Hypertensive Mice Have Decreased Antibody Responses to COVID-19 mRNA Vaccination in the Angiotensin II Model of Hypertension

The SARS-CoV-2 virus responsible for the COVID-19 pandemic continues to generate significant morbidity and mortality worldwide. One third of adults across the world have high blood pressure (hypertension). Hypertensive patients are twice as likely to be infected with COVID-19 and experience worse outcomes in COVID-19 infection. Recent evidence has demonstrated that hypertensive patients have lower vaccine-specific antibody (Ab) titers than normotensive individuals to nearly all widely used COVID vaccines, reflected by increased infection rates and hospitalizations post-vaccination. The mechanism behind why hypertensive patients develop lower Ab responses is not known. The aim of this project was to develop a mouse model to determine the mechanisms of hypertension-induced hyporesponse to vaccination seen in humans. We hypothesized that hypertensive mice would produce decreased spike-specific Abs due to a dysregulation of immune cell populations in the germinal center (GC), the hub of vaccine-specific Ab maturation. Specifically, we assessed numbers of follicular helper T cells (Tfh), a subset of T cells that typically provide help to B cells for Ab production in GCs. Hypertension was induced through subcutaneous implantation of osmotic minipumps containing Angiotensin II at a rate of 800 nanograms/kilogram/minute in 8-12 week old male BL/6 mice. Spike-specific T cell tetramer was generated in our lab through purifying spike epitope-loaded biotinylated peptide-MHCII and tetramerizing this molecule. One week following induction of hypertension, normotensive and hypertensive mice were vaccinated with two doses (prime-boost twenty-one days apart) of the widely used COVID-19 Pfizer mRNA BNT162b2 vaccine. Two weeks after the vaccine boost, Tfh numbers in spleens and draining lymph nodes of the injection site were assessed by CD4+ T cell tetramer staining and flow cytometry. Serum spike-specific antibody titers over the course of the vaccination were also assessed through enzyme-linked immunosorbent assay (ELISA). Hypertensive mice had significantly lower spike-specific IgM Ab titers (normotensive 360±125 standardized ELISA Units/ milliliter (EU/mL) vs hypertensive, 14±2 EU/mL, *p<0.05) and spike-specific IgG Ab titers (normotensive 10236±1390 EU/mL vs hypertensive, 3461±660 EU/mL, ***p<0.001) than normotensive mice. Lower spike-specific IgG Ab titers correlated with higher systolic blood pressure in mice (**, p<0.01, R 2 =0.46). The decrease in antibody production correlated with a reduction in vaccine-specific Tfh in hypertensive mouse draining lymph nodes (normotensive 3090 ± 516 Tfh cells vs hypertensive 1231 ± 421 Tfh cells, *p<0.05). Our data suggests a potential dysregulation of GC T cell interactions as the mechanism behind vaccine hyporesponsiveness during hypertension. This project is funded by the U2C/TL1 Deep South KUH PRIME U2C DK133422 and TL1 DK139566, R01 AI166756-01A1, R01 NS110749, and R01 DK083785. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.