Severe Lower Respiratory Tract Disease Research Articles

Immune Responses and Protection Profiles in Mice Induced by Subunit Vaccine Candidates Based on the Extracellular Domain Antigen of Respiratory Syncytial Virus G Protein Combined with Different Adjuvants.

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease of infants and older people. There is an urgent need for safe and effective vaccines against RSV infection. In this study, we analyzed the effects of the immune response and protection with the RSV recombinant G protein extracellular domain (Gecto) combined with various adjuvants as novel subunit vaccines in mice. All groups receiving RSV Gecto combined with adjuvants exhibited robust humoral and cellular immunity compared to those receiving an adjuvant alone or inactivated RSV vaccine. The greatest effect was observed in mice receiving Gecto combined with a CpG ODN + Alum salt adjuvant, resulting in the highest production of neutralizing antibodies against both RSV A and B subtypes, G-specific IgG and IFN-γ production in splenocytes, and interleukin-2 and interferon-γ expression in CD4+ T cells. Significant humoral and cellular immune responses were observed in mice immunized with Gecto combined with AddaS03™ or cyclosporin A adjuvants. The vaccine containing the AddaS03™ adjuvant showed significantly high expression of interleukin-4 in CD4+ T cells. Cross-protection against a challenge with either RSV A or B subtypes was observed in the Gecto plus adjuvant groups, resulting in a significant decrease in viral load and reduced pathological damage in the mouse lungs. These findings offer valuable insights into the development and application of recombinant RSV G-subunit vaccines with adjuvants.

Efficacy and safety of vaccines to prevent respiratory syncytial virus infection in infants and older adults: A systematic review and meta-analysis

ObjectivesTo determine the efficacy and safety of respiratory syncytial virus (RSV) vaccines in infants and older adults. MethodsWe performed a systematic review and meta-analysis of randomized control trials that evaluated the efficacy of maternal RSV immunization against infections in infants, as well as the efficacy of RSV vaccines in older adults. The primary outcome was the vaccine efficacy against RSV-related lower respiratory tract disease (LRTD). Grading of Recommendations Assessment, Development and Evaluation criteria was used to evaluate the level of evidence. ResultsTen trials were included in the review. For maternal vaccination, the RSV vaccine showed favourable efficacy against RSV-related LRTD (vaccine efficacy 57.3%, 95% confidence interval [CI] 31.3-73.5; low certainty) and RSV-related severe LRTD (vaccine efficacy 81.9%, 95% CI 56.8-92.4; moderate certainty) in infants within 90 days after birth. For older adults, Meta-analysis showed that RSV vaccines could also reduce the risk of RSV-related LRTD (vaccine efficacy 78.3%, 95% CI 65.6-86.3; moderate certainty) and RSV-related severe LRTD (vaccine efficacy 86.5%, 95% CI 68.3-94.3; moderate certainty). There was no significant difference in serious adverse events between RSV vaccines and placebo. ConclusionRSV vaccines have the potential to offer protection against RSV disease in both infants and older adults, without apparent safety concerns.

Effects of palivizumab prophylaxis on respiratory syncytial virus (RSV) infections in Montenegro.

Respiratory syncytial virus (RSV) is one of the most common pathogens causing severe lower respiratory tract disease in infancy and childhood. In newborns, young infants, and in infants with co-morbidities, the risk of severe infection is increased. Current protection against severe RSV infection is immunoprophylaxis with the monoclonal antibody palivizumab. The study aimed to assess the effects of palivizumab prophylaxis in the Republic of Montenegro in comparison to the pre-prophylaxis period. The study was conducted in prospective/retrospective single center format in Montenegro in the Clinical Center of Podgorica, for the period 2009-2019. A total of 104 high-risk infants in the palivizumab prophylaxis program (2014-2019 RSV seasons) and 168 high-risk children without palivizumab prophylaxis (2009-2013 RSV seasons) were enrolled. A total of 51 children (49.0%) received prophylaxis for prematurity, 33 (31.7%) for bronchopulmonary dysplasia (BPD), 13 (12.5%) for hemodynamically significant heart disease/defect (HSCHD), and 7 (6.8%) for "miscellaneous" indications. In the control group most children had prematurity (101, 60.1%), followed by BPD (59, 35.1%), HSCHD (3, 1.8%), and "miscellaneous" (5, 3.4%) conditions. Readmission to the pediatric intensive care units (PICU) due to RSV infection was significantly lower in prophylaxis group (0.0 vs 16.1%, p<0.001). No lethal outcomes were observed in high-risk children with palivizumab prophylaxis compared to 2.4% in the control group. The introduction of RSV immunoprophylaxis as well as other new protective treatment strategies for high-risk newborns led to significant improvements in infant and childcare in Montenegro. This is the first report on palivizumab prophylaxis in Montenegro, demonstrating the effectiveness and safety of palivizumab use in clinical settings.

