Longitudinal humoral analysis in RSV-infected infants identifies pre-existing RSV strain-specific G and evolving cross-reactive F antibodies.

Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection (LRTI) and hospitalization in infants. However, the mechanisms of immune control in infants remain incompletely understood. Antibody profiling against attachment (G) and fusion (F) proteins in children less than 2 years of age, with mild (outpatients) or severe (inpatients) RSV disease, indicated substantial age-dependent differences in RSV-specific immunity. Maternal antibodies were detectable for the first 3 months of life, followed by a long window of immune vulnerability between 3 and 6 months and a rapid evolution of FcγR-recruiting immunity after 6 months of age. Acutely ill hospitalized children exhibited lower G-specific antibodies compared with healthy controls. With disease resolution, RSV-infected infants generated broad functional RSV strain-specific G-responses and evolved cross-reactive F-responses, with minimal maternal imprinting. These data suggest an age-independent RSV G-specific functional humoral correlate of protection, and the evolution of RSV F-specific functional immunity with disease resolution.

Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses.

An effective vaccine for respiratory syncytial virus (RSV) is an unrealized public health goal. A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) substantially increases serum-neutralizing activity in healthy adults. We sought to determine whether DS-Cav1 vaccination induces a repertoire mirroring the pre-existing diversity from natural infection or whether antibody lineages targeting specific epitopes predominate. We evaluated RSV F-specific B cell responses before and after vaccination in six participants using complementary B cell sequencing methodologies and identified 555 clonal lineages. DS-Cav1-induced lineages recognized the prefusion conformation of F (pre-F) and were genetically diverse. Expressed antibodies recognized all six antigenic sites on the pre-F trimer. We identified 34 public clonotypes, and structural analysis of two antibodies from a predominant clonotype revealed a common mode of recognition. Thus, vaccination with DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.

Efficacy and Safety of an Ad26.RSV.preF-RSV preF Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF-RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3). RESULTS: Overall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively). CONCLUSIONS: In adults 65 years of age or older, Ad26.RSV.preF-RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.).

Intranasal respiratory syncytial virus vaccine attenuated by codon-pair deoptimization of seven open reading frames is genetically stable and elicits mucosal and systemic immunity and protection against challenge virus replication in hamsters.

Respiratory syncytial virus (RSV) is the most important viral agent of severe pediatric respiratory illness worldwide, but there is no approved pediatric vaccine. Here, we describe the development of the live-attenuated RSV vaccine candidate Min AL as well as engineered derivatives. Min AL was attenuated by codon-pair deoptimization (CPD) of seven of the 11 RSV open reading frames (ORFs) (NS1, NS2, N, P, M, SH and L; 2,073 silent nucleotide substitutions in total). Min AL replicated efficiently in vitro at the permissive temperature of 32°C but was highly temperature sensitive (shut-off temperature of 36°C). When serially passaged at increasing temperatures, Min AL retained greater temperature sensitivity compared to previous candidates with fewer CPD ORFs. However, whole-genome deep-sequencing of passaged Min AL revealed mutations throughout its genome, most commonly missense mutations in the polymerase cofactor P and anti-termination transcription factor M2-1 (the latter was not CPD). Reintroduction of selected mutations into Min AL partially rescued its replication in vitro at temperatures up to 40°C, confirming their compensatory effect. These mutations restored the accumulation of positive-sense RNAs to wild-type (wt) RSV levels, suggesting increased activity by the viral transcriptase, whereas viral protein expression, RNA replication, and virus production were only partly rescued. In hamsters, Min AL and derivatives remained highly restricted in replication in the upper and lower airways, but induced serum IgG and IgA responses to the prefusion form of F (pre F) that were comparable to those induced by wt RSV, as well as robust mucosal and systemic IgG and IgA responses against RSV G. Min AL and derivatives were fully protective against challenge virus replication. The derivatives had increased genetic stability compared to Min AL. Thus, Min AL and derivatives with selected mutations are stable, attenuated, yet highly-immunogenic RSV vaccine candidates that are available for further evaluation.

