scholarly journals Live Respiratory Syncytial Virus Attenuated by M2-2 Deletion and Stabilized Temperature Sensitivity Mutation 1030s Is a Promising Vaccine Candidate in Children

2019 ◽  
Vol 221 (4) ◽  
pp. 534-543 ◽  
Author(s):  
Elizabeth J McFarland ◽  
Ruth A Karron ◽  
Petronella Muresan ◽  
Coleen K Cunningham ◽  
Jennifer Libous ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Temperature Sensitivity ◽  
Neutralizing Antibodies ◽  
Quantitative Polymerase Chain Reaction ◽  
Regulatory Protein ◽  
Serum Antibody ◽  
Respiratory Illness ◽  
Acid Synthesis ◽  
Antibody Titers ◽  
Syncytial Virus

Abstract Background The safety and immunogenicity of live respiratory syncytial virus (RSV) candidate vaccine, LID/ΔM2-2/1030s, with deletion of RSV ribonucleic acid synthesis regulatory protein M2-2 and genetically stabilized temperature-sensitivity mutation 1030s in the RSV polymerase protein was evaluated in RSV-seronegative children. Methods Respiratory syncytial virus-seronegative children ages 6–24 months received 1 intranasal dose of 105 plaque-forming units (PFU) of LID/ΔM2-2/1030s (n = 21) or placebo (n = 11). The RSV serum antibodies, vaccine shedding, and reactogenicity were assessed. During the following RSV season, medically attended acute respiratory illness (MAARI) and pre- and postsurveillance serum antibody titers were monitored. Results Eighty-five percent of vaccinees shed LID/ΔM2-2/1030s vaccine (median peak nasal wash titers: 3.1 log10 PFU/mL by immunoplaque assay; 5.1 log10 copies/mL by reverse-transcription quantitative polymerase chain reaction) and had ≥4-fold rise in serum-neutralizing antibodies. Respiratory symptoms and fever were common (60% vaccinees and 27% placebo recipients). One vaccinee had grade 2 wheezing with rhinovirus but without concurrent LID/ΔM2-2/1030s shedding. Five of 19 vaccinees had ≥4-fold increases in antibody titers postsurveillance without RSV-MAARI, indicating anamnestic responses without significant illness after infection with community-acquired RSV. Conclusions LID/ΔM2-2/1030s had excellent infectivity without evidence of genetic instability, induced durable immunity, and primed for anamnestic antibody responses, making it an attractive candidate for further evaluation.

scholarly journals Live-Attenuated Respiratory Syncytial Virus Vaccine With M2-2 Deletion and With Small Hydrophobic Noncoding Region Is Highly Immunogenic in Children

2020 ◽  
Vol 221 (12) ◽  
pp. 2050-2059 ◽  
Author(s):  
Elizabeth J McFarland ◽  
Ruth A Karron ◽  
Petronella Muresan ◽  
Coleen K Cunningham ◽  
Charlotte Perlowski ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Regulatory Protein ◽  
Neutralizing Antibody ◽  
Respiratory Illness ◽  
Antibody Responses ◽  
Upper Respiratory Tract ◽  
Syncytial Virus ◽  
Placebo Recipients

Abstract Background Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1. Methods RSV-seronegative children aged 6–24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. Results All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. Conclusions D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. Clinical Trials Registration NCT03102034 and NCT03099291.

Humoral immunity to respiratory syncytial virus in young and elderly adults

2009 ◽  
Vol 137 (12) ◽  
pp. 1684-1686 ◽  
Author(s):  
C. TERROSI ◽  
G. Di GENOVA ◽  
B. MARTORELLI ◽  
M. VALENTINI ◽  
M. G. CUSI
Keyword(s):  
Respiratory Syncytial Virus ◽  
Neutralizing Antibodies ◽  
Serum Antibody ◽  
Age Groups ◽  
The Elderly ◽  
Elderly Subjects ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Relationship Of ◽  
The Relationship

