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A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control

A review of the value of quadrivalent influenza vaccines and their potential contribution to... HUMAN VACCINES & IMMUNOTHERAPEUTICS 2017, VOL. 13, NO. 7, 1640–1652 https://doi.org/10.1080/21645515.2017.1313375 REVIEW A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control a, b,z c a a c,# Riju Ray *,Gael Dos Santos , Philip O. Buck , Carine Claeys , Gonc ¸ alo Matias , Bruce L. Innis , a, and Rafik Bekkat-Berkani ** a b c GSK, Wavre, Belgium; Business & Decision Life Sciences, Brussels, Belgium (on behalf of GSK); GSK, Philadelphia, PA, USA ABSTRACT ARTICLE HISTORY Received 31 January 2017 The contribution of influenza B to the seasonal influenza burden varies from year-to-year. Although 2 Revised 20 March 2017 antigenically distinct influenza B virus lineages have co-circulated since 2001, trivalent influenza vaccines Accepted 25 March 2017 (TIVs) contain antigens from only one influenza B virus. B-mismatch or co-circulation of both B lineages results in increased morbidity and mortality attributable to the B lineage absent from the vaccine. KEYWORDS Quadrivalent vaccines (QIVs) contain both influenza B lineages. We reviewed currently licensed QIVs and influenza; influenza B; their value by focusing on the preventable disease burden. Modeling studies support that QIVs are mismatch; quadrivalent expected to prevent more influenza cases, hospitalisations and deaths than TIVs, although estimates of influenza vaccine the case numbers prevented vary according to local specificities. The value of QIVs is demonstrated by their capacity to broaden the immune response and reduce the likelihood of a B-mismatched season. Some health authorities have preferentially recommended QIVs over TIVs in their influenza prevention programmes. Introduction Influenza viruses are enveloped negative-strand RNA viruses United States (US), there were 830 reported laboratory-con- that are divided into 3 genera: type A, B and C. The vast major- firmed influenza deaths between 2004–2012 in children ity of human disease is caused by types A and B, which are < 18 y of age. Of these, 25% were children aged < 24 months. genetically and structurally similar, but differ in biology, evolu- Since the development of the first monovalent A/H1N1 1-3 tionary and epidemiological framework. Influenza A viruses influenza vaccines more than 75 y ago, influenza vaccines are subtyped according to 2 surface glycoproteins: haemaggluti- have always required adaptation in response to changes to nin (H) and neuraminidase (N) whereas influenza B viruses provide protection against the predominant circulating form a homogenous group segregated according to 2 antigeni- influenza viruses (Fig. 1). After influenza B was first isolated cally distinguishable lineages (B/Victoria and B/Yamagata). in 1940, bivalent (A/H1N1, B) vaccines were developed. The Influenza viruses undergo constant mutation which enables vaccine influenza A subtype was changed in 1958 and in evasion of existing host immunity leading to recurrent infec- 1969 in response to influenza A shifts that triggered severe tions that manifest as annual outbreaks. Periodically, new A pandemics (Fig. 1). Seasonal trivalent influenza vaccines subtypes emerge, resulting in a pandemic; the emergent sub- (TIVs) containing 2 influenza A -subtype viruses and one B type may replace or less frequently co-circulate with the earlier virus were first produced in 1978 after the re-appearance A subtype (Fig. 1). Currently, 2 influenza A subtypes, A/H1N1 and co-circulation of A/H1N1 with A/H3N2 viruses and A/H3N2, and the 2 influenza B lineages circulate globally (Fig. 1). Two antigenically distinct lineages of influenza B 5,6 each year. In any influenza season, several influenza types, A- viruses have circulated globally since 1985 and have co-cir- subtypes, or B-lineages may co-circulate, such that the annual culated since 2001. The influenza B-lineage vaccine strains influenza burden differs unpredictably from year-to-year, induce little or no cross-reactive protection against the 10,11 potentially fluctuating from age-group to age-group, and from alternate B-lineage, such that for TIVs, protection region-to-region. against the circulating influenza B lineage relies on correctly Influenza affects all age-groups and while most deaths occur predicting the B-lineage likely to predominate in the in older adults, influenza deaths also occur in children. In the upcoming season. The degree of similarity or difference CONTACT Rafik Bekkat-Berkani Rafik.X.Bekkat-Berkani@gsk.com 5 Crescent Drive, Philadelphia, PA 19112, USA. *Current affiliation: GSK, Research Triangle Park, NC, USA. Current affiliation: GSK, Wavre, Belgium. Current affiliation: PATH, Washington, DC, USA. **Current affiliation: GSK, Philadelphia, PA, USA. © 2017 Riju Ray, Ga€ el Dos Santos, Philip O. Buck, Carine Claeys, Gonc ¸alo Matias, Bruce L. Innis, and Rafik Bekkat-Berkani. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. B/Victoria B/Victoria Influenza B B/Yamagata A/H1N1pdm09 A/H1N1 A/H2N2 A/H3N2 A/H1N1 HUMAN VACCINES & IMMUNOTHERAPEUTICS 1641 1918 Spanish flu pandemic 1933: First isolation of A/H1N1 1936: First monovalent LAIV (USSR) 1940: First isolation of B strain 1942: First bivalent vaccine (A/H1N1,B) 1944: Bivalent A/B IIV for US military; civilians from 1945 1947: reduced vaccine efficacy - H1N1 major drift variant identified Asia flu Pandemic* 1958: A/H2N2 replaces A/H1N1 globally Bivalent vaccine changed - A/H2N2 and B Hong Kong flu Pandemic* 1968 1968: A/H3N2 replaces A/H2N2 globally Bivalent vaccine changed - A/H3N2 and B 1973: WHO issues first annual recommendations for vaccine composition 1978: Re-emergence of A/H1N1. First TIV (A/H3N2, A/H1N1, B) 1987: B/Victoria first documented appearance 1999: WHO issues separate recommendations for northern/southern hemispheres ‘Swine’ 2001: First co-circulation of B lineages flu pandemic 2012: WHO issues recommendations for QIVs 2012: first QIV (A/H3N2, A/H1N1, B/Yamagata, B/Victoria) 8 97 Figure 1. The evaluation of influenza viruses and vaccine development. Information from Hannoun et al. and McCullers et al. Asian influenza pandemic caused by the shifted A/H2N2 strain and Hong Kong influenza pandemic caused by the shifted A/H3N2 strain: both examples of A-strain shift through reassortment (sharing) of genetic material. LAIV D live-attenuated trivalent influenza vaccine; TIV D trivalent influenza vaccine; QIV D quadrivalent influenza vaccine; WHO D World Health Organization. between the circulating viruses and the strains included in value by focusing on the preventable disease burden associ- the vaccines is often referred to as “vaccine match” or “vac- ated with vaccination. We identified modeling studies esti- cine mismatch.” Areviewofinfluenza B in 26 countries mating the potential impact of QIVs compared with TIVs concluded that the type B lineage selected for inclusion in in terms of clinical outcomes prevented. the annual vaccine differs from the predominant circulating lineage in around 25% of seasons. In a mismatched sea- Clinical evaluation and characteristics of currently son, influenza vaccine effectiveness may be suboptimal licensed of QIVs against influenza B epidemics, potentially leading to an 13-18 increased public health burden during those seasons. The first QIV was licensed in 2012 and currently 3 manufac- This observation led to international cooperation among turers produce QIV in various forms (inactivated [IIV4] or the scientific community, leading to the development of live-attenuated [LAIV4]), with new vaccines under develop- 20,21 quadrivalent seasonal influenza vaccines (QIVs) that ment. Seasonal influenza vaccines induce antibody 10,19 included both of the circulating influenza B lineages. In responses against the head of the haemagglutinin glycoprotein. this work we reviewed the development of currently An haemagglutinin inhibition (HI) titer of  1:40 is generally licensed QIVs and provide an overview of their societal accepted as indicative of clinical benefit since it has been 1642 R. RAY ET AL. associated with protection from influenza illness in up to 50% complications) was 73.1% (97.5% CI 47.1–86.3). Influenza 22,23 of subjects. cases in the Q-IIV4-vaccinated group tended to be of mild clin- Cumulative evidence for the immunogenicity and safety of ical severity and were associated with substantially lower num- QIVs was obtained through studies designed to demonstrate bers of medical visits, hospitalisations, school absences and non-inferiority in terms of the HI geometric mean antibody parental absences from work than episodes of influenza in the titres (GMTs) and seroconversion rates (SCRs) to the common control group. 3 strains in the candidate QIVs compared with licensed TIVs, and to demonstrate superiority in terms of the HI GMT and IIV4s manufactured by Sanofi Pasteur SCR of the added influenza type B lineage compared with licensed TIVs containing either the B/Yamagata or B/Victoria Sanofi Pasteur manufacturers 2 IIV4s administered either lineages. Safety and reactogenicity of QIVs versus TIVs were intramuscularly (F-IIV4 licensed for use from 6 months of age) also assessed. or intradermally (Fluzone Intradermal Quadrivalent [intrader- mal F-IIV4] licensed for individuals between 18–64 y of age). Fluzone Quadrivalent: F-IIV4 was evaluated in 3 clinical tri- IIV4s manufactured by GSK als enrolling > 5,500 participants aged 6 months-9 y,  18 y 34-36 GSK produces IIV4s that are identical in antigen content but and  65 y, respectively. Non-inferiority was demonstrated manufactured and licensed separately: FluLaval Quadrivalent between F-IIV4 and IIV3s in terms of HI GMTs and SCRs for (Q-IIV4) is manufactured in Quebec, Canada, and Fluarix common strains in all of these age-groups; except for the SCR Quadrivalent (D-IIV4) is manufactured in Dresden, Ger- for the H1N1 strain in subjects aged  65 y. The failure to meet many. Both vaccines are approved for use in individuals from this non-inferiority criterion may be related to a high baseline 3 y of age. Q-IIV4 is also licensed from 6 months of age in Can- prevalence of seropositivity against this strain. Superiority of ada, the US, and Mexico. Individuals from the age of 6 months the immune response to the added influenza type B lineage through to adults > 65 y were enrolled in the clinical develop- compared with 2 licensed IIV3 formulations in terms of GMTs ment program. The results of key studies have been recently and SCRs was also demonstrated in all age-groups, except for 24-26 reviewed. the GMT ratio for the B/Victoria lineage strain in adults aged Fluarix Quadrivalent (Fluarix Tetra, Influsplit Tetra and  65 y. At least 73.2–100% of adults and 66.9%–98.8% of chil- Alpharix Tetra): In studies in adults, adolescents and children dren who received F-IIV4 had HI titres  40 after vaccination. ( 3 y of age), HI GMTs and SCRs following D-IIV4 were The safety profile of F-IIV4 was similar to