The burden of RSV, hMPV, and PIV amongst hospitalized adults in the United States from 2016 to 2019.

Respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and parainfluenza virus (PIV) hospitalize many people yearly. Though severe lower respiratory tract disease has been described in children, the elderly, and the immunocompromised, there is a gap in our understanding of RSV, hMPV, and PIV in hospitalized adults. We sought to evaluate the association of RSV, hMPV, and PIV with severe respiratory disease requiring noninvasive or mechanical ventilation and death in hospitalized adults in the United States. We conducted a retrospective, pooled, cross-sectional study of general medicine hospitalizations in the United States from 2016 to 2019 using the National Inpatient Sample published by the Agency for Healthcare Quality and Research. We used multivariable Poisson regression to estimate the likelihood of severe respiratory disease or death. We used linear regression to estimate the mean difference in length of stay for those hospitalized with and without a respiratory virus. We found that RSV (incidence rate ratio [IRR]: 1.68, 95% confidence interval [CI]: 1.61-1.74, p < .001), hMPV (IRR: 1.82, 95% CI: 1.71-1.93, p < .001), and PIV (IRR: 1.81, 95% CI: 1.68-1.94, p < .001) were independently associated with severe respiratory disease, even after adjustment. Additionally, we found the presence of a respiratory virus prolonged hospitalizations by (0.79 ± 0.27 days, p < .003) for RSV, (0.88 ± 0.28 days, p < .002) for hMPV, and (1.43 ± 0.30 days, p < .001) for PIV. RSV, hMPV, and PIV have a significant burden on hospitalized adults, even without classic risk factors.

Updates on respiratory syncytial virus prophylaxis: the past, present and future.

Human respiratory syncytial virus (RSV) causes acute respiratory infection in individuals of all age groups. It is the most common pathogen identified in infants and young children with acute lower respiratory infection. Although most infants and young children experience mild, cold-like symptoms, some infants develop severe lower respiratory tract disease such as pneumonia and bronchiolitis that may result in an emergency department visit or hospitalization. In the United States, hospitalization rates have risen during the last decades, and while premature infants with chronic lung disease and congenital heart disease are at increased risk for severe presentations, the majority of hospitalizations occur in previously healthy infants. Until recently, RSV prophylaxis was only available for former preterm infants and those with certain underlying medical conditions. The need for preventive interventions against RSV is crucial. This paper will provide a review of the vaccine development, the spectrum of RSV prophylaxis, current challenges associated with the cost, insurance coverage and equitable distribution of targeted therapies.

Educational technology for the use of palivizumab in preventing respiratory syncytial virus infection

The only medication available for preventing severe lower respiratory tract disease caused by respiratory syncytial virus in pediatric patients at high risk is Palivizumab, a humanized monoclonal antibody of immunoglobulin G subclass 1 (IgG1). The objective of this work was to validate an educational technology for the use of Palivizumab in preventing respiratory syncytial virus infections. This is methodological research that includes four stages: literature review, construction of a flowchart for healthcare professionals, preparation of an educational booklet for parents and/or caregivers, and validation of the educational booklet by judges of content and appearance. For the construction of the booklet, an integrative literature review was initially conducted to identify and understand all aspects related to the topic. This review aimed to identify and incorporate important studies that provide a relevant contribution to building a solid theoretical foundation to guide the research. A total of 57 studies were included. The educational booklet, "For those who will take care of me with Palivizumab," was constructed and validated for content and appearance by nurses (teachers and assistance). The validation process was based on the responses from the judges of content and appearance. A global Content Validation Index of 0.92 was obtained. As for appearance, the Suitability Assessment of Materials instrument was used, resulting in an overall average score of 7.91. After incorporating the judges' suggestions, the educational material was adjusted to meet the needs and expectations it aims to fulfill. Subsequently, the educational material was sent for proofreading and printing, and once ready, it will be made available to the hospital. The booklet empowers parents and/or caregivers in the prevention and health promotion of children who will use Palivizumab, while the flowchart guides healthcare professionals attending to this population.

