Conjugation of Mannans to Enhance the Potency of Liposome Nanoparticles for the Delivery of RNA Vaccines

Recent approval of mRNA vaccines to combat COVID-19 have highlighted the potential of this platform. Lipid nanoparticles (LNP) is the delivery vehicle of choice for mRNA as they prevent its enzymatic degradation by encapsulation. We have recently shown that surface exposition of mannose, incorporated in LNPs as stable cholesterol-amine conjugate, enhances the potency of self-amplifying RNA (SAM) replicon vaccines through augmented uptake by antigen presenting cells (APCs). Here, we generated a new set of LNPs whose surface was modified with mannans of different length (from mono to tetrasaccharide), in order to study the effect on antibody response of model SAM replicon encoding for the respiratory syncytial virus fusion F protein. Furthermore, the impact of the mannosylated liposomal delivery through intradermal as well as intramuscular routes was investigated. The vaccine priming response showed to improve consistently with increase in the chain length of mannoses; however, the booster dose response plateaued above the length of disaccharide. An increase in levels of IgG1 and IgG2a was observed for mannnosylated lipid nanoparticles (MLNPs) as compared to LNPs. This work confirms the potential of mannosylated SAM LNPs for both intramuscular and intradermal delivery, and highlights a disaccharide length as sufficient to ensure improved immunogenicity compared to the un-glycosylated delivery system.

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1719. Respiratory Syncytial Virus-Associated Hospitalization Rates among US Infants: A Systematic Review and Meta-Analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1897 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S843-S843

Author(s):

John M McLaughlin ◽

Farid L Khan ◽

Heinz-Josef Schmitt ◽

Yasmeen Agosti ◽

Luis Jodar ◽

...

Keyword(s):

Public Health ◽

Respiratory Syncytial Virus ◽

Active Surveillance ◽

Meta Analysis ◽

The United States ◽

Administrative Claims ◽

Prevention Strategies ◽

Hospitalization Rates ◽

Syncytial Virus ◽

The Impact

Abstract Background Understanding the true magnitude of infant respiratory syncytial virus (RSV) burden is critical for determining the potential public-health benefit of RSV prevention strategies. Although global reviews of infant RSV burden exist, none have summarized data from the United States or evaluated how RSV burden estimates are influenced by variations in study design. Methods We performed a systematic literature review and meta-analysis of studies describing RSV-associated hospitalization rates among US infants. We also examined the impact of key study characteristics on these estimates. Results After review of 3058 articles through January 2020, we identified 25 studies with 31 unique estimates of RSV-associated hospitalization rates. Among US infants < 1 year of age, annual rates ranged from 8.4 to 40.8 per 1000 with a pooled rate= 19.4 (95%CI= 17.9–20.9). Study type was associated with RSV hospitalization rates (P =.003), with active surveillance studies having pooled rates per 1000 (11.1; 95%CI: 9.8–12.3) that were half that of studies based on administrative claims (21.4; 95%CI: 19.5–23.3) or modeling approaches (23.2; 95%CI: 20.2–26.2). Conclusion Applying the pooled rates identified in our review to the 2020 US birth cohort suggests that 73,680 to 86,020 RSV-associated infant hospitalizations occur each year. To date, public-health officials have used conservative estimates from active surveillance as the basis for defining US infant RSV burden. The full range of RSV-associated hospitalization rates identified in our review better characterizes the true RSV burden in infants and can better inform future evaluations of RSV prevention strategies. Disclosures John M. McLaughlin, PhD, Pfizer (Employee, Shareholder) Farid L. Khan, MPH, Pfizer (Employee, Shareholder) Heinz-Josef Schmitt, MD, Pfizer (Employee, Shareholder) Yasmeen Agosti, MD, Pfizer (Employee, Shareholder) Luis Jodar, PhD, Pfizer (Employee, Shareholder) Eric Simões, MD, Pfizer (Consultant, Research Grant or Support) David L. Swerdlow, MD, Pfizer (Employee, Shareholder)

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Determining the Seasonality of Respiratory Syncytial Virus in the United States: The Impact of Increased Molecular Testing

The Journal of Infectious Diseases ◽

10.1093/infdis/jix275 ◽

2017 ◽

Vol 216 (3) ◽

pp. 345-355 ◽

Cited By ~ 22

Author(s):

Claire M Midgley ◽

Amber K Haynes ◽

Jason L Baumgardner ◽

Christina Chommanard ◽

Sara W Demas ◽

...

