Respiratory Syncytial Virus Vaccine Development Research Articles

A multi-center study on genetic variations in the fusion protein of respiratory syncytial virus from children with Acute Lower Respiratory Tract Infections in China during 2017–2021

Respiratory syncytial virus (RSV) is a significant cause of acute lower respiratory tract infection (ALRTI) in children under five years of age. Between 2017 and 2021, 396 complete sequences of the RSV F gene were obtained from 500 RSV-positive throat swabs collected from ten hospitals across nine provinces in China. In addition, 151 sequences from China were sourced from GenBank and GISAID, making a total of 549 RSV F gene sequences subjected to analysis. Phylogenetic and genetic diversity analyses revealed that the RSV F genes circulating in China from 2017 to 2021 have remained relatively conserved, although some amino acids (AAs) have undergone changes. AA mutations with frequencies ≥ 10% were identified at six sites and the p27 region: V384I (site I), N276S (site II), R213S (site Ø), and K124N (p27) for RSV A; F45L (site I), M152I/L172Q/S173 ​L/I185V/K191R (site V), and R202Q/I206M/Q209R (site Ø) for RSV B. Comparing mutational frequencies in RSV-F before and after 2020 revealed minor changes for RSV A, while the K191R, I206M, and Q209R frequencies increased by over 10% in RSV B. Notably, the nirsevimab-resistant mutation, S211N in RSV B, increased in frequency from 0% to 1.15%. Both representative strains aligned with the predicted RSV-F structures of their respective prototypes exhibited similar conformations, with low root-mean-square deviation values. These results could provide foundational data from China for the development of RSV mAbs and vaccines.

Respiratory syncytial virus vaccination during pregnancy for improving infant outcomes.

Respiratory syncytial virus vaccination during pregnancy for improving infant outcomes.

A Historical Perspective on Respiratory Syncytial Virus Prevention: A Journey Spanning Over Half a Century From the Setback of an Inactive Vaccine Candidate to the Success of Passive Immunization Strategy.

The efforts to prevent respiratory syncytial virus (RSV) infection in infants span over half a century. RSV vaccine development began in the 1960s, and it confronted a significant disappointment after testing a formalin-inactivated RSV (FI RSV) vaccine candidate. This inactivated RSV vaccine was not protective. A large number of the vaccinated RSV-naive children, when subsequently exposed to natural RSV infection from wild-type virus in the community, developed severe lung inflammation termed enhanced respiratory disease. This resulted in a halt in RSV vaccine development. In the 1990s, attention turned to the potential for passive protection against severe RSV disease with immunoglobulin administration. This led to studies on using standard intravenous immunoglobulins in high-risk infants, followed by high-titer RSV immunoglobulin preparation and, subsequently, the development of RSV monoclonal antibodies. Over the past 25 years, palivizumab has been recognized as a safe and effective monoclonal antibody as a prevention strategy for RSV in high-risk children. Its high cost and need for monthly administration, however, has hindered its use to ~2% of the birth cohort, neglecting the vast majority of newborns, including healthy full-term infants who comprise the largest portion of RSV hospitalizations and the greatest part of the burden of RSV disease. Still these efforts, helped pave the way for the present advances in RSV prevention that hold promise for mitigating severe RSV disease for all infants.

Neutralizing activity of anti-respiratory syncytial virus monoclonal antibody produced in Nicotiana benthamiana

ABSTRACT Respiratory syncytial virus (RSV) is a highly contagious virus that affects the lungs and respiratory passages of many vulnerable people. It is a leading cause of lower respiratory tract infections and clinical complications, particularly among infants and elderly. It can develop into serious complications such as pneumonia and bronchiolitis. The development of RSV vaccine or immunoprophylaxis remains highly active and a global health priority. Currently, GSK’s Arexvy™ vaccine is approved for the prevention of lower respiratory tract disease in older adults (>60 years). Palivizumab and currently nirsevimab are the approved monoclonal antibodies (mAbs) for RSV prevention in high-risk patients. Many studies are ongoing to develop additional therapeutic antibodies for preventing RSV infections among newborns and other susceptible groups. Recently, additional antibodies have been discovered and shown greater potential for development as therapeutic alternatives to palivizumab and nirsevimab. Plant expression platforms have proven successful in producing recombinant proteins, including antibodies, offering a potential cost-effective alternative to mammalian expression platforms. Hence in this study, an attempt was made to use a plant expression platform to produce two anti-RSV fusion (F) mAbs 5C4 and CR9501. The heavy-chain and light-chain sequences of both these antibodies were transiently expressed in Nicotiana benthamiana plants using a geminiviral vector and then purified using single-step protein A affinity column chromatography. Both these plant-produced mAbs showed specific binding to the RSV fusion protein and demonstrate effective viral neutralization activity in vitro. These preliminary findings suggest that plant-produced anti-RSV mAbs are able to neutralize RSV in vitro.

