proportion receiving targeted treatment. Cephalosporins and carbapenems were the most frequently prescribed antibiotics, reflecting high resistance rates against 3GC and carbapenems in Enterobacterales isolated from blood and urine.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

It is of interest to pinpoint SARS-CoV-2 sequence features defining vaccine resistance. In the ENSEMBLE randomized, placebo-controlled phase 3 trial, estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were measured from 484 vaccine and 1,067 placebo recipients who acquired COVID-19 during the trial. In Latin America, where Spike diversity was greatest, VE was significantly lower against Lambda than against Reference and against all non-Lambda variants [family-wise error rate (FWER) p < 0.05]. VE also differed by residue match vs. mismatch to the vaccine-strain residue at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20). VE significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 different antibody-epitope escape scores and by 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccine recipient sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against viruses with greatest distances. These results help map antigenic specificity of in vivo vaccine protection.

Eliminating morbidity caused by neglected tropical diseases by 2030.

The objective of this manuscript is to provide selective examples of the work of the Pan American Health Organization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation. Three important projects have recently been completed: 1. Finalizing the Monitoring and Evaluation Framework for the NTD Road Map (published May 2021; this PAHO/WHO CC was a member of the working group); 2. Developing new guidelines for the preventive chemotherapy of Taenia solium taeniasis (published September 2021; this PAHO/WHO CC was co-Chair; and 3. Formulating a policy brief on deworming for adolescent girls and women of reproductive age (published January 2022; this PAHO/WHO CC is co-lead). These projects are the result of the integration of expertise and experience from multiple partners, including from PAHO and WHO (where both organizations provided key leadership), this PAHO/WHO CC, government ministries, civil society organizations and universities, among others. In conclusion, this PAHO/WHO CC contributes timely guidance to country-led evidence-informed public health policy, to cost-effective program implementation and to the identification of priority research topics - all focused, ultimately, on eliminating NTD-attributable morbidity by 2030.

El objetivo de este artículo es proporcionar ejemplos seleccionados de la labor del centro colaborador de investigación y capacitación en epidemiología y control de parásitos de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), que contribuye al objetivo de la OMS de eliminar las enfermedades tropicales desatendidas para el 2030. Este centro colaborador de la OPS/OMS alinea sus actividades específicamente con los Objetivos de Desarrollo Sostenible y con los objetivos descritos en la Hoja de ruta sobre enfermedades tropicales desatendidas 2021-2030 de la OMS. Su función es contribuir al avance de las medidas mundiales sobre las enfermedades tropicales desatendidas, principalmente mediante la elaboración de políticas y la traducción de conocimiento. Recientemente se han completado tres proyectos importantes: 1) finalización del marco de seguimiento y evaluación de la Hoja de ruta sobre enfermedades tropicales desatendidas (publicado en mayo del 2021; este centro colaborador de la OPS/OMS formó parte del grupo de trabajo); 2) elaboración de nuevas directrices para la quimioterapia preventiva de la teniasis por Taenia solium (publicado en septiembre del 2021; este centro colaborador fue copresidente); y 3) formulación de un informe de políticas sobre la desparasitación de las adolescentes y las mujeres en edad reproductiva (publicado en enero del 2022; este centro colaborador fue coautor). Estos proyectos son el resultado de la integración del conocimiento y la experiencia de múltiples asociados, como la OPS y la OMS (ambas organizaciones ofrecieron un liderazgo clave), este centro colaborador de la OPS/OMS, así como varios ministerios gubernamentales, organizaciones de la sociedad civil y universidades, entre otros. En conclusión, este centro colaborador de la OPS/OMS ofrece orientaciones oportunas para las políticas de salud pública basadas en la evidencia lideradas por los países, la ejecución de programas costo-efectivos y la determinación de los temas de investigación prioritarios, todo ello destinado, en última instancia, a eliminar la morbilidad atribuible a las enfermedades tropicales desatendidas para el 2030.