RNA-RNA interactions between respiratory syncytial virus and miR-26 and miR-27 are associated with regulation of cell cycle and antiviral immunity.

microRNAs (miRNAs) regulate nearly all physiological processes but our understanding of exactly how they function remains incomplete, particularly in the context of viral infections. Here, we adapt a biochemical method (CLEAR-CLIP) and analysis pipeline to identify targets of miRNAs in lung cells infected with Respiratory syncytial virus (RSV). We show that RSV binds directly to miR-26 and miR-27 through seed pairing and demonstrate that these miRNAs target distinct gene networks associated with cell cycle and metabolism (miR-27) and antiviral immunity (miR-26). Many of the targets are de-repressed upon infection and we show that the miR-27 targets most sensitive to miRNA inhibition are those associated with cell cycle. Finally, we demonstrate that high confidence chimeras map to long noncoding RNAs (lncRNAs) and pseudogenes in transcriptional regulatory regions. We validate that a proportion of miR-27 and Argonaute 2 (AGO2) is nuclear and identify a long non-coding RNA (lncRNA) as a miR-27 target that is linked to transcriptional regulation of nearby genes. This work expands the target networks of miR-26 and miR-27 to include direct interactions with RSV and lncRNAs and implicate these miRNAs in regulation of key genes that impact the viral life cycle associated with cell cycle, metabolism, and antiviral immunity.

Respiratory syncytial virus vaccination and immunoprophylaxis: realising the potential for protection of young children.

The search for safe and efficacious products to prevent severe respiratory syncytial virus (RSV) disease in young infants has lasted more than 60 years. In high-income and middle-income countries, two new products have been authorised: an RSV monoclonal antibody for administration to infants (nirsevimab) and an RSV prefusion F maternal vaccine (RSVpreF [Pfizer, Puurs, Belgium]) for administration to pregnant people. These products are not yet available in low-income and lower-middle-income countries, where most RSV deaths occur. Other papers in this Series describe the acute burden of RSV disease in young children, the effects of RSV infection in early childhood on long-term lung health, and the burden of RSV disease and disease prevention products in older adults. In this Series paper, we briefly review the efficacy, effectiveness, and safety of nirsevimab and RSVpreF maternal vaccine for protection of infants. We then explore potential regulatory, policy, and implementation pathways and provide case studies of intervention uptake in Spain and Argentina, and considerations for use in Kenya. We also explore the health economic evidence to inform product introduction decisions. With sufficient political will and affordable pricing, RSV disease prevention in infants can become a global reality.

Prefusion F Protein-Based Respiratory Syncytial Virus Immunization in Pregnancy.

BACKGROUND: Respiratory syncytial virus (RSV), a major cause of illness and death in infants worldwide, could be prevented by vaccination during pregnancy. The efficacy, immunogenicity, and safety of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine in pregnant women and their infants are uncertain. METHODS: In a phase 2b trial, we randomly assigned pregnant women, at 24 through 36 weeks' gestation, to receive either 120 or 240 µg of RSVpreF vaccine (with or without aluminum hydroxide) or placebo. The trial included safety end points and immunogenicity end points that, in this interim analysis, included 50% titers of RSV A, B, and combined A/B neutralizing antibodies in maternal serum at delivery and in umbilical-cord blood, as well as maternal-to-infant transplacental transfer ratios. RESULTS: This planned interim analysis included 406 women and 403 infants; 327 women (80.5%) received RSVpreF vaccine. Most postvaccination reactions were mild to moderate; the incidence of local reactions was higher among women who received RSVpreF vaccine containing aluminum hydroxide than among those who received RSVpreF vaccine without aluminum hydroxide. The incidences of adverse events in the women and infants were similar in the vaccine and placebo groups; the type and frequency of these events were consistent with the background incidences among pregnant women and infants. The geometric mean ratios of 50% neutralizing titers between the infants of vaccine recipients and those of placebo recipients ranged from 9.7 to 11.7 among those with RSV A neutralizing antibodies and from 13.6 to 16.8 among those with RSV B neutralizing antibodies. Transplacental neutralizing antibody transfer ratios ranged from 1.41 to 2.10 and were higher with nonaluminum formulations than with aluminum formulations. Across the range of assessed gestational ages, infants of women who were immunized had similar titers in umbilical-cord blood and similar transplacental transfer ratios. CONCLUSIONS: RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns. (Funded by Pfizer; ClinicalTrials.gov number, NCT04032093.).

Systematic Review of the Efficacy and Safety of RSV-Specific Monoclonal Antibodies and Antivirals in Development.

Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infection amongst all ages, causing a significant global health burden. Preventative and therapeutic options for RSV infection have long been under development, and recently, several widely-publicised vaccines targeting older adult and maternal populations have become available. Promising monoclonal antibody (mAb) and antiviral (AV) therapies are also progressing in clinical trials, with the prophylactic mAb nirsevimab recently approved for clinical use in infant populations. A systematic review on current progress in this area is lacking. We performed a systematic literature search (PubMed, Embase, Web of Science, ClinicalTrials.gov, EudraCT, ANZCTR-searched Nov 29th, 2023) to identify studies on all RSV-specific mAbs and AV therapies that has undergone human clinical trials since year 2000. Data extraction focused on outcomes related to the therapeutic efficacy and safety of the intervention on trial, and all studies were graded against the OCEBM Levels of Evidence Table. Results from 59 studies were extracted, covering efficacy and safety data on six mAbs (motavizumab, motavizumab-YTE, nirsevimab, ALX-0171, suptavumab, clesrovimab) and 12 AV therapies (ALN-RSV01, RSV604, presatovir, MDT-637, lumicitabine, IFN-α1b, rilematovir, enzaplatovir, AK0529, sisunatovir, PC786, EDP-938). Of the mAbs reviewed, nirsevimab and clesrovimab hold considerable promise. The timeline for RSV-specific AV availability is less advanced, although EDP-938 and AK0529 have reported promising phase 2 efficacy and safety data. Moving forward, passive immunisation and treatment options for RSV infection will play a significant role in reducing the health burden of RSV, complementing recent advancements in vaccine development. TRIAL REGISTRATION: PROSPERO registration: CRD42022376633.

Virus neutralization assays for human respiratory syncytial virus using airway organoids.

Neutralizing antibodies are considered a correlate of protection against severe human respiratory syncytial virus (HRSV) disease. Currently, HRSV neutralization assays are performed on immortalized cell lines like Vero or A549 cells. It is known that assays on these cell lines exclusively detect neutralizing antibodies (nAbs) directed to the fusion (F) protein. For the detection of nAbs directed to the glycoprotein (G), ciliated epithelial cells expressing the cellular receptor CX3CR1 are required, but generation of primary cell cultures is expensive and labor-intensive. Here, we developed a high-throughput neutralization assay based on the interaction between clinically relevant HRSV grown on primary cells with ciliated epithelial cells, and validated this assay using a panel of infant sera. To develop the high-throughput neutralization assay, we established a culture of differentiated apical-out airway organoids (Ap-O AO). CX3CR1 expression was confirmed, and both F- and G-specific monoclonal antibodies neutralized HRSV in the Ap-O AO. In a side-by-side neutralization assay on Vero cells and Ap-O AO, neutralizing antibody levels in sera from 125 infants correlated well, although titers on Ap-O AO were consistently lower. We speculate that these lower titers might be an actual reflection of the neutralizing antibody capacity in vivo. The organoid-based neutralization assay described here holds promise for further characterization of correlates of protection against HRSV disease.

RSV Neutralizing Antibodies in Dried Blood.

BACKGROUND: The key correlate of protection of respiratory syncytial virus (RSV) vaccines and monoclonal antibodies (mAbs) is virus neutralization, measured via sera obtained through venipuncture. Dried blood obtained with a finger prick can simplify acquisition, processing, storage, and transport in trials and thereby reduce costs. In this study, we validate an assay to measure RSV neutralization in dried capillary blood. METHODS: Functional antibodies were compared between matched serum and dried blood samples from a phase 1 trial with RSM01, an investigational anti-RSV prefusion F mAb. Hep-2 cells were infected with a serial dilution of sample-virus mixture by using RSV-A2-mKate to determine the half-maximal inhibitory concentration. Stability of dried blood was evaluated over time and during temperature stress. RESULTS: Functional antibodies in dried blood were highly correlated with serum (R2 = 0.98, P < .0001). The precision of the assay for dried blood was similar to serum. The function of mAb remained stable for 9 months at room temperature and frozen dried blood samples. CONCLUSIONS: We demonstrated the feasibility of measuring RSV neutralization using dried blood as a patient-centered solution that may replace serology testing in trials against RSV or other viruses, such as influenza and SARS-CoV-2. Clinical Trials Registration. NCT05118386 (ClinicalTrials.gov).

Immunogenicity and Safety Following 1 Dose of AS01E-Adjuvanted Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults: A Phase 3 Trial.

