Heinonen et al. In addition, the latter group found that, compared with severely hospitalized patients, children with mild disease had high expression of plasma cell and inflammatory genes, lower activation of neutrophil and monocyte gene expression, and reduced inhibition of T cell and NK cell gene expression These findings may explain the lack of an immune response Notably, during RSV infection, the severity of bronchiolitis and wheezing disease was related to other factors, such as respiratory bacteria.
Nasal mucus samples obtained from children with mild and severe RSV diseases were analyzed by 16S ribosomal sequencing to characterize the microbiota The results showed that all five major bacterial communities showed the characteristics of being the dominant bacteria types. RSV infection and hospitalization were positively correlated with an abundance of Haemophilus influenzae and Streptococcus and negatively correlated with an abundance of Staphylococcus aureus.
Streptococcus pneumoniae gram positive and Haemophilus influenzae gram negative were also found to be the most common bacterial isolates in other studies of lower respiratory tract bacterial coinfections in hospitalized patients with RSV infection These results suggest that airways damaged by RSV infection may be more vulnerable to secondary bacterial infection. The preclinical and clinical development of RSV intervention can be roughly classified into three categories: monoclonal antibodies, vaccines and small molecules.
Each of these strategies has its own unique advantages and disadvantages, but each solution is expected to be a candidate to pass clinical trials. Antibodies are important prophylactic treatments for patients at risk of serious RSV infection. With the introduction of palivizumab Synagis , Medimmune voluntarily stopped using RespiGam in It was also the first antiviral mAb approved for human treatment. Palivizumab can effectively prevent RSV hospitalization for high-risk premature infants with pregnancy less than 32 weeks in the first 6 months after discharge However, due to its limited cost and effectiveness, which are similar to those of RespiGam, it is currently approved only for the prevention of RSV in premature infants and infants with cardiopulmonary diseases at birth.
Motavizumab MEDI is a second-generation palivizumab product. It mutates 13 specific amino acid residues located in the variable region of the CDR sequence of the antibody, thus enhancing its affinity and neutralization by and fold, respectively The results from a phase 3 clinical trial revealed that motavizumab showed better neutralization ability and a longer half-life than palivizumab, which makes it a promising candidate.
Over the past decade, because of the great advances in mAb screening technology, hundreds of human antibodies against RSV F proteins have been isolated and identified. Among these antibodies, many RSV F-specific antibodies have been shown to be much more effective than palivizumab.
Kwakkenbos et al. The YTE substitution enhanced the binding of IgG1 to the neonatal Fc receptor FcRN and improved its anti-degradation performance, thus prolonging the half-life of the antibody in serum the average half-life ranged from 85 to days The results also showed that nirsevimab significantly reduced the consultation rate and hospitalization rate for RSV infection by It is significantly more potent in neutralizing RSV than palivizumab and has good tolerance and a longer half-life in healthy adults However, a phase 3 trial of premature infants showed that all RSV subtype B isolates had two amino acid mutations in the epitopes, resulting in the loss of suptavumab neutralizing activity, which led to the discontinuation of its clinical development Tang et al.
RB1 effectively neutralized a variety of clinical isolates of RSV in vitro approximately fold more effectively than palivizumab, and it showed good protective effects in a cotton rat model. In addition, some other pre-F-specific antibodies are also in the preclinical development stage.
For example, Orti et al. It consists of three univalent Nb molecules connected by a glycine-serine GS linker However, upon RSV infection develops in the lower respiratory tract, inhaling RSV therapeutic antibodies through the nose may not improve the clinical course of the disease Using phage display library technology, Rossey et al.
The results indicated that these antibodies performed similar to or better than F-specific mAbs D25 and AM Recently, Tiwari et al. Moreover, RSV replication was significantly inhibited 7 days after an anchored VHH-expressing mRNA was transfected into the lungs of mice, and the antibody level persisted for at least 28 days.
This method of expressing membrane-anchored broadly neutralizing antibodies in the lungs may be promising for preventing lung infection. Antibodies against the G protein are also in preclinical development, and these antibodies have been shown to inhibit virus attachment.
