REVIEW URRENT C OPINION
Influenza viruses: update on epidemiology, clinical features, treatment and vaccination Mike Kidd
Purpose of review In the last decade, sporadic and lethal human disease caused by zoonotic avian influenza viruses, and the seasonal activity of human H1N1 2009 pandemic type have driven intense epidemiological and laboratory studies into the virus life cycle. This article highlights major developments from mid-2012 to early 2014. Recent findings Advances in molecular techniques and efficient rollout of diagnostic tests have enabled the rapid identification of clinical cases and detailed genetic sequencing of viral genomes. Studies have contributed widely to the understanding of how and when influenza viruses circulate, what determines their innate pathogenicity in particular hosts and whether host cofactors influence disease severity. Other imperatives include investigations into how influenza can be better prevented by vaccination, or treated with antiviral drugs. Summary Avian influenza viruses present a continuous threat to human populations. There is a need for sustained surveillance and downstream research to evaluate the potential for future pandemics. Keywords adjuvant, antiviral, H1N1pdm2009, H5N1, H7N9, influenza
INTRODUCTION Influenza viruses are among the most diverse pathogens known [1]. Of the three major types (A, B and C), influenza A is the most notorious with the ability to reassort segments of its naturally divided genome, producing major new variants for which host immunity may be suboptimal or nonexistent. Influenza B and C viruses have single genomes, but nevertheless have the capacity to evolve by random point mutation accumulation and evade the human immune system from year to year. Influenza C is considered to be a trivial infection in humans; influenza B is sufficiently pathogenic for protection to be warranted by annual vaccination. On a global scale, influenza A is mainly an infection of birds, which is probably the environment where continuous reassortment events take place. The term ‘avian influenza’ describes type A viruses, which primarily circulate in birds; however, some reassorted avian influenza viruses acquire the ability to infect and then transmit efficiently within mammalian species, such as pigs, horses, seals and humans (‘swine’, ‘equine’, ‘phocid’ and ‘human seasonal’ influenzas, respectively). www.co-pulmonarymedicine.com
Probably, only a small proportion of avian pandemics are detected, when the reassorted avian virus is pathogenic enough to affect the health of domestic flocks, for example highly pathogenic avian influenza (HPAI) H5N1. When avian viruses spill over into the human population, further consequences are determined by the ability of the virus to transmit between humans. Critical influential factors are host cell receptor specificity and anatomical location, replicative ability at a site (viral load present in infectious material) and closeness of contact (quantity of infectious material in contact with the host). Although direct infection of humans by avian viruses is apparently a rare event, pigs are suitable intermediate hosts that offer a steppingstone for further viral reassortants that can more readily infect humans. There have been four confirmed human pandemics in the last 100 years UCL Hospitals NHS Foundation Trust, London, UK Correspondence to Mike Kidd, PhD, Clinical Microbiology and Virology, London W1T 4EU, UK. Tel: +44 20 3447 8991; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:242–246 DOI:10.1097/MCP.0000000000000049 Volume 20 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Influenza viruses Kidd
KEY POINTS This article reviews recent developments in surveillance and research into avian influenza and its effects on human populations. The review specifically deals with the continued threat of influenza H5N1 and more recent outbreaks of H7N9, avian viruses that are highly pathogenic to humans. Prospects for a universal influenza vaccine and better antiviral drugs are then considered. The review also reviews the recent association between an adjuvanted vaccine and narcolepsy.
(1918, 1957, 1968 and 2009), and once the pandemic virus becomes a seasonal regularity in humans the background RNA mutation rate is responsible for recirculation of viruses in human populations from year to year [2].
EPIDEMIOLOGY Prior to 2013, the focus of influenza surveillance and research was on human HPAI H5N1. Since the late 1990s, this virus had become established as a pandemic in wild birds and domestic poultry, with a slow but increasing number of human fatalities associated with close exposure to infected birds. Import restrictions and vaccination of poultry flocks had reduced the circulation of the avian virus in recent years, but in 2012 there were reports of outbreaks in south-east Asia associated with reimportation of birds from China [3]. Some outbreaks were in vaccinated flocks, perhaps showing that H5N1 had acquired the ability to escape vaccine immunity. In the last 12–18 months, international influenza briefings and reports have been dominated by the appearance in China of a new influenza A virus affecting humans: H7N9. Similar to HPAI H5N1, H7N9 carries unusually high lethality for humans; current case/fatality ratio for the spring 2013 cases is 137/45, approximately 33% [4 ]. Note that case/ fatality rates may be adjusted downwards as detailed patient-based studies reveal mild or asymptomatic cases that were not detected in the initial reports [5]. Reported H7N9 cases from 2013 showed a tendency to be men, and in older age groups [6,7]. However, in contrast to HPAI H5N1, which causes devastating mortality in the flocks it infects, H7N9 infection appears to be asymptomatic in birds; therefore, it can spread silently through flocks and pose an invisible threat to humans, who become infected during slaughter and preparation of chicken carcasses. &&
