Abstract
Influenza infections continue to cause significant annual morbidity and mortality despite ongoing influenza vaccine research. Adjuvants are administered in conjunction with influenza vaccines to enhance the immune response and strengthen protection against disease. Squalene-based emulsion adjuvants including MF59, AS03, and AF03, are registered for administration with influenza vaccines and are widely used in many countries. Squalene-based emulsion adjuvants induce a strong innate immune response, enhancing antigen presentation both quantitively and qualitatively to generate strong B cell responses and antibody production. They also diversify the reactivity profiles and strengthen the affinities of antibodies against the influenza hemagglutinin, increasing protection across virus clades. In this review, we consider the mechanisms of the enhancement of innate and adaptive immune responses by squalene-based emulsionSE adjuvants and the resulting increase in magnitude and breadth of hemagglutinin-specific B cell responses. We relate observed effects of SE adjuvants and current mechanistic understandings to events in responding lymph nodes. These insights will guide the rational design and optimization of influenza vaccines to provide broad and effective protection.
Highlights
Seasonal and pandemic influenza infections in humans continue to be a significant health threat, causing tremendous economic and societal burdens annually in the United States [1,2]
As we have described above, squalene-based emulsion (SE) adjuvant effects stem from events at the site of injection that result in rapid and increased delivery of antigen, primarily cell-associated, to drive B cell responses in draining lymph nodes (LNs)
This work has established a broad understanding of mechanisms underlying SE adjuvant effects, but many details remain unclear
Summary
Seasonal and pandemic influenza infections in humans continue to be a significant health threat, causing tremendous economic and societal burdens annually in the United States [1,2]. Activated innate cells secrete additional inflammatory molecules [32,33], continuing as a positive feedback loop at the injected muscle to generate a robust innate immune response This mechanism allows SE adjuvants to create a localized transient ‘immunocompetent environment’ at the injection site, potently enhancing the antigen uptake and the activation of the APCs to migrate to the local lymph nodes and efficiently prime the adaptive system for B cell response [42]. Strong inflammatory molecule secretion by local and recruited innate cells provide positive feedback signals This mechanism allows efficient SE-induced relocalization of immunogens in a ‘bolus’ fashion, as opposed to the gradual antigen release mediated by depot-dependent Alum or CFA. The following section will explore how the SE-formulated immunogen delivery with their inflammatory signature leads to enhanced B cell responses to influenza vaccines in both magnitude and quality
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