The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a ...prefusion-stabilized conformation.
In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10
viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed.
The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval CI, 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% adjusted 95% CI, 54.6 to 89.1 for onset at ≥14 days and 85.4% adjusted 95% CI, 54.2 to 96.9 for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).
A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).
Background. Serious non-AIDS events cause substantial disease and death despite human immunodeficiency virus (HIV) suppression with antiretroviral therapy (ART). Biomarkers of inflammation, ...coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels. Methods. Plasma samples were obtained from participants starting ART during acute or chronic HIV infection and from HIV-uninfected participants from Bangkok, Thailand. Biomarkers of inflammation (C-reactive protein CRP, interleukin 6, soluble interleukin 6 receptor sIL-6R, soluble gp130, tumor necrosis factor TNF), enterocyte turnover (intestinal fatty acid binding protein I-FABP), lipopolysaccharide-induced monocyte activation (soluble CD14 sCD14), coagulation cascade activation D-dimer, and fibrosis (hyaluronic acid HA) were measured at baseline and through 96 weeks of ART. Results. CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased during ART but remained elevated compared with HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels were correlated with increases in CD4 T-cell counts. Conclusions. ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute-phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in persons with HIV infection.
Non-neutralizing IgG to the V1V2 loop of HIV-1 gp120 correlates with a decreased risk of HIV-1 infection but the mechanism of protection remains unknown. This V1V2 IgG correlate was identified in ...RV144 Thai trial vaccine recipients, who were primed with a canarypox vector expressing membrane-bound gp120 (vCP1521) and boosted with vCP1521 plus a mixture gp120 proteins from clade B and clade CRF01_AE (B/E gp120). We sought to determine whether the mechanism of vaccine protection might involve antibody-dependent complement activation. Complement activation was measured as a function of complement component C3d deposition on V1V2-coated beads in the presence of RV144 sera. Variable levels of complement activation were detected two weeks post final boosting in RV144, which is when the V1V2 IgG correlate was identified. The magnitude of complement activation correlated with V1V2-specific serum IgG and was stronger and more common in RV144 than in HIV-1 infected individuals and two related HIV-1 vaccine trials, VAX003 and VAX004, where no protection was seen. After adjusting for gp120 IgA, V1V2 IgG, gender, and risk score, complement activation by case-control plasmas from RV144 correlated inversely with a reduced risk of HIV-1 infection, with odds ratio for positive versus negative response to TH023-V1V2 0.42 (95% CI 0.18 to 0.99, p = 0.048) and to A244-V1V2 0.49 (95% CI 0.21 to 1.10, p = 0.085). These results suggest that complement activity may have contributed in part to modest protection against the acquisition of HIV-1 infection seen in the RV144 trial.
Acute human immunodeficiency virus type 1 (HIV-1) infection is a major contributor to transmission of HIV-1. An understanding of acute HIV-1 infection may be important in the development of treatment ...strategies to eradicate HIV-1 or achieve a functional cure.
We performed twice-weekly qualitative plasma HIV-1 RNA nucleic acid testing in 2276 volunteers who were at high risk for HIV-1 infection. For participants in whom acute HIV-1 infection was detected, clinical observations, quantitative measurements of plasma HIV-1 RNA levels (to assess viremia) and HIV antibodies, and results of immunophenotyping of lymphocytes were obtained twice weekly.
Fifty of 112 volunteers with acute HIV-1 infection had two or more blood samples collected before HIV-1 antibodies were detected. The median peak viremia (6.7 log10 copies per milliliter) occurred 13 days after the first sample showed reactivity on nucleic acid testing. Reactivity on an enzyme immunoassay occurred at a median of 14 days. The nadir of viremia (4.3 log10 copies per milliliter) occurred at a median of 31 days and was nearly equivalent to the viral-load set point, the steady-state viremia that persists durably after resolution of acute viremia (median plasma HIV-1 RNA level, 4.4 log10 copies per milliliter). The peak viremia and downslope were correlated with the viral-load set point. Clinical manifestations of acute HIV-1 infection were most common just before and at the time of peak viremia. A median of one symptom of acute HIV-1 infection was recorded at a median of two study visits, and a median of one sign of acute HIV-1 infection was recorded at a median of three visits.
The viral-load set point occurred at a median of 31 days after the first detection of plasma viremia and correlated with peak viremia. Few symptoms and signs were observed during acute HIV-1 infection, and they were most common before peak viremia. (Funded by the Department of Defense and the National Institute of Allergy and Infectious Diseases.).
The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ...United States, Chile, and Peru has not been known.
In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.
A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval CI, 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.
AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).
Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 ...(TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.
The 2016 WHO consolidated guidelines on the use of antiretroviral drugs defines HIV virologic failure for low and middle income countries (LMIC) as plasma HIV-RNA ≥ 1000 copies/mL. We evaluated ...virologic failure and predictors in four African countries.
