Emerging viruses: risk of pandemic

Abstract

The International Consortium on Anti-Virals (ICAV) is a nonprofit organization that aims to support the development of antivirals for life-threatening and emerging viruses. In recent years, ICAV’s emphasis has been predominantly on tropical viruses and avian influenza. The Sixth International Symposium of the ICAV was held at Trent University, Peterborough, Canada, and at MaRs Discovery District, Toronto, Canada, 4–6 May 2008. Approximately 100 participants representing 12 countries attended the symposium. This meeting report focuses on two thought-provoking presentations on topics that require immediate attention: the development of potent broad-spectrum antivirals against emerging viruses and the assessment of the risk of a H5N1 influenza pandemic.

Antivirals: targeting the host

In recent years, an increasing tide of antiviral research has diverted from the ‘old-school’ belief that a good antiviral drug must specifically and directly target a virus. This assumption was made in order to reduce the putative toxicity of nonspecific drugs acting through the host. However, by focusing on viral targets, such as polymerases, proteases and viral receptors, successful therapy has only been achieved with regards to a limited number of viruses over the past 25 years. Indeed, as mentioned by Eleanor Fish (Toronto General Research Institute, Canada), the potential of nonspecific antiviral molecules, such as interferons, which show antiviral activity against a variety of viruses, needs much more attention. Targeting the host is likely to produce broad-spectrum antivirals that have a better chance to reach third-world countries where emerging viruses are the deadliest. Several promising novel host therapeutic targets for broad-spectrum antiviral activity have been identified and were discussed at this International Consortium on Anti-Virals (ICAV) symposium. Here, the focus will be on data shown by Jonathan P Wong (Defence R&D, Canada), who presented a study on liposome-encapsulated (LE) poly ICLC.

The poly ICLC, which is made of synthetic dsRNA (I:C) complexed with poly-L-lysine and carboxymethylcellulose, is a potent immuno­modulator that induces the secretion of IFN-α, -β and -γ, activates macrophages and natural killer cells, and enhances 2´-5´-oligoadenylate synthase activity [1]. Essentially, poly ICLC triggers a broad-spectrum nonspecific innate immunity through direct interaction with the Toll-like receptor (TLR)-3 present on macrophages and dendritic cells [2].

Engagement of members of the TLR family (1–10) by pathogen-specific molecular patterns, such as dsRNA, CpG, peptidoglycan or lipopolysaccharide, triggers pleiotropic immune responses that help control microorganism infection. Since the ligand for TLR3 is dsRNA, poly ICLC is thought to be helpful against most viruses. In fact, J Wong presented data from several studies performed in mice that show the broad-spectrum protective effect of poly ICLC against various pathogenic viruses, such as Ebola, Western equine encephalitis virus, respiratory syncytial virus, SARS and even H5N1 influenza virus (A/H5N1/chicken/Henan/5/2004) [3,4]. However, poly ICLC is associated with moderate side effects in mice, which include weight loss and a significant decrease in body temperature. Interestingly, convincing data showed that encapsulation of poly ICLC in liposomes (LE poly ICLC) mitigates those side effects and enhances the in vivo stability of the poly ICLC, probably by protecting the dsRNA from RNase degradation, which results in prolonged antiviral effects. In mice, the stability and efficacy of LE poly ICLC were superior to poly ICLC [4]. A characteristic of drugs that induce innate immunity is that the effective response occurs rapidly and, therefore, may change the outcome of ongoing infection if delivered to the appropriate site. In that regard, a nasal spray of LE poly ICLC, which would deliver the drug directly to the respiratory tract, is under development and should be evaluated against airborne viruses, such as SARS and influenza. The broad-spectrum antiviral activity of LE poly ICLC shown in murine models warrants further study. Finally, the data presented did not extensively demonstrate the potential usefulness of this drug after the onset of viral infection. Thus, it may be appropriate to critically compare the efficacy of the LE poly ICLC in both preinfection and following infection by various viruses.