BACKGROUND: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds. METHODS: This ongoing phase 3 study in ≥60-year-olds evaluates immune persistence until 3 years after RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until 1 year post-dose 1. RESULTS: In total, 1653 participants were vaccinated. One month post-dose 1, neutralization titers increased 10.5-fold (RSV-A) and 7.8-fold (RSV-B) vs pre-dose 1. Titers then declined to levels 4.4-fold (RSV-A) and 3.5-fold (RSV-B) above pre-dose 1 at month 6 and remained 3.1-fold (RSV-A) and 2.3-fold (RSV-B) above pre-dose 1 levels after 1 year. RSVPreF3-binding immunoglobulin G levels and CD4+ T-cell frequencies showed similar kinetics. Solicited administration-site and systemic adverse events (mostly mild to moderate and transient) were reported by 62.2% and 49.5% of participants. Serious adverse events were reported by 3.9% of participants within 6 months post-dose 1; 1 case was considered vaccine related. CONCLUSIONS: One RSVPreF3 OA dose elicited cell-mediated and RSV-A- and RSV-B-specific humoral immune responses that declined over time but remained above pre-dose 1 levels for at least 1 year. The vaccine was well tolerated with an acceptable safety profile. Clinical Trials Registration. NCT04732871 (ClinicalTrials.gov).

Respiratory syncytial virus (RSV) is a major cause of illness and hospitalization in older adults. An RSV vaccine for older adults developed by GSK was recently approved. The vaccine was well tolerated and provided protection against RSV disease in adults aged ≥60 years during at least 1 RSV season. In this ongoing study, we are evaluating the magnitude and durability of the immune response, as well as vaccine safety, until 3 years after vaccination of adults aged ≥60 years from 5 countries. Here, we report the results of an interim analysis until 1 year after vaccination with 1 dose. In total, 1653 participants were vaccinated. We found that the vaccine induced a strong immune response that was evident 1 month after vaccination, after which it declined but persisted for at least 1 year. Study participants most often reported pain at the injection site, muscle pain, tiredness, and headache as adverse reactions, which were mostly mild to moderate and of short duration. One serious adverse reaction was considered related to the vaccine. The long-term immune response that was observed in this study is consistent with the vaccine providing protection during at least 1 RSV season.

Safety, Tolerability, and Immunogenicity of an mRNA-Based Respiratory Syncytial Virus Vaccine in Healthy Young Adults in a Phase 1 Clinical Trial.

BACKGROUND: Respiratory syncytial virus (RSV) presents a global health concern. A lipid nanoparticle-encapsulated mRNA-based RSV vaccine (mRNA-1345) that encodes the membrane-anchored RSV prefusion-stabilized F glycoprotein is under clinical investigation. METHODS: This phase 1 dose escalation study was based on a randomized, observer-blind, placebo-controlled design, and it assessed the safety and immunogenicity of mRNA-1345 in healthy adults aged 18 to 49 years. Participants were randomized to receive 1 dose of mRNA-1345 (50, 100, or 200 µg) or placebo or 3 doses of mRNA-1345 (100 µg) or placebo 56 days apart. RESULTS: mRNA-1345 was well tolerated at all dose levels. The most common solicited adverse reactions were pain, headache, fatigue, myalgia, or chills, which were all generally mild to moderate. At 1 month postinjection, a single injection of mRNA-1345 boosted RSV neutralizing antibody titers (geometric mean fold rise: RSV-A, 20.0-23.5; RSV-B, 11.7-16.0) and RSV prefusion binding antibody concentrations (geometric mean fold rise, 16.1-21.8), with no apparent dose response. Antibody levels remained above baseline through 6 months. Sequential doses of 100 µg were well tolerated but did not further boost antibody levels. CONCLUSIONS: A single mRNA-1345 injection demonstrated an acceptable safety profile in younger adults and induced a durable neutralizing antibody response, supporting its continued development. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT04528719.

Safety and Immunogenicity of an mRNA-Based RSV Vaccine Including a 12-Month Booster in a Phase 1 Clinical Trial in Healthy Older Adults.

