Jacob-Dolan Catherine, Hope David, Liu Jinyan, Waller-Pulido Alejandra, Verrette Brookelynne, Cabrera-Barragan Dalia N, Nangle Samuel J, Wang Qixin, Blanc Ross, Fisher Jana, Lasrado Ninaad, Wang Liping, Cook Anthony, Pessiant Laurent, Lewis Mark, Andersen Hanne, Hopps Markay, Scully Ingrid L, Allen Pirada Suphaphiphat, McNamara Ryan P, Anderson Annaliesa S, Barouch Dan H
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Sci Transl Med. 2025 Jul 9;17(806):eadu7646. doi: 10.1126/scitranslmed.adu7646.
The clinically approved seasonal influenza vaccines provide only 10 to 60% efficacy, necessitating strategies to improve vaccine performance. Here, we explored strategies for improving influenza vaccine efficacy using gene-based vaccines and mucosal boosting strategies in nonhuman primates. All vaccinated cynomolgus macaques were primed with the clinical quadrivalent inactivated virus (QIV) vaccine. We evaluated a rhesus adenovirus (RhAd52) vector delivered by intramuscular or mucosal routes and an mRNA vaccine encoding the hemagglutinin of A/H1N1/Wisconsin/67/2022 delivered intramuscularly as boosts compared with the QIV vaccine delivered intramuscularly and the quadrivalent live-attenuated influenza virus (LAIV) vaccine delivered intranasally. Boosting with RhAd52 and mRNA vaccines induced more robust humoral and cellular immune responses than the clinically approved vaccines and provided improved protective efficacy against a high-dose homologous challenge with A/H1N1/Wisconsin/67/2022. The RhAd52 vaccine delivered by the intratracheal route elicited robust mucosal antibody and T cell responses and provided optimal protection in the upper and lower respiratory tracts. Both peripheral and mucosal antibody responses, as well as mucosal T cell responses, correlated with protection against viral loads. Altogether, this study defines strategies for improving H1N1 seasonal influenza vaccine efficacy by using gene-based vaccines and by optimizing mucosal immunity.
临床批准的季节性流感疫苗的效力仅为10%至60%，因此需要采取提高疫苗性能的策略。在此，我们在非人灵长类动物中探索了使用基于基因的疫苗和黏膜加强策略来提高流感疫苗效力的策略。所有接种疫苗的食蟹猕猴均先用临床四价灭活病毒（QIV）疫苗进行免疫。我们评估了通过肌肉或黏膜途径递送的恒河猴腺病毒（RhAd52）载体，以及与肌肉注射的QIV疫苗和鼻内递送的四价减毒活流感病毒（LAIV）疫苗相比，肌肉注射作为加强剂的编码A/H1N1/威斯康星/67/2022血凝素的mRNA疫苗。与临床批准的疫苗相比，用RhAd52和mRNA疫苗加强免疫诱导了更强的体液和细胞免疫反应，并提高了针对A/H1N1/威斯康星/67/2022高剂量同源攻击的保护效力。经气管途径递送的RhAd52疫苗引发了强大的黏膜抗体和T细胞反应，并在上呼吸道和下呼吸道提供了最佳保护。外周和黏膜抗体反应以及黏膜T细胞反应均与针对病毒载量的保护相关。总之，本研究确定了通过使用基于基因的疫苗和优化黏膜免疫来提高H1N1季节性流感疫苗效力的策略。