SUMMARYRespiratory syncytial virus (RSV) has been demonstrated to cause substantial disease in elderly and immunocompromised subjects. The relationship of serum antibody to RSV infection and the risk of infection in elderly subjects is controversial, thus we evaluated the presence of neutralizing antibodies to RSV in healthy people of different age groups and the correlation with viral protection. Baseline blood samples from 197 subjects aged 20–80 years were analysed for the presence of anti-RSV antibodies either by indirect immunofluorescence and microneutralization test. The percentage of people who had neutralizing antibodies to RSV was significantly higher (P=0·001) in the youngest group (92·51%) compared to the frail group (36·21%). The RSV antibody level tends to wane in some older people; this factor could determine proneness to RSV re-infections in the elderly who are at a greater risk of developing severe respiratory disease.

scholarly journals Respiratory Syncytial Virus (RSV) Neutralizing Antibodies at Birth Predict Protection from RSV Illness in Infants in the First 3 Months of Life

2020 ◽  
Author(s):  
Andrea G Buchwald ◽  
Barney S Graham ◽  
Awa Traore ◽  
Fadima Cheick Haidara ◽  
Man Chen ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Cord Blood ◽  
Neutralizing Antibodies ◽  
Maternal Immunization ◽  
Young Infants ◽  
Healthy Control ◽  
Antibody Titers ◽  
Syncytial Virus ◽  
Antibody Levels ◽  
Nested Case Control

Abstract Background Respiratory syncytial virus (RSV) is a leading cause of viral pneumonia and bronchiolitis during the first 6 months of life. Placentally transferred antibodies can prevent severe RSV illness, and maternal immunization may reduce illness in young infants. Identification of protective antibody levels facilitates the advancement of vaccine candidates and maternal immunization. Methods We conducted a nested case-control study with 587 Malian mother–infant pairs, followed from birth to age 6 months. RSV cases were infants who developed influenza-like illness (ILI) or pneumonia and were RSV-positive by polymerase chain reaction. Cases were matched to healthy controls and RSV-negative ILI controls. RSV-A and RSV-B neutralizing antibodies were measured in maternal, cord blood, and infant sera at age 3 and 6 months. Results Maternal antibodies were efficiently transferred to infants. Maternal and infant RSV titers were strongly correlated. Infant antibody titers against RSV-A were 3 times higher than those against RSV-B. At birth, infants who remained healthy had significantly higher RSV-A and RSV-B titers compared with infants who subsequently contracted RSV. RSV-A inhibitory concentration (IC)80 titer >239 or RSV-B titer >60 at birth was significantly associated with being a healthy control compared with an RSV case within the first 3 months of life. RSV-A IC80 titers in cord blood were associated with decreased episodes of pneumonia. Conclusions Maternally acquired RSV antibodies were associated with protection of infants against community-detected cases of RSV-ILI and pneumonia. RSV titers in cord blood can predict whether an infant will be infected with RSV or remain uninfected.

scholarly journals Respiratory syncytial virus-neutralizing serum antibody titers in infants following palivizumab prophylaxis with an abbreviated dosing regimen

PLoS ONE ◽  
2017 ◽  
Vol 12 (4) ◽  
pp. e0176152 ◽  
Author(s):  
Jennifer Claydon ◽  
Amitava Sur ◽  
Allison Callejas ◽  
Mihoko Ladd ◽  
Eddie Kwan ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Serum Antibody ◽  
Dosing Regimen ◽  
Antibody Titers ◽  
Syncytial Virus

scholarly journals Live-Attenuated Respiratory Syncytial Virus Vaccine With Deletion of RNA Synthesis Regulatory Protein M2-2 and Cold Passage Mutations Is Overattenuated

2019 ◽  
Vol 6 (6) ◽  
Author(s):  
Coleen K Cunningham ◽  
Ruth Karron ◽  
Petronella Muresan ◽  
Elizabeth J McFarland ◽  
Charlotte Perlowski ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Neutralizing Antibodies ◽  
Rna Synthesis ◽  
Regulatory Protein ◽  
Vaccine Virus ◽  
Quantitative Culture ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Syncytial Virus ◽  
Respiratory Syncytial Virus Vaccine

