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.

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.

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.

Identification of naturally processed Zika virus peptides by mass spectrometry and validation of memory T cell recall responses in Zika convalescent subjects.

Once an obscure pathogen, Zika virus (ZIKV) has emerged as a significant global public health concern. Several studies have linked ZIKV infection in pregnant women with the development of microcephaly and other neurological abnormalities, emphasizing the need for a safe and effective vaccine to combat the spread of this disease. Preclinical studies and vaccine development efforts have largely focused on the role of humoral immunity in disease protection. Consequently, relatively little is known in regard to cellular immunity against ZIKV, although an effective vaccine will likely need to engage both the humoral and cellular arms of the immune system. To that end, we utilized two-dimensional liquid chromatography coupled with tandem mass spectrometry to identify 90 ZIKV peptides that were naturally processed and presented on HLA class I and II molecules (HLA-A*02:01/HLA-DRB1*04:01) of an immortalized B cell line infected with ZIKV (strain PRVABC59). Sequence identity clustering was used to filter the number of candidate peptides prior to evaluating memory T cell recall responses in ZIKV convalescent subjects. Peptides that individually elicited broad (4 of 7 subjects) and narrow (1 of 7 subjects) T cell responses were further analyzed using a suite of predictive algorithms and in silico modeling to evaluate HLA binding and peptide structural properties. A subset of nine broadly reactive peptides was predicted to provide robust global population coverage (97.47% class I; 70.74% class II) and to possess stable structural properties amenable for vaccine formulation, highlighting the potential clinical benefit for including ZIKV T cell epitopes in experimental vaccine formulations.

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.

Associations between markers of cellular and humoral immunity to rubella virus following a third dose of measles-mumps-rubella vaccine.

INTRODUCTION: Rubella virus (RV) was eliminated in the United States in 2004, although a small portion of the population fails to develop long-term immunity against RV even after two doses of the measles-mumps-rubella (MMR) vaccine. We hypothesized that inherent biological differences in cytokine and chemokine signaling likely govern an individual's response to a third dose of the vaccine. METHODS: Healthy young women (n = 97) were selected as study participants if they had either low or high extremes of RV-specific antibody titer after two previous doses of MMR vaccine. We measured cytokine and chemokine secretion from RV-stimulated PBMCs before and 28 days after they received a third dose of MMR vaccine and assessed correlations with humoral immune response outcomes. RESULTS: High and low antibody vaccine responders exhibited a strong pro-inflammatory cellular response, with an underlying Th1-associated signature (IL-2, IFN-γ, MIP-1ß, IP-10) and suppressed production of most Th2-associated cytokines (IL-4, IL-10, IL-13). IL-10 and IL-4 exhibited significant negative associations with neutralizing antibody titers and memory B cell ELISpot responses among low vaccine responders. CONCLUSION: IL-4 and IL-10 signaling pathways may be potential targets for understanding and improving the immune response to rubella vaccination or for designing new vaccines that induce more durable immunity.

Durability of humoral immune responses to rubella following MMR vaccination.

BACKGROUND: While administration of the measles-mumps-rubella (MMR-II®) vaccine has been effective at preventing rubella infection in the United States, the durability of humoral immunity to the rubella component of MMR vaccine has not been widely studied among older adolescents and adults. METHODS: In this longitudinal study, we sought to assess the durability of rubella virus (RV)-specific humoral immunity in a healthy population (n = 98) of adolescents and young adults at two timepoints: ~7 and ~17 years after two doses of MMR-II® vaccination. Levels of circulating antibodies specific to RV were measured by ELISA and an immune-colorimetric neutralization assay. RV-specific memory B cell responses were also measured by ELISpot. RESULTS: Rubella-specific IgG antibody titers, neutralizing antibody titers, and memory B cell responses declined with increasing time since vaccination; however, these decreases were relatively moderate. Memory B cell responses exhibited a greater decline in men compared to women. CONCLUSIONS: Collectively, rubella-specific humoral immunity declines following vaccination, although subjects' antibody titers remain well above the currently recognized threshold for protective immunity. Clinical correlates of protection based on neutralizing antibody titer and memory B cell ELISpot response should be defined.

SARS-CoV-2 Vaccine Development: Current Status.

