Sex and Age Differences in Immunity to Influenza SCORE

The Sex and Age Differences in Immunity to Influenza (SADII) SCORE is positioned to transform our understanding of the role of biological sex, gender, and aging on immune responses to influenza vaccination, which has global public health implications, affecting millions of people worldwide. The overarching hypothesis: Female-biased vaccine-induced immunity to influenza viruses is age-dependent and reflects both hormonal and genetic differences between the sexes that impact immune responses (i.e., both effector and memory) to influenza vaccine antigens. The SADII SCORE brings together investigators focused on (1) seasonal influenza vaccination in an existing age- and sex-stratified human population, (2) animal models that can test hypotheses and mechanisms of action that are inferred from studies in human populations, and (3) the contributions of age, frailty, sex, and gender to vaccine outcomes using quantitative and qualitative statistical models.  

Research Projects:

  • Research Project 1: Sex differences in longitudinal humoral immunity against influenza in the frail elderly 
    This research project is led by Dr. Sean Leng, in collaboration with the Johns Hopkins University Older Americans Independence Center. The goal of this project is to provide a detailed analysis of sex and gender differences in humoral immunity and adverse reactions to seasonal influenza vaccines in combination with age and frailty in an existing longitudinal cohort of older individuals. 
      
  • Research Project 2: Sex differences in immune responses to vaccine and circulating strains of influenza in health care workers
    This research project is led by Dr. Andrew Pekosz, in collaboration with the Johns Hopkins Center of Excellence in Influenza Research and Surveillance (JH-CEIRS). The study will characterize the number and transcriptional activity of B cells, as well as humoral immune responses and adverse reactions, following receipt of seasonal influenza vaccines. The study will be focused on men and women between the ages of 18 and 45, to provide an age- and sex-stratified cohort to assess sex differences in vaccine responses among adults. 
      
  • Research Project 3: Genetic and hormonal mechanisms of sex differences in immune responses and influenza vaccine efficacy in young and aged mice
    This research project is led by Dr. Sabra Klein. The goal of the project is to uncover the genetic, hormonal, and age-associated changes in B cells that mediate sex and age differences in vaccine-induced immunity to influenza. This will be accomplished by a systematic evaluation of the effects sex hormones and genes encoded by sex chromosomes have on the antibody response to influenza vaccination. 

Career Enhancement Core:

Director: Wendy Bennett, M.D.

The SADII Career Enhancement Core (CEC) is led by Dr. Wendy Bennett, in collaboration with the Johns Hopkins Center for Women’s Health, Sex, and Gender Differences. Aims include:  

  • Providing collaboration, networking, dissemination, and mentoring opportunities 
  • Providing pilot grant funding for early-stage investigators (i.e., investigators at the level of assistant professor or below), with emphasis on diversity of candidates, interested in incorporating sex differences into their clinical, translational, or basic science research in the broad area of immunology (e.g., asthma and allergy, autoimmunity, cancer, infectious diseases, inflammation, microbiome, and vaccines)  
  • Integrating educational opportunities focused on teaching skills and methods for incorporating sex as a biological variable and gender considerations when planning, analyzing, and reporting data, as well as research dissemination activities in regard to a broad range of existing training programs (e.g., KL2 and BIRCWH programs) 
  • Evaluating the effectiveness of the SADII CEC in expanding learning opportunities, dissemination of sex and gender research, mentorship, and funded research

Publications Citing Johns Hopkins SADII SCORE (U54AG06233)

1.         Fink AL, Engle K, Ursin RL, Tang WY, Klein SL. Biological sex affects vaccine efficacy and protection against influenza in mice. Proc Natl Acad Sci U S A 2018;115(49):12477-12482. (In eng). DOI: 10.1073/pnas.1805268115.

2.         Dhakal S, Klein SL. Host Factors Impact Vaccine Efficacy: Implications for Seasonal and Universal Influenza Vaccine Programs. J Virol 2019;93(21) (In eng). DOI: 10.1128/jvi.00797-19.

