Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents

Vaccine xxx (xxxx) xxx

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Review

Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents Chenyang Huang a, Xiaofang Fu a, Yuqing Zhou a, Fenfang Mi b, Guo Tian a, Xiaoxiao Liu a, Jie Wu a, Cheng Ding a, Danying Yan a, Lanjuan Li a, Shigui Yang a,⇑ a State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China b Zhejiang Chinese Medical University, Hangzhou 310053, China

a r t i c l e

i n f o

Article history: Received 24 June 2019 Received in revised form 31 October 2019 Accepted 25 November 2019 Available online xxxx Keywords: Quadrivalent inactivated influenza vaccine Trivalent inactivated influenza vaccine Immunogenicity Safety

a b s t r a c t Background: Children and adolescents are susceptible to influenza. Vaccination is the most important strategy for preventing influenza, yet there are few studies on the immunogenicity and safety of quadrivalent inactivated influenza vaccine (QIV) containing two A strains (H1N1 and H3N2) and two B lineages (Victoria and Yamagata). Therefore, to further clarify the immunogenicity and safety of QIV in children and adolescents, a meta-analysis was performed to provide a reference for the development of influenza prevention strategies. Methods: PubMed, EMBASE and Cochrane Library were searched for articles published as of February 12, 2019. Random clinical trials comparing the immunogenicity and safety of QIV and TIV among children and adolescents were selected. The main outcomes were comparisons of immunogenicity (seroprotection rate [SPR] and seroconversion rate [SCR] and adverse events using risk ratios (RRs). The meta-analysis was performed using random-effects models. Results: Among the 6 months up to 3 years group, QIV showed a higher SPR for B lineages than for TIV-B/ Yamagata, with pooled RRs of 3.07 (95% CI: 2.58–3.66) and 1.06 (95% CI: 1.01–1.11), respectively. For the 3 years through 18 years, QIV had a higher SCR and SPR for the Yamagata lineage than for TIV-B/Victoria, with pooled RRs of 2.30 (95% CI: 1.83–2.88) and 1.16 (95% CI: 1.03–1.30), respectively. Compared to TIVB/Yamagata, a higher SCR and SPR for the Victoria lineage was found for QIV, with RRs of 3.09 (95% CI: 1.99–4.78) and 1.72 (95% CI: 1.22–2.41), respectively. Regarding adverse events, only pain was more frequently reported for QIV than TIV ; the RR was 1.09 (95% CI: 1.02–1.17). Conclusions: The immunogenicity of QIV for common ingredients was similar to that of TIV, but the former exhibited significantly higher immunogenicity for the unique lineage. QIV also had the same reliable safety as TIV. Ó 2019 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcome measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Quality of included studies and bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: QIV, influenza quadrivalent inactivated vaccine; TIV, influenza trivalent inactivated vaccine; SCR, seroconversion rate; SPR, seroprotection rate.

⇑ Corresponding author.

E-mail address: [email protected] (S. Yang). https://doi.org/10.1016/j.vaccine.2019.11.071 0264-410X/Ó 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

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C. Huang et al. / Vaccine xxx (xxxx) xxx

7.

8. 9.

Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Immunogenicity among children aged 6 months up to 3 years (not including 3 years) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Immunogenicity among subjects aged 3 years through 18 years (including 3 years and 18 years) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding source. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRediT authorship contribution statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Supplementary material. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Influenza is an acute respiratory infection that affects 3–5 million people worldwide each year, and approximately 65,000– 290,000 deaths are caused each influenza season by related complications. Overall, influenza results in substantial economic and medical burdens worldwide [1]. Studies have reported that children, pregnant women and elderly individuals have a high risk of contracting influenza, with hospitalized patients having the highest risk [2–4]. Vaccination against influenza remains the most effective strategy and method for preventing influenza transmission and influenza-related morbidity and mortality, even though the influenza vaccine has a variable protection rate in some influenza seasons [5]. For example, the protection rate of TIV among the susceptible population is 71% to 77% when the dominant influenza virus strain and influenza vaccine strain match, whereas vaccination protection only reaches 25% to 28% in the case of mismatch [6,7]. Based on data provided by the Global Influenza Surveillance and Response System, the World Health Organization (WHO) annually selects vaccine strains and regularly adjusts the vaccine composition [6]. To date, the most widely used vaccine is TIV, which includes A (A/H1N1 and A/H3N2) and B (B/Yamagata or B/Victoria). However, the two different subtypes of the influenza B virus (Yamagata and Victoria) have varying degrees of combined cycle prevalence during each influenza season worldwide. During the 2001–2002 and 2010–2011 influenza seasons, more than half of the dominant lineages were Yamagata, which contributed significantly to influenza morbidity [8]. To solve the problem of mismatch between influenza B virus strains, a quadrivalent inactivated influenza vaccine (QIV) that includes influenza A/H3N2, A/H1N1, B/Victoria and B/ Yamagata has been developed. QIV provides reliable prevention and control in different influenza seasons [9] and has the same safety and immunogenicity as TIV [10]. Furthermore, QIV was recommended by the WHO for preventing influenza B in 2012 and was approved for vaccinating children over the age of 3 years, adults and elderly individuals by the US Food and Drug Administration in 2013 [11,12]. Studies have demonstrated that QIV can induce a better immune response than TIV to the B lineage, without affecting the immunogenicity of the other ingredients [12,13]. Additionally, a meta-analysis showed that QIV has immunogenicity equal to that of TIV but is superior against the non-TIV-B lineage in adults [10]. The National Advisory Committee on Immunization (NACI) of Canada recommended children and adolescents to use QIV as

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influenza vaccine first [14]. However, the use of QIV is not first especially recommended for children by the world’s leading vaccine academic institutions, such as WHO, ACIP (Advisory Committee on Immunization Practices), CDC (Centers for Disease Control and Prevention), JCVI (Joint Committee on Vaccination and Immunisation) and ATAGI (Australian Technical Advisory Group on Immunisation) [15–20]. So far, there are few studies on the immunogenicity and safety of QIV containing two A strains (H1N1 and H3N2) and two B lineages (Victoria and Yamagata). Therefore, this systematic review and meta-analysis was performed to determine the safety and immunogenicity of QIV in children and adolescents relative to TIV to provide data for strategy recommendations for influenza vaccination.

2. Methods 2.1. Data sources We searched PubMed, EMBASE and Cochrane Library for the published articles available as of February 12, 2019. The following search terms were used: ‘‘(quadrivalent OR tetravalent) AND (influenza OR flu) AND vaccine”. In addition, we browsed particularly relevant journals such as Vaccine and consulted the references of the obtained information. The inclusion criteria in this study were as follows. (1) The study population comprised healthy children and adolescents aged from 6 months to 18 years (6 months and 18 years included). (2) The design included an experimental QIV group and a control group including TIV-B/Victoria (containing A/H1N1, A/H3N2 and B/Victoria) or TIV-B/Yamagata (containing A/H1N1, A/H3N2 and B/Yamagata). (3) QIV contained 15 mg each of the A/H1N1, A/ H3N2, B/Victoria and B/Yamagata, and TIV contained 15 mg each of the A/H1N1 and A/H3N2 and 15 mg of the B/Victoria or B/Yamagata. (4) Both QIV and TIV contained 15 mg hemagglutinin of each ingredients for a 0.5 ml dose or 7.5 mg haemagglutinins for a 0.25 ml dose intramuscularly. The exclusion criteria included the following: (1) animal studies, experimental studies, and observational epidemiologic studies; (2) studies conducted in adults and in immunocompromised patients; (3) studies in which the data were incomplete, with the number of participants tested for serum not indicated, with the number of inoculations not indicated, or with data required for the study not obtained; and (4) studies in which the vaccine protein consisted of subunits, whole (live attenuated) viruses or a recombinant protein.

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

C. Huang et al. / Vaccine xxx (xxxx) xxx

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Fig. 1. Flow diagram for the study selection. QIV: quadrivalent influenza inactivated vaccine, TIV: trivalent influenza inactivated vaccine.

