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Evaluating the case for trivalent or quadrivalent influenza vaccines

Evaluating the case for trivalent or quadrivalent influenza vaccines HUMAN VACCINES & IMMUNOTHERAPEUTICS 2016, VOL. 12, NO. 10, 2712–2717 http://dx.doi.org/10.1080/21645515.2015.1091130 REVIEW Evaluating the case for trivalent or quadrivalent influenza vaccines David Baxter Stockport NHS Foundation Trust, Consultant in Health Protection, Manchester Medical School, University of Manchester, Manchester, UK ABSTRACT ARTICLE HISTORY Received 26 August 2015 Influenza viruses circulate widely throughout the world and it is estimated that they affect between 5 and Revised 28 August 2015 15% of the population annually. Since 1977, four viruses co-circulate – two A Viruses (H1N1 and H3N2) and Accepted 1 September 2015 two B viruses (B Yamagata and B Victoria). Type A viruses generally cause up to two thirds of annual infections, although single country studies have shown that B infections may be the predominant virus in KEYWORDS the one year in four. Trivalent Quadrivalent Influenza vaccines have traditionally included the hamagglutinins and neuraminidases from the two Influenza vaccine circulating A viruses and either B Yamagata or B Victoria – however, selecting the B strain for inclusion in these trivalent vaccines has variable success. The alternative approach is to include both B strains in a quadrivalent vaccine. Immunological studies of such vaccines show non-inferiority with a trivalent vaccine comparator, and significant superiority to the additional B strain. Quadrivalent vaccines are more expensive than trivalent preparations but theoretical evidence would suggest they are likely to be more effective and therefore play a much greater role in national immunisation programmes in the future. Introduction Influenza A and B viruses have either a round or filamen- tous shape. They are RNA viruses with 8 separate RNA seg- Influenza disease is caused by a small number of co-circulating ments that code for the 10 viral proteins, including the HA and A subtypes and B types and so the usual approach by manufac- NA glycoproteins. The segmented genome enables exchange of turers has been to develop inter-pandemic vaccines based on HA, and possibly NA genes between different subtypes so the 2 most common A subtypes and the commonest B virus – enabling antigenic shift (see below). The virus has a bilipid 1,2 i.e. a trivalent vaccine. More recently, influenza vaccines that outer membrane that is derived from the host cell as it exits the protect against an additional B type have been produced – i.e., cell and in which are embedded the HA and NA glycoproteins. a four component or quadrivalent vaccine, and this paper explores the rationale and merits of this development. Influenza disease Influenza classically starts with an abrupt onset of fever associ- ated with myalgia, headache and malaise; these features are fre- Influenza virus quently accompanied by a sore throat, non-productive cough The influenza virus was first isolated in 1933 – this was subse- and a nasal discharge. However, the spectrum of infection quently classified as influenza A virus. A separate, serologically varies from asymptomatic illness (up to a third of influenza distinct virus was isolated in 1940 and designated influenza B. infections), through an afebrile cold-like disease, to a more Influenza C virus was isolated in 1950. severe and systemic illness. In uncomplicated influenza, the ill- Influenza viruses belong to the family orthomyxoviridae and ness usually resolves within 5 days – occasionally taking a week are widely distributed among the animal kingdom. They are or so. Some patients may complain of ongoing symptoms, par- divided into different types based on variation in their ticularly easy fatigability for several weeks. expressed matrix and nucleoproteins – only types A, B and C Disease complications include a primary influenza or sec- affect humans with the latter 2 being unique human patho- ondary bacterial pneumonia; myositis with rhabdomyolysis is 2,3 gens. Type A viruses are further divided into subtypes based also described, as are aseptic meningitis, encephalitis, encepha- on differences in their haemagglutinin (HA) and neuramini- lopathy, transverse myelitis and Guillain Barre Syndrome. Car- dase (NA) surface glycoproteins: types B and C are not sub- diac complications, including myocardial infarction are typed. For type A there are 16 different HA (1-16) and 9 thought to occur more frequently in association with influenza different NA (1-9) proteins, with subtypes H1N1, H2N2 and infection. Complications are more likely in those with existing th H3N2 being responsible for the major pandemics of the 20 co-morbidity, which includes chronic lung, heart, kidney, liver century. Type B viruses also undergo antigenic drift but at a sig- and neurological diseases, diabetes, immunosuppression, asple- nificantly slower rate than A viruses. nia or hyposplenia and pregnancy. In young children, about CONTACT David Baxter dnbaxter@gmail.com © 2016 Crown copyright HUMAN VACCINES & IMMUNOTHERAPEUTICS 2713 25% of infections occur in those with underlying medical The majority (97%) of A viruses were H3N2, with 2.9% H1N1 conditions. pdm09 and 0.1% H5. Of the B strains characterized, 94.4% Transmission of influenza is mainly through the respiratory were B-Yamagata lineage and 5.6% B-Victoria lineage. route. Coughing, sneezing and even talking produce viral laden mucus particles of varying sizes – very small particles less than Disease impact 5 microns in diameter remain suspended in air and can be inhaled into the terminal bronchioles and alveoli; larger par- Influenza is the cause of considerable global morbidity, mortal- ticles may directly strike the conjunctiva or the oropharynx ity and economic burden – in terms of both lost productivity leading to disease. The largest particles may fall under gravity and treatment costs. In temperate regions, influenza is seasonal and settle on environmental surfaces where they can be trans- and thought to affect between 5% and 15% of the population ferred to mucosal surfaces on hands and cause infection. each year with a case fatality rate of <0.01% – this results in as The incubation period of influenza is usually about 2 days many as 3 to 5 million cases of severe disease and 250,000 to (with a range one to 4 days). Influenza virus is believed to be 500,000 deaths. In industrialised countries these deaths are pri- transmissible from about 24 hours prior to the onset of clinical marily among those 65 years and over, or younger individuals symptoms through to about 3 – 5 days after disease onset – it with underlying medical conditions (chronic lung or heart dis- may be up to 7 days in children and those