Dissecting Sex Differences in the Immune Response to Vaccines
Vaccines represent one of the most impactful public health interventions with the prevention of millions of infections and deaths annually worldwide. As illustrated by recent epidemic or pandemic outbreaks caused by emerging viruses such as Ebola Virus, MERS-CoV and more recently SARS-CoV-2, the need for rapid and strategic vaccine development remains paramount. Men and women differ in the immune response to vaccination with females typically developing higher antibody responses, but also experiencing more adverse reactions following vaccination than males. Yet the exact mechanisms and signaling pathways involved in the differential vaccine outcomes between the sexes remain incompletely understood. We hypothesize that: a) sex hormones regulate critical innate signaling pathways resulting in differential outcomes in vaccine reactogenicity and immunogenicity and b) gene-dosage effects resulting from escape from X-chromosome inactivation (XCI) contribute to sex-specific differences in vaccine responses. These hypotheses will be explored using data and biomaterial from two unique Phase 1 clinical trials investigating novel emergency vaccines. We propose to prospectively investigate and dissect sex-specificity in immunity to vaccines against two important emerging respiratory pathogens with pandemic potential and high global significance: MERS-CoV and SARS-CoV-2, two recently discovered novel coronaviruses. A detailed understanding of the molecular factors associated with sex-differences in vaccine-induced immune responses may ultimately allow for strategic modulation of vaccine immunity and foster individualized vaccine design.
PROJECT-RELATED PUBLICATIONS
Raadsen M, Dahlke C, Fathi A, Hardtke S, […], Sutter G, Becker S, Haagmans BL, and Addo MM and Group ‘MVA-MERS-S_DF-1 Study’.. (2024)
The Safety, Immunogenicity, and Optimal Dosing of an MVA-Based Vaccine Against MERS Coronavirus in Healthy Adults: A Phase 1b, Randomised, Placebo-Controlled, Double-Blind Clinical Trial.
Lancet Infect Dis in press
Mayer L, Weskamm LM, Fathi A, Kono M, Heidepriem J, Krähling V, Mellinghoff SC, Ly ML, Friedrich M, Hardtke S, Borregaard S, Hesterkamp T, Loeffler FF, Volz A, Sutter G, Becker S, Dahlke C, Addo MM. (2024)
MVA-based vaccine candidates encoding the native or prefusion-stabilized SARS-CoV-2 spike reveal differential immunogenicity in humans
NPJ Vaccines 9:20
Beisel C, Jordan-Paiz A, Köllmann S, Ahrenstorf AE, Padoan B, Barkhausen T, Addo MM, Altfeld M. (2023)
Sex differences in the percentage of IRF5 positive B cells are associated with higher production of TNF-α in women in response to TLR9 in humans
Biology of Sex Differences 14:11
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Anahita Fathi, Marylyn M Addo, Christine Dahlke. (2021)
Sex Differences in Immunity: Implications for the Development of Novel Vaccines Against Emerging Pathogens
Front Immunol 11:601170
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Koch T, Dahlke C, Fathi A, Kupke A, Krähling V, Okba MA, Halwe S, Rohde C, Eickmann M, Volz A, Hesterkamp T, Jambrecina A, Borregaard S, Ly ML, Zinser ME, Bartels E, Poetsch J, Neumann R, Fux R, Schmiedel S, Lohse AW, Haagmans BL, Sutter G, Becker S, Addo MM. (2020)
Safety and immunogenicity of a modified vaccinia virus Ankara vector vaccine candidate for Middle East respiratory syndrome: an open-label, phase 1 trial
Lancet Infect Dis 20:827-838
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Heidepriem J, Krähling V, Dahlke C, Wolf T, Klein F, Addo MM*, Becker S*, Loeffler F*. (2020)
