Safety and Immunogenicity Following Administration of a Live, Attenuated Monovalent 2009 H1N1 Influenza Vaccine to Children and Adults in Two Randomized Controlled Trials

Raburn M Mallory,Elissa Malkin,Li Shi,Christopher S Ambrose,Filip Dubovsky,George Kemble,Taff Jones,Terramika Bellamy,Tingting Yi,Esper Georges Kallas

doi:10.1371/journal.pone.0013755

Abstract

BackgroundThe safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 live attenuated influenza vaccine (LAIV) were evaluated in children and adults.Methods/Principal FindingsTwo randomized, double-blind, placebo-controlled studies were completed in children (2–17 y) and adults (18–49 y). Subjects were assigned 4∶1 to receive 2 doses of H1N1 LAIV or placebo 28 days apart. The primary safety endpoint was fever ≥38.3°C during days 1–8 after the first dose; the primary immunogenicity endpoint was the proportion of subjects experiencing a postdose seroresponse. Solicited symptoms and adverse events were recorded for 14 days after each dose and safety data were collected for 180 days post-final dose. In total, 326 children (H1N1 LAIV, n = 261; placebo, n = 65) and 300 adults (H1N1 LAIV, n = 240; placebo, n = 60) were enrolled. After dose 1, fever ≥38.3°C occurred in 4 (1.5%) pediatric vaccine recipients and 1 (1.5%) placebo recipient (rate difference, 0%; 95% CI: –6.4%, 3.1%). No adults experienced fever following dose 1. Seroresponse rates in children (H1N1 LAIV vs. placebo) were 11.1% vs. 6.3% after dose 1 (rate difference, 4.8%; 95% CI: –9.6%, 13.8%) and 32.0% vs. 14.5% after dose 2 (rate difference, 17.5%; 95% CI: 5.5%, 27.1%). Seroresponse rates in adults were 6.1% vs. 0% (rate difference, 6.1%; 95% CI: –5.6%, 12.6%) and 14.9% vs. 5.6% (rate difference, 9.3%; 95% CI: –0.8%, 16.3%) after dose 1 and dose 2, respectively. Solicited symptoms after dose 1 (H1N1 LAIV vs. placebo) occurred in 37.5% vs. 32.3% of children and 41.7% vs. 31.7% of adults. Solicited symptoms occurred less frequently after dose 2 in adults and children. No vaccine-related serious adverse events occurred.Conclusions/SignificanceIn subjects aged 2 to 49 years, two doses of H1N1 LAIV have a safety and immunogenicity profile similar to other previously studied and efficacious formulations of seasonal trivalent LAIV.Trial RegistrationClinicalTrials.gov NCT00946101, NCT00945893

Highlights

In response to the 2009 H1N1 influenza pandemic, MedImmune (Gaithersburg, MD) developed a live attenuated intranasal H1N1 vaccine based on the Ann Arbor 6:2 reassortant technology used to produce the annual trivalent seasonal influenza vaccine (MedImmune, Gaithersburg, MD) [1,2]
Efficacy following a single dose of Live attenuated influenza vaccines (LAIVs) is an important consideration for pandemic influenza; experiences with unadjuvanted, inactivated seasonal and H5N1 influenza vaccines indicate that two doses may be required in order to generate robust immune responses to novel influenza strains in unprimed individuals such as young children [4,5,6]
The local and systemic symptoms observed in these studies are consistent with intranasal viral replication, are comparable to what has been observed in previous studies with seasonal LAIV, and demonstrate that this H1N1 LAIV strain is appropriately attenuated

Summary

Introduction

In response to the 2009 H1N1 influenza pandemic, MedImmune (Gaithersburg, MD) developed a live attenuated intranasal H1N1 vaccine based on the Ann Arbor 6:2 reassortant technology used to produce the annual trivalent seasonal influenza vaccine (MedImmune, Gaithersburg, MD) [1,2]. Data from 3 large placebo-controlled clinical studies indicate that relatively high levels of efficacy (ranging from 60% to 90%) are seen in previously unvaccinated young children after a single dose of trivalent LAIV. Efficacy following a single dose of LAIV is an important consideration for pandemic influenza; experiences with unadjuvanted, inactivated seasonal and H5N1 influenza vaccines indicate that two doses may be required in order to generate robust immune responses to novel influenza strains in unprimed individuals such as young children [4,5,6]. The objective of the clinical studies was to evaluate the safety, tolerability, and immunogenicity of 2 doses of a monovalent intranasal A/H1N1 LAIV administered 28 days apart in children and adults prior to U.S licensure and subsequent widespread distribution of the vaccine. Interim results were provided to the US Food and Drug Administration (FDA) as they became available; this report provides the complete long-term safety and immunogenicity data for the 2 studies

Methods

Results

Discussion