immunocompro- ease for example). Pandemic disease has a similar case fatality mised. Viral transmission is thought to be more likely when but, as most, if not all, of the affected population are immuno- affected people exhibit signs and symptoms of the disease. Indi- logically na€ ıve to this novel virus, there are greater numbers of viduals with more severe disease are thought to transmit higher cases and more deaths. Thus during the recent H1N1 2009 viral loads than less symptomatic individuals – asymptomatic pandemic there were an estimated 201,200 deaths due to respi- infections are probably relatively unimportant in disease ratory diseases with a further 83,300 due to cardiovascular dis- spread. It is assumed that people treated with antivirals shed eases: the H1N1 pandemic of 1918/19 is believed have caused 2,14 virus for a shorter period and with lower viral numbers than more than 50 million deaths worldwide. untreated people. Overall, type A influenza is the cause of most serious human Disease epidemiology disease and while B strain infections occur at all ages they are more frequent in children and young adults – in children sys- Influenza disease epidemiology may usefully be considered as temic disease with neurological complications are reported, inter-pandemic and pandemic. Inter-pandemic disease in the 5-8 albeit rarely. Type C strain infections are usually regarded as northern hemisphere is seasonal, occurring in the winter very mild and uncommon although outbreaks of symptomatic months and results from the appearance, in a largely immune disease have been described and sero-prevalence studies suggest population, of a novel influenza virus variant(s) that emerges widespread infection among some populations. Due to their during the virus’s replicative cycle. As a result of the indepen- generally mild nature, C virus types are not included in the cur- dent nature of the 8 RNA gene strands (7 only in C type rently available influenza vaccines. viruses), viral replication is associated with a high frequency of re-assortment and antigenic variation resulting in point muta- tions in HA epitopes (antigenic drift) or change in whole HA Virus surveillance genes (antigenic shift). This facilitates viral evasion of the long- The World Health Organization (WHO) Global Influenza Sur- term control of infection by neutralising antibodies. With veillance Network (GISN) undertakes rolling identification of antigenic drift, although the variant differs from the parent circulating influenza viruses. Established in 1952, GISN has a virus, this difference is sufficiently small that existing antibody network of 135 National Influenza Centers (NICs) in 105 coun- to the parent virus is able to provide some, albeit incomplete tries, which sample more than 175,000 specimens from patients protection. Nevertheless, the novel variant now becomes the with influenza-like illness: about 2,000 of these are then submit- predominant strain. Over time, as protective antibody levels to ted to one of 6 WHO Collaborating Centers (CCs) for further the variant in the population increase, the cycle is repeated and antigenic and genetic characterization. Reverse transcriptase the pressure of protective population antibody leads to the PCR analysis of HA and NA genes enables early identification selection of a new, different variant. of strain divergence from the recommended vaccine composi- In contrast, pandemic disease is associated with less fre- tion. In addition, WHO CCs together with selected NICs quent, periodic emergence of a novel viral variant, which exhib- undertake serological studies to determine whether current vac- its such major differences with existing circulating strains that cines induce adequate neutralising antibody levels to recom- population antibody immunity is non-existent or extremely 10,11 mended vaccine strains. limited, and so the novel virus causes widespread disease. This Data output from GISN together with FluID and WHO is the result of antigenic shift; one mechanism that can cause Regional Offices and Member States enables fortnightly the emergence of such a pandemic strain is when 2 different updates of influenza transmission and viral characterization. influenza subtypes co-infect a susceptible cell and re-assort- st For example, as of December 1 2014, influenza update report- ment of their genetic material takes place. ing confirmed that although activity in Europe and North Since the mid-1980s there have been 2 A and 2 B influenza America had increased slightly it remained low as did global strains circulating throughout the world. The A viruses are influenza activity. Furthermore, of the 2,572 specimens tested H1N1 and H3N2 and the B viruses are B/Yamagata/16/88 and in NICs, 82.5% were influenza A and 17.5% influenza B strains. B/Victoria/287; the actual frequency varies with area of the 2714 D. BAXTER 11,16 world and time during the influenza season. For example, a The additional observation that neutralising HA and NA study in the Netherlands from 1992/3 to the 2006/7 seasons IgG titres equivalent to those in convalescent influenza survi- found that the proportion of laboratory confirmed infections vors were inducible by vaccination is the immunological basis due to AH1N1 viruses ranged from 1.3% to 58.8%; the corre- for influenza immunisation, the assumption being that these sponding figures for AH3N2 were 9.8% to 100%, and for both antibodies have a similar blocking effect on viral attachment B viruses combined 0.0% to 82.4%. The season average for B and invasion. Correlation between antibody levels (as measured viruses was 29% and in 4 of the 15 seasons studied, B viruses by haemagglutination-inhibition [HI] titres) and protection 8,17 were either the most common or were similarly common. against clinical disease is limited but the results of challenge Data for the period 2001/2 to 2010/11 (but excluding the 2009/ studies with attenuated viruses and natural experiments during 10 pandemic) from the US demonstrated similar findings with wild disease outbreaks suggest that HI antibody titres of 1:40 on average 24% of laboratory confirmed infections being due to are associated with protection from influenza illness in up to 25,26 B viruses: for Europe over the same period the corresponding 50% of subjects. figure was 23%. Influenza vaccine programmes Influenza vaccination programmes vary depending on the Disease pathogenesis and host response country – the UK operates one with both selective and univer- Infection is initiated by HA surface proteins ligating with sialic sal components. The selective program provides protection for (N-acetylneuraminic) acid containing glycans on the host tar- individuals at higher risk of infection – these include those get cell – epithelial cells of the upper respiratory