BACKGROUND:While vaccine antigen-induced antibodies are often used as proxies for vaccine efficacy, immune responses to vaccine vectors are less well-defined. We describe the kinetics of immunoglobulin (IgG) responses against the vector (vesicular stomatitis Indiana virus [VSIV]) nucleoprotein (N) and the inserted antigen (Ebola virus [EBOV]) glycoprotein (GP1,2) components of the rVSV-ZEBOV vaccine and evaluate their use as biomarkers to confirm self-reported vaccination status. METHODS:We selected 212 participants randomized to rVSV-ZEBOV (n = 107) or placebo (n = 105). Levels of IgG antibodies to EBOV GP1,2 or VSIV N were measured using an enzyme-linked immunosorbent assay and a newly developed single-molecule array (Simoa) immunoassay, respectively. RESULTS:Anti-EBOV GP1,2 and anti-VSIV N IgG were first detected 10-14 days postvaccination, further increased at 28 days, and remained stable through 360 days. Antibody titers were significantly correlated (P < 0.001) at 28 days (r = 0.47), 180 days (r = 0.45), and 360 days (r = 0.59). At 28 days, the area under the receiver operating characteristic curve (AUC) discriminated vaccinated from unvaccinated patients with high accuracy (AUC = 0.965 for anti-VSIV N IgG; AUC = 0.945 for anti-EBOV GP1,2 IgG [P < 0.001]). CONCLUSIONS:We report a reliable assay to measure vector-induced humoral responses after rVSV-ZEBOV vaccination and demonstrate the assay's utility to confirm vaccination status.

Background Despite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID). Methods Clinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes. Results Average participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model. Conclusions We discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches.

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective. Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available. Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area.

BACKGROUND:Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter Adaptive COVID-19 Treatment Trial 1, which randomized patients to remdesivir or placebo. METHODS:Longitudinal specimens collected during hospitalization from a substudy of 642 patients with COVID-19 were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed. RESULTS:Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95% CI, 1.40-2.71) for levels >245 pg/mL vs 1.04 (95% CI, .76-1.42) for levels <245 pg/mL. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive. CONCLUSIONS:Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy. CLINICAL TRIAL REGISTRATION:NCT04280705 (ClinicalTrials.gov).

A subset of antiretroviral therapy-treated persons with human immunodeficiency virus (HIV), referred to as immunological nonresponders (INRs), fails to normalize CD4+ T-cell numbers. In a case-control study involving 26 INRs (CD4 < 250 cells/µL) and 25 immunological responders (IRs; CD4 ≥ 250 cells/µL), we evaluated the potential contribution of transcriptionally competent defective HIV-1 proviruses to poor CD4+ T-cell recovery. Compared to the responders, the INRs had higher levels of cell-associated HIV RNA (P = .034) and higher percentages of HLA-DR+ CD4+ T cells (P < .001). While not encoding replication-competent viruses, the RNA transcripts frequently encoded HIV-1 Gag-p17 and Nef proteins. These transcripts and/or resulting proteins may activate pathway(s) leading to the immunological nonresponse phenotype.

In 1970, the first case of mpox (formerly known as monkeypox) was documented in an infant in Equateur Province, Democratic Republic of Congo (DRC).1 Infections with clade I monkeypox virus (MPXV) are endemic in the rainforest regions of central Africa and result from both zoonotic and human-to-human transmission. The cessation of smallpox vaccination in 1980 because of the eradication of smallpox has led to an increase in the number of individuals who are orthopox immune naïve and is felt to be responsible for a recent increase in mpox cases in the DRC. Comparisons of active surveillance in Sankuru Province from 2005 through 2007 revealed a 20-fold increase in the incidence of mpox compared with the 1980s, with a 5-fold-lower incidence among those with a smallpox vaccination scar.2.

