Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination.

Sarah M Tete,Florian Krammer,Rebecca J Cox,Sarah Lartey,Geir Bredholt,Steinar Skrede,John Wood

doi:10.1038/npjvaccines.2016.1

Abstract

Traditionally, neutralising antibodies that are directed to the major surface glycoprotein hemagglutinin (HA) head domain are measured as surrogate correlates of protection against influenza. In addition to neutralization, hemagglutinin-specific antibodies may provide protection by mediating antibody-dependent cellular cytotoxicity (ADCC). During the 2009 pandemic, vaccination induced HA-specific antibodies that were mostly directed to the conserved HA stalk domain. However, the protective role of these antibodies has not been investigated in detail. We quantified the HA head and stalk-specific antibodies, their avidity, ability to neutralise virus and activate natural killer cells in an ADCC assay. We analyzed sera obtained from 14 healthcare workers who had low hemagglutination inhibition (HI) antibody titres at 3 months after pandemic H1N1 vaccination as well as from 22 controls. Vaccination resulted in a HA stalk dominant antibody response in both low responders and controls. Revaccination of low responders, 5 months later, resulted in a boost in antibodies, with HA head-specific antibodies dominating the response. Comparative analysis of head and stalk antibody avidities revealed that stalk-specific antibodies were qualitatively superior. Furthermore, stalk-specific antibodies mediated virus neutralization and had significantly higher ADCC activity than head-specific antibodies. Despite the head and stalk-specific antibodies being lower in low responders, they had comparable antibody avidity, ADCC functionality and neutralising capacity to those of controls who had high HI titres post-vaccination. Thus, our study has demonstrated that HA stalk-specific antibodies may have an important role in protection through neutralization and ADCC in low responders who do not maintain seroprotective HI antibodies.

Highlights

Influenza pandemics occur at unpredictable intervals when a novel influenza virus arises which can place a major strain on the global healthcare system
Thirty-six healthcare workers (HCW) were recruited to the study based on their hemagglutination inhibition (HI) response and split into two groups; low responders (LRs) who failed to maintain protective HI titres by 3 months (3M) and a control group (Figure 1a)
All the controls maintained their protective HI titres at 3 mol/l, whereas HI titres decreased below protective levels for all the LRs (Figure 1b)

Summary

Introduction

Influenza pandemics occur at unpredictable intervals when a novel influenza virus arises which can place a major strain on the global healthcare system. These pandemic viruses can cause high levels of severe illness and death. In 2009, an influenza A H1N1 virus strain caused a pandemic that started in Mexico and California rapidly spread globally. Annual influenza vaccination is recommended for healthcare workers (HCW) so as to maintain the integrity of the healthcare system, reduce absenteeism and reduce influenza A transmission to vulnerable patients.[1] Vaccination of HCWs has been shown to protect hospitalised patients as well as decrease influenza-like illness and mortality in residents of care-facilities.[2] During the 2009 pandemic outbreak, the World Health Organization prioritised

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