Thus, in an ironic role reversal, humans are the sentinels for spread of H7N9 through domestic poultry. Although prompt identification and isolation of human H7N9 cases is standard practice, control of H7N9 infection has been achieved by closing live poultry markets [8 ]. Practical control measures are helped by the natural tendency of influenza viruses to show seasonality, with lower infection rates occurring during warmer, dryer months. Worryingly, at the time of writing (January 2014), another rise in the number of human cases is being recorded in the Eastern provinces of China [9], surpassing the rate of increase in 2013, and poultry market restrictions are being reimplemented. The resurgence of H7N9 infections during the cooler and wetter months generates concern that humans with H7N9 could also be infected with seasonal influenza viruses H1N1pdm2009 and H3N2, which annually circulate in humans. Coinfections offer the opportunity for reassortment of viral gene segments, and selection of a new virus with efficient transmission between humans while retaining a high degree of lethality. Characteristics of the 1918 human influenza H1N1 pandemic virus is evidence that this combination is possible, although there is no evidence that it was indeed a recombinant. In recent years, the approach of molecular epidemiology has been applied to influenza viruses, and H7N9 in particular. As genome sequencing has become widespread, cheaper and more detailed, the size and accuracy of influenza gene sequence databases has improved. Together with information of the animal source, it has been possible to use computational ‘molecular clock’ models to estimate how and when the reassortment events took place that could have occurred to produce a new influenza virus. An early report [10] on H7N9 virus detected in some of the first fatal cases in China provided a detailed analysis of its likely ancestry, with a consensus that it is a triple reassortment of other avian strains: &
(1) Haemagglutinin (H7): 95% identity with avian H7N3 viruses (2011 in Zhejiang). (2) Neuraminidase (N9): 96% identity with avian H11N9 viruses (2010 Czech Republic). (3) Remaining six viral genes: more than 97% identity with widespread avian H9N2 viruses. This highlights the scale of genetic recombination, in the avian environment, of viral gene segments that have previously been detected in geographically diverse locations. Influenza of birds is naturally a gut infection with a probable faecal– oral route of transmission, which can obviously be
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augmented through aerial distribution by migratory birds acquiring infection at lakes, pools and other areas of still water inhabited by infected aquatic wildfowl. As well as H7N9, it is also worth noting that HPAI H5N1 remains a constant threat to human populations; in January 2014, there was the first recorded death in Canada of a patient with H5N1 following return from a visit to China [11]. In the last couple of years, other unusual influenza viruses have been detected in humans; some of which also have potential for severe disease. Two isolated cases of influenza H9N2 were detected in Hong Kong: one elderly man and a 7-year-old boy. Both were independent cases, but only the elderly man had clear contact with poultry. Two cases of H10N8 have recently been detected in China; one was fatal [12]. In the United States, through 2011–2013, there were increasing reports of infection of children and adults with a novel swine influenza type, H3N2v, a variant H3N2 virus previously restricted to circulation in pigs, but which had acquired the M (matrix) gene from human influenza H1N1pdm2009. Just over 300 cases have been confirmed, with evidence of limited spread between humans. Disease was usually mild, but there were 16 hospitalizations and one death in an adult with comorbidities [13 ]. The source of initial infection in most cases has been attributed to close contact with live pigs at agricultural events [14]. This scenario highlights another dimension to the epidemiology of influenza: that there is not just one-way traffic of infection from animals to humans, but that animals can become infected with human seasonal influenza viruses (in this case, pigs were infected with human H1N1pdm2009). Although H3N2v generally causes mild disease, the apparent human–human transmission based on a single gene substitution is of concern. Animal models have shown that the presence of the M gene of H1N1pdm2009 favours adaptation to human cells, and this may be related to efficiency of viral replication generating a higher viral load in the respiratory tract [15 ]. In preparation for H3N2v to be the most likely next pandemic virus, the Centers for Disease Control has prepared a vaccine seed strain suitable for vaccine scale up. &
&&
CLINICAL FEATURES Seasonal human influenza has a wide range of disease severity, but the range of comorbidities associated with severe disease has not changed significantly in the last 2 years. As time has passed since the 2009 H1N1 pandemic, the tendency has been to regard its effects on populations as being overplayed 244
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by global and national health institutions. However, at the end of November 2013, what is probably the most exhaustive analysis of the global effects of H1N1pdm2009 was published [16 ]. This showed that the impact of the pandemic is likely to have been understated, in terms of worldwide fatalities, by approximately 10-fold. Moreover, clear variations in mortality were evident, with approximately 20-fold more fatalities occurring in Central and South America than in Australia, New Zealand and Europe. As the pandemic was first identified in Mexico, the higher mortality in this region – confirmed by this recent study – explains why global and national healthcare institutions were compelled to regard the developing pandemic as having serious consequences. The investigation also confirmed that the majority of fatalities were in individuals younger than 65 years old (65–85%), compared with prepandemic estimates in the same age group (19%). Thus, the impact of H1N1pdm2009 has an extra emphasis on economic, social and other dimensions of ‘lost person years’. &
TREATMENT The mainstay of treatment for influenza throughout 2012–2013 has continued to be oral oseltamivir and inhaled zanamivir, with zanamivir recommended for first line use in immunocompromised patients because of the rapid selection for oseltamivir resistance that occurs within individuals [17]. In the critically ill patients, the preference for double-dose oseltamivir – which found favour among intensive medicine clinicians during the H1N1pdm2009 pandemic – cannot be sustained after reviews of such treatment regimens failed to show significant clinical benefit [18 ,19]. The use of aqueous formulations of both zanamivir and oseltamivir has been mainly in critically ill cases [20], the former recently reviewed in 2013 [21]. In 2012, a novel molecular redesign of zanamivir, wherein multiple copies of the monomeric drug were attached to a carrier molecule, was reported to significantly enhance the effectiveness against early and late influenza infection in vitro [22 ]. Importantly, rather than affecting the release of progeny virions from the cell, the effect was attributable to interference with intracellular trafficking of the initially endocytosed viruses and the subsequent virus/endosome fusion. As viral resistance to the neuraminidase inhibitors is inevitable, alternative drugs for treating influenza are urgently needed. Two such candidates, ‘Inavir’ (laninamivir octanoate) and favipiravir (a pyrazine derivative compound, T-705), are showing sustained promise in clinical trials. &