3. Data extraction Two independent investigators carefully read the titles and abstracts of the publications. The data were then extracted in strict accordance with the inclusion criteria; the data included basic information regarding the literature (i.e., first author, publication date, article name, title, study period, research method, and clinical trial number) and basic data (i.e., country region, sample size, age at vaccination, vaccination type, virus strain, blood collection, time, test method and evaluation standard). In the case of disagreement, the authors either came to an agreement after discussion or consulted a third party. Where indicated, additional information was requested from the authors of the study via email. If no data were required for the analysis, we restored the required information based on the data provided in the study. 4. Outcome measures The main outcomes we observed were comparisons of the immunogenicity and adverse events after injection between QIV and TIV. The immunogenicity of the A/H1N1, A/H3N2, B/Victoria and B/ Yamagata, as determined by seroconversion rate (SCR) and seroprotection rate (SPR), was evaluated in the QIV and TIV groups. SCR was defined as the percentage of participants with hemagglutination inhibition (HI) antibody titer < 1:10 at prevaccination (day

0) and 1:40 at postvaccination (day 28) or >1:10 at prevaccination (day 0) and a  4-fold increase in antibody titer at postvaccination (day 28). SPR was defined as the proportion of subjects who achieved seroprotection with an HI antibody titer  1:40 at day 28 vaccination [21]. If research data could not be obtained from the entire study, we extracted data for a subgroup for comparison or indirectly extracted the data by modeling the u distribution based on the geometric mean titer of the antibody (Appendix 2). Considering that children and adolescents respond differently to vaccines at different stages of growth and development [22,23], the individuals were divided into two age groups of 6 months up to 3 years (not including 3 years) and 3 years through 18 years (including 3 years and 18 years) to obtain a detailed understanding of the immunogenicity of children and adolescents after injection with QIV or TIV. Comparisons of adverse events between QIV and pooled TIV (TIV-B/Victoria and TIV-B/Yamagata) within 7 days of vaccination and the incidence of unsolicited adverse events after 28 days were performed. Injection-site adverse effects (AEs) included pain, redness and swelling, and solicited systemic reactions included drowsiness, fever, irritability and loss of appetite. 4.1. Statistical analysis We classified and organized the data contained in the articles extracted. We combined dichotomous data with the relative risk

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

4

Study

Country

Type of study

Total number of subjects vaccinated

Study period

Age

QIV

Vaccine strains in QIV

Vaccine strains in TIV

Vaccine manufacturer

reported adverse events

Long Wang et al. [29]

USA

Phase II, observer-blind multi-center

280

2013.10– 2014.06

6–35 months

QIV(inactivated splitvirion)

A/California/7/2009/ (A/H1N1)

A/California/7/2009 (A/H1N1)

QIV, GlaxoSmithKline,

A/Texas/50/2012/ (A/H3N2)

A/Texas/50/2012 (A/H3N2)

Vaccines, Biomedical

B/Brisbane/60/2008/ (B/Victoria)

B/Massachusetts/2/ 2012 (B/Yamagata)

Corporation, Sainte-Foy,

Solicited injection site symptoms Solicited general symptoms Unsolicited adverse reactions Serious adverse events Sanofi Pasteur, Swiftwater, PA Solicited injection site symptoms Unsolicited adverse reactions Serious adverse event

B/Massachusetts/2/ 2012/(B/Yamagata)

Joanne M et al. [31]

Canada,

Phase II,

Dominican

double-blind,

601

2012.11.– 2013.06

6–35 months

QIV(inactivated

A/California/7/2009 (H1N1)pdm09

A/California/7/2009 (H1N1)pdm09

QIV, GlaxoSmithKline

split-virion)

A/Victoria/361/2011 (H3N2)

A/Victoria/361/ 2011(H3N2)

Quebec, Canada

B/Brisbane/60/2008 (Victoria)

B/Massachusetts/2/ 2012 /(B/ Yamagata)

TIV, Dresden,

Honduras

Stephanie Pepin et al. [35]

Jin Lee et al. [27]

Quebec, Canada; TIV,

Germany, Fluarix

B/Hubei-Wujiagang/ 158/2009 (Yamagata) A/Brisbane/59/2007 (H1N1)

A/Brisbane/59/ 2007/ (H1N1)

QIV and TIV

Latin America

A/Uruguay/716/07 (H3N2)

A/Uruguay/716/07 (H3N2)

GlaxoSmithKline,

Europe

B/Brisbane/60/2008 (B/Victoria)

B/Brisbane/60/ 2008 (B/Victoria)

Vaccines Dresden, Germany

Africa

B/Brisbane/3/2007 (B/Yamagata) A/California/7/2009 (H1N1)

A/California/7/2009 (H1N1)

QIV and TIV

A/Switzerland/ 9715293/2013 (H3N2) B/Phuket/3073/ 2013(B/Yamagata)

Green Cross Corporation;

