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The rationale for quadrivalent influenza vaccines

The rationale for quadrivalent influenza vaccines SPECIAL FOCUS REVIEW: INFLUENZA VACCINES Human Vaccines & Immunotherapeutics 8:1, 81–88; January 2012; 2012 Landes Bioscience 1, 2 Christopher S. Ambrose * and Myron J. Levin 1 2 MedImmune, LLC; Gaithersburg, MD USA; University of Colorado School of Medicine; Aurora, CO USA Keywords: influenza, public health, quadrivalent, surveillance, vaccine Abbreviations: CDC, Centers for Disease Control and Prevention; WHO, World Health Organization 5,6 different from that chosen for the vaccine. Consequently, Two antigenically distinct lineages of influenza B viruses have influenza vaccination campaigns have had limited effectiveness circulated globally since 1985. However, licensed trivalent against influenza B epidemics during seasons in which a signi- seasonal influenza vaccines contain antigens from only a ficant proportion of the disease was caused by opposite-lineage single influenza B virus and thus provide limited immunity against circulating influenza B strains of the lineage not influenza B strains. This reduced effectiveness in such seasons present in the vaccine. In recent years, predictions about could be avoided if seasonal influenza vaccines included four which B lineage will predominate in an upcoming influenza strains, one strain from each B lineage in addition to A/H1N1 season have been no better than chance alone, correct in and A/H3N2 strains. The current review describes the burden of only 5 of the 10 seasons from 2001 to 2011. Consequently, disease caused by influenza B infection, evaluates the impact of seasonal influenza vaccines could be improved by inclusion of two distinct circulating influenza B lineages, and provides data influenza B strains of both lineages. The resulting quadrivalent supporting the feasibility of the development and widespread influenza vaccines would allow influenza vaccination © 2012 Landes Bioscience. adoption of quadrivalent influenza vaccines. campaigns to respond more effectively to current global influenza epidemiology. Manufacturing capacity for seasonal Influenza B Accounts for a Significant Proportion of influenza vaccines has increased sufficiently to supply the Overall Burden of Influenza quadrivalent influenza vaccines, and methods to identify the influenza B strains to include in such vaccines are in place. Multiple manufacturers have initiated clinical studies of Both influenza A and B are orthomyxoviruses that cause annual quadrivalent influenza vaccines. Data from those studies, Do not distribute. epidemics in humans on a global scale. Influenza B predominantly taken together with epidemiologic data regarding the burden circulates in human populations, in contrast to influenza A, which of disease caused by influenza B infections, will determine circulates in multiple animal species as well as in humans. Like the safety, effectiveness, and benefit of utilizing quadrivalent influenza A, novel variant strains of influenza B continually vaccines for the prevention of seasonal influenza disease. emerge due to antigenic drift. In recent years, influenza B viruses have evolved more slowly than A/H3N2 viruses, as evidenced by a -3 lower rate of nucleotide substitution, estimated at 0.14  10 to -3 -3 Introduction 3.32  10 substitutions/site/year for influenza B vs. 2.68  10 -3 7,8 to 12.50  10 for influenza A/H3N2. The likelihood that Influenza A/H1N1, A/H3N2 and B viruses have circulated and substitutions result in amino acid changes is also lower for B 1 7 caused disease in humans on a global basis since 1977. Accord- viruses compared with A/H3N2 viruses. However, there is ingly, licensed seasonal influenza vaccines have contained three frequent segment reassortment between influenza B viruses, strains, one from each A subtype and one type B virus. Because which is often the mechanism by which new dominant B viruses new variant strains of each type/subtype continually evolve, the emerge. specific strains to be included in seasonal influenza vaccines are The incidence of influenza B can vary dramatically between chosen based on a prediction of the strains likely to circulate in influenza seasons. According to data from the US. Centers for the upcoming influenza season. Since 1985, two antigenically Disease Control and Prevention (CDC), from 2001–2002 distinct lineages of influenza B viruses have circulated globally. through 2010–2011 (excluding the 2009–2010 pandemic), influ- However, as only one lineage can be selected for inclusion in enza B was responsible for , 1% to 44% of influenza-positive current trivalent influenza vaccines, the vaccines have provided samples submitted by participating laboratories (Fig. 1A). On 3,4 limited immunity against strains of the other lineage. Addition- average, 24% of influenza samples during this period were posi- ally, in 5 of the 10 influenza seasons between 2001–2002 and tive for influenza B. European surveillance data from the same 2010–2011, the predominant circulating influenza B lineage was seasons was similar, with influenza B being responsible for 1% to 60% of influenza-positive samples and a season average of 23% (Fig. 1B). These data are consistent with a Dutch study that *Correspondence to: Christopher S. Ambrose; systematically examined cases of influenza-like illness from 1992– Email: AmbroseC@MedImmune.com 1993 through 2006–2007 and found the proportion of influenza Submitted: 07/07/11; Accepted: 07/25/11 http://dx.doi.org/10.4161/hv.8.1.17623 cases caused by influenza B to range from 0% to 82% by season, www.landesbioscience.com Human Vaccines & Immunotherapeutics 81 9 with a season average of 29%. Influenza B was responsible influenza-attributable respiratory- and circulatory-related hospita- for more than 30% of cases in 7 of the 15 seasons. Similarly, in lizations in all ages from 1979–1980 through 2000–2001, the data from Finland from 1980 to 1999, influenza B accounted estimated hospitalization rate during seasons dominated by for 20% of influenza cases among children ,17 y of age, and influenza B was 81.4 hospitalizations per 100,000, which was the predominant cause of influenza illness in 5 of the approached the hospitalization rate observed in A/H3N2- 20 seasons. predominant seasons (99.0 per 100,000) and was greater than Studies of severe influenza disease in the US have shown that observed in A/H1N1-predominant seasons (55.9 per that influenza