Assessing the protection elicited by virus-like particles expressing the RSV pre-fusion F and tandem repeated G proteins against RSV rA2 line19F infection in mice

Excessive pulmonary inflammation is the hallmark of respiratory syncytial virus (RSV) infection hindering efficacious RSV vaccine development. Yet, the vast majority of the experimental RSV vaccine studies use laboratory-adapted RSV strains that do not reflect the highly pathogenic and inflammatory nature of the virus found in clinical settings. Here, we re-evaluated the protective efficacy of the virus-like particle (VLP) vaccine co-expressing the pre-fusion (pre-F) protein and G protein with tandem repeats (Gt) reported in our previous study against the recombinant RSV rA2-line19F strain, which inflicts severe mucus production and inflammation in mice. VLP vaccine immunization elicited virus-specific serum antibody responses that mediated RSV rA2-line19F virus neutralization. VLP vaccine immunization promoted Th1 immune response development in the spleens and CD8 + T cell influx into the lungs of mice, which are essential for efficient viral clearance and dampened inflammatory response. When compared to the VLPs expressing only the pre-F antigen, those co-expressing both pre-F and Gt antigens conferred better protection in mice against rA2-line19F challenge infection. Overall, our data suggest that the pre-clinical VLP vaccine co-expressing RSV pre-F and Gt antigens can effectively protect mice against RSV strains that resemble pathogenic clinical isolates.

Research Progress in Respiratory Syncytial Virus Vaccines

In addition to being a substantial source of morbidity and mortality in older persons, respiratory syncytial virus (RSV) is a major contributor to lower respiratory tract infections in newborns and young children. Worldwide, there has been a lot of research done to provide safe and effective vaccinations against this common infection because there isn't an approved RSV vaccine. A succinct summary of current developments in RSV vaccine research is given in this abstract. Many vaccinations have reached the clinical testing stage and shown promising benefits. Live attenuated vaccines, nanoparticle vaccines, and viral vector vaccines are the three primary categories of current vaccination techniques. Additionally, the production of specific RSV antibodies such as MEDI8897 and polyclonal immunoglobulin RI-002 is being evaluated as an important research antibodies for avoiding RSV infection. The continuous dedication to RSV vaccine development gives optimism for the future prevention of RSV-related disorders across all age groups, despite the fact that challenges still exist, particularly ERD (Enhanced respiratory disease).

Vaccination for Respiratory Syncytial Virus: A Narrative Review and Primer for Clinicians.

Respiratory syncytial virus (RSV) poses a significant burden on public health, causing lower respiratory tract infections in infants, young children, older adults, and immunocompromised individuals. Recent development and licensure of effective RSV vaccines provide a promising approach to lessening the associated morbidity and mortality of severe infections. This narrative review aims to empower clinicians with the necessary knowledge to make informed decisions regarding RSV vaccination, focusing on the prevention and control of RSV infections, especially among vulnerable populations. The paper explores the available RSV vaccines and existing evidence regarding their efficacy and safety in diverse populations. Synthesizing this information for clinicians can help the latter understand the benefits and considerations associated with RSV vaccination, contributing to improved patient care and public health outcomes.

Respiratory Syncytial Virus Vaccines: A Review of the Candidates and the Approved Vaccines.

Respiratory syncytial virus (RSV) is responsible for a significant proportion of global morbidity and mortality affecting young children and older adults. In the aftermath of formalin-inactivated RSV vaccine development, the effort to develop an immunizing agent was carefully guided by epidemiologic and pathophysiological evidence of the virus, including various vaccine technologies. The pipeline of RSV vaccine development includes messenger ribonucleic acid (mRNA), live-attenuated (LAV), subunit, and recombinant vector-based vaccine candidates targeting different virus proteins. The availability of vaccine candidates of various technologies enables adjustment to the individualized needs of each vulnerable age group. Arexvy® (GSK), followed by Abrysvo® (Pfizer), is the first vaccine available for market use as an immunizing agent to prevent lower respiratory tract disease in older adults. Abrysvo is additionally indicated for the passive immunization of infants by maternal administration during pregnancy. This review presents the RSV vaccine pipeline, analyzing the results of clinical trials. The key features of each vaccine technology are also mentioned. Currently, 24 vaccines are in the clinical stage of development, including the 2 licensed vaccines. Research in the field of RSV vaccination, including the pharmacovigilance methods of already approved vaccines, promotes the achievement of successful prevention.