Epitopes of naturally acquired and vaccine-induced anti-Ebola virus glycoprotein antibodies in single amino acid resolution
Biotechnol J 15:e2000069
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Friedrich SK, Schmitz R, Bergerhausen M, Lang J, Cham LB, Duhan V, Häussinger D, Hardt C, Addo M, Prinz M, Asano K, Lang PA, Lang KS. (2020)
Usp18 Expression in CD169+ Macrophages is Important for Strong Immune Response after Vaccination with VSV-EBOV
Vaccines (Basel). 8(1):E142
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Ehrhardt S A, Zehner M, Krähling V, Cohen-Dvashi H, Kreer C, Elad N, Gruell H, Ercanoglu MS, Schommers P, Gieselmann L, Eggeling R, Dahlke C, Wolf T, Pfeifer N, Addo, MM, Diskin R, Becker S, & Klein F. (2019)
Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV
Nature medicine 25:1589–1600
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Poetsch J.H., Dahlke C, Zinser ME, Kasonta R, Lunemann S, Rechtien A, My Linh Ly, Stubbe H.C., Krähling V, Biedenkopf N, Eickmann M, Fehling SK, Olearo F, Strecker T, Sharma P, Lang KS, Lohse AW, Schmiedel S, Becker S, VSV-Ebola Consortium (VEBCON), Addo MM. (2019)
Detectable Vesicular Stomatitis Virus (VSV)–Specific Humoral and Cellular Immune Responses Following VSV– Ebola Virus Vaccination in Humans
J Infect Dis. 219:556-561
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Rechtien A, Richert L, Lorenzo H, Martrus G, Hejblum B, Dahlke C, Kasonta R, Zinser M, Stubbe H, Matschl U, Lohse A, Krähling V, Eickmann M, Becker S; VEBCON Consortium, Thiébaut R, Altfeld M, Addo MM. (2017)
Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV
Cell Rep 20:2251-2261
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Ruibal P, Oestereich L, Lüdtke A, Becker-Ziaja B, Wozniak DM, Kerber R, Herker E, Jacobs T, Kretschmer B, Severi E, Ouedraogo N, Lago M, Negredo A, Franco L, Anda P, Schmiedel S, Kreuels B, Wichmann D, Addo MM, Lohse AW, De Clerck H, Nanclares C, Jonckheere S, Van Herp M, Sprecher A, Xiaojiang G, Carrington M, Miranda O, Castro CM, Gabriel M, Drury P, Formenty P, Diallo B, Koivogui L, Magasouba N, Carroll MW, Günther S, Muñoz-Fontela C. (2016)
Unique human immune signature of Ebola virus disease in Guinea
Nature 533:100-4
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Dahlke C, Kasonta R, Lunemann S, Krähling V, Zinser ME, Biedenkopf N, Fehling SK, Ly ML, Rechtien A, Stubbe HC, Olearo F, Borregaard S, Jambrecina A, Stahl F, Strecker T, Eickmann M, Lütgehetmann M, Spohn M, Schmiedel S, Lohse AW, Becker S, Addo MM, VEBCON Consortium. (2017)
Dose-dependent T-cell Dynamics and Cytokine Cascade Following rVSV-ZEBOV Immunization
EBioMedicine 19:107-11
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Agnandji ST, Huttner A, Zinser ME, Njuguna P, Dahlke C, Fernandes JF, Yerly S, Dayer JA, Kraehling V, Kasonta R, Adegnika AA, Altfeld M, Auderset F, Bache EB, Biedenkopf N, Borregaard S, Brosnahan JS, Burrow R, Combescure C, Desmeules J, Eickmann M, Fehling SK, Finckh A, Goncalves AR, Grobusch MP, Hooper J, Jambrecina A, Kabwende AL, Kaya G, Kimani D, Lell B, Lemaître B, Lohse AW, Massinga-Loembe M, Matthey A, Mordmüller B, Nolting A, Ogwang C, Ramharter M, Schmidt-Chanasit J, Schmiedel S, Silvera P, Stahl FR, Staines HM, Strecker T, Stubbe HC, Tsofa B, Zaki S, Fast P, Moorthy V, Kaiser L, Krishna S, Becker S, Kieny MP, Bejon P*, Kremsner PG*, Addo MM*, Siegrist CA*. (2016)
Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe
N Engl J Med. 374:1647-60
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Addo MM, Altfeld M. (2014)
Sex-based differences in HIV type 1 pathogenesis
J Infect Dis. 209 Suppl 3:S86-92
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* equal contribution
