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One hundred years after the 1918 pandemic

new concepts for preparing for influenza pandemics

Pavia, Andrew

Current Opinion in Infectious Diseases: August 2019 - Volume 32 - Issue 4 - p 365–371
doi: 10.1097/QCO.0000000000000564
NOSOCOMIAL AND HEALTHCARE RELATED INFECTIONS: Edited by Trish M. Perl
Free

Purpose of review In the 100 years since the influenza pandemic of 1918–1919, the most deadly event in human history, we have made substantial progress yet we remain vulnerable to influenza pandemics This article provides a brief overview of important advances in preparing for an influenza pandemic, viewed largely from the perspective of the healthcare system.

Recent findings We have gained insights into influenza pathogenicity, the animal reservoir and have improved global surveillance for new strains and tools for assessing the pandemic risk posed by novel strains. Public health has refined plans for severity assessment, distribution of countermeasures and nonpharmaceutical approaches. Modest improvements in vaccine technology include cell culture-based vaccines, adjuvanted vaccine and recombinant technology. Conventional infection control tools will be critical in healthcare settings. New evidence suggests that influenza virus may be present in aerosols; the contribution of airborne transmission and role of N95 respirators remains unknown. Baloxavir and pimodivir are new antivirals that may improve treatment, especially for severely ill patients. Optimal use and the risk of resistance require further study.

Summary Despite the progress in pandemic preparedness, gaps remain including important scientific questions, adequate resources and most importantly, the ability to rapidly deliver highly effective vaccines.

Division of Pediatric Infectious Diseases, University of Utah, Salt Lake City, Utah, USA

Correspondence to Andrew Pavia, George and Esther Gross Presidential Professor and Chief, Division of Pediatric Infectious Diseases, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84108, USA. Tel: 1 801 581-6791; e-mail: andy.pavia@hsc.utah.edu

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INTRODUCTION

One hundred years ago, the influenza pandemic of 1918–1919 swept across the world in two major waves. It was arguably the deadliest event in human history; an estimated 50–100 million people died worldwide including 675 000 deaths in the United States [1]. The cause was unknown at the time. Influenza virus was not identified and grown until the early 1930s by Smith and Laidlaw [2]. In a remarkable scientific achievement, 1918 AH1N1 virus was reconstructed from genomic fragments from disease specimens and exhumed remains of a victim [3]. Subsequent experiments in animal models confirmed the extraordinary virulence of the 1918 virus. In humans, the case fatality ratio in 1918 of 1.7% was more than 10-fold higher than subsequent pandemics [4,5▪]. Although changes in the hemagglutinin and neuraminidase antigens led to most of the population being susceptible to the 1918 A(H1N1) virus, no single gene accounted for the increased virulence. Rather, the coordinated expression of all of the genes was necessary [3]. The intervening years witnessed an explosion of research on influenza and extensive efforts to contain the impact of seasonal and pandemic influenza. For all these efforts, many gaps remain in our understanding of influenza biology, optimal methods of prevention and treatment and in the preparedness of healthcare systems and national and local governmental agencies [4]. This article provides a brief overview of important advances in preparing for an influenza pandemic, viewed largely from the perspective of the healthcare system. It will focus on critical tools for preparation including public health tools, such as surveillance and stockpiling, vaccines, infection prevention and treatment (Table 1) [6].

Table 1

Table 1

Box 1

Box 1

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PUBLIC HEALTH

The US Department of Health and Human Services (HHS) released a revised Pandemic Influenza Plan in 2017 [7▪]. It outlines the progress in expansion of United States and global surveillance for seasonal influenza viruses and novel viruses of pandemic potential [8]. Similarly, the WHO published their updated strategy in March 2019 [9]. Advances in sequencing speed and bioinformatics now allow the complete characterization of thousands of circulating viruses each year at Centers for Disease Control and Prevention (CDC) and at the collaborating centers of the WHO Global Influenza and Response System [10,11]. However, because of the enormous reservoir of avian and animal viruses, our partial understanding of determinants of virulence and transmission and the limited resources in many countries, it is wise to remain cautious about our ability to predict the emergence of highly virulent and effectively transmitted influenza viruses. To attempt to quantify the pandemic risk of individual zoonotic viruses, the CDC developed the Influenza Risk Assessment Tool (IRAT) that scores 10 elements [12]. IRAT identified influenza A(H7N9) in China as the current influenza virus with the highest pandemic potential [13].

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 [13]. 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 [15]. 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 [18]. 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 [1]. 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▪].

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VACCINES

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 [23] in a randomized trial and a relative mortality benefit among Medicare beneficiaries over the age of 65 [24]. Adjuvanted vaccine demonstrated 63% higher relative effectiveness compared to standard IIV3 in a single season case–control study [25].