A/California/7/ 2009,A/ Switzerland/9715 293/2013,B/ Brisbane/60/2008 (B/Victoria) or B/Phuket/3073/ 2013(B/Yamagata)

QIV, Jiangsu, GDK,

Asia

Korea

Phase III, observer-blind,

Phase III, double-blind, multi-center

620

528

2014.03– 2016.06

2015.10– 2016.03

6–35 months

6 months19 years

QIV(inactivated splitvirion)

EggCultivated Quadrivalent (inactivated split-virion)

A/Switzerland/ 9715293/2013 (H3N2) B/Phuket/3073/2013

B/Brisbane/60/2008. Shi-Yuan et al. [28]

China

Phase II, double-blind,

1355

2016.01– 2016.08

3–17 years

QIV(inactivated splitvirion)

A/California/7/2009, A/Switzerland/ 9715293 /2013,B/Brisbane/ 60/2008, B/Phuket/3073/2013

Biotechnology,

Solicited injection site symptoms Solicited general symptoms Unsolicited adverse reactions Serious adverse events Solicited injection site symptoms Solicited general symptoms Unsolicited adverse reactions Serious adverse events Solicited injection site symptoms Solicited general symptoms

C. Huang et al. / Vaccine xxx (xxxx) xxx

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

Table 1 Study characteristics of included studies.

Study

Joseph B et al. [33]

Country

Type of study

TIV, Changsheng Co

unsolicited adverse reactions

USA,Czech

Phase III, double-blind, multicenter

Total number of subjects vaccinated

2738

Study period

2010.10– 2011.06

Age

3–17 years

QIV

QIV(inactivated splitvirion)

Vaccine strains in QIV

Vaccine strains in TIV

Vaccine manufacturer

Serious adverse events QIV and TIV

A/H1N1(A/ California/7/2009)

A/H1N1(A/ California/7/2009)

A/H3N2(A/Victoria/ 210/2009)

A/H3N2 (A/ Victoria/210/2009)

GlaxoSmithKline

B/Brisbane/60/2008 (B/Victoria) Brisbane/3/2007 (B/ Yamagata) A/H1N1(A/ California/7/2009) A/H3N2 (A/Victoria/ 210/2009)

B/Brisbane/60/ 2008(B/Victoria)or B/Brisbane/3/2007 (B/Yamagata). A/H1N1(A/ California/7/2009) A/H3N2 (A/ Victoria/210/2009)

Vaccines in Dresden, Germany

B/Brisbane/60/2008 B/Brisbane/3/2007 A/California/07/2009 (H1N1)

B/Brisbane/60/ 2008 or B/Brisbane/3/2007 A/California/07/ 2009(H1N1)

A/Victoria/210/2009 (H3N2)

A/Victoria/210/ 2009 (H3N2)

Sanofi Pasteur,

B/Brisbane/60/2008 (B Victoria)

B/Brisbane/60/ 2008(B/Victoria) or

Swiftwater, PA

B/Florida/04/2006 (B Yamagata) A/California/7/2009 (H1N1)

B/Florida/04/2006 (B/Yamagata) A/California/7/2009 (H1N1)

Finland

A/Texas/50/2012 (H3N2)

A/Texas/50/2012 (H3N2)

TIV, Vaxigrip,

Mexico

B/Brisbane/60/2008 (B/Victoria)

B/Brisbane/60/ 2008(B/Victoria)or

Sanofi Pasteur

Taiwan

B/Massachusetts/02/ 2012 (B Yamagata)

B/Massachusetts/ 02/2012 (B/Yamagata)

Lyon, France.

France

reported adverse events

Unsolicited adverse reactions Serious adverse events

GermanyPhilippines

Joanne M et al. [34]

USA,

Phase III, double-blind , controlled

3094

2010.10– 2011.06

3–17 years

QIV(inactivated splitvirion)

Canada,

Mexico

David P et al. [32]

Stephanie Pepin et al. [30]

SpainTaiwan USA

Poland,

Phase III, observer-blind 3-arm, multi-center

Phase III, doubleblindactive- controlled, multi-center

4348

1255

2010.11– 2012.06

2013.09– 2013.11

6 months8 years

3–8 years

QIV(inactivated splitvirion)

QIV(inactivated splitvirion)

QIV, GlaxoSmithKline, Vaccines, Dresden, Germany. TIV, Dresden, Germany,

Serious adverse events

QIV and TIV

Solicited injection site symptoms Solicited general symptoms Unsolicited adverse reactions serious adverse events Solicited injection site symptoms Solicited general symptoms Unsolicited adverse reactions Serious adverse events

QIV, GlaxoSmithKline,

C. Huang et al. / Vaccine xxx (xxxx) xxx

QIV: quadrivalent inactivated influenza vaccine; TIV: trivalent influenza inactivated vaccine; H1N1 or A/H1N1: influenza A subtype; H3N2 or A/H3N2: influenza B subtype; B/Victoria lineage; B/Yamagata lineage.

