Influenza Vaccines: From Surveillance Through Production to Protection
2010; Elsevier BV; Volume: 85; Issue: 3 Linguagem: Inglês
10.4065/mcp.2009.0615
ISSN1942-5546
AutoresPritish K. Tosh, Robert M. Jacobson, Gregory A. Poland,
Tópico(s)Pneumonia and Respiratory Infections
ResumoInfluenza is an important contributor to population and individual morbidity and mortality. The current influenza pandemic with novel H1N1 has highlighted the need for health care professionals to better understand the processes involved in creating influenza vaccines, both for pandemic as well as for seasonal influenza. This review presents an overview of influenza-related topics to help meet this need and includes a discussion of the burden of disease, virology, epidemiology, viral surveillance, and vaccine strain selection. We then present an overview of influenza vaccine—related topics, including vaccine production, vaccine efficacy and effectiveness, influenza vaccine misperceptions, and populations that are recommended to receive vaccination. English-language articles in PubMed published between January 1, 1970, and October 7, 2009, were searched using key words human influenza, influenza vaccines, influenza A, and influenza B. Influenza is an important contributor to population and individual morbidity and mortality. The current influenza pandemic with novel H1N1 has highlighted the need for health care professionals to better understand the processes involved in creating influenza vaccines, both for pandemic as well as for seasonal influenza. This review presents an overview of influenza-related topics to help meet this need and includes a discussion of the burden of disease, virology, epidemiology, viral surveillance, and vaccine strain selection. We then present an overview of influenza vaccine—related topics, including vaccine production, vaccine efficacy and effectiveness, influenza vaccine misperceptions, and populations that are recommended to receive vaccination. English-language articles in PubMed published between January 1, 1970, and October 7, 2009, were searched using key words human influenza, influenza vaccines, influenza A, and influenza B. The current influenza A pandemic with novel H1N1 and the race to develop effective vaccines against it have increased the profile of influenza and influenza vaccination among the lay public and medical professional community, making them more likely to inquire about influenza strain surveillance and vaccine development. Furthermore, deaths attributed to novel H1N1 influenza infection have highlighted the substantial contribution of influenza infection to overall morbidity and mortality and the importance of vaccination against seasonal influenza. Although seasonal influenza is the most common vaccine-preventable cause of death in the United States, influenza vaccination rates remain unacceptably low for all categories of people at highest risk.1Fiore AE Shay DK Broder K et al.Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009 [published correction appears in MMWR Recomm Rep. 2009;58(32):896-897].MMWR Recomm Rep. 2009; 58: 1-52PubMed Google Scholar, 2Cho BH Kolasa MS Messonnier ML Influenza vaccination coverage rate among high-risk children during the 2002-2003 influenza season.Am J Infect Control. 2008; 36: 582-587Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 3Loulergue P Mir O Alexandre J Ropert S Goldwasser F Launay O Low influenza vaccination rate among patients receiving chemotherapy for cancer [letter].Ann Oncol. 2008; 19: 1658Crossref PubMed Scopus (20) Google Scholar, 4Nakamura MM Lee GM Influenza vaccination in adolescents with high-risk conditions.Pediatrics. 2008; 122: 920-928Crossref PubMed Scopus (11) Google Scholar, 5Nowalk MP Lin CJ Zimmerman RK et al.Self-reported influenza vaccination rates among health care workers in a large health system.Am J Infect Control. 2008; 36: 574-581Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 6Roush SW Murphy TV Preventable Disease Table Working Group Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States.JAMA. 2007; 298: 2155-2163Crossref PubMed Scopus (152) Google Scholar, 7Shah SI Turcotte F Meng HD Influenza vaccination rates of expectant parents with neonatal intensive care admission.J Matern Fetal Neonatal Med. 2008; 21: 752-757Crossref PubMed Scopus (6) Google Scholar, 8Centers for Disease Control and Prevention (CDC) National Center for Health Statistics National Vital Statistics System. 