3.         Morgan R, Klein SL. The intersection of sex and gender in the treatment of influenza. Curr Opin Virol 2019;35:35-41. (In eng). DOI: 10.1016/j.coviro.2019.02.009.

4.         Potluri T, Fink AL, Sylvia KE, et al. Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females. NPJ Vaccines 2019;4:29. (In eng). DOI: 10.1038/s41541-019-0124-6.

5.         Potluri T, Fink AL, Sylvia KE, et al. Erratum: Author Correction: Age-associated changes in the impact of sex steroids on influenza vaccine responses in males and females. NPJ Vaccines 2019;4:35. (In eng). DOI: 10.1038/s41541-019-0130-8.

6.         Bischof E, Wolfe J, Klein SL. Clinical trials for COVID-19 should include sex as a variable. J Clin Invest 2020;130(7):3350-3352. (In eng). DOI: 10.1172/jci139306.

7.         Cheng Y, Cao X, Cao Z, et al. Effects of influenza vaccination on the risk of cardiovascular and respiratory diseases and all-cause mortality. Ageing Res Rev 2020;62:101124. (In eng). DOI: 10.1016/j.arr.2020.101124.

8.         Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ 2020;11(1):29. (In eng). DOI: 10.1186/s13293-020-00304-9.

9.         Klein SL, Dhakal S, Ursin RL, Deshpande S, Sandberg K, Mauvais-Jarvis F. Biological sex impacts COVID-19 outcomes. PLoS Pathog 2020;16(6):e1008570. (In eng). DOI: 10.1371/journal.ppat.1008570.

10.       Klein SL, Morgan R. The impact of sex and gender on immunotherapy outcomes. Biol Sex Differ 2020;11(1):24. (In eng). DOI: 10.1186/s13293-020-00301-y.

11.       Klein SL, Pekosz A, Park HS, et al. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J Clin Invest 2020;130(11):6141-6150. (In eng). DOI: 10.1172/jci142004.

12.       Leng SX, Margolick JB. Aging, sex, inflammation, frailty, and CMV and HIV infections. Cell Immunol 2020;348:104024. (In eng). DOI: 10.1016/j.cellimm.2019.104024.

13.       Li X, Leng SX. Influenza immunization among Chinese seniors: Urgent calling for improving vaccination coverage, education, and research. Aging Med (Milton) 2020;3(1):12-15. (In eng). DOI: 10.1002/agm2.12103.

14.       Mauvais-Jarvis F, Bairey Merz N, Barnes PJ, et al. Sex and gender: modifiers of health, disease, and medicine. Lancet 2020;396(10250):565-582. (In eng). DOI: 10.1016/s0140-6736(20)31561-0.

15.       Mauvais-Jarvis F, Klein SL, Levin ER. Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes. Endocrinology 2020;161(9) (In eng). DOI: 10.1210/endocr/bqaa127.

16.       Morgan R, Dhatt R, Kharel C, Muraya K. A patchwork approach to gender equality weakens the SDGs: time for cross-cutting action. Glob Health Promot 2020;27(3):3-5. (In eng). DOI: 10.1177/1757975920949735.

17.       Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol 2020;20(7):442-447. (In eng). DOI: 10.1038/s41577-020-0348-8.

18.       Sunuwar L, Frkatović A, Sharapov S, et al. Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease. JCI Insight 2020;5(20) (In eng). DOI: 10.1172/jci.insight.140978.

19.       Ursin RL, Liu H, Powell HR, et al. Differential Antibody Recognition of H3N2 Vaccine and Seasonal Influenza Virus Strains Based on Age, Vaccine Status, and Sex in the 2017-2018 Season. J Infect Dis 2020;222(8):1371-1382. (In eng). DOI: 10.1093/infdis/jiaa289.

20.       Akiyoshi K, Boersma GJ, Johnson MD, et al. Role of miR-181c in Diet-induced obesity through regulation of lipid synthesis in liver. PLoS One 2021;16(12):e0256973. (In eng). DOI: 10.1371/journal.pone.0256973.