CpG ODN enhances the efficacy of F protein vaccine against respiratory syncytial virus infection in the upper respiratory tract via CD4+ T cells

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory illness worldwide, particularly in infants and older adults. Vaccines targeting the fusion glycoprotein (F protein) —one of the surface antigens of RSV— are highly effective in preventing RSV-associated severe lower respiratory tract disease. However, the efficacy of these vaccines against upper respiratory tract challenge needs improvement. Here, we aimed to examine the efficacy of F protein vaccines with or without CpG oligodeoxynucleotide (CpG ODN) as an adjuvant in the upper and lower respiratory tracts in mice. F + CpG ODN induced higher levels of F-specific IgG than that induced by F alone; however, levels of neutralizing antibodies did not increase compared to those induced by F alone. F + CpG ODN induced T helper 1 (Th1) cells while F alone induced T helper 2 (Th2) cells. Moreover, F + CpG ODN improved the protection against RSV challenge in the upper respiratory tract compared to F alone, which was largely dependent on CD4+ T cells. Meanwhile, both F + CpG ODN and F alone protected the lower respiratory tract. In conclusion, we demonstrated that induction of F-specific Th1 cells is an effective strategy to prevent RSV challenge in the upper respiratory tract in F protein vaccines. These data support the development of novel F protein vaccines.

Respiratory syncytial virus-induced disease in healthy infants: we need to offload this burden.

In the slipstream of the extraordinary, worldwide natural experiment reducing close human contact to mitigate the spread of SARS-CoV-2, a drastically but temporarily diminished transmission of respiratory syncytial virus (RSV) in children occurred in the winter of 2020–21.1 This glimpse of a world without RSV gained momentum for the urgent need for preventive strategies for this prototypical paediatric pathogen, which causes a spectrum of mild upper-respiratory to severe lower-respiratory tract disease in young children.

Virus-like Particle Vaccine Expressing the Respiratory Syncytial Virus Pre-Fusion and G Proteins Confers Protection against RSV Challenge Infection.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in children and the elderly. However, there are no effective antiviral drugs or licensed vaccines available for RSV infection. Here, RSV virus-like particle (VLP) vaccines expressing Pre-F, G, or Pre-F and G proteins on the surface of influenza virus matrix protein 1 (M1) were produced using the baculovirus expression system, and their protective efficacy was evaluated in mice. The morphology and successful assembly of VLPs were confirmed by transmission electron microscope (TEM) and Western blot. High levels of serum IgG antibody response were detected in VLP-immunized mice, and significantly higher levels of IgG2a and IgG2b were found in the Pre-F+G VLP immunization group compared to the unimmunized control. Serum-neutralizing activity was higher in the VLP immunization groups compared to the naïve group, with Pre-F+G VLPs demonstrating superior neutralizing activity to the single antigen-expressing VLP groups. Pulmonary IgA and IgG responses were generally comparable across the immunization groups, with VLPs expressing the Pre-F antigen eliciting higher IFN-γ in spleens. The frequencies of eosinophils and IL-4-producing CD4+ T cell populations were substantially lower in the lungs of VLP-immunized mice, with the PreF+G vaccine inducing a significant increase in CD4+ and CD8+ T cells. VLP immunization significantly decreased the viral titer and inflammation in the lungs of mice, with Pre-F+G VLPs conferring the best protection. In conclusion, our present study suggests that the Pre-F+G VLPs could be a potential vaccine candidate against RSV infection.

Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults

BackgroundRespiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection.MethodsIn an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein–based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated.ResultsA total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR–confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups.ConclusionsA single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.)

