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Zika virus (ZIKV) is a major human pathogen and member of the genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
Enterovirus D68 (EV-D68) is a pathogen that causes outbreaks of respiratory illness across the world, mostly in children, and can be especially severe in those with asthma. Clusters of acute flaccid myelitis, a poliomyelitis-like neuromuscular weakness syndrome, often occur concurrent with EV-D68 respiratory outbreaks. Seroepidemiologic studies have found that the serum of nearly everyone older than 2 to 5 years contains anti-EV-D68 neutralizing antibodies, which suggests that EV-D68 is a ubiquitous pathogen of childhood. However, knowledge of the viral epitopes against which the humoral immune response is directed is only inferred from previous studies of related viruses. Although neutralizing antibodies protect newborn mice from lethal EV-D68 inoculation via nonphysiologic routes, cotton rats have a mixed phenotype of both benefit and possible exacerbation when inoculated intranasally. The human antibody response to EV-D68 needs to be studied further to clarify the role of antibodies in protection versus pathogenesis, which might differ among respiratory and neurologic disease phenotypes.
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Here we report the utility of antigen-specific T lymphocytes as a regulatable peptide delivery platform for in vivo therapy. piggyBac transposon modification of murine cells with luciferase allows us to visualize T cells after adoptive transfer. Vaccination stimulates long-term T-cell engraftment, persistence, and transgene expression enabling detection of modified cells up to 300 days after adoptive transfer. We demonstrate adoptive transfer of antigen-specific T cells expressing erythropoietin (EPO) elevating the hematocrit in mice for more than 20 weeks. We extend our observations to human T cells demonstrating inducible EPO production from Epstein-Barr virus (EBV) antigen-specific T lymphocytes. Our results reveal antigen-specific T lymphocytes to be an effective delivery platform for therapeutic molecules such as EPO in vivo, with important implications for other diseases that require peptide therapy.
OBJECTIVES - When examining vaccination coverage, researchers must make decisions about how to define outcome measures based on many factors, including the timing of doses. Different operationalizations of the same outcome can often lead to different findings and can affect the ability to make comparisons across studies. This methodological article aimed to illustrate the implications of two options for operationalizing human papillomavirus (HPV) vaccination based on timing: initiation of the first dose at any age vs before the 13th birthday (on time).
STUDY DESIGN - Cross-sectional observational design.
METHODS - The 2014 National Immunization Survey for Teens (N = 16,439 adolescents aged 13-17 years) was analyzed using multivariate logistic regression for each outcome measure and effect modification by gender.
RESULTS - Age was positively associated with initiation at any age but negatively associated with on-time initiation. Gender modified the effect of race/ethnicity for both measures of initiation, but the pattern across groups was different for the two outcomes. Gender modified the effect of provider recommendation for initiation at any age, while gender modified the effects of age and region for on-time initiation.
CONCLUSION - Decisions of how to operationalize outcomes of HPV vaccine initiation among adolescents can lead to different conclusions about the role of age and gender differences for several predictive variables. To inform the development of public health efforts that promote on-time HPV vaccination among male and female adolescents, researchers should consider the importance of dose timing when operationalizing outcome measures. We recommend including on-time receipt of the HPV vaccine as an outcome measure.
Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.
Antibodies are the principal immune effectors that mediate protection against reinfection following viral infection or vaccination. Robust techniques for human mAb isolation have been developed in the last decade. The study of human mAbs isolated from subjects with prior immunity has become a mainstay for rational structure-based, next-generation vaccine development. The plethora of detailed molecular and genetic studies coupling the structure of antigen-antibody complexes with their antiviral function has begun to reveal common principles of critical interactions on which we can build better vaccines and therapeutic antibodies. This review outlines the approaches to isolating and studying human antiviral mAbs and discusses the common principles underlying the basis for their activity. This review also examines progress toward the goal of achieving a comprehensive understanding of the chemical and physical basis for molecular recognition of viral surface proteins in order to build predictive molecular models that can be used for vaccine design.
Copyright © 2017. Published by Elsevier Inc.
Male genital human papillomavirus (HPV) prevalence and incidence has been reported to vary by geographical location. Our objective was to assess the natural history of genital HPV by country among men with a median of 48 months of follow-up. Men ages 18-70 years were recruited from United States ( = 1,326), Mexico ( = 1,349), and Brazil ( = 1,410). Genital specimens were collected every 6 months and HPV genotyping identified 37 HPV genotypes. Prevalence of HPV was compared between the three countries using the Fisher exact test. Incidence rates and 95% confidence intervals were calculated. The median time to HPV clearance among men with an incident infection was estimated using the Kaplan-Meier method. The prevalence and incidence of the genital HPV types known to cause disease in males (HPV 16 and 6) was significantly higher among men from Brazil than men from Mexico. Prevalence and incidence of those genital HPV types in the United States varied between being comparable with those of Mexico or Brazil. Although genital HPV16 duration was significantly longer in Brazil ( = 0.04) compared with Mexico and the United States, HPV6 duration was shortest in Brazil ( = 0.03) compared with Mexico and the United States. Men in Brazil and Mexico often have similar, if not higher prevalence of HPV compared with men from the United States. Currently, there is no routine screening for genital HPV among males and while HPV is common in men, and most naturally clear the infection, a proportion of men do develop HPV-related diseases. Men may benefit from gender-neutral vaccine policies. .