21.       Chen Y, Klein SL, Garibaldi BT, et al. Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Res Rev 2021;65:101205. (In eng). DOI: 10.1016/j.arr.2020.101205.

22.       Dhakal S, Loube J, Misplon JA, et al. Effect of an Adenovirus-Vectored Universal Influenza Virus Vaccine on Pulmonary Pathophysiology in a Mouse Model. J Virol 2021;95(9) (In eng). DOI: 10.1128/jvi.02359-20.

23.       Dhakal S, Ruiz-Bedoya CA, Zhou R, et al. Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model. mBio 2021;12(4):e0097421. (In eng). DOI: 10.1128/mBio.00974-21.

24.       Haupt S, Caramia F, Klein SL, Rubin JB, Haupt Y. Sex disparities matter in cancer development and therapy. Nat Rev Cancer 2021;21(6):393-407. (In eng). DOI: 10.1038/s41568-021-00348-y.

25.       Jacobsen H, Klein SL. Sex Differences in Immunity to Viral Infections. Front Immunol 2021;12:720952. (In eng). DOI: 10.3389/fimmu.2021.720952.

26.       Sarkar A, Harty S, Moeller AH, et al. The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2. Trends Mol Med 2021;27(12):1115-1134. (In eng). DOI: 10.1016/j.molmed.2021.09.009.

27.       Scully EP, Schumock G, Fu M, et al. Sex and gender differences in COVID testing, hospital admission, presentation, and drivers of severe outcomes in the DC/Maryland region. medRxiv 2021 (In eng). DOI: 10.1101/2021.04.05.21253827.

28.       Shapiro JR, Klein SL, Morgan R. Stop 'controlling' for sex and gender in global health research. BMJ Glob Health 2021;6(4) (In eng). DOI: 10.1136/bmjgh-2021-005714.

29.       Shapiro JR, Klein SL, Morgan R. COVID-19: use intersectional analyses to close gaps in outcomes and vaccination. Nature 2021;591(7849):202. (In eng). DOI: 10.1038/d41586-021-00577-z.

30.       Shapiro JR, Li H, Morgan R, et al. Sex-specific effects of aging on humoral immune responses to repeated influenza vaccination in older adults. NPJ Vaccines 2021;6(1):147. (In eng). DOI: 10.1038/s41541-021-00412-6.

31.       Tuday E, Nakano M, Akiyoshi K, et al. Degradation of Premature-miR-181b by the Translin/Trax RNase Increases Vascular Smooth Muscle Cell Stiffness. Hypertension 2021;78(3):831-839. (In eng). DOI: 10.1161/hypertensionaha.120.16690.

32.       Creisher PS, Campbell AD, Perry JL, Roznik K, Burd I, Klein SL. Influenza subtype-specific maternal antibodies protect offspring against infection but inhibit vaccine-induced immunity and protection in mice. Vaccine 2022;40(47):6818-6829. (In eng). DOI: 10.1016/j.vaccine.2022.10.003.

33.       Dhakal S, Deshpande S, McMahon M, Strohmeier S, Krammer F, Klein SL. Female-biased effects of aging on a chimeric hemagglutinin stalk-based universal influenza virus vaccine in mice. Vaccine 2022;40(11):1624-1633. (In eng). DOI: 10.1016/j.vaccine.2020.11.057.

34.       Hong GH, Hays AG, Gilotra NA. The Evolving Role of Echocardiography During the Coronavirus Disease 2019 Pandemic. Heart Int 2022;16(1):28-36. (In eng). DOI: 10.17925/hi.2022.16.1.28.

35.       Kini A, Morgan R, Kuo H, et al. Differences and disparities in seasonal influenza vaccine, acceptance, adverse reactions, and coverage by age, sex, gender, and race. Vaccine 2022;40(11):1643-1654. (In eng). DOI: 10.1016/j.vaccine.2021.04.013.

36.       Kuo H, Shapiro JR, Dhakal S, et al. Sex-specific effects of age and body mass index on antibody responses to seasonal influenza vaccines in healthcare workers. Vaccine 2022;40(11):1634-1642. (In eng). DOI: 10.1016/j.vaccine.2021.02.047.

