More than 1550 cases of influenza A(H7N9) have been diagnosed over the past several years with annual waves and a crude mortality of about 40%. During the fifth wave in the winter of 2016–2017, there was a large increase in human cases with 759 reported cases from 10 provinces. Two divergent genetic lineages of the viruses emerged and some A(H7N9) viruses had mutations conferring decreased susceptibility to neuramininidase inhibitors . In 2018–2019, almost no human cases of A(H7N9) were diagnosed. The reasons for this rapid decrease are not known but may at least in part reflect aggressive efforts to control A(H7N9) in poultry, including vaccination of flocks and efforts to limit human contact with birds in live markets. At least 40 limited clusters of human to human transmission of influenza A(H7N9) have been identified but so far the transmissibility has remained low [14▪].
Another tool of pandemic response is the ability to use scientific tools during the pandemic to rapidly get answers to critical questions, such as disease severity or the effectiveness of vaccines or antivirals. The pandemic plan outlines ways to more effectively conduct real-time science – efforts that proved frustrating during the 2009 A(H1N1) pandemic. A key lesson from 2009 was the need to rapidly understand severity to scale the response. Rapid severity assessment and stratified responses by severity are incorporated into the national plan and could be implemented at level of the healthcare system.
Public health planners have promoted nonpharmaceutical interventions as a tool to slow the spread of influenza through a community, allowing time for vaccine development and reducing the stress on the healthcare system. Historical evidence suggests a role for nonpharmaceutical interventions, such as school closure, limiting public gatherings and social distancing in slowing transmission and delaying the peak of a pandemic . Lessons learned from the 2009 pandemic and extensive modeling work are included in the guidelines. Unfortunately, the evidence base on the effectiveness and optimal implementation of many of these interventions remains limited [16,17]. CDC has revised their guidelines for community mitigation for pandemic influenza . Although CDC provides guidance, implementation of these interventions will be conducted at the local level.
Annual influenza epidemics stress healthcare facilities; an influenza pandemic will likely overwhelm the healthcare system . Healthcare facilities play a critical role in supporting a response to an influenza pandemic. They must develop response strategies internally and link these strategies with local and national public health guidance and resources. A critical role of public health authorities is to develop, maintain and deploy stockpiles of critical countermeasures, including antivirals, antibiotics, ventilators and personal protective equipment, including surgical masks and respirators [19,20]. Details on the contents of the Strategic National Stockpile (SNS) are classified, but a workshop held by the National Academy of Sciences, Engineering and Medicine identified many opportunities to improve the efficiency, effectiveness, sustainability and distribution of countermeasures in the SNS [21▪].
Vaccines have been and will remain a key strategy in dealing with a pandemic. The types of vaccines available for the prevention of seasonal influenza have expanded over the last few years [22▪▪]. Currently available vaccines are developed to protect against three (trivalent; two influenza A and 1 influenza B strains) or four (quadrivalent; two influenza A and B strains). Available vaccines include egg-grown inactivated trivalent and quadrivalent vaccines (IIV3 and IIV4), cell culture-grown quadrivalent inactivated vaccine (ccIIV4), recombinant quadrivalent vaccine (RIV4), live attenuated quadrivalent vaccine (LAIV4) and two formulations targeted for adults 65 years and older: high-dose quadrivalent egg-grown inactivated vaccine (HD-IIV4) and MF59 adjuvanted egg-grown trivalent vaccine(AIIV3). The Advisory Committee on Immunization Practices (ACIP) develops guidelines for the United States that are also influential in many other countries. These guidelines recommend that all persons over the age of 6 months receive an annual influenza vaccine. Furthermore, the guidelines recommend that persons with a history of egg allergy of any severity may receive any licensed, recommended and age-appropriate influenza vaccine (IIV, RIV4 or LAIV4). The high-dose vaccine induces higher antibody levels and demonstrated 24% greater relative to standard dose IIV against laboratory confirmed influenza  in a randomized trial and a relative mortality benefit among Medicare beneficiaries over the age of 65 . Adjuvanted vaccine demonstrated 63% higher relative effectiveness compared to standard IIV3 in a single season case–control study .