Abstract Background The live respiratory syncytial virus (RSV) candidate vaccine LIDcpΔM2-2 is attenuated through deletion of M2-2 and 5 cold-passage mutations. Methods RSV-seronegative children aged 6–24 months received a single intranasal dose of 105 plaque-forming units (PFU) of LIDcpΔM2-2 or placebo. RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. Results Four of 11 (36%) vaccinees shed vaccine virus with median peak titers of 1.6 log10 PFU/mL by quantitative culture and 4.5 log10 copies/mL by polymerase chain reaction; 45% had ≥4-fold rise in serum-neutralizing antibodies. Respiratory symptoms or fever were common in vaccinees (64%) and placebo recipients (6/6, 100%). Conclusions RSV LIDcpΔM2-2 is overattenuated. Clinical Trial Numbers. NCT02890381, NCT02948127.

scholarly journals 1718. Respiratory Syncytial Virus (RSV) Surveillance in the Department of Veterans Affairs (VA), 2010-2018

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S843-S843
Author(s):  
Cynthia Lucero-Obusan ◽  
Patricia Schirmer ◽  
Gina Oda ◽  
Mark Holodniy
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Infections ◽  
Diagnostic Testing ◽  
Fold Increase ◽  
Respiratory Illness ◽  
Veterans Affairs ◽  
Department Of Veterans Affairs ◽  
Management And Development ◽  
Syncytial Virus ◽  
National Trends

Abstract Background Respiratory Syncytial Virus (RSV) is an increasingly recognized cause of acute respiratory illness in older adults, leading to an estimated 177,000 hospitalizations and 14,000 deaths each year in the US. In adult populations, diagnostic testing for RSV has historically been underutilized. Herein, we examine national trends in RSV testing and infection across the Veterans Affairs (VA) healthcare system. Methods Electronic RSV laboratory testing results, ICD-coded hospitalizations and outpatient encounters were obtained from VA’s Praedico Surveillance System (1/1/2010-12/31/2018). Patients were reviewed for positive results, repeat testing, and demographics. Antibody tests were excluded. Results A total of 102,251 RSV results were included. Overall, 4,372 (4.3%) specimens from 4,263 unique individuals were positive with a median age of 67 years (range 0-101) and 90% were male. 1,511 individuals (35.4%) also had an RSV-coded hospitalization. RSV type was specified for only 7.8% of positives (Table). During 2010-2018 there were 2,522 RSV-coded hospitalizations (median length of stay = 4 days) among 2,444 unique individuals, which included 413 ICU stays (16.4%) and 98 deaths (3.9%) during the RSV-coded hospitalization. Approximately 78% of RSV-coded hospitalizations within VA (excluding all non-VA hospitalizations) had a documented positive test result. A greater than 15-fold increase in RSV tests performed, hospitalizations and outpatient encounters was observed from 2010-2018, although the percent testing positive remained relatively stable (Figure, Table). Figure. Testing for Respiratory Syncytial Virus (RSV), Department of Veterans Affairs, 2010-2018. Table. Select RSV Surveillance Metrics, Department of Veterans Affairs, 2010-2018 Conclusion RSV testing and identification of patients with RSV infection increased dramatically during the time period analyzed, likely due to increased availability of PCR-based multi-pathogen panels and duplex assays. While the percentage of tests positive for RSV remained relatively stable, the rise in coded hospitalizations may be due to increased testing for RSV among hospitalized Veterans with severe respiratory infections. These surveillance data may allow for further characterization of RSV disease burden estimates which can help inform clinical management and development of interventions for adults, such as vaccines and antiviral therapies. Disclosures All Authors: No reported disclosures

scholarly journals Respiratory Syncytial Virus Immunoprophylaxis with Palivizumab: 12-Year Observational Study of Usage and Outcomes in Canada

2021 ◽  
Author(s):  
Ian Mitchell ◽  
Abby Li ◽  
Candice L. Bjornson ◽  
Krista L. Lanctot ◽  
Bosco A. Paes ◽  
...  
Keyword(s):  
Risk Factors ◽  
Respiratory Syncytial Virus ◽  
Burden Of Illness ◽  
Respiratory Illness ◽  
Smoking Exposure ◽  
Key Points ◽  
Rsv Infection ◽  
History Of ◽  
Syncytial Virus ◽  
Airway Anomalies

