Abstract

BackgroundThe elderly are at high risk from influenza, in part because immunity wanes with age and through the accumulation of comorbidities. A novel plant-derived virus-like-particle (VLP) vaccine bearing influenza hemagglutinin can induce a balanced humoral and cellular response in old mice (16–18 months) while split virion vaccines elicit mostly antibodies. Because mice also collect comorbidities and lose immune competence as they age, we wished to determine how the plant-derived VLP vaccine would perform in animals approaching the end of their life-span.Materials and methodsOld (24–26 months) female BALB/c mice received two intramuscular doses of H1-VLP vaccine, an inactivated H1N1 vaccine (IIV) (both based on A/H1N1/California/07/09) (3μg each) or PBS. Serum was collected on day 42 and humoral responses were measured by enzyme-linked immunosorbent assay (ELISA), microneutralization (MN) and hemagglutination inhibition (HI) assays. Influenza-specific splenocyte CD4+ & CD8+ T cell responses were measured by flow cytometry. Full body computed tomography (CT) and structured necropsies were performed on day 42. Comorbidities including reduced lung volume (kyphosis), masses, abscesses, etc. were assessed using a standard scoring system (1–21) and mice with scores ≥5 were considered to have important comorbidities.ResultsOverall, 53.3% of the animals had significant comorbidities. Three weeks post-boost, HI and MN titres were mostly undetectable but ELISA titres were significantly higher in the H1-VLP animals compared to the IIV group (GMT (95% CI): 961 (427, 2163) vs 425 (200, 903): p = 0.03). Both CD4+(TNFα, IFNγ) and CD8+ (IFNγ) T cell responses were also greater in the H1-VLP group than the IIV.ConclusionsEven in very old mice with comorbidities, the plant-made H1-VLP vaccine elicited a stronger and more balanced immune response than IIV. Animals with fewer comorbidities tended to have the better composite (humoral and cellular) responses. These novel vaccines have the potential to address some of the limitations of current vaccines in the elderly.

Highlights

  • The health risks of influenza increase steadily with age such that >70% of the mortality associated with seasonal outbreaks occurs in those 65 years of age [1]

  • Three weeks post-boost, hemagglutination inhibition (HI) and MN titres were mostly undetectable but enzyme-linked immunosorbent assay (ELISA) titres were significantly higher in the H1-Virus-like particles (VLPs) animals compared to the inactivated H1N1 vaccine (IIV) group (GMT: 961 (427, 2163) vs 425 (200, 903): p = 0.03)

  • VLP vaccine is more immunogenic than a split vaccine in older mice antibodies (Jackson ImmunoResearch Laboratories Inc., West Grove, PA) diluted 1:50,000 in blocking buffer was added (75 μL/well, 0.5 hr at 37 ̊C). 3,3’ 5,5’-tetramethyl benzidine (TMB) substrate (100 μL /well: Millipore, Billerica, MA) was used for detection followed by 0.5 M of H2SO4 after 15 minutes (50 μL /well)

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Summary

Introduction

The health risks of influenza increase steadily with age such that >70% of the mortality associated with seasonal outbreaks occurs in those 65 years of age [1]. The efficacy of current split-virion influenza vaccines typically diminishes as people grow older. There has been increasing evidence that older individuals are protected from influenza primarily by cellular rather than antibody responses [3,4,5]. Protection is far from optimal, the elderly can derive benefit from seasonal influenza vaccination despite making little-to-no antibody response [6,7,8]. The elderly are at high risk from influenza, in part because immunity wanes with age and through the accumulation of comorbidities. A novel plant-derived virus-like-particle (VLP) vaccine bearing influenza hemagglutinin can induce a balanced humoral and cellular response in old mice (16–18 months) while split virion vaccines elicit mostly antibodies. Because mice collect comorbidities and lose immune competence as they age, we wished to determine how the plant-derived VLP vaccine would perform in animals approaching the end of their life-span.

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