The effectiveness of existing seasonal influenza vaccines varies by season and ranges from no statistically significant benefit to ∼60% protection. Ongoing challenges include: periodic mismatch between vaccine strain and circulating strains, host factors leading to reduced immunogenicity in the very young and those with decreased immune function (including the elderly), the effect of prior infection and vaccination and the long lag time required between strain selection and vaccine availability for egg-based vaccines. Recent attention has focused on the impact on immunogenicity of H3N2 vaccines due to antigenic changes that develop during adaptation of the virus to efficient growth in eggs [26,27]. Supporting this is a study showing that cell culture-grown influenza vaccine was 9–10% more effective than egg-grown IIV during the 2017–2018 season [28▪]. Despite improvements in the domestic capacity for vaccine production, current technology is neither sufficiently rapid nor scalable; the time required to produce adequate quantities of a specific pandemic vaccine remains about 5–6 months. The limitations of existing seasonal vaccines for seasonal needs as well as for a pandemic have added urgency to the quest for more rapid and flexible platforms and for a ‘universal’ influenza vaccine [29,30▪▪,31,32▪].
Rapid influenza detection tests (RIDTs) are rapid and relatively inexpensive, but their low-to-moderate sensitivity (median about 65%, reviewed in [34▪▪]) leads to low negative predictive value. However, despite the limitations of these older tests, studies have shown that the use of RIDTs leads to increased use of antivirals, decreased antibiotic use and fewer ancillary tests [34▪▪]. In a major development in the field, at least 13 molecular diagnostic assays that can deliver results in less than 3 h have been produced. A recent meta-analysis of rapid molecular tests showed that the pooled sensitivity was 90.9% [95% confidence interval (CI), 88.7–93.1%] and the pooled specificity was 96.1% (95% CI, 94.2–97.9%) [35▪].
The dominant mode of influenza spread is thought to be via large droplet and fomites. Hand hygiene and standard precautions, which include respiratory etiquette, are key measures to prevent transmission. The CDC further recommends the use of droplet precautions (mask) for 7 days after illness onset for patients with confirmed or suspected influenza in healthcare settings [42▪▪]. Some experts recommend the use of droplet and contact precautions (gowns and gloves) for all respiratory viruses in healthcare settings. This may be recommended in the setting of emergence of a novel virus. Recent experimental data have demonstrated that influenza RNA and even infectious virus can be detected in small particles in the vicinity of infected persons [43,44]. It seems likely that aerosol transmission can occur in from some patients in some setting; however, the contribution of true aerosols to influenza transmission is unknown . Trials comparing N95 respirators to surgical masks have not demonstrated superior protection by devices that protect against small droplets [46,47]. The ResPECT trial, a large cluster-randomized trial comparing N95 respirators to masks for the prevention of influenza in healthcare personnel, did not show a difference [48▪]. Respiratory protection against small droplets may be more critical in a pandemic when the mortality is high and before an effective vaccine is available. Challenges include maintaining a stockpile and supply chain, messaging and the difficulty of providing care while wearing a respirator especially during an emergency.
Pimodivir (Johnson and Johnson, New Brunswick, NJ, USA) is an inhibitor of the PB2 portion of the polymerase complex that has been evaluated in phase 2B study. The trial was stopped early because the primary virologic endpoint was met. A total of 283 patients were randomized to receive a twice-daily oral dose of pimodivir 300 mg, pimodivir 600 mg, combination therapy with pimodivir 600 mg and oseltamivir 75 mg, or placebo . A significant reduction in the area under the virus load curve was seen in all pimodivir containing arms by both PCR and viral culture. The reduction in viral area under the curve measured by PCR was greater in the combination therapy arm than monotherapy with pimodivir. Samples obtained during treatment showed mutations conferring reduced susceptibility to pimodivir in 11 patients. On the basis of the efficacy benefits of combination antiviral therapy for HIV and Hepatitis C and reduction of the treatment emergent resistance, as well as preliminary data in influenza, there is great interest in combination therapy for influenza using drugs with different mechanisms of action [49▪].