BACKGROUND:rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation. METHODS:In this open-label phase 2 randomised controlled trial, we compared antibody titres at month 36 in participants who had received a homologous booster dose at month 18 following primary immunisation with those who had received no booster. From Oct 25, 2016, to Jan 29, 2020, healthy adults aged 18 years or older deemed at occupational risk of exposure to Ebola virus due to laboratory work, clinical duties, or travel to an active endemic region were recruited from four hospital clinics in the USA and one hospital clinic in Canada and received primary vaccination with 2×107 plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18 months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18 months after randomisation) for all randomly assigned participants who completed the 36 months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18 but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227). FINDINGS:Of the 248 participants who enrolled and received their primary immunisation, 114 proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57 participants (24 [42%] of whom were female; median age was 42 years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42 years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92 participants (45 in the booster group and 47 in the no-booster group) completed 36 months of follow-up. At 18 months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10 ELISA units (EU)/mL (95% CI 7-14) to 1451 EU/mL (1118-1882); GMTs in the booster group increased from 9 EU/mL (6-16) to 1769 EU/mL (1348-2321). At month 19, GMTs were 31 408 EU/mL (23 181-42 554) for the booster group and 1406 EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146 EU/mL (7960-12 933) for the booster group and 1240 EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1 month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207 primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%) of 57 participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment. INTERPRETATION:In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18 resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18 months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure. FUNDING:The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency.

Introduction There remains a need to better identify patients at highest risk for developing severe Coronavirus Disease 2019 (COVID-19) as additional waves of the pandemic continue to impact hospital systems. We sought to characterize the association of receptor for advanced glycation end products (RAGE), SARS-CoV-2 nucleocapsid viral antigen, and a panel of thromboinflammatory biomarkers with development of severe disease in patients presenting to the emergency department with symptomatic COVID-19. Methods Blood samples were collected on arrival from 77 patients with symptomatic COVID-19, and plasma levels of thromboinflammatory biomarkers were measured. Results Differences in biomarkers between those who did and did not develop severe disease or death 7 days after presentation were analyzed. After adjustment for multiple comparisons, RAGE, SARS-CoV-2 nucleocapsid viral antigen, interleukin (IL)-6, IL-10 and tumor necrosis factor receptor (TNFR)-1 were significantly elevated in the group who developed severe disease (all p<0.05). In a multivariable regression model, RAGE and SARS-CoV-2 nucleocapsid viral antigen remained significant risk factors for development of severe disease (both p<0.05), and each had sensitivity and specificity >80% on cut-point analysis. Discussion Elevated RAGE and SARS-CoV-2 nucleocapsid viral antigen on emergency department presentation are strongly associated with development of severe disease at 7 days. These findings are of clinical relevance for patient prognostication and triage as hospital systems continue to be overwhelmed. Further studies are warranted to determine the feasibility and utility of point-of care measurements of these biomarkers in the emergency department setting to improve patient prognostication and triage.

Even before the coronavirus disease 2019 pandemic, infections were a major threat to human health, as the third leading cause of death and the leading cause of morbidity among all human diseases. Although conventional imaging studies are routinely used for patients with infections, they provide structural or anatomic information only. Molecular imaging technologies enable noninvasive visualization of molecular processes at the cellular level within intact living subjects, including patients, and hold great potential for infections. We hope that this supplement will spur interest in the field and establish new collaborations to develop and translate novel molecular imaging approaches to the clinic.