&
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(1) Inavir is a long-acting neuraminidase inhibitor that only requires once weekly nasal dosing, and in Japanese phase 3 trials a single dose was as effective as a 5-day course of oseltamivir [23]. The same study showed that it is active against oseltamivir-resistant virus, which also makes it potentially useful in a strategy for combination therapy. A multinational phase 2 trial (‘Igloo’) was announced in June 2013 [24], and is expected to conclude in early 2014. (2) Favipiravir is a nucleoside analogue, which undergoes intracellular ribosylation and phosphorylation and acts on viral RNA polymerase in a GTP-competitive manner [25]. The therapeutic index is comparable to ribavirin, and it has widespread activity against other RNA viruses [26 ]. It has also been shown to have potential use for oseltamivir-resistant strains [27]. Phase 2 studies are ongoing, but there have been no recent updates on trial information websites. &
VACCINATION Annual vaccination of susceptible human populations against influenza is routine practice in developed countries. This is necessary because of the antigenic drifting that occurs in the influenza haemagglutinin, potentially allowing the virus to evade the immune response from the previous season. There have been recent developments towards a ‘universal influenza vaccine’, which would stimulate immunity against critical yet more conserved regions of the virus, such as the haemagglutinin stem region [28], internal matrix protein M2 [29] or an amalgamation of target sites (reviewed in [30 ]). It is anticipated that such a vaccine would provide protection against new pandemic strains as well as seasonal variants. Whether such a vaccine would provide an extended period of protection – that is, for greater than one season – is not yet known. However, if such an approach is successful, it would conveniently circumvent a problem that occurs whenever a pandemic is identified: difficulty in producing sufficient antigen quickly enough for a wide coverage vaccine campaign. A previous approach was to use an adjuvant to stimulate the host immune system to better respond to the lower amount of vaccine antigen. Such an adjuvant (AS03, a squalene emulsion) was used in Pandemrix, one of the first vaccines against H1N1pdm2009. Squalene has been used in other human influenza vaccines since 1997 (e.g. MF59), and there is substantial accumulated safety data for that preparation. As part of safety and efficacy trials of a human vaccine &&
against influenza H5N1, AS03 was comprehensively evaluated for a wide range of potential immunosuppressive and neurological side-effects, and Pandemrix received its licence in 2009 in time for widespread use during the approaching winter season and anticipated second wave of H1N1pdm2009. In 2010, a report from Sweden identified a higher proportion of childhood narcolepsy cases than would be expected, in children who had received Pandemrix vaccine. It was followed by a brief concurrent report and a more extensive study from Finland [31], on the apparent association of narcolepsy with Pandemrix. Further investigations in Sweden provided stronger evidence of an association, as did reports from France [32] and the United Kingdom [33]. In December 2013, a larger pan- European study confirmed a link between AS03-adjuvanted vaccine and narcolepsy [34 ], and a biological mechanism was suggested [35]. The consistency of these main studies has prompted the UK government to review the previously rejected claims of compensation [36]. Since the initial reports from Sweden and Finland, Pandemrix has been restricted to use in adults over 20 years of age. After the link between narcolepsy and AS03containing H1N1pdm2009 vaccines was reported from Sweden and Finland, the MF59 manufacturer Novartis conducted a follow-up investigation into whether any similar clinical cases were associated with an H1N1pdm2009 vaccine containing MF59 adjuvant. Using a combination of pharmacovigilance and clinical trials databases, among almost 80 000 vaccinees with more than 5000 reported adverse events, there were no detectable cases of narcolepsy or sleep-related adverse events associated with administration of MF59-adjuvanted vaccines [37,38]. &
CONCLUSION Avian influenza A viruses present a constant threat to human and other animal populations. Continuous surveillance for new cross-species introductions is providing valuable material for research and development, particularly in the field of vaccination and antiviral treatment. Despite setbacks, primarily the adverse events associated with an adjuvanted vaccine, prospects of a nonadjuvanted universal vaccine for influenza are good. Meanwhile, the development of antiviral drugs for treatment of disease is also showing promise. Acknowledgements None.