We have made substantial progress in preparing for an influenza pandemic. Planning has evolved aided by modeling, surveillance and molecular characterization are vastly improved and plans for use of the SNS have improved. Incremental improvements in vaccines have been made and the pace of vaccine research has increased. Rapid point of care molecular diagnostics are in limited use. We are on the verge of studies of combination antiviral therapy that might greatly improve treatment. Enormous challenges remain. These include gaps in basic understanding, limited resources to develop the SNS, the need for faster, more scalable and more effective vaccine platforms and limitations of medical supply chains and clinical surge capacity. Improvements in each area are achievable but will require a level of political awareness of the threat and commitment of resources that we have not yet seen.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Morens DM, Taubenberger JK. Influenza cataclysm, 1918. N Engl J Med 2018; 379:2285–2287.
2. Smith W, Andrewes CH, Laidlaw PP. A virus obtained from influenza patients. Lancet 1933; 2:66–68.
3. Tumpey TM, Basler CF, Aguilar PV, et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 2005; 310:77–80.
4. Jester B, Uyeki T, Jernigan D. Readiness for responding to a severe pandemic 100 years after 1918. Am J Epidemiol 2018; 187:2596–2602.
5▪. Belser JA, Maines TR, Tumpey TM. Importance of 1918 virus reconstruction to current assessments of pandemic risk. Virology 2018; 524:45–55.
Reviews the insights gained from experiments with the reconstructed 1918 influenza virus.
6. Fukao K, Noshi T, Yamamoto A, et al. Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. J Antimicrob Chemother 2019; 74:654–662.
Comprehensive document outlining the most recent pandemic influenza plan from the perspective of HHS.
8. Polansky LS, Outin-Blenman S, Moen AC. Improved global capacity for influenza surveillance. Emerg Infect Dis 2016; 22:993–1001.
9. World Health Organization. Global influenza strategy 2019-2030. Geneva: World Health Organization; 2019.
10. McGinnis J, Laplante J, Shudt M, George KS. Next generation sequencing for whole genome analysis and surveillance of influenza A viruses. J Clin Virol 2016; 79:44–50.
11. Hay AJ, McCauley JW. The WHO global influenza surveillance and response system (GISRS): a future perspective. Influenza Other Respir Viruses 2018; [epub ahead of print].
12. Burke SA, Trock SC. Use of influenza risk assessment tool for prepandemic preparedness. Emerg Infect Dis 2018; 24:471–477.
13. Kile JC, Ren R, Liu L, et al. Update: increase in human infections with novel Asian Lineage Avian Influenza A(H7N9) viruses during the fifth epidemic: China, October 1, 2016-August 7, 2017. MMWR Morb Mortal Wkly Rep 2017; 66:928–932.
14▪. Wang X, Wu P, Pei Y, et al. Assessment of human-to-human transmissibility of avian influenza A(H7N9) virus across 5 waves by analyzing clusters of case patients in Mainland China, 2013-2017. Clin Infect Dis 2019; 68:623–631.
Examines 40 identified clusters of human to human transmission and estimates transmissibility of H7N9, concluding that transmission risk remains low (for now).
15. Markel H, Lipman HB, Navarro JA, et al. Nonpharmaceutical interventions implemented by US cities during the 1918-1919 influenza pandemic. JAMA 2007; 298:644–654.
16. Saunders-Hastings P, Crispo JAG, Sikora L, Krewski D. Effectiveness of personal protective measures in reducing pandemic influenza
transmission: a systematic review and meta-analysis. Epidemics 2017; 20:1–20.
17. Ahmed F, Zviedrite N, Uzicanin A. Effectiveness of workplace social distancing measures in reducing influenza transmission: a systematic review. BMC Public Health 2018; 18:518.
18. Qualls N, Levitt A, Kanade N, et al. Community mitigation guidelines to prevent pandemic influenza
: United States, 2017. MMWR Recomm Rep 2017; 66:1–34.
19. Huang HC, Araz OM, Morton DP, et al. Stockpiling ventilators for influenza andemics. Emerg Infect Dis 2017; 23:914–921.
