tetano
Editor, Senior Moderator
Clin Infect Dis
. 2020 Nov 19;ciaa1725.
doi: 10.1093/cid/ciaa1725. Online ahead of print.
Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model
Alison Han[SUP] 1 [/SUP], Lindsay Czajkowski[SUP] 1 [/SUP], Luz Angela Rosas[SUP] 2 [/SUP], Adriana Cervantes-Medina[SUP] 1 [/SUP], Yongli Xiao[SUP] 2 [/SUP], Monica Gouzoulis[SUP] 1 [/SUP], Keith Lumbard[SUP] 3 [/SUP], Sally Hunsberger[SUP] 4 [/SUP], Susan Reed[SUP] 1 [/SUP], Rani Athota[SUP] 1 [/SUP], Holly Ann Baus[SUP] 1 [/SUP], Amy Lwin[SUP] 5 [/SUP], Jerald Sadoff[SUP] 5 [/SUP], Jeffery K Taubenberger[SUP] 2 [/SUP], Matthew J Memoli[SUP] 1 [/SUP]
Affiliations
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.
Keywords: Anti-HA stalk antibody; CHIM; Challenge study; HA Stalk; Influenza A.
. 2020 Nov 19;ciaa1725.
doi: 10.1093/cid/ciaa1725. Online ahead of print.
Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model
Alison Han[SUP] 1 [/SUP], Lindsay Czajkowski[SUP] 1 [/SUP], Luz Angela Rosas[SUP] 2 [/SUP], Adriana Cervantes-Medina[SUP] 1 [/SUP], Yongli Xiao[SUP] 2 [/SUP], Monica Gouzoulis[SUP] 1 [/SUP], Keith Lumbard[SUP] 3 [/SUP], Sally Hunsberger[SUP] 4 [/SUP], Susan Reed[SUP] 1 [/SUP], Rani Athota[SUP] 1 [/SUP], Holly Ann Baus[SUP] 1 [/SUP], Amy Lwin[SUP] 5 [/SUP], Jerald Sadoff[SUP] 5 [/SUP], Jeffery K Taubenberger[SUP] 2 [/SUP], Matthew J Memoli[SUP] 1 [/SUP]
Affiliations
- PMID: 33211860
- DOI: 10.1093/cid/ciaa1725
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.
Keywords: Anti-HA stalk antibody; CHIM; Challenge study; HA Stalk; Influenza A.