B causes significant morbidity and mortality. For 100,000). Between 1990–1991 and 1998–1999, influenza B © 2012 Landes Bioscience. Do not distribute. Figure 1. Influenza B circulation as a proportion of circulating influenza strains: US and European data for 2001 to 2011. US data (A) were extracted from cumulative data reported in the final CDC weekly influenza surveillance report for each season (available at www.cdc.gov/flu/weekly/pastreports.htm). Data for 2008–2009 represent cumulative data through April 18, 2009. EU data (B) were extracted from cumulative Euroflu sentinel site data reported in the final weekly influenza surveillance bulletin for each season beginning with the 2003–2004 season (available at www.euroflu.org/cgi-files/bulletin_v2. cgi). Because Euroflu bulletins issued before 2003–2004 do not provide cumulative season data, data presented for the 2001–2002 and 2002–2003 influenza seasons were extracted from the final cumulative European Influenza Surveillance Scheme report issued in 2007 (available at www.euroflu.org/ documents/eiss_annual_report_2006-2007.pdf). 82 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 was estimated to account for 15% of all influenza-attributable children. Influenza B was responsible for 27% and 26% of respiratory- and circulatory-related deaths in the US. The influenza-attributable respiratory- and circulatory-related deaths estimated average annual deaths due to influenza B (5255) was among infants younger than 12 mo of age and children 1–4yof lower than the number attributed to A/H3N2 (28,940), but age, respectively, as compared with 17%, 12%, and 15% among higher than the number attributed to A/H1N1 (1960). individuals 5–49 y of age, 50–64 y of age, and 65 y of age and Although influenza B causes disease in all age groups, its older, respectively. incidence relative to influenza A appears to be highest among Medically-attended illnesses in both children and adults due to older children and young adults. In studies that described influ- influenza A and B are generally similar in regards to symptoms, 10,16-25 enza illness among children and adults, the proportion of illnesses severity, and rates of influenza-related complications. The caused by influenza B relative to influenza A was highest for principal differences observed across studies are that influenza B 13 14 individuals 5 to 29 y of age and 2 to 39 y of age. A study disease in children is more commonly associated with myalgia, 10,17,19,22,23 describing absenteeism among Japanese schoolchildren for the myositis, and leukopenia. Three studies found that 24 y between 1984 and 2007 demonstrated that influenza B was influenza B was less commonly associated with rhinorrhea in 10,22,23 responsible for the largest outbreaks, and outbreaks were observed children. One study noted a shorter duration of illness in 15 16 even during seasons in which many children were vaccinated. children with influenza B, but in other studies duration was 17,18 Multiple studies of medically-attended influenza in children have similar. In adults, the duration of influenza A and B illness 24,25 demonstrated that children with influenza B illness are older than was similar. 10,16-20 those with influenza A. Furthermore, while influenza B causes mortality in all age groups, it appears to be a dispropor- One Virus, Two Lineages tionate cause of pediatric influenza deaths. The CDC made US pediatric influenza deaths reportable beginning with the 2004– Although influenza B viruses are classified as a single influenza 2005 season. From 2004–2005 through 2010–2011, with the type, B viruses can be categorized into two antigenically distinct © 2012 Landes Bioscience. exception of the 2009–2010 pandemic, influenza B was phylogenetic lineages, B/Victoria/02/87-like and B/Yamagata/16/ responsible for 22–44% of reported influenza deaths in children 88-like, based on divergence in the HA1 domain of the viral 0–18 y of age each season (Fig. 2). Overall, during this period, hemagglutinin gene (Fig. 3). Before 1985, there was a single influenza B was responsible for 34% of reported pediatric lineage of influenza B in global circulation. This lineage was the influenza deaths. Thompson et al. also estimated that influenza precursor to the subsequent Yamagata lineage. The Victoria B was a disproportionate cause of influenza deaths among lineage appears to have emerged from a minor lineage of B viruses Do not distribute. Figure 2. Proportion of US pediatric influenza deaths by viral type (2004 to 2011, excluding 2009–2010 pandemic). Values in columns represent the number of deaths in each category for each season. Data for the 2004–2005 through 2008–2009 seasons were obtained via personal communication with the CDC. Pediatric influenza deaths became reportable in 2004–2005; as a result, comparable data are not available prior to 2004–2005. Data for the 2010–2011 season was obtained from the CDC 2010–2011 Influenza Season Summary (available at www.cdc.gov/flu/weekly/pastreports.htm). www.landesbioscience.com Human Vaccines & Immunotherapeutics 83 © 2012 Landes Bioscience. Do not distribute. Figure 3. Evolution of two antigenically distinct lineages of influenza B (1970–2006). Phylogenetic tree of the influenza B virus HA1 domain based on 214 sequences sampled annually between 1970 and 2006. Data for the B/Victoria/02/87-like and B/Yamagata/16/88-like lineages are shown. Representative vaccine strains are also shown. Adapted with permission from Chen R. Holmes E.C. The evolutionary dynamics of human influenza B virus. in China by 1975 but was not isolated outside of China until slowly than to influenza A. This observation likely explains the 1985. Following the global detection of Victoria-like strains in increased incidence of influenza B illness relative to influenza A 1985, the Victoria lineage dominated global circulation from among older children and young adults. An important obser- 1987 to 1989, followed by Yamagata dominance in the 1990s and vation by Bodewes et al. was that antibody responses to influenza subsequent re-emergence of the Victoria lineage in 2001–2002. B infection in children were lineage-specific, with no cross- From 2001–2002 to the present, both lineages have co-circulated reactivity between lineages. A similar pattern of limited cross- each season at varying levels (Fig. 4). reactivity occurs in response to influenza vaccination. For trivalent The pattern of varying dominance of the two influenza B inactivated