Burden of Respiratory Syncytial Virus-Associated Acute Respiratory Infections During Pregnancy.

BACKGROUND: With the licensure of maternal respiratory syncytial virus (RSV) vaccines in Europe and the United States, data are needed to better characterize the burden of RSV-associated acute respiratory infections (ARI) in pregnancy. The current study aimed to determine among pregnant individuals the proportion of ARI testing positive for RSV and the RSV incidence rate, RSV-associated hospitalizations, deaths, and perinatal outcomes. METHODS: We conducted a systematic review, following PRISMA 2020 guidelines, using 5 databases (Medline, Embase, Global Health, Web of Science, and Global Index Medicus), and including additional unpublished data. Pregnant individuals with ARI who had respiratory samples tested for RSV were included. We used a random-effects meta-analysis to generate overall proportions and rate estimates across studies. RESULTS: Eleven studies with pregnant individuals recruited between 2010 and 2022 were identified, most of which recruited pregnant individuals in community, inpatient and outpatient settings. Among 8126 pregnant individuals, the proportion with ARI that tested positive for RSV ranged from 0.9% to 10.7%, with a meta-estimate of 3.4% (95% confidence interval [CI], 1.9%-54%). The pooled incidence rate of RSV among pregnant individuals was 26.0 (95% CI, 15.8-36.2) per 1000 person-years. RSV hospitalization rates reported in 2 studies were 2.4 and 3.0 per 1000 person-years. In 5 studies that ascertained RSV-associated deaths among 4708 pregnant individuals, no deaths were reported. Three studies comparing RSV-positive and RSV-negative pregnant individuals found no difference in the odds of miscarriage, stillbirth, low birth weight, and small size for gestational age. RSV-positive pregnant individuals had higher odds of preterm delivery (odds ratio, 3.6 [95% CI, 1.3-10.3]). CONCLUSIONS: Data on RSV-associated hospitalization rates are limited, but available estimates are lower than those reported in older adults and young children. As countries debate whether to include RSV vaccines in maternal vaccination programs, which are primarily intended to protect infants, this information could be useful in shaping vaccine policy decisions.

Differences in influenza vaccination by gender identity and state-level gender equity policies: Behavioral Risk Factor Surveillance System, 2015-2019.

BACKGROUND: It is estimated that there are one million transgender and over 340,000 gender non-conforming people in the United States, many of whom face significant health disparities including access to healthcare. Although previous studies have reported greater vaccine uptake in women compared to men, national-level estimates of influenza vaccine uptake among transgender and non-binary people are unknown. This study aims to characterize differences in influenza vaccine uptake by gender identity and examine associations between vaccination status and state-level gender equity policies. METHODS: We used cross-sectional data from adults participating in the 2015-2019 United States Behavioral Risk Factors Surveillance System surveys. Weighted prevalence differences (PDs) and associated confidence intervals (CIs) of being unvaccinated against influenza by self-reported gender identity were estimated using generalized linear regression models. RESULTS: Compared to cisgender women (unvaccinated prevalence = 57.3%), the prevalence of being unvaccinated was significantly higher among cisgender men (64.4%; PD = 7.0 per 100, 95% CI: 6.7-7.4), transgender women (65.4%; PD = 8.1 per 100, 95% CI 4.0-12.2), transgender men (64.6%; PD = 7.3 per 100, 95% CI: 2.7-11.8), and gender non-conforming individuals (64.6%; PD = 7.2 per 100, 95% CI: 1.3-13.2). This pattern was similar among individuals living in states with protective versus restrictive gender equity policies. CONCLUSIONS: Our results identified a disparity in influenza vaccine uptake among individuals across the gender spectrum. To improve vaccine equity, future research should explore barriers to and facilitators of vaccine uptake by gender identity, which could inform policies and health promotion interventions to improve uptake co-designed and implemented with the transgender and non-binary communities.

An Application of an Initial Full Value of Vaccine Assessment Methodology to Measles-Rubella MAPs for Use in Low- and Middle-Income Countries.