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Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zambon M. Influenza and other emerging respiratory viruses. Medicine 2014; 42:45–51. 2. Chen R, Holmes EC. Avian influenza virus exhibits rapid evolutionary dynamics. Mol Biol Evol 2006; 23:2336–2341. 3. Avian influenza (56): Vietnam, H5N1, spread: International Society for Infectious Diseases; 2014 [Accessed on 04 January 2014]. http://www.promedmail.org/. 4. World Health Organisation. Number of confirmed human cases of avian && influenza A (H7N9) reported to WHO 2013 [Accessed on 20 January2014]. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/Data_ Reports/en/index.html. An authoritative and up-to-date summary of H7N9 cases and epidemiological analyses. 5. Ip DK, Liao Q, Wu P, et al. Detection of mild to moderate influenza A/H7N9 infection by China’s national sentinel surveillance system for influenza-like illness: case series. BMJ 2013; 346:f3693. 6. Cowling BJ, Freeman G, Wong JY, et al. Preliminary inferences on the agespecific seriousness of human disease caused by avian influenza A(H7N9) infections in China, March to April 2013. Euro Surveill 2013; 18:20475. 7. Skowronski DM, Janjua NZ, Kwindt TL, De Serres G. Virus-host interactions and the unusual age and sex distribution of human cases of influenza A(H7N9) in China, April 2013. Euro Surveill 2013; 18:20465. 8. Yu H, Wu JT, Cowling BJ, et al. Effect of closure of live poultry markets on & poultry-to-person transmission of avian influenza A H7N9 virus: an ecological study. Lancet 2014; 383:541–548. An important objective analysis of the effect of closing bird markets to reduce exposure of humans to avian influenza viruses during outbreaks. 9. Chen E, Chen Y, Fu L, et al. Human infection with avian influenza A(H7N9) virus re-emerges in China in winter 2013. Euro Surveill 2013; 18:20616. 10. Jonges M, Meijer A, Fouchier RA, et al. Guiding outbreak management by the use of influenza A(H7Nx) virus sequence analysis. Euro Surveill 2013; 18:20460. 11. Fonseca K, Lavoie M, Talbot J, et al. Avian influenza, Human (13): Canada ex China (Beijing), H5N1, Fatal, Case Report 2014 [updated 12 January 2014; Accessed on 20 January 2014]. http://www.promedmail.org/direct.php? id=20140112.2167282. 12. Avian Influenza, Human (36): China (Jiangxi) H10N8 2014 [Accessed on 26 January 2014]. http://www.promedmail.org/. 13. Jhung MA, Epperson S, Biggerstaff M, et al. Outbreak of variant influenza & A(H3N2) virus in the United States. Clin Infect Dis 2013; 57:1703–1712. Detailed analysis of the H3N2v outbreak in humans. 14. Wong KK, Gambhir M, Finelli L, et al. Transmissibility of variant influenza from swine to humans: a modeling approach. Clin Infect Dis 2013; 57 (Suppl 1): S16–S22. 15. Pearce MB, Jayaraman A, Pappas C, et al. Pathogenesis and transmission of && swine origin A(H3N2)v influenza viruses in ferrets. Proc Natl Acad Sci U SA 2012; 109:3944–3949. Important demonstration of the influence of the matrix protein in determining viral infectivity. Most of the focus has previously been on the haemagglutinin, and to some extent the neuraminidase proteins. 16. Simonsen L, Spreeuwenberg P, Lustig R, et al. Global mortality estimates for & the 2009 Influenza Pandemic from the GLaMOR project: a modeling study. PLoS Med 2013; 10:e1001558. Large-scale study highlighting the projected global effects of H1N1pdm2009, and suggesting hidden areas of morbidity and mortality. 17. Renzette N, Caffrey DR, Zeldovich KB, et al. Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro. J Virol 2014; 88:272–281.
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18. Lee N, Hui DS, Zuo Z, et al. A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza A and B infections. Clin Infect Dis 2013; 57:1511–1519. Although this study showed no clinical benefit is conferred by double-dose oseltamivir in influenza A or B cases, a clear virologic effect was observed in influenza B cases. 19. South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ 2013; 346:f3039. 20. Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet 2009; 374:1036. 21. Chan-Tack KM, GaoF A. Himaya AC, et al. Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. J Infect Dis 2013; 207:196–198. 22. Lee CM, Weight AK, Haldar J, et al. Polymer-attached zanamivir inhibits & synergistically both early and late stages of influenza virus infection. Proc Natl Acad Sci U SA 2012; 109:20385–20390. An interesting drug-design development, which appears to show that zanamivir can also have an effect on the early stages of the virus lifecycle. 23. Sugaya N, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob Agents Chemother 2010; 54:2575–2582. 24. Efficacy and Safety Study of Laninamivir Octanoate TwinCaps Dry Powder Inhaler in Adults With Influenza (Igloo). ClinicalTrials.gov: National Institues for Health, USA; 2013 [Accessed on 20 January 2014]. http://clinicaltrials.gov/ ct2/show/record/NCT01793883. 25. De Clercq E. Dancing with chemical formulae of antivirals: a panoramic view (Part 2). Biochem Pharmacol 2013; 86:1397–1410. 26. Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA & polymerase inhibitor. Antiviral Res 2013; 100:446–454. This article highlights the antiviral effects of favipiravir on a much wider spectrum of RNA viruses. 27. Tarbet EB, Vollmer AH, Hurst BL, et al. In vitro activity of favipiravir and neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic influenza A (H1N1) virus. Arch Virol 2013. [Epub ahead of print] 28. Chiu C, Wrammert J, Li GM, et al. Cross-reactive humoral responses to influenza and their implications for a universal vaccine. Ann N Y Acad Sci 2013; 1283:13–21. 29. Kumar P, Khanna M, Kumar B, et al. A conserved matrix epitope based DNA vaccine protects mice against influenza A virus challenge. Antiviral Res 2012; 93:78–85. 30. Pica N, Palese P. Toward a universal influenza virus vaccine: prospects and && challenges. Annu Rev Med 2013; 64:189–202. A very readable appraisal of the future options for better influenza vaccines. 31. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PloS One 2012; 7:e33723. 32. Dauvilliers Y, Arnulf I, Lecendreux M, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 2013; 136 (Pt 8):2486–2496. 33. Miller E, Andrews N, Stellitano L, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013; 346:f794. 34. ECDC. Narcolepsy in association with pandemic influenza vaccination & (a multicountry European epidemiological investigation). ECDC; 2012. A comprehensive investigation that confirmed individual national reports of an association between Pandemrix and narcolepsy. 35. De la Herran-Arita AK, Kornum BR, Mahlios J, et al. CD4þ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med 2013; 5:216ra176. 36. Dyer C. UK government is to reconsider claims of children who developed narcolepsy after vaccination. BMJ 2013; 347:f5645. 37. Tsai TF, Crucitti A, Nacci P, et al. Explorations of clinical trials and pharmacovigilance databases of MF59(R)-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011; 43:702–706. 38. Crucitti A, Tsai TF. Explorations of clinical trials and pharmacovigilance databases of MF59(R)-adjuvanted influenza vaccines for associated cases of narcolepsy: a six-month update. Scand J Infect Dis 2011; 43:993. &
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Influenza viruses: update on epidemiology, clinical features, treatment and vaccination Mike Kidd
