Immunogenicity and Safety of 3 Formulations of a Respiratory Syncytial Virus Candidate Vaccine in Nonpregnant Women: A Phase 2, Randomized Trial

Abstract Background Respiratory syncytial virus (RSV) is a common cause of respiratory tract illness and hospitalization in neonates and infants. RSV vaccination during pregnancy may protect offspring in their first months of life. Methods This randomized, observer-blind, multicenter, phase 2 study evaluated the immunogenicity and safety of an RSV candidate vaccine in healthy nonpregnant women aged 18–45 years. Four hundred participants were randomized (1:1:1:1) to receive a single intramuscular dose of vaccine containing 30 µg, 60 µg, or 120 µg of RSV fusion protein engineered to preferentially maintain a prefusion conformation (RSV-PreF vaccine) or placebo. Results Thirty days postvaccination, RSV-A neutralizing antibody geometric mean titers (GMTs) increased 3.75-, 4.42- and 4.36-fold; RSV-B neutralizing antibody GMTs 2.36-, 2.54- and 2.76-fold; and palivizumab competing antibody (PCA) concentrations 11.69-, 14.38- and 14.24-fold compared with baseline levels in the 30 µg, 60 µg, and 120 µg RSV-PreF groups, respectively. Antibody titers and PCA concentrations at day 30 were significantly higher with the 120 µg compared to the 30 µg RSV-PreF vaccine. All RSV-PreF vaccine formulations and the placebo had similar reactogenicity profiles. No serious adverse events were considered to be related to the RSV-PreF vaccine. Conclusions The 3 formulations of the investigational RSV-PreF vaccine were well-tolerated and induced RSV-A and RSV-B neutralizing antibodies and PCAs in healthy, nonpregnant women. Clinical Trials Registration NCT02956837.

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2855. Respiratory Syncytial Virus Neutralizing Antibodies in Cord Blood and Serum from Infants up to 2 Years of Age in a Multinational Prospective Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.160 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S74-S75

Author(s):

Joseph B Domachowske ◽

Veronique Bianco ◽

Ana Ceballos ◽

Luis Cousin ◽

Ulises D’Andrea ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Cord Blood ◽

Neutralizing Antibodies ◽

Geometric Mean ◽

Neutralizing Antibody ◽

Neutralization Assay ◽

Entire Cohort ◽

Syncytial Virus ◽

Tract Infections

Abstract Background Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections (LRTI) during infancy worldwide. High cord blood (CB) concentrations of anti-RSV neutralizing antibody (nAb) may attenuate, delay, or prevent infant infection. We report RSV A and B nAb concentrations in CB and serum from a birth cohort at different time points through 2 years of age. Methods Between 2013 and 2017, newborns from 8 countries were studied prospectively from birth to 2 years of age (NCT01995175). CB was collected at birth for the entire cohort. A subcohort of children was randomly assigned to have one blood sample collected again at either 2, 4, 6, 12, 18, or 24 months of age. Sera were analyzed for RSV A and B nAb concentrations by serum neutralization assay. Active surveillance was used to identify LRTIs during the 2-year follow-up as previously reported. Results In total, 2,401 newborns were enrolled and followed up. >99% of infants had detectable CB RSV A and B nAb. Geometric mean antibody titers (GMTs) varied by country, but were overall higher for RSV B than for RSV A (327 vs. 251; Figure 1). The lowest GMTs were seen from CB sera collected from South African newborns (197 RSV A, 255 RSV B); Canadian newborns had the highest RSV A GMT (383), while Hondurans had the highest RSV B GMT (460). 1380 infants provided follow-up serum nAb results as part of the subcohort (Figure 2). Dramatic waning of GMTs was evident, with a ~3-fold drop in GMTs at 2 months of age, and an additional ~2-fold drop between 2 and 4 months of age. At 6 and 12 months of age, 71% and 50% of infants had RSV A nAb and GMTs were at a nadir of 14. At 6, 12, and 18 months of age, RSV B nAb was detected in 98%, 69%, and 63% of infants, respectively. The RSV B nAb nadir GMT of 20 was observed at 12 months of age, while the 6- and 18-month RSV B nAb GMTs were 30 and 31, respectively. A total of 1,017 LRTIs were identified during the 2-year study period; of which, 94 (9%) were caused by RSV A and 132 (13%) by RSV B. Associations between CB nAb levels and RSV infection will be presented. Conclusion Neutralizing Ab to RSV A and B was present at birth in infants from 8 countries, and waned over time. GMTs were at a nadir at 6 to 12 months of age. Funding. GlaxoSmithKline Biologicals SA. Disclosures All Authors: No reported Disclosures.