Measles and rubella micro-array patches (MR-MAPs) are a promising innovation to address limitations of the current needle and syringe (N&S) presentation due to their single-dose presentation, ease of use, and improved thermostability. To direct and accelerate further research and interventions, an initial full value vaccine assessment (iFVVA) was initiated prior to MR-MAPs entering phase I trials to quantify their value and identify key data gaps and challenges. The iFVVA utilized a mixed-methods approach with rapid assessment of literature, stakeholder interviews and surveys, and quantitative data analyses to (i) assess global need for improved MR vaccines and how MR-MAPs could address MR problem statements; (ii) estimate costs and benefits of MR-MAPs; (iii) identify the best pathway from development to delivery; and (iv) identify outstanding areas of need where stakeholder intervention can be helpful. These analyses found that if MR-MAPs are broadly deployed, they can potentially reach an additional 80 million children compared to the N&S presentation between 2030-2040. MR-MAPs can avert up to 37 million measles cases, 400,000 measles deaths, and 26 million disability-adjusted life years (DALYs). MR-MAPs with the most optimal product characteristics of low price, controlled temperature chain (CTC) properties, and small cold chain volumes were shown to be cost saving for routine immunization (RI) in low- and middle-income countries (LMICs) compared to N&S. Uncertainties about price and future vaccine coverage impact the potential cost-effectiveness of introducing MR-MAPs in LMICs, indicating that it could be cost-effective in 16-81% of LMICs. Furthermore, this iFVVA highlighted the importance of upfront donor investment in manufacturing set-up and clinical studies and the critical influence of an appropriate price to ensure country and manufacturer financial sustainability. To ensure that MR-MAPs achieve the greatest public health benefit, MAP developers, vaccine manufacturers, donors, financiers, and policy- and decision-makers will need close collaboration and open communications.

Acute respiratory infections among individuals seeking outpatient care in the states of Washington and Michigan by pregnancy status, 2011-2016.

Background: Acute respiratory infections (ARIs) during pregnancy are associated with poor maternal and fetal outcomes. Methods: Using U.S. Flu Vaccine Effectiveness Network data (2011-2016) from Washington and Michigan, we tested for respiratory viruses among pregnant and non-pregnant outpatients matched on age, site, and season (n = 191). Results: Among all participants, detection of human coronaviruses and rhinovirus was common. We also observed differences in virus detection by pregnancy status; human coronaviruses and respiratory syncytial virus (RSV) were detected more frequently among pregnant and non-pregnant participants, respectively. Conclusions: The role of respiratory viruses in maternal ARI morbidity should be further characterized to inform implementation of prevention interventions including maternal vaccines.

CASCADIA: a prospective community-based study protocol for assessing SARS-CoV-2 vaccine effectiveness in children and adults using a remote nasal swab collection and web-based survey design.

INTRODUCTION: Although SARS-CoV-2 vaccines were first approved under Emergency Use Authorization by the Food and Drug Administration in late 2020 for adults, authorisation for young children 6 months to <5 years of age did not occur until 2022. These authorisations were based on clinical trials, understanding real-world vaccine effectiveness (VE) in the setting of emerging variants is critical. The primary goal of this study is to evaluate SARS-CoV-2 VE against infection among children aged >6 months and adults aged <50 years. METHODS: CASCADIA is a 4-year community-based prospective study of SARS-CoV-2 VE among 3500 adults and paediatric populations aged 6 months to 49 years in Oregon and Washington, USA. At enrolment and regular intervals, participants complete a sociodemographic questionnaire. Individuals provide a blood sample at enrolment and annually thereafter, with optional blood draws every 6 months and after infection and vaccination. Participants complete weekly self-collection of anterior nasal swabs and symptom questionnaires. Swabs are tested for SARS-CoV-2 and other respiratory pathogens by reverse transcription-PCR, with results of selected pathogens returned to participants; nasal swabs with SARS-CoV-2 detected will undergo whole genome sequencing. Participants who test positive for SARS-CoV-2 undergo serial swab collection every 3 days for 21 days. Serum samples are tested for SARS-CoV-2 antibody by binding and neutralisation assays. ANALYSIS: The primary outcome is SARS-CoV-2 infection. Cox regression models will be used to estimate the incidence rate ratio associated with SARS-CoV-2 vaccination among the paediatric and adult population, controlling for demographic factors and other potential confounders. ETHICS AND DISSEMINATION: All study materials including the protocol, consent forms, data collection instruments, participant communication and recruitment materials, were approved by the Kaiser Permanente Interregional Institutional Review Board, the IRB of record for the study. Results will be disseminated through peer-reviewed publications, presentations, participant newsletters and appropriate general news media.

Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Manufacturing readiness assessment for evaluation of the microneedle array patch industry: an exploration of barriers to full-scale manufacturing.

Microneedle array patch (MAP) technology is a promising new delivery technology for vaccines and pharmaceuticals, yet due to several differing and novel production methods, barriers to full-scale manufacturing exist. PATH conducted a manufacturing readiness assessment and follow-up interviews to identify both the current manufacturing readiness of the industry as well as how readiness varies by developer type and MAP type. Follow-up interviews identified barriers the industry faces in reaching full manufacturing readiness, including the perceived regulatory and investment risk of manufacturing MAPs at scale due to quality requirements and control methods, uncertain sterility requirements, lack of standard production methods (especially around dissolvable MAP drying methods), and the lack of available contract manufacturing organizations with MAP manufacturing capabilities. A Regulatory Working Group has been established to identify and address critical quality issues specific to MAP manufacturing with the aim of providing developers insight into what will be expected for MAP product approvals. Standardizing MAP production equipment and automatic, visual quality control could reduce the overall investment risk to developers and contract manufacturing organizations in pursuing pilot-scale manufacturing capabilities and ultimately lower barriers to the scale-up of full medical MAP product lines.

Evaluating Islatravir Administered Via Microneedle Array Patch for Long-Acting HIV Pre-exposure Prophylaxis Using Physiologically Based Pharmacokinetic Modelling.

BACKGROUND AND OBJECTIVES: Technologies for long-acting administration of antiretrovirals (ARVs) for the prevention and treatment of HIV are at the forefront of research initiatives aiming to tackle issues surrounding drug adherence with the current standard of once-daily oral administration. Islatravir (ISL) is an emerging ARV that shows promising characteristics for long-acting prevention and treatment both orally as well as through alternative routes of administration. Microneedle array patches (MAPs) are a pain-free and discreet transdermal delivery technology that offer extended-release administration of nanoparticulate drugs. This study aimed to utilise physiologically based pharmacokinetic (PBPK) modelling to predict the pharmacokinetics resulting from ISL administered via MAP and to identify key MAP characteristics required to sustain effective concentrations over extended dosing intervals. METHODS: A PBPK model describing the conversion of ISL to ISL-triphosphate (ISL-TP) and its whole-body disposition was developed and verified against observed clinical data for orally administered ISL in healthy adults. An intradermal PBPK model was integrated with the ISL PBPK model to predict the dose and nanoparticle release rate required for MAP administration strategies capable of achieving a minimum ISL-TP target concentration of 0.05 pmol/106 PBMCs over extended dosing intervals. MAP design was limited to a maximum therapeutic area of 20 cm2 with a dose loading of 4.09 mg/cm2 and a minimum duration of 3 months. Due to the lack of available clinical data, a range of nanoparticle release rates and MAP bioavailability scenarios were simulated to provide an overview of potential clinical outcomes. RESULTS: The ISL PBPK model was successfully verified, with predicted vs observed ratios falling within 0.5-2-fold. ISL MAP doses ranging from 15 to 80 mg were predicted to sustain ISL-TP concentrations above the minimum target concentration at 3, 6 and 12 months after administration. Nanoparticle release rate and MAP bioavailability were found to have a major impact on whether dosing strategies achieved the criteria. Minimum doses of 15 mg and 60 mg with a nanoparticle release rate of 0.0005 h-1 and bioavailability ranging from 25 to 100% were predicted to achieve effective ISL-TP concentrations up to 3 and 6 months, respectively. Doses of 15 mg and 30 mg with a nanoparticle release rate of 0.0005 h-1 were also able to attain the target concentration up to 6 months after MAP administration, albeit with a minimum bioavailability of 75% and 50%, respectively. Furthermore, when simulating a bioavailability of 100%, an 80 mg ISL MAP was predicted to sustain ISL-TP concentrations above the minimum target concentration up to 12 months after administration. CONCLUSIONS: The ISL PBPK model successfully predicted ISL and ISL-TP pharmacokinetics across a range of orally administered regimens. The integrated intradermal PBPK model outlined optimal MAP dose and nanoparticle release rates for effective ISL-TP concentrations up to 12 months, providing justification for further investigation of ISL as a candidate for MAP administration.

Evaluating the potential cost-effectiveness of microarray patches to expand access to hepatitis B birth dose vaccination in low-and middle-income countries: A modelling study.