Purpose of review In the last decade, sporadic and lethal human disease caused by zoonotic avian influenza viruses, and the seasonal activity of human H1N1 2009 pandemic type have driven intense epidemiological and laboratory studies into the virus life cycle. This article highlights major developments from mid-2012 to early 2014. Recent findings Advances in molecular techniques and efficient rollout of diagnostic tests have enabled the rapid identification of clinical cases and detailed genetic sequencing of viral genomes. Studies have contributed widely to the understanding of how and when influenza viruses circulate, what determines their innate pathogenicity in particular hosts and whether host cofactors influence disease severity. Other imperatives include investigations into how influenza can be better prevented by vaccination, or treated with antiviral drugs. Summary Avian influenza viruses present a continuous threat to human populations. There is a need for sustained surveillance and downstream research to evaluate the potential for future pandemics. Keywords adjuvant, antiviral, H1N1pdm2009, H5N1, H7N9, influenza
INTRODUCTION Influenza viruses are among the most diverse pathogens known [1]. Of the three major types (A, B and C), influenza A is the most notorious with the ability to reassort segments of its naturally divided genome, producing major new variants for which host immunity may be suboptimal or nonexistent. Influenza B and C viruses have single genomes, but nevertheless have the capacity to evolve by random point mutation accumulation and evade the human immune system from year to year. Influenza C is considered to be a trivial infection in humans; influenza B is sufficiently pathogenic for protection to be warranted by annual vaccination. On a global scale, influenza A is mainly an infection of birds, which is probably the environment where continuous reassortment events take place. The term ‘avian influenza’ describes type A viruses, which primarily circulate in birds; however, some reassorted avian influenza viruses acquire the ability to infect and then transmit efficiently within mammalian species, such as pigs, horses, seals and humans (‘swine’, ‘equine’, ‘phocid’ and ‘human seasonal’ influenzas, respectively). www.co-pulmonarymedicine.com
Probably, only a small proportion of avian pandemics are detected, when the reassorted avian virus is pathogenic enough to affect the health of domestic flocks, for example highly pathogenic avian influenza (HPAI) H5N1. When avian viruses spill over into the human population, further consequences are determined by the ability of the virus to transmit between humans. Critical influential factors are host cell receptor specificity and anatomical location, replicative ability at a site (viral load present in infectious material) and closeness of contact (quantity of infectious material in contact with the host). Although direct infection of humans by avian viruses is apparently a rare event, pigs are suitable intermediate hosts that offer a steppingstone for further viral reassortants that can more readily infect humans. There have been four confirmed human pandemics in the last 100 years UCL Hospitals NHS Foundation Trust, London, UK Correspondence to Mike Kidd, PhD, Clinical Microbiology and Virology, London W1T 4EU, UK. Tel: +44 20 3447 8991; e-mail: [email protected] Curr Opin Pulm Med 2014, 20:242–246 DOI:10.1097/MCP.0000000000000049 Volume 20 Number 3 May 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Influenza viruses Kidd
KEY POINTS This article reviews recent developments in surveillance and research into avian influenza and its effects on human populations. The review specifically deals with the continued threat of influenza H5N1 and more recent outbreaks of H7N9, avian viruses that are highly pathogenic to humans. Prospects for a universal influenza vaccine and better antiviral drugs are then considered. The review also reviews the recent association between an adjuvanted vaccine and narcolepsy.
(1918, 1957, 1968 and 2009), and once the pandemic virus becomes a seasonal regularity in humans the background RNA mutation rate is responsible for recirculation of viruses in human populations from year to year [2].
EPIDEMIOLOGY Prior to 2013, the focus of influenza surveillance and research was on human HPAI H5N1. Since the late 1990s, this virus had become established as a pandemic in wild birds and domestic poultry, with a slow but increasing number of human fatalities associated with close exposure to infected birds. Import restrictions and vaccination of poultry flocks had reduced the circulation of the avian virus in recent years, but in 2012 there were reports of outbreaks in south-east Asia associated with reimportation of birds from China [3]. Some outbreaks were in vaccinated flocks, perhaps showing that H5N1 had acquired the ability to escape vaccine immunity. In the last 12–18 months, international influenza briefings and reports have been dominated by the appearance in China of a new influenza A virus affecting humans: H7N9. Similar to HPAI H5N1, H7N9 carries unusually high lethality for humans; current case/fatality ratio for the spring 2013 cases is 137/45, approximately 33% [4 ]. Note that case/ fatality rates may be adjusted downwards as detailed patient-based studies reveal mild or asymptomatic cases that were not detected in the initial reports [5]. Reported H7N9 cases from 2013 showed a tendency to be men, and in older age groups [6,7]. However, in contrast to HPAI H5N1, which causes devastating mortality in the flocks it infects, H7N9 infection appears to be asymptomatic in birds; therefore, it can spread silently through flocks and pose an invisible threat to humans, who become infected during slaughter and preparation of chicken carcasses. &&
