Live-attenuated Respiratory Syncytial Virus Vaccines: Time for the Next Step.
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ABSTRACT:
SUBMITTER: Billard MN
PROVIDER: S-EPMC7924581 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Live-attenuated respiratory syncytial virus (RSV) vaccines offer several advantages for immunization of infants and young children: (1) they do not cause vaccine-associated enhanced RSV disease; (2) they broadly stimulate innate, humoral, and cellular immunity, both systemically and locally in the respiratory tract; (3) they are delivered intranasally; and (4) they replicate in the upper respiratory tract of young infants despite the presence of passively acquired maternally derived RSV neutralizing antibody. This chapter describes early efforts to develop vaccines through the classic methods of serial cold-passage and chemical mutagenesis, and recent efforts using reverse genetics to derive attenuated derivatives of wild-type (WT) RSV and to develop parainfluenza vaccine vectors that express RSV surface glycoproteins.
| S-EPMC4794267 | biostudies-literature
Project description:The non-specific effects (NSEs) of vaccines have been discussed for their potential long-term beneficial effects beyond direct protection against a specific pathogen. Cold-adapted, live attenuated influenza vaccine (CAIV) induces local innate immune responses that provide a broad range of antiviral immunity. Herein, we examined whether X-31ca, a donor virus for CAIVs, provides non-specific cross-protection against respiratory syncytial virus (RSV). The degree of RSV replication was significantly reduced when X-31ca was administered before RSV infection without any RSV-specific antibody responses. The vaccination induced an immediate release of cytokines and infiltration of leukocytes into the respiratory tract, moderating the immune perturbation caused by RSV infection. The potency of protection against RSV challenge was significantly reduced in TLR3-/- TLR7-/- mice, confirming that the TLR3/7 signaling pathways are necessary for the observed immediate and short-term protection. The results suggest that CAIVs provide short-term, non-specific protection against genetically unrelated respiratory pathogens. The additional benefits of CAIVs in mitigating acute respiratory infections for which vaccines are not yet available need to be assessed in future studies.
| S-EPMC5797773 | biostudies-literature
Project description:BackgroundThis United States-based study compared 2 candidate vaccines: RSV/ΔNS2/Δ1313/I1314L, attenuated by NS2 gene-deletion and temperature-sensitivity mutation in the polymerase gene; and RSV/276, attenuated by M2-2 deletion.MethodsRSV-seronegative children aged 6-24 months received RSV/ΔNS2/Δ1313/I1314L (106 plaque-forming units [PFU]), RSV/276 (105 PFU), or placebo intranasally. Participants were monitored for vaccine shedding, reactogenicity, and RSV serum antibodies, and followed over the subsequent RSV season.ResultsEnrollment occurred September 2017 to October 2019. During 28 days postinoculation, upper respiratory illness and/or fever occurred in 64% of RSV/ΔNS2/Δ1313/I1314L, 84% of RSV/276, and 58% of placebo recipients. Symptoms were generally mild. Cough was more common in RSV/276 recipients than RSV/ΔNS2/Δ1313/I1314L (48% vs 12%; P = .012) or placebo recipients (17%; P = .084). There were no lower respiratory illness or serious adverse events. Eighty-eight and 96% of RSV/ΔNS2/Δ1313/I1314L and RSV/276 recipients were infected with vaccine (shed vaccine and/or had ≥4-fold rises in RSV antibodies). Serum RSV-neutralizing titers and anti-RSV F IgG titers increased ≥4-fold in 60% and 92% of RSV/ΔNS2/Δ1313/I1314L and RSV/276 vaccinees, respectively. Exposure to community RSV during the subsequent winter was associated with strong anamnestic RSV-antibody responses.ConclusionsBoth vaccines had excellent infectivity and were well tolerated. RSV/276 induced an excess of mild cough. Both vaccines were immunogenic and primed for strong anamnestic responses.Clinical trials registrationNCT03227029 and NCT03422237.
| S-EPMC10205613 | biostudies-literature
Project description:Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in infants, the elderly and immunocompromised individuals. Despite the global burden, there is no licensed vaccine for RSV. Recent advances in the use of nanoparticle technology have provided new opportunities to address some of the limitations of conventional vaccines. Precise control over particle size and surface properties enhance antigen stability and prolong antigen release. Particle size can also be modified to target specific antigen-presenting cells in order to induce specific types of effector T-cell responses. Numerous nanoparticle-based vaccines are currently being evaluated for RSV including inorganic, polymeric and virus-like particle-based formulations. Here, we review the potential advantages of using different nanoparticle formulations in a vaccine for RSV, and discuss many examples of safe, and effective vaccines currently in both preclinical and clinical stages of testing.