We included HIV-infected participants on a WHO recommended antiretroviral therapy (ART) regimen and enrolled in the African Cohort Study between January 2013 and October 2017. Studied outcomes were virologic failure (plasma HIV-RNA ≥ 1000 copies/mL at the most recent visit), viraemia (plasma HIV-RNA ≥ 50 copies/mL at the most recent visit); and persistent viraemia (plasma HIV-RNA ≥ 50 copies/mL at two consecutive visits). Generalized linear models were used to estimate relative risks with their 95% confidence intervals.
2054 participants were included in this analysis. Viraemia, persistent viraemia and virologic failure were observed in 396 (19.3%), 160 (7.8%) and 184 (9%) participants respectively. Of the participants with persistent viraemia, only 57.5% (92/160) had confirmed virologic failure. In the multivariate analysis, attending clinical care site other than the Uganda sitebeing on 2nd line ART (aRR 1.8, 95% CI 1·28-2·66); other ART combinations not first line and not second line (aRR 3.8, 95% CI 1.18-11.9), a history of fever in the past week (aRR 3.7, 95% CI 1.69-8.05), low CD4 count (aRR 6.9, 95% CI 4.7-10.2) and missing any day of ART (aRR 1·8, 95% CI 1·27-2.57) increased the risk of virologic failure. Being on 2nd line therapy, the site where one receives care and CD4 count < 500 predicted viraemia, persistent viraemia and virologic failure.
In conclusion, these findings demonstrate that HIV-infected patients established on ART for more than six months in the African setting frequently experienced viraemia while continuing to be on ART. The findings also show that being on second line, low CD4 count, missing any day of ART and history of fever in the past week remain important predictors of virologic failure that should trigger intensified adherence counselling especially in the absence of reliable or readily available viral load monitoring. Finally, clinical care sites are different calling for further analyses to elucidate on the unique features of these sites.
Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, ...microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation.
Summary Background The limited data available for long-term Ebola virus disease health outcomes suggest that sequelae persist for longer than 1 year after infection. The magnitude of the present ...outbreak in west Africa necessitates a more complete understanding of the health effects and future medical needs of these patients. Methods We invited adult survivors of the 2007 Bundibugyo Ebola virus outbreak in Uganda and their contacts to take part in an observational study roughly 29 months after the outbreak. We collected information about health status, functional limitations, and demographics. We collected blood samples for clinical chemistry, haematology, and filovirus antibodies using ELISA. Analyses were restricted to probable and confirmed survivors and their seronegative contacts. Findings We recruited 70 survivors of the 2007 Bundibugyo Ebola virus and 223 contacts. We did analyses for 49 probable and confirmed survivors and 157 seronegative contacts. Survivors of the Bundibugyo Ebola virus were at significantly increased risk of ocular deficits (retro-orbital pain RR 4·3, 95% CI 1·9–9·6; p<0·0001, blurred vision 1·9, 1·1–3·2; p=0·018), hearing loss (2·3, 1·2–4·5; p=0·010), difficulty swallowing (2·1, 1·1–3·9; p=0·017), difficulty sleeping (1·9, 1·3–2·8; p=0·001), arthralgias (2·0, 1·1–3·6; p=0·020), and various constitutional symptoms controlling for age and sex. Chronic health problems (prevalence ratio PR 2·1, 95% CI 1·2–3·6; p=0·008) and limitations due to memory loss or confusion (PR 5·8, 1·5–22·4; p=0·010) were also reported more frequently by survivors of Bundibugyo Ebola virus. Interpretation Long-term sequelae persist for more than 2 years after Ebola virus disease. Definition of health consequences related to Ebola virus disease could improve patient care for survivors and contribute to understanding of disease pathogenesis. Funding Chemical Biological Technologies Directorate, Defense Threat Reduction Agency.
Developing HIV-1 vaccines that trigger broadly neutralizing antibodies (bnAbs) is a priority as bnAbs are considered key to elicitation of a protective immune response. To investigate whether the ...breadth of a neutralizing antibody (nAb) depended on the conservation of its epitope among circulating viruses, we examined Antibody:Envelope (Ab:Env) interactions and worldwide Env diversity. We found that sites corresponding to bnAb epitopes were as variable as other accessible, non-hypervariable Env sites (p = 0.50, Mann-Whitney U-test) with no significant relationship between epitope conservation and neutralization breadth (Spearman's ρ = -0.44, adjusted p = 0.079). However, when accounting for key sites in the Ab:Env interaction, we showed that the broadest bnAbs targeted more conserved epitopes (Spearman's ρ = -0.70, adjusted p = 5.0e-5). Neutralization breadth did not stem from the overall conservation of Ab epitopes but depended instead on the conservation of key sites of the Ab:Env interaction, revealing a mechanistic basis for neutralization breadth that could be exploited for vaccine design.
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