Objective This study aimed to evaluate palivizumab (PVZ) use, trends in indications, and outcomes of respiratory illness hospitalizations (RIH) and respiratory syncytial virus hospitalizations (RSVH). Study Design It involves a large, Canadian prospective (2005–2017) observational multicenter study of children at high risk for RSV infection. Results A total of 25,003 infants (56.3% male) were enrolled at 32 sites; 109,579 PVZ injections were administered. Indications included: prematurity (63.3%); “miscellaneous” (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%). The “miscellaneous” group increased over time (4.4% in 2005–2006 to 22.5% in 2016–2017) and included: trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual “unclassified” group. Adherence measured by expected versus actual doses plus correct interdose interval was 64.7%. A total of 2,054 RIH occurred (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH 1.6%). Risk factors for RSVH included having siblings, attending daycare, family history of atopy, smoking exposure, and crowded household. Infants with 5 risk factors were 9.0 times (95% CI or confidence interval 4.4–18.2; p < 0.0005) more likely to have RSVH than infants without risk factors. Three adverse events occurred; none were fatal. Conclusion Results are relevant to both clinicians and decision-makers. We confirmed the safety of PVZ. Use of PVZ increased steadily for children with miscellaneous conditions and medical complexity. Medical and social factors pose a risk for severe RIH and RSVH with accompanying burden of illness. A vaccine that protects against RSV is urgently required. Key Points

scholarly journals Advax-CpG Adjuvant Provides Antigen Dose-Sparing and Enhanced Immunogenicity for Inactivated Poliomyelitis Virus Vaccines

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 500
Author(s):  
Yoshikazu Honda-Okubo ◽  
Jeremy Baldwin ◽  
Nikolai Petrovsky
Keyword(s):  
Neutralizing Antibodies ◽  
Serum Antibody ◽  
Oral Polio Vaccine ◽  
Antigen Dose ◽  
Polio Vaccine ◽  
Antibody Titers ◽  
Dose Sparing ◽  
Sparing Effect ◽  
Eradicate Polio

Global immunization campaigns have resulted in a major decline in the global incidence of polio cases, with wild-type poliovirus remaining endemic in only two countries. Live oral polio vaccine (OPV) played a role in the reduction in polio case numbers; however, the risk of OPV developing into circulating vaccine-derived poliovirus makes it unsuitable for eradication programs. Trivalent inactivated polio virus (TIPV) vaccines which contain formalin-inactivated antigens produced from virulent types 1, 2 and 3 reference polio strains grown in Vero monkey kidney cells have been advocated as a replacement for OPV; however, TIPVs have weak immunogenicity and multiple boosts are required before peak neutralizing titers are reached. This study examined whether the incorporation of the novel polysaccharide adjuvant, Advax-CpG, could boost the immunogenicity of two TIPV vaccines, (i) a commercially available polio vaccine (IPOL®, Sanofi Pasteur) and (ii) a new TIPV formulation developed by Statens Serum Institut (SSI). Mice were immunized intramuscularly based on recommended vaccine dosage schedules and serum antibody titers were followed for 12 months post-immunization. Advax-CpG significantly enhanced the long-term immunogenicity of both TIPV vaccines and had at least a 10-fold antigen dose-sparing effect. An exception was the poor ability of the SSI TIPV to induce serotype type 1 neutralizing antibodies. Immunization with monovalent IPVs suggested that the low type 1 response to TIPV may be due to antigen competition when the type 1 antigen was co-formulated with the type 2 and 3 antigens. This study provides valuable insights into the complexity of the formulation of multivalent polio vaccines and supports the further development of adjuvanted antigen-sparing TIPV vaccines in the fight to eradicate polio.

scholarly journals Characterization of Pre-F-GCN4t, a Modified Human Respiratory Syncytial Virus Fusion Protein Stabilized in a Noncleaved Prefusion Conformation

2017 ◽  
Vol 91 (13) ◽  
Author(s):  
Normand Blais ◽  
Martin Gagné ◽  
Yoshitomo Hamuro ◽  
Patrick Rheault ◽  
Martine Boyer ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Respiratory Syncytial Virus ◽  
Vaccine Antigen ◽  
Significant Advance ◽  
F Protein ◽  
Syncytial Virus

