scholarly journals 1522. Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S763-S763
Author(s):  
Alison Han ◽  
Lindsay Czajkowski ◽  
Luz Angela Rosas ◽  
Adriana Cervantes-Medina ◽  
Yongli Xiao ◽  
...  
Keyword(s):  
Pharmaceutical Company ◽  
Influenza A ◽  
Controlled Trial ◽  
Influenza Infection ◽  
Healthy Human ◽  
Double Blind ◽  
Duration Of Symptoms ◽  
Viral Shedding ◽  
Influenza A H1n1 ◽  
Significant Difference

Abstract Background Influenza virus infections cause significant morbidity and mortality during yearly seasonal epidemics and during sporadic pandemics. It is imperative to identify new targets for vaccines and therapeutics. One such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein. Methods We conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. CR6261 was infused 24 hours after challenge with H1N1pdm09 and the primary efficacy outcome was area under the curve (AUC) of viral shedding. Results Between March 2015-May 2018, 104 healthy volunteers were enrolled and randomized with 91 undergoing influenza challenge, of which 49 participants (54%) received treatment with CR6261 and 42 participants (46%) received placebo. A mean of 1x106 ng/mL of serum CR6261 was detected by 24 hours after infusion. Nasal CR6261 levels reached a peak mean of 5.97x102 ng/ml 2 days after infusion. There was no statistically significant difference in the primary outcome measure between the CR6261 group and placebo (median AUC 48.56 and 25.53 respectively, P=0.31). The severity of illness was compared between the two groups, and no significant difference was observed in number of symptoms, duration of symptoms, or FLU-PRO scores. Conclusion CR6261 had no statistically significant effect on AUC of viral shedding, and no clinically significant effect on overall influenza disease. Preexisting anti-neuraminidase (NA) antibody titers were most predictive of reduced influenza disease. Nasal CR6261 levels were much lower compared to serum, which may be a factor in the limited effect of CR6261 on this upper respiratory infection. These results suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may have limited efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic or vaccine strategy. Funding This study was funded in part by the intramural program of NIAID, NIH, by the NCI Contract No. 75N910D00024, Task Order No. 75N91019F00130, and through a CRADA with Janssen Infectious Diseases and Vaccines. Disclosures Amy Lwin, RN, BSN, Janssen Pharmaceutical Company of J&J (Employee) Jerald Sadoff, MD, Janssen Pharmaceutical Company of J&J (Employee)

scholarly journals Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model

2020 ◽  
Author(s):  
Alison Han ◽  
Lindsay Czajkowski ◽  
Luz Angela Rosas ◽  
Adriana Cervantes-Medina ◽  
Yongli Xiao ◽  
...  
Keyword(s):  
Influenza A ◽  
Controlled Trial ◽  
Influenza Infection ◽  
Area Under The Curve ◽  
Surface Protein ◽  
Healthy Human ◽  
Double Blind ◽  
Duration Of Symptoms ◽  
Influenza A H1n1 ◽  
Clinically Significant

Abstract Background It is imperative to identify new targets for improved vaccines and therapeutics against influenza and one such target is the relatively conserved stalk region of the influenza A hemagglutinin (HA) surface protein. Methods We conducted a randomized, double-blind, Phase II placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. A single 50mg/kg dose of CR6261 was infused 24 hours after challenge and the primary efficacy outcome was area under the curve of viral RNA detection over time. Results Ninety-one healthy volunteers were randomized and underwent influenza challenge; 49 received CR6261 and 42 placebo. CR6261 had no statistically significant effect on AUC (AUC 48.56 log (copies/mL) x days, IQR 202 vs. AUC 25.53 log (copies/mL) x days, IQR 155), P=0.315), and no clinically significant effect on influenza disease measures including number of symptoms, duration of symptoms, or FLU-PRO scores. Preexisting anti-NA antibody titers were most predictive of reduced influenza disease. CR6261 reached a mean peak serum concentration of 1x10 6 ng/ml 15 minutes after infusion, and a mean peak of 5.97x10 2 ng/ml in the nasal mucosa 2-3 days after infusion. Conclusions The results of this study suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may be limited in efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multi-faceted strategy rather than as a standalone therapeutic.