that of the studied non-inferior to licensed D-IIV3s for common strains, and IIV3s. superior in terms of the HI GMT and SCR for the additional Fluzone Intradermal Quadrivalent: This intradermal vaccine type B lineage. Addition of the fourth strain had no impact on is licensed for use in adults aged 18–64 y and was evaluated in 27,28 37 the reactogenicity and safety profile of the vaccine. Efficacy 3360 participants in one study in the US. Non-inferiority was of D-IIV4 is supported by the demonstrated efficacy of trivalent demonstrated between the intradermal F-IIV4 and intradermal Fluarix in healthy adults aged 18–64 y; since both vaccines use IIV3 in terms of HI GMTs and SCRs to common strains, and the same manufacturing processes. In adults, Fluarix demon- superiority of the immune response to the added influenza type strated statistically significant efficacy of 66.9% against culture- B lineage compared with 2 intradermal IIV3 formulations was confirmed antigenically-matched influenza A and/or B (95% also demonstrated. At least 86% of intradermal F-IIV4 recipi- 29 37 confidence interval [CI] 51.9–77.4). ents had HI titres  40 after vaccination. The safety profile of FluLaval Quadrivalent (Flulaval Tetra): In studies in adults, intradermal F-IIV4 was similar to that of intradermal IIV3s. adolescents and children ( 3 y of age), the immunogenicity of Q-IIV4 was non-inferior to that of licensed IIV3s for common LAIV4s manufactured by AstraZeneca strains, and superior for the additional type B strain from the alternate lineage in terms of HI GMTs and SCRs. Similar to Flumist Quadrivalent (US, Canada) and Fluenz Tetra (Euro- D-IIV4, addition of the fourth strain did not impact the reacto- pean Union) are licensed for use in individuals from 2–59 y genicity and the safety profile of Q-IIV4 as compared with internationally and 2–49 y in the US. Two clinical trials con- 30,31 IIV3s. ducted in the US evaluated immunogenicity and safety in sub- 38-41 In children 6 to 35 months of age, Q-IIV4 (containing 15 mg jects aged 2–49 y. Non-inferiority of the HI antibody of each virus strain) was non-inferior to Fluzone Quadrivalent response to LAIV3s was demonstrated for common strains. (F-IIV4, Sanofi Pasteur) (containing 7.5 mg of each virus strain) Post-hoc analyses demonstrated superiority of the HI antibody for each vaccine strain, and superior in terms of the immune response for the added B lineage. The safety and reactogenic- response to both influenza B strains in 6–17 month old chil- ity of LAIV4s were similar to LAIV3s. dren and unprimed children of any age. Efficacy of Q-IIV4 was demonstrated in children aged 3¡8y The value of QIVs in reducing the burden of influenza (N D 5,220) who were randomized to receive either Q-IIV4 or B – review of the literature inactivated hepatitis A vaccine as control. Efficacy of Q-IIV4 in preventing influenza of any severity was 55.4% (95% CI Influenza B causes epidemics approximately every 2–4 42,43 39.1–67.3), and efficacy against moderate-to-severe influenza years that impact all age-groups but proportionally more 43-47 (defined as a body temperature > 39 C, acute otitis media, older children. Influenza B has been reported to be clini- 48-50 lower respiratory tract illness, or serious extra-pulmonary cally indistinguishable to influenza A, and has been linked HUMAN VACCINES & IMMUNOTHERAPEUTICS 1643 to severe disease, including encephalitis, myositis, pneumonia search string provided in Fig. 2. Articles were selected by a 3- 51-54 and fulminant disease in children. The majority of subjects step selection procedure based on 1) screening of title and with lethal influenza B in a US case series died before they abstract, 2) screening of full-text article, and 3) final screening could be hospitalised, highlighting the importance of vaccine during the data-extraction phase. The titles and abstracts prophylaxis in mitigating this risk. retrieved from the Pubmed database were screened in duplicate A systematic review of the literature describing influenza B by 2 independent researchers. The results were compared and disease published between 1995 and 2010 concluded that influ- discussed; all selected references from the 2 researchers were enza B was more likely to be severe in children than in adults. included for full text selection. Although influenza B affects all age segments, it is more com- In case of discrepancy or disagreements during the selection, a 12,55 mon among children aged 5–17 y. Influenza B accounts on third researcher was consulted and the study was discussed until average, for approximately 20–30% of influenza isolates from consensus was reached. If articles reported on the same study, the 12,56 respiratory samples across seasons, although the reported most relevant or most complete article was included in this review. frequencies vary from year-to-year and from region-to-region, If articles complemented each other, both articles were included. ranging from 0–62.9% in children and 0–48% in adults. The The reasons for exclusion of full-text papers were recorded. Danish 2015/16 influenza season was characterized by a major We identified 27 eligible studies from 14 countries that used (88%) B-lineage mismatch and it has been put forward that multiple modeling methods and highly variable background morbidity during the season may have been lower if QIVs had assumptions to estimate the potential impact of QIVs over been used instead of TIVs. More recently, a comprehensive TIVs in various immunisation scenarios (Table 1). All of the review of the influenza B burden in 9 European countries estimates were highly dependent upon the choice of baseline highlighted the scarce attention that the influenza B burden has data, such as the assumed degree of cross-protection afforded received over previous decade as compared with influenza A. by TIVs and the level of mismatch in a given season. In all This works also underscores the lack of predictable patterns in cases, the results of more conservative static models (i.e., that strain circulation seen in these countries and thus the continu- could not adjust for potential herd protection or reduction in ous risk of mismatch when there is high influenza B circulation. disease transmission) were lower than dynamic models that For QIVs, modeling studies are sometimes used to assess included herd-protection or disease transmission effects in the cost-effectiveness and whether the added value of the vaccine is model. A summary of current disease burden information and likely to offset the added cost; models may also contribute the potential impact of QIVs on the influenza burden from information about the societal value of QIVs quantifying the modeling studies is presented for selected countries below. number of preventable influenza outcomes compared with TIVs. The reported added value of QIVs comes from its capac- United States ity to provide broader immunity against influenza B, thereby reducing the likelihood of a mismatched season. A prospective study of medically-attended visits for influenza- We systematically queried the PubMed database for papers like-illness (ILI) in the US from 2009–2013 identified influenza B reporting the potential value of QIVs compared with TIVs in in 29.0% of influenza-positive respiratory specimens from terms of illness, hospitalisations and deaths averted using the patients of all ages attending outpatient clinics. In each study Figure 2. Results of the literature search (30 October 2016). Search string: “(Quadrivalent OR tetravalent) (influenza vaccine OR flu vaccine) (cost OR burden OR epidemiol- ogy OR death OR mortality OR illness OR hospitalisation OR hospitalization)” No limits applied. 1644 R. RAY ET AL. Table 1. Summary of QIV modeling data in different countries: results from a review of the literature. Illness averted by QIVs compared with TIVs Model Vaccinated Time Influenza vaccine framework population Population size horizon coverage (%) Total Cases Total hospitalisations Total Deaths North America US Static All ages 270–304 million 10 y 18–30 2,741,575 (Range 21,440 (Range 14– 1371 (Range 1– 2200–970,000) 8,200) 485) US Static All ages 311.6 million 1 y 21.3–66.6 30,251 3,512 722 US Static  65 y 41.5 million 1 y 67 26,701 1,345 211 US Static  65 y 44,704,074 10 months 64.7 39,136 1,648 458 US Dynamic All ages US population 10 y »25–60 1,973,849 annually — 1,396 annually US Dynamic All ages 313.9 million 1 y 46.2 1,382,509 18,354 2,981 US Dynamic All ages US population 13 y Weekly age- 6,267,800 (Average —— without based from 482,000 annually) immigration CDC US Dynamic All ages US population 20 y Weekly age- 16 million 137,645 16,199 based from CDC Canada Dynamic All ages 34.8 million 10 y 16.1–64.4 135,538 annually 1876 annually 328 annually Ontario, Canada Static All ages 12.8 million 2000– 27–81 2,516 annually 27 annually 5 annually Europe UK Dynamic All ages 62.8 million 10 y 17.6–71.1 88,755 annually 1050 annually 230 annually UK Static  65 and risk 63.7 million 100 y 34.07–100 1.4 million 41,780 19,906 groups 10 y 183,844 4,871 2,142 Germany Dynamic 0–15 y Approx. 80 million 20 y 26.8–33.4 79,000 annually —— 16–60 y 223,000 annually —— 61 y 93,000 annually —— All ages 395,000 annually —— Germany Dynamic All ages 81.3 million 20 y Not given 276,505 annually 5,690 annually 262 annually Finland Dynamic All ages Finnish population 20 y »10–75 40,500 annuallyy 360 annuallyy 54 annuallyy 76 yy Belgium Dynamic 2–17 y 11.16–11.63 million 10 y 50 2,953,995 16,968 1,455 Spain Static  65 y, at risk  3y 46,727,891 100 y 0–72.47 18,565 in the first year 407 in the first year 181 in the first year Italy Static All ages at risk, 17,420,318 2014– 9% QIV, 31.02 2,632 100 — 65y 2015 total France Static All ages French population 2003– Not reported 6,214 consultations 614 372 5 countries in Static 6 m-2 y 2002– 6.1–19.2 28,877 140 0 Europe 2013 2–17 y 4.1–14.0 219,163 348 4 18–49 y high risk 30.9–52.0 83,635 389 79 18–49 y low risk 6.5–12.0 133,656 110 0 50–64 y high risk 30.9–52.0 89,908 1,801 325 50–64 y low risk 14.9–25.3 86,216 515 0 65C 48.6–69.2 393,270 21,151 9,391 All ages 1,034,727 24,453 9,799 All ages Extrapolated to 27-EU 1,624,533 37,317 14,866 Asia-Pacific and Western Pacific Hong Kong Static All ages 7.2 million 1 y 11.0–39.1 91/100,000 1.8/100,000 0.046/100,000 98,99 Hong Kong Static  65 y 747,000–924,000 2001– 39.1 191.3/100,000 —— 65–79 y 601,000–666,000 104.8/100,000 0–2.4/100,000 0–0.14/100,000 80 y 146,000–258,000 451.4/100,000 0–13.1/100,000 0–0.77/100,000 All ages Not reported 25.6/100,000 —— Albany, Australia Static All ages ABS CCD 2003– 2–20 (selected 0.1/100,000 (3.8% 2.0/100,000 (2.2% 0.1/100,000 (2.1% 2013 range) reduction) reduction) reduction) Australia Static 6–59 months 173,778 2002– 41.3 4,153 23 0 5–17 y 509,239 41.3 11,824 11 0 18–49 y 2,223,249 36.2 10,240 86 1 50–64 y 1,296,098 36.2 5,731 143 6 65C y 3,221,312 74.6 36,322 3,257 675 Total 7,423,676 at risk — 68,271 3,522 683 Thailand Static All ages 66–68 million 2007– 3–12 21, 974 698 7 Taiwan Static All ages Not reported 