O objetivo deste manuscrito é fornecer exemplos seletivos do trabalho do Centro Colaborador de Pesquisa e Treinamento em Epidemiologia e Controle de Parasitos da Organização Pan-Americana da Saúde/Organização Mundial da Saúde (OPAS/OMS) que contribuem para a meta da OMS de eliminar até 2030 as doenças tropicais negligenciadas. Este CC da OPAS/OMS alinha especificamente suas atividades com os Objetivos de Desenvolvimento Sustentável e com as metas delineadas no Roteiro da OMS para Doenças Tropicais Negligenciadas 2021-2030. Seu papel é contribuir para o avanço da ação global contra doenças tropicais negligenciadas, principalmente por meio do desenvolvimento de políticas e da tradução de conhecimentos. Três importantes projetos foram concluídos recentemente: 1. Finalização da Estrutura de Monitoramento e Avaliação do Roteiro para as DTN (publicada em maio de 2021 ­ este CC da OPAS/OMS foi membro do grupo de trabalho); 2. Desenvolvimento de novas diretrizes para a quimioprofilaxia da teníase por Taenia solium (publicado em setembro de 2021 ­ este CC da OPAS/OMS foi copresidente); e 3. Formulação de orientação para políticas de desparasitação para adolescentes e mulheres em idade reprodutiva (publicado em janeiro de 2022 ­ este CC da OPAS/OMS foi cogestor). Esses projetos são o resultado da integração de conhecimentos e experiência de múltiplos parceiros, incluindo a OPAS e a OMS (onde ambas as organizações forneceram liderança essencial), este CC da OPAS/OMS, ministérios governamentais, organizações da sociedade civil e universidades, entre outros. Em suma, este CC da OPAS/OMS contribui com orientações oportunas para uma política de saúde pública liderada pelos países e informada com base em evidências, para a implementação de programas com boa relação custo-benefício e para a identificação de tópicos prioritários de pesquisa ­ todos focados, em última análise, na eliminação da morbidade atribuível às DTN até 2030.

Eliminating morbidity caused by neglected tropical diseases by 2030

[ABSTRACT]. The objective of this manuscript is to provide selective examples of the work of the Pan American Health Orga- nization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation. Three important projects have recently been completed: 1. Finalizing the Monitoring and Evaluation Framework for the NTD Road Map (published May 2021; this PAHO/WHO CC was a member of the working group); 2. Devel- oping new guidelines for the preventive chemotherapy of Taenia solium taeniasis (published September 2021; this PAHO/WHO CC was co-Chair; and 3. Formulating a policy brief on deworming for adolescent girls and women of reproductive age (published January 2022; this PAHO/WHO CC is co-lead). These projects are the result of the integration of expertise and experience from multiple partners, including from PAHO and WHO (where both organizations provided key leadership), this PAHO/WHO CC, government ministries, civil society organizations and universities, among others. In conclusion, this PAHO/WHO CC contributes timely guidance to country-led evidence-informed public health policy, to cost-effective program implementation and to the identification of priority research topics – all focused, ultimately, on eliminating NTD-attributable morbidity by 2030.

