Sialidase-based anti-influenza virus therapy protects against secondary pneumococcal infection.
BACKGROUND
DAS181 (Fludase) is a sialidase fusion protein in clinical development as a broad-spectrum anti-influenza virus (IFV) therapeutic agent. Previous reports by other investigators have raised the concern that desialylation of airway epithelium might increase susceptibility to Streptococcus pneumoniae infection.


METHODS
To address whether DAS181 would lead to an increased risk of pneumococcal infection, we tested S. pneumoniae colonization after DAS181 treatment of human A549 cells, healthy mice, and mice challenged with a lethal dose of IFV A/PR/8/34 (H1N1) or A/Victoria/3/75 (H3N2), followed by 10(4) cfu of S. pneumoniae (D39) on day 3 or day 7. DAS181 treatment was given 24-48 h after IFV challenge.


RESULTS
DAS181 treatment did not increase S. pneumoniae colonization in vitro or in vivo in healthy animals. In IFV-infected mice, DAS181 prevented pneumonia and significantly prolonged survival and inhibited the IFV titer by > or = 3 logs. None of the treated animals showed enhanced S. pneumoniae colonization of the lung. In addition, opportunistic infections with Citrobacter species or Klebsiella species occurred only in mice receiving vehicle, not in animals treated with DAS181.


CONCLUSIONS
These data indicate that DAS181 treatment does not exacerbate secondary bacterial infection in mice. DAS181 may reduce the risk of secondary bacterial infection by inhibiting IFV.
Hedlund
Maria
M
NexBio Incorporated, San Diego, California 92121, USA.
Aschenbrenner
Laura M
LM
Jensen
Kellie
K
Larson
Jeffrey L
JL
Fang
Fang
F
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000302:isolation & purification*; D053122:Influenza A Virus, H3N2 Subtype / Q000302:isolation & purification*; D007251:Influenza, Human / Q000188:drug therapy / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000382:microbiology*; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000517:prevention & control* / Q000821:virology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000254:growth & development*; D019562:Viral Load / Q000187:drug effects
D000998:Antiviral Agents; D011993:Recombinant Fusion Proteins; C525612:oplunofusp