The third pandemic: The respiratory syncytial virus landscape and specific considerations for the allergist/immunologist.

Background: Since its initial identification in 1956, respiratory syncytial virus (RSV) has been the second most common cause of mortality in infants <6 months of age and a major cause of morbidity and mortality associated with lower respiratory tract infection (LRTI) in older adults (ages >60 years) worldwide. Of particular interest to the allergist/immunologist is a growing body of evidence that suggests an association between LRTI caused by RSV in infants with later-life development of asthma, wheezing, or impaired lung function in adults. Efforts to develop a RSV vaccine have been thwarted for >70 years by the occurrence of enhanced respiratory disease (ERD), an adverse RSV vaccine reaction, in the 1960s, in which more-severe illness occurred on natural infection after vaccination of infants who were RSV naive and with a formalin-inactivated RSV vaccine. Recent advances in knowledge of the structural biology of the RSV surface fusion glycoprotein, however, have revolutionized RSV vaccine development for preventive interventions and have offered, at last, the hope of an effective and safe vaccine for the prevention of RSV disease. Objective: The purpose of this report was to examine the current evidence that supports the epidemiology, disease manifestations, molecular biology, treatments, and new vaccine development of RSV vaccines. Results: The host-immune response to RSV infection is carried out by two distinct but overlapping universes of mucosal and systemic immune systems in which a balanced set of B- and T-cell responses are involved in protective immunity that includes the mucosal immune system in which immunoglobulin A (IgA) prevails and the systemic immune system in which IgG neutralizing antibody predominates. The key to developing an effective vaccine is now thought to be linked to the availability of a stabilized prefusion F protein in the immunizing vaccine, which can perform a dual function of a balanced mucosal and/or systemic immune response as well as an effective antibody specifically directed to critical epitopes on the requisite prefusion F protein. Conclusion: The unfortunate manifestation of RSV ERD that occurred in the 1960s has led to a better understanding of the structural biology of the RSV surface fusion glycoprotein and has provided a basis for the development of more effective and safer RSV vaccines and monoclonal antibody preparations for immunoprophylaxis of the dread effects of RSV disease. There are now a large number of clinical trials in progress that are evaluating these products, which include recombinant vector, subunit, particle-based, live-attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. This article gives an overview of the many aspects of RSV disease and development of virus (RSV) vaccines of particular interest to the allergist/immunologist.

Estimating the incidence of first RSV hospitalization in children born in Ontario, Canada.

Respiratory syncytial virus (RSV) contributes significantly to morbidity in children, placing substantial burdens on health systems, thus RSV vaccine development and program implementation are a public health priority. More data on burden are needed by policymakers to identify priority populations and formulate prevention strategies as vaccines are developed and licensed. Using health administrative data, we calculated incidence rates of RSV hospitalization in a population-based birth cohort of all children born over a six-year period (May 2009 - June 2015) in Ontario, Canada. Children were followed until their first RSV hospitalization, death, 5 th birthday, or the end of the study period (June 2016). RSV hospitalizations were identified using a validated algorithm based on International Classification of Diseases, 10 th Revision, and/or laboratory-confirmed outcomes. We calculated hospitalization rates by various characteristics of interest, including calendar month, age groups, sex, comorbidities, and gestational age. The overall RSV hospitalization rate for children <5 years was 4.2 per 1,000 person-years (PY) with a wide range across age groups (from 29.6 to 0.52 per 1000PY in children aged 1 month and 36-59 months, respectively). Rates were higher in children born at a younger gestational age (23.2 per 1000PY for those born at <28 weeks versus 3.9 per 1000PY born at ≥37 weeks); this increased risk persisted as age increased. While the majority of children in our study had no comorbidities, rates were higher in children with comorbidities. For all age groups, rates were highest between December and March. Our results confirm the high burden of RSV hospitalization and highlight young infants are at additional risk, namely premature infants. These results can inform prevention efforts.

Respiratory Syncytial Virus Infection: An Update.

Respiratory syncytial virus (RSV) is a highly contagious respiratory virus that can cause mild to severe illness in children. It is the leading cause of lower respiratory tract infections (LRTI) in children under the age of one year, and it can also affect older children and adults, especially those with underlying medical conditions. In the post-COVID period, there seems to be an increase in the incidence, possibly due to 'immunity debt'. Symptoms of RSV infection in children may include fever, runny nose, and cough. In severe cases, it can lead to bronchiolitis (inflammation of the small airways in the lungs) or pneumonia (infection of the lungs). Most children with RSV infection recover within a week or two, but some may require hospitalization, especially those who are premature or have underlying medical conditions. As there is no specific treatment for RSV infection, supportive care is the mainstay of management. In severe cases, oxygen therapy or mechanical ventilation may be necessary. High flow nasal cannula seems to be beneficial.There have been promising advances in development of RSV vaccines; few trials in adults and pregnant women have reported encouraging results. The US FDA has approved two RSV vaccines for use in older adults (GSK's Arexvy and Pfizer's ABRYSVO).