[RESUMEN]. El objetivo de este artículo es proporcionar ejemplos seleccionados de la labor del centro colaborador de investigación y capacitación en epidemiología y control de parásitos de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), que contribuye al objetivo de la OMS de eliminar las enfermedades tropicales desatendidas para el 2030. Este centro colaborador de la OPS/OMS alinea sus actividades específicamente con los Objetivos de Desarrollo Sostenible y con los objetivos descritos en la Hoja de ruta sobre enfermedades tropicales desatendidas 2021-2030 de la OMS. Su función es contribuir al avance de las medidas mundiales sobre las enfermedades tropicales desatendidas, principalmente mediante la elaboración de políticas y la traducción de conocimiento. Recientemente se han completado tres proyectos importantes: 1) finalización del marco de seguimiento y evaluación de la Hoja de ruta sobre enfermedades tropicales desatendidas (publicado en mayo del 2021; este centro colaborador de la OPS/OMS formó parte del grupo de trabajo); 2) elaboración de nuevas directrices para la quimioterapia preventiva de la teniasis por Taenia solium (publicado en septiembre del 2021; este centro colaborador fue copresidente); y 3) formulación de un informe de políticas sobre la desparasitación de las adolescentes y las mujeres en edad reproductiva (publicado en enero del 2022; este centro colaborador fue coautor). Estos proyectos son el resultado de la integración del conocimiento y la experiencia de múltiples asociados, como la OPS y la OMS (ambas organi- zaciones ofrecieron un liderazgo clave), este centro colaborador de la OPS/OMS, así como varios ministerios gubernamentales, organizaciones de la sociedad civil y universidades, entre otros. En conclusión, este centro colaborador de la OPS/OMS ofrece orientaciones oportunas para las políticas de salud pública basadas en la evidencia lideradas por los países, la ejecución de programas costo-efectivos y la determinación de los temas de investigación prioritarios, todo ello destinado, en última instancia, a eliminar la morbilidad atribuible a las enfermedades tropicales desatendidas para el 2030.

[RESUMO]. O objetivo deste manuscrito é fornecer exemplos seletivos do trabalho do Centro Colaborador de Pesquisa e Treinamento em Epidemiologia e Controle de Parasitos da Organização Pan-Americana da Saúde/Organi- zação Mundial da Saúde (OPAS/OMS) que contribuem para a meta da OMS de eliminar até 2030 as doenças tropicais negligenciadas. Este CC da OPAS/OMS alinha especificamente suas atividades com os Objetivos de Desenvolvimento Sustentável e com as metas delineadas no Roteiro da OMS para Doenças Tropicais Negligenciadas 2021-2030. Seu papel é contribuir para o avanço da ação global contra doenças tropicais negligenciadas, principalmente por meio do desenvolvimento de políticas e da tradução de conhecimentos. Três importantes projetos foram concluídos recentemente: 1. Finalização da Estrutura de Monitoramento e Avaliação do Roteiro para as DTN (publicada em maio de 2021 – este CC da OPAS/OMS foi membro do grupo de trabalho); 2. Desenvolvimento de novas diretrizes para a quimioprofilaxia da teníase por Taenia solium (publicado em setembro de 2021 – este CC da OPAS/OMS foi copresidente); e 3. Formulação de orientação para políticas de desparasitação para adolescentes e mulheres em idade reprodutiva (publicado em janeiro de 2022 – este CC da OPAS/OMS foi cogestor). Esses projetos são o resultado da integração de conhecimen- tos e experiência de múltiplos parceiros, incluindo a OPAS e a OMS (onde ambas as organizações forneceram liderança essencial), este CC da OPAS/OMS, ministérios governamentais, organizações da sociedade civil e universidades, entre outros. Em suma, este CC da OPAS/OMS contribui com orientações oportunas para uma política de saúde pública liderada pelos países e informada com base em evidências, para a implementação de programas com boa relação custo-benefício e para a identificação de tópicos prioritários de pesquisa – todos focados, em última análise, na eliminação da morbidade atribuível às DTN até 2030.

