Comparative studies of infectivity, immunogenicity and cross-protective efficacy of live attenuated influenza vaccines containing nucleoprotein from cold-adapted or wild-type influenza virus in a mouse model

Isakova–Sivak, Irina; Korenkov, Daniil; Smolonogina, Tatiana; Tretiak, Tatiana; Donina, Svetlana; Rekstin, Andrey; Naykhin, Anatoly; Shcherbik, Svetlana; Pearce, Nicholas; Chen, Limei; Bousse, Tatiana

doi:10.1016/j.virol.2016.10.027

Cited by 25 publications

(24 citation statements)

References 37 publications

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“…The rationale for including recent NP in the LAIV genome composition has been discussed in the context of our previous studies in a mouse model [37,38], and in in vitro study of human donor peripheral blood mononuclear cells [36]. In this ferret study, for the first time the two strategies for enhancing the cross-protective potential of traditional LAIVs were combined, and sequential immunizations with the vaccines expressing cHAs and WT NP were compared with classical LAIVs and with cHA-based…”

Section: Discussionmentioning

confidence: 99%

Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

Isakova–Sivak¹,

Matyushenko²,

Kotomina³

et al. 2018

Preprint

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The development of universal influenza vaccines, i.e. vaccines that can provide broad protection against seasonal and potentially pandemic influenza viruses, has been a priority for more than 20 years. Several approaches have been proposed that redirect the adaptive immune responses from immunodominant hypervariable regions to low-immunogenic but highly conserved regions of viral proteins. Here we induced broadly reactive anti-hemagglutinin (HA) stalk antibody by sequential immunizations with live attenuated influenza vaccines (LAIVs) expressing chimeric HA (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. In addition, the source of the viral nucleoprotein (NP) of the LAIV strains was changed from A/Leningrad/17 master donor virus (MDV) to wild-type (WT) H1N1pdm09 virus, in order to induce CD8 T-cell immune responses more relevant to current infections. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Naïve ferrets were immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) > cHA LAIVs (NP-MDV) > LAIVs (NP-MDV). This ferret study showed that prototype universal LAIVs that combine the two approaches of inducing anti-HA stalk antibody and more relevant CD8 T-cell immune responses are highly promising candidates for further clinical development.

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Section: Discussionmentioning

confidence: 99%

Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

Isakova–Sivak¹,

Matyushenko²,

Kotomina³

et al. 2018

Preprint

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“…Indeed, only one third of the predicted the human leukocyte antigen (HLA) class I-restricted NP epitopes identified in A(H2N2) MDV Len/17 are conserved in recent A(H1N1) and A(H3N2) isolates (Machkovech et al, 2015). Additionally, we have found that at least 28 HLA class I-restricted epitopes have diverged between Len/17 MDV and recent A(H3N2) influenza virus NP (Isakova-Sivak et al, 2017).…”

Section: Introductionmentioning

confidence: 94%

Safety, immunogenicity and protection of A(H3N2) live attenuated influenza vaccines containing wild-type nucleoprotein in a ferret model

Korenkov

Laurie

Reading

et al. 2018

Infection, Genetics and Evolution

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Live attenuated influenza vaccines (LAIVs) are promising tools for the induction of broad protection from influenza due to their ability to stimulate cross-reactive T cells against influenza pathogens. One of the major targets for cytotoxic T-cell immunity is viral nucleoprotein (NP), which is relatively conserved among antigenically distant influenza viruses. Nevertheless, a diversity of epitope composition has been found in the NP protein of different lineages of influenza A viruses. The H2N2 master donor virus which is currently used as a backbone for the LAIV and donor of the six genomic segments encoding the internal proteins, A/Leningrad/134/17/57 (MDV Len/17), was isolated 60 years ago. As such, NP-specific T-cell immunity induced upon vaccination with classical LAIVs with a 6:2 genome composition containing this older NP might be suboptimal against currently circulating influenza viruses. In this study, a panel of H3N2 LAIV candidates with wild-type NP genes derived from circulating viruses were generated by reverse genetics (5:3 genome composition). These viruses displayed the cold adaptation and temperature sensitivity phenotypes of MDV Len/17 in vitro. LAIVs with both 6:2 and 5:3 genome compositions were attenuated and replicated to a similar extent in the upper respiratory tract of ferrets. LAIVs were immunogenic as high neutralizing and hemagglutination inhibition serum antibody titers were detected 21 days after infection. All vaccinated animals were protected against infection with heterologous H3N2 influenza A viruses. Thus, LAIV with a 5:3 genome composition is safe, immunogenic and can induce cross-protective immunity.

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“…Nevertheless, all three vaccines fully protected immunized mice against replications in the respiratory tract of the homologous challenge virus administered at a high dose (100 MLD 50 ), whereas this challenge virus reproduced to high titer levels in mock-immunized mice, both in the lungs and the nasal turbinates ( Figure 5 C). Although we did not measure mucosal IgA antibody levels in immunized mice, our previous results indicate that this arm of adaptive immune responses may also contribute to the protection [ 49 ]. Overall, these data suggest that the inserted immunogenic epitopes of AdV did not interfere with influenza-specific antibody immune responses induced by LAIV intranasal immunization.…”

Section: Resultsmentioning

confidence: 99%

Recombinant Live Attenuated Influenza Vaccine Viruses Carrying Conserved T Cell Epitopes of Human Adenoviruses Induce Functional Cytotoxic T Cell Responses and Protect Mice against both Infections

et al. 2020

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Human adenoviruses (AdVs) are one of the most common causes of acute respiratory viral infections worldwide. Multiple AdV serotypes with low cross-reactivity circulate in the human population, making the development of an effective vaccine very challenging. In the current study, we designed a cross-reactive AdV vaccine based on the T-cell epitopes conserved among various AdV serotypes, which were inserted into the genome of a licensed cold-adapted live attenuated influenza vaccine (LAIV) backbone. We rescued two recombinant LAIV-AdV vaccines by inserting the selected AdV T-cell epitopes into the open reading frame of full-length NA and truncated the NS1 proteins of the H7N9 LAIV virus. We then tested the bivalent vaccines for their efficacy against influenza and human AdV5 in a mouse model. The vaccine viruses were attenuated in C57BL/6J mice and induced a strong influenza-specific antibody and cell-mediated immunity, fully protecting the mice against virulent influenza virus infection. The CD8 T-cell responses induced by both LAIV-AdV candidates were functional and efficiently killed the target cells loaded either with influenza NP366 or AdV DBP418 peptides. In addition, high levels of recall memory T cells targeted to an immunodominant H2b-restricted CD8 T-cell epitope were detected in the immunized mice after the AdV5 challenge, and the magnitude of these responses correlated with the level of protection against pulmonary pathology caused by the AdV5 infection. Our findings suggest that the developed recombinant vaccines can be used for combined protection against influenza and human adenoviruses and warrant further evaluation on humanized animal models and subsequent human trials.

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Comparative studies of infectivity, immunogenicity and cross-protective efficacy of live attenuated influenza vaccines containing nucleoprotein from cold-adapted or wild-type influenza virus in a mouse model

Cited by 25 publications

References 37 publications

Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

Sequential Immunization with Universal Live Attenuated Influenza Vaccine Candidates Protects Ferrets against a High-Dose Heterologous Virus Challenge

Safety, immunogenicity and protection of A(H3N2) live attenuated influenza vaccines containing wild-type nucleoprotein in a ferret model

Recombinant Live Attenuated Influenza Vaccine Viruses Carrying Conserved T Cell Epitopes of Human Adenoviruses Induce Functional Cytotoxic T Cell Responses and Protect Mice against both Infections

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