NEJM: Vaccine for prevention of influenza in children

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Vaccine for Prevention of Mild and Moderate-to-Severe Influenza in Children

Varsha K. Jain, M.D., M.P.H., Luis Rivera, M.D., Khalequ Zaman, M.B., B.S., Ph.D., Roberto A. Espos, Jr., M.D., M.H.S.A., Chukiat Sirivichayakul, M.D., Beatriz P. Quiambao, M.D., Doris M. Rivera-Medina, M.D., Pirunghul Kerdpanich, M.D., Mehmet Ceyhan, M.D., Ener C. Dinleyici, M.D., Alejandro Cravioto, M.D., Ph.D., Mohammed Yunus, M.B., B.S., Pornthep Chanthavanich, M.D., Kriengsak Limkittikul, M.D., Zafer Kurugol, M.D., Ph.D., Emre Alhan, M.D., Adrian Caplanusi, M.D., Ph.D., Serge Durviaux, B.A., Philippe Boutet, D.V.M., Ph.D., Opokua Ofori-Anyinam, Ph.D., Vijayalakshmi Chandrasekaran, M.Sc., Ghassan Dbaibo, M.D., and Bruce L. Innis, M.D.

December 11, 2013DOI: 10.1056/NEJMoa1215817

Comments open through December 18, 2013
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Abstract
Article
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Background

Commonly used trivalent vaccines contain one influenza B virus lineage and may be ineffective against viruses of the other B lineage. We evaluated the efficacy of a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages.

Full Text of Background...
Methods

In this multinational, phase 3, observer-blinded study, we randomly assigned children 3 to 8 years of age, in a 1:1 ratio, to receive the QIV or a hepatitis A vaccine (control). The primary end point was influenza A or B confirmed by real-time polymerase chain reaction (rt-PCR). Secondary end points were rt-PCR?confirmed, moderate-to-severe influenza and rt-PCR?positive, culture-confirmed influenza. The vaccine efficacy and the effect of vaccination on daily activities and utilization of health care resources were assessed in the total vaccinated cohort (2584 children in each group) and the per-protocol cohort (2379 children in the QIV group and 2398 in the control group).

Full Text of Methods...
Results

In the total vaccinated cohort, 62 children in the QIV group (2.40%) and 148 in the control group (5.73%) had rt-PCR?confirmed influenza, representing a QIV efficacy of 59.3% (95% confidence interval [CI], 45.2 to 69.7), with efficacy against culture-confirmed influenza of 59.1% (97.5% CI, 41.2 to 71.5). For moderate-to-severe rt-PCR?confirmed influenza, the attack rate was 0.62% (16 cases) in the QIV group and 2.36% (61 cases) in the control group, representing a QIV efficacy of 74.2% (97.5% CI, 51.5 to 86.2). In the per-protocol cohort, the QIV efficacy was 55.4% (95% CI, 39.1 to 67.3), and the efficacy against culture-confirmed influenza 55.9% (97.5% CI, 35.4 to 69.9); the efficacy among children with moderate-to-severe influenza was 73.1% (97.5% CI, 47.1 to 86.3). The QIV was associated with reduced risks of a body temperature above 39?C and lower respiratory tract illness, as compared with the control vaccine, in the per-protocol cohort (relative risk, 0.29 [95% CI, 0.16 to 0.56] and 0.20 [95% CI, 0.04 to 0.92], respectively). The QIV was immunogenic against all four strains. Serious adverse events occurred in 36 children in the QIV group (1.4%) and in 24 children in the control group (0.9%).

Full Text of Results...
Conclusions

The QIV was efficacious in preventing influenza in children. (Funded by GlaxoSmithKline Biologicals; ClinicalTrials.gov number, NCT01218308.)

http://www.nejm.org/doi/full/10.1056/NEJMoa1215817?query=featured_home

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NEJM: Vaccine for prevention of influenza in children

N Engl J Med. 2014 Mar 20;370(12):1167. doi: 10.1056/NEJMc1400874#SA1.
Vaccine for prevention of influenza in children.
Esposito S, Principi N.

http://www.ncbi.nlm.nih.gov/pubmed/24645954

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Re: NEJM: Vaccine for prevention of influenza in children

N Engl J Med. 2014 Mar 20;370(12):1167-8. doi: 10.1056/NEJMc1400874.
Vaccine for prevention of influenza in children.
Jain VK, Dbaibo G, Innis BL.

http://www.flutrackers.com/forum/showthread.php?t=214818&highlight=prevention

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Re: NEJM: Vaccine for prevention of influenza in children

