Live-attenuated Vaccines Prevent Respiratory Syncytial Virus–associated Illness in Young Children

Karron, Ruth A.; Atwell, Jessica E.; McFarland, Elizabeth J.; Cunningham, Coleen K.; Muresan, Petronella; Perlowski, Charlotte; Libous, Jennifer; Spector, Stephen A.; Yogev, Ram; Aziz, Mariam; Woods, Suzanne; Wanionek, Kimberli; Collins, Peter L.; Buchholz, Ursula J.

doi:10.1164/rccm.202005-1660oc

Cited by 49 publications

(32 citation statements)

References 22 publications

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“…Live-attenuated and live-vectored vaccines typically induce broad and balanced innate, antibody, and cellular responses, including CD8 + and CD4 + T cell responses and resident lung T cells ( 39 ). In the case of HRSV, because of this broad and balanced response, live-attenuated and live-vectored vaccines are free of the Th2-mediated enhanced disease associated with inactivated HRSV vaccines ( 40 – 42 ). Similarly, replicating SARS coronavirus vaccines are unlikely to prime for the Th2 pulmonary immunopathology that has been seen upon challenge in animal models following immunization with previous inactivated coronavirus vaccine candidates ( 43 – 45 ).…”

Section: Discussionmentioning

confidence: 99%

A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

Liu

Luongo

Matsuoka

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Single-dose vaccines with the ability to restrict SARS-CoV-2 replication in the respiratory tract are needed for all age groups, aiding efforts toward control of COVID-19. We developed a live intranasal vector vaccine for infants and children against COVID-19 based on replication-competent chimeric bovine/human parainfluenza virus type 3 (B/HPIV3) that express the native (S) or prefusion-stabilized (S-2P) SARS-CoV-2 S spike protein, the major protective and neutralization antigen of SARS-CoV-2. B/HPIV3/S and B/HPIV3/S-2P replicated as efficiently as B/HPIV3 in vitro and stably expressed SARS-CoV-2 S. Prefusion stabilization increased S expression by B/HPIV3 in vitro. In hamsters, a single intranasal dose of B/HPIV3/S-2P induced significantly higher titers compared to B/HPIV3/S of serum SARS-CoV-2–neutralizing antibodies (12-fold higher), serum IgA and IgG to SARS-CoV-2 S protein (5-fold and 13-fold), and IgG to the receptor binding domain (10-fold). Antibodies exhibited broad neutralizing activity against SARS-CoV-2 of lineages A, B.1.1.7, and B.1.351. Four weeks after immunization, hamsters were challenged intranasally with 104.5 50% tissue-culture infectious-dose (TCID50) of SARS-CoV-2. In B/HPIV3 empty vector-immunized hamsters, SARS-CoV-2 replicated to mean titers of 106.6 TCID50/g in lungs and 107 TCID50/g in nasal tissues and induced moderate weight loss. In B/HPIV3/S-immunized hamsters, SARS-CoV-2 challenge virus was reduced 20-fold in nasal tissues and undetectable in lungs. In B/HPIV3/S-2P–immunized hamsters, infectious challenge virus was undetectable in nasal tissues and lungs; B/HPIV3/S and B/HPIV3/S-2P completely protected against weight loss after SARS-CoV-2 challenge. B/HPIV3/S-2P is a promising vaccine candidate to protect infants and young children against HPIV3 and SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

Liu

Luongo

Matsuoka

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Since 2011, our laboratory has evaluated 12 live-attenuated RSV vaccine candidates in clinical trials [50][51][52][53][54][55]. This experience indicates that there is a range or "window" in which vaccine virus replication is sufficiently reduced to minimize reactogenicity without unacceptable loss of immunogenicity, and that this "window" is narrow.…”