influenza vaccines (TIV), antibody responses to the lineages is likely driven by lineage-specific immunity in the lineage not contained in the vaccine are reduced in adults and In recent randomized, placebo-controlled population, with one lineage predominating until accumulated negligible in children. immunity to that lineage results in increased relative susceptibi- efficacy studies of TIV in younger adults, efficacy against lity to and spread of the other lineage. A serologic study of opposite-lineage B strains has been variable, ranging from 22% 28,29 European children 0 to 7 y of age, almost none of whom had to 52%, which is lower than the observed efficacy against been previously vaccinated against influenza, demonstrated that vaccine-matched strains of 78%. With trivalent live attenuated children accumulated natural immunity to influenza B more influenza vaccine in children, 31% efficacy has been observed 84 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 © 2012 Landes Bioscience. Do not distribute. Figure 4. Influenza B circulation by lineage: US and European data for 2001 to 2011. Data were obtained as reported for Figure 1. US data are represented in panel A (A) and European data are represented in panel B (B). The influenza B lineage (Victoria or Yamagata) recommended for inclusion in the trivalent vaccine is shown on the x-axis for each season. EU data regarding the proportion of B viruses by lineage were not available for the 2001–2002 and 2002–2003 influenza seasons. against opposite-lineage influenza B strains, which is lower than 10 influenza seasons in the US from 2001–2002 through 2010– the 86% efficacy against vaccine-matched B strains. 2011, the predominant circulating influenza B lineage was different from that contained in the vaccine (Fig. 4A). Overall, Inability to Predict Which Influenza B Lineage an estimated 46% of influenza B samples during this period were Will Circulate influenza B strains of the lineage not included in the vaccine. Similarly, in Europe from 2003–2004 through 2010–2011 (the In recent years, predictions of the predominant influenza B seasons for which data are available), the predominant lineage lineage have been no better than chance alone. In 5 of the differed from that contained in the vaccine in 4 of 8 seasons www.landesbioscience.com Human Vaccines & Immunotherapeutics 85 32 (Fig. 4B), and an estimated 58% of influenza B samples were of strategy relative to dependence on trivalent vaccines. Based on the lineage not included in the vaccine. Because inclusion of the the available input data and the assumption that quadrivalent incorrect influenza B lineage in trivalent vaccines provides vaccine production would not decrease influenza vaccine supply, suboptimal protection against circulating opposite-lineage strains, the analysis suggested that use of quadrivalent vaccines in the inaccurate prediction of the predominant influenza B lineage US during the 2001–2008 seasons would have been beneficial in leaves many vaccinated individuals with suboptimal protection each season, cumulatively resulting in approximately 2.1 million from influenza B disease. fewer cases of influenza, 20,000 fewer hospitalizations, and 1,200 The magnitude of the problem created by mismatch between fewer deaths. circulating influenza B strains and the influenza B lineage Optimal target populations for quadrivalent influenza vaccines contained in the vaccine varies by season. The most significant are a subject of ongoing discussion (FDA VRBPAC 2007, 2009, 33-35 recent examples occurred during the 2005–2006 and 2007–2008 2011). The primary benefit of a quadrivalent vaccine is in seasons. In 2005–2006, the influenza B component of the eliminating the risk that the incorrect B lineage is selected for northern hemisphere influenza vaccine was of the B/Yamagata inclusion in the vaccine. The clinical benefit is likely to be highest lineage, but 81–91% of the circulating influenza B viruses among children and young adults because of the increased antigenically characterized in the US and Europe were of the incidence of influenza B disease in these age groups, and studies B/Victoria lineage, and influenza B was found in 34–60% of all in children with live attenuated and inactivated influenza vaccines samples (Figs. 1 and 4). Similarly, in 2007–2008, the influenza B have shown little to no cross-protection against opposite-lineage component of the vaccine was of the B/Victoria lineage, but 98– strains following vaccination. However, cross-lineage protection 99% of the circulating influenza B viruses characterized in the US from vaccination is also reduced in adults, and influenza B and Europe belonged to the B/Yamagata lineage, and influenza accounts for a significant proportion of influenza-related morbi- B was found in 29–39% of all samples (Fig. 1 and 4). In other dity and mortality in all age groups, even among older adults. seasons, the magnitude of the problem was less, such as when the Because individuals of all ages would be expected to benefit from © 2012 Landes Bioscience. vaccine component was a good match to circulating strains (e.g., quadrivalent influenza vaccines, there is a strong rationale for 2002–2003 and 2010–2011) or when influenza B illness was less providing quadrivalent influenza vaccines to all indicated age common (e.g., 2003–2004 and 2009–2010). groups, as long as the incremental cost relative to trivalent vaccines is not excessive. Potential Benefits of Quadrivalent Influenza Vaccines Path Forward for Quadrivalent Vaccines Do not distribute. Based on the demonstrated burden of influenza B, the limited cross-protection between the two influenza B lineages, and the Presumably, quadrivalent influenza vaccines would be very similar inability to accurately predict which influenza B lineage will to currently licensed trivalent vaccines in regards to manufactur- circulate, it is clear that seasonal influenza vaccines could be ing processes, as well as vaccine excipients, dose, and administra- improved by the inclusion of influenza B strains from both tion. The only expected difference would be the inclusion of four lineages. The rationale for the shift from trivalent to quadrivalent influenza vaccine strains (A/H1N1, A/H3N2, and B strains of influenza vaccines is similar to that for the 1977 transition from both lineages). Influenza B strains to be included in the vaccines a bivalent (A/H3N2 and B) vaccine to a trivalent (A/H1N1, could be chosen through the current