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A PubMed search for relevant English-language articles published between January 1, 1970, and October 7, 2009, was performed to find pertinent literature using the key words human influenza, influenza vaccines, influenza A, and influenza B. Much of the morbidity and mortality of seasonal influenza results from complications of influenza infection (eg, bacterial superinfections, exacerbations of underlying illnesses) rather than from primary influenza pneumonia itself.9Thompson WW Shay DK Weintraub E et al.Mortality associated with influenza and respiratory syncytial virus in the United States.JAMA. 2003; 289: 179-186Crossref PubMed Scopus (1646) Google Scholar, 12Mamas MA Fraser D Neyses L Cardiovascular manifestations associated with influenza virus infection.Int J Cardiol. 2008; 130: 304-309Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 13de Diego C Vila-Córcoles A Ochoa O EPIVAC Study Group et al.Effects of annual influenza vaccination on winter mortality in elderly people with chronic heart disease.Eur Heart J. 2009; 30: 209-216Crossref PubMed Scopus (30) Google Scholar, 14Wat D Gelder C Hibbitts S et al.The role of respiratory viruses in cystic fibrosis.J Cyst Fibros. 2008; 7: 320-328Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 15Hutchinson AF Ghimire AK Thompson MA et al.A community-based, time-matched, case-control study of respiratory viruses and exacerbations of COPD.Respir Med. 2007; 101: 2472-2481Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 16Griffin MR Coffey CS Neuzil KM Mitchel Jr, EF Wright PF Edwards KM Winter viruses: influenza- and respiratory syncytial virus—related morbidity in chronic lung disease.Arch Intern Med. 2002; 162: 1229-1236Crossref PubMed Google Scholar In the United States alone, influenza causes 200,000 excess hospitalizations each year.17Thompson WW Shay DK Weintraub E et al.Influenza-associated hospitalizations in the United States.JAMA. 2004; 292: 1333-1340Crossref PubMed Scopus (954) Google Scholar, 18Grijalva CG Craig AS Dupont WD et al.Estimating influenza hospitalizations among children.Emerg Infect Dis. 2006; 12: 103-109Crossref PubMed Google Scholar, 19Mullooly JP Bridges CB Thompson WW et al.Influenza- and RSV-associated hospitalizations among adults.Vaccine. 2007; 25: 846-855Crossref PubMed Scopus (80) Google Scholar Furthermore, it appears that influenza-attributed mortality has increased over time in the United States, from 7000 to 32,000 annual deaths in the late 1970s to 36,000 to 72,000 annual deaths in the late 1990s.9Thompson WW Shay DK Weintraub E et al.Mortality associated with influenza and respiratory syncytial virus in the United States.JAMA. 2003; 289: 179-186Crossref PubMed Scopus (1646) Google Scholar This increase in influenza-attributable mortality likely relates to host factors, such as the increasing numbers of elderly and immunocompromised persons, and viral factors, such as intrinsic virulence and the increasingly rapid global spread of new strains. Influenza vaccination is the most effective means of protecting susceptible individuals and decreasing viral transmission within a community, prompting expansion of guidelines to recommend influenza vaccination for broader groups of people.1Fiore AE Shay DK Broder K et al.Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009 [published correction appears in MMWR Recomm Rep. 2009;58(32):896-897].MMWR Recomm Rep. 2009; 58: 1-52PubMed Google Scholar The effectiveness of the vaccine is not 100% and is, in fact, least effective in those at highest risk, namely young children, the elderly, and the immunosuppressed.1Fiore AE Shay DK Broder K et al.Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009 [published correction appears in MMWR Recomm Rep. 2009;58(32):896-897].MMWR Recomm Rep. 2009; 58: 1-52PubMed Google Scholar This has spurred research into new influenza vaccines and technologies, such as live-attenuated influenza vaccines (LAIVs), vaccine adjuvants, and other vaccine candidates still being developed, to protect those at greatest risk.20Tosh PK Boyce TG Poland GA Flu myths: dispelling the myths associated with live attenuated influenza vaccine.Mayo Clin Proc. 2008; 83: 77-84Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 21Tosh PK Poland GA Emerging vaccines for influenza.Expert Opin Emerg Drugs. 