Research

The Klein lab focuses on how sex, age, and pregnancy impact microbial pathogenesis and immune responses to vaccines

 
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Sex differences in microbial pathogenesis

Working with microbes, including influenza A and B viruses, SARS-CoV-2, and hantaviruses, and M. tuberculosis, we have shown that:

  • females mount greater innate and adaptive immune responses during infection than males;

  • sex steroid hormones, including estrogens, progesterone, and androgens, are immunomodulatory;

  • sex differences in the outcomes of viral infection depend on disease etiology; e.g., if disease is caused by an inability to control virus replication then males suffer more and if disease is caused by immunopathology, then females have worse outcomes.

 
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Sex and age differences in vaccine efficacy

Working with vaccines that protect against influenza viruses, SARS-CoV-2, and malaria parasites, we have shown that sex differences in vaccine efficacy are age-dependent and involve both sex steroid hormone concentrations and the expression of X-linked genes.

  • Females develop stronger antibody responses to vaccines and are better protected following challenge than males;

  • Sex differences in vaccine-induced immune responses and protection are greatest during reproductive ages, in both mice and humans;

  • Females have stronger activation of B cells following vaccination, including expression of Tlr7 and Aicda, which is associated with greater class switch recombination and somatic hypermutations in B cells from females than males ;

  • Elevated concentrations of estradiol in females and testosterone in males is associated with sex-specific differences in antibody response to vaccines in both humans and mice.

  • Age associated reductions in immunity following influenza and COVID-19 vaccination are greater for males than females among both healthcare workers and older aged adults.

 
zika

Pathogenesis of virus infections during pregnancy

We have developed several animal modes to interrogate the mechanisms of adverse outcomes from viral infections during pregnancy, which has enabled us to uncover:

  • Zika viruses infect trophoblasts and endothelial cells of the placenta to disrupt the integrity of the placenta structure;

  • Placental inflammation, particularly IL-1β signaling, rather than direct Zika virus infection causes congenital Zika virus syndrome;

  • SARS-CoV-2 does not typically infect the placenta or fetus, but causes placental damage, intrauterine growth restrictions, and neurodevelopment deficits that are caused by reduced antiviral defenses and control of virus replication in the respiratory tract of pregnant dams; antiviral treatments reverse the detrimental effects of SARS-CoV-2 on pregnancy outcomes.

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The immune response to SARS-CoV-2

We are very active in multiple studies evaluating how sex and age impact immunity to SARS-CoV-2 during the COVID-19 pandemic, in part through our leadership of a an NIH/NCI U54 COVID-19 Serology Center of Excellence.

  • serve as the serology core for the National Convalescent Plasma Project where we have shown that receipt of convalescent plasma early during COVID-19 reduces hospitalization by more than 50%.

  • contribute to understanding the quality and durability of vaccine-induced immunity in immunosuppressed people, including solid organ translate recipients;

  • analyze sex differences in immunity and outcomes of SARS-CoV-2 in older adults;

  • demonstrate altered immunity to SARS-CoV-2 in pregnant people;

  • developed a hamster model to interrogate sex differences in SARS-CoV-2 outcomes.

  • using electronic health records from Johns Hopkins, we show that males are more likely than females to be hospitalized with severe COVID, which is associated with elevated concentrations of inflammatory biomarkers early during the course of disease.

 Select Publications: (*= trainee research)

  • Creisher PS, Parish MA, Lei J, Liu J, Perry JL, Campbell AD, Sherer ML, Burd I, Klein SL. Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice. bioRxiv [Preprint]. 2023 Nov 12:2023.09.11.557146. doi: 10.1101/2023.09.11.557146. PMID: 37745453; PMCID: PMC10515826.*

  • Hoffmann JP, Liu JA, Seddu K, Klein SL. Sex hormone signaling and regulation of immune function. Immunity. 2023 Nov 14;56(11):2472-2491. doi: 10.1016/j.immuni.2023.10.008. PMID: 37967530.

  • St Clair LA, Chaulagain S, Klein SL, Benn CS, Flanagan KL. Sex-Differential and Non-specific Effects of Vaccines Over the Life Course. Curr Top Microbiol Immunol. 2023;441:225-251. doi: 10.1007/978-3-031-35139-6_9. Erratum in: Curr Top Microbiol Immunol. 2023;441:C1. PMID: 37695431.

  • Creisher PS, Seddu K, Mueller AL, Klein SL. Biological Sex and Pregnancy Affect Influenza Pathogenesis and Vaccination. Curr Top Microbiol Immunol. 2023;441:111-137. doi: 10.1007/978-3-031-35139-6_5. PMID: 37695427.

  • Shapiro JR, Roberts CW, Arcovio K, Reade L, Klein SL, Dhakal S. Effects of Biological Sex and Pregnancy on SARS-CoV-2 Pathogenesis and Vaccine Outcomes. Curr Top Microbiol Immunol. 2023;441:75-110. doi: 10.1007/978-3-031-35139-6_4. PMID: 37695426.