BACKGROUND: An mRNA-based respiratory syncytial virus (RSV) vaccine, mRNA-1345, is under clinical investigation to address RSV disease burden in older adults. METHODS: Based on a randomized, observer-blind, placebo-controlled design, this phase 1 dose-ranging study evaluated the safety, reactogenicity, and immunogenicity of mRNA-1345 in adults aged 65 to 79 years. Participants were randomized to receive 1 dose of mRNA-1345 (12.5, 25, 50, 100, or 200 µg) or placebo and matched mRNA-1345 booster or placebo at 12 months. RESULTS: Overall, 298 participants received the first injection and 247 received the 12-month booster injection. mRNA-1345 was generally well tolerated after both injections, with the most frequently reported solicited adverse reactions being injection site pain, fatigue, headache, arthralgia, and myalgia. Reactogenicity was higher after the booster injection but with severity, time to onset, and duration similar to the first injection. A single mRNA-1345 injection boosted RSV-A and RSV-B neutralizing antibody titers and prefusion F binding antibody (preF bAb) concentrations at 1 month (geometric mean fold rises: RSV-A, 10.2-16.5; RSV-B, 5.3-12.5; preF bAb, 7.2-12.1). RSV antibody levels remained above baseline through 12 months, indicating immune persistence. A 12-month booster injection also increased RSV-A and RSV-B neutralizing antibody titers and preF bAb concentrations; titers after booster injection were numerically lower than those after the first dose, with overlapping 95% CIs. CONCLUSIONS: mRNA-1345 was well tolerated and immunogenic following a single injection and a 12-month booster. CLINICAL TRIALS REGISTRATION: NCT04528719 (ClinicalTrials.gov).

Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion Maternal Vaccine Coadministered With Diphtheria-Tetanus-Pertussis Vaccine: A Phase 2 Study.

BACKGROUND: Respiratory syncytial virus (RSV) fusion protein stabilized in the prefusion conformation (RSVPreF3) was under investigation as a maternal vaccine. METHODS: This phase 2, randomized, placebo-controlled, single-dose, multicenter study enrolled healthy, nonpregnant women, randomized 1:1:1:1:1 to 5 parallel groups studying RSVPreF3 (60 or 120 µg) coadministered with diphtheria, tetanus, and acellular pertussis vaccine (dTpa) or placebo, and dTpa coadministered with placebo. Safety and humoral immune responses were assessed. An extension phase also assessed a RSVPreF3 120 µg vaccination 12-18 months after first vaccination. RESULTS: The safety profile of RSVPreF3 was unaffected by dose or dTpa coadministration. Solicited and unsolicited adverse events (AEs) were evenly distributed across study groups. Injection-site pain was higher following the second vaccination versus the first vaccination. Medically attended AEs were rare (<5% overall). Both RSVPreF3 dose levels (alone and with dTpa) were immunogenic, increasing levels of RSV-A neutralizing antibody ≥8-fold and anti-RSVPreF3 IgG antibody ≥11-fold at 1 month postvaccination, which persisted at 12-18 months postvaccination; modest 2-fold increases were observed with a second RSVPreF3 vaccination. CONCLUSIONS: This study indicates RSVPreF3 coadministration with dTpa induces robust immune responses and is well tolerated, regardless of the RSVPreF3 dose level used. CLINICAL TRIALS REGISTRATION: NCT04138056.

Concomitant Administration of Ad26.RSV.preF/RSV preF Protein Vaccine and High-Dose Influenza Vaccine in Adults 65 Years and Older: A Noninferiority Trial.

BACKGROUND: Since influenza and respiratory syncytial virus (RSV) carry significant burden in older adults with overlapping seasonality, vaccines for both pathogens would ideally be coadministered in this population. Here we evaluate the immunogenicity and safety of concomitant administration of Ad26.RSV.preF/RSV preF protein and high-dose seasonal influenza vaccine (Fluzone-HD) in adults ≥65 years old. METHODS: Participants were randomized 1:1 to the Coadministration or Control group. The Coadministration group received concomitant Ad26.RSV.preF/RSV preF protein and Fluzone-HD on day 1 and placebo on day 29, while the Control group received Fluzone-HD and placebo on day 1 and Ad26.RSV.preF/RSV preF protein on day 29. Influenza hemagglutination-inhibiting and RSV preF-binding antibody titers were measured postvaccination and tested for noninferiority between both groups. Safety data were collected throughout the study and analyzed descriptively. RESULTS: Coadministered Ad26.RSV.preF/RSV preF protein and Fluzone-HD vaccines induced noninferior immune responses compared to each vaccine administered alone. Seroconversion and seroprotection rates against influenza were similar between groups. Both vaccines remained well tolerated upon concomitant administration. CONCLUSIONS: Coadministration of Ad26.RSV.preF/RSV preF protein and Fluzone-HD showed an acceptable safety profile and did not hamper the immunogenicity of either vaccine, thus supporting that both vaccines can be concomitantly administered in adults ≥65 years old.