2008; 13: 21-40Crossref PubMed Scopus (22) Google Scholar Because of the immense clinical importance of this virus as well as the ever-changing nature of treatment and prevention of this disease, it is imperative for health care professionals to be well-versed in the topic of influenzavaccination so as to be able to identify those who could benefit from vaccination as well as to educate themselves and their patients. Influenza is an enveloped, single-stranded, negative-sense RNA virus in the Orthomyxoviridae family of viruses. Influenza is divided into 3 major types: A, B, and C. Influenza A viruses infect a wide variety of animals, including humans, birds, pigs, horses, and many others, although the tropism of any particular influenza virus is generally highly adapted to a particular host. Influenza B viruses infect a smaller number of species, namely humans and seals, and are a substantial cause of annual influenza epidemics. Most human influenza infections are caused by influenza A or B; influenza C viruses, which infect humans and pigs, rarely account for human infections and epidemics.22Lamb RA Krug RM Orthomyxoviridae: the viruses and their replication.in: Knipe DM Howley PM 4th ed. Fields Virology. Vol 1. Lippincott Williams & Wilkins, Philadelphia, PA2001: 1487-1531Google Scholar The influenza genome is segmented. Influenza A and B viruses have 8 segments in their genome, and influenza C viruses have 7. The major influenza types also differ in that influenza A and B viruses express hemagglutinin (HA) and neuraminidase (NA) as surface antigens, whereas influenza C viruses express an HA-esterase-fusion protein on their surface.22Lamb RA Krug RM Orthomyxoviridae: the viruses and their replication.in: Knipe DM Howley PM 4th ed. Fields Virology. Vol 1. Lippincott Williams & Wilkins, Philadelphia, PA2001: 1487-1531Google Scholar Because influenza A and B are the cause of most epidemics and are the intended targets of seasonal influenza vaccination, the following discussion on virology will focus on these 2 virus types. The 11 proteins of influenza A and B are encoded by 8 gene segments. Hemagglutinin and NA are expressed on the surface of the virus and are required for entry and exit, respectively, from the host cell (Figure 1).23Kaiser J A one-size-fits-all flu vaccine [published corrections appear in Science. 2006;312(5779):1472 and 2006;312(5776):999]?.Science. 2006; 312 (Accessed November 30, 2009.): 380-382http://www.sciencemag.org/cgi/reprint/312/5772/380.pdfCrossref PubMed Scopus (29) Google Scholar Influenza A viruses are subtyped on the basis of the major subtype of HA and NA expressed (eg, H3N2, H1N1). Matrix 2 (M2) protein is a transmembrane ion channel that acidifies the viral interior to allow for replication. Polymerase basic (PB) protein 1, PB protein 1-F2, PB protein 2, and polymerase acidic protein form influenza RNA polymerase. Like all RNA viruses, influenza RNA polymerase lacks a proofreading mechanism, resulting in frequent mutations in these genes and, consequently, a constantly changing antigenic appearance. Nucleoprotein combines with the 3 polymerase proteins to form ribonucleoprotein complexes that are transported to the nucleus by the M1 protein. Nonstructural proteins 1 and 2 are involved in expression of viral proteins and viral replication, respectively.22Lamb RA Krug RM Orthomyxoviridae: the viruses and their replication.in: Knipe DM Howley PM 4th ed. Fields Virology. Vol 1. Lippincott Williams & Wilkins, Philadelphia, PA2001: 1487-1531Google Scholar, 24Cheung TK Poon LL Biology of influenza A virus.Ann N Y Acad Sci. 2007 Apr; 1102: 1-25Crossref PubMed Scopus (30) Google Scholar Influenza viruses can undergo reassortment of these gene segments; ie, 2 or more influenza viruses infecting the same cell can exchange gene segments, thus creating a new hybrid virus with gene segments derived from the parent viruses. Hemagglutinin is a glycopeptide expressed on the surface of influenza viruses that facilitates entry of the virus into host cells.25Steinhauer DA Wharton SA Structure and function of the haemagglutinin.in: Nicholson KG Webster RG Hay AJ Textbook of Influenza. Blackwell Science, Oxford, UK1998: 54-64Google Scholar It is so named because of its property of agglutinating red blood cells. 