Timely birth dose vaccination is key for achieving elimination of hepatitis B, however, programmatic requirements for delivering current vaccine presentations to births outside of health facilities inhibits coverage within many low-and middle-income countries (LMICs). Vaccine technologies in development such as microarray patches (MAPs) could assist in overcoming these barriers, but procurement could incur higher per-dose commodity costs than current ten-dose (US$0.34) and single-dose (US$0.62) vial presentations, necessitating an evaluation of the economic value proposition for MAPs. Within 80 LMICs offering universal hepatitis B birth dose vaccination, the cost-effectiveness of using MAPs to expand coverage was evaluated using a mathematical model. We considered three potential per dose MAP prices (US$1.65, US$3.30, and US$5.00), and two potential MAP use-cases: (1) MAPs are used by lay-health workers to expand birth dose coverage outside of health facility settings, and (2) MAPs are also preferred by qualified health workers, replacing a proportion of existing coverage from vaccine vials. Analysis took the health system perspective, was costed in 2020 US$, and discounted at 3% annually. Across minimal (1% additional coverage) and maximal (10% additional and 10% replacement coverage) MAP usage scenarios, between 2.5 (interquartile range [IQR]: 1.9, 3.1) and 38 (IQR: 28,44) thousand DALYs were averted over the estimated 2020 birth cohort lifetime in 80 LMICs. Efficiency of MAPs was greatest when used to provide additional coverage (scenario 1), on average saving US$88.65 ($15.44, $171.22) per DALY averted at a price of US$5.00 per MAP. Efficiency was reduced when used to replace existing coverage (scenario 2); however, at prices up to US$5.00 per MAP, we estimate this use-case could remain cost-effective in at least 73 (91%) modelled LMICs. Our findings suggest even at higher procurement costs, MAPs are likely to represent a highly cost-effective or cost-saving mechanism to expand reach of birth dose vaccination in LMICs.

Accelerating the Development of Measles and Rubella Microarray Patches to Eliminate Measles and Rubella: Recent Progress, Remaining Challenges.

Measles and rubella microarray patches (MR-MAPs) are critical in achieving measles and rubella eradication, a goal highly unlikely to meet with current vaccines presentations. With low commercial incentive to MAP developers, limited and uncertain funding, the need for investment in a novel manufacturing facility, and remaining questions about the source of antigen, product demand, and regulatory pathway, MR-MAPs are unlikely to be prequalified by WHO and ready for use before 2033. This article describes the current progress of MR-MAPs, highlights challenges and opportunities pertinent to MR-MAPs manufacturing, regulatory approval, creating demand, and timelines to licensure. It also describes activities that are being undertaken by multiple partners to incentivise investment in and accelerate the development of MR-MAPs.

Dynamics of breast milk antibody titer in the six months following SARS-CoV-2 infection.

BACKGROUND: While a growing body of literature describes antibody dynamics in serum, little is known about breast milk antibody titers in the months following SARS-CoV-2 infection. OBJECTIVES: We evaluated the dynamics of the humoral immune response to SARS-CoV-2 in two women who were breastfeeding when infected. We assessed paired breast milk and serum samples for six months post-infection for antibodies specific to the SARS-CoV-2 receptor binding domain (RBD) of the spike protein. RESULTS: Starting at 10 days after symptom onset, IgA antibody levels were persistent over a 6-month time period in human milk. For both mothers, no detectable IgA was found in the samples collected pre-symptom onset. RBD-specific IgG and IgM antibodies in tandem serum collected from the two donors demonstrated stable IgG levels over the six-month time period post-symptom onset. CONCLUSIONS: We found that breastfeeding mothers produced a durable IgA response for up to six months following COVID-19 infection, suggesting an important role for breast milk in protection of infants.

Vaccine innovation prioritisation strategy: Findings from three country-stakeholder consultations on vaccine product innovations.