Efficacy and Safety of Respiratory Syncytial Virus (RSV) Prefusion F Protein Vaccine (RSVPreF3 OA) in Older Adults Over 2 RSV Seasons.

BACKGROUND: The adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) was efficacious against RSV-related lower respiratory tract disease (RSV-LRTD) in ≥60-years-olds over 1 RSV season. We evaluated efficacy and safety of 1 RSVPreF3 OA dose and of 2 RSVPreF3 OA doses given 1 year apart against RSV-LRTD over 2 RSV seasons post-dose 1. METHODS: In this phase 3, blinded trial, ≥60-year-olds were randomized (1:1) to receive RSVPreF3 OA or placebo pre-season 1. RSVPreF3 OA recipients were re-randomized (1:1) to receive a second RSVPreF3 OA dose (RSV_revaccination group) or placebo (RSV_1dose group) pre-season 2; participants who received placebo pre-season 1 received placebo pre-season 2 (placebo group). Efficacy of both vaccine regimens against RSV-LRTD was evaluated over 2 seasons combined (confirmatory secondary objective, success criterion: lower limits of 2-sided CIs around efficacy estimates >20%). RESULTS: The efficacy analysis comprised 24 967 participants (RSV_1dose: 6227; RSV_revaccination: 6242; placebo: 12 498). Median efficacy follow-up was 17.8 months. Efficacy over 2 seasons of 1 RSVPreF3 OA dose was 67.2% (97.5% CI: 48.2-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.6-92.0%) against severe RSV-LRTD. Efficacy over 2 seasons of a first dose followed by revaccination was 67.1% (97.5% CI: 48.1-80.0%) against RSV-LRTD and 78.8% (95% CI: 52.5-92.0%) against severe RSV-LRTD. Reactogenicity/safety of the revaccination dose were similar to dose 1. CONCLUSIONS: One RSVPreF3 OA dose was efficacious against RSV-LRTD over 2 RSV seasons in ≥60-year-olds. Revaccination 1 year post-dose 1 was well tolerated but did not seem to provide additional efficacy benefit in the overall study population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT04886596.

The respiratory syncytial virus vaccines are here: Implications for solid organ transplantation.

In 2023, the Food and Drug Administration approved 2 recombinant subunit respiratory syncytial virus (RSV) vaccines based on prefusion RSV F glycoproteins for the prevention of RSV-associated lower respiratory tract disease. These vaccines were subsequently recommended for individuals ≥60 years of age using shared clinical decision-making by the Center for Disease Control and Prevention's Advisory Committee on Immunization Practices. The development, deployment, and uptake of respiratory virus vaccines are of particular importance for solid organ recipients who are at higher risk of infectious complications and poor clinical outcomes, including from RSV-associated lower respiratory tract disease, compared to patients without immunocompromise. This review aims to summarize what is currently known about the burden of RSV disease in solid organ transplantation, to describe the currently available tools to mitigate the risk, and to highlight considerations regarding the implementation of these vaccines before and after transplantation. We also explore areas of unmet need for organ transplant recipients including questions of RSV vaccine effectiveness and safety, inequities in disease and vaccine access based on race and socioeconomic status, and expansion of coverage to immunocompromised individuals below the age of 60 years.

The Respiratory Syncytial Virus (RSV) G Protein Enhances the Immune Responses to the RSV F Protein in an Enveloped Virus-Like Particle Vaccine Candidate.

