Comment
Use of live attenuated influenza vaccines in young children in resource-poor settings Children younger than 5 years are in the age group most vulnerable to infection with influenza virus, and these infections contribute substantially to the overall harm caused to the general population. Thus, the development of safe and efficacious vaccines suitable for this age group is a high public health priority. The vulnerability of young children becomes even more obvious in densely populated, low-resource countries with poor healthcare systems and no established influenza vaccination policies. Much interest has been paid to the performance of live attenuated influenza vaccines (LAIVs) compared with inactivated vaccines in developing countries because LAIVs have higher yields during manufacture, the purification process is simpler, lot release is quicker, and they may be delivered intranasally, removing the need for needles. Russian-backbone LAIV has a long history of development, and it was a great achievement when this technology was licensed to WHO with permission to grant sublicenses to vaccine manufacturers in newly industrialised and developing countries within the framework of the WHO Influenza Vaccine Technology Transfer Project.1 As a part of this project, the Serum Institute of India, Pune, India, adopted the technology, and its LAIV is now prequalified by WHO.2 In The Lancet Global Health, two studies are reported by W Abdullah Brooks and colleagues3 and John C Victor and colleagues4 that present the safety and efficacy results for an Indian-made Russian-backbone LAIV given to young children in Bangladesh and Senegal. Both studies were randomised controlled trials, and both confirmed LAIV safety in children aged 2–5 years. Reactions within 7 days of vaccine receipt were mostly mild, and were most commonly cough (6·5% in Bangladesh and 9·7% in Senegal) and runny nose (6·1% and 17·1%). This good safety profile is in concordance with the findings in an earlier safety and immunogenicity LAIV trial done in Bangladesh in 2012.5 Also of note is that Abdullah and colleagues’ study in Bangladesh3 included a large cohort of children with history of asthma and wheezing, and no increase in any safety signals was seen in these children following the receipt of the LAIV. The vaccine efficacy differed notably between the two countries, from 57·5% (95 CI 43·6 to 68·0) in Bangladesh
to 0·0% (–26·4 to 20·9) in Senegal, despite use of the same LAIV lot. Attack rates for H1N1pdm09 viruses were high in both studies, and the absence of vaccine efficacy in Senegal was mainly due to the lack of protection against this strain, which was the predominant vaccine-matched strain, and high circulation of mismatched influenza B strains during the trial. Victor and colleagues4 could find no clear explanation for the discrepancy in vaccine efficacy between study sites. I suggest that the most reasonable explanations would be the low temperature stability of the H1N1dpm09 LAIV component. The A/California strain has 47Glu residue in the haemagglutinin 2 subunit that renders the virus unstable.6 Although the shelf life and the cold chain of the vaccine had been monitored rigorously by the manufacturer, a very hot environment in Senegal might have negatively affected the infectivity of the H1N1dpm09 component. Immunisation in an airconditioned environment might help to maintain virus infectivity. Another possibility for the differences in results could be the baseline immune statuses of the participants. Unfortunately, no immunogenicity testing was done in either trial, but the national surveillance data suggest that H1N1 viruses circulated widely in Bangladesh in the year before the study, whereas in Senegal these viruses had been detected rarely between 2010 and the time of the LAIV trial. Children in the Bangladesh study, unlike those in the Senegal study, therefore, might have had some degree of pre-existing immunity to H1N1 viruses that was boosted by the LAIV. The use of a two-dose schedule might have been more efficacious in Senegal, therefore, and should be further considered as a possible option for immunising young children who have no preexisting influenza immunity there and elsewhere. The studies by Brooks and colleagues3 and Victor and colleagues4 have more than local relevance because of the concerns about poor results from observational studies of annual effectiveness assessments of AnnArbor-backbone LAIV. Because of these results, in June 2016, the US Advisory Committee on Immunization Practices withdrew its preferential recommendation for the use of LAIV in children.7 Of note, though, other studies in Canada and Europe have shown higher
www.thelancet.com/lancetgh Published online October 13, 2016 http://dx.doi.org/10.1016/S2214-109X(16)30247-9
Lancet Glob Health 2016 Published Online October 13, 2016 http://dx.doi.org/10.1016/ S2214-109X(16)30247-9 See Online/Articles http://dx.doi.org/10.1016/ S2214-109X(16)30200-5 and http://dx.doi.org/10.1016/ S2214-109X(16)30201-7
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efficacy with the same LAIV formulation in the same influenza season8–10 and, therefore, these countries continue to recommend LAIV for children. The important work of Brooks and colleagues and Victor and colleagues will definitely contribute to the global conversation about the need to better understand the performance of LAIVs in resource-poor settings with high population densities. Work should proceed with assessments of the effects of LAIVs on influenza morbidity and mortality in children younger than 2 years, for whom the burden of severe disease due to influenza virus infection is highest in low-income countries.