100 y 0–39.49 529,874 8,126 3,590 Africa Agincourt, South Static All ages 40,383 2003– 2–20 (selected 0.3/100,000 (12.0% 4.8/100,000 (18.6% 2.0/100,000 Africa 2013 range) reduction) reduction) (17.6% reduction) yy Coverage across seasons coverage across age ranges, this study evaluated immunisation of 2–17 y olds with QIV vs. the baseline scenario of TIV vaccination of at-risk groups, yswitching from TIV to Q-LAIV in 2–18 y olds (with QIV in other age groups) was estimated to prevent an additional 76,100 infections, 540 hospitalizations, and 72 deaths compared with TIV ABS CCD D Australian Bureau of Statistics Census Collection Districts; CDC D Centers for Disease Control and Prevention in the United States; ONS D Office of National Statistics; QIV D quadrivalent influenza vaccine; TIV D trivalent influenza vaccine; US D United States; UK D United Kingdom; y D years HUMAN VACCINES & IMMUNOTHERAPEUTICS 1645 year the incidence of visits for ILI caused by influenza B was 2001–2015. During the 2011/12 influenza season the mis- highestin5–17 year-olds (range 1.0–13.3/1000 population matched influenza B lineage contributed substantially to seri- between 2010–2013). Retrospective studies reported that ous outcomes in adults; the hospital-based Serious Outcomes around 42% (n D 6,084,951) of annual influenza-attributable Surveillance Network in Canada identified influenza B in 65% office visits in < 65 y olds (2001–2009), and 30% of annual influ- of adults hospitalised with influenza, of which 68% (205/383) enza-attributable hospitalisations in all ages (1997–2009), were were due to a vaccine mismatched lineage. Around 12% of attributable to influenza B (mortality rate 30/100,000 popula- influenza B cases required admission to intensive care. The 30- 45,47 tion). In 4of 12seasons encompassedin one study,51–95% day mortality was 3% for the vaccine-matched lineage and 10% of all influenza-associated deaths were attributed to influenza B. for the mismatched lineage. The impact of using QIVs as compared with TIVs in the US Two studies estimated the potential impact of QIVs over was estimated in 7 studies (Table 1). Reed et al., estimated TIVs in Canada: one used a static model and the other a that over the 10-year period between 1999 and 2009, QIVs dynamic model. The static model estimated that use of QIV could have prevented 2.7 million more influenza cases, 21,440 would prevent 2,516 cases, 27 hospitalisations and 5 deaths more hospitalisations and 1,371 more deaths than TIVs. The annually in addition to TIVs. The dynamic model estimated preventable burden each year ranged from 2,200–970,000 ill- that use of QIVs would prevent 135,538 cases, 1,876 hospital- nesses, 14–8,200 hospitalisations and 1–485 deaths. The all-age isations and 328 deaths annually in Canada compared in addi- estimate obtained by another static model appeared similar, tion to TIVs. suggesting that QIVs would prevent 30,251 more influenza cases annually than TIVs. United Kingdom (UK) Using data from a study that compared the difference between vaccination with QIVs vs. no vaccination and vaccina- Modeling studies conducted over 12–14 seasons (1995/1996/ tion with TIVs vs. no vaccination, it can be estimated that in 1997–2009) with results extrapolated to the total UK population one average year, use of QIV rather than TIVs among  65- estimated seasonal rates for general practitioner visits, hospital- year-olds, would prevent 26,701 illnesses, 1,345 hospitalisations isations and deaths attributable to respiratory disease caused by and 211 deaths in this age-group. A second study that consid- influenza B of 355/100,000, 2/100,000, and 1/100,000 population 43,69 ered adults aged 65 y and older estimated that using QIVs respectively. Around one-third of visits to a general practi- instead of TIVs would prevent 39,136 additional influenza tioner for otitis media were attributed to influenza type B. The cases, 1,648 additional hospitalisations and 458 additional number and rate of hospitalisations due to influenza B-attribut- deaths, annually. Differences in the model and in the underly- able respiratory disease was highest in 5–17 year-olds and ing assumptions likely account for the different estimates. exceeded that due to influenza A in some seasons. Four studies used dynamic models that incorporated effects of Over a 13-year period in Scotland (2000–2012), influenza B disease transmission and herd-protection in the model (Table 1). detections were close to, or exceeded influenza A detections for As a result, the estimates obtained from these models were higher 6 out of 13 seasons. than thosefrommore conservativestaticmodels: Crepey et al., Two studies in the UK have compared the impact of TIVs estimated that use of QIVs in the US would have averted 15.8% and QIVs in those  65 y of age and clinical at-risk groups, 68,71 more influenza B cases, or more than 6.2 million influenza cases and its implementation in the whole population. In a static (average 482,000 per year), than TIVs over the 13-year study model that considered vaccination of elderly and at-risk groups, period (2000–2013). Using a similar model, de Boer et al., esti- QIVs are expected to prevent a total of 183,844 cases, 4,871 mated that replacing TIVs with QIVs in the next 20 y (2014–2034) hospitalisations and 2,142 deaths due to influenza B over a 63 71 would reduce influenza B cases by 27.2%, or 16 million cases. cumulative 10-year time horizon. A separate study using a Mullikin et al., calculated influenza illnesses prevented by TIVs, dynamic model reported that vaccination of all age-groups QIVs (or an adjuvanted TIV in elderly with TIV in other ages) (current vaccine coverage rates) was estimated to prevent compared with no vaccination, and estimated that in an average 88,755 cases, 1,050 hospitalisations and 230 deaths due to influ- season with an average vaccine match (obtained using 1999–2014 enza B annually. US data), vaccination with QIVs would prevent 1,382,509 more ill- nesses than vaccination with TIVs (an estimate which is higher Germany than the upper range of that from Crepey et al. ), 18,354 hospital- isations and 2,981 deaths. Brogan et al., estimated that over a 10- In a prospective surveillance study of children 16 y of age year period, QIVs instead of TIVs would prevent 1,973,849 addi- hospitalised with acute respiratory infection, influenza B was tional influenza cases and 1,396 deaths annually. These studies associated with pneumonia in 36% of cases (5/14) and by myo- illustrate that although the impact of QIVs may vary in any influ- sitis in 7% (1/14). In the same study, influenza A infection enza season, the multi-year cumulative benefitofQIVsoverTIVs was associated with pneumonia in 25% (26/102) of cases, otitis are predicted to result in substantial societal benefit. This is partic- media in 25% (26/102) of cases, anaemia and syncope each in ularly true for a dynamic model that accounts for herd immunity. one case. Two studies used a simulation model that incorporated cross-immunising events and waning/boosting of immunity Canada 73,74 over a 20-year time horizon. One study estimated that com- B-lineage mismatches between the vaccine and circulating pared with TIVs, QIVs would prevent 11.2% more influenza B strain occurred in 7 out of 15 seasons in Canada between cases. Each year this would reduce the annual number of 1646 R. RAY ET AL. influenza cases by 3.6% in 0–15 y olds, 4.0% in 16–60 y olds, that QIVs would have prevented an estimated 1,624,533 influ- 6.9% in those aged  61 y and 4.3% (or 395,000 cases) overall. enza cases, 37,317 hospitalisations and 14,866 deaths. The The second study estimated that QIVs would prevent 4% majority of hospitalisations and almost all deaths prevented more influenza cases, 5.7% more hospitalisations and 6.4% would have been in high-risk groups or the elderly. more deaths than TIVs. Hong Kong Finland Using hospital records to identify laboratory-confirmed influ- A dynamic model using data from the 2000 to 2009 influenza enza cases between 2000–2010, Chan et al., estimated that the seasons estimated that in the Finnish population, QIVs would average annual incidence of hospital admission (all ages) due to prevent 40,500 cases, 360 hospitalisations and 54 deaths each influenza B was 20.6/100,000 population. The highest annual year compared with TIV. The number of cases was estimated hospitalisations rates were in children < 5 y and 5–9 y of age to be even further reduced if the QIV used in 2–18 y olds was (median 238/100,000 and 152/100,000, respectively). Both LAIV4. influenza B lineages co-circulated for 9 out of the 10 study years. In the 6 y where a single influenza B lineage predomi- nated (defined as > 80% of identified strains), a mismatch Belgium between the predominant B-strain and the vaccine strain Extending the current Belgian influenza immunisation strategy occurred in 4. Modeling using Hong Kong death statistics and from individuals at-risk (including those aged 50 y or over) to sentinel laboratory surveillance between 1998–2009 estimated include children 2–17 y of age was assessed in a dynamic an annual excess mortality of 2.5/100,000 person-years due to model. Assuming 50% coverage of QIVs among 2–17 y olds, influenza B, increasing to 20.3/100,000 person-years in adults 2.95 million cases of influenza were calculated to be averted aged  65. over a 10-year period compared with no vaccination of this age Static models estimated that compared with TIVs, QIVs group. Most (63%, or 1,869,582) of these averted cases were used at all ages would prevent 91 influenza illnesses per due to indirect effects in adults in whom vaccine coverage rates 100,000 population, 1.8/100,000 hospitalisations and 0.046/ with TIV were assumed to be unchanged. Of a total of 16,968 100,000 deaths over 1 y (Table 1). Vaccination of  65 year- averted hospitalisations and 1,455 averted deaths, 11,567 and olds with QIV between 2001 and 2009 is estimated to have pre- 1,455, respectively, were in adults. vented 191.3 influenza illnesses per 100,000 population in elderly, with the highest reduction in those aged  80 y (reduc- tion of 451.4 illness per 100,000 population). Spain Switching from TIVs to QIVs in at-risk individuals from 3 y of Australia age and in those aged 65 y and over was estimated to prevent an additional 18,565 influenza cases, 407 hospitalisations and The 2015 influenza season in Australia was dominated by influ- 77 84 181 deaths in the first year after implementation. enza B, which accounted for 62% of all cases notified; 38% of influenza B isolates were the B/Victoria lineage not included in the 2015 southern hemisphere TIVs. The highest influenza B Italy notification rate was in children 5–9 y of age, followed by 0–4y QIVs were introduced in Italy for the 2015/16 season. Assum- and 0–14 y. ing that QIVs were used in 9% of the population targeted by A static model using 2003–2013 data from a single town in the national immunisation program (all individuals at risk and Western Australia estimated that compared with TIVs, QIVs those aged  65 y), 1,601 additional cases of uncomplicated would reduce influenza illness by 3.8%, hospitalisations by influenza and 1,031 additional cases of complicated influenza 2.2% and deaths by 2.1%. The authors noted that there was a were estimated to be averted compared with TIVs used alone. good match between the vaccine and circulating lineages dur- ing the study period in Australia, under which scenario the benefit of QIVs over TIVs is marginal. The same study also France investigated the impact of QIVs over TIVs in a rural area of By switching from QIVs to TIVs in France during an average South Africa, and reported a greater impact due to a higher epidemic season between 2003 and 2012, it was estimated that degree of mismatch in the seasons studied (Table 1). 