Effective outbreak preparedness and response requires products available in sufficient quantities and delivered where and when needed. Clearly, providing prompt diagnosis and health care is challenging in the Democratic Republic of the Congo and other Ebola virus disease-epidemic countries, as stated by Olivier Mbaya and colleagues; less than a third of the 181 people who had Ebola virus disease during 2020–22 had received mAb-114 or REGN-EB3.1Crozier I Britson KA Wolfe DN et al.The evolution of medical countermeasures for Ebola virus disease: lessons learned and next steps.Vaccines. 2022; 101213Crossref Scopus (4) Google Scholar But, despite the commitment of leading research organisations such as the Congolese Institut National de Recherche Biomédicale and the US National Institutes of Health, relying on remaining drugs from trial batches under expanded access use, without formal regulatory authorisation and with limited supply channels falls short of being a satisfactory, sustainable solution, for the Democratic Republic of the Congo and more broadly, patients with Ebola virus disease in all at-risk countries. Should a major outbreak happen tomorrow in Africa, there will be no readily available stocks of either products with regulatory approval by local or regional health authorities to roll out swiftly. There is also no clear pathway for local authorities or emergency first responders such as WHO and Médecins Sans Frontières to purchase and deliver these treatments where needed. As documented in our Personal View,2Torreele E Boum Y Adjaho I et al.Breakthrough treatments for Ebola virus disease, but no access-what went wrong, and how can we do better?.Lancet Infect Dis. 2023; (published online Jan 19.)https://doi.org/10.1016/S1473-3099(22)00810-6Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar safety and efficacy evidence obtained collectively through the PALM clinical trial3Mulangu S Dodd LE Davey Jr, RT et al.A randomized, controlled trial of Ebola virus disease therapeutics.N Engl J Med. 2019; 381: 2293-2303Crossref PubMed Scopus (973) Google Scholar was handed over to the pharmaceutical companies Ridgeback and Regeneron, which then registered these treatments with the US Food and Drug Administration in 2020, and also enjoyed a lucrative priority review voucher. However, these companies did not do their part to enable affordable access, nor did any of the organisations in charge of the PALM trial set in place the right conditions for these research and licencing collaborations to guarantee timely availability and access. Ridgeback is understood to have no capacity to produce mAb-114 before 2024 at the earliest, and Regeneron's REGN-EB3 is stockpiled by the US government.4RegeneronPress release July 2020: Barda procures Regeneron's REGN-EB3 investigational Ebola treatment for national preparedness.https://investor.regeneron.com/news-releases/news-release-details/barda-procures-regenerons-regn-eb3-investigational-ebolaDate: Feb 19, 2023Google Scholar This situation epitomises the limitations of relying on goodwill and charity approaches for epidemic preparedness, and the need for an enforceable end-to-end approach that includes access from start.2Torreele E Boum Y Adjaho I et al.Breakthrough treatments for Ebola virus disease, but no access-what went wrong, and how can we do better?.Lancet Infect Dis. 2023; (published online Jan 19.)https://doi.org/10.1016/S1473-3099(22)00810-6Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar When issuing its Ebola virus disease treatment guidelines in August, 2022, WHO expressed concerns that access to these therapeutics is challenging and pricing and future supply remain unknown, and even warned that this strong recommendation could exacerbate health inequity.5WHOTherapeutics for Ebola virus disease.https://www.who.int/publications/i/item/9789240055742Date: 19 August 2022Date accessed: March 6, 2023Google Scholar It is time for the international community and for national authorities of the affected countries to step up efforts to complete the unfinished agenda, and ensure equitable access to Ebola treatments where and when needed, reflecting the collective effort many organisations have put into their development, including setting up and conducting a very challenging clinical trial. Building on lessons learnt from COVID-19, these efforts should include exploring technology transfer and local production of these life-saving health technologies, for greater autonomy and resilience in the region. We declare no competing interests. On the importance and challenges of global access to proven life-saving treatments for EbolavirusAs noted by Els Torreele and colleagues,1 among the key ethical standards of medical research is the principle that communities who participate in research receive benefit from the results of that research.2 Providing breakthrough therapies to patients who can benefit from them is a crucial mandate, requiring global coordination to address logistical challenges of product access, distribution, and administration that often arise in low-resource settings. Full-Text PDF Breakthrough treatments for Ebola virus disease, but no access—what went wrong, and how can we do better?Three years since proving effective for Ebola virus disease in a clinical trial, two breakthrough treatments are registered and stockpiled in the USA but still not registered and generally available in the countries most affected by this deadly infection of epidemic potential. Analysing the reasons for this, we see a fragmentation of the research and development value chain, with different stakeholders taking on different steps of the research and development process, without the public health-focused leadership needed to ensure the end goal of equitable access in countries where Ebola virus disease is prevalent. Full-Text PDF