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

Journal of Virology ◽

10.1128/jvi.02437-16 ◽

2017 ◽

Vol 91 (13) ◽

Cited By ~ 18

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.

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Immunogenicity and safety of a third dose, and immune persistence of CoronaVac vaccine in healthy adults aged 18-59 years: interim results from a double-blind, randomized, placebo-controlled phase 2 clinical trial

10.1101/2021.07.23.21261026 ◽

2021 ◽

Author(s):

Hongxing Pan ◽

Qianhui Wu ◽

Gang Zeng ◽

Juan Yang ◽

Deyu Jiang ◽

...

Keyword(s):

Large Scale ◽

Dose Group ◽

Geometric Mean ◽

Development Program ◽

Neutralizing Antibody ◽

Immune Memory ◽

High Dose ◽

Phase 2 ◽

Serious Adverse Events ◽

Double Blind

Background Large-scale vaccination is being implemented globally with CoronaVac, an inactivated vaccine against coronavirus disease 2019 (COVID-19). Immunogenicity and safety profiles of homologous two-dose schedules have been published. We report interim results of immune persistence, and the immunogenicity and safety of a third dose of CoronaVac. Methods In this ongoing, placebo-controlled, double-blind phase 2 trial in 18-to-59-year-olds, we randomly assigned subjects, 1:1:1:1, to one of four schedules to receive a third dose, 28 days or 6 months after two two-dose regimens (14-day or 28-day apart): schedule 1: days 0, 14, 42; schedule 2: days 0, 14, 194; schedule 3: days 0, 28, 56; schedule 4: days 0, 28, 208. For each schedule, participants were randomly assigned to either a medium-dose group (3 μg per 0.5 mL of aluminum hydroxide diluent per dose), a high-dose group (6 μg), or a placebo group (2:2:1). The primary outcome was geometric mean titers (GMTs) of neutralizing antibody to live SARS-CoV-2. Results Overall, 540 participants received a third dose. In the 3 μg group, neutralizing antibody titers induced by the first two doses declined after 6-8 months to below the seropositive cutoff (GMT: 4.1 [95%CI 3.3-5.2] for Schedule 2 and 6.7 [95%CI 5.2-8.6] for Schedule 4). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for Schedule 2, and 143.1 [95%CI 110.8-184.7] for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 μg group. The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2 in all vaccination cohorts. None of the fourteen serious adverse events were considered to be related to vaccination. Conclusions A third dose of CoronaVac administered 6 or more months after a second dose effectively recalled specific immune response to SARS-CoV-2, resulting in a remarkable increase in antibody levels, and indicating that a two-dose schedule generates good immune memory. Optimizing the timing of a booster dose should take into account immunogenicity, vaccine efficacy/effectiveness, local epidemic situation, infection risk, and vaccine supply. (Funded by the National Key Research and Development Program, Beijing Science and Technology Program and National Science Fund for Distinguished Young Scholars; ClinicalTrials.gov number, NCT04352608.)

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Phase 1 Safety and Immunogenicity Study of a Respiratory Syncytial Virus Vaccine With an Adenovirus 26 Vector Encoding Prefusion F (Ad26.RSV.preF) in Adults Aged ≥60 Years

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa193 ◽

2020 ◽

Vol 222 (6) ◽

pp. 979-988 ◽

Cited By ~ 6

Author(s):

Kristi Williams ◽

Arangassery Rosemary Bastian ◽

Robert Allen Feldman ◽

Edmund Omoruyi ◽

Els de Paepe ◽

...