Human T cells efficiently control RSV infection.

Respiratory syncytial virus (RSV) infection causes significant morbidity and mortality in infants, immunocompromised individuals, and older individuals. There is an urgent need for effective antivirals and vaccines for high-risk individuals. We used 2 complementary in vivo models to analyze RSV-associated human lung pathology and human immune correlates of protection. RSV infection resulted in widespread human lung epithelial damage, a proinflammatory innate immune response, and elicited a natural adaptive human immune response that conferred protective immunity. We demonstrated a key role for human T cells in controlling RSV infection. Specifically, primed human CD8+ T cells or CD4+ T cells effectively and independently control RSV replication in human lung tissue in the absence of an RSV-specific antibody response. These preclinical data support the development of RSV vaccines, which also elicit effective T cell responses to improve RSV vaccine efficacy.

Respiratory Syncytial Virus Infection: Treatments and Clinical Management.

Respiratory syncytial virus (RSV) is a major healthcare concern, especially for immune-compromised individuals and infants below 5 years of age. Worldwide, it is known to be associated with incidences of morbidity and mortality in infants. Despite the seriousness of the issue and continuous rigorous scientific efforts, no approved vaccine or available drug is fully effective against RSV. The purpose of this review article is to provide insights into the past and ongoing efforts for securing effective vaccines and therapeutics against RSV. The readers will be able to confer the mechanism of existing therapies and the loopholes that need to be overcome for future therapeutic development against RSV. A methodological approach was applied to collect the latest data and updated results regarding therapeutics and vaccine development against RSV. We outline the latest throughput vaccination technologies and prophylactic development efforts linked with RSV. A range of vaccination approaches with the already available vaccine (with limited use) and those undergoing trials are included. Moreover, important drug regimens used alone or in conjugation with adjuvants or vaccines are also briefly discussed. After reading this article, the audience will be able to understand the current standing of clinical management in the form of the vaccine, prophylactic, and therapeutic candidates against RSV. An understanding of the biological behavior acting as a reason behind the lack of effective therapeutics against RSV will also be developed. The literature indicates a need to overcome the limitations attached to RSV clinical management, drugs, and vaccine development that could be explained by dealing with the challenges of current study designs with continuous improvement and further work and approval on novel therapeutic applications.

The Quest for a Respiratory Syncytial Virus Vaccine for Older Adults: Thinking beyond the F Protein.

Respiratory syncytial virus (RSV) is a common cause of paediatric respiratory tract infection and causes a significant health burden in older adults. Natural immunity to RSV is incomplete, permitting recurrent symptomatic infection over an individual's lifespan. When combined with immunosenescence, this increases older adults' susceptibility to more severe disease symptoms. As RSV prophylaxis is currently limited to infants, older adults represent an important target population for RSV vaccine development. The relationship between RSV and our immune systems is complex, and these interactions require deeper understanding to tailor an effective vaccine candidate towards older adults. To date, vaccine candidates targeting RSV antigens, including pre-F, F, G (A), G (B), M2-1, and N, have shown efficacy against RSV infection in older adults in clinical trial settings. Although vaccine candidates have demonstrated robust neutralising IgG and cellular responses, it is important that research continues to investigate the RSV immune response in order to further understand how the choice of antigenic target site may impact vaccine effectiveness. In this article, we discuss the Phase 3 vaccine candidates being tested in older adults and review the hurdles that must be overcome to achieve effective protection against RSV.

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.

Burden of respiratory syncytial virus infection in older and high-risk adults: a systematic review and meta-analysis of the evidence from developed countries.

