Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity
Not Available
Martins, Karen A. O.↗
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Virus-like particle vaccine primes immune responses preventing inactivated-virus vaccine-enhanced disease against respiratory syncytial virus
Formalin inactivated respiratory syncytial virus (FI-RSV) vaccination caused vaccine-enhanced respiratory disease (ERD) upon exposure to RSV in children. Virus-like particles presenting RSV F fusion protein (F VLP) are known to increase T helper type-1 (Th1) immune responses and avoid ERD in animal models. We hypothesized that F VLP would prime immune responses preventing ERD upon subsequent exposure to ERD-prone FI-RSV. Here, we demonstrated that heterologous F VLP priming and FI-RSV boosting of mice prevented FI-RSV vaccine-enhanced lung inflammation and eosinophilia upon RSV challenge. F VLP priming redirected pulmonary T cells toward effector CD8 T cells producing Th1 cytokines and significantly suppressed pulmonary Th2 cytokines. This study suggests that RSV F VLP priming would modulate and shift immune responses to subsequent exposure to ERD-prone FI-RSV vaccine and RSV infection, suppressing Th2 immune-mediated pulmonary histopathology and eosinophilia. - Highlights: • RSV F VLP priming dictates the type of subsequent immune responses to FI-RSV. • F VLP priming redirects pulmonary T cells toward effector CD8 T cells. • F VLP priming suppresses Th2 immune-mediated pulmonary histopathology.
60 APPLIED LIFE SCIENCES↗
Epidemiological investigation of coccidiosis and associated risk factors in broiler chickens immunized with live anticoccidial vaccines in China
Coccidiosis is a costly intestinal disease of chickens caused by Eimeria species. This infection is associated with high mortality, reduced feed efficiency, and slowed body weight gain. The diagnosis and control of coccidiosis becomes challenging due to the fact that chickens can be infected by seven different Eimeria species and often occur mixed-species co-infections. Grasping the epidemiology of Eimeria species is crucial to estimate the efficiency of poultry management. This study aimed to explore the distribution of Eimeria species in broiler chickens in China after administering live anticoccidial vaccines. A total of 634 samples were obtained, and the survey results showed that the prevalence of Eimeria was 86.12% (546/634), and the most common species were E. acervulina (65.62%), E. necatrix (50.95%), E. mitis (50.79%), E. tenella (48.42%), and E. praecox (41.80%). Most samples indicated mixed-species infections (an average of 3.29 species per positive sample). Notably, 63.98% of samples contain 3 to 5 Eimeria species within a single fecal sample. The most prevalent combinations were E. acervulina – E. tenella (38.96%) and E. acervulina – E. necatrix (37.22%). Statistical analysis showed that flocks vaccinated with trivalent vaccines were significantly positive for E. necatrix in grower chickens (OR = 3.30, p < 0.05) compared with starter chickens, and tetravalent vaccinated flocks showed that starter chickens demonstrated a higher susceptibility to E. tenella – E. brunetti (OR = 2.03, p < 0.05) and E. acervulina – E. maxima (OR = 2.05, p < 0.05) compared with adult chickens. Geographically, in the case of tetravalent vaccine-immunized flocks, a substantial positive association was observed between E. necatrix infection rates and flocks from eastern (OR = 3.88, p < 0.001), central (OR = 2.65, p = 0.001), and southern China (OR = 3.17, p < 0.001) compared with southwestern China. This study also found a positive association between E. necatrix (OR = 1.64, p < 0.05), E. acervulina (OR = 1.59, p < 0.05), and E. praecox (OR = 1.81, p < 0.05) infection and coccidiosis occurrence compared with non-infected flocks in tetravalent vaccinated flocks. This molecular epidemiological investigation showed a high prevalence of Eimeria species in the field. The emergent species, E. brunetti and E. praecox , might be incorporated into the widely-used live vaccines in the future. These insights could be useful in refining coccidiosis control strategies in the poultry industry.