tract, macro- aged 6 months to 64 years with chronic lung, heart, renal, liver phages, monocytes and leucocytes. Key sequential steps in viral and neurological conditions, the immunocompromised, people pathogenesis at a cellular level are receptor mediated endocyto- with diabetes, individuals with asplenia or hyposplenia and sis, uncoating, nuclear transcription of viral mRNAs, synthesis pregnant women. Healthcare workers and registered carers are of viral proteins in the cytoplasm, viral nucleocapsid assembly also offered immunisation. The universal program provides in the nucleus, followed by their transport to the plasma mem- Fluenz Tetra (AstraZeneca) nasal spray suspension which is a brane where budding and release of new virions through the live attenuated quadrivalent vaccine to infants and children action of the NA molecule, the second key surface expressed aged 2, 3 and 4 years with an expected extension of the pro- 4,18-20 viral protein takes place. Release of the virus from the cell gram to those under 17 years over the next few years. is associated with cell lysis. The host immune response to influenza virus infection Influenza vaccines 2,21 involves both innate and adaptive mechanisms. Innate mechanisms include the mucociliary apparatus of the upper The first influenza vaccines were developed in the 1930s and and lower respiratory tract and recognition of influenza patho- approved for use in the USA in 1945, live attenuated vaccines gen associated molecular patterns by cell surface expressed pat- were administered subcutaneously and shown to lead to a rise tern recognition receptors on dendritic cells (DCs). These in neutralising antibodies that persisted for about 3 months. In include toll-like receptors, NOD-like receptors and retinoic the UK concern at that time about using live organisms led to acid inducible gene receptors. Activation of DCs cause release their replacement with formaldehyde inactivated whole virus of type 1 interferons (IFN) and proinflammatory cytokines; the preparations. former induce an antiviral state in adjacent cells through the There are 4 commercially available influenza vaccine types – transcription of many IFN-stimulated genes while the latter killed/ inactivated, split virus, subunit and live attenuated. cause both local and systemic inflammation. Virally infected Killed inactivated vaccines were the first developed with virus cells are subsequently targeted and apoptosed by natural killer grown in chick embryo allantoic fluids. Current inactivated cells and cell remnants are removed by macrophages and vaccines are subject to better purification methods and because neutrophils. they are now free of bacterial endotoxin, they are less reacto- If the influenza virus is able to overcome these innate bar- genic than earlier preparations. Split virus vaccines are manu- riers and establish infection, then adaptive mechanisms, involv- factured by treating whole viruses with ether to disrupt the ing both antibodies and CD8 T cells, are activated. Neutralising bilipid membrane – the resulting preparation contains all the antibodies are produced by B cells against most of the 10 pro- viral proteins together with part of the bilipid membrane. Sub- teins encoded by the 8 RNA genes – those against HA block unit vaccines are produced by treating whole viruses with target cell attachment and assist in viral clearance and are also detergent (for example sodium dodecyl sulfate) – the resulting highly effective at preventing subsequent reinfection with the preparation largely contains both HA and NA, although it is same virus type/ subtype. Although it is generally agreed that subsequently enriched for both in the final vaccine. Live attenu- immunity is monotypic, previous infection with different ated influenza vaccines are produced by inserting the HA and strains of wild influenza may provide heterotypic immunity NA genes from the circulating influenza viruses predicted to be against related subtypes through generating neutralising anti- most prevalent during the next influenza season, into an HA/ bodies against more highly conserved areas of the HA mole- NA deleted influenza virus strain that is able to replicate effi- cule. Neutralising antibodies against NA have been shown to ciently in fertilised chicken eggs and also grows well at lower reduce disease severity but their role in preventing infection than normal body temperatures. As a result it will grow well in 23,24 requires further study. the nasal mucosa where the temperature is lower than the body HUMAN VACCINES & IMMUNOTHERAPEUTICS 2715 but is unable to cause respiratory tract infection; the immune Vaccine efficacy response is generated in the upper respiratory tract mucosa The vaccine efficacies of intramuscularly administered single blocking viral attachment if exposure occurs. dose whole virus A and B vaccines were studied in the 1940s Vaccine dose is determined by the viral strain(s) against and estimated to be »80%, provided subsequent wild infection which immunity is directed – interpandemic vaccine is admin- was due to a virus of the same immunological type as that used istered to individuals primed by previous vaccination or infec- to make the vaccine. Currently, it is believed that vaccine effi- tion with currently circulating strains, one dose of 15 mgis cacy is presumed to be between 70 and 90% although Cochrane generally sufficient. In contrast, young children, the majority of 28-30 reviews have suggested a considerably lower efficacy. In the whom are immunologically na€ ıve to influenza viruses, require elderly vaccine efficacy for prevention of influenza-like illness 2 doses to both prime and enable a reduction in dose so limit- may be lower (»20%) but reduction in disease severity includ- ing reactogenicity. 1,31,32 ing hospitalisation and premature death is observed. Inactivated/ split/ subunit vaccines induce a systemic IgG The problem of antigenic drift/ shift and monotypic immu- response and, as influenza disease is rarely viraemic, it is nity became apparent in the USA in 1947 when an influenza A thought that in order to provide protection this IgG passes into vaccine was shown to be ineffective at preventing an epidemic the respiratory tract mucus membrane where it exerts a neu- 33-35 of influenza A disease. There were 2 approaches used in tralising antibody effect with no IgA response. Furthermore, vaccine development during the 1950s to address this; based on high antibody titres have been shown to prevent disease the premise that the numbers of influenza strains were finite, 1,26,27 whereas lower titres modify disease severity. multistrain inactivated vaccines with about 4 antigenic compo- In adults, neutralising antibodies to HA appear within about nents were advocated in the USA. In contrast, based on the 7 