BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized ...(2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.
A growing and compelling body of evidence demonstrates that children born into poverty, whether in high-, middle-, or low-income countries, are at heightened risk for compromised health and ...developmental outcomes throughout the life course. To address these knowledge gaps and identify the next set of research priorities, a global health meeting was held by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) on Feb 11th and 12th, 2015 on the Bethesda, Maryland campus of the US National Institutes of Health. The primary objective of this NICHD Global Health Meeting was to identify research priorities that are key to understanding the interrelationships and impact of nutritional status and inflammation due to specific infections or noncommunicable diseases on child neurodevelopment and brain function from fetal life through adolescence in LRS.
Pregnancies occur during HIV-1 vaccine clinical trials, despite requirements for women of reproductive potential to use effective contraception. Deployment of an effective HIV-1 vaccine regimen will ...likely target adolescents and young adults and therefore safety for pregnant and breastfeeding women will need to be addressed.
We performed a retrospective, cross-protocol analysis to identify and compare pregnancy outcomes reported in 53 Phase 1 and Phase 2a HIV-1 vaccine clinical trials conducted by the HIV Vaccine Trials Network (HVTN).
Two thousand six hundred seventy-three women of reproductive potential were identified and 193 pregnancies were reported. 39 of 53 (74%) studies had at least one pregnancy reported with an overall pregnancy rate of 3.15 per 100 woman-years (w-yr). While active contraception use was required during study participation, 13 of the 53 studies also contained a long-term follow up period during which pregnancy was no longer discouraged. The pregnancy rate during main study participation was 3.09 per 100 w-yr, while pregnancies occurred at a slightly greater rate in the long-term follow up period (3.22 per 100 w-yr). Adverse pregnancy outcomes were reported at similar rates between vaccinees and placebo recipients when vaccine vectors, adjuvant used, or geographic region were examined.
Although there is considerable heterogeneity amongst the different vaccine trials, there appears to be no obvious indication of increased risk of adverse pregnancy or birth outcomes in these early phase HIV-1 vaccine studies. More complete data on pregnancy outcomes should be collected in early phase HIV-1 vaccine clinical trials to better inform subsequent efficacy trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a randomized, double-blind, placebo-controlled phase 3 trial of the ChAdOx1 nCoV-19 vaccine in over 32,000 participants from the United States, Chile, and Peru, the incidence of serious adverse ...effects was low (including no cases of vaccine-induced immune thrombotic thrombocytopenia) and the vaccine efficacy was 74%. Efficacy was documented in a range of demographic subgroups.
Pregnant women are a vulnerable group who are needed in clinical research studies to advance prevention and treatment options for this population. Yet, pregnant women remain underrepresented in ...clinical research. Through the lens of the socioecological model, we highlight reported barriers and facilitators to recruitment and retention of pregnant women in studies that sought their participation. We trace historical, policy-based reasons for the exclusion of pregnant women in clinical studies to present-day rationale for inclusion of this group. The findings highlight why it has been difficult to recruit and retain this population over time. A body of literature suggests that integrative sampling and recruitment methods that leverage the influence and reach of prenatal providers will overcome recruitment challenges. We argue that these strategies, in combination with building strong engagement with existing community-based organizations, will enable teams to more effectively promote and retain pregnant women in future longitudinal cohort studies.
BACKGROUND. We report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial. METHODS. Adults at increased risk of SARS-CoV-2 infection were ...randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCRpositive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively. FINDINGS. Data cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the doubleblind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/ critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen. CONCLUSION. AZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median followup (AZD1222 group) of 6 months.
•Three doses of novel subtype C gp145 Env protein with alum in a Phase 1 HIV vaccine trial were safe and well-tolerated.•Participants demonstrated effector binding antibodies, Env-specific ...CD4 + T-cell, and tier 1 neutralizing antibodies.•However, the regimen failed to induce tier 2 or heterologous neutralizing antibody responses.
An approach to a preventive HIV vaccine is induction of effective broadly neutralizing antibodies (bnAbs) and effector binding antibodies (bAbs). Preclinical studies suggest that trimeric envelope (Env) proteins may elicit nAbs, which led to the development of the recombinant gp145 subtype C Env protein (gp145 C.6980) immunogen. HVTN 122 was a Phase 1 trial that evaluated the safety, tolerability, and immunogenicity of gp145 C.6980 in adults.
Healthy, HIV-1 seronegative adults received three intramuscular injections of gp145 C.6980 with aluminum hydroxide (alum) at months 0, 2, and 6 at either 300 mcg (high dose, n = 25) or 100 mcg (low dose, n = 15), or placebo/saline (placebo, n = 5). Participants were followed for 12 months.