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Fields Virology. Vol 1. Lippincott Williams & Wilkins, Philadelphia, PA2001: 1487-1531Google Scholar Nine major NA subtypes of influenza A have been identified. Unlike antibodies directed against HA, NA-specific antibodies alone are not sufficient to prevent infection but may be able to mitigate the severity and duration of disease.31Powers DC Kilbourne ED Johansson BE Neuraminidase-specific antibody responses to inactivated influenza virus vaccine in young and elderly adults.Clin Diagn Lab Immunol. 1996; 3: 511-516PubMed Google Scholar, 32Kilbourne ED Laver WG Schulman JL Webster RG Antiviral activity of antiserum specific for an influenza virus neuraminidase.J Virol. 1968; 2: 281-288PubMed Google Scholar, 33Murphy BR Kasel JA Chanock RM Association of serum anti-neuraminidase antibody with resistance to influenza in man.N Engl J Med. 1972; 286: 1329-1332Crossref PubMed Google Scholar During the 1968 Hong Kong influenza pandemic, vaccine directed at an H2N2 virus had 54% efficacy against the pandemic H3N2 strain, suggesting partial protection conferred by antibodies directed against NA.34Eickhoff TC Meiklejohn G Protection against Hong Kong influneza by adjuvant vaccine containing A2-Ann Arbor-67.Bull World Health Organ. 1969; 41: 562-563PubMed Google Scholar Neuraminidase is also the target for the NA-inhibitor (NI) class of antivirals (eg, oseltamivir and zanamivir). 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Two classes of antiviral medications are currently used to treat and prevent influenza infections, the adamantanes and NIs.46Harper SA Bradley JS Englund JA et al.Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional out-break management: clinical practice guidelines of the Infectious Diseases Society of America.Clin Infect Dis. 2009; 48: 1003-1032Crossref PubMed Scopus (241) Google Scholar The adamantanes amantadine and rimantadine act on the M2 protein of influenza A, although a single mutation at amino acid 31 in the matrix gene renders high-level resistance to these medications.47Tang JW Ngai KL Wong JC Lam WY Chan PK Emergence of adamantane-resistant influenza A(H3N2) viruses in Hong Kong between 1997 and 2006.J Med Virol. 2008; 80: 895-901Crossref PubMed Scopus (12) Google Scholar The adamantanes are not effective against influenza B, and the development of wide-spread adamantane resistance in seasonal H3N2 (99%) and seasonal H1N1 (10%) strains during the 2008-2009 season has limited their utility.1Fiore AE Shay DK Broder K et al.Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009 [published correction appears in MMWR Recomm Rep. 2009;58(32):896-897].MMWR Recomm Rep. 2009; 58: 1-52PubMed Google Scholar Two NIs are available for treatment of influenza A and B infections: oseltamivir (oral) and zanamivir (inhaled). 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When the strain type is unknown and both novel H1N1 and seasonal influenza are circulating, empiric treatment with either zanamivir alone or oseltamivir in combination with rimantadine should be used for infected patients at high risk of complications and for low-risk patients who present within 48 hours of symptom onset.46Harper SA Bradley JS Englund JA et al.Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional out-break management: clinical practice guidelines of the Infectious Diseases Society of America.Clin Infect Dis. 2009; 48: 1003-1032Crossref PubMed Scopus (241) Google Scholar Influenza B infections can be treated with oseltamivir or zanamivir. Influenza A (seasonal H1N1) infections can be treated with either rimantadine or zanamivir, and influenza A (H3N2) infections can be treated with oseltamivir or zanamivir. Early in the current influenza pandemic, most isolates of novel influenza H1N1 have been resistant to the adamantanes but have, with rare exception, remained susceptible to oseltamivir, and treatment with oseltamivir or zanamivir is recommended.51Centers for Disease Control and Prevention (CDC) Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients—Seattle, Washington, 2009.MMWR Morb Mortal Wkly Rep. 2009; 58: 893-896PubMed Google Scholar, 52Centers for Disease Control and Prevention (CDC) Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 Season.http://www.cdc.gov/h1n1flu/recommendations.htmGoogle Scholar Some concerns have been published regarding the