days. Given that the majority will have been previously view that at any one time only one virus was dominant, vac- exposed to the same or similar epitopes through earlier infec- cines in the UK were developed containing one dominant A, tion, this is the response of primed individuals so the time to 33,35 and one dominant B strain only. respond in na€ ıve children may be different and presumably Vaccine dosage for either the subunit or live attenuated vac- longer. cines is age dependent – see the summary of product character- The duration of antibody response is difficult to determine istics for details of the schedules. as this is influenced by prior immunisation with common epit- opes and asymptomatic infection post vaccination. In children, approximately 60% of those who responded had detectable Trivalent/ quadrivalent influenza vaccines antibody 10-15 months later compared with 91% of adults. One approach to comparing the 3 or 4 component vaccines is As previously discussed, vaccine induced immunity is to measure HI titres in groups randomized to receive one or almost certainly not variant-specific due to shared epitopes. other vaccines. Assuming that a titer 1:40 is associated with Such heterovariant immunity will influence how vaccine for- protection then the proportion protected and their average mulation is changed on an annual basis in response to antigenic titres can be determined. drift. In contrast, intersubtypic immunity is insignificant as evi- In a study of children aged 3-17 years comparing Fluarix denced by pandemic disease when a new subtype appears. (trivalent; GSK) with Fluarix Tetra (quadrivalent; GSK) and measuring HI antibodies 28 days post one or 2 doses of vaccine, Trivalent and quadrivalent influenza vaccines equivalence for the 3 common strains (2 As and one B) was shown with the quadrivalent preparation, although as expected Until recently, influenza vaccines have been trivalent prepara- the latter generated higher titres against the additional B strain. tions containing HA and NA proteins from A/H1N1 and A/ The same methodology in a study of adults aged 18 years and H3N2, together with a B type virus as recommended annually older, but using only one dose of vaccine gave similar results. by the WHO. However, because there are 2 B types with limited Immunological studies based on HI IgG titres >1:40, measur- heterotypic immunity, circulating globally since the mid-1980s, ing seroconversion and seroprotection have shown non-inferi- there is the potential for vaccine mismatch depending on ority with the trivalent components and superiority with the whether B/Yamagata or B/Victoria are chosen for inclusion in alternate lineage B strain. There were no differences between the seasonal vaccine. Indeed, the predicted B strain included in the trivalent and quadrivalent preparations with regard to the recommended northern hemisphere seasonal influenza vac- 36-41 safety and reactogenicity. cine was incorrect during 5 of the 10 influenza seasons 2001/2 There is an increased cost associated with the use of quadri- to 2010/11. valent vaccines but modeling studies suggest a significant socie- The value of a quadrivalent vaccine is determined by prior tal cost saving even if the cost is significantly higher than the exposure to similar epitopes (i.e. heterovariant immunity) 42-44 trivalent preparation. either by wild disease or vaccination, host age (although this will in part be correlated with prior disease exposure, old age is associated with a reduced antibody response), the route of vac- Conclusions cine administration, the antigen dose, the inclusion of an adju- vant, the match-up between vaccine strain and circulating Throughout the world, 4 influenza viruses co-circulate every strain, and the time interval between vaccination and disease year; these are AH1N1, AH3N2, B/Yamagata and B/Victoria; exposure (for optimal protection this should be between 2 and in the Northern hemisphere, influenza is believed to affect 4 months after vaccination). between 5 and 15% of the population annually with a case 2716 D. 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Edinburgh and London: E valent influenza vaccine candidate versus inactivated trivalent influ- and S Livingstone Ltd; 1965 enza vaccine: a phase III, randomized trial in adults aged 18 years. [34] Sigel MM, Shaffer FW, Kirber MW, Light AB, Henle W. Influenza A BMC Infect Dis 2013; 13:343; PMID:23883186; http://dx.doi.org/ in a vaccinated population. JAMA 1948; 136(7):437-41; PMID: 10.1186/1471-2334-13-343 22997639; http://dx.doi.org/10.1001/jama.1948.02890240003002 [41] Block SL, Yi T, Sheldon E, Dubovsky F, Falloon J. A randomized, [35] Salk JE. An interpretation of the significance of influenza virus varia- double-blind noninferiority study of quadrivalent live attenuated tion for the development of an effective vaccine. Bull N Y Acad Med influenza vaccine in adults. Vaccine 2011; 29(50):9391-7; 1952; 28(11):748-65; PMID:12987937 PMID:21983154; http://dx.doi.org/10.1016/j.vaccine.2011.09.109 [36] Domachowske JB, Pankow-Culot H, Bautista M, Feng Y, Claeys C, [42] Lee BY, Bartsch SM, Willig AM. The economic value of a Peeters M, Innis BL, Jain V. A randomized trial of candidate inacti- quadrivalent versus trivalent influenza vaccine. Vaccine 2012; vated quadrivalent influenza vaccine versus trivalent influenza vac- 30(52):7443-6; PMID:23084849; http://dx.doi.org/10.1016/j. cines in children aged 3-17 years. J Infect Dis 2013; 207(12):1878-87; vaccine.2012.10.025 PMID:23470848; http://dx.doi.org/10.1093/infdis/jit091 [43] Lee BY, Bartsch SM, Willig AM. Corrigendum to “The economic [37] Greenberg DP, Robertson CA, Noss MJ, Blatter MM, Biedenbender value of a quadrivalent versus trivalent influenza vaccine” [Vaccine R, Decker MD. Safety and immunogenicity of a quadrivalent inacti- 2012;30:7443-6]. Vaccine 2013; 31(20):2477-9; http://dx.doi.org/ vated influenza vaccine compared to licensed trivalent inactivated 10.1016/j.vaccine.2013.04.013 influenza vaccines in adults. Vaccine 2013; 31(5):770-6; [44] Van Bellinghen LA, Meier G, Van Vlaenderen I. The potential cost- PMID:23228813; http://dx.doi.org/10.1016/j.vaccine.2012.11.074 effectiveness of quadrivalent versus trivalent influenza vaccine in [38] Tinoco JC, Pavia-Ruz N, Cruz-Valdez A, Aranza Doniz C, Chan- elderly people and clinical risk groups in the UK: a lifetime multi- drasekaran V, Dewe W, Liu A, Innis BL, Jain VK. Immunogenic- cohort model. PLoS One 2014; 9(6):e98437; PMID:24905235; http:// ity, reactogenicity, and safety of inactivated quadrivalent dx.doi.org/10.1371/journal.pone.0098437 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Vaccines & Immunotherapeutics Taylor & Francis

Evaluating the case for trivalent or quadrivalent influenza vaccines

Human Vaccines & Immunotherapeutics , Volume 12 (10): 6 – Oct 2, 2016

