AuNP-M2e\u2009+\u2009sCpG vaccination of juvenile mice generates lifelong protective immunity to influenza A virus infection

Lynn Bimler,Amber Y Song,Duy T Le,Silke Paust,Ashleigh Murphy Schafer

doi:10.1186/s12979-019-0162-y

Abstract

BackgroundInfluenza virus infection causes significant morbidity and mortality worldwide. Humans fail to make a universally protective memory response to influenza A because of high mutation rates in the immune-dominant influenza epitopes. We seek the development of a universal influenza A vaccine. The extracellular domain of the M2-ion channel (M2e) is an ideal antigenic target, as it is highly conserved, has a low mutation rate, and is essential for viral entry and replication. Considering the potential of a universal influenza vaccine for lifelong protection, we aimed to examine this potential using a recently published gold nanoparticle M2e vaccine with CpG as an adjuvant (AuNP-M2e + sCpG). Intranasal vaccination induces an M2e-specific memory response, which is protective against lethal infection with H1N1, H3N2, and H5N1 serotypes, in young BALB/c mice. Protection with AuNP-M2e + sCpG has been published up to 8 months after vaccination. However, the highest risk population during most influenza seasons is adults over 65 years old. Additionally, the efficacy of many vaccines decrease after aging and requiring booster vaccinations to remain effective.ResultsTo determine if the AuNP-M2e + sCpG vaccine is a viable option as a universal vaccination capable of protection through geriatric age, we tested if the AuNP-M2e + sCpG vaccination loses efficacy after aging mice to geriatric age (over 18 months). Our data shows that mice aged 15 months after vaccination (~ 18–21 months old) retain significant M2e-specific antibody titers in total IgG, IgG1, IgG2a, and IgG2b. These mice are significantly protected from lethal influenza challenge (H1N1, 8.3 PFU). Further, these antibody titers increase upon infection with influenza A and remain elevated for 3 months, suggesting the elderly mice retain effective M2e-specific memory B cells.ConclusionsOur results demonstrate that protective M2e-specific memory in mice developed at a young age can persist until geriatric age. Additionally, this memory is protective and M2e-specific B cells produced by vaccination with AuNP-M2e + sCpG are maintained and functional. If the results of this study persist in humans, they suggest that a universal influenza A vaccine could be administered early in life and maintain lifelong protection into geriatric age.

Highlights

Influenza virus infection causes significant morbidity and mortality worldwide
To determine if the AuNPM2e + soluble CpG (sCpG) vaccine is a viable option as a universal vaccination and to begin to test it if might require re-administrations during a lifetime, we tested if the Gold nanoparticles (AuNP)-M2-ion channel (M2e) + sCpG vaccination loses efficacy after aging mice to geriatric age [31]
Repeated au-NP-M2e + sCpG vaccination of BALB/c mice induces long-term M2e-specific antibody titers of all Immunoglobulin G (IgG) subclasses We further analyzed the effect of the third AuNPM2e + sCpG vaccination by monitoring serum titer immediately post vaccination and 15 months post-vaccination (Fig. 2a)

Summary

Introduction

Humans fail to make a universally protective memory response to influenza A because of high mutation rates in the immune-dominant influenza epitopes. Worldwide up to 650,000 people die from influenza each year, including an average of 42,000 people within the United States, approximately 80% of whom are above the age of 65 [1,2,3]. The influenza vaccine must be updated annually because influenza virus lacks proofreading mechanisms during replication resulting in a high mutation rate. These mutations are especially prevalent in the most immunogenic proteins of influenza, and their accumulation is referred to as antigenic drift. During the 2013–2014 influenza season, the vaccine was 52% effective and vaccinated adults were 52–79% less likely to die as a result of influenza; the year (2014–2015), effectiveness of the vaccine dropped to 19% [8,9,10]

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