Mouse models susceptible to HCoV-229E and HCoV-NL63 and cross protection from challenge with SARS-CoV-2

Human coronavirus 229E (HCoV-229E) and NL63 (HCoV-NL63) are endemic causes of upper respiratory infections such as the "common cold" but may occasionally cause severe lower respiratory tract disease in the elderly and immunocompromised patients. There are no approved antiviral drugs or vaccines for these common cold coronaviruses (CCCoV). The recent emergence of COVID-19 and the possible cross-reactive antibody and T cell responses between these CCCoV and SARS-CoV-2 emphasize the need to develop experimental animal models for CCCoV. Mice are an ideal experimental animal model for such studies, but are resistant to HCoV-229E and HCoV-NL63 infections. Here, we generated 229E and NL63 mouse models by exogenous delivery of their receptors, human hAPN and hACE2 using replication-deficient adenoviruses (Ad5-hAPN and Ad5-hACE2), respectively. Ad5-hAPN- and Ad5-hACE2-sensitized IFNAR-/- and STAT1-/- mice developed pneumonia characterized by inflammatory cell infiltration with virus clearance occurring 7 d post infection. Ad5-hAPN- and Ad5-hACE2-sensitized mice generated virus-specific T cells and neutralizing antibodies after 229E or NL63 infection, respectively. Remdesivir and a vaccine candidate targeting spike protein of 229E and NL63 accelerated viral clearance of virus in these mice. 229E- and NL63-infected mice were partially protected from SARS-CoV-2 infection, likely mediated by cross-reactive T cell responses. Ad5-hAPN- and Ad5-hACE2-transduced mice are useful for studying pathogenesis and immune responses induced by HCoV-229E and HCoV-NL63 infections and for validation of broadly protective vaccines, antibodies, and therapeutics against human respiratory coronaviruses including SARS-CoV-2.

Prevention and Treatment Strategies for Respiratory Syncytial Virus (RSV)

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease, especially in young children. Despite its global impact on healthcare, related to its high prevalence and its association with significant morbidity, the current therapy is still mostly supportive. Moreover, while more than 50 years have passed since the first trial of an RSV vaccine (which unfortunately caused enhanced RSV disease), no vaccine has been approved for RSV prevention. In the last two decades, our understanding of the pathogenesis and immunopathology of RSV have continued to evolve, leading to significant advancements in RSV prevention strategies. These include both the development of new potential vaccines and the successful implementation of passive immunization, which, together, will provide coverage from infancy to old age. In this review, we provide an update of the current treatment options for acute disease (RSV-specific and -non-specific) and different therapeutic approaches focusing on RSV prevention.

Effects of neutrophil extracellular traps during human respiratory syncytial virus infection in vitro.

The human respiratory syncytial virus (hRSV) is the most common cause of severe lower respiratory tract diseases in young children worldwide, leading to a high number of hospitalizations and significant expenditures for health systems. Neutrophils are massively recruited to the lung tissue of patients with acute respiratory diseases. At the infection site, they release neutrophil extracellular traps (NETs) that can capture and/or inactivate different types of microorganisms, including viruses. Evidence has shown that the accumulation of NETs results in direct cytotoxic effects on endothelial and epithelial cells. Neutrophils stimulated by the hRSV-F protein generate NETs that are able to capture hRSV particles, thus reducing their transmission. However, the massive production of NETs obstructs the airways and increases disease severity. Therefore, further knowledge about the effects of NETs during hRSV infections is essential for the development of new specific and effective treatments. This study evaluated the effects of NETs on the previous or posterior contact with hRSV-infected Hep-2 cells. Hep-2 cells were infected with different hRSV multiplicity of infection (MOI 0.5 or 1.0), either before or after incubation with NETs (0.5-16 μg/mL). Infected and untreated cells showed decreased cellular viability and intense staining with trypan blue, which was accompanied by the formation of many large syncytia. Previous contact between NETs and cells did not result in a protective effect. Cells in monolayers showed a reduced number and area of syncytia, but cell death was similar in infected and non-treated cells. The addition of NETs to infected tissues maintained a similar virus-induced cell death rate and an increased syncytial area, indicating cytotoxic and deleterious damages. Our results corroborate previously reported findings that NETs contribute to the immunopathology developed by patients infected with hRSV.