Keyword(s):

Older Adults ◽

Respiratory Syncytial Virus ◽

Adverse Events ◽

Immune Responses ◽

Phase 1 ◽

Geometric Mean ◽

High Dose ◽

Serious Adverse Events ◽

Syncytial Virus ◽

Vector Particles

Abstract Background Despite the high disease burden of respiratory syncytial virus (RSV) in older adults, there is no approved vaccine. We evaluated the experimental RSV vaccine, Ad26.RSV.preF, a replication-incompetent adenovirus 26 vector encoding the F protein stabilized in prefusion conformation. Methods This phase 1 clinical trial was performed in healthy adults aged ≥60 years. Seventy-two participants received 1 or 2 intramuscular injections of low-dose (LD; 5 × 1010 vector particles) or high-dose (HD; 1 × 1011 vector particles) Ad26.RSV.preF vaccine or placebo, with approximately 12 months between doses and 2-year follow-up for safety and immunogenicity outcomes. Results Solicited adverse events were reported by 44% of vaccine recipients and were transient and mild or moderate in intensity. No serious adverse events were related to vaccination. After the first vaccination, geometric mean titers for RSV-A2 neutralization increased from baseline (432 for LD and 512 for HD vaccine) to day 29 (1031 for LD and 1617 for HD). Pre-F–specific antibody geometric mean titers and median frequencies of F-specific interferon γ–secreting T cells also increased substantially from baseline. These immune responses were still maintained above baseline levels 2 years after immunization and could be boosted with a second immunization at 1 year. Conclusions Ad26.RSV.preF (LD and HD) had an acceptable safety profile and elicited sustained humoral and cellular immune responses after a single immunization in older adults.

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RESPIRATORY SYNCYTIAL VIRUS NEUTRALIZING ANTIBODIES IN PERSONS RESIDING IN CHICAGO, ILLINOIS

PEDIATRICS ◽

10.1542/peds.34.6.761 ◽

1964 ◽

Vol 34 (6) ◽

pp. 761-770

Author(s):

Marc Beem ◽

Rosalie Egerer ◽

Julia Anderson

Keyword(s):

Virus Infection ◽

Antibody Titer ◽

Neutralizing Antibodies ◽

Geometric Mean ◽

Indirect Evidence ◽

Neutralizing Antibody ◽

Single Strain ◽

Wild Strains ◽

Antibody Titers ◽

Syncytial Virus

The R.S. virus neutralization test was examined in terms of several factors bearing on the consistency and specificity of antibody response to a single strain (Randall) of this virus. It was found that this virus detected significant rises in antibody titer in 90% of 30 patients over 6 months of age who were infected with wild strains of R.S. virus between the years 1958 and 1962. Heterologous neutralizing antibodies to R.S. virus did not occur following human infections with various myxoviruses, adenoviruses, enteroviruses and herpesvirus. Indirect evidence was presented indicating that tile neutralizing activity of human serums is due to specific antibody and not due to non-specific, heat stable neutralizing substance. The titer of R.S. neutralizing antibodies was determined in the serums of 26 parturient mothers, and their 27 newborn babies, and 186 other individuals between the ages of 6 months and 69 years. Longitudinal observations of antibody titer were also conducted on 12 other infants. Neutralizing antibodies to R.S. virus were found to reach the term fetus at undiminished titer. In the longitudinal observations, serum neutralizing antibody titers were found to fall during the first months of life, decreasing by half in an average time of 43 days. Neutralizing antibodies, actively formed in response to R.S. virus infection, were observed to occur with rapidly increasing frequency in relation to age in subjects older than 6 months. These serologic findings indicated that among individuals residing in the metropolitan Chicago area, R.S. virus infection has been experienced by many during the first 2 years of life, most by school age, and all by 7 years of age. Geometric mean antibody titers were found to show a small, but probably significant, increase with age. The restriction of low titer reactors to pre-school children was noted. These serologic findings were interpreted as evidence that re-infections with R.S. virus occur, perhaps quite commonly.