Respiratory syncytial virus (RSV) is a serious human respiratory pathogen, but no RSV vaccine has been licensed. Many vaccine candidates are focused on the viral F protein since the F protein is more conserved than the viral G protein across RSV strains and serotypes; thus, the F protein is thought more likely to induce a broader range of protection from infection. However, it is the G protein that binds the likely receptor, CX3CR1, in lung ciliated epithelial cells, raising the question of the importance of the G protein in vaccine candidates. Using virus-like particle (VLP) vaccine candidates, we have directly compared VLPs containing only the prefusion F protein (pre-F), only the G protein, or both glycoproteins. We report that VLPs containing both glycoproteins bind to anti-F-protein-specific monoclonal antibodies differently than do VLPs containing only the prefusion F protein. In RSV-naive cotton rats, VLPs assembled with only the pre-F protein stimulated extremely weak neutralizing antibody (NAb) titers, as did VLPs assembled with G protein. However, VLPs assembled with both glycoproteins stimulated quite robust neutralizing antibody titers, induced improved protection of the animals from RSV challenge compared to pre-F VLPs, and induced significantly higher levels of antibodies specific for F protein antigenic site 0, site III, and the AM14 binding site than did VLPs containing only the pre-F protein. These results indicate that assembly of pre-F protein with G protein in VLPs further stabilized the prefusion conformation or otherwise altered the conformation of the F protein, increasing the induction of protective antibodies. IMPORTANCE Respiratory syncytial virus (RSV) results in significant disease in infants, young children, and the elderly. Thus, development of an effective vaccine for these populations is a priority. Most ongoing efforts in RSV vaccine development have focused on the viral fusion (F) protein; however, the importance of the inclusion of G in vaccine candidates is unclear. Here, using virus-like particles (VLPs) assembled with only the F protein, only the G protein, or both glycoproteins, we show that VLPs assembled with both glycoproteins are a far superior vaccine in a cotton rat model compared with VLPs containing only F protein or only G protein. The results show that the presence of G protein in the VLPs influences the conformation of the F protein and the immune responses to F protein, resulting in significantly higher neutralizing antibody titers and better protection from RSV challenge. These results suggest that inclusion of G protein in a vaccine candidate may improve its effectiveness.

Mycobacterium bovis BCG Given at Birth Followed by Inactivated Respiratory Syncytial Virus Vaccine Prevents Vaccine-Enhanced Disease by Promoting Trained Macrophages and Resident Memory T Cells.

Respiratory syncytial virus (RSV) infects more than 60% of infants in their first year of life. Since an experimental formalin-inactivated (FI) RSV vaccine tested in the 1960s caused enhanced respiratory disease (ERD), few attempts have been made to vaccinate infants. ERD is characterized by Th2-biased responses, lung inflammation, and poor protective immune memory. Innate immune memory displays an increased nonspecific effector function upon restimulation, a process called trained immunity, or a repressed effector function upon restimulation, a process called tolerance, which participates in host defense and inflammatory disease. Mycobacterium bovis bacillus Calmette-Guérin (BCG) given at birth can induce trained immunity as well as heterologous Th1 responses. We speculate that BCG given at birth followed by FI-RSV may alleviate ERD and enhance protection through promoting trained immunity and balanced Th immune memory. Neonatal mice were given BCG at birth and then vaccinated with FI-RSV+Al(OH)3. BCG/FI-RSV+Al(OH)3 induced trained macrophages, tissue-resident memory T cells (TRM), and specific cytotoxic T lymphocytes (CTL) in lungs and inhibited Th2 and Th17 cell immune memory, all of which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented the innate tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. Therefore, BCG given at birth to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants. IMPORTANCE RSV is the leading cause of severe lower respiratory tract infection of infants. ERD, characterized by Th2-biased responses, inflammation, and poor immune memory, has been an obstacle to the development of safe and effective killed RSV vaccines. Innate immune memory participates in host defense and inflammatory disease. BCG given at birth can induce trained immunity as well as heterologous Th1 responses. Our results showed that BCG/FI-RSV+Al(OH)3 induced trained macrophages, TRM, specific CTL, and balanced Th cell immune memory, which contributed to inhibition of ERD and increased protection. Notably, FI-RSV+Al(OH)3 induced tolerant macrophages, while BCG/FI-RSV+Al(OH)3 prevented tolerance through promoting trained macrophages. Moreover, inhibition of ERD was attributed to trained macrophages or TRM in lungs but not memory T cells in spleens. BCG at birth as an adjuvant to regulate trained immunity and TRM may be a new strategy for developing safe and effective RSV killed vaccines for young infants.

Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein elicits antibodies targeting a membrane-proximal epitope.

IMPORTANCE: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants, infecting all children by age 5. RSV also causes substantial morbidity and mortality in older adults, and a vaccine for older adults based on a prefusion-stabilized form of the viral F glycoprotein was recently approved by the FDA. Here, we investigate a set of antibodies that belong to the same public clonotype and were isolated from individuals vaccinated with a prefusion-stabilized RSV F protein. Our results reveal that these antibodies are highly potent and recognize a previously uncharacterized antigenic site on the prefusion F protein. Vaccination with prefusion RSV F proteins appears to boost the elicitation of these neutralizing antibodies, which are not commonly elicited by natural infection.