A phase I randomized, double-blind, controlled trial of 2009 influenza A (H1N1) inactivated monovalent vaccines with different adjuvant systems

Vaccine ◽  
2011 ◽  
Vol 29 (48) ◽  
pp. 8974-8981 ◽  
Author(s):  
Alexander R. Precioso ◽  
João L. Miraglia ◽  
Lúcia Maria A. Campos ◽  
Alessandra C. Goulart ◽  
Maria do Carmo S.T. Timenetsky ◽  
...  
Keyword(s):  
Phase I ◽  
Influenza A ◽  
Controlled Trial ◽  
Double Blind ◽  
Influenza A H1n1

scholarly journals A Rapid Immune Response to 2009 Influenza A(H1N1) Vaccines in Adults: A Randomized, Double‐Blind, Controlled Trial

2010 ◽  
Vol 202 (5) ◽  
pp. 675-680 ◽  
Author(s):  
Jiang Wu ◽  
Wei Li ◽  
Hua‐Qing Wang ◽  
Jiang‐Ting Chen ◽  
Min Lv ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza A ◽  
Controlled Trial ◽  
Double Blind ◽  
Influenza A H1n1

scholarly journals Long-Acting Neuraminidase Inhibitor Laninamivir Octanoate (CS-8958) versus Oseltamivir as Treatment for Children with Influenza Virus Infection

2010 ◽  
Vol 54 (6) ◽  
pp. 2575-2582 ◽  
Author(s):  
Norio Sugaya ◽  
Yasuo Ohashi
Keyword(s):  
Virus Infection ◽  
Influenza A ◽  
H1n1 Virus ◽  
Controlled Trial ◽  
Influenza Virus Infection ◽  
Neuraminidase Inhibitor ◽  
Double Blind ◽  
Influenza A H1n1 ◽  
B Virus ◽  
Long Acting

ABSTRACT We conducted a double-blind, randomized controlled trial to compare a long-acting neuraminidase inhibitor, laninamivir octanoate, with oseltamivir. Eligible patients were children 9 years of age and under who had febrile influenza symptoms of no more than 36-h duration. Patients were randomized to 1 of 3 treatment groups: a group given 40 mg laninamivir (40-mg group), a group given 20 mg laninamivir (20-mg group), and an oseltamivir group. Laninamivir octanoate was administered as a single inhalation. Oseltamivir (2 mg/kg of body weight) was administered orally twice daily for 5 days. The primary end point was the time to alleviation of influenza illness. The primary analysis included 184 patients (61, 61, and 62 in the 40-mg group, 20-mg group, and oseltamivir group, respectively). Laninamivir octanoate markedly reduced the median time to illness alleviation in comparison with oseltamivir in patients infected with oseltamivir-resistant influenza A (H1N1) virus, and the reductions were 60.9 h for the 40-mg group and 66.2 h for the 20-mg group. On the other hand, there were no significant differences in the times to alleviation of illness between the laninamivir groups and oseltamivir group for patients with influenza A (H3N2) or B virus infection. Laninamivir octanoate was well tolerated. The most common adverse events were gastrointestinal events. Laninamivir octanoate was an effective and well-tolerated treatment for children with oseltamivir-resistant influenza A (H1N1) virus infection. Further study will be needed to confirm clinical efficacy against influenza A (H3N2) or B virus infection. Its ease of administration is noteworthy, because a single inhalation is required during the course of illness.

scholarly journals Intravenous Penciclovir for Treatment of Herpes Simplex Infections in Immunocompromised Patients: Results of a Multicenter, Acyclovir-Controlled Trial

1999 ◽  
Vol 43 (5) ◽  
pp. 1192-1197 ◽  
Author(s):  
Hillard M. Lazarus ◽  
Robert Belanger ◽  
Anna Candoni ◽  
Mickaël Aoun ◽  
Regina Jurewicz ◽  
...  
Keyword(s):  
Herpes Simplex ◽  
Median Time ◽  
Day Treatment ◽  
Controlled Trial ◽  
Complete Healing ◽  
Double Blind ◽  
Viral Shedding ◽  
Hematologic Disorder ◽  
Significant Difference ◽  
Hsv Infections

ABSTRACT The efficacy and safety of penciclovir (PCV) for the treatment of herpes simplex virus (HSV) infections in immunocompromised (IC) patients were studied in a double-blind, acyclovir (ACV)-controlled, multicenter study. A total of 342 patients with mucocutaneous HSV infections received 5 mg of PCV per kg every 12 or 8 h (q12h or q8h) or 5 mg of ACV per kg q8h, beginning within 72 h of lesion onset and continuing for up to 7 days. The mean age of the patients was 49 years; 94% were white and 52% were female. The main reasons for their IC states were hematologic disorder (63%) and transplant plus hematologic disorder (16%). Clinical and virological assessments were performed daily during the 7-day treatment and then every other day until lesion healing. The primary efficacy parameter addressed new lesion formation. Secondary end points focused on viral shedding, healing, and pain. Approximately 20% of patients in each treatment group developed new lesions during therapy; thus, equivalence with ACV (defined prospectively) was demonstrated for both q12h and q8h PCV regimens. For all three treatment groups, the median time to the cessation of viral shedding was 4 days and the median time to complete healing was 8 days; there were no statistically significant differences in the rates of complete healing or the cessation of viral shedding when the results for PCV q12h and q8h were compared with those for ACV q8h. In addition, there was no statistically significant difference between PCV q12h or q8h, compared with ACV q8h, for the resolution of pain. PCV was well tolerated, with an adverse event profile comparable to that of ACV. In conclusion, PCV q12h is a well-tolerated and effective therapy for mucocutaneous HSV infection in IC patients and offers a reduced frequency of dosing compared with ACV q8h.