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HUMAN VACCINES & IMMUNOTHERAPEUTICS 2016, VOL. 12, NO. 10, 2712–2717 http://dx.doi.org/10.1080/21645515.2015.1091130 REVIEW Evaluating the case for trivalent or quadrivalent influenza vaccines David Baxter Stockport NHS Foundation Trust, Consultant in Health Protection, Manchester Medical School, University of Manchester, Manchester, UK ABSTRACT ARTICLE HISTORY Received 26 August 2015 Influenza viruses circulate widely throughout the world and it is estimated that they affect between 5 and Revised 28 August 2015 15% of the population annually. Since 1977, four viruses co-circulate – two A Viruses (H1N1 and H3N2) and Accepted 1 September 2015 two B viruses (B Yamagata and B Victoria). Type A viruses generally cause up to two thirds of annual infections, although single country studies have shown that B infections may be the predominant virus in KEYWORDS the one year in four. Trivalent Quadrivalent Influenza vaccines have traditionally included the hamagglutinins and neuraminidases from the two Influenza vaccine circulating A viruses and either B Yamagata or B Victoria – however, selecting the B strain for inclusion in these trivalent vaccines has variable success. The alternative approach is to include both B strains in a quadrivalent vaccine. Immunological studies of such vaccines show non-inferiority with a trivalent vaccine comparator, and significant superiority to the additional B strain. Quadrivalent vaccines are more expensive than trivalent preparations but theoretical evidence would suggest they are likely to be more effective and therefore play a much greater role in national immunisation programmes in the future. Introduction Influenza A and B viruses have either a round or filamen- tous shape. They are RNA viruses with 8 separate RNA seg- Influenza disease is caused by a small number of co-circulating ments that code for the 10 viral proteins, including the HA and A subtypes and B types and so the usual approach by manufac- NA glycoproteins. The segmented genome enables exchange of turers has been to develop inter-pandemic vaccines based on HA, and possibly NA genes between different subtypes so the 2 most common A subtypes and the commonest B virus – enabling antigenic shift (see below). The virus has a bilipid 1,2 i.e. a trivalent vaccine. More recently, influenza vaccines that outer membrane that is derived from the host cell as it exits the protect against an additional B type have been produced – i.e., cell and in which are embedded the HA and NA glycoproteins. a four component or quadrivalent vaccine, and this paper explores the rationale and merits of this development. Influenza disease Influenza classically starts with an abrupt onset of fever associ- ated with myalgia, headache and malaise; these features are fre- Influenza virus quently accompanied by a sore throat, non-productive cough The influenza virus was first isolated in 1933 – this was subse- and a nasal discharge. However, the spectrum of infection quently classified as influenza A virus. A separate, serologically varies from asymptomatic illness (up to a third of influenza distinct virus was isolated in 1940 and designated influenza B. infections), through an afebrile cold-like disease, to a more Influenza C virus was isolated in 1950. severe and systemic illness. In uncomplicated influenza, the ill- Influenza viruses belong to the family orthomyxoviridae and ness usually resolves within 5 days – occasionally taking a week are widely distributed among the animal kingdom. They are or so. Some patients may complain of ongoing symptoms, par- divided into different types based on variation in their ticularly easy fatigability for several weeks. expressed matrix and nucleoproteins – only types A, B and C Disease complications include a primary influenza or sec- affect humans with the latter 2 being unique human patho- ondary bacterial pneumonia; myositis with rhabdomyolysis is 2,3 gens. Type A viruses are further divided into subtypes based also described, as are aseptic meningitis, encephalitis, encepha- on differences in their haemagglutinin (HA) and neuramini- lopathy, transverse myelitis and Guillain Barre Syndrome. Car- dase (NA) surface glycoproteins: types B and C are not sub- diac complications, including myocardial infarction are typed. For type A there are 16 different HA (1-16) and 9 thought to occur more frequently in association with influenza different NA (1-9) proteins, with subtypes H1N1, H2N2 and infection. Complications are more likely in those with existing th H3N2 being responsible for the major pandemics of the 20 co-morbidity, which includes chronic lung, heart, kidney, liver century. Type B viruses also undergo antigenic drift but at a sig- and neurological diseases, diabetes, immunosuppression, asple- nificantly slower rate than A viruses. nia or hyposplenia and pregnancy. In young children, about CONTACT David Baxter dnbaxter@gmail.com © 2016 Crown copyright HUMAN VACCINES & IMMUNOTHERAPEUTICS 2713 25% of infections occur in those with underlying medical The majority (97%) of A viruses were H3N2, with 2.9% H1N1 conditions. pdm09 and 0.1% H5. Of the B strains characterized, 94.4% Transmission of influenza is mainly through the respiratory were B-Yamagata lineage and 5.6% B-Victoria lineage. route. Coughing, sneezing and even talking produce viral laden mucus particles of varying sizes – very small particles less than Disease impact 5 microns in diameter remain suspended in air and can be inhaled into the terminal bronchioles and alveoli; larger par- Influenza is the cause of considerable global morbidity, mortal- ticles may directly strike the conjunctiva or the oropharynx ity and economic burden – in terms of both lost productivity leading to disease. The largest particles may fall under gravity and treatment costs. In temperate regions, influenza is seasonal and settle on environmental surfaces where they can be trans- and thought to affect between 5% and 15% of the population ferred to mucosal surfaces on hands and cause infection. each year with a case fatality rate of <0.01% – this results in as The incubation period of influenza is usually about 2 days many as 3 to 5 million cases of severe disease and 250,000 to (with a range one to 4 days). Influenza virus is believed to be 500,000 deaths. In industrialised countries these deaths are pri- transmissible from about 24 hours prior to the onset of clinical marily among those 65 years and over, or younger individuals symptoms through to about 3 – 5 days after disease onset – it with underlying medical conditions (chronic lung or heart dis- may be up to 7 days in children and those immunocompro- ease for example). Pandemic disease has a similar case fatality mised. Viral transmission