Liao, Shenquan↗
Precancer Atlas to Drive Precision Prevention Trials
Cancer development is a complex process driven by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer elimination, but making this a reality will take a fundamental rethinking and deep understanding of premalignant biology. Here, we propose a national concerted effort to create a Precancer Atlas (PCA), integrating multi-omics and immunity – basic tenets of the neoplastic process. The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. Emerging genetic and pharmacologic (metformin) disruption of mitochondrial (mt) respiration increased autophagy to prevent cancer in a Li-Fraumeni mouse model (biology reproduced in clinical pilot) and revealed profound influences of subtle changes in mt DNA background variation on obesity, aging, and cancer risk. The elaborate communication between the immune system and neoplasia includes an increasingly complex cellular microenvironment and dynamic interactions between host genetics, environmental factors, and microbes in shaping the immune response. Cancer vaccines are in early murine and clinical precancer studies, building on the recent successes of immunotherapy and HPV vaccine immune prevention. Molecular monitoring in Barrett's esophagus to avoid overdiagnosis/treatment highlights an important PCA theme. Next generation sequencing (NGS) discovered age-related clonal hematopoiesis of indeterminate potential (CHIP). Ultra-deep NGS reports over the past year have redefined the premalignant landscape remarkably identifying tiny clones in the blood of up to 95% of women in their 50s, suggesting that potentially premalignant clones are ubiquitous. Similar data from eyelid skin and peritoneal and uterine lavage fluid provide unprecedented opportunities to dissect the earliest phases of stem/progenitor clonal (and microenvironment) evolution/diversity with new single-cell and liquid biopsy technologies. Cancer mutational signatures reflect exogenous or endogenous processes imprinted over time in precursors. In conclusion, accelerating the prevention of cancer will require a large-scale, longitudinal effort, leveraging diverse disciplines (from genetics, biochemistry, and immunology to mathematics, computational biology, and engineering), initiatives, technologies, and models in developing an integrated multi-omics and immunity PCA – an immense national resource to interrogate, target, and intercept events that drive oncogenesis.
59 BASIC BIOLOGICAL SCIENCES↗
Prophylactic treatment with PEGylated bovine IFNλ3 effectively bridges the gap in vaccine-induced immunity against FMD in cattle
Foot-and-mouth disease (FMD) is a vesicular disease of cloven-hoofed animals with devastating economic implications. The current FMD vaccine, routinely used in enzootic countries, requires at least 7 days to induce protection. However, FMD vaccination is typically not recommended for use in non-enzootic areas, underscoring the need to develop new fast-acting therapies for FMD control during outbreaks. Interferons (IFNs) are among the immune system’s first line of defense against viral infections. Bovine type III IFN delivered by a replication defective adenovirus (Ad) vector has effectively blocked FMD in cattle. However, the limited duration of protection—usually only 1–3 days post-treatment (dpt)—diminishes its utility as a field therapeutic. Here, we test whether polyethylene glycosylation (PEGylation) of recombinant bovine IFNλ3 (PEGboIFNλ3) can extend the duration of IFN-induced prevention of FMDV infection in both vaccinated and unvaccinated cattle. We treated groups of heifers with PEGboIFNλ3 alone or in combination with an adenovirus-based FMD O1Manisa vaccine (Adt-O1M) at either 3 or 5 days prior to challenge with homologous wild type FMDV. We found that pre-treatment with PEGboIFNλ3 was highly effective at preventing clinical FMD when administered at either time point, with or without co-administration of Adt-O1M vaccine. PEGboIFNλ3 protein was detectable systemically for >10 days and antiviral activity for 4 days following administration. Furthermore, in combination with Adt-O1M vaccine, we observed a strong induction of FMDV-specific IFNγ+ T cell response, demonstrating its adjuvanticity when co-administered with a vaccine. Our results demonstrate the promise of this modified IFN as a pre-exposure prophylactic therapy for use in emergency outbreak scenarios.
biotherapeutics↗
Hepatitis A virus immunity and vaccination among at-risk persons receiving HIV medical care
Not Available
DeGroote, Nicholas P.↗
Mathematical model of a personalized neoantigen cancer vaccine and the human immune system
Cancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4 + and CD8 + T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patient’s immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patient’s major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). This model, although complex, can be used to describe, simulate, and predict the behavior of the human immune system to a personalized cancer vaccine.