Keyword(s):

United States ◽

Respiratory Syncytial Virus ◽

The United States ◽

Molecular Testing ◽

Syncytial Virus ◽

The Impact

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Construction and characterization of recombinant vaccinia viruses co-expressing a respiratory syncytial virus protein and a cytokine

Journal of General Virology ◽

10.1099/0022-1317-82-9-2107 ◽

2001 ◽

Vol 82 (9) ◽

pp. 2107-2116 ◽

Cited By ~ 20

Author(s):

Teresa R. Johnson ◽

Julie E. Fischer ◽

Barney S. Graham

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Vaccinia Virus ◽

Antigen Expression ◽

Virus Protein ◽

Recombinant Vaccinia ◽

Vaccinia Viruses ◽

Ifn Γ ◽

Syncytial Virus ◽

The Impact

Recombinant vaccinia viruses are well-characterized tools that can be used to define novel approaches to vaccine formulation and delivery. While vector co-expression of immune mediators has enormous potential for optimizing the composition of vaccine-induced immune responses, the impact on antigen expression and vector antigenicity must also be considered. Co-expression of IL-4 increased vaccinia virus vector titres, while IFN-γ co-expression reduced vaccinia virus replication in BALB/c mice and in C57BL/6 mice infected with some recombinant viruses. Protection against respiratory syncytial virus (RSV) challenge was similar in mice immunized with vaccinia virus expressing RSV G glycoprotein and IFN-γ, even though the replication efficiency of the vector was diminished. These data demonstrate the ability of vector-expressed cytokine to influence the virulence of the vector and to direct the development of selected immune responses. This suggests that the co-expression of cytokines and other immunomodulators has the potential to improve the safety of vaccine vectors while improving the immunogenicity of vaccine antigens.

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Disability-adjusted Life Years for respiratory syncytial virus in children under 2 years

10.21203/rs.3.rs-20260/v3 ◽

2020 ◽

Author(s):

jefferson buendia ◽

Fernando Polack ◽

Juana Patricia Sanchez Villamil

Keyword(s):

Respiratory Syncytial Virus ◽

Statistical Parameter ◽

Epidemiological Surveillance ◽

Years Of Life Lost ◽

Disability Adjusted Life Years ◽

Disability Adjusted Life ◽

Life Years ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Abstract BACKGROUND: Respiratory syncytial virus infection is the leading cause of bronchiolitis in Colombia. There is growing evidence about the impact of Respiratory syncytial virus on society in terms of years of life lost due to this condition. The objective of the present study is to determine the Disability-Adjusted Life Years for respiratory syncytial virus in children under 2 years in ColombiaMETHODS: Data from the national epidemiological surveillance system were used to estimate DALYs, calculated from the sum of years of life lost and years lived with disability due to RSV infection in Colombia. A bootstrapped method with 10000 iterations was used to estimate each statistical parameter using the package DALY calculator in R. RESULTS: In 2019, 260 873 years of life (CI95% 208 180- 347 023) were lost due to RSV bronchiolitis in Colombian children under 2 years. The estimated rate was 20 DALYs / 1000 person-year (95% CI 16 – 27).CONCLUSION: This is the first report estimating the impact of RSV bronchiolitis morbidity and mortality in Colombia. The findings of the present study suggest that the actual burden and cost of bronchiolitis due to RSV is high. Prevention strategies, such as RSV vaccination, to reduce morbidity associated with RSV infection should be encouraged in our country.