Thus, in an ironic role reversal, humans are the sentinels for spread of H7N9 through domestic poultry. Although prompt identification and isolation of human H7N9 cases is standard practice, control of H7N9 infection has been achieved by closing live poultry markets [8 ]. Practical control measures are helped by the natural tendency of influenza viruses to show seasonality, with lower infection rates occurring during warmer, dryer months. Worryingly, at the time of writing (January 2014), another rise in the number of human cases is being recorded in the Eastern provinces of China [9], surpassing the rate of increase in 2013, and poultry market restrictions are being reimplemented. The resurgence of H7N9 infections during the cooler and wetter months generates concern that humans with H7N9 could also be infected with seasonal influenza viruses H1N1pdm2009 and H3N2, which annually circulate in humans. Coinfections offer the opportunity for reassortment of viral gene segments, and selection of a new virus with efficient transmission between humans while retaining a high degree of lethality. Characteristics of the 1918 human influenza H1N1 pandemic virus is evidence that this combination is possible, although there is no evidence that it was indeed a recombinant. In recent years, the approach of molecular epidemiology has been applied to influenza viruses, and H7N9 in particular. As genome sequencing has become widespread, cheaper and more detailed, the size and accuracy of influenza gene sequence databases has improved. Together with information of the animal source, it has been possible to use computational ‘molecular clock’ models to estimate how and when the reassortment events took place that could have occurred to produce a new influenza virus. An early report [10] on H7N9 virus detected in some of the first fatal cases in China provided a detailed analysis of its likely ancestry, with a consensus that it is a triple reassortment of other avian strains: &
(1) Haemagglutinin (H7): 95% identity with avian H7N3 viruses (2011 in Zhejiang). (2) Neuraminidase (N9): 96% identity with avian H11N9 viruses (2010 Czech Republic). (3) Remaining six viral genes: more than 97% identity with widespread avian H9N2 viruses. This highlights the scale of genetic recombination, in the avian environment, of viral gene segments that have previously been detected in geographically diverse locations. Influenza of birds is naturally a gut infection with a probable faecal– oral route of transmission, which can obviously be
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augmented through aerial distribution by migratory birds acquiring infection at lakes, pools and other areas of still water inhabited by infected aquatic wildfowl. As well as H7N9, it is also worth noting that HPAI H5N1 remains a constant threat to human populations; in January 2014, there was the first recorded death in Canada of a patient with H5N1 following return from a visit to China [11]. In the last couple of years, other unusual influenza viruses have been detected in humans; some of which also have potential for severe disease. Two isolated cases of influenza H9N2 were detected in Hong Kong: one elderly man and a 7-year-old boy. Both were independent cases, but only the elderly man had clear contact with poultry. Two cases of H10N8 have recently been detected in China; one was fatal [12]. In the United States, through 2011–2013, there were increasing reports of infection of children and adults with a novel swine influenza type, H3N2v, a variant H3N2 virus previously restricted to circulation in pigs, but which had acquired the M (matrix) gene from human influenza H1N1pdm2009. Just over 300 cases have been confirmed, with evidence of limited spread between humans. Disease was usually mild, but there were 16 hospitalizations and one death in an adult with comorbidities [13 ]. The source of initial infection in most cases has been attributed to close contact with live pigs at agricultural events [14]. This scenario highlights another dimension to the epidemiology of influenza: that there is not just one-way traffic of infection from animals to humans, but that animals can become infected with human seasonal influenza viruses (in this case, pigs were infected with human H1N1pdm2009). Although H3N2v generally causes mild disease, the apparent human–human transmission based on a single gene substitution is of concern. Animal models have shown that the presence of the M gene of H1N1pdm2009 favours adaptation to human cells, and this may be related to efficiency of viral replication generating a higher viral load in the respiratory tract [15 ]. In preparation for H3N2v to be the most likely next pandemic virus, the Centers for Disease Control has prepared a vaccine seed strain suitable for vaccine scale up. &
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CLINICAL FEATURES Seasonal human influenza has a wide range of disease severity, but the range of comorbidities associated with severe disease has not changed significantly in the last 2 years. As time has passed since the 2009 H1N1 pandemic, the tendency has been to regard its effects on populations as being overplayed 244
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by global and national health institutions. However, at the end of November 2013, what is probably the most exhaustive analysis of the global effects of H1N1pdm2009 was published [16 ]. This showed that the impact of the pandemic is likely to have been understated, in terms of worldwide fatalities, by approximately 10-fold. Moreover, clear variations in mortality were evident, with approximately 20-fold more fatalities occurring in Central and South America than in Australia, New Zealand and Europe. As the pandemic was first identified in Mexico, the higher mortality in this region – confirmed by this recent study – explains why global and national healthcare institutions were compelled to regard the developing pandemic as having serious consequences. The investigation also confirmed that the majority of fatalities were in individuals younger than 65 years old (65–85%), compared with prepandemic estimates in the same age group (19%). Thus, the impact of H1N1pdm2009 has an extra emphasis on economic, social and other dimensions of ‘lost person years’. &
TREATMENT The mainstay of treatment for influenza throughout 2012–2013 has continued to be oral oseltamivir and inhaled zanamivir, with zanamivir recommended for first line use in immunocompromised patients because of the rapid selection for oseltamivir resistance that occurs within individuals [17]. In the critically ill patients, the preference for double-dose oseltamivir – which found favour among intensive medicine clinicians during the H1N1pdm2009 pandemic – cannot be sustained after reviews of such treatment regimens failed to show significant clinical benefit [18 ,19]. The use of aqueous formulations of both zanamivir and oseltamivir has been mainly in critically ill cases [20], the former recently reviewed in 2013 [21]. In 2012, a novel molecular redesign of zanamivir, wherein multiple copies of the monomeric drug were attached to a carrier molecule, was reported to significantly enhance the effectiveness against early and late influenza infection in vitro [22 ]. Importantly, rather than affecting the release of progeny virions from the cell, the effect was attributable to interference with intracellular trafficking of the initially endocytosed viruses and the subsequent virus/endosome fusion. As viral resistance to the neuraminidase inhibitors is inevitable, alternative drugs for treating influenza are urgently needed. Two such candidates, ‘Inavir’ (laninamivir octanoate) and favipiravir (a pyrazine derivative compound, T-705), are showing sustained promise in clinical trials. &