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Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

Table 1 (continued)

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C. Huang et al. / Vaccine xxx (xxxx) xxx

Fig. 2a. Seroconversion rate (SCR) for QIV versus TIV-B/Yamagata at day 21 postvaccination (children from 6 months up to 3 years).

(RR) of the SCR, SPR and adverse reaction rates; the combined effects are presented by forest maps with bias RRs and 95% CIs. Studies with small sample sizes, which may cause publication bias, were evaluated using funnel plots. We assessed the heterogeneity of the original documents using the I2 test [24], whereby an I2 value of more than 75% indicated high heterogeneity; in such cases, the random effects model was applied. If heterogeneity was due to race, age or region, subgroup analysis or sensitivity analysis, sources were identified. A p-value<0.05 was considered statistically significant. Review Manager Version 5.3 software was used in this study[25].

was completed independently by two reviewers. If the reviewer opinions were inconsistent, a third party decided. 6. Sensitivity analysis By sequentially deleting individual studies, we carefully observed the effects of individual studies on the RR values of the effect size and the impact on the amount of combined effects. If the total result changed significantly after eliminating a study or some studies, we considered whether to exclude that study or more studies. In addition, if the heterogeneity was significantly reduced after deleting a study, the study was considered to be the main source of heterogeneity and was further evaluated.

5. Quality of included studies and bias 7. Results To reduce the system bias generated by small-sample studies, we used the Cochrane risk bias tool to evaluate the quality of randomized controlled trials (RCTs) among the included studies [26]. The risk of selection bias, implementation bias, measurement bias, follow-up bias, and reporting bias a given study were evaluated in detail, and a bias-risk summary graph was generated. The process

A total of 2021 articles were retrieved in the initial search. After review of titles and abstracts and removal of duplicates, 17 articles remained for full review. The diagram of the study selection workflow is shown in Fig. 1. Nine RCTs that met the inclusion criteria were included, with 14,819 children and adolescents, in the final

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Fig. 2b. Seroprotection rate (SPR) for QIV versus TIV-B/Yamagata at day 21 postvaccination (children from 6 months up to 3 years).

meta-analysis [27–35]. The characteristics of the nine studies are described in Table 1. Of the 9 studies included, three [29,32,35], were observer blind, and the others were double blind. Overall, approximately 2% of participants withdrew from clinical trials and were lost during follow-up for various reasons, which had no significant effect on outcomes. The details provided for participants in the clinical trials included demographic characteristics, vaccination status (including unprimed children and primed children, and their definition criteria were the same) and regional characteristics. In addition, the measurement of immunogenicity indicators in all studies was consistent. Therefore, the research bias as a whole was accepted and overwhelmingly low, including selection bias, implementation bias, measurement bias and reporting bias. The specific quality evaluation of the included studies is shown in Appendix 1.

7.1. Immunogenicity among children aged 6 months up to 3 years (not including 3 years) Among the population inoculated with QIV or TIV-B/Yamagata, the SCRs for the A/H1N1, A/H3N2, B/Victoria and B/Yamagata were directly reported in four studies and indirectly extracted by modeling for one study (Appendix 2). The SCRs for the H1N1, H3N2 and B/Yamagata were not significantly different between QIV and TIV-B/Yamagata, athough QIV had a significantly higher SCR for the B/Victoria lineage, with a pooled RR of 4.74 (95% CI: 2.76– 8.14, p < 0.00001) (Fig. 2a).

