A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial.

BACKGROUND: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children. METHODS: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18-40 years for the adult cohort, 15-18 months for toddlers, or 9-10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete. FINDINGS: Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0-97·2) seroconverted to measles and 100% (58/58; 93·8-100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2-95·2) and 100% (59/59; 93·9-100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events. INTERPRETATION: The safety and immunogenicity data support the accelerated development of the MRV-MNP. FUNDING: Bill & Melinda Gates Foundation.

The Effects of Vaccination Status and Age on Clinical Characteristics and Severity of Measles Cases in the United States in the Post-Elimination Era, 2001-2022.

BACKGROUND: Despite high vaccine-effectiveness, wild-type measles can occur in previously vaccinated persons. We compared the clinical presentation and disease severity of measles by vaccination status and age in the post-elimination era in the United States. METHODS: We included U.S. measles cases reported from 2001-2022. Breakthrough measles was defined as cases with ≥1 documented dose of measles-containing vaccine, classic measles as the presence of rash, fever, and ≥1 symptoms (cough, coryza, or conjunctivitis), and severe disease as the presence of pneumonia, encephalitis, hospitalization, or death. Vaccinated cases with low and high avidity IgG were classified as primary (PVF) and secondary (SVF) vaccine failures, respectively. RESULTS: Among 4,056 confirmed measles cases, 2,799 (69%) were unvaccinated, 475 (12%) were breakthrough infections, and 782 (19%) had unknown vaccination; 1,526 (38%), 1,174 (29%), and 1,355 (33%) were aged <5, 5-19, and ≥20 years, respectively. We observed a general decline in classic presentation and severe disease with an increase in the number of doses, and less complications among children aged 5-19 years compared to other age-groups. Among 93 breakthrough cases with avidity results, 11 (12%) and 76 (82%) were classified as PVF and SVF, respectively, with a higher proportion of PVFs having a classic measles presentation and severe disease than SVFs. DISCUSSION: Breakthrough measles cases tended to have milder disease with less complications. A small proportion of breakthrough infections were due to PVF than SVF. It is critical to maintain high MMR vaccination coverage in the United States to prevent serious measles illnesses.

Measles - United States, January 1, 2020-March 28, 2024.

Measles is a highly infectious febrile rash illness and was declared eliminated in the United States in 2000. However, measles importations continue to occur, and U.S. measles elimination status was threatened in 2019 as the result of two prolonged outbreaks among undervaccinated communities in New York and New York City. To assess U.S. measles elimination status after the 2019 outbreaks and to provide context to understand more recent increases in measles cases, CDC analyzed epidemiologic and laboratory surveillance data and the performance of the U.S. measles surveillance system after these outbreaks. During January 1, 2020-March 28, 2024, CDC was notified of 338 confirmed measles cases; 97 (29%) of these cases occurred during the first quarter of 2024, representing a more than seventeenfold increase over the mean number of cases reported during the first quarter of 2020-2023. Among the 338 reported cases, the median patient age was 3 years (range = 0-64 years); 309 (91%) patients were unvaccinated or had unknown vaccination status, and 336 case investigations included information on ≥80% of critical surveillance indicators. During 2020-2023, the longest transmission chain lasted 63 days. As of the end of 2023, because of the absence of sustained measles virus transmission for 12 consecutive months in the presence of a well-performing surveillance system, U.S. measles elimination status was maintained. Risk for widespread U.S. measles transmission remains low because of high population immunity. However, because of the increase in cases during the first quarter of 2024, additional activities are needed to increase U.S. routine measles, mumps, and rubella vaccination coverage, especially among close-knit and undervaccinated communities. These activities include encouraging vaccination before international travel and rapidly investigating suspected measles cases.

The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity.

This article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus-mediated disease. The initial sections focus on seasonal coronaviruses, SARS-CoV, and MERS-CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS-CoV-2 and COVID-19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS-CoV-2.

Preparation and Biological Properties of Oligonucleotide-Functionalized Virus-like Particles.