©2017 American Association for Cancer Research.
Approximately one-quarter of human papillomavirus (HPV) infections are acquired by adolescents, with a higher burden among racial/ethnic minorities. However, racial/ethnic minorities have been underrepresented in previous HPV vaccine trials. Ongoing and future HPV vaccine optimization trials would benefit from racially- and ethnically-diverse sample of adolescent trial participants. This study examined factors influencing parental willingness to consent to their adolescents' participation in HPV vaccine clinical trials and tested for possible racial differences. A convenience sample of parents of adolescents (N = 256) completed a cross-sectional survey. Chi square analyses were used to assess racial differences in parental HPV vaccine awareness and intentions and willingness to consent to their child participating in an HPV vaccine clinical trial. Ordinal logistic regression was used to identify factors associated with willingness. Approximately 47% of parents were willing to allow their adolescent to participate in HPV vaccine clinical trials (30.7% African American and 48.3% Caucasian, p = .081). African Americans had lower HPV vaccine awareness (p = .006) but not lower intentions to vaccinate (p = .086). Parental willingness was positively associated with the following variables: Child's age (p < .039), Perceived Advantages of HPV Vaccination for Adolescents (p = .002), Parental Trust in Medical Researchers (p < .001), and Level of Ease in Understanding Clinical Trial Information (p = .010). Educating parents about the advantages of HPV vaccines for younger adolescents using low-literacy educational materials and building trust between parents and researchers may increase parental willingness to consent to adolescent participation in HPV vaccine clinical trials.
BACKGROUND - Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
OBJECTIVE AND METHODS - We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
RESULTS - Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
CONCLUSIONS - Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
TRIAL REGISTRATION - ClinicalTrials.gov NCT01573312.
The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses responsible for dengue fever and dengue hemorrhagic fever. People exposed to DENV develop antibodies (Abs) that strongly neutralize the serotype responsible for infection. Historically, infection with DENV serotype 4 (DENV4) has been less common and less studied than infections with the other three serotypes. However, DENV4 has been responsible for recent large and sustained epidemics in Asia and Latin America. The neutralizing antibody responses and the epitopes targeted against DENV4 have not been characterized in human infection. In this study, we mapped and characterized epitopes on DENV4 recognized by neutralizing antibodies in people previously exposed to DENV4 infections or to a live attenuated DENV4 vaccine. To study the fine specificity of DENV4 neutralizing human antibodies, B cells from two people exposed to DENV4 were immortalized and screened to identify DENV-specific clones. Two human monoclonal antibodies (MAbs) that neutralized DENV4 were isolated, and their epitopes were finely mapped using recombinant viruses and alanine scan mutation array techniques. Both antibodies bound to quaternary structure epitopes near the hinge region between envelope protein domain I (EDI) and EDII. In parallel, to characterize the serum neutralizing antibody responses, convalescence-phase serum samples from people previously exposed to primary DENV4 natural infections or a monovalent DENV4 vaccine were analyzed. Natural infection and vaccination also induced serum-neutralizing antibodies that targeted similar epitope domains at the EDI/II hinge region. These studies defined a target of neutralizing antigenic site on DENV4 targeted by human antibodies following natural infection or vaccination. The four serotypes of dengue virus are the causative agents of dengue fever and dengue hemorrhagic fever. People exposed to primary DENV infections develop long-term neutralizing antibody responses, but these principally recognize only the infecting serotype. An effective vaccine against dengue should elicit long-lasting protective antibody responses to all four serotypes simultaneously. We and others have defined antigenic sites on the envelope (E) protein of viruses of dengue virus serotypes 1, 2, and 3 targeted by human neutralizing antibodies. The epitopes on DENV4 E protein targeted by the human neutralizing antibodies and the mechanisms of serotype 4 neutralization are poorly understood. Here, we report the properties of human antibodies that neutralize dengue virus serotype 4. People exposed to serotype 4 infections or a live attenuated serotype 4 vaccine developed neutralizing antibodies that bound to similar sites on the viral E protein. These studies have provided a foundation for developing and evaluating DENV4 vaccines.
Copyright © 2017 American Society for Microbiology.