Immunisation against influenza in low-income and middle-income countries
Authors: Maharaj Kishan Bhan, Bireshwar Sinha
Journal: The Lancet Global Health (2019)

Influenza is a substantial contributor to the significant burden of lower respiratory tract infections (LRTI) globally. It is estimated that influenza accounts for over 10% of all LRTI episodes and the incidence is highest in children younger than 5 years and older people (aged >65 years). The risk of severe disease (hospitalisation [ie, admission to hospital]) and of death is also highest for these groups.1GBD 2017 Influenza CollaboratorsMortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017.Lancet Respir Med. 2019; 7: 69-89Summary Full Text Full Text PDF PubMed Scopus (223) Google Scholar Influenza during pregnancy is associated with an increased risk of hospitalisation and adverse birth outcomes.2Fell DB Savitz DA Kramer MS et al.Maternal influenza and birth outcomes: systematic review of comparative studies.BJOG. 2017; 124: 48-59Crossref PubMed Scopus (95) Google Scholar, 3Louie JK Acosta M Jamieson DJ Honein MA Severe 2009 H1N1 influenza in pregnant and postpartum women in California.N Engl J Med. 2010; 362: 27-35Crossref PubMed Scopus (554) Google Scholar, 4Haberg SE Trogstad L Gunnes N et al.Risk of fetal death after pandemic influenza virus infection or vaccination.N Engl J Med. 2013; 368: 333-340Crossref PubMed Scopus (241) Google Scholar The WHO Strategic Advisory Group of Experts universally recommends immunisation of pregnant women against influenza, children aged 6–23 months, older people, and other high-risk groups on the basis of country-specific epidemiology. Intramuscular trivalent inactivated influenza vaccines (IIV3) are the only licensed products for use in children aged 6–24 months, people aged 50 years or older, and for pregnant women. Non-pregnant individuals aged 2–49 years can receive either IIV3 or trivalent live attenuated influenza vaccines (LAIVs). A quadrivalent LAIV (two A and two B strains) has been licensed in the USA for use in children older than 6 months; further research and clinical evaluation is encouraged.5WHOVaccines against influenza: WHO position paper. World Health Organization, Geneva2012Google Scholar Influenza vaccines are grossly underused in India and other low-income and middle-income countries (LMICs), although a licensed IIV3 is available. Lack of clarity on the priority target population in the country, and limited data on the burden, seasonality, circulating strains, and vaccine efficacy in the local context all contribute to the underuse of available vaccines. In 2017, estimates showed that influenza contributes to around 25–49 hospitalisations for lower respiratory tract infections per 10 000 population and 26 000 (16 000–37 000) annual deaths in India.1GBD 2017 Influenza CollaboratorsMortality, morbidity, and hospitalisations due to influenza lower respiratory tract infections, 2017: an analysis for the Global Burden of Disease Study 2017.Lancet Respir Med. 2019; 7: 69-89Summary Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 6Hirve S Krishnan A Dawood FS et al.Incidence of influenza-associated hospitalization in rural communities in western and northern India, 2010–2012: a multi-site population-based study.J Infect. 2015; 70: 160-170Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar Several of the influenza-related knowledge gaps in the context of LMICs are addressed to an extent in the household randomised controlled trial by Wayne M Sullender and colleagues,7Sullender WM Fowler KB Gupta V et al.Efficacy of inactivated trivalent influenza vaccine in rural India: a 3-year cluster-randomised controlled trial.Lancet Glob Health. 2019; 7: e940-e950Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar published in The Lancet Global Health. This trial reported efficacy and immunogenicity of a IIV3 (Vaxigrip) in rural India among children aged between 6 months and 10 years, compared with an inactivated polio vaccine (control group), from 2009 to 2012. Based on table 2 of the Article, the cumulative incidence of real-time RT-PCR-confirmed influenza in the control group of the trial (9% [95% CI 8·2–9·8]) suggests a substantial burden of disease, consistent with previous reports from LMICs;8Ram Purakayastha D Vishnubhatla S Rai SK Broor S Krishnan A Estimation of burden of influenza among under-five children in India: a meta-analysis.J Trop Pediatr. 2018; 64: 441-453Crossref PubMed Scopus (4) Google Scholar the highest incidence of 11·4% (95% CI 9·7–13·3) was observed among children aged 6–35 months. IIV3 showed good immunogenicity over the 3 years of the study. The total vaccine efficacy against laboratory-confirmed influenza-associated febrile acute respiratory infection over the 3-year period of 45·1% (95% CI 35·2–53·5) is similar to that reported from an earlier trial of IIV3 in Germany and Finland, among children aged 6–72 months.9Vesikari T Knuf M Wutzler P et al.Oil-in-water emulsion adjuvant with influenza vaccine in young children.N Engl J Med. 2011; 365: 1406-1416Crossref PubMed Scopus (258) Google Scholar The variability of the vaccine efficacy in the Indian trial was considerable. Direct total vaccine efficacy was lowest in year 1 (25·6% [95% CI 6·8–40·6]), which was explained by the predominant circulation of the influenza A (H1N1)pdm strain that was not a component of the vaccine. Further, vaccination commenced in the months of October and November in this study, which was actually after the peak of influenza activity that occurred during the months of July to September. The highest total vaccine efficacy in year 3 (74·2% [95% CI 57·8–84·3]) was expected because the vaccine and circulating strains were well matched. In year 3, a significant indirect protection (vaccine efficacy 38% [95% CI 7·4–58·6]) was noted. The authors recognise the limitations in statistical power because of the fewer numbers of cases in year 3. The study does not report efficacy against severe disease. Several issues need to be re-emphasised. First, deeper understanding of country-specific epidemiology of the disease is crucial in LMICs to improve efficacy of the available vaccine. Effective national surveillance systems need to be established to provide timely and high-quality estimates of burden, overall and in high-risk groups (pregnant women, children, older people, and others), seasonality, and circulating strains and subtypes. The strain selection and timing of immunisation would also become more appropriate with the availability of surveillance-generated national data. These locally applicable epidemiology and cost-effectiveness data would enable policy for national immunisation programmes. The current influenza vaccines are moderately efficacious and cumbersome to manufacture. The development of more efficacious and easier to produce vaccines needs to be prioritised. A universal influenza vaccine that is efficacious against all strains of this virus is a goal worthy of pursuit. The concepts of rationale vaccine designs deploying insights from structural biology and new approaches to immunogen design and vaccine formulation provide a way forward. We declare no competing interests. Efficacy of inactivated trivalent influenza vaccine in rural India: a 3-year cluster-randomised controlled trialIIV3 provided variable direct and indirect protection against influenza infection. Indirect protection was significant during the year of highest direct protection and should be considered when quantifying the effect of vaccination programmes. 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