Collarini et al. This antibody showed good virus clearance activity in a mice model for infection prevention and treatment and is expected to be an attractive candidate for the clinical treatment of RSV. Anderson et al. Lee et al. These antibodies may be used as alternatives to prevent RSV infection. However, the N-terminus and C-terminus of the extracellular domain of the G protein also contain multiple antibody-binding protected sites An effective vaccine to protect high-risk groups from severe RSV infection will be indispensable.
In the s, clinical trials of a formalin-inactivated RSV vaccine for infants aggravated RSV disease and eventually led to the death of two infants. Currently, dozens of promising vaccines are being developed to prevent RSV infection, and they are mainly attenuated vaccines, subunit vaccines and vector-based vaccines. The most fundamental principle of RSV vaccine design, regardless of type, always follows the principle that RSV-neutralizing antibodies need to be introduced into airway mucosa in the most reasonable way possible One of the basic goals of live attenuated vaccines is to limit the replication of RSV in recipients through traditional measures such as heating or chemical treatment or reverse genetic techniques to maintain an appropriate and natural balance of B and T cell responses, thereby avoiding vaccine-enhanced diseases.
Currently, there are approximately 30 active clinical trials of live attenuated RSV vaccines registered at ClinicalTrials. In addition, Meissa Vaccines produced the highly attenuated vaccine MV by optimizing the codons of the NS2, NS1 and G genes, as well as by deleting the SH gene, which had been proven to have a strong protective effect in a cotton rat model.
Recently, Jenkins et al. The former mutation did not inhibit virus production in Vero cell culture but greatly reduced the transmission of the virus in human bronchial epithelium, and the latter mutation reduced the cleavage of the vaccine virus in Vero cells, thus increasing the yield and making the production more economical. In cotton rat treated with this candidate vaccine, RSV replication was undetectable even at a dose of 10 5 plaque-forming units PFU , and it was sufficient to completely protect against RSV A2 infection after PFUs immunization This may be a potential candidate for a live attenuated RSV vaccine.
For these vaccines, the focus is primarily on the epitopes that can induce a B cell response to produce strong neutralizing activity for generating vaccines with long-term protective effects. This kind of vaccine can minimize the production of non-neutralizing or weakly neutralizing antibodies in the process of immunization, thus weakening antibody-dependent enhancement ADE GlaxoSmithKline has produced two F-based vaccines, GSKA and GSKA, that have been subjected to phase 2 clinical evaluations for safety and immune response in the elderly and pregnant women, respectively.
Both of these vaccines stimulated a strong immune response and were well tolerated Currently, the company is preparing for the implementation of phase 3 clinical trials. It failed to protect newborns of vaccinated pregnant women in its phase 3 clinical trial One of reason contributing to this clinical result may be due to the fact that the postfusion conformation cannot elicit a wider range of neutralizing antibodies as the prefusion conformation This needle-free vaccine may be better received by sensitive groups such as babies because it does not require skin preparation.
In addition, Marcandalli et al. The nanoparticle scaffold I consists of 20 trimers and 12 pentamers for a total of subunits. The two-component feature of this scaffold enables it to produce highly ordered, monodisperse immunogens. A stable pre-F DS-Cav1 trimer protein was presented on the outside of the nanoparticle substrate in the form of repeated arrays.
When mice and nonhuman primates were inoculated, the immunogenicity of nanoparticles containing 20 DS-Cav1 trimers was fold greater than that of the trimer DS-Cav1 alone Most recently, Swanson et al. Each of the optimized pre-F-NP contain 8 pre-F proteins.
Pre-F-NP induced persistent pre-F-specific antibodies and produced effective neutralizing antibody responses in mouse and nonhuman primate models. These results encourage the continued development of these promising nano RSV vaccines. Vector-based vaccines transmit RSV antigens through vectors and induce specific immune responses.