  • Dhakal S, Park HS, Seddu K, Lee J, Creisher PS, Davis KM, Hernandez IR, Maul RW, Klein SL. Estradiol Mediates Greater Germinal Center Responses to Influenza Vaccination in Female than Male Mice. bioRxiv [Preprint]. 2023 Nov 27:2023.11.27.568847. doi: 10.1101/2023.11.27.568847. PMID: 38077071; PMCID: PMC10705292.*

  • Creisher PS, Perry JL, Zhong W, Lei J, Mulka KR, Ryan WH 3rd, Zhou R, Akin EH, Liu A, Mitzner W, Burd I, Pekosz A, Klein SL. Adverse outcomes in SARS-CoV-2-infected pregnant mice are gestational age-dependent and resolve with antiviral treatment. J Clin Invest. 2023 Oct 16;133(20):e170687. doi: 10.1172/JCI170687. PMID: 37581940; PMCID: PMC10575736.*

  • Park HS, Barranta C, Yin A, Lee JS, Caputo CA, Li M, Yoon S, Sitaras I, Jedlicka A, Eby Y, Ram M, Fernandez RE, Baker OR, Shenoy AG, Mosnaim GS, Fukuta Y, Patel B, Heath SL, Levine AC, Meisenberg BR, Spivak ES, Anjan S, Huaman MA, Blair JE, Currier JS, Paxton JH, Gerber JM, Petrini JR, Broderick PB, Rausch W, Cordisco ME, Hammel J, Greenblatt B, Cluzet VC, Cruser D, Oei K, Abinante M, Hammitt LL, Sutcliffe CG, Forthal DN, Zand MS, Cachay ER, Raval JS, Kassaye SG, Marshall CE, Yarava A, Lane K, McBee NA, Gawad AL, Karlen N, Singh A, Ford DE, Jabs DA, Appel LJ, Shade DM, Lau B, Ehrhardt S, Baksh SN, Shapiro JR, Ou J, Gniadek TJ, Caturegli P, Wu J, Ndahiro N, Betenbaugh MJ, Ziman A, Hanley DF, Casadevall A, Shoham S, Bloch EM, Gebo KA, Tobian AAR, Laeyendecker O, Pekosz A, Klein SL, Sullivan DJ. Antibody Correlates of Protection for COVID-19 Convalescent Plasma Associated with Reduced Outpatient Hospitalizations. medRxiv [Preprint]. 2023 Apr 24:2023.04.13.23288353. doi: 10.1101/2023.04.13.23288353. PMID: 37131659; PMCID: PMC10153328.*

  • Creisher, P.S., Campbell, A.D., Perry, J.L., Roznik, K., Burd, I., & Klein, S.L. 2022. Influenza subtype-specific antibodies protect against infection but inhibit vaccine-induced immunity and protection in murine offspring. Vaccine, 40 (47). PMC 1879428*

  • Ursin, R.L., Dhakal, S., Liu, H., Jayaraman, S., Park, H-S., Powell, H.R., Sherer, M., Littlefield, K., Fink, A.L., Ma, Z, Mueller, A., Chen, A.P., Wang, A., Woldetsadik, Y., Gearhart, P.J., Larman, B., Maul, R.W., Pekosz, A., Klein, S.L.  2022. Greater breadth of vaccine-induced immunity in females than males is mediated by increased antibody diversity in germinal center B cells. mBio, doi:10.1128/mbio.01839-22. PMC9426573*

  • Gupta, M., Srikrishna, G., Klein, S.L., & Bishai, W.R. 2022. Genetic and hormonal mechanisms mediating sex differences in tuberculosis. Trends in Immunology, doi:10.1016/j.it/2022/06/004.*

  • Shapiro, J.R., Sitaras, I., Park, H-S., Aytenfisu, T.Y., Caputo, C., Li, M., Lee, J., Johnston, T.S., Li, H.,  Wouters, C., Hauk, P., Jacobsen, H., Li, Y., Abrams, E., Yoon, S., Kocot, A.J., Yang, T., Huang, Y., Cramer, S.M., Betenbaugh, M.J., Debes, W.A., Morgan, R., Milstone, A.M., Karaba, A.H., Pekosz, A., Leng, S.X., & Klein, S.L. 2022. Association of frailty, age, and biological sex with SARS-CoV-2 mRNA vaccine-induced immunity in older adults. Clinical Infectious Diseases, 75 (Suppl 1): S61-71. PMC9376280*