Forty-five participants were enrolled. High and low doses of the study protein were well-tolerated, with mild or moderate reactogenicity commonly reported. Only one adverse event (mild injection site pruritis) in one participant (low dose) was considered product-related; there were no dose-limiting toxicities. High and low dose recipients demonstrated robust bAb responses to vaccine-matched consensus gp140 Env and subtype-matched gp120 Env proteins two weeks post-last vaccination (response rates >90 %), while no responses were detected to a heterologous subtype-matched V1V2 antigen. No significant differences were seen between high and low dose groups. Participants in both experimental arms demonstrated nAb response rates of 76.5 % to a tier 1 virus (MW9635.26), but no responses to tier 2 isolates. Env-specific CD4 + T-cell responses were elicited in 36.4 % of vaccine recipients, without significant differences between groups; no participants demonstrated CD8 + T-cell responses.
Three doses of novel subtype C gp145 Env protein with alum were safe and well-tolerated. Participants demonstrated bAb, Env-specific CD4 + T-cell, and tier 1 nAb responses, but the regimen failed to induce tier 2 or heterologous nAb responses.
Clinical Trials Registration: NCT03382418
Phase 3 Safety and Efficacy of AZD1222 Sproule, Stephanie; Buchbinder, Susan; Guerreros Benavides, Alfredo ...
The New England journal of medicine,
12/2021, Letnik:
385, Številka:
25
Journal Article
Abstract
Background
SARS-CoV-2 vaccine efficacy (VE) against asymptomatic infection and impact on viral shedding during breakthrough infections have critical implications for pandemic control. ...AZD1222 (ChAdOx1 nCoV-19; 2 doses, 4 weeks apart) demonstrated VE of 74.0% (95% CI 65.3, 80.5) against the primary endpoint of symptomatic RT-PCR-confirmed COVID-19 and safety in a Phase 3, 2:1 randomized, placebo-controlled study in the US, Chile and Peru (n=32,451). Here we present exploratory analyses on asymptomatic infections determined by nucleocapsid (N) seroconversion and time to viral clearance in participants with symptomatic infections determined by N seroconversion (primary data cut, March 5, 2021).
Methods
N seroconversion was assessed at all scheduled and illness visits in the fully vaccinated analysis set (Table). In this analysis, symptomatic infections are defined as N seroconversion ≥ 15 days post second dose in participants who attended an illness visit with ≥ 1 qualifying COVID-19 symptom and had ≥ 1 positive RT-PCR result for SARS-CoV-2. Asymptomatic infections are defined as N seroconversion ≥ 15 days post second dose in participants who did not meet the criteria for symptomatic infections. In participants with symptomatic infections, viral shedding in saliva was assessed for 28 days and cumulative incidence of viral clearance was determined.
Table. AZD1222 VE against symptomatic and potentially asymptomatic SARS-CoV-2 infections as determined by N seroconversion
Results
Overall, 358 participants had SARS-CoV-2 infections as determined by N seroconversion (Table). Incidences per 1000 person-years of symptomatic infections were 25.62 for AZD1222 vs 103.42 for placebo (VE 75.23%; 95% CI 65.33, 82.31) and of asymptomatic infections were 51.24 vs 111.95 (VE 54.24%; 95% CI 39.99, 65.10) (Table). Sensitivity analyses for N seroconversion using the primary endpoint and CDC criteria for defining symptomatic/asymptomatic status were supportive. Median time to viral clearance in saliva in participants with symptomatic infections was 11 days (AZD1222, n=52) vs 16 days (placebo, n=92) (Figure).
Figure. Viral clearance in saliva samples in participants with symptomatic infections as determined by N seroconversion
Conclusion
AZD1222 resulted in lower yet meaningful VE against asymptomatic compared to symptomatic infections, as determined by N seroconversion, and shortened viral shedding in symptomatic SARS-CoV-2 breakthrough infections vs placebo, highlighting its potential contribution to reducing viral transmission.
Funding Statement
Disclosures
Ann R. Falsey, MD, AstraZeneca (Individual(s) Involved: Self): Grant/Research Support; BioFire Diagnostics (Individual(s) Involved: Self): Grant/Research Support; Janssen (Individual(s) Involved: Self): Grant/Research Support; Merck, Sharpe and Dohme (Individual(s) Involved: Self): Grant/Research Support; Novavax (Individual(s) Involved: Self): Other Financial or Material Support, Paid DSMB member; Pfizer (Individual(s) Involved: Self): Grant/Research Support Merlin L. Robb, M.D., Henry M. Jackson Foundation (Other Financial or Material Support, This work was conducted under a funding agreement with the USG through an INteragency Personnel Agreement) Hong-Van Tieu, M.D, M.S., National Institutes of Health (Grant/Research Support) Lawrence Corey, MD, NIH (Grant/Research Support) Kathleen Neuzil, MD, MPH, NIH (Grant/Research Support, Other Financial or Material Support, Dr. Neuzil is the CoVPN co-chair with testing of COVID-19 vaccines with salary support from NIH.)Pfizer (Grant/Research Support) Jill Maaske, M.D., AstraZeneca (Employee, Shareholder) Brett Jepson, n/a, AstraZeneca (Other Financial or Material Support, On assignment to AstraZeneca)Cytel, Inc. (Employee) Stephanie Sproule, n/a, AstraZeneca (Other Financial or Material Support, Fees for statistical consulting.) Elizabeth Kelly, n/a, AstraZeneca (Employee, Shareholder)
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