Investment, collaboration, and coordination have been key

BACKGROUND For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Objectives:People with HIV-1 (PWH) on effective antiretroviral therapy (ART) continue to exhibit chronic systemic inflammation, immune activation, and persistent elevations in markers of HIV-1 infection [including HIV-DNA, cell-associated HIV-RNA (CA HIV-RNA), and antibodies to HIV-1 proteins] despite prolonged suppression of plasma HIV-RNA levels less than 50 copies/ml. Here, we investigated the hypothesis that nonreplicating but transcriptionally and translationally competent 'defective' HIV-1 proviruses may be one of drivers of these phenomena.Design:A combined cohort of 23 viremic and virologically suppressed individuals on ART were studied.Methods:HIV-DNA, CA HIV-RNA, western blot score (measure of anti-HIV-1 antibodies as a surrogate for viral protein expression in vivo), and key biomarkers of inflammation and coagulation (IL-6, hsCRP, TNF-alpha, tissue factor, and D-dimer) were measured in peripheral blood and analyzed using a combined cross-sectional and longitudinal approaches. Sequences of HIV-DNA and CA HIV-RNA obtained via 5'-LTR-to-3'-LTR PCR and single-genome sequencing were also analyzed.Results:We observed similar long-term persistence of multiple, unique, transcriptionally active 'defective' HIV-1 provirus clones (average: 11 years., range: 4-20 years) and antibody responses against HIV-1 viral proteins among all ART-treated participants evaluated. A direct correlation was observed between the magnitude of HIV-1 western blot score and the levels of transcription of 'defective' HIV-1 proviruses (r = 0.73, P < 0.01). Additional correlations were noted between total CD8(+) T-cell counts and HIV-DNA (r = 0.52, P = 0.01) or CA HIV-RNA (r = 0.65, P < 0.01).Conclusion:These findings suggest a novel interplay between transcription and translation of 'defective' HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.

Background: The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants may have contributed to prolonging the pandemic, and increasing morbidity and mortality related to coronavirus disease 2019 (COVID-19). This article describes the dynamics of circulating SARS-CoV-2 variants identified during the different COVID-19 waves in Mali between April and October 2021. Methods: The respiratory SARS-CoV-2 complete spike (S) gene from positive samples was sequenced. Generated sequences were aligned by Variant Reporter v3.0 using the Wuhan-1 strain as the reference. Mutations were noted using the GISAID and Nextclade platforms. Results: Of 16,797 nasopharyngeal swab samples tested, 6.0% (1008/16,797) tested positive for SARS-CoV-2 on quantitative reverse transcription polymerase chain reaction. Of these, 16.07% (162/1008) had a cycle threshold value <= 28 and were amplified and sequenced. The complete S gene sequence was recovered from 80 of 162 (49.8%) samples. Seven distinct variants were identified: Delta (62.5%), Alpha (1.2%), Beta (1.2%), Eta (30.0%), 20B (2.5%), 19B (1.2%) and 20A (1.2%). Conclusions and perspectives: Several SARS-CoV-2 variants were present during the COVID-19 waves in Mali between April and October 2021. The continued emergence of new variants highlights the need to strengthen local real-time sequencing capacity and genomic surveillance for better and coordinated national responses to SARS-CoV-2.

Background Discrimination of bacterial and viral etiologies of childhood community-acquired pneumonia (CAP) is often challenging. Unnecessary antibiotic administration exposes patients to undue risks and may engender antimicrobial resistance. This study aimed to develop a prediction model using epidemiological, clinical and laboratory data to differentiate between bacterial and viral CAP. Methods Data from 155 children with confirmed bacterial or mixed bacterial and viral infection ( N = 124) and viral infection ( N = 31) were derived from a comprehensive assessment of causative pathogens [Partnerships for Enhanced Engagement in Research-Pneumonia in Pediatrics (PEER-PePPeS)] conducted in Indonesia. Epidemiologic, clinical and biomarker profiles (hematology and inflammatory markers) were compared between groups. The area under the receiver operating characteristic curve (AUROC) for varying biomarker levels was used to characterize performance and determine cut-off values for discrimination of bacterial and mixed CAP versus viral CAP. Diagnostic predictors of bacterial and mixed CAP were assessed by multivariate logistic regression. Results Diarrhea was more frequently reported in bacterial and mixed CAP, while viral infections more frequently occurred during Indonesia’s rainy season. White blood cell counts (WBC), absolute neutrophil counts (ANC), neutrophil-lymphocyte ratio (NLR), C-reactive protein (CRP), and procalcitonin (PCT) were significantly higher in bacterial and mixed cases. After adjusting for covariates, the following were the most important predictors of bacterial or mixed CAP: rainy season (aOR 0.26; 95% CI 0.08–0.90; p = 0.033), CRP ≥5.70 mg/L (aOR 4.71; 95% CI 1.18–18.74; p = 0.028), and presence of fever (aOR 5.26; 95% CI 1.07–25.91; p = 0.041). The model assessed had a low R-squared (Nagelkerke R 2 = 0.490) but good calibration ( p = 0.610 for Hosmer Lemeshow test). The combination of CRP and fever had moderate predictive value with sensitivity and specificity of 62.28 and 65.52%, respectively. Conclusion Combining clinical and laboratory profiles is potentially valuable for discriminating bacterial and mixed from viral pediatric CAP and may guide antibiotic use. Further studies with a larger sample size should be performed to validate this model.