Respiratory syncytial virus (RSV) significantly impacts the health of older and high-risk adults (those with comorbidities). We aimed to synthesise the evidence on RSV disease burden and RSV-related healthcare utilisation in both populations. We searched Embase and MEDLINE for papers published between 2000 and 2019 reporting the burden and clinical presentation of symptomatic RSV infection and the associated healthcare utilisation in developed countries in adults aged ≥60 years or at high risk. We calculated pooled estimates using random-effects inverse variance-weighted meta-analysis. 103 out of 3429 articles met the inclusion criteria. Among older adults, RSV caused 4.66% (95% CI 3.34-6.48%) of symptomatic respiratory infections in annual studies and 7.80% (95% CI 5.77-10.45%) in seasonal studies; RSV-related case fatality proportion (CFP) was 8.18% (95% CI 5.54-11.94%). Among high-risk adults, RSV caused 7.03% (95% CI 5.18-9.48%) of symptomatic respiratory infections in annual studies, and 7.69% (95% CI 6.23-9.46%) in seasonal studies; CFP was 9.88% (95% CI 6.66-14.43%). Data paucity impaired the calculation of estimates on population incidence, clinical presentation, severe outcomes and healthcare-related utilisation. Older and high-risk adults frequently experience symptomatic RSV infection, with appreciable mortality; however, detailed data are lacking. Increased surveillance and research are needed to quantify population-based disease burden and facilitate RSV treatments and vaccine development.

The burden and surveillance of RSV disease in young children in Belgium-expert opinion.

The Belgian population-based RSV surveillance should be improved, and a hospital-led reporting system should be put in place to enable the evaluation of the true burden of RSV disease in Belgium and to improve disease management in the future. • RSV bronchiolitis is a very important cause of infant hospitalization. • The burden of disease in the community is poorly studied and underestimated. • This expert opinion summarizes knowledge gaps and offers insights that allow improvement of local surveillance systems in order to establish a future-proof RSV surveillance system.

Level of maternal antibodies against respiratory syncytial virus (RSV) nucleoprotein at birth and risk of RSV very severe lower respiratory tract infection.

The nucleoprotein (N protein) of respiratory syncytial virus (RSV) is a candidate antigen for new RSV vaccine development. The aim of the present study was to investigate the association between maternal antibody titers against the RSV N protein at birth and the newborns' risk of developing very severe lower respiratory tract infection (VS-LRTI). In this single-center prospective cohort study, 578 infants born during the RSV epidemic season in France were included. Among these, 36 were hospitalized for RSV VS-LRTI. A generalized linear model was used to test the occurrence of a VS-LRTI in function of sex, mode of delivery, parity of the mother, type of pregnancy, date of birth in relation to the peak of the epidemic, and antibody titer against N protein. All cord blood samples had detectable antibodies against N protein. The mean titers were significantly lower in newborns with risk factors for RSV severe LRTI (preterm infants, birth before the peak epidemic, multiparous mother). There was no association between antibody titer against the N protein and a protection against VS-LRTI. Further studies are needed to support the hypothesis that transfer of maternal antibodies against the RSV N protein can provide a significant immune protection early in infancy and that N protein candidate vaccine may be a suitable target for maternal vaccine.

Virus-like particles coexpressing the PreF and Gt antigens of respiratory syncytial virus confer protection in mice.

Aims: The purpose of this study was to assess the protective efficacy of virus-like particles (VLPs) co-expressing the pre-fusogenic (PreF) and G proteinwith tandem repeats (Gt) antigens of respiratory syncytial virus (RSV) in mice. Materials & methods: VLP constructs expressing PreF, Gt or both were used to immunize mice, and the protective efficacies were evaluated using antibody responses, neutralizing antibody titers, T-cell responses, histopathological assessment and plaque assay. Results: PreF+Gt VLP immunization elicited strong RSV-specific antibody responses and pulmonary T-cell responses that contributed to lessening virus titer and inflammation. Conclusion: Our findings suggest that coexpressing PreF and Gt antigens elicits better protection than either one alone. This combinatorial approach could assist in future RSV vaccine development.

Correlates of Protection Against Respiratory Syncytial Virus Infection in Infancy.

The highest morbidity and mortality from respiratory syncytial virus (RSV) infection occurs in young infants. Immunization of expectant mothers during pregnancy has the potential to substantially reduce the burden of RSV disease in a majority of infants. Correlates of protection (COP) are important in guiding the development of maternal RSV vaccines and the design of maternal RSV vaccine trials, as immune response to candidate vaccines should mirror protective RSV immunity at birth. Here, we review the literature reporting correlations between RSV immune measures at birth and clinical RSV outcomes during infancy. Less than a dozen studies have investigated immunological COP with RSV disease or related hospitalization, yielding inconsistent findings overall. The differences in findings between studies could be due to differences in inclusion/exclusion criteria (e.g., the inclusion of older infants who may benefit less from maternal antibodies or infants followed during inter-seasonal periods where RSV is absent), differences in semi-quantitative RSV antibody neutralization assays, or differences in RSV outcome measures such as the sensititivity/specificity of diagnostic tests. Future research in this field should seek to standardize RSV immunological measures and outcomes, expand the breadth of functional RSV measures beyond antibody neutralization, and consider infants' age and seasonality of RSV infection.