Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model

Matthew J Memoli,Tyler Bristol,Richard T Davey,Lindsay Czajkowski,John H Powers,Susan Reed,Alison Han,Kyle Risos,Sarah Fargis,Jeffery K Taubenberger,Rani Athota,Pamela A Shaw,Anne Moscona

doi:10.1128/mbio.00417-16

Abstract

ABSTRACTDespite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms.

Highlights

Despite long-term investment, influenza continues to be a significant worldwide problem
Two of the four disease severity measures, those related to duration of disease demonstrated a significant decrease in severity in those in the Ն1:40 hemagglutination inhibition (HAI) titer group compared to the Ͻ1:40 HAI titer group (Fig. 2)
When grouped by baseline neuraminidase inhibition (NAI) titers, those participants with high titers (Ն1:40) had only minimal increases in NAI GMT after challenge, but unlike HAI titer, every participant with a low NAI titer had a rise in NAI titer after challenge, regardless of clinical outcome (Fig. 7C). In this human influenza challenge study, participants with a prechallenge HAI titer of Ն1:40 showed significantly less incidence of mild to moderate influenza disease (MMID) and some reduction in the duration of disease compared to participants with low HAI titers (Ͻ1:40) following experimental infection with a wild-type influenza A/H1N1pdm virus

Summary

Introduction

Despite long-term investment, influenza continues to be a significant worldwide problem. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. We demonstrate that higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza

Methods

Results

Conclusion