Eliminating morbidity caused by neglected tropical diseases by 2030 / Eliminar la morbilidad causada por las enfermedades tropicales desatendidas para el 2030 / Eliminação até 2030 da morbidade causada pelas doenças tropicais negligenciadas

ABSTRACT The objective of this manuscript is to provide selective examples of the work of the Pan American Health Organization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation. Three important projects have recently been completed: 1. Finalizing the Monitoring and Evaluation Framework for the NTD Road Map (published May 2021; this PAHO/WHO CC was a member of the working group); 2. Developing new guidelines for the preventive chemotherapy of Taenia solium taeniasis (published September 2021; this PAHO/WHO CC was co-Chair; and 3. Formulating a policy brief on deworming for adolescent girls and women of reproductive age (published January 2022; this PAHO/WHO CC is co-lead). These projects are the result of the integration of expertise and experience from multiple partners, including from PAHO and WHO (where both organizations provided key leadership), this PAHO/WHO CC, government ministries, civil society organizations and universities, among others. In conclusion, this PAHO/WHO CC contributes timely guidance to country-led evidence-informed public health policy, to cost-effective program implementation and to the identification of priority research topics - all focused, ultimately, on eliminating NTD-attributable morbidity by 2030.

RESUMEN El objetivo de este artículo es proporcionar ejemplos seleccionados de la labor del centro colaborador de investigación y capacitación en epidemiología y control de parásitos de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), que contribuye al objetivo de la OMS de eliminar las enfermedades tropicales desatendidas para el 2030. Este centro colaborador de la OPS/OMS alinea sus actividades específicamente con los Objetivos de Desarrollo Sostenible y con los objetivos descritos en la Hoja de ruta sobre enfermedades tropicales desatendidas 2021-2030 de la OMS. Su función es contribuir al avance de las medidas mundiales sobre las enfermedades tropicales desatendidas, principalmente mediante la elaboración de políticas y la traducción de conocimiento. Recientemente se han completado tres proyectos importantes: 1) finalización del marco de seguimiento y evaluación de la Hoja de ruta sobre enfermedades tropicales desatendidas (publicado en mayo del 2021; este centro colaborador de la OPS/OMS formó parte del grupo de trabajo); 2) elaboración de nuevas directrices para la quimioterapia preventiva de la teniasis por Taenia solium (publicado en septiembre del 2021; este centro colaborador fue copresidente); y 3) formulación de un informe de políticas sobre la desparasitación de las adolescentes y las mujeres en edad reproductiva (publicado en enero del 2022; este centro colaborador fue coautor). Estos proyectos son el resultado de la integración del conocimiento y la experiencia de múltiples asociados, como la OPS y la OMS (ambas organizaciones ofrecieron un liderazgo clave), este centro colaborador de la OPS/OMS, así como varios ministerios gubernamentales, organizaciones de la sociedad civil y universidades, entre otros. En conclusión, este centro colaborador de la OPS/OMS ofrece orientaciones oportunas para las políticas de salud pública basadas en la evidencia lideradas por los países, la ejecución de programas costo-efectivos y la determinación de los temas de investigación prioritarios, todo ello destinado, en última instancia, a eliminar la morbilidad atribuible a las enfermedades tropicales desatendidas para el 2030.

RESUMO O objetivo deste manuscrito é fornecer exemplos seletivos do trabalho do Centro Colaborador de Pesquisa e Treinamento em Epidemiologia e Controle de Parasitos da Organização Pan-Americana da Saúde/Organização Mundial da Saúde (OPAS/OMS) que contribuem para a meta da OMS de eliminar até 2030 as doenças tropicais negligenciadas. Este CC da OPAS/OMS alinha especificamente suas atividades com os Objetivos de Desenvolvimento Sustentável e com as metas delineadas no Roteiro da OMS para Doenças Tropicais Negligenciadas 2021-2030. Seu papel é contribuir para o avanço da ação global contra doenças tropicais negligenciadas, principalmente por meio do desenvolvimento de políticas e da tradução de conhecimentos. Três importantes projetos foram concluídos recentemente: 1. Finalização da Estrutura de Monitoramento e Avaliação do Roteiro para as DTN (publicada em maio de 2021 - este CC da OPAS/OMS foi membro do grupo de trabalho); 2. Desenvolvimento de novas diretrizes para a quimioprofilaxia da teníase por Taenia solium (publicado em setembro de 2021 - este CC da OPAS/OMS foi copresidente); e 3. Formulação de orientação para políticas de desparasitação para adolescentes e mulheres em idade reprodutiva (publicado em janeiro de 2022 - este CC da OPAS/OMS foi cogestor). Esses projetos são o resultado da integração de conhecimentos e experiência de múltiplos parceiros, incluindo a OPAS e a OMS (onde ambas as organizações forneceram liderança essencial), este CC da OPAS/OMS, ministérios governamentais, organizações da sociedade civil e universidades, entre outros. Em suma, este CC da OPAS/OMS contribui com orientações oportunas para uma política de saúde pública liderada pelos países e informada com base em evidências, para a implementação de programas com boa relação custo-benefício e para a identificação de tópicos prioritários de pesquisa - todos focados, em última análise, na eliminação da morbidade atribuível às DTN até 2030.

Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study.

BACKGROUND: People infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity. METHODS AND FINDINGS: This analysis comprises an observational cohort of 329 HIV-seronegative adults in the United States (n = 167) and Peru (n = 162) convalescing from SARS-CoV-2 infection from May through October 2020. The mean age was 48 years (range 18 to 86), 54% of the cohort overall was Hispanic, and 34% identified as White. nAb titers were measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression was applied to define associations between nAb titers and demographic variables, disease severity and time from infection or disease onset, and comorbidities within and across US and Peruvian cohorts over time. nAb titers peaked 28 to 42 days post-diagnosis and were higher in participants with a history of severe Coronavirus Disease 2019 (COVID-19) (p < 0.001). Diabetes, age >55 years, male sex assigned at birth, and, in some cases, body mass index were also independently associated with higher nAb titers, whereas hypertension was independently associated with lower nAb titers. nAb titers did not differ by race, underlying pulmonary disease or smoking. Two months post-enrollment, nAb ID50 (ID80) titers declined 3.5 (2.8)-fold overall. Study limitations in this observational, convalescent cohort include survivorship bias and missing early viral loads and acute immune responses to correlate with the convalescent responses we observed. CONCLUSIONS: In summary, in our cohort, nAb titers after SARS-CoV-2 infection peaked approximately 1 month post-diagnosis and varied by age, sex assigned at birth, disease severity, and underlying comorbidities. Our data show great heterogeneity in nAb responses among people with recent COVID-19, highlighting the challenges of interpreting natural history studies and gauging responses to vaccines and therapeutics among people with recent infection. Our observations illuminate potential correlations of demographic and clinical characteristics with nAb responses, a key element for protection from COVID-19, thus informing development and implementation of preventative and therapeutic strategies globally. TRIAL REGISTRATION: ClinicalTrials.gov NCT04403880.

Underutilization and Quality Gaps in Blood Culture Processing in Public Hospitals of Peru.

Correct processing of blood cultures may impact individual patient management, antibiotic stewardship, and scaling up of antimicrobial resistance surveillance. To assess the quality of blood culture processing, we conducted four assessments at 16 public hospitals across different regions of Peru. We assessed the following standardized quality indicators: 1) positivity and contamination rates, 2) compliance with recommended number of bottles/sets and volume of blood sampled, 3) blood culture utilization, and 4) possible barriers for compliance with recommendations. Suboptimal performance was found, with a median contamination rate of 4.2% (range 0-15.1%), with only one third of the participating hospitals meeting the target value of < 3%; and a median positivity rate of 4.9% (range 1-8.1%), with only 6 out of the 15 surveilled hospitals meeting the target of 6-12%. None of the assessed hospitals met both targets. The median frequency of solitary blood cultures was 71.9% and only 8.9% (N = 59) of the surveyed adult bottles met the target blood volume of 8 - 12 mL, whereas 90.5% (N = 602) were underfilled. A high frequency of missed opportunities for ordering blood cultures was found (69.9%, 221/316) among patients with clinical indications for blood culture sampling. This multicenter study demonstrates important shortcomings in the quality of blood culture processing in public hospitals of Peru. It provides a national benchmark of blood culture utilization and quality indicators that can be used to monitor future quality improvement studies and diagnostic stewardship policies.

