Wellness and Multiple Sclerosis: The National MS Society Establishes a Wellness Research Working Group and Research Priorities

Background: People with multiple sclerosis (MS) have identified “wellness” and associated behaviors as a high priority based on “social media listening” undertaken by the National MS Society (i.e. the Society). Objective: The Society recently convened a group that consisted of researchers with experience in MS and wellness-related research, Society staff members, and an individual with MS for developing recommendations regarding a wellness research agenda. Method: The members of the group engaged in focal reviews and discussions involving the state of science within three approaches for promoting wellness in MS, namely diet, exercise, and emotional wellness. Results: That process informed a group-mediated activity for developing and prioritizing research goals for wellness in MS. This served as a background for articulating the mission and objectives of the Society’s Wellness Research Working Group. Conclusion: The primary mission of the Wellness Research Working Group is the provision of scientific evidence supporting the application of lifestyle, behavioral, and psychosocial approaches for promoting optimal health of mind, body, and spirit (i.e. wellness) in people with MS as well as managing the disease and its consequences

Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization

T cells are an important component of immune responses, and their function is influenced by their expression of inhibitory receptors. Immunization with alternative serotype adenovirus (Ad) vectors induces highly functional T cell responses with lower programmed cell death 1 (PD-1) expression and increased boostability relative to Ad5 vectors. However, a detailed phenotypic characterization of other inhibitory receptors is lacking, and it is unknown whether Ad5-induced CD8 T cells eventually recover function with time. In this report, we measure the expression of various inhibitory receptors and memory markers during early and late time points following vaccination with Ad5 and alternative serotype Ad vectors. CD8 T cells induced by Ad5 exhibited increased expression of the inhibitory receptor Tim-3 and showed decreased central memory differentiation as compared with alternative serotype Ad vectors, even a year following immunization. Moreover, relative to Ad5-primed mice, Ad26-primed mice exhibited substantially improved recall of SIV Gag-specific CD8 T cell responses following heterologous boosting with MVA or Ad35 vectors. We also demonstrate that low doses of Ad5 priming resulted in more boostable immune responses with lower PD-1 expression as compared to high Ad5 doses, suggesting a role for vector dose in influencing immune dysfunction following Ad5 vaccination. These data suggest that Ad5 vectors induce a long-term pattern of immune exhaustion that can be partly overcome by lowering vector dose and modulating inhibitory signals

ANXIETY, DEPRESSION, AND HOSTILITY IN PRIMIPAROUS FATHERS AS A FUNCTION OF CHILDBIRTH EXPERIENCE

Childbirth has been described as an important period for the development of the maternal role. Similarly, the father\u27s psychological reactions to childbirth might influence his growth into fatherhood. Fathers, however, have received less attention than mothers in the literature. Research has suggested that parturition is an event of great psychological significance for men. The father\u27s reactions to childbirth are reportedly more positive if he becomes more actively involved in the process. Previous studies, though, have often employed unstandardized assessment procedures and have usually examined very few features of the father\u27s experience. The objectives of the present research were to evaluate some of the psychological effects of childbirth on first-time fathers and to determine in what ways differences in (1) the father\u27s level of participation and in (2) childbirth complications were associated with differences in reactions to the birth experience. It was hypothesized that for all fathers, relatively more positive reactions would be associated with prenatal training, attendance at the delivery, early and extensive contact with the baby, a less complicated delivery, a shorter labor, and a wife who was relatively more conscious during delivery. In addition, for fathers whose wives had cesareans, it was further hypothesized that relatively more positive reactions would be associated with prenatal training which dealt with cesareans and with greater advanced warning that a cesarean would be performed. Subjects were 110 primiparous fathers of full term, singleton infants recruited from the maternity ward of Nassau Hospital in Mineola, New York. Ages ranged from 20 to 42 with a mean of 29. The sample was predominantly white (94%), American born (90%), and well educated (58% completed college). Most of the fathers had prenatal training (90%) and attended the delivery (79%). One-third of the births were by cesarean section. Fathers\u27 reactions to the birth were assessed using the anxiety, depression, and hostility scales of the Multiple Affect Adjective Check List (MAACL). Participation and extent of complications were assessed through a Postpartum Questionnaire (PPQ) designed for the study. Within 48 hours of the birth fathers were asked to complete the MAACL four times in order to describe: (1) how they generally felt; (2) how they felt during labor; (3) how they felt during delivery; and (4) how they felt postpartum. The PPQ was administered after the MAACL\u27s. Results indicated that father\u27s postpartum anxiety, depression, and hostility did not differ from their general levels of these affects. However, anxiety, depression, and hostility during birth were higher than either postpartum or general levels. In addition, anxiety and depression during delivery were higher than during labor. Prenatal training was associated with lower depression (during delivery). Father attendance at delivery was associated with lower anxiety and depression (during both labor and delivery) and with lower hostility (during delivery). Earlier father-infant contact was associated with lower depression (during labor). A less complicated delivery was associated with lower anxiety and depression (during delivery). A relatively more conscious wife was associated with lower anxiety and depression (during both labor and delivery). None of the other predictions were supported. More positive reactions were associated with greater participation and fewer complications. Moreover, in complicated births, paternal participation was lower. When a high level of participation accompanied complications, the father\u27s reactions were more positive than when participation was curtailed. The results suggest that opportunity for husband-wife interaction may be one of the most significant determinants of paternal reactions

Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE: To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors

Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE: To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors

Transient CD4+ T Cell Depletion Results in Delayed Development of Functional Vaccine-Elicited Antibody Responses

ABSTRACT We have recently demonstrated that CD4+ T cell help is required at the time of adenovirus (Ad) vector immunization for the development of functional CD8+ T cell responses, but the temporal requirement for CD4+ T cell help for the induction of antibody responses remains unclear. Here we demonstrate that induction of antibody responses in C57BL/6 mice can occur at a time displaced from the time of Ad vector immunization by depletion of CD4+ T cells. Transient depletion of CD4+ T cells at the time of immunization delays the development of antigen-specific antibody responses but does not permanently impair their development or induce tolerance against the transgene. Upon CD4+ T cell recovery, transgene-specific serum IgG antibody titers develop and reach a concentration equivalent to that in undepleted control animals. These delayed antibody responses exhibit no functional defects with regard to isotype, functional avidity, expansion after boosting immunization, or the capacity to neutralize a simian immunodeficiency virus (SIV) Env-expressing pseudovirus. The development of this delayed transgene-specific antibody response is temporally linked to the expansion of de novo antigen-specific CD4+ T cell responses, which develop after transient depletion of CD4+ T cells. These data demonstrate that functional vaccine-elicited antibody responses can be induced even if CD4+ T cell help is provided at a time markedly separated from the time of vaccination. IMPORTANCE: CD4+ T cells have a critical role in providing positive help signals to B cells, which promote robust antibody responses. The paradigm is that helper signals must be provided immediately upon antigen exposure, and their absence results in tolerance against the antigen. Here we demonstrate that, in contrast to the current model that the absence of CD4+ T cell help at priming results in long-term antibody nonresponsiveness, antibody responses can be induced by adenovirus vector immunization or alum-adjuvanted protein immunization even if CD4+ T cell help is not provided until >1 month after immunization. These data demonstrate that the time when CD4+ T cell help signals must be provided is more dynamic and flexible than previously appreciated. These data suggest that augmentation of CD4+ T cell helper function even after the time of vaccination can enhance vaccine-elicited antibody responses and thereby potentially enhance the immunogenicity of vaccines in immunocompromised individuals

Immediate dysfunction of vaccine-elicited CD8+ T cells primed in the absence of CD4+ T cells

CD4(+) T cell help is critical for optimal CD8(+) T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8(+) T cell responses in the absence of CD4(+) T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4(+) T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8(+) T cell functionality and differentiation. Unhelped CD8(+) T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8(+) T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4(+) T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4(+) T cell help is required to promote both the expansion and acquisition of effector functions by CD8(+) T cells, which is accomplished by preventing immediate dysfunction