20. Abramovich MN, Hershey JC, Callies B, et al. Hospital influenza pandemic stockpiling needs: a computer simulation. Am J Infect Control 2017; 45:272–277.
21▪. National Academies of Sciences Engineering and Medicine. The Nation's Medical Countermeasure Stockpile: Opportunities to Improve the Efficiency, Effectiveness, and Sustainability of the CDC Strategic National Stockpile: Workshop Summary. 2016; Washington, DC: National Academies Press,
Proceedings of a workshop that focused on ways to improve the SNS, a critical tool for pandemic response.
22▪▪. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2018–19 Influenza Season. MMWR Recomm Rep 2018; 67:1–20.
The CDC Advisory Committee review of the types, effectiveness and recommended use of influenza vaccines. Of note, all types of influenza vaccines may be safely given to persons with a history of egg allergy.
23. Wilkinson K, Wei Y, Szwajcer A, et al. Efficacy and safety of high-dose influenza vaccine
in elderly adults: a systematic review and meta-analysis. Vaccine 2017; 35:2775–2780.
24. Shay DK, Chillarige Y, Kelman J, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines among US medicare beneficiaries in preventing postinfluenza deaths during 2012-2013 and 2013-2014. J Infect Dis 2017; 215:510–517.
25. Van Buynder PG, Konrad S, Van Buynder JL, et al. The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine
(TIV) in the elderly. Vaccine 2013; 31:6122–6128.
26. Zost SJ, Parkhouse K, Gumina ME, et al. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci U S A 2017; 114:12578–12583.
27. Sullivan SG, Chilver MB, Carville KS, et al. Low interim influenza vaccine
effectiveness, Australia, 1 May to 24 September 2017. Euro Surveill 2017; 22:1–7.
28▪. Izurieta HS, Chillarige Y, Kelman J, et al. Relative effectiveness of cell-cultured and egg-based influenza vaccines among the U.S. elderly, 2017-18. J Infect Dis 2018; [epub ahead of print].
This study directly compared the effectiveness of cell culture-based vaccine to conventional egg-grown vaccine against H3N2 virus and demonstrated ∼10% greater effectivenss for the vaccine that was derived without egg passage.
29. Paules CI, Marston HD, Eisinger RW, et al. The pathway to a universal influenza vaccine
. Immunity 2017; 47:599–603.
30▪▪. Erbelding EJ, Post DJ, Stemmy EJ, et al. A universal influenza vaccine
: the strategic plan for the National Institute of Allergy and Infectious Diseases. J Infect Dis 2018; 218:347–354.
The authors identify the characteristics of a universal influenza vaccine and lay out a series of step-wise improvements to get there. It identifies the many gaps in our understanding of influenza immunology that must be overcome.
31. Crank MC, Mascola JR, Graham BS. Preparing for the next influenza pandemic: the development of a universal influenza vaccine
. J Infect Dis 2019; 219:S107–S109.
32▪. Morens DM, Taubenberger JK. Making universal influenza vaccines: lessons from the 1918 pandemic. J Infect Dis 2019; 219 (Suppl_1):S5–S13.
This article provides historical perspective and describes challenges in influenza vaccinology.
33. Kanekiyo M, Ellis D, King NP. New vaccine design and delivery technologies. J Infect Dis 2019; 219:S88–S96.
34▪▪. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis 2018; 68:895–902.
These guidelines update those published before the 2009 pandemic and review the evidence for influenza diagnostic, antiviral therapy, adjunctive therapy, chemoprophylaxis and management of institutional outbreaks. They emphasize new risk groups, including pregnant women, the use of molecular diagnostics and targeted antiviral therapy for those at the greatest risk of complications, including high-risk patients and all hospitalized patients with influenza.
35▪. Vos LM, Bruning AHL, Reitsma JB, et al. Rapid molecular tests for influenza, respiratory syncytial virus, and other respiratory viruses: a systematic review of diagnostic accuracy and clinical impact studies. Clin Infect Dis 2019; [epub ahead of print].
Systematic review of studies of the diagnostic accuracy and clinical impact of rapid molecular tests for respiratory viruses.
36▪▪. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med 2017; 5:401–411.