An intranasal recombinant NDV-BRSV Fopt vaccine is safe and reduces lesion severity in a colostrum-deprived calf model of RSV infection

Human respiratory syncytial virus (HRSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, yet no safe, effective vaccine is commercially available. Closely related bovine RSV (BRSV) causes respiratory disease in young calves, with many similar features to those seen in HRSV. We previously showed that a Newcastle disease virus (NDV)-vectored vaccine expressing the F glycoprotein of HRSV reduced viral loads in lungs of mice and cotton rats and protected from HRSV. However, clinical signs and pathogenesis of disease in laboratory animals following HRSV infection differs from that observed in human infants. Thus, we examined whether a similar vaccine would protect neonatal calves from BRSV infection. Codon-optimized rNDV vaccine (rNDV-BRSV Fopt) was constructed and administered to colostrum-deprived calves. The rNDV-BRSV Fopt vaccine was well-tolerated and there was no evidence of vaccine-enhanced disease in the upper airways or lungs of these calves compared to the non-vaccinated calves. We found two intranasal doses reduces severity of gross and microscopic lesions and decreases viral load in the lungs. Furthermore, serum neutralizing antibodies were generated in vaccinated calves. Finally, reduced lung CXC chemokine levels were observed in vaccinated calves after BRSV challenge. In summary, we have shown that rNDV-BRSV Fopt vaccine is safe in colostrum-deprived calves, and is effective in reducing lung lesions, and decreasing viral load in upper respiratory tract and lungs after challenge.

LB748. Efficacy And Safety Of Bivalent Respiratory Syncytial Virus (RSVpreF) Vaccine In Older Adults

Abstract Background Respiratory syncytial virus (RSV) is an important cause of disease in older adults and is associated with high morbidity and mortality, especially in those with high-risk conditions. Illness can vary from mild upper respiratory tract symptoms to more severe lower respiratory tract disease. After over 50 years of research, there is now hope for an RSV vaccine for any population, including older adults. An investigational bivalent RSV A and B, stabilized RSV prefusion F subunit vaccine (RSVpreF) was assessed successfully in a pivotal phase 3 efficacy study in older adults. (NCT05035212). Methods The primary efficacy objective of this Phase 3, global, multicenter, randomized, double-blinded, placebo-controlled study was to evaluate the prevention of RSV associated lower respiratory tract illness (LRTI-RSV) in up to 40,000 adults ≥60 years of age during the first winter season (September 2021-June 2022). Two primary endpoints were tested sequentially – LRTI-RSV with ≥2 and ≥3 symptoms. A pre-planned efficacy interim analysis (IA) was to be conducted by an external Data Monitoring Committee (DMC) upon accrual of at least 29 cases of LRTI-RSV with ≥2 symptoms. With efficacy demonstrated for cases with ≥2 symptoms and sufficient cases with ≥ 3 symptoms accrued, an efficacy analysis of cases with ≥ 3 symptoms was to be conducted. The ongoing study is collecting additional safety and descriptive efficacy data. Results At the time of the IA, approximately 34,000 participants received either RSVpreF 120 µg (60 µg each of RSVpreF from RSV A and RSV B) or placebo (1:1 randomization). Forty-four LRTI-RSV cases with ≥2 symptoms were accrued with 11 cases in the RSVpreF group and 33 cases in the placebo group corresponding to a VE of 66.7% (96.66% CI: 28.8%, 85.8%). Sixteen LRTI-RSV cases with ≥3 symptoms were accrued with 2 cases in the RSVpreF group and 14 cases in the placebo group corresponding to a VE of 85.7% (96.66% CI: 32.0%, 98.7%). The investigational vaccine was well-tolerated with no safety concerns. Conclusion Despite unpredictable RSV activity due to the COVID-19 pandemic, the primary objective of the study was met demonstrating that RSVpreF had a favorable safety profile and was highly efficacious in preventing LRTI-RSV with ≥2 symptoms and ≥3 symptoms in older adults 60 years and older. Disclosures Edward E. Walsh, MD, Janssen: Honoraria|Merck: Grant/Research Support|Pfizer: Grant/Research Support Fernando Polack, MD, I-trials: Ownership Interest|Pfizer: Grant/Research Support Agnieszka Zareba, MD PhD, Pfizer: employee of Pfizer Ann R. Falsey, MD, BioFire Diagnostics: Grant/Research Support|Janssen: Grant/Research Support|Merck Sharp &amp; Dohme: Grant/Research Support|Novavax: Advisor/Consultant|Pfizer: Grant/Research Support Gonzalo Perez Marc, MD, I-trials: Board Member|I-trials: Ownership Interest|Pfizer: Grant/Research Support Qin Jiang, PhD, Pfizer: employee of Pfizer Kathy Schneider, PhD, Pfizer: employee of Pfizer David Cooper, PhD, Pfizer: employee of Pfizer Maria Maddalena Lino, PhD, Pfizer: employee of Pfizer Annaliesa S. Anderson, PhD, Pfizer: employee of Pfizer|Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Katherin U Jensen, PhD, Pfizer: employee of Pfizer Kena A. Swanson, Ph.D., Pfizer: employee of Pfizer Alejandra C. Gurtman, M.D., Pfizer: employee of Pfizer William C. Gruber, MD, Pfizer Inc: Employee|Pfizer Inc: Stocks/Bonds Beate Schmoele-Thoma, MD, Pfizer: employee of Pfizer.

