Vaccination with Deglycosylated Modified Hemagglutinin Broadly Protects against Influenza Virus Infection in Mice and Ferrets

Zhang, Limin; Chen, Junyu; Shen, Chenguang; Wang, Guosong; Lu, Zhen; Zeng, Dian; Gao, Ying; Chen, Huiqing; Xia, Ningshao; Chen, Yixin

doi:10.3390/vaccines10081304

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…Another concern with utilizing a viral vector for an LD vaccine is that the Bb proteins are glycosylated differently by Borrelia than when produced by mammalian cells, which is how a viral vector is developed. This could change the immune response to a bacterial protein induced by a viral vector [ 46 ]. In this study, we showed that the borrelial antigen BBI39 must be incorporated into the RABV virion to elicit high-titer anti-BBI39 antibodies.…”

Section: Discussionmentioning

confidence: 99%

The Development of a Rabies Virus-Vectored Vaccine against Borrelia burgdorferi, Targeting BBI39

Rios,

Bhattachan,

Vavilikolanu

et al. 2024

Vaccines

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Lyme disease (LD) is the most common tick-borne illness in the United States (U.S.), Europe, and Asia. Borrelia burgdorferi, a spirochete bacterium transmitted by the tick vector Ixodes scapularis, causes LD in the U.S. If untreated, Lyme arthritis, heart block, and meningitis can occur. Given the absence of a human Lyme disease vaccine, we developed a vaccine using the rabies virus (RABV) vaccine vector BNSP333 and an outer surface borrelial protein, BBI39. BBI39 was previously utilized as a recombinant protein vaccine and was protective in challenge experiments; therefore, we decided to utilize this protective antigen in a rabies virus-vectored vaccine against Borrelia burgdorferi. To incorporate BBI39 into the RABV virion, we generated a chimeric BBI39 antigen, BBI39RVG, by fusing BBI39 with the final amino acids of the RABV glycoprotein by molecular cloning and viral recovery with reverse transcription genetics. Here, we have demonstrated that the BBI39RVG antigen was incorporated into the RABV virion via immunofluorescence and Western blot analysis. Mice vaccinated with our BPL inactivated RABV-BBI39RVG (BNSP333-BBI39RVG) vaccine induced high amounts of BBI39-specific antibodies, which were maintained long-term, up to eight months post-vaccination. The BBI39 antibodies neutralized Borrelia in vaccinated mice when challenged with Borrelia burgdorferi by either syringe injection or infected ticks and they reduced the Lyme disease pathology of arthritis in infected mouse joints. Overall, the RABV-based LD vaccine induced more and longer-term antibodies compared to the recombinant protein vaccine. This resulted in lower borrelial RNA in RABV-based vaccinated mice compared to recombinant protein vaccinated mice. The results of this study indicate the successful use of BBI39 as a vaccine antigen and RABV as a vaccine vector for LD.

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Section: Discussionmentioning

confidence: 99%

The Development of a Rabies Virus-Vectored Vaccine against Borrelia burgdorferi, Targeting BBI39

Rios,

Bhattachan,

Vavilikolanu

et al. 2024

Vaccines

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“…Perhaps, in the case of surface proteins such as HA or NA, glycosylation may not keep pace with the high rate of their induced expression and deployment to the cell membrane or, possibly, the progeny virus envelope. A recent study demonstrated that an unglycosylated HA induced a broader protective response than the corresponding fully glycosylated HA [50].…”

Section: Discussionmentioning

confidence: 99%

Very Broadly Effective Hemagglutinin-Directed Influenza Vaccines with Anti-Herpetic Activity

Bloom,

Lilly,

Canty

et al. 2024

Vaccines

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A universal vaccine that generally prevents influenza virus infection and/or illness remains elusive. We have been exploring a novel approach to vaccination involving replication-competent controlled herpesviruses (RCCVs) that can be deliberately activated to replicate efficiently but only transiently in an administration site in the skin of a subject. The RCCVs are derived from a virulent wild-type herpesvirus strain that has been engineered to contain a heat shock promoter-based gene switch that controls the expression of, typically, two replication-essential viral genes. Additional safety against inadvertent replication is provided by an appropriate secondary mechanism. Our first-generation RCCVs can be activated at the administration site by a mild local heat treatment in the presence of an antiprogestin. Here, we report that epidermal vaccination with such RCCVs expressing a hemagglutinin or neuraminidase of an H1N1 influenza virus strain protected mice against lethal challenges by H1N1 virus strains representing 75 years of evolution. Moreover, immunization with an RCCV expressing a subtype H1 hemagglutinin afforded full protection against a lethal challenge by an H3N2 influenza strain, and an RCCV expressing a subtype H3 hemagglutinin protected against a lethal challenge by an H1N1 strain. Vaccinated animals continued to gain weight normally after the challenge. Protective effects were even observed in a lethal influenza B virus challenge. The RCCV-based vaccines induced robust titers of in-group, cross-group and even cross-type neutralizing antibodies. Passive immunization suggested that observed vaccine effects were at least partially antibody-mediated. In summary, RCCVs expressing a hemagglutinin induce robust and very broad cross-protective immunity against influenza.

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“…Human viruses including influenza A virus (IAV) and SARS-CoV-2 use host-made glycans to facilitate infection and to shield the conserved epitopes on the virus surface from immune response. Vaccination with mono-glycosylated hemagglutinin (HA) or inactivated IAV-induced cross-strain protection against influenza virus infections ( 10 , 30 – 31 ). Interestingly, the HA stem-specific antibodies are broadly protective against most type A influenza viruses ( 32 , 33 ), and previous studies showed that deletion of the glycans in HA elicited a high level of stem-specific antibodies ( 34 – 37 ) and T cell response ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Low-sugar universal mRNA vaccine against coronavirus variants with deletion of glycosites in the S2 or stem of SARS-CoV-2 spike messenger RNA (mRNA)

Cheng,

Wu,

Wang

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Since the outbreak of Severe Acute Respiratory Syndrome Virus-2 (SARS-CoV-2) in 2019, more than 15 million spike protein sequences have been identified, raising a new challenge for the development of a broadly protective vaccine against the various emerging variants. We found that the virus, like most other human viruses, depends on host-made glycans to shield the conserved epitopes on spike protein from immune response and demonstrated that deletion of the glycan shields exposed highly conserved epitopes and elicited broadly protective immune responses. In this study, we identified 17 conserved epitopes from 14 million spike protein sequences and 11 of the conserved epitopes are in the S2 domain, including the six most conserved epitopes in the stem region. We also demonstrated that deletion of the glycosites in the spike messenger RNA (mRNA) S2 domain or the stem region exposed the highly conserved epitopes and elicited broadly protective immune responses, particularly CD-8 + T cell response against various SARS-CoV-2 variants, and other human coronaviruses including MERS, SARS viruses, and those causing common cold.

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Vaccination with Deglycosylated Modified Hemagglutinin Broadly Protects against Influenza Virus Infection in Mice and Ferrets

Cited by 3 publications

References 35 publications

The Development of a Rabies Virus-Vectored Vaccine against Borrelia burgdorferi, Targeting BBI39

The Development of a Rabies Virus-Vectored Vaccine against Borrelia burgdorferi, Targeting BBI39

Very Broadly Effective Hemagglutinin-Directed Influenza Vaccines with Anti-Herpetic Activity

Low-sugar universal mRNA vaccine against coronavirus variants with deletion of glycosites in the S2 or stem of SARS-CoV-2 spike messenger RNA (mRNA)

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