This large randomized trial evaluated the impact of routine rapid multiplex PCR on admission for patients with acute respiratory illness. There was no difference in the number of patients started on antibiotics but those in the rapid viral testing group were more likely to receive a single dose or less than 48 hours of antibiotics. There was a striking increase in appropriate use of influenza antivirals.
37. Busson L, Bartiaux M, Brahim S, et al. Contribution of the FilmArray respiratory panel in the management of adult and pediatric patients attending the emergency room during 2015-2016 influenza epidemics: an interventional study. Int J Infect Dis 2019; 83:32–39.
38. Busson L, Mahadeb B, De Foor M, et al. Contribution of a rapid influenza diagnostic test to manage hospitalized patients with suspected influenza. Diagn Microbiol Infect Dis 2017; 87:238–242.
39. Linehan E, Brennan M, O’Rourke S, et al. Impact of introduction of xpert flu assay for influenza PCR testing on obstetric patients: a quality improvement project. J Matern Fetal Neonatal Med 2018; 31:1016–1020.
40. Chu HY, Englund JA, Huang D, et al. Impact of rapid influenza PCR testing on hospitalization and antiviral use: a retrospective cohort study. J Med Virol 2015; 87:2021–2026.
41. Pavia AT. Reducing diagnostic uncertainty to improve treatment of respiratory infections. Lancet Respir Med 2017; 5:364–365.
CDC guidance emphasizes tools to control seasonal influenza transmission in healthcare setting, including respiratory etiquette for patients, vaccination of healthcare personnel, use of droplet precautions, excluding ill personnel and appropriate infection control during aerosol-generating procedures. These would be the starting point during a pandemic.
43. Yan J, Grantham M, Pantelic J, et al. Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community. Proc Natl Acad Sci U S A 2018; 115:1081–1086.
44. Rule AM, Apau O, Ahrenholz SH, et al. Healthcare personnel exposure in an emergency department during influenza season. PLoS One 2018; 13:e0203223.
45. Tellier R, Li Y, Cowling BJ, Tang JW. Recognition of aerosol transmission of infectious agents: a commentary. BMC Infect Dis 2019; 19:101.
46. Offeddu V, Yung CF, Low MSF, Tam CC. Effectiveness of masks and respirators against respiratory infections in healthcare workers: a systematic review and meta-analysis. Clin Infect Dis 2017; 65:1934–1942.
47. Smith JD, MacDougall CC, Johnstone J, et al. Effectiveness of N95 respirators versus surgical masks in protecting healthcare workers from acute respiratory infection: a systematic review and meta-analysis. CMAJ 2016; 188:567–574.
48▪. Radonovich LJ, Simberkoff MS, Bessesen MT, Brown AC, Cummings D, Gaydos C, et al. Results of the Respiratory Protection Effectiveness Clinical Trial (ResPECT). Abstr 1716. IDWeek 2018; San Francisco, CA. 2018
Large cluster-randomized trial provides the most rigorous test yet of N95 masks. Full results should be published this year.
49▪. Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis 2019; 32:176–186.
Up-to-date review of influenza antivirals targeting the viral polymerase complex, covering all stages of development.
50▪▪. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018; 379:913–923.
Pivotal study for licensure of baloxavir in healthy outpatients. Clinical benefit was similar to oseltamivir with a little over 1 day reduction in time to symptom alleviation but baloxavir had more potent antiviral effect. This might translate into clinical benefit in more severely ill patients, currently under study. Emergence of mutations conferring decreased susceptibility in 10% is a concern.
51. Ison MG, Portsmouth S, Yoshida Y, et al. Phase 3 trial of baloxavir marboxil in high risk influenza patients (CAPSTONE-2 Study). Abstract LB16. IDWeek 2018; San Francisco, CA: Open Forum Infectious Diseases; 2018
52. Finberg RW, Lanno R, Anderson D, et al. Phase 2b study of pimodivir (JNJ-63623872) as monotherapy or in combination with oseltamivir for treatment of acute uncomplicated seasonal influenza A: TOPAZ Trial. J Infect Dis 2019; 219:1026–1034.