development of antiviral resistance with monotherapy.53Poland GA Jacobson RM Ovsyannikova IG Influenza virus resistance to antiviral agents: a plea for rational use.Clin Infect Dis. 2009; 48: 1254-1256Crossref PubMed Scopus (64) Google Scholar In adults, the use of NIs has been shown to reduce influenza symptoms by approximately 1 day as well as influenza-related complications and hospitalizations.54Jefferson TO Demicheli V Di Pietrantonj C Jones M Rivetti D Neuraminidase inhibitors for preventing and treating influenza in healthy adults.Cochrane Database Syst Rev. 2006; 3 (CD001265)Google Scholar, 55Kaiser L Wat C Mills T Mahoney P Ward P Hayden F Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations.Arch Intern Med. 2003; 163: 1667-1672Crossref PubMed Scopus (307) Google Scholar, 56Nordstrom BL Sung I Suter P Szneke P Risk of pneumonia and other complications of influenza-like illness in patients treated with oseltamivir.Curr Med Res Opin. 2005; 21: 761-768Crossref PubMed Scopus (48) Google Scholar, 57Jefferson T Demicheli V Rivetti D Jones M Di Pietrantonj C Rivetti A Antivirals for influenza in healthy adults: systematic review [published correction appears in Lancet. 2006;367(9528)2060].Lancet. 2006; 367: 303-313Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Studies of NIs in children have shown a reduction in influenza symptoms by approximately 1.25 days as well as a reduction in influenza complications and subsequent physician visits.58Whitley RJ Hayden FG Reisinger KS et al.Oral oseltamivir treatment of influenza in children [published correction appears in Pediatr Infect Dis J. 2001;20(4):421].Pediatr Infect Dis J. 2001; 20: 127-133Crossref PubMed Scopus (437) Google Scholar, 59Barr CE Schulman K Iacuzio D Bradley JS Effect of oseltamivir on the risk of pneumonia and use of health care services in children with clinically diagnosed influenza.Curr Med Res Opin. 2007; 23: 523-531Crossref PubMed Scopus (38) Google Scholar, 60Mäkelä MJ Pauksens K Rostila T et al.Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study.J Infect. 2000; 40: 42-48Abstract Full Text PDF PubMed Scopus (145) Google Scholar, 61Monto AS Fleming DM Henry D et al.Efficacy and safety of the neuraminidase inhibitor zanamivirin in the treatment of influenza A and B virus infections.J Infect Dis. 1999; 180: 254-261Crossref PubMed Scopus (214) Google Scholar Given the rapidly evolving nature of antiviral resistance, updated recommendations, such as those by the Infectious Diseases Society of America, the Centers for Disease Control and Prevention (CDC), and the American Academy of Pediatrics, should be consulted when deciding on treatment or chemoprophylaxis for patients.46Harper SA Bradley JS Englund JA et al.Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional out-break management: clinical practice guidelines of the Infectious Diseases Society of America.Clin Infect Dis. 2009; 48: 1003-1032Crossref PubMed Scopus (241) Google Scholar, 62Centers for Disease Control and Prevention (CDC) CDC issues interim recommendations for the use of influenza antiviral medications in the setting of oseltamivir resistance among circulating influenza A (H1N1) viruses, 2008-09 influenza season. Health Alert Network Web site.http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279Date: December 19, 2008Google Scholar Circulating influenza viruses are constantly mutating. Minor antigenic changes due to random mutational events, called antigenic drift, are responsible for annual influenza epidemics. The changes to HA and NA that occur help the virus evade the immune response generated in a host population through prior infection or vaccination. Much less frequently, but with much more dire consequences, a circulating strain of influenza will develop with a new major antigenic type of HA or NA to which the population has no prior exposure (Figure 2). These antigenic shifts are responsible for influenza pandemics, characterized by infection so widespread as to cause societal disruption and global mortality often measured in the millions. Antigenic shifts can occur as a result of direct mutational changes of a zoonotic influenza to produce efficient human-to-human transmission. Such a mutational change likely occurred during the 1918 "Spanish Flu" pandemic; evidence suggests that a highly pa
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