Evaluation of oseltamivir prophylaxis regimens for reducing influenza virus infection, transmission and disease severity in a ferret model of household contact

Abstract

Objectives: The emergence of the pandemic influenza A(H1N1)pdm09 virus in 2009 saw a significant increase in the therapeutic and prophylactic use of neuraminidase inhibitors (NAIs) to mitigate the impact of this highly transmissible virus. Prior to the pandemic, many countries stockpiled NAIs and developed pandemic plans for the use of antiviral drugs, based on either treatment of high-risk individuals and/or prophylaxis of contacts. However, to date there has been a lack of in vivo models to test the efficacy of treatment or prophylaxis with NAIs, for influenza-infected individuals or exposed contacts, in a household setting.

Methods: A ferret model of household contact was developed to study the efficacy of different prophylaxis regimens in preventing infection in contact ferrets exposed to influenza A(H1N1)pdm09-infected index ferrets.

Results: Among the different prophylactic regimens, contact ferrets receiving oseltamivir prophylaxis twice daily showed better outcomes than those receiving oseltamivir once daily. Benefits included a significant delay in the time to secondary infection, lower weight loss and higher activity levels. The treatment of index ferrets at 36 h post-infection did not influence either secondary infection rates or clinical symptoms in exposed contact ferrets. Neither prophylaxis nor treatment prevented infection or reduced the duration of viral shedding, although clinical symptoms did improve in infected animals receiving prophylaxis.

Conclusions: Different oseltamivir prophylaxis regimens did not prevent infections, but consistently resulted in a reduction in symptoms in infected ferrets. However, oseltamivir prophylaxis failed to reduce viral titres, which warrants further investigation in humans.

Keywords: A(H1N1)pdm09; antiviral; neuraminidase inhibitors; pandemic.

Figure 1.

Experimental outline of the treatment and prophylaxis regimens used. (a) Pre- and (b) post-exposure prophylaxis of contact ferrets (C; blue) 24 h prior to or 24 h after A(H1N1)pdm09 exposure to NI index ferrets (green) in a co-housed environment. NI ferrets were infected by co-housing with AI index ferrets (red) for 48 h. Experiments in (a) and (b) were carried out once. (c) Post-exposure prophylaxis of contact ferrets following 12 h of exposure to AI ferrets. (d) Treatment of AI ferrets after 36 h post-infection (p.i.) with A(H1N1)pdm09. Experiments in (c) and (d) were carried out twice. SID, 5 mg/kg oseltamivir once daily; BID, 5 mg/kg oseltamivir twice daily. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Clinical symptoms of contact ferrets receiving 24 h pre-exposure prophylaxis. (a) Proportion of uninfected contact ferrets (SID versus BID versus no intervention, *P < 0.05; log-rank test for trend in Kaplan–Meier curve). (b) Percentage weight loss. (c) Body temperature. (d) Activity score of treated contact ferrets relative to ferrets with no intervention. (e) Virus titre in nasal washes. (f) Serum antibody titre. Contact ferrets, n = 6 in each group. For (b), (c), (d) and (e), data are mean ± SEM. SID 24 h pre-exposure versus no intervention, #P < 0.05, ###P < 0.001; BID 24 h pre-exposure versus no intervention, *P < 0.05, **P < 0.01, ***P < 0.001; two-tailed unpaired t-test. SID, 5 mg/kg oseltamivir once daily; BID, 5 mg/kg oseltamivir twice daily.

Figure 3.

Clinical symptoms of contact ferrets receiving 24 h post-exposure prophylaxis. (a) Proportion of uninfected contacts. (b) Percentage weight loss. (c) Body temperature. (d) Relative activity score of treated contact ferrets compared with ferrets with no intervention. (e) Virus titre in nasal washes. (f) Serum antibody titre. Contact ferrets, n = 6 in each group. For (b), (c), (d) and (e), data are mean ± SEM. SID 24 h post-exposure versus no intervention, #P < 0.05, ##P < 0.01, ###P < 0.001; BID 24 h post-exposure versus no intervention, *P < 0.05, **P < 0.01, ***P < 0.001; SID 24 h post-exposure versus no BID 24 h post-exposure, @P < 0.05, @@P < 0.01; two-tailed unpaired t-test. SID, 5 mg/kg oseltamivir once daily; BID, 5 mg/kg oseltamivir twice daily.

Figure 4.

Clinical symptoms of contact ferrets receiving 12 h post-exposure prophylaxis. (a) Proportion of uninfected contacts [*P < 0.05, log-rank test (Mantel–Cox) on Kaplan–Meier curve]. (b) Percentage weight loss. (c) Body temperature. (d) Relative activity score of treated contact ferrets compared with ferrets with no intervention. (e) Virus titre in nasal washes. (f) Serum antibody titre. Contact ferrets, n = 12 in each group. For (b), (c) and (d), data are mean ± SEM of all individual ferrets from two independent experiments. Contact BID 12 h post-exposure versus no intervention, *P < 0.05, ***P < 0.001; two-tailed unpaired t-test. BID, 5 mg/kg oseltamivir twice daily.

Figure 5.

Clinical symptoms of untreated contact ferrets co-housed with oseltamivir-treated index ferrets 36 h post-infection (p.i.). (a) Proportion of uninfected contacts. (b) Percentage weight loss. (c) Body temperature. (d) Relative activity score of treated contact ferrets compared with ferrets with no intervention. (e) Virus titre in nasal washes. (f) Serum antibody titre. Contact ferrets, n = 12 in each group. For (b), (c) and (d), data are mean ± SEM of all individual ferrets from two independent experiments. BID index 36 h p.i. versus no intervention: #P < 0.05; two-tailed unpaired t-test. BID, 5 mg/kg oseltamivir twice daily.