processes for strain selection. A/H3N2, B) vaccine, which was based on the lack of cross- In fact, the World Health Organization (WHO) recommenda- protection between A/H3N2 and A/H1N1. The inclusion of tions for the 2011–2012 northern hemisphere seasonal influenza both influenza B lineages would provide a direct benefit to vaccine formulation already identify candidate vaccine strains vaccine recipients whenever a large number of circulating influ- from both influenza B lineages. enza B viruses does not match the lineage chosen for trivalent Multiple manufacturers have initiated clinical studies to vaccines, either because the lineage prediction was incorrect or evaluate the immunogenicity and safety of quadrivalent influenza 33,37-44 because both lineages co-circulated to a significant degree. vaccines relative to trivalent vaccines in children and adults. Moreover, in seasons in which influenza B circulation is minimal In the past, efforts to advance quadrivalent influenza vaccines or B viruses are well matched to the trivalent vaccine strain, were complicated by concerns about influenza vaccine manufac- vaccination with a quadrivalent influenza vaccine would still turing capacity, but now capacity has increased to the point that provide benefit to the individual by increasing immunity to introduction of quadrivalent vaccines should not impact the both lineages of influenza B, with potential clinical benefit in overall supply of influenza vaccines. In 2006, the WHO subsequent seasons. Accumulated immunity may be more estimated that global manufacturing capacity for seasonal trivalent relevant for influenza B than for influenza A because antigenic In 2009, capacity influenza vaccine was 347 million doses. drift is more limited with influenza B viruses. From a public increased to 876 million doses due to investments by manufac- health perspective, if quadrivalent vaccines led to fewer mis- turers and governments. However, only 66% of the available matched seasonal vaccine campaigns, the public’s confidence and global capacity in 2009 was utilized for production of 2008–2009 31 46 acceptance of influenza vaccination might also be enhanced. seasonal influenza vaccines. Production of quadrivalent vaccines The CDC recently conducted an analysis to quantify the could help maintain the current global manufacturing capacity, potential public health impact of a quadrivalent influenza vaccine which would also enhance pandemic preparedness since the 86 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 capacity could be redirected to manufacture monovalent B lineages have been circulating since 1985 and the predominant pandemic doses. influenza B lineage has been unpredictable in recent years, Widespread utilization of quadrivalent influenza vaccines will quadrivalent vaccines would more accurately reflect the current require confirmation that quadrivalent influenza vaccines pro- epidemiology of influenza and would allow vaccination cam- duce immune responses in children and adults comparable to paigns to more effectively protect their target populations. those observed with trivalent seasonal influenza vaccines. Addi- Multiple manufacturers have initiated clinical studies of quadri- tionally, clinical studies must confirm that quadrivalent influenza valent influenza vaccines. Data from those studies, as well as vaccines have an acceptable safety profile in children and adults. epidemiologic data regarding the burden of influenza B infections, Cost-effectiveness analyses comparing quadrivalent and trivalent will determine the safety, effectiveness, and benefit of utilizing vaccines will also be required if there is a significant incremental quadrivalent vaccines for the prevention of seasonal influenza cost associated with quadrivalent vaccines. Lastly, acceptance of disease. quadrivalent influenza vaccines by providers, payers, and the Acknowledgments general public will require education regarding the benefits and safety of vaccines containing the additional strain. C.S.A. is an employee of MedImmune and was invited by Susanna Esposito, Guest Editor, to author this review. M.J.L. Conclusion has served as a consultant for MedImmune. Formatting of the manuscript was provided by Complete Healthcare Quadrivalent formulations represent a next logical step for sea- Communications, Inc. (Chadds Ford, PA) and funded by sonal influenza vaccines. Because 2 antigenically distinct influenza MedImmune. References 10. Peltola V, Ziegler T, Ruuskanen O. Influenza A and B 19. Shen CF, Huang SC, Wang SM, Wang JR, Liu CC. virus infections in children. Clin Infect Dis 2003; Decreased leukocytes and other characteristics of 1. Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, 36:299-305; PMID:12539071; http://dx.doi.org/10. laboratory findings of influenza virus infections in Singleton JA, et al. Prevention and control of influenza © 2012 Landes Bioscience. 1086/345909 children. J Microbiol Immunol Infect 2008; 41:294- with vaccines: recommendations of the Advisory 300; PMID:18787735 11. 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A global pandemic 0b013e318174e0f8 vaccine in children (NCT01091246). Available at: influenza vaccine action plan. Vaccine 2006; 24:6367- http://www.clinicaltrials.gov/ct2/show/NCT01091246. 31. Reed C, Meltzer M, Finelli L, Fiore A. Public health 70; PMID:17240560; http://dx.doi.org/10.1016/j. Accessed June 28, 2011. impact of including two influenza B strains in seasonal vaccine.2006.07.021 influenza vaccines. Available at: http://www.fda.gov/ 38. ClinicalTrials.gov. A study to evaluate the safety and 46. Collin N, de Radigues X. World Health Organization AdvisoryCommittees/CommitteesMeetingMaterials/ immunogenicity of GSK Biologicals’ seasonal influ- H1N1 Vaccine Task Force. Vaccine production BloodVaccinesandOtherBiologics/VaccinesandRelated enza vaccine in adults (NCT01196975). Available at: capacity for seasonal and pandemic (H1N1) 2009 BiologicalProductsAdvisoryCommittee/ucm176375. http://www.clinicaltrials.gov/ct2/show/NCT01196975. influenza. Vaccine 2009; 27:5184-6; PMID:19563891; htm. Accessed March 29, 2011. Accessed June 28, 2011. http://dx.doi.org/10.1016/j.vaccine.2009.06.034 © 2012 Landes Bioscience. 32. Reed C, Meltzer M, Finelli L, Fiore A. Public health 39. ClinicalTrials.gov. Trial to evaluate safety and immu- impact of including two influenza B strains in seasonal nogenicity of GSK Biologicals’ influenza vaccine influenza vaccines. Presented at: Options for the Con- GSK2584786A in healthy children (NCT01195779). trol of Influenza VII; September 3-7, 2010; Hong Available at: http://www.clinicaltrials.gov/ct2/show/ NCT01195779. Accessed June 28, 2011. Kong SAR, China. 33. US Food and Drug Administration. February 25, 2011: Vaccines and Related Biological Products Advisory Committee Meeting Transcript. Strain selection for the influenza virus vaccine for the 2011-2012 season. Do not distribute. Available at: http://www.fda.gov/AdvisoryCommittees/ CommitteesMeetingMaterials/BloodVaccinesandOther Biologics/VaccinesandRelatedBiologicalProductsAdvisory Committee/ucm249303.htm. Accessed June 28, 2011. 88 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Vaccines & Immunotherapeutics Taylor & Francis