ABSTRACT The human respiratory syncytial virus (hRSV) fusion (F) protein is considered a major target of the neutralizing antibody response to hRSV. This glycoprotein undergoes a major structural shift from the prefusion (pre-F) to the postfusion (post-F) state at the time of virus-host cell membrane fusion. Recent evidences suggest that the pre-F state is a superior target for neutralizing antibodies compared to the post-F state. Therefore, for vaccine purposes, we have designed and characterized a recombinant hRSV F protein, called Pre-F-GCN4t, stabilized in a pre-F conformation. To show that Pre-F-GCN4t does not switch to a post-F conformation, it was compared with a recombinant post-F molecule, called Post-F-XC. Pre-F-GCN4t was glycosylated and trimeric and displayed a conformational stability different from that of Post-F-XC, as shown by chemical denaturation. Electron microscopy analysis suggested that Pre-F-GCN4t adopts a lollipop-like structure. In contrast, Post-F-XC had a typical elongated conical shape. Hydrogen/deuterium exchange mass spectrometry demonstrated that the two molecules had common rigid folding core and dynamic regions and provided structural insight for their biophysical and biochemical properties and reactivity. Pre-F-GCN4t was shown to deplete hRSV-neutralizing antibodies from human serum more efficiently than Post-F-XC. Importantly, Pre-F-GCN4t was also shown to bind D25, a highly potent monoclonal antibody specific for the pre-F conformation. In conclusion, this construct presents several pre-F characteristics, does not switch to the post-F conformation, and presents antigenic features required for a protective neutralizing antibody response. Therefore, Pre-F-GCN4t can be considered a promising candidate vaccine antigen. IMPORTANCE Human respiratory syncytial virus (RSV) is a global leading cause of infant mortality and adult morbidity. The development of a safe and efficacious RSV vaccine remains an important goal. The RSV class I fusion (F) glycoprotein is considered one of the most promising vaccine candidates, and recent evidences suggest that the prefusion (pre-F) state is a superior target for neutralizing antibodies. Our study presents the physicochemical characterization of Pre-F-GCN4t, a molecule designed to be stabilized in the pre-F conformation. To confirm its pre-F conformation, Pre-F-GCN4t was analyzed in parallel with Post-F-XC, a molecule in the post-F conformation. Our results show that Pre-F-GCN4t presents characteristics of a stabilized pre-F conformation and support its use as an RSV vaccine antigen. Such an antigen may represent a significant advance in the development of an RSV vaccine.

scholarly journals Induction of mucosal immunity and protection by intranasal immunization with a respiratory syncytial virus subunit vaccine formulation

2014 ◽  
Vol 95 (2) ◽  
pp. 301-306 ◽  
Author(s):  
R. Garg ◽  
L. Latimer ◽  
E. Simko ◽  
V. Gerdts ◽  
A. Potter ◽  
...  
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
Lymph Nodes ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Affinity Maturation ◽  
Protein Formulation ◽  
Cross Presentation ◽  
Mucosal Surfaces ◽  
Syncytial Virus

The majority of infections, including those caused by respiratory syncytial virus (RSV), occur at mucosal surfaces. As no RSV vaccine is available our goal is to produce an effective subunit vaccine with an adjuvant suitable for mucosal delivery and cross-presentation. A truncated secreted version of the RSV fusion (ΔF) protein formulated with polyI : C, an innate defence regulator peptide and polyphosphazene, induced local and systemic immunity, including affinity maturation of RSV F-specific IgG, IgA and virus-neutralizing antibodies, and F-specific CD8+ T-cells in the lung, when delivered intranasally. Furthermore, this ΔF protein formulation promoted the production of CD8+ central memory T-cells in the mediastinal lymph nodes and provided protection from RSV challenge. Formulation of ΔF protein with this adjuvant combination enhanced uptake by lung dendritic cells and trafficking to the draining lymph nodes. The ΔF protein formulation was confirmed to be highly efficacious and safe in cotton rats.

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