is thought to be more likely when but, as most, if not all, of the affected population are immuno- affected people exhibit signs and symptoms of the disease. Indi- logically na€ ıve to this novel virus, there are greater numbers of viduals with more severe disease are thought to transmit higher cases and more deaths. Thus during the recent H1N1 2009 viral loads than less symptomatic individuals – asymptomatic pandemic there were an estimated 201,200 deaths due to respi- infections are probably relatively unimportant in disease ratory diseases with a further 83,300 due to cardiovascular dis- spread. It is assumed that people treated with antivirals shed eases: the H1N1 pandemic of 1918/19 is believed have caused 2,14 virus for a shorter period and with lower viral numbers than more than 50 million deaths worldwide. untreated people. Overall, type A influenza is the cause of most serious human Disease epidemiology disease and while B strain infections occur at all ages they are more frequent in children and young adults – in children sys- Influenza disease epidemiology may usefully be considered as temic disease with neurological complications are reported, inter-pandemic and pandemic. Inter-pandemic disease in the 5-8 albeit rarely. Type C strain infections are usually regarded as northern hemisphere is seasonal, occurring in the winter very mild and uncommon although outbreaks of symptomatic months and results from the appearance, in a largely immune disease have been described and sero-prevalence studies suggest population, of a novel influenza virus variant(s) that emerges widespread infection among some populations. Due to their during the virus’s replicative cycle. As a result of the indepen- generally mild nature, C virus types are not included in the cur- dent nature of the 8 RNA gene strands (7 only in C type rently available influenza vaccines. viruses), viral replication is associated with a high frequency of re-assortment and antigenic variation resulting in point muta- tions in HA epitopes (antigenic drift) or change in whole HA Virus surveillance genes (antigenic shift). This facilitates viral evasion of the long- The World Health Organization (WHO) Global Influenza Sur- term control of infection by neutralising antibodies. With veillance Network (GISN) undertakes rolling identification of antigenic drift, although the variant differs from the parent circulating influenza viruses. Established in 1952, GISN has a virus, this difference is sufficiently small that existing antibody network of 135 National Influenza Centers (NICs) in 105 coun- to the parent virus is able to provide some, albeit incomplete tries, which sample more than 175,000 specimens from patients protection. Nevertheless, the novel variant now becomes the with influenza-like illness: about 2,000 of these are then submit- predominant strain. Over time, as protective antibody levels to ted to one of 6 WHO Collaborating Centers (CCs) for further the variant in the population increase, the cycle is repeated and antigenic and genetic characterization. Reverse transcriptase the pressure of protective population antibody leads to the PCR analysis of HA and NA genes enables early identification selection of a new, different variant. of strain divergence from the recommended vaccine composi- In contrast, pandemic disease is associated with less fre- tion. In addition, WHO CCs together with selected NICs quent, periodic emergence of a novel viral variant, which exhib- undertake serological studies to determine whether current vac- its such major differences with existing circulating strains that cines induce adequate neutralising antibody levels to recom- population antibody immunity is non-existent or extremely 10,11 mended vaccine strains. limited, and so the novel virus causes widespread disease. This Data output from GISN together with FluID and WHO is the result of antigenic shift; one mechanism that can cause Regional Offices and Member States enables fortnightly the emergence of such a pandemic strain is when 2 different updates of influenza transmission and viral characterization. influenza subtypes co-infect a susceptible cell and re-assort- st For example, as of December 1 2014, influenza update report- ment of their genetic material takes place. ing confirmed that although activity in Europe and North Since the mid-1980s there have been 2 A and 2 B influenza America had increased slightly it remained low as did global strains circulating throughout the world. The A viruses are influenza activity. Furthermore, of the 2,572 specimens tested H1N1 and H3N2 and the B viruses are B/Yamagata/16/88 and in NICs, 82.5% were influenza A and 17.5% influenza B strains. B/Victoria/287; the actual frequency varies with area of the 2714 D. BAXTER 11,16 world and time during the influenza season. For example, a The additional observation that neutralising HA and NA study in the Netherlands from 1992/3 to the 2006/7 seasons IgG titres equivalent to those in convalescent influenza survi- found that the proportion of laboratory confirmed infections vors were inducible by vaccination is the immunological basis due to AH1N1 viruses ranged from 1.3% to 58.8%; the corre- for influenza immunisation, the assumption being that these sponding figures for AH3N2 were 9.8% to 100%, and for both antibodies have a similar blocking effect on viral attachment B viruses combined 0.0% to 82.4%. The season average for B and invasion. Correlation between antibody levels (as measured viruses was 29% and in 4 of the 15 seasons studied, B viruses by haemagglutination-inhibition [HI] titres) and protection 8,17 were either the most common or were similarly common. against clinical disease is limited but the results of challenge Data for the period 2001/2 to 2010/11 (but excluding the 2009/ studies with attenuated viruses and natural experiments during 10 pandemic) from the US demonstrated similar findings with wild disease outbreaks suggest that HI antibody titres of 1:40 on average 24% of laboratory confirmed infections being due to are associated with protection from influenza illness in up to 25,26 B viruses: for Europe over the same period the corresponding 50% of subjects. figure was 23%. Influenza vaccine programmes Influenza vaccination programmes vary depending on the Disease pathogenesis and host response country – the UK operates one with both selective and univer- Infection is initiated by HA surface proteins ligating with sialic sal components. The selective program provides protection for (N-acetylneuraminic) acid containing glycans on the host tar- individuals at higher risk of infection – these include those get cell – epithelial cells of the upper respiratory tract, macro- aged 6 months to 64 years with chronic lung, heart, renal, liver phages, monocytes and leucocytes. Key