Background There is an incompletely understood increased risk for cardiovascular disease (CVD) among people with HIV (PWH). We investigated if a collection of biomarkers were associated with CVD among PWH. Mendelian randomization (MR) was used to identify potentially causal associations. Methods Data from follow-up in 4 large trials among PWH were used to identify 131 incident CVD cases and they were matched to 259 participants without incident CVD (controls). Tests of associations between 460 baseline protein levels and case status were conducted. Results Univariate analysis found CLEC6A, HGF, IL-6, IL-10RB, and IGFBP7 as being associated with case status and a multivariate model identified 3 of these: CLEC6A (odds ratio [OR] = 1.48, P = .037), HGF (OR = 1.83, P = .012), and IL-6 (OR = 1.45, P = .016). MR methods identified 5 significantly associated proteins: AXL, CHI3L1, GAS6, IL-6RA, and SCGB3A2. Conclusions These results implicate inflammatory and fibrotic processes as contributing to CVD. While some of these biomarkers are well established in the general population and in PWH (IL-6 and its receptor), some are novel to PWH (HGF, AXL, and GAS6) and some are novel overall (CLEC6A). Further investigation into the uniqueness of these biomarkers in PWH and the role of these biomarkers as targets among PWH is warranted.

In the last 100 years, the world has experienced four influenza pandemics, with an occurrence every 15-30 years resulting in an annual probability of 3% to 7% [1].More recently, other pathogens including SARS, MERS, and the recent SARS CoV-2, have stressed the need to improve pandemic preparedness and response capabilities.Developing strategies to promote robust basic and applied research with continuous monitoring of the human/ animal interface to generate new knowledge applicable to public health policies and measures is critical to enhancing rapid responses to these outbreaks.Early detection and fast response to an epidemic or pandemic can be improved through an effective communication structure between countries worldwide.Such a structure should include strategically placed clinical research programmes and associated infrastructures.

Background There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. Methods TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 x 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 x 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. Findings Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1 & BULL;11 (95% CI 0 & BULL;80-1 & BULL;55; p=0 & BULL;54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1 & BULL;04, 95% CI 0 & BULL;77-1 & BULL;41; p=0 & BULL;78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1 & BULL;40, 95% CI 0 & BULL;94-2 & BULL;08; p=0 & BULL;10).