FA2 were ineffective or no longer under development. Pre-F, developed by Janssen, is a vector-based vaccine based on human adenovirus 26 strain Ad26 expressing stable pre-F protein Moreover, the high titer of RSV-neutralizing antibody produced after immunization could last for more than 30 weeks and produced protective immunity to RSV virus in the lung and nasal cavity.
A phase 2a clinical trial conducted with elderly patients older than 60 years of age showed that Ad Another clinical study evaluating the safety and immunogenicity of Ad The safety and responsiveness of intranasal injection of the SeVRSV vaccine were evaluated in healthy adults aged years in a phase 1 clinical trial.
The study showed that the vaccine was well tolerated In contrast to the previous two vector-based vaccines, this vector contains genes that encode three proteins F, N and M of RSV. In a phase 1 clinical trial of 72 healthy adults aged years, ChAdRSV was not found to cause significant safety issues, and its specific humoral and cellular immune responses were high The results of a phase 2 clinical evaluation of the dose and vaccination regimen of MVA-BN-RSV in adults older than 55 years showed that MVA-BN-RSV was safe and that a single dose could induce a cellular immune response biased towards Th1 cells and an antibody response that lasted for more than one-half year Currently, a phase 3 clinical trial is being planned.
An mRNA vaccine can also induce strong humoral and cellular immune responses at the same time. Ribavirin, a nucleoside analog, is the only clinically approved antiviral inhibitor for the treatment of RSV infection. However, the drug is restricted for the treatment of children because of concerns about teratogenicity and occupational exposure At present, the development of small-molecule inhibitors of RSV infection is mainly based on two modes of action: in one mode, the invading virions are blocked from binding to the F protein on the surface of RSV, and in the other mode, the production of new virions is inhibited by blocking viral transcription and replication.
In a challenge study of intranasal RSV infection in healthy adults, participants treated with GS had a lower viral load and lower neutrophil count and total mucus weight than those in the control group, reducing the severity of clinical disease Another phase 2b study performed to evaluate the efficacy of presatovir in RSV LRTI in patients with hematopoietic cell transplants HCTs did not improve virological or clinical outcomes despite it being well tolerated Similar to GS, it blocks the invasion of virus particles by combining with pre-F with high affinity Kd value of 7.
Roymans et al. Oral treatment of newborn lambs with JNJ effectively inhibited identifiable acute lower respiratory infections, even when treatment was delayed until external symptoms of RSV disease became apparent Another potentially interesting target is the N protein, which is an important component of the polymerase complex and the most conserved viral protein that plays an indispensable role in RNA transcription and replication.
RSV, an analog of 1,4-benzodiazepine, has been found to hinder optimal viral transcription by directly binding to RSV N Some promising antiviral activities were shown in early clinical studies, but the studies were stopped because of its poor efficacy. Then, EDP was identified after re-optimization of 1,4-benzodiazepine. The results showed that it inhibited RSV by blocking RSV N to prevent the virus from entering the postreplication stage of its life cycle.
In another phase 2b clinical trial conducted with RSV-infected lung transplant patients, although ALN-RSV01 showed good tolerance and reduced the risk of bronchiolitis obliterans syndrome after RSV infection, there was no significant difference in viral parameters or symptom scores between the treatment group and the control group The development of inhibitors for RSV L is also an attractive target for antiviral intervention.
TMEM16A is a major secretory anion channel in airway epithelial cells that is upregulated during airway inflammation and asthma. Recently, Pearson et al. Most recently, Risso-Ballester et al. It has been more than 60 years since RSV was discovered, and RSV has become one of the most important pathogens causing respiratory diseases in the world.
With continuous exploration, the roles of the various components of RSV are being explored in-depth, and the mysterious veil surrounding the mechanism by which RSV invades the host and its stepwise interaction with the host is being lifted. In the past decade, researchers have identified several key host cell receptors. In particular, the recent discovery of IGF1R, the main receptor of RSV infection in host cells, will undoubtedly stimulate many research ideas.
