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Background: Influenza is a cause of febrile acute respiratory infection (FARI) in India; however, few influenza vaccine trials have been conducted in India. We assessed absolute and relative efficacy of live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) among children aged 2 to 10 years in rural India through a randomized, triple-blind, placebo-controlled trial conducted over 2 years., Methods and Findings: In June 2015, children were randomly allocated to LAIV, IIV, intranasal placebo, or inactivated polio vaccine (IPV) in a 2:2:1:1 ratio. In June 2016, vaccination was repeated per original allocation. Overall, 3,041 children received LAIV (n = 1,015), IIV (n = 1,010), nasal placebo (n = 507), or IPV (n = 509). Mean age of children was 6.5 years with 20% aged 9 to 10 years. Through weekly home visits, nasal and throat swabs were collected from children with FARI and tested for influenza virus by polymerase chain reaction. The primary outcome was laboratory-confirmed influenza-associated FARI; vaccine efficacy (VE) was calculated using modified intention-to-treat (mITT) analysis by Cox proportional hazards model (PH) for each year. In Year 1, VE was 40.0% (95% confidence interval (CI) 25.2 to 51.9) for LAIV and 59.0% (95% CI 47.8 to 67.9) for IIV compared with controls; relative efficacy of LAIV compared with IIV was -46.2% (95% CI -88.9 to -13.1). In Year 2, VE was 51.9% (95% CI 42.0 to 60.1) for LAIV and 49.9% (95% CI 39.2 to 58.7) for IIV; relative efficacy of LAIV compared with IIV was 4.2% (95% CI -19.9 to 23.5). No serious adverse vaccine-attributable events were reported. Study limitations include differing dosage requirements for children between nasal and injectable vaccines (single dose of LAIV versus 2 doses of IIV) in Year 1 and the fact that immunogenicity studies were not conducted., Conclusions: In this study, we found that LAIV and IIV vaccines were safe and moderately efficacious against influenza virus infection among Indian children., Trial Registration: Clinical Trials Registry of India CTRI/2015/06/005902., Competing Interests: The authors have declared that no competing interests exist.

Background: Influenza causes substantial morbidity and mortality worldwide, however, reliable burden estimates from developing countries are limited, including India. We aimed to quantify influenza-associated mortality for India utilizing 2010-2013 nationally representative data sources for influenza virus circulation and deaths., Methods: Virological data were obtained from the influenza surveillance network of 10 laboratories led by National Institute of Virology, Pune covering eight states from 2010-2013. Death data were obtained from the nationally representative Sample Registration System for the same time period. Generalized linear regression with negative binomial distribution was used to model weekly respiratory and circulatory deaths by age group and proportion of specimens positive for influenza by subtype; excess deaths above the seasonal baseline were taken as an estimate of influenza-associated mortality counts and rates. Annual excess death rates and the 2011 India Census data were used to estimate national influenza-associated deaths., Results: Estimated annual influenza-associated respiratory mortality rates were highest for those ≥65 years (51.1, 95% confidence interval (CI) = 9.2-93.0 deaths/100 000 population) followed by those <5 years (9.8, 95% CI = 0-21.8/100 000). Influenza-associated circulatory death rates were also higher among those ≥65 years (71.8, 95% CI = 7.9-135.8/100 000) as compared to those aged <65 years (1.9, 95% CI = 0-4.6/100 000). Across all age groups, a mean of 127 092 (95% CI = 64 046-190,139) annual influenza-associated respiratory and circulatory deaths may occur in India., Conclusions: Estimated influenza-associated mortality in India was high among children <5 years and adults ≥65 years. These estimates may inform strategies for influenza prevention and control in India, such as possible vaccine introduction., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2020 by the Journal of Global Health. All rights reserved.)

Background: No estimates of influenza-associated mortality exist for India., Objective: To evaluate national mortality and viral surveillance data from India for assessing their appropriateness in estimating influenza-associated mortality using varied analytic approaches., Methods: We reviewed influenza virus surveillance data from a national influenza surveillance network. We also reviewed national mortality data from Civil Registration System (CRS), Medical Certification of Cause of Death (MCCD) and the Sample Registration System (SRS). We compared and scored the different sources of mortality data using specific criteria, including the process of cause of death assignment, sample size, proportion of ill-defined deaths, representativeness and availability of time series data. Each of these 5 parameters was scored on a scale from 1 to 5. To evaluate how to generate an influenza-associated mortality estimate for India, we also reviewed 4 methodologic approaches to assess the appropriateness of their assumptions and requirements for these data sets., Results: The influenza virus surveillance data included year-round sample testing for influenza virus and was found to be suitable for influenza mortality estimation modelling. Based on scoring for the 5 mortality data criteria, the SRS data had the highest score with 20 of 25 possible score, whereas MCCD and CRS scored 16 and 12, respectively. The SRS which used verbal autopsy survey methods was determined to be nationally representative and thus adequate for estimating influenza-associated mortality. Evaluation of the modelling methods demonstrated that Poisson regression, risk difference and mortality multiplier methods could be applied to the Indian setting., Conclusion: Despite significant challenges, it is possible to estimate influenza-associated mortality in India., (© 2017 The Authors. Influenza and Other Respiratory Viruses. Published by John Wiley & Sons Ltd.)

Evidence on influenza vaccine effectiveness from low and middle countries (LMICs) is limited due to limited institutional capacities; lack of adequate resources; and lack of interest by ministries of health for influenza vaccine introduction. There are concerns that the highest ethical standards will be compromised during trials in LMICs leading to mistrust of clinical trials. These factors pose regulatory and operational challenges to researchers in these countries. We conducted a community-based vaccine trial to assess the efficacy of live attenuated influenza vaccine and inactivated influenza vaccine in rural north India. Key regulatory challenges included obtaining regulatory approvals, reporting of adverse events, and compensating subjects for trial-related injuries; all of which were required to be completed in a timely fashion. Key operational challenges included obtaining audio-visual consent; maintaining a low attrition rate; and administering vaccines during a narrow time period before the influenza season, and under extreme heat. We overcame these challenges through advanced planning, and sustaining community engagement. We adapted the trial procedures to cope with field conditions by conducting mock vaccine camps; and planned for early morning vaccination to mitigate threats to the cold chain. These lessons may help investigators to confront similar challenges in other LMICs.