Thermostable H1 hemagglutinin stem with M2e epitopes provides broad cross-protection against group1 and 2 influenza A viruses

Jeeva Subbbiah; Judy Oh; Ki Hye Kim; Chong Hyun Shin; Bo Ryoung Park; Noopur Bhatnagar; Yu Jin Jung; Youri Lee; Bao Zhong Wang; Baik Lin Seong; Sang Moo Kang

doi:10.1016/j.omtm.2022.05.007

Thermostable H1 hemagglutinin stem with M2e epitopes provides broad cross-protection against group1 and 2 influenza A viruses

Jeeva Subbbiah, Judy Oh, Ki Hye Kim, Chong Hyun Shin, Bo Ryoung Park, Noopur Bhatnagar, Yu Jin Jung, Youri Lee, Bao Zhong Wang, Baik Lin Seong, Sang Moo Kang

Research output: Contribution to journal › Article › peer-review

Abstract

Hemagglutinin (HA) stem-based vaccines have limitations in providing broad and effective protection against cross-group influenza viruses, despite being a promising universal vaccine target. To overcome the limited cross-protection and low efficacy by HA stem vaccination, we genetically engineered a chimeric conjugate of thermostable H1 HA stem and highly conserved M2e repeat (M2e-H1stem), which was expressed at high yields in Escherichia coli. M2e-H1stem protein presented native-like epitopes reactive to antisera of live virus infection. M2e-H1stem protein vaccination of mice induced strong M2e- and HA stem-specific immune responses, conferring broadly effective cross-protection against both antigenically distinct group 1 (H1N1, H5N1, and H9N2 subtypes) and group 2 (H3N2 and H7N9 subtypes) seasonal and pandemic potential influenza viruses. M2e-H1stem vaccination generated CD4⁺ and CD8⁺ T cell responses and antibody-dependent cytotoxic cellular and humoral immunity, which contributed to enhancing cross-protection. Furthermore, comparable broad cross-group protection was observed in older aged mice after M2e-H1stem vaccination. This study provides evidence warranting further development of chimeric M2e-stem proteins as a promising universal influenza vaccine candidate in adult and aged populations.

Original language	English
Pages (from-to)	38-51
Number of pages	14
Journal	Molecular Therapy - Methods and Clinical Development
Volume	26
DOIs	https://doi.org/10.1016/j.omtm.2022.05.007
Publication status	Published - 2022 Sept 8

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health and National Institute of Allergy and Infectious Diseases grants AI093772 (S.-M.K.), AI154656 (S.-M.K.), and AI147042 (S.-M.K). The following reagents were obtained from BEI Resources, NIAID, NIH: mouse adapted A/Fort Monmouth/1/1947 H1N1 (NR-28618), reassortant A/Nanchang/933/1995 H3N2 with A/PR8 backbone (NR-3692), A/Hong Kong/1/1968 H3N2 (NR-28634), and SARS-CoV-2 foldon-linked spike protein (NR-52396). A/Hong Kong/1073/99 H9N2 influenza virus (FR-732) was obtained from International Reagent Resource.

Funding Information:
This study was supported by National Institutes of Health and National Institute of Allergy and Infectious Diseases grants AI093772 (S.-M.K.), AI154656 (S.-M.K.), and AI147042 (S.-M.K). The following reagents were obtained from BEI Resources, NIAID, NIH: mouse adapted A/Fort Monmouth/1/1947 H1N1 (NR-28618), reassortant A/Nanchang/933/1995 H3N2 with A/PR8 backbone (NR-3692), A/Hong Kong/1/1968 H3N2 (NR-28634), and SARS-CoV-2 foldon-linked spike protein (NR-52396). A/Hong Kong/1073/99 H9N2 influenza virus (FR-732) was obtained from International Reagent Resource. S.-M.K. and J.S. conceptualized and designed the research. J.S. designed the vaccine construct and generated the M2e-H1stem vaccine. J.S. J.O. and K.-H.K. characterized the vaccine antigens. J.S. J.O. K.-H.K. C.H.S. B.R.P. N.B. Y.-J.J. and Y.L. performed research. B.-Z.W. and B.-L.S. contributed to providing critical reagents. J.S. C.H.S. and S.-M.K. wrote the paper. All authors discussed the results and approved the final version of the manuscript. Some data presented in this manuscript will be included in the patent application. The authors declare no competing interests.