60 APPLIED LIFE SCIENCES↗
Vaccine based on antibody-dependent cell-mediated cytotoxicity epitope on the H1N1 influenza virus increases mortality in vaccinated mice
Antibody-dependent cell-mediated cytotoxicity bridges humoral immunity and cellular immunity. Thus vaccine candidates which can elicit both broadly neutralizing antibodies and potent antibody-dependent cell-mediated cytotoxicity (ADCC) are recommended. Previously, a panel of functional epitopes that can elicit ADCC effects is isolated and characterized on the H1N1 Influenza Virus. Based on these identified epitopes, an epitope vaccine against H1N1 infection has been designed. The serum of vaccine immunized mice show potent ADCC activities in comparison with vector control group and HA ecto domain vaccinated group. However, the release of IL-6 and TNFα is higher in lung of epitope vaccine immunized mice. The viral load is also higher in epitope vaccine immunized mice. In addition, the epitope vaccine immunized mice showed lower survive rate than both empty vector immunized mice and HA ectodomain immunized mice. Passive transfer of serum from epitope vaccine immunized mice to healthy adult mice can decrease the survival rate of recipients after viral challenge. Our data suggested that ADCC epitope based vaccine has a mortality promoting effect rather than protective effect after H1N1 viral challenge. This result provides indications in future vaccine design with a consideration of balancing humoral immune response and cellular immune response.
60 APPLIED LIFE SCIENCES↗
A combined designed CSP and Pfs48/45 infection and transmission blocking vaccine for malaria
Abstract The multiple stages of the malaria parasite life cycle hampers vaccine development. Combining a pre-erythrocytic antigen with a transmission-blocking antigen would target two independent stages of the life cycle for disease control, resulting in a multistage vaccine that can prevent infection and disease transmission simultaneously. Here, we generated a self-assembled ferritin nanoparticle vaccine that simultaneously presents designed immunogens CSPj5c and 17-4 from the infection-blocking circumsporozoite and the transmission-blocking Pfs48/45 antigens. These immunogens were designed, through structure-based approaches, to retain protective epitopes and confer protection upon vaccination. Immunization with CSPj5c-17-4-ferritin nanoparticles conferred protection against challenge with transgenic sporozoites expressingPlasmodium falciparumCSP in mice, and purified IgGs from immunized rabbits elicited potent transmission-reducing activity. Addition of the engineered 17-4 improved the immune responses to CSPj5c and protection from sporozoite challenge. CSPj5c-17-4-ferritin is therefore a promising multistage malaria vaccine with a potential role in malaria control.
Immunology↗
Comprehensive compartmental model and calibration algorithm for the study of clinical implications of the population-level spread of COVID-19: a study protocol
The complex dynamics of the coronavirus disease 2019 (COVID-19) pandemic has made obtaining reliable long-term forecasts of the disease progression difficult. Simple mechanistic models with deterministic parameters are useful for short-term predictions but have ultimately been unsuccessful in extrapolating the trajectory of the pandemic because of unmodelled dynamics and the unrealistic level of certainty that is assumed in the predictions. We propose a 22-compartment epidemiological model that includes compartments not previously considered concurrently, to account for the effects of vaccination, asymptomatic individuals, inadequate access to hospital care, post-acute COVID-19 and recovery with long-term health complications. Additionally, new connections between compartments introduce new dynamics to the system and provide a framework to study the sensitivity of model outputs to several concurrent effects, including temporary immunity, vaccination rate and vaccine effectiveness. Subject to data availability for a given region, we discuss a means by which population demographics (age, comorbidity, socioeconomic status, sex and geographical location) and clinically relevant information (different variants, different vaccines) can be incorporated within the 22-compartment framework. Considering a probabilistic interpretation of the parameters allows the model's predictions to reflect the current state of uncertainty about the model parameters and model states. We propose the use of a sparse Bayesian learning algorithm for parameter calibration and model selection. This methodology considers a combination of prescribed parameter prior distributions for parameters that are known to be essential to the modelled dynamics and automatic relevance determination priors for parameters whose relevance is questionable. This is useful as it helps prevent overfitting the available epidemiological data when calibrating the parameters of the proposed model. Population-level administrative health data will serve as partial observations of the model states.
