Novel TLR4 adjuvant elicits protection against homologous and heterologous Influenza A infection

Haupt, Robert; Harberts, Erin; Kitz, Robert; Strohmeier, Shirin; Krammer, Florian; Ernst, Robert K.; Frieman, Matthew B.

doi:10.1016/j.vaccine.2021.06.085

Cited by 17 publications

(26 citation statements)

References 25 publications

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“…Previous pre-clinical vaccine studies using BECC470 as an adjuvant have shown that BECC470 generated a balanced Th1/Th2 immune response 19 . To investigate the Th1 and Th2 immune response elicited by IN and IM BReC-CoV-2 vaccination, IgG1 (Th2) and IgG2c (Th1) subtypes were analyzed in the serum.…”

Section: Resultsmentioning

confidence: 99%

“…BECC adjuvants have been successfully used in both viral and bacterial pre-clinical vaccine formulations and are shown to generate a balanced Th1/Th2 response 18 . Viral vaccine studies with Influenza virus H1N1 showed decreased viral titers and weight loss when influenza hemagglutinin antigen was adjuvanted with BECC470, as well as elicited a balanced Th1/Th2 immune response 19 .…”

Section: Introductionmentioning

confidence: 99%

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Intranasal administration of BReC-CoV-2 COVID-19 vaccine protects K18-hACE2 mice against lethal SARS-CoV-2 challenge

et al. 2022

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SARS-CoV-2 is a viral respiratory pathogen responsible for the current global pandemic and the disease that causes COVID-19. All current WHO approved COVID-19 vaccines are administered through the muscular route. We have developed a prototype two-dose vaccine (BReC-CoV-2) by combining the Receptor Binding Domain (RBD) antigen, via conjugation to Diphtheria toxoid (EcoCRM®). The vaccine is adjuvanted with Bacterial Enzymatic Combinatorial Chemistry (BECC), BECC470. Intranasal (IN) administration of BreC-CoV-2 in K18-hACE2 mice induced a strong systemic and localized immune response in the respiratory tissues which provided protection against the Washington strain of SARS-CoV-2. Protection provided after IN administration of BReC-CoV-2 was associated with decreased viral RNA copies in the lung, robust RBD IgA titers in the lung and nasal wash, and induction of broadly neutralizing antibodies in the serum. We also observed that BReC-CoV-2 vaccination administered using an intramuscular (IM) prime and IN boost protected mice from a lethal challenge dose of the Delta variant of SARS-CoV-2. IN administration of BReC-CoV-2 provided better protection than IM only administration to mice against lethal challenge dose of SARS-CoV-2. These data suggest that the IN route of vaccination induces localized immune responses that can better protect against SARS-CoV-2 than the IM route in the upper respiratory tract.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intranasal administration of BReC-CoV-2 COVID-19 vaccine protects K18-hACE2 mice against lethal SARS-CoV-2 challenge

et al. 2022

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“…Protection in aged mice with BECC-adjuvanted vaccine Using young adult (6-8-week-old) mice, we previously reported protection from IAV challenge after vaccination with H1 (A/California/04/2009) formulated with BECC438 and BECC470 [16]; 0.04 μg rHA elicited protection from homologous challenge in formulations adjuvanted with 50 μg BECC438 or BECC470, unlike those adjuvanted with 100 μg of alum or 50 μg PHAD [16]. As a follow-up to these experiments, we wanted to assess adjuvant induced protection in aged (~12-month-old) mice to determine if immunosenescence observed in aging could be recovered through the use of the BECCbased adjuvant system.…”

Section: Resultsmentioning

confidence: 99%

“…These differences in BECC adjuvant lipid A structure have been shown to stimulate an innate immune response greater than phosphorylated hexa-acyl disaccharide (PHAD), a monophosphorylated lipid A, but less than E. coli [14,15]. Previously, we showed that novel BECC-derived BECC438 and BECC470 stimulate a balanced Th1/Th2 immune response and elicit protection from homologous in uenza virus infection and in 6-8-week-old mice, with either prime-boost or prime only vaccination schedule [16]. BECC's balanced response provided superior protection from weight loss, lung viral titer reduction, and reduction of adverse lung pathology, when compared to the Th2-driven adjuvant alhydrogel (alum), an aluminum salt or Th1-driven PHAD, a toll like receptor (TLR) 4 ligand and synthetic monophosphoryl lipid A (4' position).…”

Section: Adjuvants Boost Immune Protectionmentioning

confidence: 99%

“…Because there was BECC-adjuvanted vaccine protection in young adult mice [16] and aged mice (Figures 2G, H and 3G, H) we followed up stalk binding by testing antibody reactivity to commercially sourced HA1 antigen which includes the HA head domain, but lacks broadly cross-reactive stalk epitopes. In the sera of young adult mice, we not only found signi cantly higher levels of stalk antibody in BECC438 and BECC470-adjuvanted mice, but the same with HA1-only reactive antibody compared to PHAD (p=0.0008 and p=0.0002) (Figure 4F and 4H).…”

Section: Becc Adjuvant Induced Antibody Reduces Disease Burdenmentioning

confidence: 99%

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Enhancing the Protection of Influenza Virus Vaccines with BECC TLR4 Adjuvant in Aged Mice

Frieman

Haupt

Baracco

et al. 2022

Preprint

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Influenza A virus (IAV) is a leading cause of respiratory disease worldwide often resulting in severe morbidity and mortality. We have previously shown that the Bacterial Enzymatic Combinatorial Chemistry (BECC) adjuvants, BECC438 and BECC470, formulated with an influenza virus hemagglutinin (HA) protein vaccine, offer greater protection from influenza virus challenge in mouse respiratory models using adult mice than standard HA:adjuvant combinations. In this study, we determined that immunization with HA+BECC adjuvants also significantly broadened the epitopes targeted on HA as compared with other adjuvants, resulting in increased titers of antibodies directed against the highly conserved HA stalk domain. Importantly, we demonstrate that BECC470 combined with an influenza virus HA protein antigen in a prime-only immunization regimen was able to achieve complete protection from challenge in a ~12-month-old mouse aged model. Together, this demonstrates the heightened protection provided by the BECC470 adjuvant in an influenza virus vaccine model and shows the enhanced immune response, as compared to other adjuvants elicited by the formulation of HA with BECC470.

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Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

Strobl,

Zucchetta,

Vašíček

et al. 2024

Angewandte Chemie

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Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, toll‐like receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of Lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1'‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1')βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation.

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Novel TLR4 adjuvant elicits protection against homologous and heterologous Influenza A infection

Cited by 17 publications

References 25 publications

Intranasal administration of BReC-CoV-2 COVID-19 vaccine protects K18-hACE2 mice against lethal SARS-CoV-2 challenge

Intranasal administration of BReC-CoV-2 COVID-19 vaccine protects K18-hACE2 mice against lethal SARS-CoV-2 challenge

Enhancing the Protection of Influenza Virus Vaccines with BECC TLR4 Adjuvant in Aged Mice

Nonreducing Sugar Scaffold Enables the Development of Immunomodulatory TLR4‐specific LPS Mimetics with Picomolar Potency

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