As part of the Vaccine Innovation Prioritisation Strategy (VIPS), three immunization-stakeholder consultations were conducted between September 2018 and February 2020 to ensure that countries' needs drove the prioritization of vaccine product innovations. All consultations targeted respondents with immunization program experience. They included: (1) an online survey to identify immunization implementation barriers and desired vaccine attributes in three use settings, (2) an online survey to identify and evaluate the most important immunization challenges for ten exemplar vaccines, and (3) in-depth interviews to better understand the perceived programmatic benefits and challenges that could be addressed by nine innovations and to rank the innovations that could best address current challenges. The first consultation included responses from 442 participants in 61 countries, representing 89% of the 496 respondents who correctly completed at least one section of the online survey. For facility-based settings, missed opportunities for vaccination due to reluctance to open multidose vaccine vials was the barrier most frequently selected by respondents. In community-based (outreach) and campaign settings, limited access to immunization services due to geographic barriers was most frequently selected. Multidose presentations with preservative or single-dose presentations were most frequently selected as desired vaccine attributes for facility-based settings while improved thermostability was most frequently selected for outreach and campaign settings. The second online survey was completed by 220 respondents in 54 countries. For the exemplar vaccines, vaccine ineffectiveness or wastage due to heat or freeze exposure and missed opportunities due to multidose vial presentations were identified as the greatest vaccine-specific challenges. In-depth interviews with 84 respondents in six countries ranked microarray patches, dual-chamber delivery devices, and heat-stable/controlled temperature chain qualified liquid vaccines as the three innovations that could have the greatest impact in helping address current immunization program challenges. These findings informed the VIPS prioritization and provided broader application to designing immunization interventions to better meet country needs.

Combined Enzyme- and Transition Metal-Catalyzed Strategy for the Enantioselective Syntheses of Nitrogen Heterocycles: (-)-Coniine, DAB-1, and Nectrisine.

The enantioselective syntheses of (-)-coniine, DAB-1, and nectrisine have been developed, utilizing a complementary strategy of enzyme- and transition metal-catalyzed reactions. The initial stereocenter was set with >99% enantioselectivity via an enzyme-catalyzed hydrocyanation reaction. Substrate incompatibilities with the natural enzyme were overcome by tactical utilization of ruthenium-catalyzed olefin metathesis to functionalize an enzyme-derived (R)-allylic fragment. The piperidine and pyrrolidine alkaloid natural products were obtained by a route that leveraged regio- and stereoselective palladium-catalyzed 1,3-substitutive reactions.

Potential use of microarray patches for vaccine delivery in low- and middle- income countries.

Microarray patches (MAPs), also referred to as microneedle patches, are a novel methodology that have the potential to overcome barriers to vaccine delivery in low- and middle-income countries (LMICs), and transform the way that vaccines are delivered within immunization programs. The World Health Organization's Initiative for Vaccine Research and its partners are working to understand how MAPs could ease vaccine delivery and increase equitable access to vaccines in LMICs. Global stakeholders have been engaged to evaluate technical, economic, and programmatic challenges; to validate assumptions where possible; and to propose areas of focus to facilitate future vaccine-MAP product development. This report summarizes those learnings.

Evaluating the cost per child vaccinated with full versus fractional-dose inactivated poliovirus vaccine.

INTRODUCTION: Inactivated poliovirus vaccine (IPV) shortages and evidence of improved immunogenicity of two intradermal (ID) fractional IPV (fIPV) doses compared with one full intramuscular dose led to recommendations for fIPV delivery. To provide evidence on the economics of fIPV, we estimated the cost per child vaccinated using full-dose IPV compared with fIPV in routine and campaign settings. We evaluated the impact on costs of alternative devices facilitating ID administration, vaccine vial sizes, and prices. METHODS: We used an Excel-based model to estimate the commodity and delivery costs for providing IPV. Commodity costs included vaccine price per dose adjusted for wastage, prices for vaccine administration devices, and safety boxes. Delivery costs included storage costs at each level of the supply chain, transport costs for commodities between levels, and human resource costs for vaccine administration. Model inputs were obtained from various databases and published literature. All costs are reported in 2018 US dollars. RESULTS: In both campaign and routine settings, fIPV had a lower cost per child vaccinated than full dosing, despite the assumed higher vaccine wastage with fIPV in routine settings, and even when novel ID administration devices were used. In routine settings, costs per child fully vaccinated with fractional doses were 15% to 48% lower than those with full-dose delivery across different vial sizes. The cost per child vaccinated ranged from $1.84 to $2.65 for fractional doses, depending on the administration device, compared with $3.57 for full dose, when using 5-dose vials. The magnitude of cost reductions with fIPV relative to full-dose IPV was largest with smaller vial sizes and higher vaccine price. CONCLUSION: Adopting fIPV can reduce costs per child vaccinated compared with using full doses, especially as IPV prices increase in the short term and more so when two full doses could be recommended in the future.