In the midst of the severe acute respiratory syndrome coronavirus 2 pandemic and its attendant morbidity and mortality, safe and efficacious vaccines are needed that induce protective and long-lived immune responses. More than 120 vaccine candidates worldwide are in various preclinical and phase 1 to 3 clinical trials that include inactivated, live-attenuated, viral-vectored replicating and nonreplicating, protein- and peptide-based, and nucleic acid approaches. Vaccines will be necessary both for individual protection and for the safe development of population-level herd immunity. Public-private partnership collaborative efforts, such as the Accelerating COVID-19 Therapeutic Interventions and Vaccines mechanism, are key to rapidly identifying safe and effective vaccine candidates as quickly and efficiently as possible. In this article, we review the major vaccine approaches being taken and issues that must be resolved in the quest for vaccines to prevent coronavirus disease 2019. For this study, we scanned the PubMed database from 1963 to 2020 for all publications using the following search terms in various combinations: SARS, MERS, COVID-19, SARS-CoV-2, vaccine, clinical trial, coronavirus, pandemic, and vaccine development. We also did a Web search for these same terms. In addition, we examined the World Health Organization, Centers for Disease Control and Prevention, and other public health authority websites. We excluded abstracts and all articles that were not written in English.

Degradable Hydrogels for the Delivery of Immune-modulatory Proteins in the Wound Environment.

Chronic wounds represent a growing clinical problem for which limited treatment strategies exist. Defects in immune cell-mediated healing play an important role in chronic wound development, presenting an attractive clinical target in the treatment of chronic wounds. However, efforts to improve healing through the application of growth factors and cytokines have been limited by the rapid degradation and diffusion of these molecules in the wound environment. In this study we sought to overcome the challenge of rapid diffusion through the development of a hydrogel delivery system in which protein cargo can be released into the wound environment at a constant and tunable rate. This system was used to deliver the intercellular adhesion molecule-1 (ICAM-1) in order to target endogenous cells upstream of growth factor and cytokine production and circumvent the issue of their rapid degradation. We demonstrated that our delivery system was able to release cargo at different and highly controllable rates and thereby improved cargo retention in the wound environment. Additionally, treatment with ICAM-1 in the delivery system improved healing in both ICAM-1-deficient mice and an aged mouse model of delayed healing, highlighting a potential clinical benefit for this protein in the treatment of chronic wounds.

Immunoinformatic identification of B cell and T cell epitopes in the SARS-CoV-2 proteome.

A novel coronavirus (SARS-CoV-2) emerged from China in late 2019 and rapidly spread across the globe, infecting millions of people and generating societal disruption on a level not seen since the 1918 influenza pandemic. A safe and effective vaccine is desperately needed to prevent the continued spread of SARS-CoV-2; yet, rational vaccine design efforts are currently hampered by the lack of knowledge regarding viral epitopes targeted during an immune response, and the need for more in-depth knowledge on betacoronavirus immunology. To that end, we developed a computational workflow using a series of open-source algorithms and webtools to analyze the proteome of SARS-CoV-2 and identify putative T cell and B cell epitopes. Utilizing a set of stringent selection criteria to filter peptide epitopes, we identified 41 T cell epitopes (5 HLA class I, 36 HLA class II) and 6 B cell epitopes that could serve as promising targets for peptide-based vaccine development against this emerging global pathogen. To our knowledge, this is the first study to comprehensively analyze all 10 (structural, non-structural and accessory) proteins from SARS-CoV-2 using predictive algorithms to identify potential targets for vaccine development.

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.

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.

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.

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: A systems-level overview of immune cell biology and strategies for improving vaccine responses.

Immunosenescence contributes to a decreased capacity of the immune system to respond effectively to infections or vaccines in the elderly. The full extent of the biological changes that lead to immunosenescence are unknown, but numerous cell types involved in innate and adaptive immunity exhibit altered phenotypes and function as a result of aging. These manifestations of immunosenescence at the cellular level are mediated by dysregulation at the genetic level, and changes throughout the immune system are, in turn, propagated by numerous cellular interactions. Environmental factors, such as nutrition, also exert significant influence on the immune system during aging. While the mechanisms that govern the onset of immunosenescence are complex, systems biology approaches allow for the identification of individual contributions from each component within the system as a whole. Although there is still much to learn regarding immunosenescence, systems-level studies of vaccine responses have been highly informative and will guide the development of new vaccine candidates, novel adjuvant formulations, and immunotherapeutic drugs to improve vaccine responses among the aging population.