  • Dhakal, S. Ruiz-Bedoya, C., Zhou, R., Cheisher, P.S., Villano, J.S., Littlefield, K., Castillo, J. R., Marinho, P., Jedlicka, A., Ordonez, A.A., Majewski, N., Betenbaugh, M.J., Flavahan, K., Mueller, A.L., Looney, M.M., Quijada, D., Wood, M., Mota, F., Pieterse, L., Metcalf Pate, K.A., Karakousis, P.C., Mankowski, J., Pekosz, A., Jain, S.K., & Klein, S.L. 2021. Sex differences in lung pathology and SARS-CoV-2 antibody responses in golden Syrian hamsters. mBio, 12:e00974-21. PMC*

  • Sherer, M.L., Lei, J., Creisher, P., Jang, M., Reddy, R., Voegtline, K., Olson, S., Littlefield, K., Park, H-.S., Ursin, R. L., Ganesan, A., Boyer, T., Brown, D.M., Walch, S.N., Antar, A.A.R., Manabe, Y.C., Jones-Beatty, K., Golden, W.C., Satin, A.J., Sheffield, J.S., Pekosz, A., Klein, S.L., Burd, I. 2021. Pregnancy alters IL-1b expression and antiviralantibody responses during SARS-CoV-2 infection. American Journal of Obstetrics and Gynecology, doi: 10.1016/j.ajog.2021.03.028.* Klein and Burd are co-senior authors.

  • Kuo, H., Shapiro, J.R., Dhakal, S., Morgan, R. Lui, H., Fink, A. L., Westerbeck, J.W., Sylvia, K.E., Park, H-.S., Ursin, R.L., Shae, P., Shaw-Saliba, K., Fenstermacher, K. J., Gearhart, P., Rothman, R. E., Pekosz, A., & Klein, S. L. 2021. Sex-specific effects of age and body mass index on antibody responses to seasonal influenza vaccines in healthcare workers. Vaccine, doi: 10.1016/j.vaccine.2021.02.047.

  • Klein, S. L., Pekosz, A., Park, H-.S., Ursin, R. L., Shapiro, J., Benner, S., Littlefield, K., Kumar, S., Naik, H., Betenbaugh, M. J., Shrestha, R., Wu, A., Hughes, R., Burgess, I., Caturegli, P., Laeyendecker, O., Quinn, T. C., Sullivan, D., Shoham, S., Redd, A. D., Bloch, E. M., Casadevall, A., Tobian, A. A. R. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population.  Journal of Clinical Investigation,doi: 10.1172/JCI142004. PMC7325184

  • Ursin, R. L., Liu, H., Powell, H. R., Westerbeck, J., Shaw-Saliba, K., Sylvia, K., Fenstermacher, K. J., Mehoke, T., Theilen, P., Rothman, R. E., Pekosz, A., & Klein, S. L. 2020. Differential antibody recognition of H3N2 vaccine and seasonal influenza virus strains based on age, vaccine status, and sex in the 2017-18 season. Journal of Infectious Diseases, Jun 4:jiaa289. doi: 10.1093/infdis/jiaa289.*

  • Scully, E., Haverfield, J., Ursin, R. L., Tannenbaum, C., & Klein. S. L. 2020. Sex is a variable in immune responses and COVID-19 outcomes. Nature Reviews Immunology, doi: 10.1038/s41577-020-0348-8.

  • vom Steeg, L.G., Dhakal, S., Woldetsadik, Y., Park, H-.S., Mulka, K.R., Reilly, E.C, Topham, D.J., & Klein, S.L. 2020. Androgen receptor signaling in the lungs mitigates inflammation and promotes recovery from influenza in mice. PLoS Pathogens, 16(7):e1008506.*

  • Potluri, T., Fink, A. L., Sylvia, K.E., Dhakal, S., Vermillion, M. S., vom Steeg, L. G.,  Deshpande, S., Narasimhan, H., & Klein, S. L. 2019. Age-associated changes in the impact of sex steroids on influenza vaccine efficacy in males and females. npj Vaccine. 4:29, doi.org/10.1038/s41541-019-0124-6. PMC6626024.* One of the top five accessed papers of 2019.

  • Fink, A. L., Engle, K., Ursin, R., Tang, W-. Y., & Klein, S. L. 2018. Biological sex affects vaccine efficacy and protection against influenza in mice. Proceedings of the National  Academy of Sciences, 115 (49), 12477-82. PMC6298067*

  • Vermillion, M. S., Ursin, R., Kuok, D. I. T., vom Steeg, L. G., Wohlgemuth, N, Hall, O. J., Fink, A. L., Sasse, E., Nelson, A., Ndeh, R., McGrath-Morrow, S., Mitzner, W., Chan, M., Pekosz, A. & Klein, S. L. 2018. Production of amphiregulin and recovery from influenza is greater in males than females. Biology of Sex Differences, 9, 24. One of the top downloaded papers of 2018.

  • Klein, S. L., & Flanagan, K. L. 2016. Sex differences in immune responses. Nature Reviews Immunology, 16(10), 626-38. PMID: 27546235, doi: 10.1038/nri.2016.90

Complete List of Published Work in MyBibliography