PrEP-001 prophylactic effect against rhinovirus and influenza virus - RESULTS of 2 randomized trials

Bruce Albert Malcolm, Caroline Anne Aerts, Kristof Johan Dubois, Frederik Joris Geurts, Kris Marien, Sarah Rusch, Alex Henri Van Dijck, Rene Verloes, Johan Vingerhoets, Bruce Albert Malcolm, Caroline Anne Aerts, Kristof Johan Dubois, Frederik Joris Geurts, Kris Marien, Sarah Rusch, Alex Henri Van Dijck, Rene Verloes, Johan Vingerhoets

Abstract

Background: PrEP-001 Nasal Powder, a proprietary formulation of polyriboinosinic and polyribocytidylic acid effectively elicits a cellular innate immune response in nasal epithelium. The aim of these 2 studies was to investigate the safety and efficacy of PrEP-001 prophylaxis against rhinovirus (HRV-A16) and influenza-A (H3N2-IAV).

Methods: Healthy subjects randomly received 2 doses of PrEP-001 or placebo, 48 and 24 h pre-challenge with 10 TCID50 of HRV-A16 (Study 1) or H3N2-IAV (Study 2).

Results: In Study 1, PrEP-001 reduced median total symptom score from 38.5 to 4.5 (p = 0.004), median symptom duration from 6.0 to 1.7 days and median mucus production from 15 g to 3 g. The percentage of subjects classified as ill was reduced 3-fold (placebo 73%, PrEP-001 23%, p = 0.002). In Study 2, PrEP-001 reduced median total symptom score from 8.0 to 4.1 (p = 0.021), median symptom duration from 4.6 to 3.7 days and median mucus production from 3.6 g to 1.5 g. The percentage of subjects classified as ill was reduced 2-fold (placebo 48%, PrEP-001 24%, p = 0.064). PrEP-001 reduced peak viral shedding in both studies, as assessed by qRT-PCR of nasal lavage. Seroconversion rates were comparable between placebo and PrEP-001 (Study 1: 77% [both arms]; Study 2: placebo 73%, PrEP-001 80%). PrEP-001 was well-tolerated, with no clinically significant adverse events.

Conclusions: PrEP-001 reduced the number of individuals with clinical illness and attenuated severity and duration of HRV-A16 and H3N2-IAV infections without compromising seroconversion, and was well-tolerated. This supports further evaluation of PrEP-001 as a potential pan-viral prophylaxis for upper respiratory tract infections.

Clinical trial registration: Study 1, HRV-A16 study: EudraCT Number 2012-005579-14 (study conducted before ClinicalTrials.gov registration required). Study 2, H3N2-IAV study: EudraCT Number 2015-002895-26 and ClinicalTrials.gov: NCT03220048.

Keywords: Innate immune response; Nasal; Poly I:C; Prophylaxis; Upper respiratory viral infections; Viral disease.

Copyright © 2018. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
CONSORT diagram.
Fig. 2
Fig. 2
Mean (SE) total symptom scores over time.