Avian influenza: waiting for the pandemic

Among the viruses that could cause the next pandemic, the highly pathogenic avian influenza (HPAI) is unequivocally the most likely to do so. In fact, world experts, such as Albert Osterhaus (Erasmus MC, The Netherlands), are not wondering if a new avian influenza pandemic will occur but, rather, when? The team led by A Osterhaus was the first to identify a human infection by the HPAI strain H5N1 back in 1997 [5]. Since 2003, the WHO has recorded 382 cases of H5N1 human infection and 241 deaths (63%), with the majority of cases reported in Indonesia and Vietnam. The unusually high fatality rate of the H5N1 strain in humans is reminiscent of that observed in the 1918 avian influenza H1N1 pandemic (Spanish influenza), which killed over 50 million people worldwide. At present, H5N1 is still not properly adapted to humans. The relatively small number of reported zoonotic transmissions and the rare cases of human-to-human transmission of H5N1 indicate that massive doses of virus are required for human transmission. A Osterhaus and others suggested that the absence of H5N1 in the upper respiratory tract in humans limited the excretion of the virus by coughing and restrained human-to-human transmission. Adaptive mutation(s) that could allow the virus to replicate efficiently in both the lower and upper respiratory tracts may well trigger the next pandemic. In that regard, the virus has already acquired an adaptive mutation in the PB2 gene (lysine 627) that improves the viral replication at mammalian body temperatures, thereby, allowing H5N1 replication in the upper respiratory tract of mice [6] and, perhaps, of humans [7]. Since additional mutation/reassortment seems necessary prior to efficient human-to-human transmission, one can ask if the HPAI of the H5N1 subtype will remain prevalent in birds long enough for those mutations to be promoted in humans or mammalian species that can host the virus. It is now known that the register of mammalian hosts for H5N1 includes feline species, such as the leopard, tiger and domestic cat. The proximity of domestic cats with humans and birds is particularly worrisome since it can increase the promiscuous transmission of HPAI to humans.

The worldwide surveillance of H5N1 in migratory birds indicates that wild duck species, particularly mallards, can play a major role as long-distance virus vectors. Unlike most birds infected with HPAI, mallard ducks do not become ill and, thus, may have spread H5N1 across the Middle East, Europe and Africa [8]. Nevertheless, recent genetic analysis of the H5N1 clade present in Africa demonstrated that no new reintroduction of the H5N1 virus has occurred in Africa since 2006. This suggests that unusual water bird movement associated with cold weather in the Black Sea was responsible for the first introduction of H5N1 into Africa. Therefore, will H5N1 fade away? Will a new strain of HPAI replace H5N1? The reported cases of H5N1 in humans for the first few months of 2008 have shown an enhanced mortality rate (73%) and no evidence of a reduction in case number. Therefore, is the world prepared for the next HPAI pandemic?

A Osterhaus doubts that we are adequately protected against such an eventuality. In the event of a pandemic, the production of traditional vaccines based on egg inoculation would take 4–6 months. During this time, the pandemic would spread to millions of individuals, leading to a large number of fatalities. To counteract this scenario, stockpiles of prepandemic vaccines or antivirals such as Tamiflu^® (oseltamavir) and Relenza^® (zanamivir) represent one of the very few options available to minimize the spread and morbidity of the virus. However, a prepandemic vaccine could be completely ineffective and mutations in HPAI of H5N1 subtype that confer resistance to Tamiflu (e.g., H274Y) have already been observed. Furthermore, as stated by Anne Marie Hayes (Roche, USA), Tamiflu must be taken prior to day 6 postinfection with H5N1 in order to achieve any reduction in mortality. Although Tamiflu may represent an extremely valuable tool against the next pandemic, there is no guarantee that the drug would remain active against the emergent HPAI. Obviously, vaccination with the pandemic strains is still the ultimate protection but, as A Osterhaus pointed out, one chicken lays one egg a day and this only gives one vaccine shot; therefore, we are facing a mathematical dilemma. There will be a shortage of eggs required to produce 7 billion shots. Alternative strategies have been discussed, such as the utilization of an adjuvanted vaccine, which would reduce the quantity of antigens required [9]. In addition, moving from egg-based ‘old’-technology vaccine production to ‘state-of-the-art’ cell-culture systems would certainly help to resolve the requirement for eggs as well as shorten the manufacturing time. Will the next HPAI pandemic emerge this year, in the near future, or 10–20 years from now? In the absence of a clear answer, we must improve our preparedness by diversifying our antiviral options.

Conclusion

Endemic and emergent viruses remain important human pandemic threats. Consequently, the development of antivirals should be prioritized. However, because of the uncertain nature of pandemics, the pharmaceutical industry is reluctant to allocate funds to viruses such as Ebola, Lhassa or SARS. The ICAV symposium 2008 brought together researchers from around the world whoare concerned about the lack of antiviral research regarding lethal viruses. Assessment of the ongoing antiviral research in industry clearly indicates that a limited number of viruses are considered and that most emerging viruses are overlooked. Therefore, further applied studies on antivirals, financed by the public sector, are required. For many developing countries, management of viral outbreaks have proven to be extremely difficult. It was pointed out that the development of broad-spectrum antivirals represents an attractive approach to simplifying effective treatment and reducing costs.

Acknowledgments

We thank Dr Lorin Charlton for critically reviewing the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.