Preparing for the Next Pandemic

Osterholm, Michael T.

doi:10.1056/nejmp058068

Cited by 550 publications

(289 citation statements)

References 4 publications

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“…Furthermore, oseltamivir has been shown to ease influenza-re-lated clinical symptoms of seasonal strains (18)(19)(20)(21). Many countries have now included the use of oseltamivir as a major component of their influenza pandemic preparedness strategies (22)(23)(24)(25), and it was used extensively in patients experiencing both mild and severe influenza-related symptoms during the 2009 pandemic (18,26).…”

mentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

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During the first wave of the 2009 pandemic, caused by a H1N1 influenza virus (pH1N1) of swine origin, antivirals were the only form of therapeutic available to control the proliferation of disease until the conventional strain-matched vaccine was produced. Oseltamivir is an antiviral that inhibits the sialidase activity of the viral neuraminidase (NA) protein and was shown to be effective against pH1N1 viruses in ferrets. Furthermore, it was used in humans to treat infections during the pandemic and is still used for current infections without reported complication or exacerbation of illness. However, in an evaluation of the effectiveness of oseltamivir against pH1N1 infection, we unexpectedly observed an exacerbation of disease in virus-infected mice treated with oseltamivir, transforming an otherwise mild illness into one with high morbidity and mortality. In contrast, an identical treatment regime alleviated all signs of illness in mice infected with the pathogenic mouse-adapted virus A/WSN/33 (H1N1). The worsened clinical outcome with pH1N1 viruses occurred over a range of oseltamivir doses and treatment schedules and was directly linked to a reduction in NA enzymatic activity. Our results suggest that the suppression of NA activity with antivirals may exacerbate disease in a host-dependent manner by increasing replicative fitness in viruses that are not optimally adapted for replication in that host. IMPORTANCEHere, we report that treatment of pH1N1-infected mice with oseltamivir enhanced disease progression, transforming a mild illness into a lethal infection. This raises a potential pitfall of using the mouse model for evaluation of the therapeutic efficacy of neuraminidase inhibitors. We show that antiviral efficacy determined in a single animal species may not represent treatment in humans and that caution should be used when interpreting the outcome. Furthermore, increased virulence due to oseltamivir treatment was the effect of a shift in the hemagglutinin (HA) and neuraminidase (NA) activity balance. This is the first study that has demonstrated that altering the HA/NA activity balance by reduction in NA activity can result in an increase in virulence in any animal model from nonpathogenic to lethal and the first to demonstrate a situation in which treatment with a NA activity inhibitor has an effect opposite to the intended therapeutic effect of ameliorating the infection.

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confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

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“…This hypothesis suggests opportunities for prevention and treatment during the next pandemic (e.g., with bacterial vaccines and antimicrobial drugs), particularly if a pandemic strain-specifi c vaccine is unavailable or inaccessible to isolated, crowded, or medically underserved populations. M any infl uenza experts, policy makers, and knowledgeable observers believe that a novel infl uenza A (H1N1) strain directly caused most deaths during the 1918-19 pandemic, often from a hemorrhagic pneumonitis that rapidly progressed to acute respiratory distress syndrome and death (1)(2)(3). Not surprisingly, plans and resources to respond to the next infl uenza pandemic focus almost exclusively on the virus, i.e., preventive vaccines and antiviral treatment of infections with a novel infl uenza strain (4).…”

mentioning

confidence: 99%

Deaths from Bacterial Pneumonia during 1918–19 Influenza Pandemic

Brundage

Shanks²

2008

Emerg. Infect. Dis.

341

308

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“…The question is whether it will be caused by H5N1, the avian influenza virus strain, or one of the previously known human influenza strains [52]. The recent avian influenza outbreak in east Asia has met two of the three widely recognized prerequisites for a human pandemic:…”

Section: Pandemic Influenza -Human and Avian Influenza Virusesmentioning

confidence: 99%

Potential Agents of Bioterrorism: Historical Perspective and an Overview

Khardori

2006

Bioterrorism Preparedness

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Preparing for the Next Pandemic

Cited by 550 publications

References 4 publications

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Deaths from Bacterial Pneumonia during 1918–19 Influenza Pandemic

Potential Agents of Bioterrorism: Historical Perspective and an Overview

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