The rationale for quadrivalent influenza vaccines

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Taylor & Francis
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Copyright © 2012 Landes Bioscience
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2164-554X
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Abstract

SPECIAL FOCUS REVIEW: INFLUENZA VACCINES Human Vaccines & Immunotherapeutics 8:1, 81–88; January 2012; 2012 Landes Bioscience 1, 2 Christopher S. Ambrose * and Myron J. Levin 1 2 MedImmune, LLC; Gaithersburg, MD USA; University of Colorado School of Medicine; Aurora, CO USA Keywords: influenza, public health, quadrivalent, surveillance, vaccine Abbreviations: CDC, Centers for Disease Control and Prevention; WHO, World Health Organization 5,6 different from that chosen for the vaccine. Consequently, Two antigenically distinct lineages of influenza B viruses have influenza vaccination campaigns have had limited effectiveness circulated globally since 1985. However, licensed trivalent against influenza B epidemics during seasons in which a signi- seasonal influenza vaccines contain antigens from only a ficant proportion of the disease was caused by opposite-lineage single influenza B virus and thus provide limited immunity against circulating influenza B strains of the lineage not influenza B strains. This reduced effectiveness in such seasons present in the vaccine. In recent years, predictions about could be avoided if seasonal influenza vaccines included four which B lineage will predominate in an upcoming influenza strains, one strain from each B lineage in addition to A/H1N1 season have been no better than chance alone, correct in and A/H3N2 strains. The current review describes the burden of only 5 of the 10 seasons from 2001 to 2011. Consequently, disease caused by influenza B infection, evaluates the impact of seasonal influenza vaccines could be improved by inclusion of two distinct circulating influenza B lineages, and provides data influenza B strains of both lineages. The resulting quadrivalent supporting the feasibility of the development and widespread influenza vaccines would allow influenza vaccination © 2012 Landes Bioscience. adoption of quadrivalent influenza vaccines. campaigns to respond more effectively to current global influenza epidemiology. Manufacturing capacity for seasonal Influenza B Accounts for a Significant Proportion of influenza vaccines has increased sufficiently to supply the Overall Burden of Influenza quadrivalent influenza vaccines, and methods to identify the influenza B strains to include in such vaccines are in place. Multiple manufacturers have initiated clinical studies of Both influenza A and B are orthomyxoviruses that cause annual quadrivalent influenza vaccines. Data from those studies, Do not distribute. epidemics in humans on a global scale. Influenza B predominantly taken together with epidemiologic data regarding the burden circulates in human populations, in contrast to influenza A, which of disease caused by influenza B infections, will determine circulates in multiple animal species as well as in humans. Like the safety, effectiveness, and benefit of utilizing quadrivalent influenza A, novel variant strains of influenza B continually vaccines for the prevention of seasonal influenza disease. emerge due to antigenic drift. In recent years, influenza B viruses have evolved more slowly than A/H3N2 viruses, as evidenced by a -3 lower rate of nucleotide substitution, estimated at 0.14  10 to -3 -3 Introduction 3.32  10 substitutions/site/year for influenza B vs. 2.68  10 -3 7,8 to 12.50  10 for influenza A/H3N2. The likelihood that Influenza A/H1N1, A/H3N2 and B viruses have circulated and substitutions result in amino acid changes is also lower for B 1 7 caused disease in humans on a global basis since 1977. Accord- viruses compared with A/H3N2 viruses. However, there is ingly, licensed seasonal influenza vaccines have contained three frequent segment reassortment between influenza B viruses, strains, one from each A subtype and one type B virus. Because which is often the mechanism by which new dominant B viruses new variant strains of each type/subtype continually evolve, the emerge. specific strains to be included in seasonal influenza vaccines are The incidence of influenza B can vary dramatically between chosen based on a prediction of the strains likely to circulate in influenza seasons. According to data from the US. Centers for the upcoming influenza season. Since 1985, two antigenically Disease Control and Prevention (CDC), from 2001–2002 distinct lineages of influenza B viruses have circulated globally. through 2010–2011 (excluding the 2009–2010 pandemic), influ- However, as only one lineage can be selected for inclusion in enza B was responsible for , 1% to 44% of influenza-positive current trivalent influenza vaccines, the vaccines have provided samples submitted by participating laboratories (Fig. 1A). On 3,4 limited immunity against strains of the other lineage. Addition- average, 24% of influenza samples during this period were posi- ally, in 5 of the 10 influenza seasons between 2001–2002 and tive for influenza B. European surveillance data from the same 2010–2011, the predominant circulating influenza B lineage was seasons was similar, with influenza B being responsible for 1% to 60% of influenza-positive samples and a season average of 23% (Fig. 1B). These data are consistent with a Dutch study that *Correspondence to: Christopher S. Ambrose; systematically examined cases of influenza-like illness from 1992– Email: AmbroseC@MedImmune.com 1993 through 2006–2007 and found the proportion of influenza Submitted: 07/07/11; Accepted: 07/25/11 http://dx.doi.org/10.4161/hv.8.1.17623 