scholarly journals A Phase 2 randomized, double-blind, placebo-controlled trial of the monoclonal antibody MHAA4549A in patients with acute uncomplicated influenza A infection

2021 ◽  
Author(s):  
Jeremy J Lim ◽  
Sadia Dar ◽  
Dirk Venter ◽  
Juan P Horcajada ◽  
Priya Kulkarni ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Viral Load ◽  
Median Time ◽  
Influenza A ◽  
Controlled Trial ◽  
Human Monoclonal Antibody ◽  
Phase 2 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Viral Shedding

Abstract Background MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, neutralizes influenza A virus in animal and human volunteer challenge studies. We investigated MHAA4549A safety and tolerability, efficacy, and pharmacokinetics in outpatients with acute, uncomplicated influenza A infection. Methods This was a Phase 2, randomized, double-blind, placebo-controlled trial of single intravenous (IV) doses of 3600 mg or 8400 mg MHAA4549A, or IV placebo in adult outpatients testing positive for influenza A. Patients were enrolled across 35 sites in 6 countries. Randomization and dosing occurred ≤ 72 hours of symptom onset; study duration was 14 weeks. The primary endpoint was the nature and frequency of adverse events (AEs). Secondary endpoints included median time to alleviation of all influenza symptoms, effects on nasopharyngeal viral load and duration of viral shedding, and MHAA4549A serum pharmacokinetics. Results Of 125 randomized patients, 124 received study treatment, with 99 confirmed positive for influenza A by central testing. Frequency of AEs between MHAA4549A and placebo groups was similar; nausea was most common (8 patients; 6.5%). MHAA4549A serum exposure was confirmed in all MHAA4549A-treated patients and was dose proportional. No hospitalizations or deaths occurred. Between MHAA4549A and placebo groups, no statistically significant differences occurred in median time to alleviation of all symptoms, nasopharyngeal viral load, or duration of viral shedding. Conclusions While MHAA4549A was safe and well-tolerated with confirmed exposure, the antibody did not improve clinical outcomes in patients with acute uncomplicated influenza A infection.

scholarly journals 2750. Sequential Influenza A H1N1 and Influenza A H3N2 Challenge Infections in Healthy Volunteers

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S969-S969 ◽  
Author(s):  
Alison Han ◽  
Luca Giurgea ◽  
Adriana Cervantes-Medina ◽  
Kristina Edwards ◽  
Luz Angela Rosas ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Influenza A ◽  
Reverse Genetics ◽  
Clinical Symptoms ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
Wild Type ◽  
Viral Shedding ◽  
Influenza A H1n1 ◽  
The Impact

Abstract Background Seasonal influenza causes significant annual morbidity and mortality. The effects of yearly exposures on immunity are not clear and recent observations have demonstrated that long lasting protection against a matched strain may not naturally occur. The 2018–2019 influenza season consisted of an initial peak of H1N1 infections followed by a wave of H3N2 infections. These consecutive waves raise questions about how influenza immunity is affected by sequential exposure to different influenza strains. Challenge studies provide a unique opportunity to study this phenomenon. Here we describe a subset of participants who were sequentially infected in two separate challenge studies with wild-type H1N1 and H3N2 viruses. Methods Healthy volunteers completed two sequential influenza challenge studies at the NIH Clinical Center. Participants were inoculated with reverse genetics, cell-based, GMP wild-type influenza viruses, A(H1N1)pdm09 and A(H3N2) strains. Participants remained isolated in the hospital for a minimum of 9 days and were monitored daily for viral shedding and clinical symptoms. After discharge, participants were followed for 2 months. Results Between 2014 and 2017, 14 healthy volunteers were exposed to Influenza A(H1N1) and Influenza A(H3N2). Time between infections ranged from 2 months to 2 years. Thirteen (93%) participants developed confirmed influenza infection after H1N1 challenge and 9 (64%) after H3N2 challenge. Eight (57%) participants developed confirmed infections after both exposures. Variable degrees of symptoms, shedding, and disease severity were observed. Systemic antibody responses to the HA and NA of both H1N1 and H3N2 varied over time during these sequential infections. Conclusion More than half of all participants who completed 2 sequential H1N1 and H3N2 challenge studies demonstrated confirmed infection to both viruses. These sequential infections had varying effects on the disease experienced and the immunity that developed after infection. These observations are important in understanding the impact of sequential exposures on influenza immunity. Disclosures All authors: No reported disclosures.