AIDSVAX protein boost improves breadth and magnitude of vaccine-induced HIV-1 envelope-specific responses after a 7-year rest period.

BACKGROUND: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses. METHODS: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5). RESULTS: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag. CONCLUSIONS: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine.

Maternal postpartum deworming and infant milk intake: Secondary outcomes from a trial.

The World Health Organization recommends deworming to reduce soil-transmitted helminth (STH)-attributable morbidity in women of reproductive age, including pregnant and lactating women, to reduce blood loss, iron deficiency anaemia and nutrient malabsorption. This study assessed the impact of maternal postpartum deworming with albendazole approximately 1 day after delivery on infant milk intake among a subset of 216 randomly selected mother-infant pairs recruited into a large trial in Peru. Infant milk intake was measured using the deuterium-oxide method at 1- and 6-month postpartum. Maternal STH infection was measured at 6-month postpartum. At 1-month postpartum, mean intake was 756 ± 16 and 774 ± 18 mL day-1 in the albendazole and placebo groups, respectively (mean difference: -18 mL day-1 ; 95% CI: -65, 30). At 6-month postpartum, mean intake was 903 ± 16 and 908 ± 18 mL day-1 in the albendazole and placebo groups, respectively (mean difference: -5 mL day-1 ; 95% CI: -52, 43). There was no statistically significant difference in milk intake between groups at either time point. At 6-month postpartum, mothers infected with Trichuris trichiura had infants with higher milk intakes (adjusted mean difference: 70 mL day-1 ; 95% CI: 20, 120) compared with uninfected mothers. However, there was no statistically significant difference in infant milk intake between mothers who had moderate-and-heavy intensity infection compared with the comparison group (mothers with no and light intensity infection). A lower prevalence and intensity of infection, and inclusion of uninfected mothers in both arms of the trial, resulting in effect dilution, may explain the null findings.

Ruling out early trimester pregnancy when implementing community-based deworming programs.

BACKGROUND: Large-scale deworming programs have, to date, mostly targeted preschool- and school-age children. As community-based deworming programs become more common, deworming will be offered to women of reproductive age. The World Health Organization recommends preventive chemotherapy be administered to pregnant women only after the first trimester. It is therefore important for deworming programs to be able to identify women in early pregnancy. Our objective was to validate a short questionnaire which could be used by deworming program managers to identify and screen out women in early pregnancy. METHODOLOGY/PRINCIPAL FINDINGS: In May and June 2018, interviewers administered a questionnaire, followed by a pregnancy test, to 1,203 adult women living in the Peruvian Amazon. Regression analyses were performed to identify questions with high predictive properties (using the pregnancy test as the gold standard). Test parameters were computed at different decision tree nodes (where nodes represented questions). With 106 women confirmed to be pregnant, the positive predictive value of asking the single question 'Are you pregnant?' was 100%, at a 'cost' of a false negative rate of 1.9% (i.e. 21 women were incorrectly identified as not pregnant when they were truly pregnant). Additional questions reduced the false negative rate, but increased the false positive rate. Rates were dependent on both the combination and the order of questions. CONCLUSIONS/SIGNIFICANCE: To identify women in early pregnancy when deworming programs are community-based, both the number and order of questions are important. The local context and cultural acceptability of different questions should inform this decision. When numbers are manageable and resources are available, pregnancy tests can be considered at different decision tree nodes to confirm pregnancy status. Trade-offs in terms of efficiency and misclassification rates will need to be considered to optimize deworming coverage in women of reproductive age.

Antigenic competition in CD4+ T cell responses in a randomized, multicenter, double-blind clinical HIV vaccine trial.

