Matchett William E, Malewana Goda Baddage Rakitha, Mudrick Haley, Medlyn Michael J, Barry Michael A
Virology and Gene Therapy (VGT) Graduate Program, Mayo Clinic, Rochester, MN 55905, USA.
Mayo Summer Undergraduate Research Fellow (SURF), Mayo Clinic, Rochester, MN 55905, USA.
Vaccines (Basel). 2020 Feb 2;8(1):64. doi: 10.3390/vaccines8010064.
Most infections occur at mucosal surfaces. Providing a barrier of protection at these surfaces may be a useful strategy to combat the earliest events in infection when there are relatively few pathogens to address. The majority of vaccines are delivered systemically by the intramuscular (IM) route. While IM vaccination can drive mucosal immune responses, mucosal immunization at intranasal (IN) or oral sites can lead to better immune responses at mucosal sites of viral entry. In macaques, IN immunization with replicating single-cycle adenovirus (SC-Ads) and protein boosts generated favorable mucosal immune responses. However, there was an apparent "distance effect" in generating mucosal immune responses. IN immunization generated antibodies against HIV envelope (env) nearby in the saliva, but weaker responses in samples collected from the distant vaginal samples. To improve on this, we tested here if SC-Ads expressing genetic adjuvants could be used to amplify antibody responses in distant vaginal samples when they are codelivered with SC-Ads expressing clade C HIV env immunogen. SC-Ads env 1157 was coadministered with SC-Ads expressing 4-1BBL, granulocyte macrophage colony-stimulating factor (GMCSF), IL-21, or toxin fragments by IN or IM routes. These data show that vaginal antibody responses were markedly amplified after a single immunization by the IN or IM routes, with SC-Ad expressing HIV env if this vaccine is complemented with SC-Ads expressing genetic adjuvants. Furthermore, the site and combination of adjuvants appear to "tune" these antibody responses towards an IgA or IgG isotype bias. Boosting these priming SC-Ad responses with another SC-Ad or with SOSIP native-like env proteins markedly amplifies env antibody levels in vaginal washes. Together, this data may be useful in informing the choice of route of delivery adenovirus and peptide vaccines against HIV-1.
大多数感染发生在黏膜表面。在这些表面提供保护屏障可能是一种有效的策略，可在病原体数量相对较少时对抗感染的早期事件。大多数疫苗通过肌肉注射（IM）途径进行全身给药。虽然IM疫苗接种可驱动黏膜免疫反应，但鼻内（IN）或口服部位的黏膜免疫接种可在病毒进入的黏膜部位引发更好的免疫反应。在猕猴中，用复制性单周期腺病毒（SC-Ads）和蛋白质加强免疫进行IN免疫可产生良好的黏膜免疫反应。然而，在产生黏膜免疫反应方面存在明显的“距离效应”。IN免疫在唾液中产生了针对HIV包膜（env）的抗体，但在从较远的阴道样本中采集的样本中反应较弱。为了改善这一点，我们在此测试了表达基因佐剂的SC-Ads与表达C亚型HIV env免疫原的SC-Ads共同给药时，是否可用于增强较远阴道样本中的抗体反应。SC-Ads env 1157通过IN或IM途径与表达4-1BBL、粒细胞巨噬细胞集落刺激因子（GMCSF）、IL-21或毒素片段的SC-Ads共同给药。这些数据表明，如果这种疫苗与表达基因佐剂的SC-Ads互补，通过IN或IM途径单次免疫后，阴道抗体反应会显著增强。此外，佐剂的给药部位和组合似乎会将这些抗体反应“调整”为偏向IgA或IgG同种型。用另一种SC-Ad或SOSIP天然样env蛋白加强这些初始SC-Ad反应，可显著提高阴道冲洗液中env抗体水平。总之，这些数据可能有助于指导针对HIV-1的腺病毒和肽疫苗给药途径的选择。
