Coexpressed RIG-I Agonist Enhances Humoral Immune Response to Influenza Virus DNA Vaccine

Luke, Jeremy; Simon, Gregory G.; Söderholm, Jonas; Errett, John S.; August, J. Thomas; Gale, Michael; Hodgson, Clague P.; Williams, James A.

doi:10.1128/jvi.01250-10

Cited by 73 publications

(60 citation statements)

References 77 publications

(76 reference statements)

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“…We found that mice im- munized with sparing doses of vaccine antigens with RIG-I ligand had long-lasting IgG and HAI antibodies sustained at significantly higher levels and were protected against a lethal pandemic virus challenge. Recently, two other studies also suggested the use of RIG-I agonists in boosting influenza immunity (27,45). However, the abilities of these molecules to offer antigen-sparing effects, induction of HAI antibodies, and protection against pandemic influenza virus challenge were not investigated in these studies.…”

Section: Discussionmentioning

confidence: 99%

Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity

Kulkarni

Rasheed

Bhaumik

et al. 2014

J Virol

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Pattern recognition receptors (PRR) sense certain molecular patterns uniquely expressed by pathogens. Retinoic-acid-inducible gene I (RIG-I) is a cytosolic PRR that senses viral nucleic acids and induces innate immune activation and secretion of type I interferons (IFNs). Here, using influenza vaccine antigens, we investigated the consequences of activating the RIG-I pathway for antigen-specific adaptive immune responses. We found that mice immunized with influenza vaccine antigens coadministered with 5=ppp-double-stranded RNA (dsRNA), a RIG-I ligand, developed robust levels of hemagglutination-inhibiting antibodies, enhanced germinal center reaction, and T follicular helper cell responses. In addition, RIG-I activation enhanced antibody affinity maturation and plasma cell responses in the draining lymph nodes, spleen, and bone marrow and conferred protective immunity against virus challenge. Importantly, activation of the RIG-I pathway was able to reduce the antigen requirement by 10-to 100-fold in inducing optimal influenza-specific cellular and humoral responses, including protective immunity. The effects induced by 5=ppp-dsRNA were significantly dependent on type I IFN and IPS-1 (an adapter protein downstream of the RIG-I pathway) signaling but were independent of the MyD88-and TLR3-mediated pathways. Our results show that activation of the RIG-I-like receptor pathway programs the innate immunity to achieve qualitatively and quantitatively enhanced protective cellular adaptive immune responses even at low antigen doses, and this indicates the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines. IMPORTANCEThe recently discovered RNA helicase family of RIG-I-like receptors (RLRs) is a critical component of host defense mechanisms responsible for detecting viruses and triggering innate antiviral cytokines that help control viral replication and dissemination. In this study, we show that the RLR pathway can be effectively exploited to enhance adaptive immunity and protective immune memory against viral infection. Our results show that activation of the RIG-I pathway along with influenza vaccination programs the innate immunity to induce qualitatively and quantitatively superior protective adaptive immunity against pandemic influenza viruses. More importantly, RIG-I activation at the time of vaccination allows induction of robust adaptive responses even at low vaccine antigen doses. These results highlight the potential utility of exploiting the RIG-I pathway to enhance viralvaccine-specific immunity and have broader implications for designing better vaccines in general.

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Section: Discussionmentioning

confidence: 99%

Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity

Kulkarni

Rasheed

Bhaumik

et al. 2014

J Virol

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show abstract

“…[40][41][42][43][44] Since the influenza viruses mutate frequently, the virus strains for new vaccine production require continuous manufacturing update, in order to be antigenically well-matched to the circulating strains. For this reason, a vaccine shaped on invariant regions of the virus, providing broadly cross-reactive protection could represent a long-sought goal, particularly for emerging pandemics.…”

Section: Tm -Adjuvanted Vaccinesmentioning

confidence: 99%

Cross-protection against drifted influenza viruses

Orsi

Ansaldi

Florentiis

et al. 2013

Human Vaccines & Immunotherapeutics

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“…32 Co-immunization with retinoic acid inducible-gene I (RIG-I) agonist enhances humoral immune response induced by influenza virus DNA vaccine. 33 Consistently, boosting innate immune PRR signaling by co-expressing intracellular adaptor molecules or downstream transcription factors as genetic adjuvants are efficient strategies for enhancing immunogenic of DNA vaccines. 34,35 These results imply that AIM2 might serve as an adjuvant and enhance the immunogenicity of pVP1 vaccine and efficiently induce CVB3-specific immune responses.…”

Section: Discussionmentioning

confidence: 99%

Mucosal co-immunization with AIM2 enhances protective SIgA response and increases prophylactic efficacy of chitosan-DNA vaccine against coxsackievirus B3-induced myocarditis

Chai

Yan²,

Xu³

et al. 2014

Human Vaccines & Immunotherapeutics

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Coexpressed RIG-I Agonist Enhances Humoral Immune Response to Influenza Virus DNA Vaccine

Cited by 73 publications

References 77 publications

Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity

Activation of the RIG-I Pathway during Influenza Vaccination Enhances the Germinal Center Reaction, Promotes T Follicular Helper Cell Induction, and Provides a Dose-Sparing Effect and Protective Immunity

Cross-protection against drifted influenza viruses

Mucosal co-immunization with AIM2 enhances protective SIgA response and increases prophylactic efficacy of chitosan-DNA vaccine against coxsackievirus B3-induced myocarditis

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