A total of 3 studies reported the SPRs for the A/H1N1, A/H3N2, B/Victoria and B/Yamagata in the population inoculated with QIV or TIV-B/Yamagata. Although the SPRs for H1N1 and H3N2 were not significantly different between QIV and TIV-B/Yamagata, compared to TIV-B/Yamagata, QIV had a significantly higher SPR for both the Victoria and Yamagata lineage, with pooled RRs of 3.07 (95% CI: 2.58–3.66, p < 0.00001) and 1.06 (95% CI: 1.01–1.11, p = 0.03), respectively (Fig. 2b). There were only two primary studies for inoculation with QIV or TIV-B/Victoria, and a further meta-analysis was not conducted. However, according to indirect extraction modeling Pepin’s study [35], QIV was superior to TIV-B/Victoria with regard to the SCRs for B/Yamagata lineage, with an RR of 2.07 (95% CI: 1.77–2.42, p < 0.00001). In contrast, the SCRs for H1N1, H3N2 and B/Victoria were not significantly different between QIV and TIV-B/Victoria. In addition, the immunogenicity of the A/H1N1, A/H3N2, B/Victoria and B/Yamagata was compared between QIV and pooled TIV (integrated B/Victoria and B/Yamagata). Although the SCRs for the H1N1, H3N2 and B/Yamagata were not significantly different between QIV and pooled TIV, QIV showed a higher SCR for the B/ Victoria lineage, with a pooled RR of 2.31 (95% CI: 1.07–4.97, p = 0.03) (Appendix 3). 7.2. Immunogenicity among subjects aged 3 years through 18 years (including 3 years and 18 years) Among the population inoculated with QIV or TIV-B/Victoria, four studies reported SCRs for the A/H1N1, A/H3N2, B/Victoria

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

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Fig. 3a. Seroconversion rate (SCR) for QIV versus TIV-B/Victoria at day 21 postvaccination (children and adolescents aged 3 years through 18 years).

and B/Yamagata; one study [30] only reported SCRs for A/H1N1, A/ H3N2 and B/Victoria. The SCRs for the H1N1 and Victoria did not differ significantly between QIV and TIV-B/Victoria. Nonetheless, compared to TIV-B/Victoria, QIV exhibited a significantly higher SCR for the Yamagata lineage; the pooled RR was 2.30 (95% CI: 1.83–2.88, p < 0.00001). Additionally, a higher SCR for the H3N2 was observed for QIV, with a pooled RR of 1.04 (95% CI: 1.01– 1.07, p = 0.01) (Fig. 3a). Four studies reported SPRs for the A/H1N1, A/H3N2, B/Victoria and B/Yamagata in the population inoculated with QIV or TIV-B/ Victoria. The SPRs for the H1N1, H3N2, and B/Victoria were not significantly different between QIV and TIV-B/Victoria, although QIV had a higher SPR for the Yamagata lineage, with a pooled RR of 1.16 (95% CI: 1.03–1.30, p = 0.02) (Fig. 3b). For those inoculated with QIV or TIV-B/Yamagata, apart from one study [31] that only reported SCRs for the A/H1N1, A/H3N2 and B/Yamagata, six studies reported SCRs for the A/H1N1, A/

H3N2, B/Victoria and B/Yamagata. The SCRs for the H1N1, H3N2 and Yamagata did not differ significantly between QIV and TIV-B/ Yamagata, although QIV had a significantly higher SCR for the Victoria lineage, with an RR of 3.09 (95% CI: 1.99–4.78, p < 0.00001) (Fig. 4a). Five studies reported SPRs for the quadrivalent in the population inoculated with QIV or TIV-B/Yamagata. The SPRs for the H1N1, H3N2 and Yamagata were not significantly different between QIV and TIV-B/Yamagata, however, QIV had a higher SPR for the Victoria, with an RR of 1.72 (95% CI: 1.22–2.41, p = 0.002) (Fig. 4b). Furthermore, when comparing the immunogenicity of QIV with that of pooled TIV (integrated B/Victoria and B/Yamagata), the SCRs for the H1N1 and H3N2 did not differ significantly. Higher SCRs for both the Victoria and Yamagata lineage, with pooled RRs of 1.36 (95% CI: 1.07–1.73, p = 0.01) and 1.25 (95% CI: 1.06–1.47, p = 0.009), respectively (Appendix 4), and a higher SPR for the

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

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Fig. 3b. Seroprotection rate (SPR) for QIV versus TIV-B/Victoria at day 21 postvaccination (children and adolescents aged 3 years through 18 years).

H1N1, with a pooled RR of 1.13 (95% CI: 1.02–1.25, p = 0.02), were found for QIV (Appendix 5).