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Irina Isakova-Sivak Department of Virology, Institute of Experimental Medicine, Saint Petersburg 197376, Russia
[email protected]
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At the end of the Bangladesh study, my laboratory was asked by the study sponsor (PATH) to test the masked influenza-positive specimens for wild-type or vaccine-type virus. I did not participate in the study design, study conduct, or data analysis.
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Copyright © The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license.
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Rudenko L, van den Bosch H, Kiseleva I, et al. Live attenuated pandemic influenza vaccine: clinical studies on A/17/California/2009/38 (H1N1) and licensing of the Russian-developed technology to WHO for pandemic influenza preparedness in developing countries. Vaccine 2011; 29 (suppl 1): A40–44.
Rudenko L, Yeolekar L, Kiseleva I, Isakova-Sivak I. Development and approval of live attenuated influenza vaccines based on Russian master donor viruses: process challenges and success stories. Vaccine 2016; 34: 5436–41. Brooks WA, Zaman K, Lewis KDC, et al. Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: a randomised, double-blind, placebo-controlled trial. Lancet Glob Health 2016; published online Oct 13. http://dx.doi.org/10.1016/S2214109X(16)30200-5. Victor JC, Lewis KDC, Diallo A, et al. Efficacy of a Russian-backbone live attenuated influenza vaccine among children in Senegal: a randomised, double-blind, placebo-controlled trial. Lancet Glob Health 2016; published online Oct 13. http://dx.doi.org/10.1016/S2214-109X(16)30201-7. Ortiz JR, Goswami D, Lewis KD, et al. Safety of Russian-backbone seasonal trivalent, live-attenuated influenza vaccine in a phase II randomized placebo-controlled clinical trial among children in urban Bangladesh. Vaccine 2015; 33: 3415–21. Cotter CR, Jin H, Chen Z. A single amino acid in the stalk region of the H1N1pdm influenza virus HA protein affects viral fusion, stability and infectivity. PLoS pathogens 2014; 10: e1003831. Flannery B, Chung J. Influenza vaccine effectiveness, including LAIV vs IIV in children and adolescents, US Flu VE Network, 2015–16. June 22, 2016. http://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2016-06/ influenza-05-flannery.pdf (accessed Sept 26, 2016). Flannery B, Chung J. Influenza vaccine effectiveness in adults and children in primary care in the UK: provisional end-of-season results 2015–16. June, 2016. https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/530756/Influenza_vaccine_effectiveness_in_ primary_care_in_children.pdf (accessed Sept 26, 2016). Chambers C, Skowronski DM, Sabaiduc S, et al. Interim estimates of 2015/16 vaccine effectiveness against influenza A(H1N1)pdm09, Canada, February 2016. Euro Surveill 2016; 21: 30168. Nohynkek H, Baum U, Syrjänen R, Ikonen N, Sundman J, Jokinen J. Effectiveness of the live attentuated and the inactivated influenza vaccine in two-year-olds—a nationwide cohort study Finland, influenza season 2015/16. Euro Surveill 2016; published online Sept 22. DOI:10.2807/15607917.ES.2016.21.38.30346.
www.thelancet.com/lancetgh Published online October 13, 2016 http://dx.doi.org/10.1016/S2214-109X(16)30247-9
