Chaulagain Sabal, Sachithanandham Jaiprasath, Liu Jennifer A, Creisher Patrick S, Park Han-Sol, Lee John S, Guebre-Xabier Mimi, Patel Nita, Smith Gale, Pekosz Andrew, Klein Sabra L
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
Novavax, Inc., 21 Firstfield Road, Gaithersburg, MD 20878, USA.
Vaccine. 2025 Jun 21;61:127409. doi: 10.1016/j.vaccine.2025.127409.
Sex and age impact immune responses to diverse vaccines. Using a preclinical mouse model, we investigated immune responses to a COVID-19 spike (S) protein-based vaccine and booster doses in adult (25 weeks) and aged (64 weeks) male and female C57BL/6 mice. Mice were intramuscularly vaccinated with either two doses of NVX-CoV2373 (Ancestral Wuhan-Hu-1) or two doses of NVX-CoV2373 followed by a booster of NVX-CoV2540 (Omicron BA.5) in 3-week intervals. Steroid concentrations, antibody titers, and immune cell frequencies in draining lymph nodes were quantified. Three weeks post-boost, subsets of mice were challenged with SARS-CoV-2 (Mu variant B.1.621) to measure cross-protection against an antigenically distinct strain. After two ancestral vaccine doses, adult females had greater binding antibody titers than either adult males or aged females, that were positively correlated with circulating estradiol concentrations. Adult females also had greater cross-neutralizing antibodies and had lower viral titers in respiratory tissues following live virus challenge than adult males. Aged mice, particularly males, had lower antibody titers and frequencies of B and follicular helper T cells than adult mice that were not cross-protective against B.1.621 challenge. Immunization with the BA.5 booster improved antibody responses and B and T cell frequencies in both adults and aged mice, eliminating sex and age differences in immunity and protection from SARS-CoV-2 challenge. These data highlight that there are limits to cross-protective immunity, particularly among males and aged individuals, that can be improved through booster doses that more closely match the challenge SARS-CoV-2 virus.
性别和年龄会影响对多种疫苗的免疫反应。我们使用临床前小鼠模型，研究了成年（25周）和老年（64周）雄性和雌性C57BL/6小鼠对基于新冠病毒刺突（S）蛋白的疫苗及加强剂量疫苗的免疫反应。小鼠分别间隔3周肌肉注射两剂NVX-CoV2373（原始武汉-胡-1株）或两剂NVX-CoV2373，随后再注射一剂NVX-CoV2540（奥密克戎BA.5）。对引流淋巴结中的类固醇浓度、抗体滴度和免疫细胞频率进行了定量分析。加强免疫后3周，对部分小鼠用新冠病毒（Mu变异株B.1.621）进行攻击，以检测针对抗原性不同毒株的交叉保护作用。接种两剂原始疫苗后，成年雌性小鼠的结合抗体滴度高于成年雄性小鼠和老年雌性小鼠，且与循环雌二醇浓度呈正相关。成年雌性小鼠还具有更强的交叉中和抗体，并且在活病毒攻击后，其呼吸道组织中的病毒滴度低于成年雄性小鼠。老年小鼠，尤其是老年雄性小鼠，其抗体滴度以及B细胞和滤泡辅助性T细胞的频率低于成年小鼠，对B.1.621攻击无交叉保护作用。用BA.5加强免疫可改善成年和老年小鼠的抗体反应以及B细胞和T细胞频率，消除了性别和年龄在免疫及对新冠病毒攻击的保护方面的差异。这些数据表明，交叉保护性免疫存在局限性，尤其是在雄性和老年个体中，而通过与攻击的新冠病毒更匹配的加强剂量疫苗可改善这种情况。