7.3. Safety Among the nine included studies, seven [27–32,35] reported solicited injection-site symptoms, six [27–30,32,35] reported solicited general symptoms, eight [27–30,32–35] reported unsolicited adverse reactions, and nine reported serious adverse events. The occurrence of solicited injection-site symptoms, solicited general symptoms, unsolicited adverse reactions and serious adverse events were not significantly different between QIV and pooled TIV (Appendix 6). Solicited injection-site symptoms and pain were the most common occurrences in children. The occurrence of fever and irritability did not differ significantly between QIV and pooled TIV, although a significantly higher occurrence of pain, with an RR of 1.09 (95% CI: 1.02–1.17, p = 0.02), was associated with QIV (Appendix 7). In addition, three studies reported serious adverse events in the subgroup of children under 3 years of age. The occurrence of serious adverse events was not significantly different between QIV and pooled TIV.

7.4. Sensitivity analysis When comparing SPR and SCR between QIV and TIV-B/ Yamagata, one study [27] was removed because the TIV in this RCT contained only the Victoria lineage. During the pooled analysis of adverse events, we excluded the number of febrile events in one study [29] because it focused on fever within 4 days postvaccination, but other studies on fever within 7 days postvaccination. We also performed sensitivity analysis on other outcomes, revealing no significant differences in the results after either study was excluded.

8. Discussion This study is the first meta-analysis comparing the immunogenicity and safety of QIV and TIV in children and adolescents. Compared with TIV-B/Yamagata in children between 6 months and 3 years, QIV yielded no difference in SCR and SPR for the A (H1N1 and H3N2), which is consistent with previous studies in adults [10]. However, compared with TIV-B/Yamagata, QIV exclusively containing the B/Victoria lineage resulted in a higher vaccination immunogenicity for the B/Victoria lineage. In contrast, QIV

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

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Fig. 4a. Seroconversion rate (SCR) for QIV versus TIV-B/Yamagata at day 21 postvaccination (children and adolescents aged 3 years through 18 years).

failed to show a higher SCR for the B/Yamagata lineage than the TIV-B/Yamagata lineage. Similar results were also found in the comparison between QIV and TIV-B/Victoria, regardless of whether the groups included children aged 6 months up to 3 years or children aged 3 years through 18 years. Considering that QIV contained an exclusive composition compared with TIV, the results suggest a higher vaccination immunogenicity for the corresponding B lineages in children and adolescents. Currently, the most widely used vaccine is TIV, which only evokes limited cross-immunization against the missing B lineage. During each influenza season, two different subtypes of influenza B virus (Yamagata and Victoria) frequently alternate or circulate simultaneously around the world. The dominant influenza virus strains often does not match the influenza vaccine strains, which significantly reduces the effectiveness of the vaccine protection [36,37]. The prevalence and incidence of hospitalization due to influenza B attributable respiratory disease is highest in children

and even exceeds that caused by influenza A in some seasons [38,39]. Furthermore, the rate of influenza-associated deaths caused by influenza B [40–42] is quite high, even at 95% in some seasons [43]. Studies in some countries and regions showed that QIV would be expected to result in substantial health benefits, reducing the number of symptomatic influenza cases, medical visits, complications, hospitalizations for complications and deaths, in comparison with TIV [42,44–46]. It has been commonly considered that the SCR and SPR for the corresponding B lineage do not differ significantly different between QIV and TIV-B/Yamagata or TIV-B/ Victoria, mostly because TIV containing B/Yamagata or B/Victoria might well match the dominant B virus. In addition, although QIV had a higher SPR for the Yamagata lineage than TIV-B/ Victoria and a higher SPR for the Victoria lineage than TIV-B/ Yamagata, the SPR for Victoria and Yamagata were not significantly different between QIV and pooled TIV. Further clinical trials and cohort studies are needed.

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

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Fig. 4b. Seroprotection rate (SPR) for QIV versus TIV-B/Yamagata at day 21 postvaccination (children and adolescents aged 3 years through 18 years).