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▪].

Erbelding et al. [30▪▪] at the National Institutes of Health (NIH) laid out the steps toward a true universal vaccine. Progress would start with vaccines effective across all variants of a subtype, then vaccines that demonstrate activity against multiple subtypes (e.g. H1/H3/H7) and eventually vaccines that protect against all influenza A viruses (Table 2). To achieve this goal, we need a deeper understanding of natural immunity to influenza including better understanding of immune imprinting (including the concept of ‘original antigenic sin’), the role of T-cell-mediated direct immunity, the role of T cells in controlling B-cell responses and better correlates of protection. Many novel approaches to antigen design, novel adjuvants and new antigen display and delivery platforms are under investigation [33].

Table 2

Table 2

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DIAGNOSTICS

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▪].

CDC maintains a list of Food and Drug Administration-cleared assays at https://www.cdc.gov/flu/professionals/diagnosis/table-nucleic-acid-detection.html. The recently updated “Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines on the Diagnosis, Treatment, Chemoprophylaxis and Institutional Outbreak Management” recommend the use of newer rapid molecular assays for influenza rather than RIDTs [34▪▪]. A number of studies of the impact of these assays have been published; the study quality, platform studied and results are heterogeneous [35▪]. The existing studies generally suggest improved patient outcomes, including decreased duration of antibiotics, more appropriate and timely use of antivirals and possible decreased length of stay [36▪▪,37–40]. One large randomized clinical trial evaluated the routine use of a rapid multiplex viral PCR test on admission compared to standard care for patients with acute respiratory illness. They found 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 antibiotics or less than 48 h of antibiotics. There was a large increase in appropriate use of influenza antivirals [36▪▪]. More high-quality impact studies are needed [41].

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TRANSMISSION AND INFECTION CONTROL

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 [45]. 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.

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TREATMENT

The recently updated IDSA Guidelines [34▪▪] extensively reviews the evidence and provides recommendations for the use of neuraminidase inhibitors (NAIs) for the treatment and prophylaxis of influenza. WHO is in the process of revising their guidance on clinical management of influenza and they are expected to be released in 2019. The IDSA Guidelines recommend early initiation of NAI treatment for outpatients at higher risk of complications of influenza and those with severe, complicated or progressive disease and for all hospitalized patients with influenza. NAI's though have some limitations. They provide only modest benefits in otherwise healthy outpatients with uncomplicated influenza and have modest antiviral effect. Although resistance among circulating viruses has been uncommon since the highly resistant (A)H1N1 strains in 2007–2008, a single mutation (H275Y) can confer resistance to both oseltamivir and peramivir and some mutations confer broad cross resistance to all NAIs. New agents with different mechanisms of action are under development, and one has been licensed in the United States [49▪]. Baloxavir marboxil (Roche, Nutley, NJ, USA) is an inhibitor of the cap-dependent endonuclease component of the polymerase complex. Baloxavir is approved for the treatment of acute uncomplicated influenza in patients 12 years and older. In the pivotal phase 3 randomized controlled trial, baloxavir was compared to oseltamivir and placebo in 1066 otherwise healthy patients aged 12–64 years with uncomplicated influenza for no more than 48 h [50▪▪]. A single dose of baloxavir significantly shortened the median time to alleviation of symptoms by 26.5 h compared with placebo (P < 0.001) but was not significantly superior to 5 days of twice daily oseltamivir. The median duration of infectious virus detection in respiratory tract specimens was significantly shorter for baloxavir compared to oseltamivir (24 versus 72 h). Among participants with paired samples, treatment-emergent mutations conferring decreases susceptibility to baloxavir were detected in 10%. A second phase 3 trial compared baloxavir with oseltamivir and placebo in outpatients with at least one high-risk condition. The results have been presented but not yet published [51]. The combination of baloxavir and oseltamivir showed synergistic effects in vitro and in an animal model [6].

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 [52]. 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▪].

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CONCLUSION

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.

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Acknowledgements

I would like to thank the members of the IDSA Influenza Guidelines Committee for their expertise, hard work and inspiration.

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Financial support and sponsorship

A.P. receives funding from the NIH (1 R01 AI135114-01A1, 1R01AI125642-01) and the Bill and Melinda Gates Foundation for work not related to influenza.

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Conflicts of interest

A.P. has served as a consultant to Genentech and Merck. He has received honoraria from Medscape for CME material and receives royalties as an editor of The Sanford Guide.

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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
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REFERENCES

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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.

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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.

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This article provides historical perspective and describes challenges in influenza vaccinology.

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Systematic review of studies of the diagnostic accuracy and clinical impact of rapid molecular tests for respiratory viruses.

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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.
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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.
Keywords:

influenza antiviral; influenza vaccine; pandemic influenza; personal protective equipment

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