| S-EPMC7737143 | biostudies-literature
Project description:We recently developed a system for the generation of infectious bovine respiratory syncytial virus (BRSV) from cDNA. Here, we report the recovery of fully viable chimeric recombinant BRSVs (rBRSVs) that carry human respiratory syncytial virus (HRSV) glycoproteins in place of their BRSV counterparts, thus combining the replication machinery of BRSV with the major antigenic determinants of HRSV. A cDNA encoding the BRSV antigenome was modified so that the complete G and F genes, including the gene start and gene end signals, were replaced by their HRSV A2 counterparts. Alternatively, the BRSV F gene alone was replaced by that of HRSV Long. Each antigenomic cDNA directed the successful recovery of recombinant virus, yielding rBRSV/A2 and rBRSV/LongF, respectively. The HRSV G and F proteins or the HRSV F in combination with BRSV G were expressed efficiently in cells infected with the appropriate chimeric virus and were efficiently incorporated into recombinant virions. Whereas BRSV and HRSV grew more efficiently in bovine and human cells, respectively, the chimeric rBRSV/A2 exhibited intermediate growth characteristics in a human cell line and grew better than either parent in a bovine line. The cytopathology induced by the chimera more closely resembled that of BRSV. BRSV was confirmed to be highly restricted for replication in the respiratory tract of chimpanzees, a host that is highly permissive for HRSV. Interestingly, the rBRSV/A2 chimeric virus was somewhat more competent than BRSV for replication in chimpanzees but remained highly restricted compared to HRSV. This showed that the substitution of the G and F glycoproteins alone was not sufficient to induce efficient replication in chimpanzees. Thus, the F and G proteins contribute to the host range restriction of BRSV but are not the major determinants of this phenotype. Although rBRSV/A2 expresses the major neutralization and protective antigens of HRSV, chimpanzees infected with this chimeric virus were not significantly protected against subsequent challenge with wild-type HRSV. This suggests that the growth restriction of rBRSV/A2 was too great to provide adequate antigen expression and that the capacity of this chimeric vaccine candidate for replication in primates will need to be increased by the importation of additional HRSV genes.
| S-EPMC111453 | biostudies-literature
Project description:BackgroundRespiratory syncytial virus (RSV) is a leading cause of lower respiratory tract illness (LRTI) in children. Several promising live-attenuated RSV vaccines are in development. Defining additional markers of attenuation could enhance clinical trials.MethodsWe used clinical data, virologic data, and nasal wash (NW) specimens from 20 RSV-naive children enrolled in studies of 4 live-attenuated RSV vaccines. Seven received minimally attenuated cpts248/955 or cpts530/1009 (group 1), 6 received moderately attenuated cpts248/404 (group 2), and 7 received highly attenuated rA2cp248/404/1030/ΔSH (group 3). NW specimens were tested for cytokines and chemokines via an electrochemiluminescence biosensor assay.ResultsGroup 1 exhibited 1 instance of LRTI and significantly higher rates of fever than groups 2 or 3; there were no significant differences in peak titers of vaccine virus in NW specimens. In contrast, levels of interferon γ, interleukin 1β, interleukin 2, interleukin 6, and interleukin 13 were significantly greater in NW specimens from group 1, compared with those from group 3. Maximum increases in levels of most cytokines occurred after peak viral replication but coincided with clinical illness.ConclusionsSubstantial increases in proinflammatory, antiinflammatory, T-helper 1, T-helper 2, and regulatory cytokines were detected in children who received minimally attenuated live RSV vaccines but not in children who received highly attenuated vaccines. Levels of cytokines in NW specimens may be useful biomarkers of attenuation for live RSV vaccines.