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Estimated Burden of Community-Onset Respiratory Syncytial Virus–Associated Hospitalizations Among Children Aged <2 Years in the United States, 2014–15

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piz087 ◽

2019 ◽

Vol 9 (5) ◽

pp. 587-595 ◽

Cited By ~ 5

Author(s):

Carmen S Arriola ◽

Lindsay Kim ◽

Gayle Langley ◽

Evan J Anderson ◽

Kyle Openo ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Census Data ◽

The United States ◽

Surveillance Network ◽

Detection Probabilities ◽

Syncytial Virus ◽

Us Children ◽

Us Census ◽

The Impact ◽

Community Onset

Abstract Background Respiratory syncytial virus (RSV) is a major cause of hospitalizations in young children. We estimated the burden of community-onset RSV-associated hospitalizations among US children aged <2 years by extrapolating rates of RSV-confirmed hospitalizations in 4 surveillance states and using probabilistic multipliers to adjust for ascertainment biases. Methods From October 2014 through April 2015, clinician-ordered RSV tests identified laboratory-confirmed RSV hospitalizations among children aged <2 years at 4 influenza hospitalization surveillance network sites. Surveillance populations were used to estimate age-specific rates of RSV-associated hospitalization, after adjusting for detection probabilities. We extrapolated these rates using US census data. Results We identified 1554 RSV-associated hospitalizations in children aged <2 years. Of these, 27% were admitted to an intensive care unit, 6% needed mechanical ventilation, and 5 died. Most cases (1047/1554; 67%) had no underlying condition. Adjusted age-specific RSV hospitalization rates per 100 000 population were 1970 (95% confidence interval [CI],1787 to 2177), 897 (95% CI, 761 to 1073), 531 (95% CI, 459 to 624), and 358 (95% CI, 317 to 405) for ages 0–2, 3–5, 6–11, and 12–23 months, respectively. Extrapolating to the US population, an estimated 49 509–59 867 community-onset RSV-associated hospitalizations among children aged <2 years occurred during the 2014–2015 season. Conclusions Our findings highlight the importance of RSV as a cause of hospitalization, especially among children aged <2 months. Our approach to estimating RSV-related hospitalizations could be used to provide a US baseline for assessing the impact of future interventions.

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Modelling the household-level impact of a maternal respiratory syncytial virus (RSV) vaccine in a high-income setting

BMC Medicine ◽

10.1186/s12916-020-01783-8 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Patricia T. Campbell ◽

Nicholas Geard ◽

Alexandra B. Hogan

Keyword(s):

Respiratory Syncytial Virus ◽

Vaccine Trial ◽

Population Level ◽

High Income ◽

Demographic Model ◽

Model Framework ◽

Substantial Impact ◽

Rsv Infection ◽

Syncytial Virus ◽

The Impact

Abstract Background Respiratory syncytial virus (RSV) infects almost all children by the age of 2 years, with the risk of hospitalisation highest in the first 6 months of life. Development and licensure of a vaccine to prevent severe RSV illness in infants is a public health priority. A recent phase 3 clinical trial estimated the efficacy of maternal vaccination at 39% over the first 90 days of life. Households play a key role in RSV transmission; however, few estimates of population-level RSV vaccine impact account for household structure. Methods We simulated RSV transmission within a stochastic, individual-based model framework, using an existing demographic model, structured by age and household and parameterised with Australian data, as an exemplar of a high-income country. We modelled vaccination by immunising pregnant women and explicitly linked the immune status of each mother-infant pair. We quantified the impact on children for a range of vaccine properties and uptake levels. Results We found that a maternal immunisation strategy would have the most substantial impact in infants younger than 3 months, reducing RSV infection incidence in this age group by 16.6% at 70% vaccination coverage. In children aged 3–6 months, RSV infection was reduced by 5.3%. Over the first 6 months of life, the incidence rate for infants born to unvaccinated mothers was 1.26 times that of infants born to vaccinated mothers. The impact in older age groups was more modest, with evidence of infections being delayed to the second year of life. Conclusions Our findings show that while individual benefit from maternal RSV vaccination could be substantial, population-level reductions may be more modest. Vaccination impact was sensitive to the extent that vaccination prevented infection, highlighting the need for more vaccine trial data.

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