Future experiments should be directed to determining how the F protein interacts with IGF1R at the atomic level. The elucidation of the structure of the F protein before and after fusion will undoubtedly play a guiding role in antibody development and vaccine design. Further study on the molecular structure that triggers the fusion of the F protein with the host membrane may stimulate new targets for the design of antibodies and small-molecule inhibitors. Although no antibodies, vaccines or inhibitors have been approved, with the exception of palivizumab, there are approximately 30 clinical interventions being evaluated and a large number of preclinical candidates.
In the next five to ten years, the clinical prevention and treatment of RSV infection can be highly anticipated. However, similar to other RNA viruses, surface glycoproteins are the prone to mutation. Therefore, for the development of antibodies and small-molecule inhibitors, the global mutations and distribution of RSV must be identified and monitored because they may affect the results of clinical trials and even the efficacy of future products.
Therapy consisting of a cocktail of two or more antibodies or small-molecule inhibitors should also be considered because this type of synergistic approach may reduce viral escape from host immunity.
Although combination therapy has been proven to be a key strategy for achieving synergy and preventing the development of drug resistance by other viruses, whether this strategy will be effective in RSV treatment remains to be determined.
In addition, the timing of starting treatment may also be critical. For example, if anti-RSV treatment is used early in the course of infection, it is more likely to show clinical benefits.
Current research and clinical progress data on the prevention of RSV infection are optimistic, and we believe that more than one effective program will be approved and marketed in the near future to improve our ability to control RSV infection.
Zifang Shang completed the literature collection, the article writing, and the drawing of all the pictures and tables. Shuguang Tan provided the proofreading of the article, and Dongli Ma provided guidance and suggestions for the article writing. National Center for Biotechnology Information , U. Int J Biol Sci. Published online Sep Find articles by Zifang Shang. Find articles by Shuguang Tan.
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Competing Interests: The authors have declared that no competing interest exists. Received Jul 9; Accepted Sep Abstract Respiratory syncytial virus RSV is one of the most important viral pathogens causing respiratory tract infection in infants, the elderly and people with poor immune function, which causes a huge disease burden worldwide every year.
Introduction RSV was first isolated from chimpanzees with respiratory diseases in 1. Open in a separate window. Figure 1. Genome structure, entry and the life cycle The virion genome structure Human RSV is mainly composed of two subtypes A and B , which belong to the Orthopneumovirus genus in the Pneumoviridae family and Mononegavirales order, and is prone to genetic changes.
Figure 2. Entry of RSV and its host binding receptors The process by which RSV virions enter host cells is primarily initiated by the binding of virions to the surface molecules of host cells and the fusion of the virus and host cell membranes.
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Federal Government. Read our disclaimer for details. Last Update Posted : September 2, Study Description. In this randomised, placebo-controlled, double-blind Phase 2a study, healthy male and female participants years of age will be given an investigational RSV vaccine RSVpreF and challenged with RSV one month later. The purpose of this research study is to assess the safety, immunogenicity and efficacy of RSVpreF using a human viral challenge model.
Detailed Description:. FDA Resources. Arms and Interventions. A single dose of mcg RSVpreF for intramuscular injection. A single intramuscular injection of Placebo to match active vaccine.
A single Placebo dose for intramuscular injection to match experimental vaccine. Outcome Measures. Culture lab-confirmed symptomatic RSV infection defined as: One quantifiable viral culture and Either one or more positive clinical symptoms from different categories in the symptom scoring system or one Grade 2 symptom from any category.
Number of unsolicited adverse events AEs within 30 days after vaccination. Number of medically attended AEs from vaccination to study end. Eligibility Criteria. Inclusion Criteria: An informed consent document signed and dated by the participant and the Investigator.
Aged between 18 and 50 years. In good health with no history, or current evidence, of clinically significant medical conditions, and no clinically significant test abnormalities that will interfere with participant safety.
A documented medical history prior to enrolment. Females of childbearing potential must have a negative pregnancy test prior to enrolment. Documented status as being surgically sterile e.
The following criteria apply to female and male participants: Female participants of childbearing potential must use one form of highly effective contraception. Hormonal methods must be in place from at least 2 weeks prior to the first study visit.
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