Value profile for respiratory syncytial virus vaccines and monoclonal antibodies.

Respiratory syncytial virus (RSV) is the predominant cause of acute lower respiratory infection (ALRI) in young children worldwide, yet no licensed RSV vaccine exists to help prevent the millions of illnesses and hospitalizations and tens of thousands of young lives taken each year. Monoclonal antibody (mAb) prophylaxis exists for prevention of RSV in a small subset of very high-risk infants and young children, but the only currently licensed product is impractical, requiring multiple doses and expensive for the low-income settings where the RSV disease burden is greatest. A robust candidate pipeline exists to one day prevent RSV disease in infant and pediatric populations, and it focuses on two promising passive immunization approaches appropriate for low-income contexts: maternal RSV vaccines and long-acting infant mAbs. Licensure of one or more candidates is feasible over the next one to three years and, depending on final product characteristics, current economic models suggest both approaches are likely to be cost-effective. Strong coordination between maternal and child health programs and the Expanded Program on Immunization will be needed for effective, efficient, and equitable delivery of either intervention. This 'Vaccine Value Profile' (VVP) for RSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations, and in collaboration with stakeholders from the WHO headquarters. All contributors have extensive expertise on various elements of the RSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Safety, tolerability, and immunogenicity of inactivated poliovirus vaccine with or without E.coli double mutant heat-labile toxin (dmLT) adjuvant in healthy adults; a phase 1 randomized study.

BACKGROUND: Inactivated trivalent poliovirus vaccine (IPV) induces humoral immunity, which protects against paralytic poliomyelitis but does not induce sufficient mucosal immunity to block intestinal infection. We assessed the intestinal immunity in healthy adults in Belgium conferred by a co-formulation of IPV with the mucosal adjuvant double mutant Labile Toxin (dmLT) derived from Escherichia coli. METHODS: Healthy fully IPV-vaccinated 18-45-year-olds were randomly allocated to three groups: on Day 1 two groups received one full dose of IPV (n = 30) or IPV + dmLT (n = 30) in a blinded manner, and the third received an open-label dose of bivalent live oral polio vaccine (bOPV types 1 and 3, n = 20). All groups received a challenge dose of bOPV on Day 29. Participants reported solicited and unsolicited adverse events (AE) using study diaries. Mucosal immune responses were measured by fecal neutralization and IgA on Days 29 and 43, with fecal shedding of challenge viruses measured for 28 days. Humoral responses were measured by serum neutralizing antibody (NAb). RESULTS: Solicited and unsolicited AEs were mainly mild-to-moderate and transient in all groups, with no meaningful differences in rates between groups. Fecal shedding of challenge viruses in both IPV groups exceeded that of the bOPV group but was not different between IPV and IPV + dmLT groups. High serum NAb responses were observed in both IPV groups, alongside modest levels of fecal neutralization and IgA. CONCLUSIONS: Addition of dmLT to IPV administered intramuscularly neither affected humoral nor intestinal immunity nor decreased fecal virus shedding following bOPV challenge. The tolerability of the dose of dmLT used in this study may allow higher doses to be investigated for impact on mucosal immunity. Registered on ClinicalTrials.gov - NCT04232943.

Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.

RSV neutralization assays - Use in immune response assessment.

Respiratory syncytial virus (RSV) is a leading cause of respiratory illness among children and infants worldwide, yet no licensed vaccine exists to reduce the risk of disease. At least 16 RSV vaccine candidates are currently in clinical development and many are designed to induce robust virus neutralizing immune responses. RSV neutralizing antibody (nAb)-mediated interventions such as intravenous immunoglobulin (IVIG) and palivizumab provide passive protection against serious lower respiratory tract disease due to RSV, validating nAbs as a correlate of protection. To identify correlates of protection for vaccine candidates that have demonstrated their protective efficacy, an investigator can use assays designed to measure nAb responses. However, there is no standard method of measurement; individual laboratories have developed their own methods to measure the ability of nAbs to reduce the infectivity of a defined virus dose in a variety of cell lines, leading to establishment of the broad variety of RSV neutralization assay formats currently in use. Standardizing the RSV neutralization assay is an essential step toward better assessment of nAb responses to vaccine candidates. Use of a common reference standard by all makes comparing the immunogenicity of different vaccine candidates feasible. In the context of vaccine development, the WHO 1st International Standard for Antiserum to RSV (RSV IS) has been shown to be suitable for harmonizing results across laboratories and assay formats used to measure nAb titers to RSV/A and RSV/B in human sera. This review describes the broad variety of RSV virus neutralization assay formats currently in use and the importance of the RSV IS for harmonization of results across formats and across laboratories. It also outlines good practices for key assay components and data analysis to promote the quality and consistency of measuring RSV nAb titers in serum specimens.