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Structure of a Major Antigenic Site on the Respiratory Syncytial Virus Fusion Glycoprotein in Complex with Neutralizing Antibody 101F

Journal of Virology ◽

10.1128/jvi.01579-10 ◽

2010 ◽

Vol 84 (23) ◽

pp. 12236-12244 ◽

Cited By ~ 71

Author(s):

Jason S. McLellan ◽

Man Chen ◽

Jung-San Chang ◽

Yongping Yang ◽

Albert Kim ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Neutralizing Antibodies ◽

Antigenic Site ◽

Neutralizing Antibody ◽

Structural Basis ◽

Effective Vaccine ◽

Linear Epitope ◽

Peptide Epitope ◽

Fusion Glycoprotein ◽

Syncytial Virus

ABSTRACT Respiratory syncytial virus (RSV) is a major cause of pneumonia and bronchiolitis in infants and elderly people. Currently there is no effective vaccine against RSV, but passive prophylaxis with neutralizing antibodies reduces hospitalizations. To investigate the mechanism of antibody-mediated RSV neutralization, we undertook structure-function studies of monoclonal antibody 101F, which binds a linear epitope in the RSV fusion glycoprotein. Crystal structures of the 101F antigen-binding fragment in complex with peptides from the fusion glycoprotein defined both the extent of the linear epitope and the interactions of residues that are mutated in antibody escape variants. The structure allowed for modeling of 101F in complex with trimers of the fusion glycoprotein, and the resulting models suggested that 101F may contact additional surfaces located outside the linear epitope. This hypothesis was supported by surface plasmon resonance experiments that demonstrated 101F bound the peptide epitope ∼16,000-fold more weakly than the fusion glycoprotein. The modeling also showed no substantial clashes between 101F and the fusion glycoprotein in either the pre- or postfusion state, and cell-based assays indicated that 101F neutralization was not associated with blocking virus attachment. Collectively, these results provide a structural basis for RSV neutralization by antibodies that target a major antigenic site on the fusion glycoprotein.

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Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab003 ◽

2021 ◽

Author(s):

Jerald Sadoff ◽

Els De Paepe ◽

John DeVincenzo ◽

Efi Gymnopoulou ◽

Joris Menten ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Geometric Mean ◽

Area Under The Curve ◽

Neutralizing Antibody ◽

Healthy Adults ◽

Controlled Study ◽

Double Blind ◽

Post Immunization ◽

Rsv Infection ◽

Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) is a significant cause of severe lower respiratory tract disease in children and older adults, but has no approved vaccine. This study assessed the potential of Ad26.RSV.preF to protect against RSV infection and disease in an RSV human challenge model. Methods In this double-blind, placebo-controlled study, healthy adults aged 18–50 years were randomized 1:1 to receive 1x1011 vp Ad26.RSV.preF or placebo intramuscularly. Twenty-eight days post-immunization, volunteers were challenged intranasally with RSV-A (Memphis 37b). Assesments included viral load (VL), RSV infections, clinical symptom score (CSS), safety and immunogenicity. Results Post-challenge, VL, RSV infections and disease severity were lower in Ad26.RSV.preF (n=27) versus placebo (n=26) recipients: median VL-AUC (area under the curve) qRT-PCR: 0.0 versus 236.0 (P=.012; predefined primary endpoint); median VL-AUC quantitative culture: 0.0 versus 109; RSV infections 11 (40.7%) versus 17 (65.4%); median RSV AUC-CSS 35 versus 167, respectively. From baseline to 28 days post-immunization, geometric mean fold-increases in RSV A2 neutralizing antibody titers of 5.8 and 0.9 were observed in Ad26.RSV.preF and placebo, respectively. Ad26.RSV.preF was well tolerated. Conclusions Ad26.RSV.preF demonstrated protection from RSV infection through immunization in a human challenge model, and therefore could potentially protect against natural RSV infection and disease. Clinical Trials Registration NCT03334695

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Broad Antibody and Cellular Immune Response From a Phase 2 Clinical Trial With a Novel Multivalent Poxvirus-Based Respiratory Syncytial Virus Vaccine

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa460 ◽

2020 ◽

Cited By ~ 2

Author(s):

Elke Jordan ◽

Steven J Lawrence ◽

Thomas P H Meyer ◽

Darja Schmidt ◽

Stephanie Schultz ◽

...