Correspondence
Vaccine for Prevention of Influenza in Children

N Engl J Med 2014; 370:1167-1168March 20, 2014DOI: 10.1056/NEJMc1400874
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To the Editor:

Jain et al. (Dec. 26 issue)1 claim that a quadrivalent influenza vaccine (QIV) is efficacious in preventing influenza in children, although their efficacy data are similar to those obtained with the use of the traditional trivalent influenza vaccine (TIV).2 What additional benefit does QIV offer over TIV? Why did they randomly assign patients to receive QIV or hepatitis A vaccine rather than QIV or TIV? We do not think that developing vaccines simply on the basis of including the hemagglutinin antigens of ?best guess? A and B strains is sufficient for the global prevention of influenza because it does not avoid the risk of a mismatch between the influenza A strains selected for the vaccine and those actually circulating during the influenza season,3 nor does it reduce the delay in the availability of pandemic vaccines.4 Cross-reactive human B-cell and T-cell epitopes between influenza A and B strains have been identified recently in humans.5 Would it not be more appropriate to consider new strategies on the basis of conserved vaccine targets as a means of providing global protection against influenza?

Susanna Esposito, M.D.
Universit? degli Studi di Milano, Milan, Italy
susanna.esposito@unimi.it

Nicola Principi, M.D.
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

No potential conflict of interest relevant to this letter was reported.
5 References

1

Jain VK, Rivera L, Zaman K, et al. Vaccine for prevention of mild and moderate-to-severe influenza in children. N Engl J Med 2013;369:2481-2491
Full Text | Web of Science | Medline

2

DiazGranados CA, Denis M, Plotkin S. Seasonal influenza vaccine efficacy and its determinants in children and non-elderly adults: a systematic review with meta-analyses of controlled trials. Vaccine 2012;31:49-57
CrossRef | Web of Science | Medline

3

Chen J, Deng YM. Influenza virus antigenic variation, host antibody production and new approach to control epidemics. Virol J 2009;6:30-30
CrossRef | Web of Science | Medline

4

Partridge J, Kieny MP. Global production of seasonal and pandemic (H1N1) influenza vaccines in 2009-2010 and comparison with previous estimates and global action plan targets. Vaccine 2010;28:4709-4712
CrossRef | Web of Science | Medline

5

Terajima M, Babon JA, Co MD, Ennis FA. Cross-reactive human B cell and T cell epitopes between influenza A and B viruses. Virol J 2013;10:244-244
CrossRef | Web of Science | Medline

The authors reply: Because efficacy estimates of inactivated TIV in children were not robust, we evaluated the benefit of inactivated QIV measured as absolute efficacy (as compared with hepatitis A vaccine, not TIV) to show the underappreciated benefits of vaccinating healthy children to prevent moderate-to-severe influenza and to reduce clinic visits, hospitalization, and school and parental-work absenteeism. The A subtype and B lineage?specific vaccine efficacy estimates that we generated also apply to TIV made by the same process.

The additional benefit of QIV is direct protection against both B types in the vaccine. This is supported by its efficacy against the three strains prevalent in the trial and its similar immunogenicity for all four vaccine strains, whereas, in children 3 to 8 years old, TIV is far less immunogenic than QIV against the added B strain in QIV.1,2

We acknowledge that inactivated influenza vaccines are limited because they immunize predominantly against the globular head of hemagglutinin, which drifts.3 We agree that the ultimate goal is a vaccine that is based on conserved targets that could eliminate annual vaccination. Nevertheless, our study shows the health gains accruable now by administering QIV to children.

Varsha K. Jain, M.D., M.P.H.
GlaxoSmithKline Vaccines, King of Prussia, PA

Ghassan Dbaibo, M.D.
American University of Beirut, Beirut, Lebanon
gdbaibo@aub.edu.lb

Bruce L. Innis, M.D.
GlaxoSmithKline Vaccines, King of Prussia, PA

Since publication of their article, the authors report no further potential conflict of interest.
3 References

1

Langley JM, Carmona Martinez A, Chatterjee A, et al. Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: a phase III randomized controlled trial in children. J Infect Dis 2013;208:544-553
CrossRef | Web of Science | Medline

2

Domachowske JB, Pankow-Culot H, Bautista M, et al. A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years. J Infect Dis 2013;207:1878-1887
CrossRef | Web of Science | Medline

3

Krammer F, Palese P. Universal influenza virus vaccines: need for clinical trials. Nat Immunol 2014;15:3-5
CrossRef | Web of Science | Medline

http://www.nejm.org/doi/full/10.1056/NEJMc1400874?af=R&rss=currentIssue&