Publisher Copyright:
© 2022 The Author(s)

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Genetics

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10.1016/j.omtm.2022.05.007

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Subbbiah, J., Oh, J., Kim, K. H., Shin, C. H., Park, B. R., Bhatnagar, N., Jung, Y. J., Lee, Y., Wang, B. Z., Seong, B. L., & Kang, S. M. (2022). Thermostable H1 hemagglutinin stem with M2e epitopes provides broad cross-protection against group1 and 2 influenza A viruses. Molecular Therapy - Methods and Clinical Development, 26, 38-51. https://doi.org/10.1016/j.omtm.2022.05.007

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title = "Thermostable H1 hemagglutinin stem with M2e epitopes provides broad cross-protection against group1 and 2 influenza A viruses",

abstract = "Hemagglutinin (HA) stem-based vaccines have limitations in providing broad and effective protection against cross-group influenza viruses, despite being a promising universal vaccine target. To overcome the limited cross-protection and low efficacy by HA stem vaccination, we genetically engineered a chimeric conjugate of thermostable H1 HA stem and highly conserved M2e repeat (M2e-H1stem), which was expressed at high yields in Escherichia coli. M2e-H1stem protein presented native-like epitopes reactive to antisera of live virus infection. M2e-H1stem protein vaccination of mice induced strong M2e- and HA stem-specific immune responses, conferring broadly effective cross-protection against both antigenically distinct group 1 (H1N1, H5N1, and H9N2 subtypes) and group 2 (H3N2 and H7N9 subtypes) seasonal and pandemic potential influenza viruses. M2e-H1stem vaccination generated CD4+ and CD8+ T cell responses and antibody-dependent cytotoxic cellular and humoral immunity, which contributed to enhancing cross-protection. Furthermore, comparable broad cross-group protection was observed in older aged mice after M2e-H1stem vaccination. This study provides evidence warranting further development of chimeric M2e-stem proteins as a promising universal influenza vaccine candidate in adult and aged populations.",

author = "Jeeva Subbbiah and Judy Oh and Kim, {Ki Hye} and Shin, {Chong Hyun} and Park, {Bo Ryoung} and Noopur Bhatnagar and Jung, {Yu Jin} and Youri Lee and Wang, {Bao Zhong} and Seong, {Baik Lin} and Kang, {Sang Moo}",

note = "Funding Information: This study was supported by National Institutes of Health and National Institute of Allergy and Infectious Diseases grants AI093772 (S.-M.K.), AI154656 (S.-M.K.), and AI147042 (S.-M.K). The following reagents were obtained from BEI Resources, NIAID, NIH: mouse adapted A/Fort Monmouth/1/1947 H1N1 (NR-28618), reassortant A/Nanchang/933/1995 H3N2 with A/PR8 backbone (NR-3692), A/Hong Kong/1/1968 H3N2 (NR-28634), and SARS-CoV-2 foldon-linked spike protein (NR-52396). A/Hong Kong/1073/99 H9N2 influenza virus (FR-732) was obtained from International Reagent Resource. Funding Information: This study was supported by National Institutes of Health and National Institute of Allergy and Infectious Diseases grants AI093772 (S.-M.K.), AI154656 (S.-M.K.), and AI147042 (S.-M.K). The following reagents were obtained from BEI Resources, NIAID, NIH: mouse adapted A/Fort Monmouth/1/1947 H1N1 (NR-28618), reassortant A/Nanchang/933/1995 H3N2 with A/PR8 backbone (NR-3692), A/Hong Kong/1/1968 H3N2 (NR-28634), and SARS-CoV-2 foldon-linked spike protein (NR-52396). A/Hong Kong/1073/99 H9N2 influenza virus (FR-732) was obtained from International Reagent Resource. S.-M.K. and J.S. conceptualized and designed the research. J.S. designed the vaccine construct and generated the M2e-H1stem vaccine. J.S. J.O. and K.-H.K. characterized the vaccine antigens. J.S. J.O. K.-H.K. C.H.S. B.R.P. N.B. Y.-J.J. and Y.L. performed research. B.-Z.W. and B.-L.S. contributed to providing critical reagents. J.S. C.H.S. and S.-M.K. wrote the paper. All authors discussed the results and approved the final version of the manuscript. Some data presented in this manuscript will be included in the patent application. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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doi = "10.1016/j.omtm.2022.05.007",

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T1 - Thermostable H1 hemagglutinin stem with M2e epitopes provides broad cross-protection against group1 and 2 influenza A viruses