The failure to develop effective vaccines and therapeutics for pathogens of high consequence pre-emptively was recognised during the 2014–15 outbreak of Zaire Ebola virus disease in west Africa. The world was unarmed to confront the outbreak despite discovery of the virus in 1976 and a history of repeated subsequent outbreaks. The consequences were dire, with high morbidity and mortality, economic disruption, and global threats.1WHOWHO Statement on the 1st meeting of the IHR Emergency Committee on the 2014 Ebola outbreak in West Africa. World Health Organization, Geneva2014Google Scholar, 2Dixon MG Schafer IJ Ebola viral disease outbreak—West Africa, 2014.MMWR Morb Mortal Wkly Rep. 2014; 63: 548-551PubMed Google Scholar Although three of the five species of Ebola virus (Zaire, Bundibugyo, and Sudan) are associated with large outbreaks in Africa, advanced global research and development has primarily focused on the Zaire strain.3Laupland KB Valiquette L Ebola virus disease.Can J Infect Dis Med Microbiol. 2014; 25: 128-129Crossref PubMed Scopus (31) Google Scholar The costly price of this strategy was reflected in the recent Sudan Ebola virus outbreak in Uganda, where countermeasures were inadequate.4Lucey DR New Uganda Sudan ebolavirus outbreak means FDA-licensed vaccine for Zaire ebolavirus cannot be used.https://www.idsociety.org/science-speaks-blog/2022/new-uganda-sudan-ebolavirus-outbreak-means-fda-licensed-vaccine-for-zaire-ebolavirus-cannot-be-used/#/+/0/publishedDate_na_dt/desc/Date: Sept 21, 2022Date accessed: December 18, 2022Google Scholar Here, we describe key lessons learned during the establishment of a rapid clinical research infrastructure in Liberia to assess the benefits of therapeutic and vaccine candidates during the 2014–15 outbreak of Ebola virus disease in west Africa to inform strategies for research during outbreaks.5Kamradt-Scott A Harman S Wenham C Smith 3rd, F Civil–military cooperation in Ebola and beyond.Lancet. 2016; 387: 104-105Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar In Liberia and the USA, strong political leadership at the highest level initiated the entire process for the establishment of the clinical research infrastructure in the country to assess the vaccine and therapeutic candidates for Ebola virus disease during the 2014–15 outbreak. The champions were the then Minister of Health and Social Welfare of Liberia, the late Walter Gwenigale; the former US Ambassador to Liberia, Deborah Malac; and the former US Secretary of Health and Human Services, Sylvia M Burwell. The US National Institute of Allergy and Infectious Diseases (NIAID) partnered with the Liberian Ministry of Health and Social Welfare to develop a research programme to study two experimental vaccines, rVSV and ChAd3, and the monoclonal antibody ZMapp.6Kennedy SB Bolay F Kieh M et al.Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia.N Engl J Med. 2017; 377: 1438-1447Crossref PubMed Scopus (164) Google Scholar Alignment of research priorities was essential. With a potentially limited time window and an urgency to assess the benefits of investigational vaccines, a decision was taken to use the existing phase 1 trial data to move to a combined phase 2/3 trial. Once it (fortunately) became clear that the outbreak was coming under control through standard public health measures, the study was converted to a pure phase 2 trial with concurrence from the international Data and Safety Monitoring Board. These decisions showed mutual respect and trust between the USA (NIAID) and Liberia, with an alignment on joint research priorities. Similar considerations could be appropriate in other outbreaks. Building a partnership between US and local experts enabled the research to operate smoothly within an organisational and governance structure that was created with the USA. The Ambassador to Liberia, Malac, and Liberian Minister of Health and Social Welfare, Gwenigale, were the key decision makers. A buddy system was created, with US scientists from the National Institutes of Health and their Liberian counterparts assigned to supervise different functions of the research. These functions were data information and technology, pharmacy, site development and management, protocol development, laboratory, training, regulatory and ethics, and social mobilisation and communication teams (figure). The research partnership was initially named the Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) and involved multiple face-to-face and virtual meetings to plan and execute the research. Leveraging existing capabilities from the Ebola response structures was an essential element for the rapid establishment of the clinical research activities. The Liberia Institute for Biomedical Research that was destroyed by the 14-year Liberian civil war had been upgraded with support from the US Government to be used as a research laboratory for Ebola diagnostics. It was also converted to being able to store and test blood samples from the research participants. Liberian scientists and experts who were supporting the Ebola response joined the research enterprise. Focusing efforts on social mobilisation and communication, and community engagement was crucial in minimising the fear and distrust towards experimental vaccines. The PREVAIL team leveraged the existing social mobilisation and community engagement pillar that was used during the Ebola response to overcome the initial resistance to any new effort to contain the outbreak. These initial fears, distrust, and resistance to all Ebola response activities were precipitated by pre-existing distrust in government, traditional practices, media disinformation, and certain cultural beliefs and norms. However, these were eventually overcome by the implementation of well structured social mobilisation, community engagement, and communication strategies, which contributed substantially to the successful recruitment of participants for the vaccine trial. Similar challenges with any new research effort in any environment, regardless of the country, have been seen during the COVID-19 pandemic. Negotiating the ethical and regulatory hurdles governing the clinical trial required navigating politics and dealing with polarising fears and misinformation fuelled by the media and civil society. At one point, the Ministry of Justice put an injunction on the clinical trial, and it took the then Liberian Vice President, Joseph Boakai, to politically resolve the impasse. As a result, the capacity of the Liberia Medicines and Health Regulatory Authority and the National Research Ethics Board were strengthened to meet international standards. In Liberia, we lost the element of speed and, therefore, were not able to reap the full benefits of clinical trials during outbreaks. The first visit of NIAID to Liberia was in early October, 2014. However, the dose for the vaccine study was not finalised until the end of January, 2015, with the first patient enrolled on Feb 2, 2015. As a result, a phase 3 efficacy trial was not able to be conducted (appendix); however, the preliminary safety and immunogenicity data from the Liberian trial were able to help inform the ring trial in Guinea,7Gsell PS Camacho A Kucharski AJ et al.Ring vaccination with rVSV-ZEBOV under expanded access in response to an outbreak of Ebola virus disease in Guinea, 2016: an operational and vaccine safety report.Lancet Infect Dis. 2017; 17: 1276-1284Summary Full Text Full Text PDF PubMed Scopus (67) Google Scholar which eventually led to licensure of the first Ebola Zaire vaccine. Following the 2014–15 Ebola virus outbreak, clinical research has become a critical response strategy during pandemics and epidemics, as evidenced in the licensure and use of vaccines and therapeutics such as ERVEBO, REGN-EB3, mAb114,6Kennedy SB Bolay F Kieh M et al.Phase 2 placebo-controlled trial of two vaccines to prevent Ebola in Liberia.N Engl J Med. 2017; 377: 1438-1447Crossref PubMed Scopus (164) Google Scholar, 9Roby C 5 experimental treatments introduced in latest DRC Ebola outbreak.https://www.devex.com/news/5-experimental-treatments-introduced-in-latest-drc-ebola-outbreak-93303Date: Aug 17, 2018Date accessed: December 18, 2022Google Scholar, 10National Academies of Sciences, Engineering, and MedicineIntegrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017Google Scholar, 11Lévy Y Lane C Piot P et al.Prevention of Ebola virus disease through vaccination: where we are in 2018.Lancet. 2018; 392: 787-790Summary Full Text Full Text PDF PubMed Scopus (47) Google Scholar remdesivir, dexamethasone, and nirmatrelvir-ritonavir. A review of the west African research response by the US National Academies concluded that science and ethics do not change during an outbreak and that adequately powered, randomised controlled trials are the quickest way to get the most effective countermeasures to the largest number of people in the shortest period of time. These lessons can be transferred to subsequent outbreaks to help determine the safety and efficacy of experimental countermeasures. We declare no competing interests. Download .pdf (.19 MB) Help with pdf files Supplementary appendix