6,214 consultations for influenza, 614 additional hospitalisa- A second static model estimated that the use of QIVs instead tions and 372 deaths would have been averted. of TIVs in children and adults at-risk for influenza (eligible for free vaccination as defined in the Australian Immunisation handbook) between 2002 and 2012, would have reduced influ- European Union enza cases, hospitalisations and deaths by 1.02% (68,271), 2.4% A static model using data from France, Germany, Italy, Spain (n D 3,522) and 3.7% (n D 683), respectively. The highest and the UK, estimated that replacement of TIVs with QIVs impact of QIV was in young children and the elderly. In adults during 2002–2013 (2009 season excluded) would have pre- aged 65 y and over, QIVs were estimated to prevent an addi- vented 1,034,727 additional influenza cases, 24,453 hospitalisa- tional 10.1 hospitalisations and 2.1 deaths per 100,000 person- tions and 9,799 deaths. Extrapolation to the 27-EU suggested years over TIVs. HUMAN VACCINES & IMMUNOTHERAPEUTICS 1647 Table 2. Current recommendations for influenza vaccination using quadrivalent seasonal influenza vaccines (QIVs). Countries/authorities with permissive recommendations Year recommended Age/group indicated for QIVs for QIVs use World Health Organization 2012 Pregnant women, Children <5 y, Health care workers, Elderly >65 y, Chronic conditions Germany 2013 Pregnant women, Children <5 y, Health care workers, Elderly >65 y, Chronic conditions United States 2013 Children (6 months) & Adults Hong Kong 2013 Children ( 3 y) & Adults Canada 2014 From 6 months of age Italy 2014 Children ( 3 y) & Adults France 2014 Children ( 3 y) & Adults Belgium 2015 From age 2 y Brazil 2014 Elderly 60C y Countries preferentially recommending QIVs United Kingdom 2013 Children 2–7 y and children at risk 2–18 y. Germany 2014 All long-distance travelers Brazil 2015 Elderly Australia 2015 From 6 months of age QIV D quadrivalent seasonal influenza vaccine (LAIV or IIV4) Current recommendations for QIVs from clinical trials and observational studies suggest that B- mismatched seasons are accompanied by a higher public health Since licensure of the first QIV in 2012, an increasing number 15,51 burden than well-matched seasons. Although the risk of of countries use QIVs either permissively (TIVs or QIVs), or breakthrough influenza A from vaccine strain mismatch preferentially (TIVs available but QIVs preferred) (Table 2). remains, the risk of breakthrough influenza B from vaccine However, while several supranational organisations acknowl- lineage mismatch can be eliminated by QIV. edge that QIVs may improve protection against influenza B Brazil is unique with regards to the pattern of influenza and strains compared with TIVs, at this time, most health authori- viral circulating in this heterogeneous climate. A recent review ties do not preferentially recommend one over the other paper highlighted that over a 9 y follow-up period, influenza B (Table 2). Health authorities are generally concerned that with lineages circulated in 3 seasons, of which, during one season, a trend toward an increased influenza vaccine uptake overall, there was a high degree of mismatch between the vaccine line- preferential recommendations may be counterproductive if a age and the predominant circulating lineage (91.4% [2013]). preferred product is not sufficiently manufactured and supplied Within tropical and sub-tropical regions such as Brazil, influ- to cover the entire population to be vaccinated. enza B can have protracted circulation patterns and co-circula- After successful pilot programmes in 2013 and 2014, influ- tion of both B-lineages may not be uncommon, thus further enza vaccination using LAIV4 is now offered to 2–4 y old highlighting the added value of QIVs in these countries. school children in the UK, as well as to at-risk groups from 6 Modeling the impact of QIVs over TIVs is challenging, not month to 17 y of age. This innovative initiative aims to reduce least because of the unpredictable disease burden that differs disease incidence in children and transmission to older age- markedly from year-to-year. As might therefore be antici- groups, thereby achieving societal benefit at the overall popula- pated, evaluations from different countries all show very large tion level. variability in the seasonal impact of QIVs. Analyses that project cumulative effects over multiple seasons based on antecedent virus circulation patterns are therefore most informative. The Conclusions published dynamic models showed substantially greater Although varying from year-to-year, on average, influenza B improvement in health outcomes based on the use of QIVs as causes up to one-third of influenza infections each season. A compared with the more conservative static models. However, large body of evidence from numerous countries demonstrates although dynamic models better reflect the real-world impact that influenza B accounts for a significant proportion of the of vaccination, dynamic transmission models are inherently overall burden of influenza that inundates healthcare services more complex and require a greater degree of assumptions in annually. Once thought to cause predominantly mild illness, terms of model inputs. numerous studies now indicate that there is little difference in Influenza vaccines typically show reduced efficacy in the the clinical symptomatology and outcomes of influenza B vs. A. elderly due to immune senescence and novel TIVs developed Hospitalisations and mortality attributable to influenza B may for use in this age-group include an increased antigen dose or have previously been underestimated, with studies reporting adjuvant to overcome this limitation. Modeling studies suggest higher mortality following influenza B infection than A in that the benefits of enhanced TIV formulations in the elderly 13,89-91 some years. In parallel, the 2 influenza B lineages fre- (high-dose or adjuvanted TIVs) may be as great, or greater 60,61,64 quently co-circulate, and due to the complexity involved in than those provided by QIVs. This underscores the fact accurately forecasting which B viruses will circulate, mis- that in older adults, improvements in vaccine efficacy can be matches between the B strain selected for TIVs and circulating achieved by improving the immune response and by broaden- 4,92 strains have occurred in up to one-half of seasons. Evidence ing coverage. However, even with high-dose TIV, efficacy 1648 R. RAY ET AL. against influenza B due to the lineage included in the vaccine References is clearly higher than efficacy against influenza B due to the [1] McCauley J, Hongo S, Kaverin N, Kochs G, Lamb R, et al. Family - lineage absent from the vaccine. An enhanced QIV in this orthomyxoviridae. In: King AMQ, Lefkowitz E, Adams MJ, Carstens population appears to be the optimal vaccine choice. EB, editors. Virus taxonomy: Ninth Report of the International Com- Influenza vaccines have been in use since 1936 and the move mittee on Taxonomy of Viruses. San Diego: Elsevier; 2012; 749-61. [2] Chen R, Holmes EC. The evolutionary dynamics of human influ- from TIVs to QIVs is the most recent adaption of seasonal enza B virus. J Mol Evol 2008; 66:655-63; PMID:18504518; https:// influenza vaccines in response to changes in global circulating doi.org/10.1007/s00239-008-9119-z influenza strains. Based on the available evidence from clinical [3] Tan Y, Guan W, Lam TT-Y, Pan S, Wu S, Zhan Y, Viboud C, trials, epidemiological studies and modeling, several countries Holmes EC, Yang Z. 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Prevention and vaccine effectiveness in coming seasons will provide comple- control of influenza with vaccines: Recommendations of the Advi- mentary information on the potential added benefits of QIVs sory Committee on Immunization Practices (ACIP), 2010. MMWR on influenza prevention, which may lead more countries to Recomm Rep 2010; 59:1-62 adopt definitive recommendations for QIVs use. [6] Rota PA, Wallis TR, Harmon MW, Rota JS, Kendal AP, Nerome K. Cocirculation of two distinct evolutionary lineages of influenza type B virus since 1983. Virology 1990; 175:59-68; PMID:2309452; https://doi.org/10.1016/0042-6822(90)90186-U Trademark statement [7] Wong KK, Jain S, Blanton L, Dhara R, Brammer L, Fry AM, Finelli L. Influenza-associated pediatric deaths in the United States, 2004– FluLaval, Fluarix, Alpharix and Influsplit are trademarks of the 2012. Pediatrics 2013; 132:796-804; PMID:24167165; https://doi. GSK group of companies. Fluzone Quadrivalent and Fluzone org/10.1542/peds.2013-1493 Intradermal Quadrivalent are trademarks of Sanofi Pasteur. [8] Hannoun C. The evolving of influenza viruses and influenza vac- Flumist Quadrivalent and Fluenz Tetra are trademarks of cines. Expert Rev Vaccines 2013; 12:1085-94; PMID:24024871; https://doi.org/10.1586/14760584.2013.824709 AstraZeneca. [9] Shaw MW, Xu X, Li Y, Normand S, Ueki RT, Kunimoto GY, Hall H, Klimov A, Cox NJ, Subbarao K. Reappearance and global spread of variants of influenza B/Victoria/2/87 lineage viruses in Disclosure of potential conflicts of interest the 2000–2001 and 2001–2002 seasons. Virology 2002; 303:1-8; PMID:12482653; https://doi.org/10.1006/viro.2002.1719 Riju Ray, Rafik Bekkat-Berkani, Philip O. Buck, Carine Claeys and [10] Belshe RB. The need for quadrivalent vaccine against seasonal influ- Gonc ¸alo Matias are employees of the GSK group of companies. Bruce L. enza. Vaccine 2010; 28:Suppl 4:D45-53; PMID:20713260; https:// Innis reports he was employed by the GSK group of companies at the time doi.org/10.1016/j.vaccine.2010.08.028 of the study and is now an employee of PATH. Riju Ray, Rafik Bekkat-Ber- [11] Skowronski DM, De Serres G, Dickinson J, Petric M, Mak A, Fon- kani, Philip O. Buck, Carine Claeys and Bruce L. Innis report ownership of seca K, Kwindt TL, Chan T, Bastien N, Charest H, et al. Compo- stock options and/or restricted shares in the GSK group of companies. nent-specific effectiveness of trivalent influenza vaccine as Ga€el Dos Santosreports he was employed by Business & Decision Life Sci- monitored through a sentinel surveillance network in Canada, ences (on behalf of GSK) at the time of the study and is now employee of 2006–2007. J Infect Dis 2009; 199:168-79; PMID:19086914; https:// the GSK group of companies. doi.org/10.1086/595862 [12] Caini S, Huang QS, Ciblak MA, Kusznierz G, Owen R, Wangchuk S, Henriques CMP, Njouom R, Fasce RA, Yu H, et al. Epidemiologi- cal and virological characteristics of influenza B: Results of the Acknowledgments Global Influenza B Study. Influenza Other Respir Viruses 2015; 9: The authors thank Philippe Buchy for critically reviewing the manuscript. Suppl 1:3-12; PMID:26256290; https://doi.org/10.1111/irv.12319 The authors also thank Joanne Wolter (Independent medical writer, on [13] Lo Y-C, Chuang J-H, Kuo H-W, Huang W-T, Hsu Y-F, Liu M-T, behalf of GSK) for providing writing services, and Bruno Dumont and Chen C-H, Huang H-H, Chang C-H, Chou J-H, et al. 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A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control

