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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 25; p. e2316376121
• Main Authors: Afroz, Sharmin, Saul, Sirle, Dai, Jin, Surman, Sonja, Liu, Xueqiao, Park, Hong-Su, Le Nouën, Cyril, Lingemann, Matthias, Dahal, Bibha, Coleman, John Robert, Mueller, Steffen, Collins, Peter Leon, Buchholz, Ursula Johanna, Munir, Shirin
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.06.2024
• Subjects: Animals; Antibodies, Viral - blood; Antibodies, Viral - immunology; Antiviral agents; Chlorocebus aethiops; Codon - genetics; Cricetinae; Drug development; Exo-a-sialidase; Hamsters; Hemagglutinins; Humans; Immunogenicity; Interferon; Lungs; Mesocricetus; Nose; Open reading frames; Open Reading Frames - genetics; Packaging; Parainfluenza; Parainfluenza Vaccines - genetics; Parainfluenza Vaccines - immunology; Parainfluenza Virus 3, Human - genetics; Parainfluenza Virus 3, Human - immunology; Pediatrics; Proteins; Replication; Respirovirus Infections - immunology; Respirovirus Infections - prevention & control; Respirovirus Infections - virology; Vaccines; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vero Cells; Viral Proteins - genetics; Viral Proteins - immunology; Viral Vaccines - genetics; Viral Vaccines - immunology; Virions; Virus Replication; Viruses; intranasal vaccine; live attenuated vaccine; human parainfluenza virus type 3; parainfluenza virus vaccine; codon pair deoptimization
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2316376121

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 to generate 12 viruses designated Min-N, Min-P, Min-M, Min-FHN, Min-L, Min-NP, Min-NPM, Min-NPL, Min-PM, Min-PFHN, Min-MFHN, and Min-PMFHN. CPD 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.