AU - Subbbiah, Jeeva

AU - Oh, Judy

AU - Kim, Ki Hye

AU - Shin, Chong Hyun

AU - Park, Bo Ryoung

AU - Bhatnagar, Noopur

AU - Jung, Yu Jin

AU - Lee, Youri

AU - Wang, Bao Zhong

AU - Seong, Baik Lin

AU - Kang, Sang Moo

N1 - Funding Information: This study was supported by National Institutes of Health and National Institute of Allergy and Infectious Diseases grants AI093772 (S.-M.K.), AI154656 (S.-M.K.), and AI147042 (S.-M.K). The following reagents were obtained from BEI Resources, NIAID, NIH: mouse adapted A/Fort Monmouth/1/1947 H1N1 (NR-28618), reassortant A/Nanchang/933/1995 H3N2 with A/PR8 backbone (NR-3692), A/Hong Kong/1/1968 H3N2 (NR-28634), and SARS-CoV-2 foldon-linked spike protein (NR-52396). A/Hong Kong/1073/99 H9N2 influenza virus (FR-732) was obtained from International Reagent Resource. Funding Information: This study was supported by National Institutes of Health and National Institute of Allergy and Infectious Diseases grants AI093772 (S.-M.K.), AI154656 (S.-M.K.), and AI147042 (S.-M.K). The following reagents were obtained from BEI Resources, NIAID, NIH: mouse adapted A/Fort Monmouth/1/1947 H1N1 (NR-28618), reassortant A/Nanchang/933/1995 H3N2 with A/PR8 backbone (NR-3692), A/Hong Kong/1/1968 H3N2 (NR-28634), and SARS-CoV-2 foldon-linked spike protein (NR-52396). A/Hong Kong/1073/99 H9N2 influenza virus (FR-732) was obtained from International Reagent Resource. S.-M.K. and J.S. conceptualized and designed the research. J.S. designed the vaccine construct and generated the M2e-H1stem vaccine. J.S. J.O. and K.-H.K. characterized the vaccine antigens. J.S. J.O. K.-H.K. C.H.S. B.R.P. N.B. Y.-J.J. and Y.L. performed research. B.-Z.W. and B.-L.S. contributed to providing critical reagents. J.S. C.H.S. and S.-M.K. wrote the paper. All authors discussed the results and approved the final version of the manuscript. Some data presented in this manuscript will be included in the patent application. The authors declare no competing interests. Publisher Copyright: © 2022 The Author(s)

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Y1 - 2022/9/8

N2 - Hemagglutinin (HA) stem-based vaccines have limitations in providing broad and effective protection against cross-group influenza viruses, despite being a promising universal vaccine target. To overcome the limited cross-protection and low efficacy by HA stem vaccination, we genetically engineered a chimeric conjugate of thermostable H1 HA stem and highly conserved M2e repeat (M2e-H1stem), which was expressed at high yields in Escherichia coli. M2e-H1stem protein presented native-like epitopes reactive to antisera of live virus infection. M2e-H1stem protein vaccination of mice induced strong M2e- and HA stem-specific immune responses, conferring broadly effective cross-protection against both antigenically distinct group 1 (H1N1, H5N1, and H9N2 subtypes) and group 2 (H3N2 and H7N9 subtypes) seasonal and pandemic potential influenza viruses. M2e-H1stem vaccination generated CD4+ and CD8+ T cell responses and antibody-dependent cytotoxic cellular and humoral immunity, which contributed to enhancing cross-protection. Furthermore, comparable broad cross-group protection was observed in older aged mice after M2e-H1stem vaccination. This study provides evidence warranting further development of chimeric M2e-stem proteins as a promising universal influenza vaccine candidate in adult and aged populations.

AB - Hemagglutinin (HA) stem-based vaccines have limitations in providing broad and effective protection against cross-group influenza viruses, despite being a promising universal vaccine target. To overcome the limited cross-protection and low efficacy by HA stem vaccination, we genetically engineered a chimeric conjugate of thermostable H1 HA stem and highly conserved M2e repeat (M2e-H1stem), which was expressed at high yields in Escherichia coli. M2e-H1stem protein presented native-like epitopes reactive to antisera of live virus infection. M2e-H1stem protein vaccination of mice induced strong M2e- and HA stem-specific immune responses, conferring broadly effective cross-protection against both antigenically distinct group 1 (H1N1, H5N1, and H9N2 subtypes) and group 2 (H3N2 and H7N9 subtypes) seasonal and pandemic potential influenza viruses. M2e-H1stem vaccination generated CD4+ and CD8+ T cell responses and antibody-dependent cytotoxic cellular and humoral immunity, which contributed to enhancing cross-protection. Furthermore, comparable broad cross-group protection was observed in older aged mice after M2e-H1stem vaccination. This study provides evidence warranting further development of chimeric M2e-stem proteins as a promising universal influenza vaccine candidate in adult and aged populations.

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Thermostable H1 hemagglutinin stem with M2e epitopes provides broad cross-protection against group1 and 2 influenza A viruses

Abstract

Bibliographical note

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UN SDGs

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