Section: Plos Pathogensmentioning

confidence: 99%

Reversion mutations in phosphoprotein P of a codon-pair-deoptimized human respiratory syncytial virus confer increased transcription, immunogenicity, and genetic stability without loss of attenuation

et al. 2021

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Recoding viral genomes by introducing numerous synonymous nucleotide substitutions that create suboptimal codon pairs provides new live-attenuated vaccine candidates. Because recoding typically involves a large number of nucleotide substitutions, the risk of de-attenuation is presumed to be low. However, this has not been thoroughly studied. We previously generated human respiratory syncytial virus (RSV) in which the NS1, NS2, N, P, M and SH ORFs were codon-pair deoptimized (CPD) by 695 synonymous nucleotide changes (Min A virus). Min A exhibited a global reduction in transcription and protein synthesis, was restricted for replication in vitro and in vivo, and exhibited moderate temperature sensitivity. Here, we show that under selective pressure by serial passage at progressively increasing temperatures, Min A regained replication fitness and lost its temperature sensitivity. Whole-genome deep sequencing identified numerous missense mutations in several genes, in particular ones accumulating between codons 25 and 34 of the phosphoprotein (P), a polymerase cofactor and chaperone. When re-introduced into Min A, these P mutations restored viral transcription to wt level, resulting in increased protein expression and RNA replication. Molecular dynamic simulations suggested that these P mutations increased the flexibility of the N-terminal domain of P, which might facilitate its interaction with the nucleoprotein N, and increase the functional efficiency of the RSV transcription/replication complex. Finally, we evaluated the effect of the P mutations on Min A replication and immunogenicity in hamsters. Mutation P[F28V] paradoxically reduced Min A replication but not its immunogenicity. The further addition of one missense mutation each in M and L generated a version of Min A with increased genetic stability. Thus, this study provides further insight into the adaptability of large-scale recoded RNA viruses under selective pressure and identified an improved CPD RSV vaccine candidate.

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“…RSV-related morbidity seems to be underestimated in other age groups than the pediatric age group; however, awareness on the impact of RSV in adults is increasing, and estimates report at least 10% of pneumonia cases in adults to be RSV-related [ 6 , 7 ]. Efforts towards RSV prevention have resulted in passive immunoprophylaxis with monoclonal antibodies administered to high-risk patients, while clinical trials on possible vaccines are still being conducted with no product licensed to date [ 8 , 9 ]. The risk factors of a more severe clinical course of the disease have mainly been studied in hospital settings, and include prematurity, younger age, and comorbidities related to pulmonary or cardiac conditions, but regarding the risk of hospitalization, air pollution is of special interest [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Air Pollutants’ Concentrations Are Associated with Increased Number of RSV Hospitalizations in Polish Children

Wrotek

Badyda

Czechowski

et al. 2021

JCM

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Respiratory syncytial virus (RSV) contributes significantly to pediatric hospitalizations. An association between air pollution and an increased number of RSV cases has been suggested. We sought to evaluate the short-term impact of air pollutants on RSV hospitalizations in Polish children in the period 2010–2019. Daily concentrations of PM10 and PM2.5 (particulate matter with an aerodynamic diameter less than or equal to 10 μm and 2.5 μm, respectively) and nitrogen dioxide (NO2) were analyzed in general regression models (GRM) to establish their influence and full interaction scheme. Significant seasonal and annual periodicity among 53,221 hospitalizations was observed; finally, data from the 2012–2019 RSV high-risk seasons created models for seven agglomerations. The addition of PM2.5, PM10, and NO2 to the basic model for RSV seasonality explained 23% (4.9–31%, univariate model) to 31.4% (8.4–31%, multivariate model) of the variance in RSV hospitalizations. A 10 μg/m3 increase in PM2.5, PM10, and NO2 concentrations was associated with 0.134 (0.087–0.16), 0.097 (0.031–0.087), and 0.212 (0.04–0.29) average increases in hospitalizations, respectively. In the multivariate models, PM2.5, PM10, and NO2 alone, as well as PM2.5–NO2, PM2.5–PM10, and PM10–NO2 interactions, were associated with hospitalizations in some of the locations, while the metaregression showed statistically significant interactions between each of the pollutants, and between the pollutants and the year of the study. The inclusion of PM2.5, PM10, and NO2 in GRM explains a significant number of RSV hospitalizations. The pollutants act alone and interact together in a varied manner. Reducing air contamination might decrease the costs of hospital healthcare.

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Live-attenuated Vaccines Prevent Respiratory Syncytial Virus–associated Illness in Young Children

Cited by 49 publications

References 22 publications

A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

A single intranasal dose of a live-attenuated parainfluenza virus-vectored SARS-CoV-2 vaccine is protective in hamsters

Reversion mutations in phosphoprotein P of a codon-pair-deoptimized human respiratory syncytial virus confer increased transcription, immunogenicity, and genetic stability without loss of attenuation

Air Pollutants’ Concentrations Are Associated with Increased Number of RSV Hospitalizations in Polish Children

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