Impact and cost-effectiveness of potential interventions against infant respiratory syncytial virus (RSV) in 131 low-income and middle-income countries using a static cohort model.

OBJECTIVES: Interventions to prevent childhood respiratory syncytial virus (RSV) disease are limited and costly. New interventions are in advanced stages of development and could be available soon. This study aims to evaluate the potential impact and cost-effectiveness of two interventions to prevent childhood RSV-a maternal vaccine and a monoclonal antibody (mAb). DESIGN: Using a static population-based cohort model, we evaluate impact and cost-effectiveness of RSV interventions, from a health systems perspective. The assumed baseline efficacy and duration of protection were higher for the mAb (60%-70% efficacy, protection 6 months) compared with the maternal vaccine (40%-60% efficacy, protection 3 months). Both interventions were evaluated at US$3 and US$5 per dose for Gavi and non-Gavi countries, respectively. A range of input values were considered to explore uncertainty. SETTINGS: 131 low-income and middle-income countries. PARTICIPANTS: Pregnant women and live birth cohorts. INTERVENTIONS: Maternal vaccine given to pregnant women and mAb given to young infants. PRIMARY AND SECONDARY OUTCOME MEASURES: Disability-adjusted life years averted, severe case averted, deaths averted, incremental cost effectiveness ratios. RESULTS: Under baseline assumptions, maternal vaccine and mAbs were projected to avert 25% and 55% of RSV-related deaths among infants younger than 6 months of age, respectively. The average incremental cost-effectiveness ratio per disability-adjusted life year averted was US$1342 (range US$800-US$1866) for maternal RSV vaccine and US$431 (range US$167-US$692) for mAbs. At a 50% gross domestic product per capita threshold, maternal vaccine and mAbs were cost-effective in 60 and 118 countries, respectively. CONCLUSIONS: Both interventions are projected to be impactful and cost-effective in many countries, a finding that would be enhanced if country-specific Gavi cofinancing to eligible countries were included. mAbs, with assumed higher efficacy and duration of protection, are expected to be more cost-effective than RSV maternal vaccines at similar prices. Final product characteristics will influence this finding.

Inferring antenatal care visit timing in low- and middle-income countries: Methods to inform potential maternal vaccine coverage.

BACKGROUND: The timing of antenatal care (ANC) visits directly affect health intervention coverage and impact, especially for those interventions requiring strict gestational age windows for administration, such as maternal respiratory syncytial virus (RSV) vaccine. Existing nationally representative population-based surveys do not record the timing of ANC visits beyond the first, limiting the availability of reliable data around timing of subsequent ANC visits in most low- and middle-income countries (LMICs). Here, we describe a model that estimates the timing of ANC visits by gestational age using publicly available multi-country survey data. METHODS AND FINDINGS: We used the Demographic and Health Surveys (DHS) data from 69 LMICs. We used several factors to estimate the timing of subsequent ANC visits by gestation age: the timing of the first ANC visit (ANC1) in a given pregnancy, derived from the DHS; the country's reported average ANC coverage at each ANC visit (ANC1 through the fourth ANC visit [ANC4]); and the World Health Organization's guidance on recommended ANC visit. We then used the timing of ANC visit by gestation age to predict the coverage of a potential maternal RSV vaccine administered at 24-36 weeks of gestation. We calculated the maternal immunization coverage by summing the number of eligible women vaccinated at any ANC visit divided by the total number of pregnant women. We find, in general, countries with higher ANC1 coverage were predicted to have higher vaccination coverage. In 82% of countries, the modeled vaccine coverage is less than ANC4 coverage. CONCLUSIONS: The methods illustrated in this paper have implications on the precision of estimating impact and programmatic feasibility of time-critical interventions, especially for pregnant women. The methods can be easily adapted to vaccine demand forecasts models, vaccine impact assessments, and cost-effectiveness analyses and can be adapted to other maternal interventions that have administration timing restrictions.

Tracking progress in universal influenza vaccine development.

Conventional influenza vaccines are designed to stimulate neutralizing antibodies against immunodominant but highly variable hemagglutinin antigens. Inherent limitations include suboptimal protection against rapidly changing seasonal influenza viruses and a lack of protection against antigenically novel pandemic influenza. New technologies for developing influenza vaccines that induce more broadly protective and durable immunity are a growing area of research and focus on a variety of approaches, including targeting conserved antigens and stimulating cross-reactive T cell responses. This review highlights a new effort to track the development of universal influenza vaccine technologies. The Universal Influenza Vaccine Technology Landscape is intended to provide stakeholders and funders with a common source of information to monitor research progress and identify opportunities for informed investments and collaboration.

Lessons learned from the Advancing Maternal Immunization collaboration: identifying evidence gaps for informed respiratory syncytial virus maternal immunization decision-making.

