Efficacy of live attenuated and inactivated influenza vaccines among children in rural India: A 2-year, randomized, triple-blind, placebo-controlled trial

Abstract

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.

Nasal shedding of vaccine viruses after immunization with a Russian‐backbone live attenuated influenza vaccine in India

“…However, LAIV had no statistically significant efficacy against influenza A(H1N1)pdm09 virus in either year. 18 Although the nasal shedding results seem to corroborate efficacy results in our study, vaccine virus shedding in humans does not adequately predict the clinical efficacy of LAIV across trials. 22 Several hypotheses have been proposed as potential reasons surface.…”

“…Children aged 2–10 years received a single dose of trivalent LAIV or intranasal placebo across two consecutive years, 2015 and 2016, as per the initial allocation. The details of the study have been published 18 . Based on operational considerations, around 10% of nasal vaccine (LAIV or nasal placebo) were randomly selected to study the uptake of LAIV among the study participants.…”

Estimation of Relative Vaccine Effectiveness in Influenza: A Systematic Review of Methodology

“…We assessed 19 of the 22 RCTs included using the ROB-2 tool, as four publications related to different subgroup results from the same overall trial. 83,86,87,92 We found 26% of studies (n = 5) 73,77,98,108,115 were at low risk of bias, deemed 47% of studies (n = 9) 82,90,96,100,104–107,109 to have some concerns of bias, and classified the remaining 26% (n = 5) 81,83,95,97,102 studies as at high risk of bias overall. The measurement of outcome domain was at the highest risk of bias with three studies being classified as high risk.…”

“…We assessed 19 of the 22 RCTs included using the ROB-2 tool, as four publications related to different subgroup results from the same overall trial. 83,86,87,92 We found 26% of studies (n = 5) 73,77,98,108,115 were at low risk of bias, FIGURE 2. Relative outcome estimated by study design.…”

Optimizing the Live Attenuated Influenza A Vaccine Backbone for High-Risk Patient Groups

“…LAIV mimics a natural infection, which brings the advantage of triggering mucosal (7), cellular and cross-protective (8,9) immune responses. Hence, LAIV vaccine effectiveness (VE) ranges from 40 to 69%, which is equivalent to the VE observed for IIVs (10)(11)(12)(13)(14). The nature of this vaccine, however, excludes key-populations from LAIV recommendation guidelines.…”