37.       Leng SX, Pawelec G. Single-cell immune atlas for human aging and frailty. Life Med 2022;1(2):67-70. (In eng). DOI: 10.1093/lifemedi/lnac013.

38.       Mulka KR, Beck SE, Solis CV, et al. Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters. Am J Pathol 2022;192(2):195-207. (In eng). DOI: 10.1016/j.ajpath.2021.10.009.

39.       Park HS, Shapiro JR, Sitaras I, et al. Adaptive immune responses in vaccinated patients with symptomatic SARS-CoV-2 Alpha infection. JCI Insight 2022;7(5) (In eng). DOI: 10.1172/jci.insight.155944.

40.       Rosen NS, Pavlovic N, Duvall C, et al. Cardiac sarcoidosis outcome differences: A comparison of patients with de novo cardiac versus known extracardiac sarcoidosis at presentation. Respir Med 2022;198:106864. (In eng). DOI: 10.1016/j.rmed.2022.106864.

41.       Ruiz-Bedoya CA, Mota F, Ordonez AA, et al. (124)I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection. Mol Imaging Biol 2022;24(1):135-143. (In eng). DOI: 10.1007/s11307-021-01638-5.

42.       Scott SC, Shao XM, Niknafs N, et al. Sex-specific differences in immunogenomic features of response to immune checkpoint blockade. Front Oncol 2022;12:945798. (In eng). DOI: 10.3389/fonc.2022.945798.

43.       Shapiro JR, Sitaras I, Park HS, et al. Association of Frailty, Age, and Biological Sex With Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine-Induced Immunity in Older Adults. Clin Infect Dis 2022;75(Suppl 1):S61-s71. (In eng). DOI: 10.1093/cid/ciac397.

44.       Ursin RL, Dhakal S, Liu H, et al. Greater Breadth of Vaccine-Induced Immunity in Females than Males Is Mediated by Increased Antibody Diversity in Germinal Center B Cells. mBio 2022;13(4):e0183922. (In eng). DOI: 10.1128/mbio.01839-22.

45.       Wood SN, Yirgu R, Wondimagegnehu A, et al. Impact of the COVID-19 pandemic on intimate partner violence during pregnancy: evidence from a multimethods study of recently pregnant women in Ethiopia. BMJ Open 2022;12(4):e055790. (In eng). DOI: 10.1136/bmjopen-2021-055790.

46.       Akiyoshi K, Fujimori T, Fu X, et al. Adenosine A(2A) Receptor Regulates microRNA-181b Expression in Aorta: Therapeutic Implications for Large-Artery Stiffness. J Am Heart Assoc 2023;12(14):e028421. (In eng). DOI: 10.1161/jaha.122.028421.

47.       Bennett WL, Martin L, Shea P, et al. Establishment of a Private Foundation-Academic Partnership to Promote Careers of Early-Stage Investigators Examining the Influence of Sex and Gender on Health and Health Care. J Womens Health (Larchmt) 2023;32(8):858-864. (In eng). DOI: 10.1089/jwh.2022.0510.

48.       Bennett WL, McRae-Clark AL, Morrow MMB. Mechanisms of Career Enhancement at Specialized Centers of Research Excellence (SCORE) on Sex Differences. J Womens Health (Larchmt) 2023;32(8):840-842. (In eng). DOI: 10.1089/jwh.2023.0371.

49.       Dhakal S, Park HS, Seddu K, et al. Estradiol Mediates Greater Germinal Center Responses to Influenza Vaccination in Female than Male Mice. bioRxiv 2023 (In eng). DOI: 10.1101/2023.11.27.568847.

50.       Shapiro JR, Privor-Dumm L, Rosser EN, Leng SX, Klein SL, Morgan R. The intersection of gender and race in older adults' decision to receive COVID-19 vaccines. Vaccine 2023;41(1):211-218. (In eng). DOI: 10.1016/j.vaccine.2022.09.043.

