Human parainfluenza virus 3 vaccine candidates attenuated by codon- pair deoptimization are immunogenic and protective in hamsters

• 成果类型: Article
• 署名作者: Afroz, Sharmin; Saul, Sirle; Dai, Jin; Surman, Sonja; Liu, Xueqiao; Park, Hong- Su; Le Nouen, Cyril; Lingemann, Matthias; Dahal, Bibha; Coleman, John Robert; Mueller, Steffen; Collins, Peter Leon; Buchholz, Ursula Johanna; Munir, Shirin
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15155
• DOI: 10.1073/pnas.2316376121
• 发表日期: 2024-06-18
• 关键词: respiratory syncytial virus; influenza-virus; cotton rats; type-3; infection; expression; fusion; transmissibility; identification; hemagglutinin

摘要

Human parainfluenza virus type 3 (HPIV3) is a major pediatric respiratory pathogen lacking available vaccines or antiviral drugs. We generated live- attenuated HPIV3 vaccine candidates by codon- pair deoptimization (CPD). HPIV3 open reading frames (ORFs) encoding the nucleoprotein (N), phosphoprotein (P), matrix (M), fusion (F), hemagglutinin-neuraminidase (HN), and polymerase (L) were modified singly or in combination of N or L severely reduced growth in vitro and was not further evaluated. CPD of P or M was associated with increased and decreased interferon (IFN) response in vitro, respectively, but had little effect on virus replication. In Vero cells, CPD of F and HN delayed virus replication, but final titers were comparable to wild- type (wt) HPIV3. In human lung epithelial A549 cells, CPD F and HN induced a stronger IFN response, viral titers were reduced 100- fold, and the expression of F and HN proteins was significantly reduced without affecting N or P or the relative packaging of proteins into virions. Following intranasal infection in hamsters, replication in the nasal turbinates and lungs tended to be the most reduced for viruses bearing CPD F and HN, with maximum reductions of approximately 10- fold. Despite decreased in vivo replication (and lower expression of CPD F and HN in vitro), all viruses induced titers of serum HPIV3- neutralizing antibodies similar to wt and provided complete protection against HPIV3 challenge. In summary, CPD of HPIV3 yielded promising vaccine candidates suitable for further development.