scholarly journals 1524. Sex Differences in Influenza: The Challenge Study Experience

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S764-S764
Author(s):  
Luca Giurgea ◽  
Adriana Cervantes-Medina ◽  
Alison Han ◽  
Lindsay Czajkowski ◽  
Holly Baus ◽  
...  
Keyword(s):  
Sex Differences ◽  
Influenza A ◽  
Animal Studies ◽  
Influenza Infection ◽  
Reproductive Age ◽  
Experimental Therapy ◽  
Duration Of Symptoms ◽  
Biological Sex ◽  
Viral Shedding ◽  
The Impact

Abstract Background Our understanding of the impact of biological sex on influenza-associated disease and the mechanisms that underpin it is still incomplete. Further investigation of sex-linked effects on influenza pathogenesis and clinical outcomes may help tailor vaccine strategies. Animal studies have shown female mice experience more symptoms than male mice during influenza infection. Similarly, human females of reproductive age have higher rates of influenza and influenza-related hospitalizations. However, data is sometimes conflicting and may be confounded by other important differences in baseline characteristics. Human challenge studies have demonstrated the importance of NAI titers as a correlate of protection and may also provide an ideal opportunity to study sex differences in a homogenous group of participants controlled for confounders. Methods Data from 168 volunteers who underwent Influenza A/California/04/2009/H1N1 challenge studies affiliated with NIAID’s LID Clinical Studies Unit were compiled to compare differences between sexes. Participants were included in the analysis if they received a challenge dose of virus of 107 TCID50 and were excluded if they had received any vaccines or experimental therapy during the study period. Results Baseline differences between male and female participants were observed in NAI titers but not HAI titers or age. Outcomes of interest included presence of viral shedding/duration which were similar among sexes. However, symptom number and duration were higher among female participants (p=0.008 and p=0.045 respectively). Ongoing data analysis also shows females have lower post-challenge NAI titers than males. Conclusion Female participants in our H1N1 challenge studies had more symptoms and a longer duration of symptoms compared to their male counterparts. Differences in NAI titers may potentially explain the observed relationship between sex and symptoms associated with influenza. Disclosures All Authors: No reported disclosures

Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial

The Lancet ◽  
2010 ◽  
Vol 375 (9708) ◽  
pp. 56-66 ◽  
Author(s):  
Xiao-Feng Liang ◽  
Hua-Qing Wang ◽  
Jun-Zhi Wang ◽  
Han-Hua Fang ◽  
Jiang Wu ◽  
...  
Keyword(s):  
Pandemic Influenza ◽  
Influenza A ◽  
Controlled Trial ◽  
Double Blind ◽  
Influenza A H1n1

scholarly journals Effects of Heat-Killed Levilactobacillus brevis KB290 in Combination with β-Carotene on Influenza Virus Infection in Healthy Adults: A Randomized Controlled Trial

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 3039
Author(s):  
Shohei Satomi ◽  
Naoko Waki ◽  
Chinatsu Arakawa ◽  
Kazuhiko Fujisawa ◽  
Shigenori Suzuki ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
Controlled Trial ◽  
Winter Season ◽  
Influenza Virus Infection ◽  
Virus Infections ◽  
Double Blind ◽  
Significant Difference ◽  
Β Carotene

Influenza, a seasonal acute respiratory disease caused primarily by the influenza virus A or B, manifests with severe symptoms leading to considerable morbidity and mortality and is a major concern worldwide. Therefore, effective preventive measures against it are required. The aim of this trial was to evaluate the preventive effects of heat-killed Levilactobacillus brevis KB290 (KB290) in combination with β-carotene (βC) on influenza virus infections in healthy Japanese subjects aged between 20 and 59 y throughout the winter season. We performed a randomized, double-blind, placebo-controlled, parallel-group trial from 16 December 2019 to 8 March 2020, comparing KB290 + βC beverage with placebo beverage. The primary endpoint was the incidence of influenza based on a doctor’s certificate. The incidence of influenza was not significantly different between the two groups. However, the subgroup analysis showed a significant difference between the two groups (influenza incidence: the KB290 + βC group 1.9%, and the placebo group 3.9%) in the subgroup of subjects aged ˂40 y, but not in the subgroup of subjects aged ≥40 y. The results of this trial suggest that the combination of KB290 and βC might be a possible candidate supplement for protection against the seasonal influenza virus infection in humans aged <40 y, although further clinical studies are needed to confirm the concrete preventive effect of this combination on influenza.

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