Oligonucleotides are powerful molecules for programming function and assembly. When arrayed on nanoparticle scaffolds in high density, the resulting molecules, spherical nucleic acids (SNAs), become imbued with unique properties. We used the copper-catalyzed azide-alkyne cycloaddition to graft oligonucleotides on Qß virus-like particles to see if such structures also gain SNA-like behavior. Copper-binding ligands were shown to promote the click reaction without degrading oligonucleotide substrates. Reactions were first optimized with a small-molecule fluorogenic reporter and were then applied to the more challenging synthesis of polyvalent protein nanoparticle-oligonucleotide conjugates. The resulting particles exhibited the enhanced cellular uptake and protection from nuclease-mediated oligonucleotide cleavage characteristic of SNAs, had similar residence time in the liver relative to unmodified particles, and were somewhat shielded from immune recognition, resulting in nearly 10-fold lower antibody titers relative to unmodified particles. Oligonucleotide-functionalized virus-like particles thus provide an interesting option for protein nanoparticle-mediated delivery of functional molecules.

Performance Characteristics of Six Immunoglobulin M Enzyme-Linked Immunosorbent Assays Used for Laboratory Confirmation of Measles.

Laboratory confirmation of infection is an essential component of measles surveillance. Detection of measles-specific IgM in serum by enzyme-linked immunosorbent assay (ELISA) is the most common method used to confirm measles infection. ELISA formats vary, as does the sensitivity and specificity of each assay. Specimens collected within 3 days of rash onset can yield a false-negative result, which can delay confirmation of measles cases. Interfering substances can yield a false-positive result, leading to unnecessary public health interventions. The IgM capture assay developed at the Centers for Disease Control (CDC) was compared against five commercially available ELISA kits for the ability to detect measles virus-specific IgM in a panel of 90 well-characterized specimens. Serum samples were tested in triplicate using each commercial kit as recommended by the manufacturer. Using the CDC measles IgM capture assay as the reference test; the sensitivity and specificity for each commercial kit ranged from 50 to 83% and 86.9 to 98%, respectively. Discrepant results were observed for samples tested with all five commercial kits and ranged from 13.8 to 28.8% of the specimens tested. False-positive results occurred in 2.0 to 13.1% of sera, while negative results were observed in 16.7 to 50% of sera that were positive by the CDC measles IgM capture assay. Evaluation and interpretation of measles IgM serologic results can be complex, particularly in measles elimination settings. The performance characteristics of a measles IgM assay should be carefully considered when selecting an assay to achieve high-quality measles surveillance.

Public Health Actions to Control Measles Among Afghan Evacuees During Operation Allies Welcome - United States, September-November 2021.

On August 29, 2021, the United States government oversaw the emergent establishment of Operation Allies Welcome (OAW), led by the U.S. Department of Homeland Security (DHS) and implemented by the U.S. Department of Defense (DoD) and U.S. Department of State (DoS), to safely resettle U.S. citizens and Afghan nationals from Afghanistan to the United States. Evacuees were temporarily housed at several overseas locations in Europe and Asia* before being transported via military and charter flights through two U.S. international airports, and onward to eight U.S. military bases,† with hotel A used for isolation and quarantine of persons with or exposed to certain infectious diseases.§ On August 30, CDC issued an Epi-X notice encouraging public health officials to maintain vigilance for measles among Afghan evacuees because of an ongoing measles outbreak in Afghanistan (25,988 clinical cases reported nationwide during January-November 2021) (1) and low routine measles vaccination coverage (66% and 43% for the first and second doses, respectively, in 2020) (2).

Single-Point Mutations in Qß Virus-like Particles Change Binding to Cells.

Virus-like particles (VLPs) constitute large, polyvalent platforms onto which a wide variety of functional units can be grafted. Their use in biological settings often depends on their specific binding to cells or receptors of interest; this can be compromised by excessive nonspecific association with other cells. We found that lysine residues mediate such nonspecific interactions, presumably by virtue of protonation and interaction with anionic membrane lipid headgroups and/or complementary residues of cell surface proteins and polysaccharides. Chemical acylation of surface-exposed amines of the Qß VLP led to a significant reduction in the association of particles with mammalian cells. Single-point mutations of particular lysine residues to either glutamine, glutamic acid, tryptophan, or phenylalanine were mostly well-tolerated and formed intact capsids, but the introduction of double and triple mutants was far less forgiving. Introduction of glutamic acid at position 13 (K13E) led to a dramatic increase in cellular binding, whereas removal of the lysine at position 46 (K46Q) led to an equally striking reduction. Several plasma membrane components were found to specifically interact with the Qß capsid irrespective of surface charge. These results suggest that specific cellular interactions are engaged or obviated by such mutations and provide us with more "benign" particles to which can be added binding functionality for targeted delivery applications.