cases caused by influenza B to range from 0% to 82% by season, www.landesbioscience.com Human Vaccines & Immunotherapeutics 81 9 with a season average of 29%. Influenza B was responsible influenza-attributable respiratory- and circulatory-related hospita- for more than 30% of cases in 7 of the 15 seasons. Similarly, in lizations in all ages from 1979–1980 through 2000–2001, the data from Finland from 1980 to 1999, influenza B accounted estimated hospitalization rate during seasons dominated by for 20% of influenza cases among children ,17 y of age, and influenza B was 81.4 hospitalizations per 100,000, which was the predominant cause of influenza illness in 5 of the approached the hospitalization rate observed in A/H3N2- 20 seasons. predominant seasons (99.0 per 100,000) and was greater than Studies of severe influenza disease in the US have shown that observed in A/H1N1-predominant seasons (55.9 per that influenza B causes significant morbidity and mortality. For 100,000). Between 1990–1991 and 1998–1999, influenza B © 2012 Landes Bioscience. Do not distribute. Figure 1. Influenza B circulation as a proportion of circulating influenza strains: US and European data for 2001 to 2011. US data (A) were extracted from cumulative data reported in the final CDC weekly influenza surveillance report for each season (available at www.cdc.gov/flu/weekly/pastreports.htm). Data for 2008–2009 represent cumulative data through April 18, 2009. EU data (B) were extracted from cumulative Euroflu sentinel site data reported in the final weekly influenza surveillance bulletin for each season beginning with the 2003–2004 season (available at www.euroflu.org/cgi-files/bulletin_v2. cgi). Because Euroflu bulletins issued before 2003–2004 do not provide cumulative season data, data presented for the 2001–2002 and 2002–2003 influenza seasons were extracted from the final cumulative European Influenza Surveillance Scheme report issued in 2007 (available at www.euroflu.org/ documents/eiss_annual_report_2006-2007.pdf). 82 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 was estimated to account for 15% of all influenza-attributable children. Influenza B was responsible for 27% and 26% of respiratory- and circulatory-related deaths in the US. The influenza-attributable respiratory- and circulatory-related deaths estimated average annual deaths due to influenza B (5255) was among infants younger than 12 mo of age and children 1–4yof lower than the number attributed to A/H3N2 (28,940), but age, respectively, as compared with 17%, 12%, and 15% among higher than the number attributed to A/H1N1 (1960). individuals 5–49 y of age, 50–64 y of age, and 65 y of age and Although influenza B causes disease in all age groups, its older, respectively. incidence relative to influenza A appears to be highest among Medically-attended illnesses in both children and adults due to older children and young adults. In studies that described influ- influenza A and B are generally similar in regards to symptoms, 10,16-25 enza illness among children and adults, the proportion of illnesses severity, and rates of influenza-related complications. The caused by influenza B relative to influenza A was highest for principal differences observed across studies are that influenza B 13 14 individuals 5 to 29 y of age and 2 to 39 y of age. A study disease in children is more commonly associated with myalgia, 10,17,19,22,23 describing absenteeism among Japanese schoolchildren for the myositis, and leukopenia. Three studies found that 24 y between 1984 and 2007 demonstrated that influenza B was influenza B was less commonly associated with rhinorrhea in 10,22,23 responsible for the largest outbreaks, and outbreaks were observed children. One study noted a shorter duration of illness in 15 16 even during seasons in which many children were vaccinated. children with influenza B, but in other studies duration was 17,18 Multiple studies of medically-attended influenza in children have similar. In adults, the duration of influenza A and B illness 24,25 demonstrated that children with influenza B illness are older than was similar. 10,16-20 those with influenza A. Furthermore, while influenza B causes mortality in all age groups, it appears to be a dispropor- One Virus, Two Lineages tionate cause of pediatric influenza deaths. The CDC made US pediatric influenza deaths reportable beginning with the 2004– Although influenza B viruses are classified as a single influenza 2005 season. From 2004–2005 through 2010–2011, with the type, B viruses can be categorized into two antigenically distinct © 2012 Landes Bioscience. exception of the 2009–2010 pandemic, influenza B was phylogenetic lineages, B/Victoria/02/87-like and B/Yamagata/16/ responsible for 22–44% of reported influenza deaths in children 88-like, based on divergence in the HA1 domain of the viral 0–18 y of age each season (Fig. 2). Overall, during this period, hemagglutinin gene (Fig. 3). Before 1985, there was a single influenza B was responsible for 34% of reported pediatric lineage of influenza B in global circulation. This lineage was the influenza deaths. Thompson et al. also estimated that influenza precursor to the subsequent Yamagata lineage. The Victoria B was a disproportionate cause of influenza deaths among lineage appears to have emerged from a minor lineage of B viruses Do not distribute. Figure 2. Proportion of US pediatric influenza deaths by viral type (2004 to 2011, excluding 2009–2010 pandemic). Values in columns represent the number of deaths in each category for each season. Data for the 2004–2005 through 2008–2009 seasons were obtained via personal communication with the CDC. Pediatric influenza deaths became reportable in 2004–2005; as a result, comparable data are not available prior to 2004–2005. Data for the 2010–2011 season was obtained from the CDC 2010–2011 Influenza Season Summary (available at www.cdc.gov/flu/weekly/pastreports.htm). www.landesbioscience.com Human Vaccines & Immunotherapeutics 83 © 2012 Landes Bioscience. Do not distribute. Figure 3. Evolution of two antigenically distinct lineages of influenza B (1970–2006). Phylogenetic tree of the influenza B virus HA1 domain based on 214 sequences sampled annually between 1970 and 2006. Data for the B/Victoria/02/87-like and B/Yamagata/16/88-like lineages are shown. Representative vaccine strains are also shown. Adapted with permission from Chen R. Holmes E.C. The evolutionary dynamics of human influenza B virus. in China