In an increasingly crowded vaccine landscape, global and country decision-makers will require evidence-based and disease-specific information when prioritizing new public health interventions. The Advancing Maternal Immunization collaboration (AMI) was designed to develop a cross-program strategy to advance respiratory syncytial virus (RSV) maternal immunization (MI) availability and accessibility in low- and middle-income countries by completing a comprehensive RSV MI gap analysis and developing an actionable roadmap report. By engaging and coordinating key stakeholders using a web-based communication platform and developing standardized tools, AMI was able to facilitate interaction and consensus between members. This paper describes the methodology used to create and manage AMI's work. We share lessons learned from our approach to inform other groups conducting similar work requiring cross-sectoral engagement. This approach could be adapted to efficiently conduct gap analyses for other health interventions that require input and coordination across a variety of topic areas, disciplines, geographies, and stakeholders.

The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates.

The global burden of disease caused by respiratory syncytial virus (RSV) is increasingly recognised, not only in infants, but also in older adults (aged ≥65 years). Advances in knowledge of the structural biology of the RSV surface fusion glycoprotein have revolutionised RSV vaccine development by providing a new target for preventive interventions. The RSV vaccine landscape has rapidly expanded to include 19 vaccine candidates and monoclonal antibodies (mAbs) in clinical trials, reflecting the urgency of reducing this global health problem and hence the prioritisation of RSV vaccine development. The candidates include mAbs and vaccines using four approaches: (1) particle-based, (2) live-attenuated or chimeric, (3) subunit, (4) vector-based. Late-phase RSV vaccine trial failures highlight gaps in knowledge regarding immunological protection and provide lessons for future development. In this Review, we highlight promising new approaches for RSV vaccine design and provide a comprehensive overview of RSV vaccine candidates and mAbs in clinical development to prevent one of the most common and severe infectious diseases in young children and older adults worldwide.

A multi-laboratory study of diverse RSV neutralization assays indicates feasibility for harmonization with an international standard.

A current barrier to the standardized evaluation of respiratory syncytial virus (RSV) vaccine candidates is the wide variety of virus neutralization assay formats currently in use for assessing immunogenicity. Assay formats vary widely in labor intensiveness, duration, and sample throughput. Furthermore, the cell lines and virus strains used are not consistent among formats. The purpose of this multi-laboratory study was to assess the variability across a diverse array of assay formats that quantitate RSV neutralizing antibodies. Using a common specimen panel, the degree of overall agreement among existing assays was evaluated to inform on the need for harmonization of assay results. A total of 12 laboratories participated in the blinded survey study by testing a panel comprised of 57 samples chosen to span the reportable titer range of the assays. An independent statistical analysis was conducted to measure overall agreement of assay results. This analysis showed that precision was consistently high, whereas agreement varied widely among assays. To examine whether agreement could be improved, we conducted a harmonization exercise using a variety of sample types as pseudo standards. The results showed that the level of agreement could be improved, and provided information on the suitability of samples for developing an international standard.

Advances in RSV vaccine research and development - A global agenda.

Respiratory syncytial virus (RSV) is an important cause of viral lower respiratory tract illness in infants and children globally, but no vaccine is currently available to protect these vulnerable populations. Live-attenuated vaccine approaches have been in development for decades, but achieving the appropriate balance between immunogenicity and safety has proven difficult. Immunoprophylaxis with the neutralizing monoclonal antibody palivizumab is limited to high-risk infants, but cost requirements for multiple dosing make its use impractical in low- and middle-income countries. A growing number of RSV vaccine candidates using a variety of technologies and targeting diverse populations has emerged in recent years. There are now 60 RSV vaccine candidates in development that target pediatric and elderly populations. While most are at a preclinical stage, 16 candidates are in clinical development. This review summarizes current RSV vaccine research and development, including an overview of the vaccine platforms being used, the development stage of individual vaccine candidates, and gaps to be addressed to facilitate use of these vaccines to meet global health needs.

The inability of tegaserod to affect platelet aggregation and coronary artery tone at supratherapeutic concentrations.