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Abstract

HUMAN VACCINES & IMMUNOTHERAPEUTICS 2017, VOL. 13, NO. 7, 1640–1652 https://doi.org/10.1080/21645515.2017.1313375 REVIEW A review of the value of quadrivalent influenza vaccines and their potential contribution to influenza control a, b,z c a a c,# Riju Ray *,Gael Dos Santos , Philip O. Buck , Carine Claeys , Gonc ¸ alo Matias , Bruce L. Innis , a, and Rafik Bekkat-Berkani ** a b c GSK, Wavre, Belgium; Business & Decision Life Sciences, Brussels, Belgium (on behalf of GSK); GSK, Philadelphia, PA, USA ABSTRACT ARTICLE HISTORY Received 31 January 2017 The contribution of influenza B to the seasonal influenza burden varies from year-to-year. Although 2 Revised 20 March 2017 antigenically distinct influenza B virus lineages have co-circulated since 2001, trivalent influenza vaccines Accepted 25 March 2017 (TIVs) contain antigens from only one influenza B virus. B-mismatch or co-circulation of both B lineages results in increased morbidity and mortality attributable to the B lineage absent from the vaccine. KEYWORDS Quadrivalent vaccines (QIVs) contain both influenza B lineages. We reviewed currently licensed QIVs and influenza; influenza B; their value by focusing on the preventable disease burden. Modeling studies support that QIVs are mismatch; quadrivalent expected to prevent more influenza cases, hospitalisations and deaths than TIVs, although estimates of influenza vaccine the case numbers prevented vary according to local specificities. The value of QIVs is demonstrated by their capacity to broaden the immune response and reduce the likelihood of a B-mismatched season. Some health authorities have preferentially recommended QIVs over TIVs in their influenza prevention programmes. Introduction Influenza viruses are enveloped negative-strand RNA viruses United States (US), there were 830 reported laboratory-con- that are divided into 3 genera: type A, B and C. The vast major- firmed influenza deaths between 2004–2012 in children ity of human disease is caused by types A and B, which are < 18 y of age. Of these, 25% were children aged < 24 months. genetically and structurally similar, but differ in biology, evolu- Since the development of the first monovalent A/H1N1 1-3 tionary and epidemiological framework. Influenza A viruses influenza vaccines more than 75 y ago, influenza vaccines are subtyped according to 2 surface glycoproteins: haemaggluti- have always required adaptation in response to changes to nin (H) and neuraminidase (N) whereas influenza B viruses provide protection against the predominant circulating form a homogenous group segregated according to 2 antigeni- influenza viruses (Fig. 1). After influenza B was first isolated cally distinguishable lineages (B/Victoria and B/Yamagata). in 1940, bivalent (A/H1N1, B) vaccines were developed. The Influenza viruses undergo constant mutation which enables vaccine influenza A subtype was changed in 1958 and in evasion of existing host immunity leading to recurrent infec- 1969 in response to influenza A shifts that triggered severe tions that manifest as annual outbreaks. Periodically, new A pandemics (Fig. 1). Seasonal trivalent influenza vaccines subtypes emerge, resulting in a pandemic; the emergent sub- (TIVs) containing 2 influenza A -subtype viruses and one B type may replace or less frequently co-circulate with the earlier virus were first produced in 1978 after the re-appearance A subtype (Fig. 1). Currently, 2 influenza A subtypes, A/H1N1 and co-circulation of A/H1N1 with A/H3N2 viruses and A/H3N2, and the 2 influenza B lineages circulate globally (Fig. 1). Two antigenically distinct lineages of influenza B 5,6 each year. In any influenza season, several influenza types, A- viruses have circulated globally since 1985 and have co-cir- subtypes, or B-lineages may co-circulate, such that the annual culated since 2001. The influenza B-lineage vaccine strains influenza burden differs unpredictably from year-to-year, induce little or no cross-reactive protection against the 10,11 potentially fluctuating from age-group to age-group, and from alternate B-lineage, such that for TIVs, protection region-to-region. against the circulating influenza B lineage relies on correctly Influenza affects all age-groups and while most deaths occur predicting the B-lineage likely to predominate in the in older adults, influenza deaths also occur in children. In the upcoming season. The degree of similarity or difference CONTACT Rafik Bekkat-Berkani Rafik.X.Bekkat-Berkani@gsk.com 5 Crescent Drive, Philadelphia, PA 19112, USA. *Current affiliation: GSK, Research Triangle Park, NC, USA. Current affiliation: GSK, Wavre, Belgium. Current affiliation: PATH, Washington, DC, USA. **Current affiliation: GSK, Philadelphia, PA, USA. © 2017 Riju Ray, Ga€ el Dos Santos, Philip O. Buck, Carine Claeys, Gonc ¸alo Matias, Bruce L. Innis, and Rafik Bekkat-Berkani. Published with license by Taylor & Francis. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted. B/Victoria B/Victoria Influenza B B/Yamagata A/H1N1pdm09 A/H1N1 A/H2N2 A/H3N2 A/H1N1 HUMAN VACCINES & IMMUNOTHERAPEUTICS 1641 1918 Spanish flu pandemic 1933: First isolation of A/H1N1 1936: First monovalent LAIV (USSR) 1940: First isolation of B strain 1942: First bivalent vaccine (A/H1N1,B) 1944: Bivalent A/B IIV for US military; civilians from 1945 1947: reduced vaccine efficacy - H1N1 major drift variant identified Asia flu Pandemic* 1958: A/H2N2 replaces A/H1N1 globally Bivalent vaccine changed - A/H2N2 and B Hong Kong flu Pandemic* 1968 1968: A/H3N2 replaces A/H2N2 globally Bivalent vaccine changed - A/H3N2 and B 1973: WHO issues first annual recommendations for vaccine composition 1978: Re-emergence of A/H1N1. First TIV (A/H3N2, A/H1N1, B) 1987: B/Victoria first documented appearance 1999: WHO issues separate recommendations for northern/southern hemispheres ‘Swine’ 2001: First co-circulation of B lineages flu pandemic 2012: WHO issues recommendations for QIVs 2012: first QIV (A/H3N2, A/H1N1, B/Yamagata, B/Victoria) 8 97 Figure 1. The evaluation of influenza viruses and vaccine development. Information from Hannoun et al. and McCullers et al. Asian influenza pandemic caused by the shifted A/H2N2 strain and Hong Kong influenza pandemic caused by the shifted A/H3N2 strain: both examples of A-strain shift through reassortment (sharing) of genetic material. LAIV D live-attenuated trivalent influenza vaccine; TIV D trivalent influenza vaccine; QIV D quadrivalent influenza vaccine; WHO D World Health Organization. between the circulating viruses and the strains included in value by focusing on the preventable disease burden associ- the vaccines is often referred to as “vaccine match” or “vac- ated with vaccination. We identified modeling studies esti- cine mismatch.” Areviewofinfluenza B in 26 countries mating the potential impact of QIVs compared with TIVs concluded that the type B lineage selected for inclusion in in terms of clinical outcomes prevented. the annual vaccine differs from the predominant circulating lineage in around 25% of seasons. In a mismatched sea- Clinical evaluation and characteristics of currently son, influenza vaccine effectiveness may be suboptimal licensed of QIVs against influenza B epidemics, potentially leading to an 13-18 increased public health burden during those seasons. The first QIV was licensed in 2012 and currently 3 manufac- This observation led to international cooperation among turers produce QIV in various forms (inactivated [IIV4] or the scientific community, leading to the development of live-attenuated [LAIV4]), with new vaccines under develop- 20,21 quadrivalent seasonal influenza vaccines (QIVs) that ment. Seasonal influenza vaccines induce antibody 10,19 included both of the circulating influenza B lineages. In responses against the head of the haemagglutinin glycoprotein. this work we reviewed the development of currently An haemagglutinin inhibition (HI) titer of  1:40 is generally licensed QIVs and provide an overview of their societal accepted as indicative of clinical benefit since it has been 1642 R. RAY ET AL. associated with protection from influenza illness in up to 50% complications) was 73.1% (97.5% CI 47.1–86.3). Influenza 22,23 of subjects. cases in the Q-IIV4-vaccinated group tended to be of mild clin- Cumulative evidence for the immunogenicity and safety of ical severity and were associated with substantially lower num- QIVs was obtained through studies designed to demonstrate bers of medical visits, hospitalisations, school absences and non-inferiority in terms of the HI geometric mean antibody parental absences from work than episodes of influenza in the titres (GMTs) and seroconversion rates (SCRs) to the common control group. 