116. Potential Clinical Impact of Respiratory Syncytial Virus (RSV) Vaccination in Older Adults in the United States

Abstract Background RSV causes acute respiratory disease (ARD), including severe lower respiratory tract disease (LRTD) in older adults, which can lead to hospitalization and death. Currently, there are no vaccines approved to prevent RSV disease. This study estimated the potential clinical impact of a hypothetical RSV vaccine over a 1-year time horizon in older adults aged ≥ 60 years. Methods A decision-analytic model was developed (Figure 1). A strategy was used where the entire US population aged ≥ 60 years was given a single dose vaccine with an assumed efficacy of 75% against ARD, LRTD, and LRTD-hospitalizations and compared to a population who did not receive a vaccine. Given the uncertainty around RSV hospitalization rates, 2 base-case scenarios were created: (1) hospitalization rates that used RSV-specific claim codes and (2) hospitalization rates increased by 49% to account for underreporting in claims; Table 1 shows key inputs. One-way sensitivity analyses were used to assess the impact of specific parameter estimates. Results The vaccine would prevent 1.8 million and 0.6 million upper respiratory disease and LRTD cases, respectively; Figure 2 shows additional results for both base-case scenarios. The number needed to vaccinate (NNV) to prevent 1 LRTD case is 119; the NNV to prevent 1 LRTD hospitalization or death ranges from 792 to 1180 and 10,452 to 15,574, respectively. Sensitivity analyses indicate that results mainly depend on vaccine efficacy, and incidence of ARD and LRTD. Conclusion There is substantial US public health benefit associated with utilization of an effective RSV vaccine in individuals ≥ 60 years of age to reduce RSV-associated morbidity and mortality; however, the magnitude of impact depends on RSV epidemiology, which is still being defined for older adults. Several model parameters were based on assumptions, and robust evidence generation is needed including the efficacy of an RSV vaccine, which is an important consideration in assessing the impact of vaccination in this age group. Disclosures Kelly Fust, MS, Quadrant Health Economics Inc: Contractor at Quadrant Health Economics Inc who was funded by Moderna to perform this study Michele Kohli, PhD, Quadrant Health Economics Inc: Shareholder at Quadrant Health Economics Inc who was funded by Moderna to perform this study|Quadrant Health Economics Inc: Stocks/Bonds Catherine A. Panozzo, PhD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Philip Buck, PhD, MPH, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds Parinaz Ghaswalla, PhD, Moderna, Inc.: Salary|Moderna, Inc.: Stocks/Bonds.

EE338 The Potential Benefit of Respiratory Syncytial Virus (RSV) Vaccination in Older Adults: A Comparison of the United States (US) and United Kingdom (UK)

RSV causes acute respiratory disease (ARD), including severe lower respiratory tract disease (LRTD), which can result in hospitalization and death. The study objective was to compare the potential benefit of a hypothetical RSV vaccination strategy in US versus UK older adults.