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Influenza viruses Kidd
(1) Inavir is a long-acting neuraminidase inhibitor that only requires once weekly nasal dosing, and in Japanese phase 3 trials a single dose was as effective as a 5-day course of oseltamivir [23]. The same study showed that it is active against oseltamivir-resistant virus, which also makes it potentially useful in a strategy for combination therapy. A multinational phase 2 trial (‘Igloo’) was announced in June 2013 [24], and is expected to conclude in early 2014. (2) Favipiravir is a nucleoside analogue, which undergoes intracellular ribosylation and phosphorylation and acts on viral RNA polymerase in a GTP-competitive manner [25]. The therapeutic index is comparable to ribavirin, and it has widespread activity against other RNA viruses [26 ]. It has also been shown to have potential use for oseltamivir-resistant strains [27]. Phase 2 studies are ongoing, but there have been no recent updates on trial information websites. &
VACCINATION Annual vaccination of susceptible human populations against influenza is routine practice in developed countries. This is necessary because of the antigenic drifting that occurs in the influenza haemagglutinin, potentially allowing the virus to evade the immune response from the previous season. There have been recent developments towards a ‘universal influenza vaccine’, which would stimulate immunity against critical yet more conserved regions of the virus, such as the haemagglutinin stem region [28], internal matrix protein M2 [29] or an amalgamation of target sites (reviewed in [30 ]). It is anticipated that such a vaccine would provide protection against new pandemic strains as well as seasonal variants. Whether such a vaccine would provide an extended period of protection – that is, for greater than one season – is not yet known. However, if such an approach is successful, it would conveniently circumvent a problem that occurs whenever a pandemic is identified: difficulty in producing sufficient antigen quickly enough for a wide coverage vaccine campaign. A previous approach was to use an adjuvant to stimulate the host immune system to better respond to the lower amount of vaccine antigen. Such an adjuvant (AS03, a squalene emulsion) was used in Pandemrix, one of the first vaccines against H1N1pdm2009. Squalene has been used in other human influenza vaccines since 1997 (e.g. MF59), and there is substantial accumulated safety data for that preparation. As part of safety and efficacy trials of a human vaccine &&
against influenza H5N1, AS03 was comprehensively evaluated for a wide range of potential immunosuppressive and neurological side-effects, and Pandemrix received its licence in 2009 in time for widespread use during the approaching winter season and anticipated second wave of H1N1pdm2009. In 2010, a report from Sweden identified a higher proportion of childhood narcolepsy cases than would be expected, in children who had received Pandemrix vaccine. It was followed by a brief concurrent report and a more extensive study from Finland [31], on the apparent association of narcolepsy with Pandemrix. Further investigations in Sweden provided stronger evidence of an association, as did reports from France [32] and the United Kingdom [33]. In December 2013, a larger pan- European study confirmed a link between AS03-adjuvanted vaccine and narcolepsy [34 ], and a biological mechanism was suggested [35]. The consistency of these main studies has prompted the UK government to review the previously rejected claims of compensation [36]. Since the initial reports from Sweden and Finland, Pandemrix has been restricted to use in adults over 20 years of age. After the link between narcolepsy and AS03containing H1N1pdm2009 vaccines was reported from Sweden and Finland, the MF59 manufacturer Novartis conducted a follow-up investigation into whether any similar clinical cases were associated with an H1N1pdm2009 vaccine containing MF59 adjuvant. Using a combination of pharmacovigilance and clinical trials databases, among almost 80 000 vaccinees with more than 5000 reported adverse events, there were no detectable cases of narcolepsy or sleep-related adverse events associated with administration of MF59-adjuvanted vaccines [37,38]. &
CONCLUSION Avian influenza A viruses present a constant threat to human and other animal populations. Continuous surveillance for new cross-species introductions is providing valuable material for research and development, particularly in the field of vaccination and antiviral treatment. Despite setbacks, primarily the adverse events associated with an adjuvanted vaccine, prospects of a nonadjuvanted universal vaccine for influenza are good. Meanwhile, the development of antiviral drugs for treatment of disease is also showing promise. Acknowledgements None.
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Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Zambon M. Influenza and other emerging respiratory viruses. Medicine 2014; 42:45–51. 2. Chen R, Holmes EC. Avian influenza virus exhibits rapid evolutionary dynamics. Mol Biol Evol 2006; 23:2336–2341. 3. Avian influenza (56): Vietnam, H5N1, spread: International Society for Infectious Diseases; 2014 [Accessed on 04 January 2014]. http://www.promedmail.org/. 4. World Health Organisation. Number of confirmed human cases of avian && influenza A (H7N9) reported to WHO 2013 [Accessed on 20 January2014]. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/Data_ Reports/en/index.html. An authoritative and up-to-date summary of H7N9 cases and epidemiological analyses. 5. Ip DK, Liao Q, Wu P, et al. Detection of mild to moderate influenza A/H7N9 infection by China’s national sentinel surveillance system for influenza-like illness: case series. BMJ 2013; 346:f3693. 