3 strains in the candidate QIVs compared with licensed TIVs, and to demonstrate superiority in terms of the HI GMT and IIV4s manufactured by Sanofi Pasteur SCR of the added influenza type B lineage compared with licensed TIVs containing either the B/Yamagata or B/Victoria Sanofi Pasteur manufacturers 2 IIV4s administered either lineages. Safety and reactogenicity of QIVs versus TIVs were intramuscularly (F-IIV4 licensed for use from 6 months of age) also assessed. or intradermally (Fluzone Intradermal Quadrivalent [intrader- mal F-IIV4] licensed for individuals between 18–64 y of age). Fluzone Quadrivalent: F-IIV4 was evaluated in 3 clinical tri- IIV4s manufactured by GSK als enrolling > 5,500 participants aged 6 months-9 y,  18 y 34-36 GSK produces IIV4s that are identical in antigen content but and  65 y, respectively. Non-inferiority was demonstrated manufactured and licensed separately: FluLaval Quadrivalent between F-IIV4 and IIV3s in terms of HI GMTs and SCRs for (Q-IIV4) is manufactured in Quebec, Canada, and Fluarix common strains in all of these age-groups; except for the SCR Quadrivalent (D-IIV4) is manufactured in Dresden, Ger- for the H1N1 strain in subjects aged  65 y. The failure to meet many. Both vaccines are approved for use in individuals from this non-inferiority criterion may be related to a high baseline 3 y of age. Q-IIV4 is also licensed from 6 months of age in Can- prevalence of seropositivity against this strain. Superiority of ada, the US, and Mexico. Individuals from the age of 6 months the immune response to the added influenza type B lineage through to adults > 65 y were enrolled in the clinical develop- compared with 2 licensed IIV3 formulations in terms of GMTs ment program. The results of key studies have been recently and SCRs was also demonstrated in all age-groups, except for 24-26 reviewed. the GMT ratio for the B/Victoria lineage strain in adults aged Fluarix Quadrivalent (Fluarix Tetra, Influsplit Tetra and  65 y. At least 73.2–100% of adults and 66.9%–98.8% of chil- Alpharix Tetra): In studies in adults, adolescents and children dren who received F-IIV4 had HI titres  40 after vaccination. ( 3 y of age), HI GMTs and SCRs following D-IIV4 were The safety profile of F-IIV4 was similar to that of the studied non-inferior to licensed D-IIV3s for common strains, and IIV3s. superior in terms of the HI GMT and SCR for the additional Fluzone Intradermal Quadrivalent: This intradermal vaccine type B lineage. Addition of the fourth strain had no impact on is licensed for use in adults aged 18–64 y and was evaluated in 27,28 37 the reactogenicity and safety profile of the vaccine. Efficacy 3360 participants in one study in the US. Non-inferiority was of D-IIV4 is supported by the demonstrated efficacy of trivalent demonstrated between the intradermal F-IIV4 and intradermal Fluarix in healthy adults aged 18–64 y; since both vaccines use IIV3 in terms of HI GMTs and SCRs to common strains, and the same manufacturing processes. In adults, Fluarix demon- superiority of the immune response to the added influenza type strated statistically significant efficacy of 66.9% against culture- B lineage compared with 2 intradermal IIV3 formulations was confirmed antigenically-matched influenza A and/or B (95% also demonstrated. At least 86% of intradermal F-IIV4 recipi- 29 37 confidence interval [CI] 51.9–77.4). ents had HI titres  40 after vaccination. The safety profile of FluLaval Quadrivalent (Flulaval Tetra): In studies in adults, intradermal F-IIV4 was similar to that of intradermal IIV3s. adolescents and children ( 3 y of age), the immunogenicity of Q-IIV4 was non-inferior to that of licensed IIV3s for common LAIV4s manufactured by AstraZeneca strains, and superior for the additional type B strain from the alternate lineage in terms of HI GMTs and SCRs. Similar to Flumist Quadrivalent (US, Canada) and Fluenz Tetra (Euro- D-IIV4, addition of the fourth strain did not impact the reacto- pean Union) are licensed for use in individuals from 2–59 y genicity and the safety profile of Q-IIV4 as compared with internationally and 2–49 y in the US. Two clinical trials con- 30,31 IIV3s. ducted in the US evaluated immunogenicity and safety in sub- 38-41 In children 6 to 35 months of age, Q-IIV4 (containing 15 mg jects aged 2–49 y. Non-inferiority of the HI antibody of each virus strain) was non-inferior to Fluzone Quadrivalent response to LAIV3s was demonstrated for common strains. (F-IIV4, Sanofi Pasteur) (containing 7.5 mg of each virus strain) Post-hoc analyses demonstrated superiority of the HI antibody for each vaccine strain, and superior in terms of the immune response for the added B lineage. The safety and reactogenic- response to both influenza B strains in 6–17 month old chil- ity of LAIV4s were similar to LAIV3s. dren and unprimed children of any age. Efficacy of Q-IIV4 was demonstrated in children aged 3¡8y The value of QIVs in reducing the burden of influenza (N D 5,220) who were randomized to receive either Q-IIV4 or B – review of the literature inactivated hepatitis A vaccine as control. Efficacy of Q-IIV4 in preventing influenza of any severity was 55.4% (95% CI Influenza B causes epidemics approximately every 2–4 42,43 39.1–67.3), and efficacy against moderate-to-severe influenza years that impact all age-groups but proportionally more 43-47 (defined as a body temperature > 39 C, acute otitis media, older children. Influenza B has been reported to be clini- 48-50 lower respiratory tract illness, or serious extra-pulmonary cally indistinguishable to influenza A, and has been linked HUMAN VACCINES & IMMUNOTHERAPEUTICS 1643 to severe disease, including encephalitis, myositis, pneumonia search string provided in Fig. 2. Articles were selected by a 3- 51-54 and fulminant disease in children. The majority of subjects step selection procedure based on 1) screening of title and with lethal influenza B in a US case series died before they abstract, 2) screening of full-text article, and 3) final screening could be hospitalised, highlighting the importance of vaccine during the data-extraction phase. The titles and abstracts prophylaxis in mitigating this risk. retrieved from the Pubmed database were screened in duplicate A systematic review of the literature describing influenza B by 2 independent researchers. The results were compared and disease published between 1995 and 2010 concluded that influ- discussed; all selected references from the 2 researchers were enza B was more likely to be severe in children than in adults. included for full text selection. Although influenza B affects all age segments, it is more com- In case of discrepancy or disagreements during the selection, a 12,55 mon among children aged 5–17 y. Influenza B accounts on third researcher was consulted and the study was discussed until average, for approximately 20–30% of influenza isolates from consensus was reached. If articles reported on the same study, the 12,56 respiratory samples across seasons, although the reported most relevant or most complete article was included in this review. frequencies vary from year-to-year and from region-to-region, If articles complemented each other, both articles were included. ranging from 0–62.9% in children and 0–48% in adults. The The reasons for exclusion of full-text papers were recorded. Danish 2015/16 influenza season was characterized by a major We identified 27 eligible studies from 14 countries that used (88%) B-lineage mismatch and it has been put forward that multiple modeling methods and highly variable background morbidity during the season may have been lower if QIVs had assumptions to estimate the potential impact of QIVs over been used instead of TIVs. More recently, a comprehensive TIVs in various immunisation scenarios (Table 1). All of the review of the influenza B burden in 9 European countries estimates were highly dependent upon the choice of baseline highlighted the scarce attention that the influenza B burden has data, such as the assumed degree of cross-protection afforded received over previous decade as compared with influenza A. by TIVs and the level of mismatch in a given season. In all This works also underscores the lack of predictable patterns in cases, the results of more conservative static models (i.e., that strain circulation seen in these countries and thus the continu- could not adjust for potential herd protection or reduction in ous risk of mismatch when there is high influenza B circulation. disease transmission) were lower than dynamic models that For QIVs, modeling studies are sometimes used to assess included herd-protection or disease transmission effects in the cost-effectiveness and whether the added value of the vaccine is model. A summary of current disease burden information and likely to offset the added cost; models may also contribute the potential impact of QIVs on the influenza burden from information about the societal value of QIVs quantifying the modeling studies is presented for selected countries below. number of preventable influenza outcomes compared with TIVs. The reported added value of QIVs comes from its capac- United States ity to provide broader immunity against influenza B, thereby reducing the likelihood of a mismatched season. A prospective study of medically-attended visits for influenza- We systematically queried the PubMed database for papers like-illness (ILI) in the US from 2009–2013 identified influenza B reporting the potential value of QIVs compared with TIVs in in 29.0% of influenza-positive respiratory specimens from terms of illness, hospitalisations and deaths averted using the patients of all ages attending outpatient clinics. In each study Figure 2. Results of the literature search (30 October 2016). Search string: “(Quadrivalent OR tetravalent) (influenza vaccine OR flu vaccine) (cost OR burden OR epidemiol- ogy OR death OR mortality OR illness OR hospitalisation OR hospitalization)” No limits applied. 1644 R. RAY ET AL. Table 1. Summary of QIV modeling data in different countries: results from a review of the literature. Illness averted by QIVs compared with TIVs Model Vaccinated Time Influenza vaccine framework population Population size horizon coverage (%) Total Cases Total hospitalisations Total Deaths North America US Static All ages 270–304 million 10 y 18–30 2,741,575 (Range 21,440 (Range 14– 1371 (Range 1– 2200–970,000) 8,200) 485) US Static All ages 311.6 million 1 y 21.3–66.6 30,251 3,512 722 US Static  65 y 41.5 million 1 y 67 26,701 1,345 211 US Static  65 y 44,704,074 10 months 64.7 39,136 1,648 458 US Dynamic All ages US population 10 y »25–60 1,973,849 annually — 1,396 annually US Dynamic All ages 313.9 million 1 y 46.2 1,382,509 18,354 2,981 US Dynamic All ages US population 13 y Weekly age- 6,267,800 (Average —— without based from 482,000 annually) immigration CDC US Dynamic All ages US population 20 y Weekly age- 16 million 137,645 16,199 based from CDC Canada Dynamic All ages 34.8 million 10 y 16.1–64.4 135,538 annually 1876 annually 328 annually Ontario, Canada Static All ages 12.8 million 2000– 27–81 2,516 annually 27 annually 5 annually Europe UK Dynamic All ages 62.8 million 10 y 17.6–71.1 88,755 annually 1050 annually 230 annually UK Static  65 and risk 63.7 million 100 y 34.07–100 1.4 million 41,780 19,906 groups 10 y 183,844 4,871 2,142 Germany Dynamic 0–15 y Approx. 