by 1975 but was not isolated outside of China until slowly than to influenza A. This observation likely explains the 1985. Following the global detection of Victoria-like strains in increased incidence of influenza B illness relative to influenza A 1985, the Victoria lineage dominated global circulation from among older children and young adults. An important obser- 1987 to 1989, followed by Yamagata dominance in the 1990s and vation by Bodewes et al. was that antibody responses to influenza subsequent re-emergence of the Victoria lineage in 2001–2002. B infection in children were lineage-specific, with no cross- From 2001–2002 to the present, both lineages have co-circulated reactivity between lineages. A similar pattern of limited cross- each season at varying levels (Fig. 4). reactivity occurs in response to influenza vaccination. For trivalent The pattern of varying dominance of the two influenza B inactivated influenza vaccines (TIV), antibody responses to the lineages is likely driven by lineage-specific immunity in the lineage not contained in the vaccine are reduced in adults and In recent randomized, placebo-controlled population, with one lineage predominating until accumulated negligible in children. immunity to that lineage results in increased relative susceptibi- efficacy studies of TIV in younger adults, efficacy against lity to and spread of the other lineage. A serologic study of opposite-lineage B strains has been variable, ranging from 22% 28,29 European children 0 to 7 y of age, almost none of whom had to 52%, which is lower than the observed efficacy against been previously vaccinated against influenza, demonstrated that vaccine-matched strains of 78%. With trivalent live attenuated children accumulated natural immunity to influenza B more influenza vaccine in children, 31% efficacy has been observed 84 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 © 2012 Landes Bioscience. Do not distribute. Figure 4. Influenza B circulation by lineage: US and European data for 2001 to 2011. Data were obtained as reported for Figure 1. US data are represented in panel A (A) and European data are represented in panel B (B). The influenza B lineage (Victoria or Yamagata) recommended for inclusion in the trivalent vaccine is shown on the x-axis for each season. EU data regarding the proportion of B viruses by lineage were not available for the 2001–2002 and 2002–2003 influenza seasons. against opposite-lineage influenza B strains, which is lower than 10 influenza seasons in the US from 2001–2002 through 2010– the 86% efficacy against vaccine-matched B strains. 2011, the predominant circulating influenza B lineage was different from that contained in the vaccine (Fig. 4A). Overall, Inability to Predict Which Influenza B Lineage an estimated 46% of influenza B samples during this period were Will Circulate influenza B strains of the lineage not included in the vaccine. Similarly, in Europe from 2003–2004 through 2010–2011 (the In recent years, predictions of the predominant influenza B seasons for which data are available), the predominant lineage lineage have been no better than chance alone. In 5 of the differed from that contained in the vaccine in 4 of 8 seasons www.landesbioscience.com Human Vaccines & Immunotherapeutics 85 32 (Fig. 4B), and an estimated 58% of influenza B samples were of strategy relative to dependence on trivalent vaccines. Based on the lineage not included in the vaccine. Because inclusion of the the available input data and the assumption that quadrivalent incorrect influenza B lineage in trivalent vaccines provides vaccine production would not decrease influenza vaccine supply, suboptimal protection against circulating opposite-lineage strains, the analysis suggested that use of quadrivalent vaccines in the inaccurate prediction of the predominant influenza B lineage US during the 2001–2008 seasons would have been beneficial in leaves many vaccinated individuals with suboptimal protection each season, cumulatively resulting in approximately 2.1 million from influenza B disease. fewer cases of influenza, 20,000 fewer hospitalizations, and 1,200 The magnitude of the problem created by mismatch between fewer deaths. circulating influenza B strains and the influenza B lineage Optimal target populations for quadrivalent influenza vaccines contained in the vaccine varies by season. The most significant are a subject of ongoing discussion (FDA VRBPAC 2007, 2009, 33-35 recent examples occurred during the 2005–2006 and 2007–2008 2011). The primary benefit of a quadrivalent vaccine is in seasons. In 2005–2006, the influenza B component of the eliminating the risk that the incorrect B lineage is selected for northern hemisphere influenza vaccine was of the B/Yamagata inclusion in the vaccine. The clinical benefit is likely to be highest lineage, but 81–91% of the circulating influenza B viruses among children and young adults because of the increased antigenically characterized in the US and Europe were of the incidence of influenza B disease in these age groups, and studies B/Victoria lineage, and influenza B was found in 34–60% of all in children with live attenuated and inactivated influenza vaccines samples (Figs. 1 and 4). Similarly, in 2007–2008, the influenza B have shown little to no cross-protection against opposite-lineage component of the vaccine was of the B/Victoria lineage, but 98– strains following vaccination. However, cross-lineage protection 99% of the circulating influenza B viruses characterized in the US from vaccination is also reduced in adults, and influenza B and Europe belonged to the B/Yamagata lineage, and influenza accounts for a significant proportion of influenza-related morbi- B was found in 29–39% of all samples (Fig. 1 and 4). In other dity and mortality in all age groups, even among older adults. seasons, the magnitude of the problem was less, such as when the Because individuals of all ages would be expected to benefit from © 2012 Landes Bioscience. vaccine component was a good match to circulating strains (e.g., quadrivalent influenza vaccines, there is a strong rationale for 2002–2003 and 2010–2011) or when influenza B illness was less providing quadrivalent influenza vaccines to all indicated age common (e.g., 2003–2004 and 2009–2010). groups, as long as the incremental cost relative to trivalent vaccines is not excessive. Potential Benefits of Quadrivalent Influenza Vaccines Path Forward for Quadrivalent Vaccines Do not distribute. Based