sequential steps in viral and neurological conditions, the immunocompromised, people pathogenesis at a cellular level are receptor mediated endocyto- with diabetes, individuals with asplenia or hyposplenia and sis, uncoating, nuclear transcription of viral mRNAs, synthesis pregnant women. Healthcare workers and registered carers are of viral proteins in the cytoplasm, viral nucleocapsid assembly also offered immunisation. The universal program provides in the nucleus, followed by their transport to the plasma mem- Fluenz Tetra (AstraZeneca) nasal spray suspension which is a brane where budding and release of new virions through the live attenuated quadrivalent vaccine to infants and children action of the NA molecule, the second key surface expressed aged 2, 3 and 4 years with an expected extension of the pro- 4,18-20 viral protein takes place. Release of the virus from the cell gram to those under 17 years over the next few years. is associated with cell lysis. The host immune response to influenza virus infection Influenza vaccines 2,21 involves both innate and adaptive mechanisms. Innate mechanisms include the mucociliary apparatus of the upper The first influenza vaccines were developed in the 1930s and and lower respiratory tract and recognition of influenza patho- approved for use in the USA in 1945, live attenuated vaccines gen associated molecular patterns by cell surface expressed pat- were administered subcutaneously and shown to lead to a rise tern recognition receptors on dendritic cells (DCs). These in neutralising antibodies that persisted for about 3 months. In include toll-like receptors, NOD-like receptors and retinoic the UK concern at that time about using live organisms led to acid inducible gene receptors. Activation of DCs cause release their replacement with formaldehyde inactivated whole virus of type 1 interferons (IFN) and proinflammatory cytokines; the preparations. former induce an antiviral state in adjacent cells through the There are 4 commercially available influenza vaccine types – transcription of many IFN-stimulated genes while the latter killed/ inactivated, split virus, subunit and live attenuated. cause both local and systemic inflammation. Virally infected Killed inactivated vaccines were the first developed with virus cells are subsequently targeted and apoptosed by natural killer grown in chick embryo allantoic fluids. Current inactivated cells and cell remnants are removed by macrophages and vaccines are subject to better purification methods and because neutrophils. they are now free of bacterial endotoxin, they are less reacto- If the influenza virus is able to overcome these innate bar- genic than earlier preparations. Split virus vaccines are manu- riers and establish infection, then adaptive mechanisms, involv- factured by treating whole viruses with ether to disrupt the ing both antibodies and CD8 T cells, are activated. Neutralising bilipid membrane – the resulting preparation contains all the antibodies are produced by B cells against most of the 10 pro- viral proteins together with part of the bilipid membrane. Sub- teins encoded by the 8 RNA genes – those against HA block unit vaccines are produced by treating whole viruses with target cell attachment and assist in viral clearance and are also detergent (for example sodium dodecyl sulfate) – the resulting highly effective at preventing subsequent reinfection with the preparation largely contains both HA and NA, although it is same virus type/ subtype. Although it is generally agreed that subsequently enriched for both in the final vaccine. Live attenu- immunity is monotypic, previous infection with different ated influenza vaccines are produced by inserting the HA and strains of wild influenza may provide heterotypic immunity NA genes from the circulating influenza viruses predicted to be against related subtypes through generating neutralising anti- most prevalent during the next influenza season, into an HA/ bodies against more highly conserved areas of the HA mole- NA deleted influenza virus strain that is able to replicate effi- cule. Neutralising antibodies against NA have been shown to ciently in fertilised chicken eggs and also grows well at lower reduce disease severity but their role in preventing infection than normal body temperatures. As a result it will grow well in 23,24 requires further study. the nasal mucosa where the temperature is lower than the body HUMAN VACCINES & IMMUNOTHERAPEUTICS 2715 but is unable to cause respiratory tract infection; the immune Vaccine efficacy response is generated in the upper respiratory tract mucosa The vaccine efficacies of intramuscularly administered single blocking viral attachment if exposure occurs. dose whole virus A and B vaccines were studied in the 1940s Vaccine dose is determined by the viral strain(s) against and estimated to be »80%, provided subsequent wild infection which immunity is directed – interpandemic vaccine is admin- was due to a virus of the same immunological type as that used istered to individuals primed by previous vaccination or infec- to make the vaccine. Currently, it is believed that vaccine effi- tion with currently circulating strains, one dose of 15 mgis cacy is presumed to be between 70 and 90% although Cochrane generally sufficient. In contrast, young children, the majority of 28-30 reviews have suggested a considerably lower efficacy. In the whom are immunologically na€ ıve to influenza viruses, require elderly vaccine efficacy for prevention of influenza-like illness 2 doses to both prime and enable a reduction in dose so limit- may be lower (»20%) but reduction in disease severity includ- ing reactogenicity. 1,31,32 ing hospitalisation and premature death is observed. Inactivated/ split/ subunit vaccines induce a systemic IgG The problem of antigenic drift/ shift and monotypic immu- response and, as influenza disease is rarely viraemic, it is nity became apparent in the USA in 1947 when an influenza A thought that in order to provide protection this IgG passes into vaccine was shown to be ineffective at preventing an epidemic the respiratory tract mucus membrane where it exerts a neu- 33-35 of influenza A disease. There were 2 approaches used in tralising antibody effect with no IgA response. Furthermore, vaccine development during the 1950s to address this; based on high antibody titres have been shown to prevent disease the premise that the numbers of influenza strains were finite, 1,26,27 whereas lower titres modify disease severity. multistrain inactivated vaccines with about 4 antigenic compo- In adults, neutralising antibodies to HA appear within about nents were advocated in the USA. In contrast, based on the 7 days. Given that the majority will have been previously view that at any one time only one virus was