80 million 20 y 26.8–33.4 79,000 annually —— 16–60 y 223,000 annually —— 61 y 93,000 annually —— All ages 395,000 annually —— Germany Dynamic All ages 81.3 million 20 y Not given 276,505 annually 5,690 annually 262 annually Finland Dynamic All ages Finnish population 20 y »10–75 40,500 annuallyy 360 annuallyy 54 annuallyy 76 yy Belgium Dynamic 2–17 y 11.16–11.63 million 10 y 50 2,953,995 16,968 1,455 Spain Static  65 y, at risk  3y 46,727,891 100 y 0–72.47 18,565 in the first year 407 in the first year 181 in the first year Italy Static All ages at risk, 17,420,318 2014– 9% QIV, 31.02 2,632 100 — 65y 2015 total France Static All ages French population 2003– Not reported 6,214 consultations 614 372 5 countries in Static 6 m-2 y 2002– 6.1–19.2 28,877 140 0 Europe 2013 2–17 y 4.1–14.0 219,163 348 4 18–49 y high risk 30.9–52.0 83,635 389 79 18–49 y low risk 6.5–12.0 133,656 110 0 50–64 y high risk 30.9–52.0 89,908 1,801 325 50–64 y low risk 14.9–25.3 86,216 515 0 65C 48.6–69.2 393,270 21,151 9,391 All ages 1,034,727 24,453 9,799 All ages Extrapolated to 27-EU 1,624,533 37,317 14,866 Asia-Pacific and Western Pacific Hong Kong Static All ages 7.2 million 1 y 11.0–39.1 91/100,000 1.8/100,000 0.046/100,000 98,99 Hong Kong Static  65 y 747,000–924,000 2001– 39.1 191.3/100,000 —— 65–79 y 601,000–666,000 104.8/100,000 0–2.4/100,000 0–0.14/100,000 80 y 146,000–258,000 451.4/100,000 0–13.1/100,000 0–0.77/100,000 All ages Not reported 25.6/100,000 —— Albany, Australia Static All ages ABS CCD 2003– 2–20 (selected 0.1/100,000 (3.8% 2.0/100,000 (2.2% 0.1/100,000 (2.1% 2013 range) reduction) reduction) reduction) Australia Static 6–59 months 173,778 2002– 41.3 4,153 23 0 5–17 y 509,239 41.3 11,824 11 0 18–49 y 2,223,249 36.2 10,240 86 1 50–64 y 1,296,098 36.2 5,731 143 6 65C y 3,221,312 74.6 36,322 3,257 675 Total 7,423,676 at risk — 68,271 3,522 683 Thailand Static All ages 66–68 million 2007– 3–12 21, 974 698 7 Taiwan Static All ages Not reported 100 y 0–39.49 529,874 8,126 3,590 Africa Agincourt, South Static All ages 40,383 2003– 2–20 (selected 0.3/100,000 (12.0% 4.8/100,000 (18.6% 2.0/100,000 Africa 2013 range) reduction) reduction) (17.6% reduction) yy Coverage across seasons coverage across age ranges, this study evaluated immunisation of 2–17 y olds with QIV vs. the baseline scenario of TIV vaccination of at-risk groups, yswitching from TIV to Q-LAIV in 2–18 y olds (with QIV in other age groups) was estimated to prevent an additional 76,100 infections, 540 hospitalizations, and 72 deaths compared with TIV ABS CCD D Australian Bureau of Statistics Census Collection Districts; CDC D Centers for Disease Control and Prevention in the United States; ONS D Office of National Statistics; QIV D quadrivalent influenza vaccine; TIV D trivalent influenza vaccine; US D United States; UK D United Kingdom; y D years HUMAN VACCINES & IMMUNOTHERAPEUTICS 1645 year the incidence of visits for ILI caused by influenza B was 2001–2015. During the 2011/12 influenza season the mis- highestin5–17 year-olds (range 1.0–13.3/1000 population matched influenza B lineage contributed substantially to seri- between 2010–2013). Retrospective studies reported that ous outcomes in adults; the hospital-based Serious Outcomes around 42% (n D 6,084,951) of annual influenza-attributable Surveillance Network in Canada identified influenza B in 65% office visits in < 65 y olds (2001–2009), and 30% of annual influ- of adults hospitalised with influenza, of which 68% (205/383) enza-attributable hospitalisations in all ages (1997–2009), were were due to a vaccine mismatched lineage. Around 12% of attributable to influenza B (mortality rate 30/100,000 popula- influenza B cases required admission to intensive care. The 30- 45,47 tion). In 4of 12seasons encompassedin one study,51–95% day mortality was 3% for the vaccine-matched lineage and 10% of all influenza-associated deaths were attributed to influenza B. for the mismatched lineage. The impact of using QIVs as compared with TIVs in the US Two studies estimated the potential impact of QIVs over was estimated in 7 studies (Table 1). Reed et al., estimated TIVs in Canada: one used a static model and the other a that over the 10-year period between 1999 and 2009, QIVs dynamic model. The static model estimated that use of QIV could have prevented 2.7 million more influenza cases, 21,440 would prevent 2,516 cases, 27 hospitalisations and 5 deaths more hospitalisations and 1,371 more deaths than TIVs. The annually in addition to TIVs. The dynamic model estimated preventable burden each year ranged from 2,200–970,000 ill- that use of QIVs would prevent 135,538 cases, 1,876 hospital- nesses, 14–8,200 hospitalisations and 1–485 deaths. The all-age isations and 328 deaths annually in Canada compared in addi- estimate obtained by another static model appeared similar, tion to TIVs. suggesting that QIVs would prevent 30,251 more influenza cases annually than TIVs. United Kingdom (UK) Using data from a study that compared the difference between vaccination with QIVs vs. no vaccination and vaccina- Modeling studies conducted over 12–14 seasons (1995/1996/ tion with TIVs vs. no vaccination, it can be estimated that in 1997–2009) with results extrapolated to the total UK population one average year, use of QIV rather than TIVs among  65- estimated seasonal rates for general practitioner visits, hospital- year-olds, would prevent 26,701 illnesses, 1,345 hospitalisations isations and deaths attributable to respiratory disease caused by and 211 deaths in this age-group. A second study that consid- influenza B of 355/100,000, 2/100,000, and 1/100,000 population 43,69 ered adults aged 65 y and older estimated that using QIVs respectively. Around one-third of visits to a general practi- instead of TIVs would prevent 39,136 additional influenza tioner for otitis media were attributed to influenza type B. The cases, 1,648 additional hospitalisations and 458 additional number and rate of hospitalisations due to influenza B-attribut- deaths, annually. Differences in the model and in the underly- able respiratory disease was highest in 5–17 year-olds and ing assumptions likely account for the different estimates. exceeded that due to influenza A in some seasons. Four studies used dynamic models that incorporated effects of Over a 13-year period in Scotland (2000–2012), influenza B disease transmission and herd-protection in the model (Table 1). detections were close to, or exceeded influenza A detections for As a result, the estimates obtained from these models were higher 6 out of 13 seasons. than thosefrommore conservativestaticmodels: Crepey et al., Two studies in the UK have compared the impact of TIVs estimated that use of QIVs in the US would have averted 15.8% and QIVs in those  65 y of age and clinical at-risk groups, 68,71 more influenza B cases, or more than 6.2 million influenza cases and its implementation in the whole population. In a static (average 482,000 per year), than TIVs over the 13-year study model that considered vaccination of elderly and at-risk groups, period (2000–2013). Using a similar model, de Boer et al., esti- QIVs are expected to prevent a total of 183,844 cases, 4,871 mated that replacing TIVs with QIVs in the next 20 y (2014–2034) hospitalisations and 2,142 deaths due to influenza B over a 63 71 would reduce influenza B cases by 27.2%, or 16 million cases. cumulative 10-year time horizon. A separate study using a Mullikin et al., calculated influenza illnesses prevented by TIVs, dynamic model reported that vaccination of all age-groups QIVs (or an adjuvanted TIV in elderly with TIV in other ages) (current vaccine coverage rates) was estimated to prevent compared with no vaccination, and estimated that in an average 88,755 cases, 1,050 hospitalisations and 230 deaths due to influ- season with an average vaccine match (obtained using 1999–2014 enza B annually. US data), vaccination with QIVs would prevent 1,382,509 more ill- nesses than vaccination with TIVs (an estimate which is higher Germany than the upper range of that from Crepey et al. ), 18,354 hospital- isations and 2,981 deaths. Brogan et al., estimated that over a 10- In a prospective surveillance study of children 16 y of age year period, QIVs instead of TIVs would prevent 1,973,849 addi- hospitalised with acute respiratory infection, influenza B was tional influenza cases and 1,396 deaths annually. These studies associated with pneumonia in 36% of cases (5/14) and by myo- illustrate that although the impact of QIVs may vary in any influ- sitis in 7% (1/14). In the same study, influenza A infection enza season, the multi-year cumulative benefitofQIVsoverTIVs was associated with pneumonia in 25% (26/102) of cases, otitis are predicted to result in substantial societal benefit. This is partic- media in 25% (26/102) of cases, anaemia and syncope each in ularly true for a dynamic model that accounts for herd immunity. one case. Two studies used a simulation model that incorporated cross-immunising events and waning/boosting of immunity Canada 73,74 over a 20-year time horizon. One study estimated that com- B-lineage mismatches between the vaccine and circulating pared with TIVs, QIVs would prevent 11.2% more influenza B strain occurred in 7 out of 15 seasons in Canada between cases. Each year this would reduce the annual number of 1646 R. RAY ET AL. influenza cases by 3.6% in 0–15 y olds, 4.0% in 16–60 y olds, that QIVs would have prevented an estimated 1,624,533 influ- 6.9% in those aged  61 y and 4.3% (or 395,000 cases) overall. enza cases, 37,317 hospitalisations and 14,866 deaths. The The second study estimated that QIVs would prevent 4% majority of hospitalisations and almost all deaths prevented more influenza cases, 5.7% more hospitalisations and 6.4% would have been in high-risk groups or the elderly. more deaths than TIVs. Hong Kong Finland Using hospital records to identify laboratory-confirmed influ- A dynamic model using data from the 2000 to 2009 influenza enza cases between 2000–2010, Chan et al., estimated that the seasons estimated that in the Finnish population, QIVs would average annual incidence of hospital admission (all ages) due to prevent 40,500 cases, 360 hospitalisations and 54 deaths each influenza B was 20.6/100,000 population. The highest annual year compared with TIV. The number of cases was estimated hospitalisations rates were in children < 5 y and 5–9 y of age to be even further reduced if the QIV used in 2–18 y olds was (median 238/100,000 and 152/100,000, respectively). Both LAIV4. influenza B lineages co-circulated for 9 out of the 10 study years. In the 6 y where a single influenza B lineage predomi- nated (defined as > 80% of identified strains), a mismatch Belgium between the predominant B-strain and the vaccine strain Extending the current Belgian influenza immunisation strategy occurred in 4. Modeling using Hong Kong death statistics and from individuals at-risk (including those aged 50 y or over) to sentinel laboratory surveillance between 1998–2009 estimated include children 2–17 y of age was assessed in a dynamic an annual excess mortality of 2.5/100,000 person-years due to model. Assuming 50% coverage of QIVs among 2–17 y olds, influenza B, increasing to 20.3/100,000 person-years in adults 2.95 million cases of influenza were calculated to be averted aged  65. over a 10-year period compared with no vaccination of this age Static models estimated that compared with TIVs, QIVs group. Most (63%, or 1,869,582) of these averted cases were used at all ages would prevent 91 influenza illnesses per due to indirect effects in adults in whom vaccine coverage rates 100,000 population, 1.8/100,000 hospitalisations and 0.046/ with TIV were assumed to be unchanged. Of a total of 16,968 100,000 deaths over 1 y (Table 1). Vaccination of  65 year- averted hospitalisations and 1,455 averted deaths, 11,567 and olds with QIV between 2001 and 2009 is estimated to have pre- 1,455, respectively, were in adults. vented 191.3 influenza illnesses per 100,000 population in elderly, with the highest reduction in those aged  80 y (reduc- tion of 451.4 illness per 100,000 population). Spain Switching from TIVs to QIVs in at-risk individuals from 3 y of Australia age and in those aged 65 y and over was estimated to prevent an additional 18,565 influenza cases, 407 hospitalisations and The 2015 influenza season in Australia was dominated by influ- 77 84 181 deaths in the first year after implementation. enza B, which accounted for 62% of all cases notified; 38% of influenza B isolates were the B/Victoria lineage not included in the 2015 southern hemisphere TIVs. The highest influenza B Italy notification rate was in children 5–9 y of age, followed by 0–4y QIVs were introduced in Italy for the 2015/16 season. Assum- and 0–14 y. ing that QIVs were used in 9% of the population targeted by A static model using 2003–2013 data from a single town in the national immunisation program (all individuals at risk and Western Australia estimated that compared with TIVs, QIVs those aged  65 y), 1,601 additional cases of uncomplicated would reduce influenza illness by 3.8%, hospitalisations by influenza and 1,031 additional cases of complicated influenza 2.2% and deaths by 2.1%. The authors noted that there was a were estimated to be averted compared with TIVs used alone. good match between the vaccine and circulating lineages dur- ing the study period in Australia, under which scenario the benefit of QIVs over TIVs is marginal. The same study also France investigated the impact of QIVs over TIVs in a rural area of By switching from QIVs to TIVs in France during an average South Africa, and reported a greater impact due to a higher epidemic season between 2003 and 2012, it was estimated that degree of mismatch in the seasons studied (Table 1). 