Stabilization of Near-Infrared Fluorescent Proteins by Packaging in Virus-like Particles.

Near-IR fluorescent Qß virus-like particles (VLPs) were produced in a high yield by packaging highly red-shifted monomeric and dimeric versions of biliverdin-dependent fluorescent proteins within the capsid shell. The simple addition of biliverdin hydrochloride to the medium during or after Escherichia coli protein expression was enough to produce fully matured encapsidated fluorophores. The packaged near-IR proteins exhibited identical photochemical properties to their nonencapsidated analogues but were far more stable toward heat, chaotrope-induced denaturation, and proteolysis. Noninvasive in vivo imaging showed the VLPs to traffic primarily to the liver after systemic injection in mice, revealing that the particles were easily detected by a standard instrument.

Lung Tissue Delivery of Virus-Like Particles Mediated by Macrolide Antibiotics.

Macrophage cells are present in high abundance in the lung to intercept invading microorganisms that gain access through airway mucosal surfaces. Several bacterial pathogens have evolved the capacity to evade the innate immune response by establishing infections within pulmonary macrophages upon phagocytosis, leading to prolonged disease. Macrolide antibiotics such as azithromycin and clarithromycin accumulate in phagocytic cells and have been shown to preferentially distribute in tissues where populations of these cells reside. We employed this class of molecules as targeting ligands to direct virus-like particles (VLPs) to lung-resident macrophages. VLP-macrolide conjugates showed enhanced uptake into RAW 264.7 macrophage cells in culture, with azithromycin displaying the greatest effect; distinct differences were also observed for different macrocycle structures and orientations on the particle surface. Activation of macrophage cells was stimulated by particle uptake toward an intermediate activation state, in contrast to previous reports using macrolide-functionalized gold nanorods that stimulated a cytotoxic macrophage response. Attached azithromycin was also able to direct VLPs to the lungs in mice, with significant accumulation within 2 h of systemic injection. These results suggest that this new class of bioconjugate could serve as an effective platform for intracellular drug delivery in the context of pulmonary infections.

Immunosenescence and human vaccine immune responses.

The age-related dysregulation and decline of the immune system-collectively termed "immunosenescence"-has been generally associated with an increased susceptibility to infectious pathogens and poor vaccine responses in older adults. While numerous studies have reported on the clinical outcomes of infected or vaccinated individuals, our understanding of the mechanisms governing the onset of immunosenescence and its effects on adaptive immunity remains incomplete. Age-dependent differences in T and B lymphocyte populations and functions have been well-defined, yet studies that demonstrate direct associations between immune cell function and clinical outcomes in older individuals are lacking. Despite these knowledge gaps, research has progressed in the development of vaccine and adjuvant formulations tailored for older adults in order to boost protective immunity and overcome immunosenescence. In this review, we will discuss the development of vaccines for older adults in light of our current understanding-or lack thereof-of the aging immune system. We highlight the functional changes that are known to occur in the adaptive immune system with age, followed by a discussion of current, clinically relevant pathogens that disproportionately affect older adults and are the central focus of vaccine research efforts for the aging population. We conclude with an outlook on personalized vaccine development for older adults and areas in need of further study in order to improve our fundamental understanding of adaptive immunosenescence.

Measles IgG Avidity Assay.

Measles IgG avidity assays determine the overall strength of molecular binding between measles-specific IgG antibodies and measles virus antigens. Avidity results can distinguish recent from distant measles virus infections. Individuals who are immunologically naïve to measles virus develop low-avidity antibodies upon measles virus infection or first-time vaccination. Within 4-6 months, antibodies mature to high avidity. Measles avidity assays are most useful in the context of measles elimination. In such settings, avidity and epidemiological and clinical information are used to classify measles breakthrough infections for control and surveillance purposes and to assist in case confirmation when other laboratory results are inconclusive or nonexistent. We present a highly accurate end-titer measles avidity assay that delivers results based on IgG quality (avidity) that are independent of IgG concentration.

Serosurveillance for Measles and Rubella.