References

    1. Caskey M., Lefebvre F., Filali-Mouhim A., Cameron M.J., Goulet J.P., Haddad E.K. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J. Exp. Med. 2011;208(12):2357–2366.
    1. Chidekel A.S., Rosen C.L., Bazzy A.R. Rhinovirus infection associated with serious lower respiratory illness in patients with bronchopulmonary dysplasia. Pediatr. Infect. Dis. J. 1997;16(1):43–47.
    1. Chughtai A.A., Wang Q., Dung T.C., Macintyre C.R. The presence of fever in adults with influenza and other viral respiratory infections. Epidemiol. Infect. 2017;145(1):148–155.
    1. de Clercq E. Degradation of poly(inosinic acid) - poly(cytidylic acid) [(I)n - (C)n] by human plasma. Eur. J. Biochem. 1979;93(1):165–172.
    1. DeVincenzo J., Cehelsky J.E., Alvarez R., Elbashir S., Harborth J., Toudjarska I. Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV) Antivir. Res. 2008;77(3):225–231.
    1. Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect. Dis. 2005;5(11):718–725.
    1. Eccles R. Mechanisms of symptoms of the common cold and influenza. Br. J. Hosp. Med. (Lond) 2007;68(2):71–75.
    1. Fendrick A.M., Monto A.S., Nightengale B., Sarnes M. The economic burden of non- influenza-related viral respiratory tract infection in the United States. Arch. Intern Med. 2003;163(4):487–494.
    1. Fiore A.E., Fry A., Shay D., Gubareva L., Bresee J.S., Uyeki T.M. Antiviral agents for the treatment and chemoprophylaxis of influenza –- recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm. Rep. 2011;60(1):1–24.
    1. Ghosh S., Champlin R., Couch R., Englund J., Raad I., Malik S. Rhinovirus infections in myelosuppressed adult blood and marrow transplant recipients. Clin. Infect. Dis. 1999;29(3):528–532. [see comment]
    1. Gubareva L.V., Kaiser L., Hayden F.G. Infuenza virus nuriminidase inhibitors. Lancet. 2000;355:827–835.
    1. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 2010;11(5):373–384.
    1. Kim J.O., Hodinka R.L. Serious respiratory illness associated with rhinovirus infection in a pediatric population. Clin. Diagn Virol. 1998;10(1):57–65.
    1. Koyama S., Ishii K.J., Coban C., Akira S. Innate immune response to viral infection. Cytokine. 2008;43(3):336–341.
    1. Kumar A., Zhang J., Yu F.S. Toll-like receptor 3 agonist poly(I: C)-induced antiviral response in human corneal epithelial cells. Immunology. 2006;117(1):11–21.
    1. Lee N.L., Wong C.K., Hui D.S., Chan P.K. Role of toll-like receptors in naturally occurring influenza virus infection. Hong Kong Med. J. 2014;20(Suppl. 6):11–15.
    1. Mackay I.M., Arden K.E., Nitsche A. Real-time PCR in virology. Nucleic Acids Res. 2002;30(6):1292–1305.
    1. Mian M.F., Ahmed A.N., Rad M., Babaian A., Bowdish D., Ashkar A.A. Length of dsRNA (poly I: C) drives distinct innate immune responses, depending on the cell type. J. Leukoc. Biol. 2013;94(5):1025–1036.
    1. Mogensen T.H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 2009;22(2):240–273. Table of Contents.
    1. Molinari N.A., Ortega-Sanchez I.R., Messonnier M.L., Thompson W.W., Wortley P.M., Weintraub E. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25(27):5086–5096.
    1. National Institute of Allergy and Infectious Diseases. Common Cold Facts [Available from: .
    1. Nordlund J.J., Wolff S.M., Levy H.B. Inhibition of biologic activity of poly I: poly C by human plasma. Proc. Soc. Exp. Biol. Med. 1970;133(2):439–444.
    1. Pan L.N., Zhu W., Li C., Xu X.L., Guo L.J., Lu Q. Toll-like receptor 3 agonist Poly I: C protects against simulated cerebral ischemia in vitro and in vivo. Acta Pharmacol. Sin. 2012;33(10):1246–1253.
    1. Pichlmair A., Schulz O., Tan C.P., Rehwinkel J., Kato H., Takeuchi O. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J. Virol. 2009;83(20):10761–10769.
    1. Savan R. Post-transcriptional regulation of interferons and their signaling pathways. J. Interferon Cytokine Res. 2014;34(5):318–329.
    1. Slater L., Bartlett N.W., Haas J.J., Zhu J., Message S.D., Walton R.P. Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium. PLoS Pathog. 2010;6(11)
    1. Stowell N.C., Seideman J., Raymond H.A., Smalley K.A., Lamb R.J., Egenolf D.D. Long- term activation of TLR3 by poly(I: C) induces inflammation and impairs lung function in mice. Respir. Res. 2009;10:43.
    1. Takeuchi O., Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–820.
    1. Tan W.C., Xiang X., Qiu D., Ng T.P., Lam S.F., Hegele R.G. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am. J. Med. 2003;115(4):272–277.
    1. Thompson M.R., Kaminski J.J., Kurt-Jones E.A., Fitzgerald K.A. Pattern recognition receptors and the innate immune response to viral infection. Viruses. 2011;3(6):920–940.
    1. Turner R.B. Rhinovirus: more than just a common cold virus. J. Infect. Dis. 2007;195(6):765–766.
    1. Turner R.B., Couch R.B. Rhinoviruses. In: Knipe D.M., Howley P.M., editors. Fields Virology. fifth ed. Lippincott Williams & Williams; Philadelphia: 2007. pp. 895–909.
    1. Weinberger B., Herndler-Brandstetter D., Schwanninger A., Weiskopf D., Grubeck- Loebenstein B. Biology of immune responses to vaccines in elderly persons. Clin. Infect. Dis. 2008;46(7):1078–1084.
    1. Wong J.P., Saravolac E.G., Sabuda D., Levy H.B., Kende M. Prophylactic and therapeutic efficacies of poly() against respiratory influenza A virus infection in mice. Antimicrob. Agents Chemother. 1995;39(11):2574–2576.
    1. Zhao J., Wohlford-Lenane C., Zhao J., Fleming E., Lane T.E., McCray P.B., Jr. Intranasal treatment with poly(I*C) protects aged mice from lethal respiratory virus infections. J. Virol. 2012;86(21):11416–11424.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する