51.       Shapiro JR, Seddu K, Park HS, et al. The intersection of biological sex and gender in adverse events following seasonal influenza vaccination in older adults. Immun Ageing 2023;20(1):43. (In eng). DOI: 10.1186/s12979-023-00367-3.

52.       Shapiro JR, Seddu K, Park HS, et al. The intersection of biological sex and gender in adverse events following seasonal influenza vaccination in older adults. Res Sq 2023 (In eng). DOI: 10.21203/rs.3.rs-2557775/v1.

53.       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. (In eng). DOI: 10.1007/978-3-031-35139-6_9.

54.       St Clair LA, Chaulagain S, Klein SL, Benn CS, Flanagan KL. Correction to: Sex-Differential and Non-specific Effects of Vaccines Over the Life Course. Curr Top Microbiol Immunol 2023;441:C1. (In eng). DOI: 10.1007/978-3-031-35139-6_11.

55.       Sunuwar L, Tomar V, Wildeman A, Culotta V, Melia J. Hepatobiliary manganese homeostasis is dynamic in the setting of inflammation or infection in mice. Faseb j 2023;37(9):e23123. (In eng). DOI: 10.1096/fj.202300539R.

56.       Swanson NJ, Marinho P, Dziedzic A, et al. 2019-2020 H1N1 clade A5a.1 viruses have better in vitro fitness compared with the co-circulating A5a.2 clade. Sci Rep 2023;13(1):10223. (In eng). DOI: 10.1038/s41598-023-37122-z.

57.       Velasquez FC, Roman B, Hernández-Ochoa EO, et al. Contribution of skeletal muscle-specific microRNA-133b to insulin resistance in heart failure. Am J Physiol Heart Circ Physiol 2023;324(5):H598-h609. (In eng). DOI: 10.1152/ajpheart.00250.2022.

58.       Wilson JL, Akin E, Zhou R, et al. The Influenza B Virus Victoria and Yamagata Lineages Display Distinct Cell Tropism and Infection-Induced Host Gene Expression in Human Nasal Epithelial Cell Cultures. Viruses 2023;15(9) (In eng). DOI: 10.3390/v15091956.

59.       Yirgu R, Wondimagegnehu A, Qian J, et al. Needs and unmet needs for support services for recently pregnant intimate partner violence survivors in Ethiopia during the COVID-19 pandemic. BMC Public Health 2023;23(1):725. (In eng). DOI: 10.1186/s12889-023-15634-7.

60.       Briggs K, Tomar V, Ollberding N, et al. Crohn's Disease-Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism. Inflamm Bowel Dis 2024;30(8):1379-1388. (In eng). DOI: 10.1093/ibd/izae003.

61.       Casubhoy I, Kretz A, Tan HL, et al. A scoping review of global COVID-19 vaccine hesitancy among pregnant persons. NPJ Vaccines 2024;9(1):131. (In eng). DOI: 10.1038/s41541-024-00913-0.

62.       Creisher PS, Parish MA, Lei J, et al. Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice. mBio 2024;15(2):e0306523. (In eng). DOI: 10.1128/mbio.03065-23.

63.       Crilly NP, Zita MD, Beaver AK, et al. A murine model of Trypanosoma brucei-induced myocarditis and cardiac dysfunction. bioRxiv 2024 (In eng). DOI: 10.1101/2023.10.05.560950.

64.       Dhakal S, Park HS, Seddu K, et al. Estradiol mediates greater germinal center responses to influenza vaccination in female than male mice. mBio 2024;15(4):e0032624. (In eng). DOI: 10.1128/mbio.00326-24.

65.       Dunn SE, Perry WA, Klein SL. Mechanisms and consequences of sex differences in immune responses. Nat Rev Nephrol 2024;20(1):37-55. (In eng). DOI: 10.1038/s41581-023-00787-w.

66.       Yin A, Wang N, Shea PJ, et al. Sex and gender differences in adverse events following influenza and COVID-19 vaccination. Biol Sex Differ 2024;15(1):50. (In eng). DOI: 10.1186/s13293-024-00625-z.