dominant, vac- exposed to the same or similar epitopes through earlier infec- cines in the UK were developed containing one dominant A, tion, this is the response of primed individuals so the time to 33,35 and one dominant B strain only. respond in na€ ıve children may be different and presumably Vaccine dosage for either the subunit or live attenuated vac- longer. cines is age dependent – see the summary of product character- The duration of antibody response is difficult to determine istics for details of the schedules. as this is influenced by prior immunisation with common epit- opes and asymptomatic infection post vaccination. In children, approximately 60% of those who responded had detectable Trivalent/ quadrivalent influenza vaccines antibody 10-15 months later compared with 91% of adults. One approach to comparing the 3 or 4 component vaccines is As previously discussed, vaccine induced immunity is to measure HI titres in groups randomized to receive one or almost certainly not variant-specific due to shared epitopes. other vaccines. Assuming that a titer 1:40 is associated with Such heterovariant immunity will influence how vaccine for- protection then the proportion protected and their average mulation is changed on an annual basis in response to antigenic titres can be determined. drift. In contrast, intersubtypic immunity is insignificant as evi- In a study of children aged 3-17 years comparing Fluarix denced by pandemic disease when a new subtype appears. (trivalent; GSK) with Fluarix Tetra (quadrivalent; GSK) and measuring HI antibodies 28 days post one or 2 doses of vaccine, Trivalent and quadrivalent influenza vaccines equivalence for the 3 common strains (2 As and one B) was shown with the quadrivalent preparation, although as expected Until recently, influenza vaccines have been trivalent prepara- the latter generated higher titres against the additional B strain. tions containing HA and NA proteins from A/H1N1 and A/ The same methodology in a study of adults aged 18 years and H3N2, together with a B type virus as recommended annually older, but using only one dose of vaccine gave similar results. by the WHO. However, because there are 2 B types with limited Immunological studies based on HI IgG titres >1:40, measur- heterotypic immunity, circulating globally since the mid-1980s, ing seroconversion and seroprotection have shown non-inferi- there is the potential for vaccine mismatch depending on ority with the trivalent components and superiority with the whether B/Yamagata or B/Victoria are chosen for inclusion in alternate lineage B strain. There were no differences between the seasonal vaccine. Indeed, the predicted B strain included in the trivalent and quadrivalent preparations with regard to the recommended northern hemisphere seasonal influenza vac- 36-41 safety and reactogenicity. cine was incorrect during 5 of the 10 influenza seasons 2001/2 There is an increased cost associated with the use of quadri- to 2010/11. valent vaccines but modeling studies suggest a significant socie- The value of a quadrivalent vaccine is determined by prior tal cost saving even if the cost is significantly higher than the exposure to similar epitopes (i.e. heterovariant immunity) 42-44 trivalent preparation. either by wild disease or vaccination, host age (although this will in part be correlated with prior disease exposure, old age is associated with a reduced antibody response), the route of vac- Conclusions cine administration, the antigen dose, the inclusion of an adju- vant, the match-up between vaccine strain and circulating Throughout the world, 4 influenza viruses co-circulate every strain, and the time interval between vaccination and disease year; these are AH1N1, AH3N2, B/Yamagata and B/Victoria; exposure (for optimal protection this should be between 2 and in the Northern hemisphere, influenza is believed to affect 4 months after vaccination). between 5 and 15% of the population annually with a case 2716 D. BAXTER fatality rate <0.01%. Type A infections are generally more fre- influenza/surveillance_monitoring/updates/2014_12_01_update_ GIP_surveillance/en/ quent than B with the former on average causing just over 2 [13] WHO. Influenza (Seasonal) 2014 [cited 2015 15/05/2015]. Available thirds of all laboratory confirmed cases. However, single coun- from: http://www.who.int/mediacentre/factsheets/fs211/en/ try studies have demonstrated that B infections may be the pre- [14] Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, Cheng PY, dominant virus in about one year in 4. There are 2 strains of B Bandaranayake D, Breiman RF, Brooks WA, Buchy P, et al. Esti- virus with B/Yamagata usually being more common than B/ mated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Victoria. Analysis of neutralising HA antibodies (as measured Lancet Infect Dis 2012; 12(9):687-95; PMID:22738893; http://dx.doi. by HI IgG) suggest that titres >1:40 provide effective protection org/10.1016/S1473-3099(12)70121-4 against homologous strain infection and provide the theoretical [15] Waffarn EE, Baumgarth N. Protective B Cell Responses to Flu—No basis for vaccination. Influenza vaccines have usually been tri- Fluke! J Immunol 2011; 186(7):3823-9; PMID:21422252; http://dx. valent preparations with 2 A strains and one B strain but select- doi.org/10.4049/jimmunol.1002090 [16] Rota PA, Wallis TR, Harmon MW, Rota JS, Kendal AP, Nerome K. ing the B strain for inclusion in the vaccine in the following Cocirculation of two distinct evolutionary lineages of influenza type year has variable success. The alternative approach is to include B virus since 1983. Virology 1990; 175(1):59-68; PMID:2309452; both B strains in a quadrivalent vaccine. Immunological studies http://dx.doi.org/10.1016/0042-6822(90)90186-U of such vaccines show non-inferiority with a trivalent vaccine [17] Dijkstra F, Donker GA, Wilbrink B, Van Gageldonk-Lafeber AB, comparator and significant superiority to the additional B Van Der Sande MA. Long time trends in influenza-like illness and associated determinants in The Netherlands. Epidemiol strain. Quadrivalent vaccines are more expensive than trivalent Infect 2009; 137(4):473-9; PMID:18789176; http://dx.doi.org/ preparations but the theoretical evidence would suggest they 10.1017/;S095026880800126X are likely to be more effective and therefore play a much greater [18] Yang ML, Chen YH, Wang SW, Huang YJ, Leu CH, Yeh NC, Chu role in national immunisation programmes. CY,Lin CC,Shieh GS,ChenYL, et al.Galectin-1binds to influenza virus and ameliorates influenza virus pathogenesis. 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Journal

Human Vaccines & ImmunotherapeuticsTaylor & Francis

Published: Oct 2, 2016

Keywords: Trivalent Quadrivalent Influenza vaccine

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