Measles and rubella remain global health threats, despite the availability of safe and effective vaccines. Estimates of population immunity are crucial for achieving elimination goals and assessing the impact of vaccination programs, yet conducting well-designed serosurveys can be challenging, especially in resource-limited settings. In this review, we provide a comprehensive assessment of 130 measles and rubella studies published from January 2014 to January 2024. Methodologies and design aspects of serosurveys varied greatly, including sample size, assay type, and population demographics. Most studies utilized enzyme immunoassays for IgG detection. Sample sizes showed diverse sampling methods but favored convenience sampling despite its limitations. Studies spanned 59 countries, predominantly including adults, and revealed disparities in seroprevalence across demographics, regions, and notably among migrants and women. Age-related declines in antibodies were observed, particularly among infants, and correlations between vaccination status and seropositivity varied. We conclude with an outlook on measles and rubella serosurveillance, emphasizing the need for proper survey design and the advantages of standardized, multiplex serology assays.

Measles and Rubella Diagnostic and Classification Challenges in Near- and Post-Elimination Countries.

Measles and rubella are vaccine-preventable viral diseases and can be prevented by safe, highly effective vaccination with measles- and rubella-containing vaccines. Given the myriad causes of febrile exanthems, laboratory surveillance for both measles and rubella is important to document the incidence of these diseases and to track the progress and maintenance of elimination in near- and post-elimination settings. Diagnostic challenges can hinder effective surveillance and classification challenges can hinder efforts to demonstrate achievement or maintenance of elimination. In this report, we review diagnostic and classification challenges for measles and rubella in near- and post-elimination settings.

Breakthrough Measles among Vaccinated Adults Born during the Post-Soviet Transition Period in Mongolia.

Mongolia experienced a nationwide measles outbreak during 1 March 2015-31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults, suggesting a possible role of vaccine failure. Advanced laboratory methods, coupled with detailed epidemiological investigations, can help classify cases as vaccine failure, failure to vaccinate, or both. In this report, we conducted a study of cases to identify risk factors for breakthrough infection for a subset of laboratory-confirmed measles cases. Of the 193 cases analyzed, only 19 (9.8%) reported measles vaccination history, and 170 (88%) were uncertain. Measles-specific IgG avidity testing classified 120 (62%) cases as low IgG avidity, indicating no prior exposure to measles. Ten of these cases with low IgG avidity had a history of measles vaccination, indicating primary vaccine failure. Overall, sixty cases (31%) had high IgG avidity, indicating breakthrough infection after prior exposure to measles antigen through vaccination or natural infection, but the IgG avidity results were highly age-dependent. This study found that among young children aged 9 months-5 years, breakthrough infection was rare (4/82, 5%); however, among young adults aged 15-25 years, breakthrough infection due to secondary vaccine failure (SVF) occurred on a large scale during this outbreak, accounting for the majority of cases (42/69 cases, 61%). The study found that large-scale secondary vaccine failure occurred in Mongolia, which highlights the potential for sustained outbreaks in post-elimination settings due to "hidden" cohorts of young adults who may have experienced waning immunity. This phenomenon may have implications for the sustainability of measles elimination in countries that remain vulnerable to the importation of the virus from areas where it is still endemic. Until global measles elimination is achieved, enhanced surveillance and preparedness for future outbreaks in post- or peri-elimination countries may be required.

Long-term Neutralizing Antibody Levels Against Measles and Rubella Viruses Among Adults With 3 Doses of Measles-Mumps-Rubella Vaccine.

