A Randomized Study of Immune Plasma for the Treatment of Severe Influenza

Beigel, John H.; Tebas, Pablo; Elie-Turenne, Marie-Carmelle; Bajwa, Ednan; Bell, Todd E.; Cairns, Charles B.; Shoham, Shmuel; Deville, Jaime G.; Feucht, Eric; Feinberg, Judith; Luke, Thomas; Raviprakash, Kanakatte; Danko, Janine; O’Neil, Dorothy; Metcalf, Julia A.; King, Karen; Burgess, Timothy H.; Aga, Evgenia; Lane, H. Clifford; Hughes, Michael D.; Davey, Richard T.

The lack of a measurable anti-viral effect is difficult to interpret. The need for virologic efficacy endpoints in influenza therapeutics has been well argued [12] but, to date, even oseltamivir has not shown conclusive efficacy in terms of decreased viral shedding. The prior study with anti-influenza convalescent plasma [2] did report a difference in rate of decrease of viral shedding, though the cohort design and high mortality in the control arm make direct comparisons to this study difficult. The prior study with hyper-immune antiinfluenza immunoglobulin did show virologic benefit on day 3 and 5, though as previously noted did not show clinical benefit for the primary analysis population. [11] Currently the FDA does not consider virologic endpoints alone to be sufficient as primary endpoints given the lack of a predictive relationship between reductions in viral titers and clinical benefit, as well as substantial variability in methods of quantifying viral shedding. [13] The use of HAI titer as a measure of immunity in the prevention of influenza is well established, [14] and therefore an increase in HAI titers by plasma might be anticipated to decrease viral shedding. Additionally, several hundred units of plasma are screened each week to support this study, so the assay needed to be scalable for high throughput. For these reasons, units for this study were screened by HAI. However, the prior cohort study with anti-influenza convalescent plasma screened units by neutralizing antibody titer (NAT). [2] While NAT and HAI are generally related, there is not sufficient data to know which is the more appropriate method for screening plasma units. Additionally, it is possible that systemically administered antibodies do not sufficiently permeate mucosal surfaces in order to affect viral replication.