Summary
VRC‐HIVMAB060‐00‐AB (VRC01) is a broadly neutralizing HIV‐1 monoclonal antibody (mAb) isolated from the B cells of an HIV‐infected patient. It is directed against the HIV‐1 CD4 binding site ...and is capable of potently neutralizing the majority of diverse HIV‐1 strains. This Phase I dose‐escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose‐limiting toxicities. Mean 28‐day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28‐day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half‐life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti‐VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half‐life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV‐1 prevention efficacy studies.
Abstract
Background
Filgotinib (FIL) is an oral, selective Janus kinase inhibitor, shown to be effective and well tolerated in patients (pt) with rheumatoid arthritis (RA) and other inflammatory ...diseases (IBD/AS/PsA). DARWIN 3, an ongoing, open-label, long-term extension of phase 2b studies evaluates the longer-term safety and efficacy of FIL in RA.
Methods
The study evaluated pt outcomes for methotrexate (MTX) inadequate responders completing the 24-week DARWIN 1 (FIL+MTX) and DARWIN 2 (FIL monotherapy) studies. We present an interim analysis at week 156 following FIL 200 or 100 mg/day treatment. Event rate: total events/total years of exposure of FIL; Exposure: until data cut-off in patients on the study at the time of analysis.
Results
Eight hundred and seventy-seven patients completed the parent studies. Seven hundred and thirty-nine enrolled in DARWIN 3 (497 DARWIN 1, 242 DARWIN 2); most DARWIN 1 and 2 patients were female (81.5%, 81.8%), white (75.3%, 74.8%); mean age was 53 and 52 years, respectively. Mean baseline MTX dose in the FIL+MTX group: 16.8mg/week. At week 156, 59.9% of patients remained on study. Most common reasons for discontinuation were adverse events (26.5%) and subject request (9.1%). Total exposure to FIL was 2203 pt-years; mean exposure ± standard deviation (SD): 3.04 ± 1.22 years for FIL+MTX and 2.86 ± 1.21 years for FIL monotherapy. Treatment-emergent adverse events (TEAEs): 419 (84.3%) patients on FIL+MTX and 203 (83.9%) patients on FIL monotherapy; serious TEAEs occurred in 45 (9.1%) and 33 (13.6%), respectively. Adverse event of special interest (AESI) rates remained low at week 156 (Table 1). Grade ≥3 toxicities in >1% of patients were decreased lymphocytes (4.2%/1%), decreased neutrophils (1.0/1.2%), increased fasting triglycerides (2.2/0%) and decreased fasting triglycerides (0/3.3%) for FIL+MTX/FIL monotherapy respectively. 5 deaths occurred (FIL+MTX: 2, FIL monotherapy: 3) none after week 132. Clinical efficacy was shown at week 156 in both FIL+MTX and FIL monotherapy groups, using observed cases as measured by ACR20 (87.2% and 89.7%)/ACR50 (72.4 and 63.0)/ACR70 (45.5 and 40.0) DAS28(CRP) ≤3.2 (69.0 and 64.7) and DAS28(CRP) <2.6 (53.4 and 45.6).
Conclusion
FIL was generally well tolerated; no new safety signals emerged. No safety differences observed in patients receiving FIL+MTX or FIL monotherapy. Efficacy was sustained up to week 156 in both treatment groups.
Given the prevalence of jaundice in newborns, and the consequences of untreated hyperbilirubinemia, the long-awaited revised clinical practice guidelines for hyperbilirubinemia were finally released ...in August 2022 by the American Academy of Pediatrics as an update to the 2004 guidelines on the same topic. As new evidence and data become available, it is important for pediatricians and neonatologists to re-assess their clinical decision-making over time to ensure that patients are receiving the best care possible. With improvements in medical equipment and medical technology, and growing concerns about the overtreatment of hyperbilirubinemia, the newest clinical practice guidelines attempt to tackle the prevention, risk assessment, monitoring, and treatment of hyperbilirubinemia with these things in mind.
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Cast into the spotlight because of recent legislative actions, gender-affirming care is a hot topic of discussion across the country when it comes to pediatric health care. And yet there is a great ...deal of misinformation being perpetuated about gender-affirming care that may be harmful to youth who identify as transgender and gender diverse (TGD). In addition, TGD youth continue to be an underserved and marginalized group that receive disparate health care at baseline. It is our role as pediatricians to understand the current landscape of evidence and guidance available to promote the health of TGD youth while reducing discrimination through education, nonjudgmental holistic treatment, and advocacy at local and national levels.
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The coronavirus disease 2019 (COVID-19) pandemic has transformed the world. It has highlighted health inequities, the lack of social safety nets, and the limitations of health care systems. But it ...has also paved the way for medical ingenuity and technological advances in the face of these extreme challenges. One such medical marvel is the COVID-19 vaccine. The ability to rapidly create and mass produce a safe and effective vaccine for both adults and children has been essential to minimizing the harm of COVID-19, reducing the burden on hospitals and ushering in some semblance of return to pre-COVID times. Although vaccine hesitancy and long-standing health inequities have limited the number of children who have received the COVID-19 vaccine, the recommended vaccines remain a vital tool in ensuring healthy growth and development of children.
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Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress ...active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression.
Chimpanzee Adenovirus Vector Ebola Vaccine Ledgerwood, Julie E; DeZure, Adam D; Stanley, Daphne A ...
New England journal of medicine/The New England journal of medicine,
03/2017, Letnik:
376, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The unprecedented 2014 epidemic of Ebola virus disease (EVD) prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee ...adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species, that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation.
We conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2×10
particle units or 2×10
particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 8 weeks after vaccination; in addition, longer-term vaccine durability was assessed at 48 weeks after vaccination.
In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2×10
particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2×10
particle-unit dose than in the group that received the 2×10
particle-unit dose (geometric mean titer against the Zaire antigen at week 4, 2037 vs. 331; P=0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2×10
particle-unit dose than among those who received the 2×10
particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P=0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P=0.07) at week 4. Assessment of the durability of the antibody response showed that titers remained high at week 48, with the highest titers in those who received the 2×10
particle-unit dose.
Reactogenicity and immune responses to cAd3-EBO vaccine were dose-dependent. At the 2×10
particle-unit dose, glycoprotein Zaire-specific antibody responses were in the range reported to be associated with vaccine-induced protective immunity in challenge studies involving nonhuman primates, and responses were sustained to week 48. Phase 2 studies and efficacy trials assessing cAd3-EBO are in progress. (Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 ClinicalTrials.gov number, NCT02231866 .).
An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability ...of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.
Chikungunya virus (CHIKV) is a global public health threat, having been identified in >60 countries in Asia, Africa, Europe, and the Americas. There is no cure for or licensed vaccine against CHIKV ...infection. Initial attempts at CHIKV vaccine development began in the early 1960s. Whole-inactivated and virus-like particle (VLP) vaccines are 2 of the current approaches being evaluated. Success of these approaches is dependent on a safe, well-tolerated vaccine that is immunogenic and deployable in regard to manufacturing, stability, and delivery characteristics.
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