59 BASIC BIOLOGICAL SCIENCES↗
Bifacial effects of engineering tumour cell-derived exosomes on human natural killer cells
Extracellular vesicles (EVs) are nano vesicular structures that are secreted by almost all kinds of cells. Exosomes are small EVs derived from endosomes, with a diameter between 30–100 nm. Tumour-derived exosomes carry many molecules and factors from tumour cells. These exosomes are recognized and taken up by immunocytes. However, tumour-derived exosomes can not only suppress immune cell functions but also help tumours escape immune surveillance in the tumour microenvironment. The present work investigated the effect of exosomes derived from genetical modified K562 cells (GMK cells), which express IL-15, IL-18 and 4-1BBL (TNFSF9) on their surface. The results showed that these GME exosomes, carrying IL-15, IL-18 and 4-1BBL proteins similar to their host cells, could activate NK cells, increase the cytotoxicity of NK cells on some tumour cells in a short treatment (4 h) and promote NK cells proliferation. However, with an extended treatment time (48 h), these exosomes could inhibite the cytotoxicity of NK cells by inhibiting activated receptor expression on NK cells. These results indicated the bifacial effects of GMK exosomes on NK cells, which will be helpful to explore the possibility of using transformed exosomes as an anti-tumour immune vaccine or a therapeutic tool in future.
60 APPLIED LIFE SCIENCES↗
Characterization of the antispike IgG immune response to COVID-19 vaccines in people with a wide variety of immunodeficiencies
Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA–based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.
60 APPLIED LIFE SCIENCES↗
Vaccination with a DNA vaccine encoding CD317-targeting HBs antigen elicits enhanced immunity in mice
Highlights: • DNA vaccine encoding CD317-targeting HBsAg induces more potent humoral immunity. • DNA vaccine encoding CD317-targeting HBsAg elicits more robust T cell response. • DNA vaccine encoding CD317-targeting HBsAg is a promising candidate for preventing HBV infection. Conventional hepatitis B virus (HBV) vaccines fail to induce protective antibody titers in 5–10% of immune-competent vaccines. Therefore, safe and effective HBV vaccines are still clinically needed.
60 APPLIED LIFE SCIENCES↗
A single intranasal immunization with a subunit vaccine formulation induces higher mucosal IgA production than live respiratory syncytial virus
Respiratory syncytial virus (RSV) causes serious respiratory illness in infants and elderly. RSV infection induces short-lived immunity, which leaves people prone to re-infection. In contrast, the RSV fusion (F) protein formulated with a novel adjuvant (∆F/TriAdj) elicits long term protective immunity. A comparison of RSV-immunized mice to mice vaccinated with a single dose of ∆F/TriAdj showed no difference in IgG1 and IgG2a production; however, local IgA secreting memory B cell development and B cell IgA production were significantly lower in RSV vaccinated mice than in ∆F/TriAdj-immunized mice. This indicates a potential reason as to why long-term immunity is not induced by RSV infection. The comparison also revealed that germinal center lymphocyte populations were higher in ∆F/TriAdj-vaccinated mice. Furthermore, ∆F/TriAdj induced higher gene expression of activation-induced cytidine deaminase (AID), as well as IL-6, IL-21, TGF-β cytokines, which are key players in IgA class switch recombination, ultimately leading to a sustained long-term memory response. - Highlights: •Immune responses to adjuvanted RSV F protein, ∆F/TriAdj, and RSV were compared. •∆F/TriAdj stimulates more local IgA production than RSV. •∆F/TriAdj induces more local IgA secreting memory B cells than RSV. •Germinal center lymphocyte populations are higher in ∆F/TriAdj-vaccinated mice. •∆F/TriAdj induces higher gene expression of AID, IL-6, IL-21, and TGF-β than RSV.