The levels of immune response to SARS-CoV-2 infection or vaccination are poorly understood in African populations and is complicated by cross-reactivity to endemic pathogens as well as differences in host responsiveness. To begin to determine the best approach to minimize false positive antibody levels to SARS-CoV-2 in an African population, we evaluated three commercial assays, namely Bio-Rad Platelia SARS-CoV-2 Total Antibody (Platelia), Quanterix Simoa Semi-Quantitative SARS-CoV-2 IgG Antibody Test (anti-Spike), and the GenScript cPass™ SARS-CoV-2 Neutralization Antibody Detection Kit (cPass) using samples collected in Mali in West Africa prior to the emergence of SARS-CoV-2. A total of one hundred samples were assayed. The samples were categorized in two groups based on the presence or absence of clinical malaria. Overall, thirteen out of one hundred (13/100) samples were false positives with the Bio-Rad Platelia assay and one of the same one hundred (1/100) was a false positive with the anti-Spike IgG Quanterix assay. None of the samples tested with the GenScript cPass assay were positive. False positives were more common in the clinical malaria group, 10/50 (20%) vs. the non-malaria group 3/50 (6%); p = 0.0374 using the Bio-Rad Platelia assay. Association between false positive results and parasitemia by Bio-Rad remained evident, after adjusting for age and sex in multivariate analyses. In summary, the impact of clinical malaria on assay performance appears to depend on the assay and/or antigen being used. A careful evaluation of any given assay in the local context is a prerequisite for reliable serological assessment of anti-SARS-CoV-2 humoral immunity.