An Overview of Respiratory Syncytial Virus Vaccine Development

Respiratory viral diseases constitute significant global health burdens, bringing about a huge number of hospitalizations every year. Respiratory Syncytial Virus (RSV) is the main cause of severe lower respiratory tract diseases in under-five children and adults above 65 years of age. RSV associated infection can present with symptoms similar to that of the common cold and in severe cases, can present as pneumonia or bronchitis, while in complicated cases, they may lead to extrapulmonary consequences in the brain and other tissues and organs RSV causes a respiratory tract infection that affects 64 million people per year worldwide. It hospitalizes 3 million children under 5 years old and approximately 336,000 older adults annually. Vaccination could signicantly relieve the burden of RSV disease. There are no authorized vaccines to forestall RSV diseases, and the main prophylaxis at present is the monoclonal antibody palivizumab. However, its use is restricted to high-risk individuals, it is also very expensive and moderately effective, and hence the need to explore other vaccine options that will be more effective, safe, and affordable and therapeutics for infants and high-risk populations like health care workers. Anatomic understanding of antigenicity is a critical step in the pathway towards the development of a structure-based vaccine; a supersite specific strategy will be advantageous as we can focus on the target with utmost accuracy hence the aim of this review.

Immunization with a mucosal, post-fusion F/G protein-based polyanhydride nanovaccine protects against BRSV infection in neonatal calves

Abstract Human respiratory syncytial virus (HRSV) is a leading cause of severe acute lower respiratory tract (LRT) disease in young children worldwide. Currently, there is no approved vaccine for HRSV. Bovine RSV (BRSV) is closely related to HRSV and is the cause of severe acute LRT disease in young cattle. A neonatal calf model presents an opportunity to test HRSV vaccines and study a naturally susceptible host-pathogen interaction similar to HRSV infection. We tested the efficacy of a polyanhydride nanoparticle-vaccine (nanovaccine) encapsulating the post-fusion F and G proteins from BRSV and CpG adjuvant in neonatal calves with maternally-derived antibodies (MDA). A prime-boost immunization of neonatal calves with the BRSV post-fusion F/G CpG nanovaccine induced clinical protection in the presence of MDA. Vaccinated calves developed moderate or no clinical symptoms and were mostly protected from virus-associated lung pathology compared to unvaccinated controls. Calves that received a mucosal/systemic nanovaccine immunization had complete virological protection against BRSV infection in the lungs, which correlated with BRSV-specific immune responses in the bronchoalveolar lavage. Vaccination with the nanovaccine induced anamnestic BRSV-specific IgA titers in the lungs and systemic T cell responses with BRSV-specific CD4+ T cell proliferation and antigen-specific IL-17 and IFNγ secretion. Overall, the BRSV post-fusion F/G CpG nanovaccine is a promising candidate for further studies to protect neonatal calves and infants from RSV infection.

RSV inhibits myeloid cell recruitment during S. aureus coinfection

Abstract Respiratory syncytial virus (RSV) infects almost all humans by the age of 2. RSV more often causes severe lower respiratory tract disease in younger children and older adults, which may be exacerbated by increased susceptibility to secondary bacterial infection (coinfection). Like influenza, it is thought that RSV may predispose the lung to opportunistic infections with strains of bacteria normally present as colonizers of the nasopharynx, predominantly Staphylococcus aureus and Streptococcus pneumoniae. While there has been significant investigation into mechanisms of RSV/bacterial coinfection, models that faithfully replicate the pathology of human RSV infection have not been fully explored. To examine this aspect, we infected mice with a strain of RSV (rA2-line 19F, 2×105 PFU) that induces significant IL-13, mucus, and airway hyperresponsiveness. We found that RSV infection six days prior to S. aureus infection (5×107 CFU) reduces bacterial clearance. Flow cytometry data suggest that RSV infection alters cellular recruitment in response to S. aureus, largely by reducing neutrophils and monocytes. Surprisingly, we saw increased levels of the monocyte chemokine CCL2, suggesting compensatory chemokine production in response to dampened cellular recruitment. Additionally, we observed no change in several cytokines that exacerbate inflammation during influenza/S. aureus coinfection, including IL-1β, IL-6, and TNFα. Together, these data suggest a markedly different mechanism of increased susceptibility to bacterial infection during RSV, characterized by reduced--rather than overexuberant--myeloid cell recruitment. Supported by grants from NIH (R35HL144481 to Beth Moore, T32HL007517 to Helen Rich) and the Michigan Postdoctoral Pioneer Program at the University of Michigan Medical School.