Prophylactic Efficacy of Intranasally Administered HSP Nanoparticles for Treating a Lethal SARS-CoV Infection in BALB/c Mice

HSP nanoparticle (sHsp-PCN) is a small heat shock protein cage nanoparticle that elicits the formation of inducible broncho-alveolar lymphatic tissue (iBALT) in the lungs. iBALT is a transient tertiary lymphatic tissue that acts like conventional secondary lymphatic tissues in that it generates local primary immune responses—B and T cell protective responses is induced by antigen presentation by APCs. Thus, it might be useful in priming the local immune environment of the lung to prophylactically treat infectious lung disease. A series of experiments were done to determine how to treat a lethal SARS-CoV infection in BALB/c mice with sHsp-PCN. In each experiment, 15 mice were treated intranasally (I.N.) with PSS and10 mice were treated I.N. with sHsp-PCN or with Poly IC:LC at 1 mg/kg, a known inhibitor of death in the lethal SARS-CoV mouse model. When mice were pretreated with sHsp-PCN one time at days −17, −13, −9, −5, −2, all mice survived the infection as did mice treated I.N. with Poly IC:LC (1 mg/kg, qd X +4, +24) with all untreated, infected mice dying. sHsp-PCN was well tolerated in sham infected and infected mice; all mice gained weight. When sHsp-PCN was administered less often prophylactically (qd X1, days −17, −13; qd X1, days −9, −5, −2; qd X1, days −5, −2; qd X1, day −2; or qd X1, day −2, +8 h), the percentage of survivors decreased to 45%, 50%, 50%, 30%, 10%, respectively. As expected, when sHsp-PCN was administered therapeutically (bid X1 at −4 h, +8 h; qd X1 on day 1; qd X2 on days 1, 2; or −4 h, +8 h, days 1, 2), it did not significantly prevent death. In a moderately lethal infection, sHsp-PCN pretreatment appeared to be dose responsive, with 80% survivors at a 5-mg/kg dose, 60% survival with a 2-mg/kg dose, and 40% survivors in mice 0.1 mg/kg; 40% of mice survived receiving PSS. Thus, sHsp-PCN appears to be an effective prophylactic treatment for lethal infections in BALB/c mice induced by mouse-adapted SARS-CoV. The data suggest that this technology might represent a novel way of ameliorating if not preventing pulmonary virus infections in general and should be further pursued.