Many countries have implemented influenza vaccination as targeted programs for people at high risk for influenza-related complications, while some countries such as Canada and the United States (US) recommend universal vaccination against seasonal influenza.1-3
Influenza viruses typically circulate widely in the United States annually, from the late fall through the early spring. Although most persons with influenza recover, however, influenza can cause severe illness and death, particularly among older adults, very young children, pregnant women, and those with certain chronic medical conditions.4,5
Influenza vaccination in Canada aims to prevent serious outcomes such as hospitalization and death. Routine annual influenza vaccination for all persons aged ≥6 months who do not have contraindications has been recommended by CDC and CDC’s Advisory Committee on Immunization Practices (ACIP) since 2010.6 The present document outlines the antiviral drugs for chemoprophylaxis and influenza illness therapy in pediatric and adult settings and their mode of action.
Most of the current seasonal influenza vaccines include 2 influenza A strains and 1 influenza B strain. Trivalent inactivated vaccines (TIV) and live attenuated influenza vaccines (LAIV) are available. TIVs are the only influenza vaccines licensed for vaccination of children < two years of age, persons aged ≥ 50 years and pregnant women. There are 3 types of TIVs: whole virus vaccines, split virus vaccines, and subunit vaccines. In split virus vaccines, the virus has been disrupted by a detergent whereas, in subunit vaccines, the HA and NA antigens have been purified by removal of other viral components.
To enhance immunogenicity, some current formulations of TIV include adjuvants such as oil-in-water adjuvants or virosomes. Most multi-dose vials of TIV contain the preservative thiomersal; limited supplies of TIV in thiomersal-free, single-vial and prefilled syringes are available, but at a higher cost. Current TIVs are not licensed for children. A quadrivalent LAIV for intranasal application containing 2 influenza A strains and 2 influenza B strains was licensed in the USA in 2012. In 2003, a trivalent live attenuated, cold-adapted influenza vaccine (CAIV-T), based on a different attenuated subtype-A donor strain was licensed in the USA for intranasal use in healthy individuals aged 2–49 years. The manufacture of influenza vaccines is based on viral propagation in embryonated eggs or appropriate cell cultures. To ensure optimal vaccine efficacy against prevailing strains in both the northern and southern hemispheres, the antigenic composition of the vaccines is revised twice annually and adjusted to the antigenic characteristics of circulating influenza viruses obtained within the WHO global influenza surveillance and response system (GISRS).
Influenza vaccination is recommended annually to ensure an optimal match between the vaccine and prevailing influenza strains, and because, unlike the long-lasting, strain-specific immunity following natural infection, influenza vaccines induce protection of relatively short duration, particularly in the elderly. In Canada, a number of influenza vaccines are currently licensed for use. These include 6 inactivated TIVs; split virus or subunit TIVs for intramuscular injection (Agriflu [Seqirus], Fluviral™ [GSK], Fluzone, Vaxigrip [Sanofi Pasteur], and Influvac [BGP Pharma ULC], and an MF59-adjuvanted TIV (Fluad[Seqirus]).1 Three QIVs are also available; a live attenuated influenza vaccine (LAIV) for intranasal administration (FluMist Quadrivalent [MedImmune/AstraZeneca]) and 2 split-virion, inactivated QIVs (FluLaval™ TETRA [GSK] and Fluzone Quadrivalent [Sanofi Pasteur]).1 TIVs and QIVs are recommended for use in healthy adults and those with chronic health problems from 18 y of age.1 NACI preferentially recommends QIV for use in infants from 6 to 23 months of age and LAIV for children 2 to 6 y of age. In the 2015/16 season, NACI offered no preference between TIV, QIV, or MF59-adjuvanted TIV for those 65 y of age and older.1 Agriflu and Fluad are trademarks of Seqirus.FluLaval and Fluviral are trademarks of the GSK group of companies. FluMist is a trademark of MedImmune, LLC/the AstraZeneca group of companies. Fluzone and Vaxigrip are trademarks of Sanofi Pasteur. Influvac is a trademark of Abbott Biologicals B.V.
There are 2 classes of antiviral drugs for influenza: (i) transmembrane ion channel (M2 protein) inhibitors (amantadine, rimantadine) and (ii) neuraminidase inhibitors (oseltamivir and zanamivir, and more recently peramivir and laninamivir). WHO recommends neuraminidase inhibitors as the first-line treatment for those requiring antiviral therapy, as most of the currently circulating viruses are resistant to the M2 inhibitors. For high-risk individuals, NA inhibitors should be administered early in the course of the disease. Among NA inhibitors, oseltamivir is most widely used, with accumulated safety data that include treatment in young children and pregnant women.