| S-EPMC3693589 | biostudies-literature
Project description:Human respiratory syncytial virus (RSV) is the most important viral cause of serious pediatric respiratory illness worldwide. Currently, the most promising live-attenuated vaccine candidate is a temperature-sensitive (ts) cDNA-derived virus named rA2cp248/404/1030ΔSH, in reference to its set of attenuating mutations. In a previous clinical study, more than one-third of postvaccination nasal wash isolates exhibited partial loss of the ts phenotype. Most of this instability appeared to be due to reversion at a missense point mutation called 1030. This 1030 mutation is a single-nucleotide tyrosine-to-asparagine substitution at position 1321 (Y1321N) of the polymerase L protein that contributes to the ts and attenuation phenotypes of the vaccine candidate. The goals of the present study were to identify a reversion-resistant codon at position 1321 conferring a comparable level of attenuation and to use this to develop a genetically stable version of the vaccine virus. We modified wild-type (wt) RSV to insert each of the 20 possible amino acids at position 1321; 19 viruses were recoverable. We also investigated small deletions at or near this position, but these viruses were not recoverable. Phenotypic analysis identified alternative attenuating amino acids for position 1321. Several of these amino acids were predicted, based on the genetic code, to be refractory to deattenuation. Classical genetics, using temperature stress tests in vitro combined with nucleotide sequencing, confirmed this stability but identified a second site with a compensatory mutation at position 1313. It was possible to stabilize the 1313 site as well, providing a stable 1030 mutation. Further stress tests identified additional incidental mutations, but these did not reverse the ts/attenuation phenotype. An improved version of the vaccine candidate virus was constructed and validated in vitro by temperature stress tests and in vivo by evaluation of attenuation in seronegative chimpanzees. In addition to developing an improved version of this promising live-attenuated RSV vaccine candidate, this study demonstrated the propensity of an RNA virus to escape from attenuation but also showed that, through systematic analysis, genetics can be used to cut off the routes of escape.
| S-EPMC3457269 | biostudies-literature
Project description:Despite existing vaccines and enormous efforts in biomedical research, influenza annually claims 250,000-500,000 lives worldwide, motivating the search for new, more effective vaccines that can be rapidly designed and easily produced. We applied the previously described synthetic attenuated virus engineering (SAVE) approach to influenza virus strain A/PR/8/34 to rationally design live attenuated influenza virus vaccine candidates through genome-scale changes in codon-pair bias. As attenuation is based on many hundreds of nucleotide changes across the viral genome, reversion of the attenuated variant to a virulent form is unlikely. Immunization of mice by a single intranasal exposure to codon pair-deoptimized virus conferred protection against subsequent challenge with wild-type (WT) influenza virus. The method can be applied rapidly to any emerging influenza virus in its entirety, an advantage that is especially relevant when dealing with seasonal epidemics and pandemic threats, such as H5N1- or 2009-H1N1 influenza.
| S-EPMC2902615 | biostudies-literature
Project description:After decades of work, several interventions to prevent severe respiratory syncytial virus (RSV) disease in high-risk infant and older adult populations have finally been approved. There were many setbacks along the road to victory. In this review, I will discuss the impact of RSV on human health and how structure-based vaccine design set the stage for numerous RSV countermeasures to advance through late phase clinical evaluation. While there are still many RSV countermeasures in preclinical and early-stage clinical trials, this review will focus on products yielding long-awaited efficacy results. Finally, I will discuss some challenges and next steps needed to declare a global victory against RSV.
| S-EPMC10519952 | biostudies-literature
Project description:Human respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract illness (LRTI), and no vaccine against LRTI has proven to be safe and effective in infants. Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice. The constructed recombinant plasmids harbored (5' to 3') a T7 promoter, hammerhead ribozyme, RSV Long strain antigenomic cDNA with cold-passaged (cp) mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain (A2cpts) or further combined with SH gene deletion (A2cptsΔSH), HDV ribozyme (δ), and a T7 terminator. These vectors were subsequently co-transfected with four helper plasmids encoding N, P, L, and M2-1 viral proteins into BHK/T7-9 cells, and the recovered viruses were then passaged in Vero cells. The rescued recombinant RSVs (rRSVs) were named rRSV-Long/A2cp, rRSV-Long/A2cpts, and rRSV-Long/A2cptsΔSH, respectively, and stably passaged in vitro, without reversion to wild type (wt) at sites containing introduced mutations or deletion. Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed temperature-sensitive (ts) phenotype in vitro and in vivo, all rRSVs were significantly attenuated in vivo. Furthermore, BALB/c mice immunized with rRSVs produced Th1-biased immune response, resisted wtRSV infection, and were free from enhanced respiratory disease. We showed that the combination of ΔSH with attenuation (att) mutations of cpts contributed to improving att phenotype, efficacy, and gene stability of rRSV. By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains, we have laid an important foundation for the development of RSV live attenuated vaccines.
| S-EPMC8379332 | biostudies-literature