Keyword(s):

Immune Response ◽

Respiratory Syncytial Virus ◽

Cellular Immune Response ◽

Fold Increase ◽

The Elderly ◽

Surface Proteins ◽

Phase 2 ◽

Serious Adverse Events ◽

Syncytial Virus ◽

Cellular Immune

Abstract Background Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in young children and the elderly. Protective immunity is not generated after repeated infections, but vaccination may hopefully prove effective. Methods This phase 2 clinical study investigated a multivalent RSV vaccine (MVA-BN-RSV) designed to induce broad antibody and cellular immune responses by encoding RSV surface proteins F, G (for both A and B subtypes), and internal antigens (M2, N). This study evaluated the immune response in adults aged ≥55 years to identify the optimal MVA-BN-RSV dose and vaccination schedule. Results A single dose increased the levels of neutralizing (plaque reduction neutralization test to RSV A and B) and total (IgG and IgA ELISA) antibodies (1.6 to 3.4-fold increase from baseline) and induced a broad Th1-biased cellular immune response (interferon-γ ELISPOT) to all 5 vaccine inserts (5.4 to 9.7-fold increases). Antibody responses remained above baseline for 6 months. A 12-month booster dose elicited a booster effect in antibody and T-cell responses (up to 2.8-fold from preboost levels). No drug-related serious adverse events were reported. Conclusions MVA-BN-RSV induces a broad immune response that persists at least 6 months and can be boosted at 12 months, without significant safety findings. Clinical Trials Registration NCT02873286

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

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa049 ◽

2020 ◽

Vol 221 (12) ◽

pp. 2050-2059 ◽

Cited By ~ 3

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.

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Safety and Immunogenicity of the Respiratory Syncytial Virus Vaccine RSV/ΔNS2/Δ1313/I1314L in RSV-Seronegative Children

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz408 ◽

2019 ◽

Vol 222 (1) ◽

pp. 82-91 ◽

Cited By ~ 6

Author(s):

Ruth A Karron ◽

Cindy Luongo ◽

Jocelyn San Mateo ◽

Kimberli Wanionek ◽

Peter L Collins ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Rational Design ◽

Controlled Trial ◽

Geometric Mean ◽

Neutralizing Antibody ◽

Temperature Sensitive ◽

Double Blind ◽

Respiratory Tract Illness ◽

Syncytial Virus ◽

Respiratory Syncytial Virus Vaccine

Abstract Background Respiratory syncytial virus (RSV) is the leading global cause of severe pediatric acute respiratory tract illness, and a vaccine is needed. RSV/ΔNS2/Δ1313/I1314L contains 2 attenuating elements: (1) deletion of the interferon antagonist NS2 gene and (2) deletion of codon 1313 of the RSV polymerase gene and the stabilizing missense mutation I1314L. This live vaccine candidate was temperature-sensitive, genetically stable, replication restricted, and immunogenic in nonhuman primates. Methods A single intranasal dose of RSV/ΔNS2/Δ1313/I1314L was evaluated in a double-blind, placebo-controlled trial (vaccine-placebo ratio, 2:1) at 106 plaque-forming units (PFU) in 15 RSV-seropositive children and at 105 and 106 PFU in 21 and 30 RSV-seronegative children, respectively. Results In RSV-seronegative children, the 105 PFU dose was overattenuated, but the 106 PFU dose was well tolerated, infectious (RSV/ΔNS2/Δ1313/I1314L replication detected in 90% of vaccinees), and immunogenic (geometric mean serum RSV plaque-reduction neutralizing antibody titer, 1:64). After the RSV season, 9 of 20 vaccinees had increases in the RSV titer that were significantly greater than those in 8 of 10 placebo recipients (1:955 vs 1:69, respectively), indicating that the vaccine primed for anamnestic responses after natural RSV exposure. Conclusion Rational design yielded a genetically stable candidate RSV vaccine that is attenuated yet immunogenic in RSV-seronegative children, warranting further evaluation. Clinical Trials Registration NCT01893554.

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