Early and widespread use of NA inhibitors has been associated with reduced hospitalization and mortality, particularly during the 2009 pandemic. Prophylactic use of NA inhibitors or treatment of immunosuppressed patients are associated with higher probability of emergence of antiviral resistance, hence careful monitoring is warranted. Rimantadine, an M2 ion channel blocker similar to amantadine (Symmetrel, Endo Pharmaceuticals, USA) but with fewer side effects, is licensed in the United States but not in Canada. Although a rationale for marketing rimantadine in Canada has recently been published, 7 it is not currently approved for use. Cross-resistance occurs between amantadine and rimantadine. The prophylactic efficacy of amantadine has been evaluated in four placebo-controlled trials in children eight years of age and older.8 Amantadine reduced the incidence of laboratory-confirmed influenza illness by 80%.
The NAIs are effective against recently emerging avian strains of influenza A H5N1 9,10 but virtually all these highly virulent strains are resistant to amantadine. Zanamivir prophylactic efficacy has not been evaluated in controlled trials in children. However, children five to 17 years of age were included in a placebo-controlled trial of zanamivir for postexposure prophylaxis of influenza in families. Zanamivir (Relenza, GlaxoSmithKline, USA) reduced the incidence of laboratory-confirmed illness from 18% (30 of 168 families) to 4% (six of 169 families), a statistically significant difference. In a similar study of oseltamivir 11, postexposure prophylaxis (75 mg daily for seven days) reduced the incidence of laboratory-confirmed influenza in families from 23% (18 of 79 households treated with placebo) to 3.6% (three of 84 households treated with oseltamivir), a protective efficacy of 84%. Zanamivir and oseltamivir (Tamiflu, Roche Laboratories Inc, USA) should not be used if the duration of symptoms has been longer than 48 h because effectiveness is negligible after this time unless the patient has significant immunodeficiency and has a progressive respiratory disease. Ribavirin a neuraminidase, administered to children ill with influenza as aerosol or oral tablets has been demonstrated to ameliorate symptoms and to be acceptably safe. However, ribavirin is not licensed for influenza treatment or prophylaxis in Canada. Influenza vaccination is recommended annually to ensure an optimal match between the vaccine and prevailing influenza strains, and because, unlike the long-lasting, strain-specific immunity following natural infection, influenza vaccines induce protection of relatively short duration, particularly in the elderly.
- Public Health Agency of Canada An advisory committee statement (ACS) – National Advisory Committee on Immunization (NACI). Statement on Seasonal Influenza Vaccine for 2015–2016; Available from: http://www.phac-aspc.gc.ca/naci-ccni/flu-2015-grippe-eng.php[Accessed 18February2016]
- Australian Government Department of Health Clinical advice for immunisation providers regarding the administration of 2014 seasonal influenza vaccines. March 2014; Available from: http://www.immunise.health.gov.au/internet/immunise/Publishing.nsf/content/ATAGI-advice-TIV[Accessed 18February2016]
- United States Centers for Disease Control and Prevention CDC’s advisory committee on immunization practices (ACIP) recommends universal annual influenza vaccination. 2010; Available from: http://www.cdc.gov/media/pressrel/2010/r100224.htm[Accessed 18February2016]
- Excess pneumonia and influenza associated hospitalization during influenza epidemics in the United States, 1970-78. Barker WH Am J Public Health. 1986 Jul; 76(7):761-5.
- Influenza- and RSV-associated hospitalizations among adults. Mullooly JP, Bridges CB, Thompson WW, Chen J, Weintraub E, Jackson LA, Black S, Shay DK, Vaccine Safety Datalink Adult Working Group. Vaccine. 2007 Jan 15; 25(5):846-55.
- Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, Iskander JK, Wortley PM, Shay DK, Bresee JS, Cox NJ, Centers for Disease Control and Prevention (CDC). MMWR Recomm Rep. 2010 Aug 6; 59(RR-8):1-62.
- A case for rimantadine to be marketed in Canada for prophylaxis of influenza A virus infection. Marra F, Marra CA, Stiver HG Can Respir J. 2003 Oct; 10(7):381-8
- Aoki FY. Amantadine and rimantadine. In: Nicholson KG, Webster RG, Hay AJ, eds. Textbook of Influenza. Oxford: Blackwell Science, 1998:457-76.
- Update: influenza activity–United States and worldwide, May-October 2004. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004 Oct 29; 53(42):993-5
- The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses. Leneva IA,Roberts N, Govorkova EA, Goloubeva OG, Webster RG. Antiviral Res. 2000 Nov; 48(2):101-15.
- Human infection by avian influenza A H5N1. Yuen KY, Wong SS Hong Kong Med J. 2005 Jun; 11(3):189-99.