Background: A third dose of measles-mumps-rubella vaccine (MMR) may be administered for various reasons, but data on long-term immunity are limited. We assessed neutralizing antibody levels against measles and rubella among adults up to 11 years after receipt of a third MMR dose. Methods: In this longitudinal study, healthy adults who received a third MMR dose as young adults (ages 18-28 years) were recalled around 5 years and 9-11 years after the third dose. Measles and rubella antibody levels were assessed by plaque-reduction and immunocolorimetric neutralization assays, respectively. Antibody concentrations <120 mIU/mL and <10 U/mL were considered potentially susceptible to measles and rubella, respectively. Geometric mean concentrations (GMCs) and 95% confidence intervals (CIs) over time were estimated from generalized estimating equation models. Results: Approximately 5 and 9-11 years after receipt of the third dose, 405 and 304 adults were assessed, respectively. Measles GMC was 428 mIU/mL (95% CI, 392-468 mIU/mL) 5 years postvaccination, declining to 381 mIU/mL (95% CI, 339-428 mIU/mL) 11 years postvaccination. At the last follow-up visit (9-11 years postvaccination), 10% of participants were potentially susceptible to measles infection. Rubella GMCs were stable throughout the follow-up period (63 U/mL to 65 U/mL); none of the participants was susceptible to rubella at the last follow-up visit. Conclusions: Eleven years after receiving a third MMR dose, measles and rubella neutralizing antibody levels remained high in adults. However, on the basis of waning antibody levels, some adults may become susceptible to measles infection over time despite receipt of 3 vaccine doses.

The Global Measles and Rubella Laboratory Network Supports High-Quality Surveillance.

With 762 laboratories, the Global Measles and Rubella Laboratory Network (GMRLN) is the largest laboratory network coordinated by the World Health Organization (WHO). Like the Global Polio Laboratory Network, the GMRLN has multiple tiers, including global specialized laboratories, regional reference laboratories, national laboratories, and, in some countries, subnational laboratories. Regional networks are supervised by regional laboratory coordinators reporting to a global coordinator at WHO headquarters. Laboratories in the GMRLN have strong links to national disease control and vaccination programs. The GMRLN's goal is to support member states in obtaining timely, complete, and reliable laboratory-based surveillance data for measles and rubella as part of the strategy for achieving measles and rubella elimination. Surveillance data are reported to the national program and are included in annual reports on the status of measles and rubella elimination to national verification committees for review by regional verification commissions. Quality within the GMRLN is ensured by monitoring performance through external quality assurance programs, confirmatory and quality control testing, accreditation, and coordination of corrective action and training where needed. The overall performance of the laboratories has remained high over the years despite many challenges, particularly the COVID-19 pandemic. The GMRLN is well-positioned to support high-quality laboratory-based surveillance for measles and rubella and to transition to supporting laboratory testing for other pathogens, including vaccine-preventable diseases.

A general synthesis of bis-indolylpiperazine-2,5-diones.

The one-pot synthesis of three dragmacidin derivatives is reported. Sarcosine anhydride (4) is brominated and immediately reacted with the corresponding indole to produce the products, namely 3,6-bis(5'-methoxy-3'-indolyl)-1,4-dimethylpiperazine-2,5-dione (1), 3,6-bis(7'-methyl-3'-indolyl)-1,4-dimethylpiperazine-2,5-dione (2) and 3,6-bis-(6'-chloro-3'-indolyl)-1,4-dimethylpiperazine-2,5-dione (3), which are characterized by 1H-NMR.

Inflammasome Activity in Response to Influenza Vaccination Is Maintained in Monocyte-Derived Peripheral Blood Macrophages in Older Adults.

Introduction: Each year, a disproportionate number of the total seasonal influenza-related hospitalizations (90%) and deaths (70%) occur among adults who are >65 years old. Inflammasome activation has been shown to be important for protection against influenza infection in animal models but has not yet been demonstrated in humans. We hypothesized that age-related dysfunction (immunosenescence) of the inflammasome may be associated with poor influenza-vaccine response among older adults. Methods: A cohort of younger (18-40 years of age) and older (≥65 years of age) adults was recruited prior to the 2014-2015 influenza season. We measured hemagglutination inhibition (HAI) titers in serum before and 28 days after receipt of the seasonal inactivated influenza vaccine. Inflammasome-related gene expression and protein secretion were quantified in monocyte-derived macrophages following stimulation with influenza A/H1N1 virus. Results: Younger adults exhibited higher HAI titers compared to older adults following vaccination, although inflammasome-related protein secretion in response to influenza stimulation was similar between the age groups. Expression of P2RX7 following influenza stimulation was lower among older adults. Interestingly, CFLAR expression was significantly higher among females (p = 2.42 × 10-5) following influenza stimulation and this gene may play an important role in the development of higher HAI antibody titers among older females. Conclusion: Inflammasome activation in response to influenza vaccination appears to be maintained in monocyte-derived macrophages from older adults and does not explain the poor influenza vaccine responses generally observed among this age group.