One hundred years after the deadly influenza pandemic in 1918, a significant progress in vaccine and drug development for the prevention and treatment of influenza has been made. Nonetheless, influenza still poses a heavy burden to the global as well as local healthcare services. At the Hong Kong Academy of Medicine 25th Anniversary Congress, novel strategies in the prevention and treatment of influenza diseases were presented by Professor Ivan F.N. Hung of the University of Hong Kong (HKU).
The 2017-2018 season has been proven to be one of the worst influenza seasons since the 2009 H1N1 pandemic.1,2 According to the Morbidity and Mortality Weekly Report (MMWR) by the United States (U.S.) Centers for Disease Control and Prevention (CDC), the peak percentage of outpatients due to influenza in the U.S. almost reached 8%, with ~110 hospitalizations per 100,000 people.1 Referring to the weekly report by the Centre for Health Protection (CHP) for local influenza activities,2 Prof. Hung noted that “we had a very bad season and a very surprising summer peak in 2017, which was due to drifted H3 [strain].”
On top of the intramuscular inactivated influenza vaccines (IIVs) and the intranasal live-attenuated influenza vaccines (LAIVs), an egg-free, quadrivalent, recombinant influenza vaccine (RIV4) is now licensed for use in the U.S. (but not yet available in Hong Kong, as mentioned by Prof. Hung). A systematic review and meta-analysis of LAIVs by Osterholm et al. found a consistently higher level of protection in young children aged between 6 months to 7 years, but there was a lack of evidence for protection in adults aged 65 years or older.3
Meanwhile, a randomized, double-blind, multicenter trial (n=9,003) found better protection with RIV4 as compared to standard-dose quadrivalent IIV (IIV4) against confirmed influenza-like illness among older adults.4 “But whether that will actually bring better clinical protection [is yet to be determined] by further studies,” Prof. Hung said.
The topical application of imiquimod, a synthetic Toll-like receptor 7 (TLR7), before intradermal trivalent influenza vaccine (TIV) has been investigated by Prof. Hung and his team in a double-blind, randomized controlled trial.5 “If you apply the TLR7 agonist before giving the intradermal vaccine, it is able to stimulate further the dendritic cells uptake, and hence giving a much more profound antibody response downstream both in the T- and B-cells,” he explained. In the study, pretreatment with imiquimod produced a better efficacy of the intradermal TIV even against heterologous non-vaccine and antigenically drifted viruses.5
The emergence of a multi-drug resistance influenza virus also remains a concern. Referring to a case report that was published in the New England Journal of Medicine, a 5-year-old boy had resistance to neuraminidase inhibitors oseltamivir (H275Y mutation) and zanamivir (I223R mutation) that emerged during treatment.6
Prof. Hung then presented different novel strategies that have been explored for treating influenza, including the use of anti-influenza plasma and combination therapy (e.g. oseltamivir, clarithromycin, plus naproxen) in severe influenza cases.7,8 Baloxavir marboxil, a selective inhibitor of influenza cap-dependent endonuclease, is the latest addition to the influenza antiviral armamentarium.9 Approved by the United States Food and Drug Administration (FDA) for the treatment of acute uncomplicated influenza in patients 12 years of age and older who have been symptomatic for no more than 48 hours, the single-dose baloxavir marboxil has demonstrated its efficacy in two randomized clinical trials of 1,832 patients.10
Concluding his presentation, Prof. Hung said that “prevention is of course the most important strategy of all for influenza infection.” In cases where influenza treatment is needed, there is limited effect with current neuraminidase inhibitors due to emergence of resistance, but future approaches would likely involve a combination of antiviral therapies, such as baloxavir marboxil plus oseltamivir.
1. Centers for Disease Control and Prevention (CDC). Influenza Activity — United States, September 30–December 1, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(49):1369–1371.
2. Centre for Health Protection (CHP). Local Situation of Influenza Activity (as of Oct 10, 2018). Flu Express (Accessed December 27, 2018, at https://www.chp.gov.hk/files/pdf/fluexpress_week40_11_10_2018_eng.pdf).
3. Osterholm MT, Kelley NS, Sommer A, et al. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(1):36-44.
4. Dunkle LM, Izikson R, Patriarca P, et al. Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. N Engl J Med. 2017;376(25):2427-2436.
5. Hung IF, Zhang AJ, To KK, et al. Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial. Lancet Infect Dis. 2016;16(2):209-18.
6. van der Vries E, Stelma FF, Boucher CA. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. N Engl J Med. 2010;363(14):1381-2.
7. Beigel JH, Tebas P, Elie-Turenne MC, et al. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med. 2017;5(6):500-511.
8. Hung IFN, To KKW, Chan JFW, et al. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017;151(5):1069-1080.
9. Hayden FG, Sugaya N1, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018;379(10):913-923.
10. FDA approves new drug to treat influenza. FDA News Release. 2018 (Accessed December 28, 2018, at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624226.htm).