The Role of Biological Sex in Pre-Clinical (Mouse) MRNA Vaccine Studies

Overview

Journal Vaccines (Basel)

Date 2024 Mar 28

PMID 38543916

Authors

Burcu Binici

Zahra Rattray

Avi Schroeder

Yvonne Perrie

Affiliations

Soon will be listed here.

Abstract

In this study, we consider the influence of biological sex-specific immune responses on the assessment of mRNA vaccines in pre-clinical murine studies. Recognising the established disparities in immune function attributed to genetic and hormonal differences between individuals of different biological sexes, we compared the mRNA expression and immune responses in mice of both biological sexes after intramuscular injection with mRNA incorporated within lipid nanoparticles. Regarding mRNA expression, no significant difference in protein (luciferase) expression at the injection site was observed between female and male mice following intramuscular administration; however, we found that female BALB/c mice exhibit significantly greater total IgG responses across the concentration range of mRNA lipid nanoparticles (LNPs) in comparison to their male counterparts. This study not only contributes to the scientific understanding of mRNA vaccine evaluation but also emphasizes the importance of considering biological sex in vaccine study designs during pre-clinical evaluation in murine studies.

Citing Articles

mRNA lipid nanoparticle formulation, characterization and evaluation.

Ma Y, VanKeulen-Miller R, Fenton O Nat Protoc. 2025; .

PMID: 40069324 DOI: 10.1038/s41596-024-01134-4.

References

Poley M, Mora-Raimundo P, Shammai Y, Kaduri M, Koren L, Adir O . Nanoparticles Accumulate in the Female Reproductive System during Ovulation Affecting Cancer Treatment and Fertility. ACS Nano. 2022; 16(4):5246-5257. PMC: 7613117. DOI: 10.1021/acsnano.1c07237. View

Fukushima A, Yamaguchi T, Ishida W, Fukata K, Taniguchi T, Liu F . Genetic background determines susceptibility to experimental immune-mediated blepharoconjunctivitis: comparison of Balb/c and C57BL/6 mice. Exp Eye Res. 2005; 82(2):210-8. DOI: 10.1016/j.exer.2005.06.010. View

Mehew J, Johnson R, Roberts D, Harvala H . Convalescent plasma for COVID-19: male gender, older age and hospitalisation associated with high neutralising antibody levels, England, 22 April to 12 May 2020. Euro Surveill. 2020; 25(45). PMC: 7667632. DOI: 10.2807/1560-7917.ES.2020.25.45.2001754. View

Alberer M, Gnad-Vogt U, Hong H, Mehr K, Backert L, Finak G . Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet. 2017; 390(10101):1511-1520. DOI: 10.1016/S0140-6736(17)31665-3. View

Kadel S, Kovats S . Sex Hormones Regulate Innate Immune Cells and Promote Sex Differences in Respiratory Virus Infection. Front Immunol. 2018; 9:1653. PMC: 6062604. DOI: 10.3389/fimmu.2018.01653. View

Kodde C, Tafelski S, Balamitsa E, Nachtigall I, Bonsignore M . Factors Influencing Antibody Response to SARS-CoV-2 Vaccination. Vaccines (Basel). 2023; 11(2). PMC: 9967627. DOI: 10.3390/vaccines11020451. View

Chen B, Su Y, Chang C, Burnouf P, Chuang K, Chen C . Measurement of Pre-Existing IgG and IgM Antibodies against Polyethylene Glycol in Healthy Individuals. Anal Chem. 2016; 88(21):10661-10666. DOI: 10.1021/acs.analchem.6b03109. View

Gniadek T, Thiede J, Matchett W, Gress A, Pape K, Fiege J . SARS-CoV-2 neutralization and serology testing of COVID-19 convalescent plasma from donors with nonsevere disease. Transfusion. 2020; 61(1):17-23. PMC: 7995753. DOI: 10.1111/trf.16101. View

Yan Y, Gause K, Kamphuis M, Ang C, OBrien-Simpson N, Lenzo J . Differential roles of the protein corona in the cellular uptake of nanoporous polymer particles by monocyte and macrophage cell lines. ACS Nano. 2013; 7(12):10960-70. DOI: 10.1021/nn404481f. View

10.

Di J, Du Z, Wu K, Jin S, Wang X, Li T . Biodistribution and Non-linear Gene Expression of mRNA LNPs Affected by Delivery Route and Particle Size. Pharm Res. 2022; 39(1):105-114. PMC: 8791091. DOI: 10.1007/s11095-022-03166-5. View

11.

Fink A, Engle K, Ursin R, Tang W, Klein S . Biological sex affects vaccine efficacy and protection against influenza in mice. Proc Natl Acad Sci U S A. 2018; 115(49):12477-12482. PMC: 6298067. DOI: 10.1073/pnas.1805268115. View

12.

Breznik J, Schulz C, Ma J, Sloboda D, Bowdish D . Biological sex, not reproductive cycle, influences peripheral blood immune cell prevalence in mice. J Physiol. 2021; 599(8):2169-2195. DOI: 10.1113/JP280637. View

13.

Green M, Peer V, Magid A, HaGani N, Anis E, Nitzan D . Gender Differences in Adverse Events Following the Pfizer-BioNTech COVID-19 Vaccine. Vaccines (Basel). 2022; 10(2). PMC: 8875740. DOI: 10.3390/vaccines10020233. View

14.

Markmann A, Giallourou N, Bhowmik D, Hou Y, Lerner A, Martinez D . Sex Disparities and Neutralizing-Antibody Durability to SARS-CoV-2 Infection in Convalescent Individuals. mSphere. 2021; 6(4):e0027521. PMC: 8386415. DOI: 10.1128/mSphere.00275-21. View

15.

Engler R, Nelson M, Klote M, VanRaden M, Huang C, Cox N . Half- vs full-dose trivalent inactivated influenza vaccine (2004-2005): age, dose, and sex effects on immune responses. Arch Intern Med. 2008; 168(22):2405-14. DOI: 10.1001/archinternmed.2008.513. View

16.

Li F, Boon A, Michelson A, Foraker R, Zhan M, Payne P . Estrogen hormone is an essential sex factor inhibiting inflammation and immune response in COVID-19. Sci Rep. 2022; 12(1):9462. PMC: 9175532. DOI: 10.1038/s41598-022-13585-4. View

17.

Petkov S, Heuts F, Krotova O, Kilpelainen A, Engstrom G, Starodubova E . Evaluation of immunogen delivery by DNA immunization using non-invasive bioluminescence imaging. Hum Vaccin Immunother. 2013; 9(10):2228-36. PMC: 3906409. DOI: 10.4161/hv.25561. View

18.

Roved J, Westerdahl H, Hasselquist D . Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. Horm Behav. 2016; 88:95-105. DOI: 10.1016/j.yhbeh.2016.11.017. View

19.

Gote V, Bolla P, Kommineni N, Butreddy A, Nukala P, Palakurthi S . A Comprehensive Review of mRNA Vaccines. Int J Mol Sci. 2023; 24(3). PMC: 9917162. DOI: 10.3390/ijms24032700. View

20.

Ashkarran A, Gharibi H, Grunberger J, Saei A, Khurana N, Mohammadpour R . Sex-Specific Silica Nanoparticle Protein Corona Compositions Exposed to Male and Female BALB/c Mice Plasmas. ACS Bio Med Chem Au. 2023; 3(1):62-73. PMC: 9936498. DOI: 10.1021/acsbiomedchemau.2c00040. View