6. Cowling BJ, Freeman G, Wong JY, et al. Preliminary inferences on the agespecific seriousness of human disease caused by avian influenza A(H7N9) infections in China, March to April 2013. Euro Surveill 2013; 18:20475. 7. Skowronski DM, Janjua NZ, Kwindt TL, De Serres G. Virus-host interactions and the unusual age and sex distribution of human cases of influenza A(H7N9) in China, April 2013. Euro Surveill 2013; 18:20465. 8. Yu H, Wu JT, Cowling BJ, et al. Effect of closure of live poultry markets on & poultry-to-person transmission of avian influenza A H7N9 virus: an ecological study. Lancet 2014; 383:541–548. An important objective analysis of the effect of closing bird markets to reduce exposure of humans to avian influenza viruses during outbreaks. 9. Chen E, Chen Y, Fu L, et al. Human infection with avian influenza A(H7N9) virus re-emerges in China in winter 2013. Euro Surveill 2013; 18:20616. 10. Jonges M, Meijer A, Fouchier RA, et al. Guiding outbreak management by the use of influenza A(H7Nx) virus sequence analysis. Euro Surveill 2013; 18:20460. 11. Fonseca K, Lavoie M, Talbot J, et al. Avian influenza, Human (13): Canada ex China (Beijing), H5N1, Fatal, Case Report 2014 [updated 12 January 2014; Accessed on 20 January 2014]. http://www.promedmail.org/direct.php? id=20140112.2167282. 12. Avian Influenza, Human (36): China (Jiangxi) H10N8 2014 [Accessed on 26 January 2014]. http://www.promedmail.org/. 13. Jhung MA, Epperson S, Biggerstaff M, et al. Outbreak of variant influenza & A(H3N2) virus in the United States. Clin Infect Dis 2013; 57:1703–1712. Detailed analysis of the H3N2v outbreak in humans. 14. Wong KK, Gambhir M, Finelli L, et al. Transmissibility of variant influenza from swine to humans: a modeling approach. Clin Infect Dis 2013; 57 (Suppl 1): S16–S22. 15. Pearce MB, Jayaraman A, Pappas C, et al. Pathogenesis and transmission of && swine origin A(H3N2)v influenza viruses in ferrets. Proc Natl Acad Sci U SA 2012; 109:3944–3949. Important demonstration of the influence of the matrix protein in determining viral infectivity. Most of the focus has previously been on the haemagglutinin, and to some extent the neuraminidase proteins. 16. Simonsen L, Spreeuwenberg P, Lustig R, et al. Global mortality estimates for & the 2009 Influenza Pandemic from the GLaMOR project: a modeling study. PLoS Med 2013; 10:e1001558. Large-scale study highlighting the projected global effects of H1N1pdm2009, and suggesting hidden areas of morbidity and mortality. 17. Renzette N, Caffrey DR, Zeldovich KB, et al. Evolution of the influenza A virus genome during development of oseltamivir resistance in vitro. J Virol 2014; 88:272–281.
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18. Lee N, Hui DS, Zuo Z, et al. A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza A and B infections. Clin Infect Dis 2013; 57:1511–1519. Although this study showed no clinical benefit is conferred by double-dose oseltamivir in influenza A or B cases, a clear virologic effect was observed in influenza B cases. 19. South East Asia Infectious Disease Clinical Research Network. Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial. BMJ 2013; 346:f3039. 20. Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet 2009; 374:1036. 21. Chan-Tack KM, GaoF A. Himaya AC, et al. Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. J Infect Dis 2013; 207:196–198. 22. Lee CM, Weight AK, Haldar J, et al. Polymer-attached zanamivir inhibits & synergistically both early and late stages of influenza virus infection. Proc Natl Acad Sci U SA 2012; 109:20385–20390. An interesting drug-design development, which appears to show that zanamivir can also have an effect on the early stages of the virus lifecycle. 23. Sugaya N, Ohashi Y. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection. Antimicrob Agents Chemother 2010; 54:2575–2582. 24. Efficacy and Safety Study of Laninamivir Octanoate TwinCaps Dry Powder Inhaler in Adults With Influenza (Igloo). ClinicalTrials.gov: National Institues for Health, USA; 2013 [Accessed on 20 January 2014]. http://clinicaltrials.gov/ ct2/show/record/NCT01793883. 25. De Clercq E. Dancing with chemical formulae of antivirals: a panoramic view (Part 2). Biochem Pharmacol 2013; 86:1397–1410. 26. Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA & polymerase inhibitor. Antiviral Res 2013; 100:446–454. This article highlights the antiviral effects of favipiravir on a much wider spectrum of RNA viruses. 27. Tarbet EB, Vollmer AH, Hurst BL, et al. In vitro activity of favipiravir and neuraminidase inhibitor combinations against oseltamivir-sensitive and oseltamivir-resistant pandemic influenza A (H1N1) virus. Arch Virol 2013. [Epub ahead of print] 28. Chiu C, Wrammert J, Li GM, et al. Cross-reactive humoral responses to influenza and their implications for a universal vaccine. Ann N Y Acad Sci 2013; 1283:13–21. 29. Kumar P, Khanna M, Kumar B, et al. A conserved matrix epitope based DNA vaccine protects mice against influenza A virus challenge. Antiviral Res 2012; 93:78–85. 30. Pica N, Palese P. Toward a universal influenza virus vaccine: prospects and && challenges. Annu Rev Med 2013; 64:189–202. A very readable appraisal of the future options for better influenza vaccines. 31. Partinen M, Saarenpaa-Heikkila O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PloS One 2012; 7:e33723. 32. Dauvilliers Y, Arnulf I, Lecendreux M, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain 2013; 136 (Pt 8):2486–2496. 33. Miller E, Andrews N, Stellitano L, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013; 346:f794. 34. ECDC. Narcolepsy in association with pandemic influenza vaccination & (a multicountry European epidemiological investigation). ECDC; 2012. A comprehensive investigation that confirmed individual national reports of an association between Pandemrix and narcolepsy. 35. De la Herran-Arita AK, Kornum BR, Mahlios J, et al. CD4þ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med 2013; 5:216ra176. 36. Dyer C. UK government is to reconsider claims of children who developed narcolepsy after vaccination. BMJ 2013; 347:f5645. 37. Tsai TF, Crucitti A, Nacci P, et al. Explorations of clinical trials and pharmacovigilance databases of MF59(R)-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011; 43:702–706. 38. Crucitti A, Tsai TF. Explorations of clinical trials and pharmacovigilance databases of MF59(R)-adjuvanted influenza vaccines for associated cases of narcolepsy: a six-month update. Scand J Infect Dis 2011; 43:993. &
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