In 2007, the results from a meta analysis of 29 clinical studies indicated that tegaserod (Zelnorm®), a 5-hydroxytryptamine(4) (5-HT(4)) receptor agonist with gastrointestinal prokinetic activity, was associated with an increased incidence of cardiovascular ischemic events, resulting in its withdrawal from many markets around the world. Stimulation of platelet aggregation has been proposed to explain the phenomenon. However, data from recent epidemiological studies have suggested that there is no correlation between tegaserod use and the incidence of cardiovascular ischemia. In this study, the influence of tegaserod, at concentrations up to tenfold higher than the total plasma C (max) for the 6 mg clinical dose, has been investigated on platelet aggregation under standard conditions with platelet-rich plasma (PRP) obtained from healthy human subjects. Additionally, the influence of tegaserod on coronary artery tone was evaluated as an alternative pro-ischemic mechanism. The positive control, thrombopoietin, but not tegaserod, demonstrated a statistically significant increase in platelet aggregation using the same PRP samples with either adenosine diphosphate (ADP) or ADP plus 5-HT as an aggregation agonist. Tegaserod had no contractile activity in either porcine or human isolated coronary artery preparations, and only a small and variable response in canine coronary arteries at concentrations higher than those achieved clinically. Taken together, these studies do not identify a mechanism for the ischemic events that have been attributed to tegaserod in humans.

Modulation of immunogenicity and allergenicity by controlling the number of immunostimulatory oligonucleotides linked to Amb a 1.

BACKGROUND: Immunostimulatory DNA sequences (ISS) are potent immunomodulators that can drive T(H)1 responses to antigens or allergens. This effect can be dramatically enhanced by direct linkage of ISS to the protein. OBJECTIVE: Evaluate the effects of the number of ISS bound to the major ragweed allergen Amb a 1 on immunogenicity and allergenicity. METHODS: Immunogenicity in mice and allergenicity using PBMC or sera from subjects with ragweed allergy were assayed. RESULTS: Both antibody induction in vivo and antibody recognition in vitro were highly sensitive to the number of ISSs linked. IgE recognition of Amb a 1 in competitive ELISA or histamine release assays was inhibited by ISS linkage and showed an inverse relationship to the number of ISSs bound. Type and magnitude of antibody induction in mice was also highly dependent on the number of ISS bound. At the highest ISS to protein ratios, antibody induction was very low. Moderate ISS to protein ratios induced high antibody responses in which IgG(2a) generally predominated. Low ISS to protein ratios produced the highest overall antibody responses in which IgG(1) predominated. In contrast, varied ISS to protein ratios did not affect T-cell responses. In both in vivo mouse studies and in vitro human PBMC studies, all ISS to protein ratios evaluated induced similar responses represented by high levels of IFN-gamma and low levels of T(H)2 cytokines. CONCLUSION: Controlling the number of ISS bound to a protein allows manipulation of antibody recognition and induction while retaining the potent T(H)1 properties of an ISS-linked protein. CLINICAL IMPLICATIONS: Immunostimulatory DNA sequence-linked Amb a 1 conjugate represents a safe, novel therapeutic approach for treating ragweed allergy.

Telavancin, a multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane integrity in methicillin-resistant Staphylococcus aureus.

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited late-stage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N'-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K(+). The timing of these changes correlated with rapid , concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.

In vitro activity of TD-6424 against Staphylococcus aureus.

TD-6424, a rapidly bactericidal agent with multiple mechanisms of action, is more potent in vitro and more rapidly bactericidal than currently available agents against methicillin-susceptible and methicillin-resistant Staphylococcus aureus. TD-6424 produces a postantibiotic effect with a duration of 4 to 6 h against these organisms. The results suggest potential efficacy against susceptible and resistant strains of S. aureus.

Multivalent drug design. Synthesis and in vitro analysis of an array of vancomycin dimers.

The design, synthesis, and in vitro microbiological analysis of an array of forty covalently linked vancomycin dimers are reported. This work was undertaken to systematically probe the impact of linkage orientation and linker length on biological activity against susceptible and drug-resistant Gram-positive pathogens. To prepare the array, monomeric vancomycin synthons were linked through four distinct positions of the glycopeptide (C-terminus (C), N-terminus (N), vancosamine residue (V), and resorcinol ring (R)) in 10 unique pairwise combinations. Amphiphilic, peptide-based linkers of four different lengths (11, 19, 27, and 43 total atoms) were employed. Both linkage orientation and linker length were found to affect in vitro antibacterial potency. The V-V series displayed the greatest potency against vancomycin-susceptible organisms and vancomycin-resistant Enterococcus faecalis (VRE) of VanB phenotype, while the C-C, C-V, and V-R series displayed the most promising broad-spectrum activity that included VRE of VanA phenotype. Dimers bearing the shortest linkers were in all cases preferred for activity against VRE. The effects of linkage orientation and linker length on in vitro potency were not uniform; for example, (1) no single compound displayed activity that was superior against all test organisms to that of vancomycin or the other dimers, (2) linker length effects varied with test organism, and (3) whereas one-half of the dimers were more potent than vancomycin against methicillin-susceptible Staphylococcus aureus (MSSA), only one dimer was more potent against methicillin-resistant S. aureus (MRSA) and glycopeptide-intermediate susceptible S. aureus (GISA). In interpreting the results, we have considered the potential roles of multivalency and of other phenomena.