According to our meta-analysis, the main reported adverse reactions in the analyzed studies at 21 days after vaccination included diarrhea, nasopharyngitis, cough and oropharyngeal pain. Regardless, the incidence of adverse reactions was not significantly different between QIV and TIV, and these adverse reactions generally disappeared quickly. In addition to these findings, QIV only resulted in an increased incidence of pain compared with that caused by TIV. This is partly because the QIV preparation process adds B/Victoria or B/Yamagata to the basic TIV antigens: the total amount of 3 antigens per 0.5 ml of TIV is 45 mg, and this amount is increased to 60 mg for QIV, which may in turn increase the incidence of pain [47]. Despite an increased incidence of pain, QIV has reliable safety, as shown by tracking and investigating serious adverse events. No cases of death occurred among the serious adverse events, and no deaths were related to the vaccination against influenza, including QIV and TIV. Overall, there is no statistically significant difference in the incidence of adverse reactions between QIV and currently widely used TIV. There are several limitations to this study. First, the heterogeneity between the data reported in the literature may be due to participants being from different races and different areas, differences

in the dose injected, different exposure experiences (vaccination or infection) of the participants prior to the study, different ages, and different vaccine production companies. Second, as our metaanalysis only compared inactivated QIV and inactivated TIV, the results may not apply to comparisons among live attenuated influenza vaccines, subunit influenza vaccines and influenza vaccines with adjuvants. Third, the proportion of vaccine-primed participants and unprimed participants was different in the nine studies, which may partly confound the results. Moreover, our research may have been influenced by language, publication or database bias. Due to the limited number of studies included in the metaanalysis, we did not assess publication bias.

9. Conclusion First, in each age group of children and adolescents, the immunogenicity of QIV for common influenza ingredients was similar to that of TIV, but QIV had a significantly higher immunogenicity for the unique B lineage than did TIV. QIV induced antibody reactions against all four ingredients, in particular,

Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071

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promoting a higher antibody titer than TIV lacking the corresponding B lineage. Second, QIV had the same reliable safety as TIV among children and adolescents, but QIV yielded a relatively more frequent occurrence of pain. TIV currently accounts for the majority of seasonal influenza vaccines. However, in the upcoming influenza season, one of the two B lineages may be prevalent, making it very difficult to predict the predominant B lineage.

Funding source This study was supported by grants from the National Natural Science Foundation of China (81672005, U1611264, 81001271, 81721091), the Mega-Project of National Science and Technology for the 12th and 13th Five-Year Plan of China (2018ZX10715014-002 and 2014ZX10004008).

Financial disclosure The authors have no financial relationships relevant to this article to disclose.

Authors contribution Chenyang Huang: Writing - original draft, Formal analysis, Conceptualization, Data curation. Xiaofang Fu: Data curation, Supervision, Investigation. Yuqing Zhou: Investigation, Validation, Methodology. Fenfang Mi: Data curation, Resources. Guo Tian: Methodology, Validation. Xiaoxiao Liu: Data curation, Conceptualization. Jie Wu: Visualization, Software. Cheng Ding: Supervision, Formal analysis. Danying Yan: Investigation, Data curation. Prof. Lanjuan Li: Project administration, Supervision. Prof. Shigui Yang: Project administration, Funding acquisition, Writing - review editing.

CRediT authorship contribution statement Chenyang Huang: Writing - original draft, Formal analysis, Conceptualization, Data curation. Xiaofang Fu: Data curation, Supervision, Investigation. Yuqing Zhou: Investigation, Validation, Methodology. Fenfang Mi: Data curation, Resources. Guo Tian: Methodology, Validation. Xiaoxiao Liu: Data curation, Conceptualization. Jie Wu: Visualization, Software. Cheng Ding: Supervision, Formal analysis. Danying Yan: Investigation, Data curation. Lanjuan Li: Project administration, Supervision. Shigui Yang: Project administration, Funding acquisition, Writing - review editing.

Declaration of Competing Interest he authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement This research was funded by National Natural Science Foundation of China, grant number [81672005, 81001271], the key joint project for data centre of the National Natural Science Foundation of China and Guangdong Provincial Government, grant number [U1611264], the Mega-Project of National Science and Technology of China, grant number [2018ZX10715014, 2013ZX10004904, 2014ZX10004008, 2013ZX10004901], Zhejiang. Laboratory Project.

Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2019.11.071.

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Please cite this article as: C. Huang, X. Fu, Y. Zhou et al., Comparison of the immunogenicity and safety of quadrivalent and tetravalent influenza vaccines in children and adolescents, Vaccine, https://doi.org/10.1016/j.vaccine.2019.11.071