T cell responses have been implicated in reduced risk of HIV acquisition in uninfected persons and control of viral replication in HIV-infected individuals. HIV Gag-specific T cells have been predominantly associated with post-infection control, whereas Env antigens are the target for protective antibodies; therefore, inclusion of both antigens is common in HIV vaccine design. However, inclusion of multiple antigens may provoke antigenic competition, reducing the potential effectiveness of the vaccine. HVTN 084 was a randomized, multicenter, double-blind phase 1 trial to investigate whether adding Env to a Gag/Pol vaccine decreases the magnitude or breadth of Gag/Pol-specific T cell responses. Fifty volunteers each received one intramuscular injection of 1 × 1010 particle units (PU) of rAd5 Gag/Pol and EnvA/B/C (3:1:1:1 mixture) or 5 × 109 PU of rAd5 Gag/Pol. CD4+ T cell responses to Gag/Pol measured 4 weeks after vaccination by cytokine expression were significantly higher in the group vaccinated without Env, whereas CD8+ T cell responses did not differ significantly between the two groups. Mapping of individual epitopes revealed greater breadth of the Gag/Pol-specific T cell response in the absence of Env compared to Env coimmunization. Addition of an Env component to a Gag/Pol vaccine led to reduced Gag/Pol CD4+ T cell response rate and magnitude as well as reduced epitope breadth, confirming the presence of antigenic competition. Therefore, T cell-based vaccine strategies should aim at choosing a minimalist set of antigens to reduce interference of individual vaccine components with the induction of the maximally achievable immune response.

Evaluating the impact of policies recommending PrEP to subpopulations of men and transgender women who have sex with men based on demographic and behavioral risk factors.

INTRODUCTION: Developing guidelines to inform the use of antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention in resource-limited settings must necessarily be informed by considering the resources and infrastructure needed for PrEP delivery. We describe an approach that identifies subpopulations of cisgender men who have sex with men (MSM) and transgender women (TGW) to prioritize for the rollout of PrEP in resource-limited settings. METHODS: We use data from the iPrEx study, a multi-national phase III study of PrEP for HIV prevention in MSM/TGW, to build statistical models that identify subpopulations at high risk of HIV acquisition without PrEP, and with high expected PrEP benefit. We then evaluate empirically the population impact of policies recommending PrEP to these subpopulations, and contrast these with existing policies. RESULTS: A policy recommending PrEP to a high risk subpopulation of MSM/TGW reporting condomless receptive anal intercourse over the last 3 months (estimated 3.3% 1-year HIV incidence) yields an estimated 1.95% absolute reduction in 1-year HIV incidence at the population level, and 3.83% reduction over 2 years. Importantly, such a policy requires rolling PrEP out to just 59.7% of MSM/TGW in the iPrEx population. We find that this policy is identical to that which prioritizes MSM/TGW with high expected PrEP benefit. It is estimated to achieve nearly the same reduction in HIV incidence as the PrEP guideline put forth by the US Centers for Disease Control, which relies on the measurement of more behavioral risk factors and which would recommend PrEP to a larger subset of the MSM/TGW population (86% vs. 60%). CONCLUSIONS: These findings may be used to focus future mathematical modelling studies of PrEP in resource-limited settings on prioritizing PrEP for high-risk subpopulations of MSM/TGW. The statistical approach we took could be employed to develop PrEP policies for other at-risk populations and resource-limited settings.

Bayesian Methods for Exposure Misclassification Adjustment in a Mediation Analysis: Hemoglobin and Malnutrition in the Association Between Ascaris and IQ.