on the demonstrated burden of influenza B, the limited cross-protection between the two influenza B lineages, and the Presumably, quadrivalent influenza vaccines would be very similar inability to accurately predict which influenza B lineage will to currently licensed trivalent vaccines in regards to manufactur- circulate, it is clear that seasonal influenza vaccines could be ing processes, as well as vaccine excipients, dose, and administra- improved by the inclusion of influenza B strains from both tion. The only expected difference would be the inclusion of four lineages. The rationale for the shift from trivalent to quadrivalent influenza vaccine strains (A/H1N1, A/H3N2, and B strains of influenza vaccines is similar to that for the 1977 transition from both lineages). Influenza B strains to be included in the vaccines a bivalent (A/H3N2 and B) vaccine to a trivalent (A/H1N1, could be chosen through the current processes for strain selection. A/H3N2, B) vaccine, which was based on the lack of cross- In fact, the World Health Organization (WHO) recommenda- protection between A/H3N2 and A/H1N1. The inclusion of tions for the 2011–2012 northern hemisphere seasonal influenza both influenza B lineages would provide a direct benefit to vaccine formulation already identify candidate vaccine strains vaccine recipients whenever a large number of circulating influ- from both influenza B lineages. enza B viruses does not match the lineage chosen for trivalent Multiple manufacturers have initiated clinical studies to vaccines, either because the lineage prediction was incorrect or evaluate the immunogenicity and safety of quadrivalent influenza 33,37-44 because both lineages co-circulated to a significant degree. vaccines relative to trivalent vaccines in children and adults. Moreover, in seasons in which influenza B circulation is minimal In the past, efforts to advance quadrivalent influenza vaccines or B viruses are well matched to the trivalent vaccine strain, were complicated by concerns about influenza vaccine manufac- vaccination with a quadrivalent influenza vaccine would still turing capacity, but now capacity has increased to the point that provide benefit to the individual by increasing immunity to introduction of quadrivalent vaccines should not impact the both lineages of influenza B, with potential clinical benefit in overall supply of influenza vaccines. In 2006, the WHO subsequent seasons. Accumulated immunity may be more estimated that global manufacturing capacity for seasonal trivalent relevant for influenza B than for influenza A because antigenic In 2009, capacity influenza vaccine was 347 million doses. drift is more limited with influenza B viruses. From a public increased to 876 million doses due to investments by manufac- health perspective, if quadrivalent vaccines led to fewer mis- turers and governments. However, only 66% of the available matched seasonal vaccine campaigns, the public’s confidence and global capacity in 2009 was utilized for production of 2008–2009 31 46 acceptance of influenza vaccination might also be enhanced. seasonal influenza vaccines. Production of quadrivalent vaccines The CDC recently conducted an analysis to quantify the could help maintain the current global manufacturing capacity, potential public health impact of a quadrivalent influenza vaccine which would also enhance pandemic preparedness since the 86 Human Vaccines & Immunotherapeutics Volume 8 Issue 1 capacity could be redirected to manufacture monovalent B lineages have been circulating since 1985 and the predominant pandemic doses. influenza B lineage has been unpredictable in recent years, Widespread utilization of quadrivalent influenza vaccines will quadrivalent vaccines would more accurately reflect the current require confirmation that quadrivalent influenza vaccines pro- epidemiology of influenza and would allow vaccination cam- duce immune responses in children and adults comparable to paigns to more effectively protect their target populations. those observed with trivalent seasonal influenza vaccines. Addi- Multiple manufacturers have initiated clinical studies of quadri- tionally, clinical studies must confirm that quadrivalent influenza valent influenza vaccines. Data from those studies, as well as vaccines have an acceptable safety profile in children and adults. epidemiologic data regarding the burden of influenza B infections, Cost-effectiveness analyses comparing quadrivalent and trivalent will determine the safety, effectiveness, and benefit of utilizing vaccines will also be required if there is a significant incremental quadrivalent vaccines for the prevention of seasonal influenza cost associated with quadrivalent vaccines. Lastly, acceptance of disease. quadrivalent influenza vaccines by providers, payers, and the Acknowledgments general public will require education regarding the benefits and safety of vaccines containing the additional strain. C.S.A. is an employee of MedImmune and was invited by Susanna Esposito, Guest Editor, to author this review. M.J.L. Conclusion has served as a consultant for MedImmune. Formatting of the manuscript was provided by Complete Healthcare Quadrivalent formulations represent a next logical step for sea- Communications, Inc. (Chadds Ford, PA) and funded by sonal influenza vaccines. Because 2 antigenically distinct influenza MedImmune. References 10. Peltola V, Ziegler T, Ruuskanen O. Influenza A and B 19. Shen CF, Huang SC, Wang SM, Wang JR, Liu CC. virus infections in children. Clin Infect Dis 2003; Decreased leukocytes and other characteristics of 1. Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, 36:299-305; PMID:12539071; http://dx.doi.org/10. laboratory findings of influenza virus infections in Singleton JA, et al. Prevention and control of influenza © 2012 Landes Bioscience. 1086/345909 children. J Microbiol Immunol Infect 2008; 41:294- with vaccines: recommendations of the Advisory 300; PMID:18787735 11. 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Available at: http://www.fda.gov/AdvisoryCommittees/ CommitteesMeetingMaterials/BloodVaccinesandOther Biologics/VaccinesandRelatedBiologicalProductsAdvisory Committee/ucm249303.htm. Accessed June 28, 2011. 88 Human Vaccines & Immunotherapeutics Volume 8 Issue 1

Journal

Human Vaccines & ImmunotherapeuticsTaylor & Francis

Published: Jan 1, 2012

Keywords: influenza; public health; quadrivalent; surveillance; vaccine

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