Molina Estupiñan Jenny Lorena, Foroutan Pajoohian Poorya, Pedersen Gabriel Kristian, Christensen Dennis, Marchi Serena, Montomoli Emanuele, Bjarnarson Stefanía P, Jonsdottir Ingileif, Aradottir Pind Audur Anna
Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavík, Iceland.
Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavík, Iceland.
Front Immunol. 2025 Jul 31;16:1646677. doi: 10.3389/fimmu.2025.1646677. eCollection 2025.
Childhood vaccination provides protection against infectious diseases, but multiple vaccinations are required to achieve this. In situations like influenza epidemics or COVID-19 pandemic, vaccine demands may exceed production capacity, highlighting the need for dose-sparing strategies. Adjuvants can boost and modulate immune responses to vaccines and could reduce the antigen doses needed to confer protection. Herein we evaluated the dose-sparing effects of the novel adjuvants dmLT, mmCT, CAF01, and CAF08b and alum (aluminum hydroxide) on primary neonatal antibody (Ab) response to a conjugate vaccine against , Pn1-CRM, and a recombinant influenza hemagglutinin (HA) protein vaccine. The primary Ab levels of neonatal mice immunized once with a full dose of Pn1-CRM or HA were low. mmCT and CAF08b enhanced Pn1-specific IgG Abs elicited by fractional doses of Pn1-CRM, providing eightfold dose sparing of the vaccine, whereas dmLT and CAF01 provided fivefold and twofold dose sparing, respectively. These adjuvants elicited protective Pn1-specific Ab levels against bacteremia (91%-63%) and pneumonia (50%-38%) in neonatal mice when combined with a half-dose of Pn1-CRM. In addition, mmCT, CAF01, and CAF08b enhanced the persistence of Pn1-specific IgG Ab-secreting cells (ASCs) in bone marrow compared with a full dose of vaccine only. With the influenza HA vaccine, CAF08b provided 40-fold dose sparing, while CAF01 and mmCT provided twofold dose sparing. CAF08b induced the micro-neutralization (MN) titers above protective levels in 100% and 86% of mice receiving 1/8 and 1/40 of HA dose, respectively, and CAF01 in 88% and 50% of mice receiving 1/4 and 1/8 dose of HA, respectively, whereas only 38% of mice receiving a full-dose HA without adjuvant reached the protective MN levels. Furthermore, these adjuvants provided cross-protective Abs and ASCs against a closely related heterologous influenza strain. In contrast, aluminum hydroxide did not provide any dose-sparing effects. Collectively, our results demonstrate that mmCT, CAF01, and CAF08b enhanced the protective humoral responses and had large dose-sparing effects on both Pn1-CRM and HA vaccines, although the adjuvant effect was clearly vaccine-dependent. The results support the potential use of safe adjuvants in situations when vaccine production capacity is limited, including vaccination of pediatric populations that may be of high risk.
儿童疫苗接种可预防传染病，但需要多次接种才能实现这一目标。在流感流行或新冠疫情等情况下，疫苗需求可能超过生产能力，这凸显了采用剂量节省策略的必要性。佐剂可以增强和调节对疫苗的免疫反应，并可减少提供保护所需的抗原剂量。在此，我们评估了新型佐剂dmLT、mmCT、CAF01和CAF08b以及明矾（氢氧化铝）对新生儿针对结合疫苗Pn1-CRM和重组流感血凝素（HA）蛋白疫苗的初次抗体（Ab）反应的剂量节省效果。用全剂量的Pn1-CRM或HA免疫一次的新生小鼠的初次Ab水平较低。mmCT和CAF08b增强了由部分剂量的Pn1-CRM引发的Pn1特异性IgG Abs，使疫苗的剂量节省了八倍，而dmLT和CAF01分别提供了五倍和两倍的剂量节省。当与半剂量的Pn1-CRM联合使用时，这些佐剂在新生小鼠中引发了针对菌血症（91%-63%）和肺炎（50%-38%）的保护性Pn1特异性Ab水平。此外，与仅使用全剂量疫苗相比，mmCT、CAF01和CAF08b增强了骨髓中Pn1特异性IgG Ab分泌细胞（ASC）的持久性。对于流感HA疫苗，CAF08b提供了40倍的剂量节省，而CAF01和mmCT提供了两倍的剂量节省。CAF08b分别在接受1/8和1/40 HA剂量的小鼠中诱导100%和86%的小鼠产生高于保护水平的微中和（MN）滴度，CAF01分别在接受1/4和1/8 HA剂量的小鼠中诱导88%和50%的小鼠产生高于保护水平的微中和（MN）滴度，而仅接受无佐剂全剂量HA的小鼠中只有38%达到保护性MN水平。此外，这些佐剂提供了针对密切相关的异源流感毒株的交叉保护性Ab和ASC。相比之下，氢氧化铝没有提供任何剂量节省效果。总体而言，我们的结果表明，mmCT、CAF01和CAF08b增强了保护性体液反应，并且对Pn1-CRM和HA疫苗都有很大的剂量节省效果，尽管佐剂效果明显依赖于疫苗。这些结果支持在疫苗生产能力有限的情况下，包括对可能具有高风险的儿科人群进行疫苗接种时，安全佐剂的潜在用途。