6,214 consultations for influenza, 614 additional hospitalisa- A second static model estimated that the use of QIVs instead tions and 372 deaths would have been averted. of TIVs in children and adults at-risk for influenza (eligible for free vaccination as defined in the Australian Immunisation handbook) between 2002 and 2012, would have reduced influ- European Union enza cases, hospitalisations and deaths by 1.02% (68,271), 2.4% A static model using data from France, Germany, Italy, Spain (n D 3,522) and 3.7% (n D 683), respectively. The highest and the UK, estimated that replacement of TIVs with QIVs impact of QIV was in young children and the elderly. In adults during 2002–2013 (2009 season excluded) would have pre- aged 65 y and over, QIVs were estimated to prevent an addi- vented 1,034,727 additional influenza cases, 24,453 hospitalisa- tional 10.1 hospitalisations and 2.1 deaths per 100,000 person- tions and 9,799 deaths. Extrapolation to the 27-EU suggested years over TIVs. HUMAN VACCINES & IMMUNOTHERAPEUTICS 1647 Table 2. Current recommendations for influenza vaccination using quadrivalent seasonal influenza vaccines (QIVs). Countries/authorities with permissive recommendations Year recommended Age/group indicated for QIVs for QIVs use World Health Organization 2012 Pregnant women, Children <5 y, Health care workers, Elderly >65 y, Chronic conditions Germany 2013 Pregnant women, Children <5 y, Health care workers, Elderly >65 y, Chronic conditions United States 2013 Children (6 months) & Adults Hong Kong 2013 Children ( 3 y) & Adults Canada 2014 From 6 months of age Italy 2014 Children ( 3 y) & Adults France 2014 Children ( 3 y) & Adults Belgium 2015 From age 2 y Brazil 2014 Elderly 60C y Countries preferentially recommending QIVs United Kingdom 2013 Children 2–7 y and children at risk 2–18 y. Germany 2014 All long-distance travelers Brazil 2015 Elderly Australia 2015 From 6 months of age QIV D quadrivalent seasonal influenza vaccine (LAIV or IIV4) Current recommendations for QIVs from clinical trials and observational studies suggest that B- mismatched seasons are accompanied by a higher public health Since licensure of the first QIV in 2012, an increasing number 15,51 burden than well-matched seasons. Although the risk of of countries use QIVs either permissively (TIVs or QIVs), or breakthrough influenza A from vaccine strain mismatch preferentially (TIVs available but QIVs preferred) (Table 2). remains, the risk of breakthrough influenza B from vaccine However, while several supranational organisations acknowl- lineage mismatch can be eliminated by QIV. edge that QIVs may improve protection against influenza B Brazil is unique with regards to the pattern of influenza and strains compared with TIVs, at this time, most health authori- viral circulating in this heterogeneous climate. A recent review ties do not preferentially recommend one over the other paper highlighted that over a 9 y follow-up period, influenza B (Table 2). Health authorities are generally concerned that with lineages circulated in 3 seasons, of which, during one season, a trend toward an increased influenza vaccine uptake overall, there was a high degree of mismatch between the vaccine line- preferential recommendations may be counterproductive if a age and the predominant circulating lineage (91.4% [2013]). preferred product is not sufficiently manufactured and supplied Within tropical and sub-tropical regions such as Brazil, influ- to cover the entire population to be vaccinated. enza B can have protracted circulation patterns and co-circula- After successful pilot programmes in 2013 and 2014, influ- tion of both B-lineages may not be uncommon, thus further enza vaccination using LAIV4 is now offered to 2–4 y old highlighting the added value of QIVs in these countries. school children in the UK, as well as to at-risk groups from 6 Modeling the impact of QIVs over TIVs is challenging, not month to 17 y of age. This innovative initiative aims to reduce least because of the unpredictable disease burden that differs disease incidence in children and transmission to older age- markedly from year-to-year. As might therefore be antici- groups, thereby achieving societal benefit at the overall popula- pated, evaluations from different countries all show very large tion level. variability in the seasonal impact of QIVs. Analyses that project cumulative effects over multiple seasons based on antecedent virus circulation patterns are therefore most informative. The Conclusions published dynamic models showed substantially greater Although varying from year-to-year, on average, influenza B improvement in health outcomes based on the use of QIVs as causes up to one-third of influenza infections each season. A compared with the more conservative static models. However, large body of evidence from numerous countries demonstrates although dynamic models better reflect the real-world impact that influenza B accounts for a significant proportion of the of vaccination, dynamic transmission models are inherently overall burden of influenza that inundates healthcare services more complex and require a greater degree of assumptions in annually. Once thought to cause predominantly mild illness, terms of model inputs. numerous studies now indicate that there is little difference in Influenza vaccines typically show reduced efficacy in the the clinical symptomatology and outcomes of influenza B vs. A. elderly due to immune senescence and novel TIVs developed Hospitalisations and mortality attributable to influenza B may for use in this age-group include an increased antigen dose or have previously been underestimated, with studies reporting adjuvant to overcome this limitation. Modeling studies suggest higher mortality following influenza B infection than A in that the benefits of enhanced TIV formulations in the elderly 13,89-91 some years. In parallel, the 2 influenza B lineages fre- (high-dose or adjuvanted TIVs) may be as great, or greater 60,61,64 quently co-circulate, and due to the complexity involved in than those provided by QIVs. This underscores the fact accurately forecasting which B viruses will circulate, mis- that in older adults, improvements in vaccine efficacy can be matches between the B strain selected for TIVs and circulating achieved by improving the immune response and by broaden- 4,92 strains have occurred in up to one-half of seasons. Evidence ing coverage. However, even with high-dose TIV, efficacy 1648 R. RAY ET AL. against influenza B due to the lineage included in the vaccine References is clearly higher than efficacy against influenza B due to the [1] McCauley J, Hongo S, Kaverin N, Kochs G, Lamb R, et al. 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Fluzone Quadrivalent and Fluzone org/10.1542/peds.2013-1493 Intradermal Quadrivalent are trademarks of Sanofi Pasteur. [8] Hannoun C. The evolving of influenza viruses and influenza vac- Flumist Quadrivalent and Fluenz Tetra are trademarks of cines. Expert Rev Vaccines 2013; 12:1085-94; PMID:24024871; https://doi.org/10.1586/14760584.2013.824709 AstraZeneca. [9] Shaw MW, Xu X, Li Y, Normand S, Ueki RT, Kunimoto GY, Hall H, Klimov A, Cox NJ, Subbarao K. Reappearance and global spread of variants of influenza B/Victoria/2/87 lineage viruses in Disclosure of potential conflicts of interest the 2000–2001 and 2001–2002 seasons. Virology 2002; 303:1-8; PMID:12482653; https://doi.org/10.1006/viro.2002.1719 Riju Ray, Rafik Bekkat-Berkani, Philip O. Buck, Carine Claeys and [10] Belshe RB. The need for quadrivalent vaccine against seasonal influ- Gonc ¸alo Matias are employees of the GSK group of companies. Bruce L. enza. Vaccine 2010; 28:Suppl 4:D45-53; PMID:20713260; https:// Innis reports he was employed by the GSK group of companies at the time doi.org/10.1016/j.vaccine.2010.08.028 of the study and is now an employee of PATH. Riju Ray, Rafik Bekkat-Ber- [11] Skowronski DM, De Serres G, Dickinson J, Petric M, Mak A, Fon- kani, Philip O. Buck, Carine Claeys and Bruce L. Innis report ownership of seca K, Kwindt TL, Chan T, Bastien N, Charest H, et al. Compo- stock options and/or restricted shares in the GSK group of companies. nent-specific effectiveness of trivalent influenza vaccine as Ga€el Dos Santosreports he was employed by Business & Decision Life Sci- monitored through a sentinel surveillance network in Canada, ences (on behalf of GSK) at the time of the study and is now employee of 2006–2007. J Infect Dis 2009; 199:168-79; PMID:19086914; https:// the GSK group of companies. doi.org/10.1086/595862 [12] Caini S, Huang QS, Ciblak MA, Kusznierz G, Owen R, Wangchuk S, Henriques CMP, Njouom R, Fasce RA, Yu H, et al. Epidemiologi- cal and virological characteristics of influenza B: Results of the Acknowledgments Global Influenza B Study. Influenza Other Respir Viruses 2015; 9: The authors thank Philippe Buchy for critically reviewing the manuscript. Suppl 1:3-12; PMID:26256290; https://doi.org/10.1111/irv.12319 The authors also thank Joanne Wolter (Independent medical writer, on [13] Lo Y-C, Chuang J-H, Kuo H-W, Huang W-T, Hsu Y-F, Liu M-T, behalf of GSK) for providing writing services, and Bruno Dumont and Chen C-H, Huang H-H, Chang C-H, Chou J-H, et al. 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Journal

Human Vaccines & ImmunotherapeuticsTaylor & Francis

Published: Jul 3, 2017

Keywords: influenza; influenza B; mismatch; quadrivalent influenza vaccine

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