BACKGROUND: Soil-transmitted helminth infections have been found to be associated with child development. The objective was to investigate hemoglobin levels and malnutrition as mediators of the association between Ascaris infection and intelligence quotient (IQ) scores in children. METHODS: We conducted a longitudinal cohort study in Iquitos, Peru, between September 2011 and July 2016. A total of 1760 children were recruited at 1 year of age and followed up annually to 5 years. We measured Ascaris infection and malnutrition at each study visit, and hemoglobin levels were measured as of age 3. The exposure was defined as the number of detected Ascaris infections between age 1 and 5. We measured IQ scores at age 5 and used Bayesian models to correct exposure misclassification. RESULTS: We included a sample of 781 children in the analysis. In results adjusted for Ascaris misclassification, mean hemoglobin levels mediated the association between Ascaris infection and IQ scores. The natural direct effects (not mediated by hemoglobin) (95% CrI) and natural indirect effects (mediated by hemoglobin) (95% CrI) were compared with no or one infection: -0.9 (-4.6, 2.8) and -4.3 (-6.9, -1.6) for the effect of two infections; -1.4 (-3.8, 1.0) and -1.2 (-2.0, -0.4) for three infections; and -0.4 (-3.2, 2.4) and -2.7 (-4.3, -1.0) for four or five infections. CONCLUSION: Our results are consistent with the hypothesis that hemoglobin levels mediate the association between Ascaris infection and IQ scores. Additional research investigating the effect of including iron supplements in STH control programs is warranted.

Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax. METHODS: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia. RESULTS: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention. CONCLUSIONS: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).

Tafenoquine versus Primaquine to Prevent Relapse of Plasmodium vivax Malaria.

BACKGROUND: Tafenoquine, a single-dose therapy for Plasmodium vivax malaria, has been associated with relapse prevention through the clearance of P. vivax parasitemia and hypnozoites, termed "radical cure." METHODS: We performed a phase 3, prospective, double-blind, double-dummy, randomized, controlled trial to compare tafenoquine with primaquine in terms of safety and efficacy. The trial was conducted at seven hospitals or clinics in Peru, Brazil, Colombia, Vietnam, and Thailand and involved patients with normal glucose-6-phosphate dehydrogenase (G6PD) enzyme activity and female patients with moderate G6PD enzyme deficiency; all patients had confirmed P. vivax parasitemia. The patients were randomly assigned, in a 2:1 ratio, to receive a single 300-mg dose of tafenoquine or 15 mg of primaquine once daily for 14 days (administered under supervision); all patients received a 3-day course of chloroquine and were followed for 180 days. The primary safety outcome was a protocol-defined decrease in the hemoglobin level (>3.0 g per deciliter or ≥30% from baseline or to a level of <6.0 g per deciliter). Freedom from recurrence of P. vivax parasitemia at 6 months was the primary efficacy outcome in a planned patient-level meta-analysis of the current trial and another phase 3 trial of tafenoquine and primaquine (per-protocol populations), and an odds ratio for recurrence of 1.45 (tafenoquine vs. primaquine) was used as a noninferiority margin. RESULTS: A protocol-defined decrease in the hemoglobin level occurred in 4 of 166 patients (2.4%; 95% confidence interval [CI], 0.9 to 6.0) in the tafenoquine group and in 1 of 85 patients (1.2%; 95% CI, 0.2 to 6.4) in the primaquine group, for a between-group difference of 1.2 percentage points (95% CI, -4.2 to 5.0). In the patient-level meta-analysis, the percentage of patients who were free from recurrence at 6 months was 67.0% (95% CI, 61.0 to 72.3) among the 426 patients in the tafenoquine group and 72.8% (95% CI, 65.6 to 78.8) among the 214 patients in the primaquine group. The efficacy of tafenoquine was not shown to be noninferior to that of primaquine (odds ratio for recurrence, 1.81; 95% CI, 0.82 to 3.96). CONCLUSIONS: Among patients with normal G6PD enzyme activity, the decline in hemoglobin level with tafenoquine did not differ significantly from that with primaquine. Tafenoquine showed efficacy for the radical cure of P. vivax malaria, although tafenoquine was not shown to be noninferior to primaquine. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; GATHER ClinicalTrials.gov number, NCT02216123 .).