60 APPLIED LIFE SCIENCES↗
Conscientious vaccination exemptions in kindergarten to eighth-grade children across Texas schools from 2012 to 2018: A regression analysis
Background: As conscientious vaccination exemption (CVE) percentages rise across the United States, so does the risk and occurrence of outbreaks of vaccine-preventable diseases such as measles. In the state of Texas, the median CVE percentage across school systems more than doubled between 2012 and 2018. During this period, the proportion of schools surpassing a CVE percentage of 3% rose from 2% to 6% for public schools, 20% to 26% for private schools, and 17% to 22% for charter schools. The aim of this study was to investigate this phenomenon at a fine scale. Methods and findings: Here, we use beta regression models to study the socioeconomic and geographic drivers of CVE trends in Texas. Using annual counts of CVEs at the school system level from the 2012–2013 to the 2017–2018 school year, we identified county-level predictors of median CVE percentage among public, private, and charter schools, the proportion of schools below a high-risk threshold for vaccination coverage, and five-year trends in CVEs. Since the 2012–2013 school year, CVE percentages have increased in 41 out of 46 counties in the top 10 metropolitan areas of Texas. We find that 77.6% of the variation in CVE percentages across metropolitan counties is explained by median income, the proportion of the population that holds a bachelor's degree, the proportion of the population that self-reports as ethnically white, the proportion of the population that is English speaking, and the proportion of the population that is under the age of five years old. Across the 10 top metropolitan areas in Texas, counties vary considerably in the proportion of school systems reporting CVE percentages above 3%. Sixty-six percent of that variation is explained by the proportion of the population that holds a bachelor’s degree and the proportion of the population affiliated with a religious congregation. Three of the largest metropolitan areas—Austin, Dallas–Fort Worth, and Houston—are potential vaccination exemption "hotspots," with over 13% of local school systems above this risk threshold. The major limitations of this study are inconsistent school-system-level CVE reporting during the study period and a lack of geographic and socioeconomic data for individual private schools. Conclusions: In this study, we have identified high-risk communities that are typically obscured in county-level risk assessments and found that public schools, like private schools, are exhibiting predictable increases in vaccination exemption percentages. As public health agencies confront the reemerging threat of measles and other vaccine-preventable diseases, findings such as ours can guide targeted interventions and surveillance within schools, cities, counties, and sociodemographic subgroups.
59 BASIC BIOLOGICAL SCIENCES↗
Network Effects of Risk Behavior Change Following Prophylactic Interventions
We formulated a network-based model to understand how risk behavior change in conjunction with failure of prophylactic interventions can lead to unintended outcomes where ‘‘less (intervention) is more (effective).’’ Our model captures the distinction between one- and two-sided risk behavior change. In one-sided situations (e.g. influenza/H1N1) it is sufficient for either individual in an interaction to exhibit risk behavior change whereas in two-sided situations (e.g. AIDS/HIV) it is necessary for both individuals in the interaction to exhibit risk behavior change, for a potential transmission of the disease. A central discovery is that this phenomenon occurs at differing levels of intervention coverage depending upon the ‘‘sidedness’’ of the interaction. We find that for one-sided interactions, sufficiently high vaccination coverage is necessary for mitigating the effects of risk behavior; for two-sided interactions, it is essential to combine prophylactic treatments with programs aimed at reducing risky behavior. Furthermore, again dependent on the ‘‘sidedness,’’ targeting highly connected nodes can be strictly worse than uniformly random interventions at the same level of coverage.
97 MATHEMATICS AND COMPUTING↗
Adult immunization policies in advanced economies: vaccination recommendations, financing, and vaccination coverage
Objectives: While many countries have robust child immunization programs and high child vaccination coverage, vaccination of adults has received less attention. The objective of this study was to describe the adult vaccination policies in developed countries. Methods: From 2010 to 2011, we conducted a survey of 33 advanced economies as defined by the International Monetary Fund. The survey asked about national recommendations for adults for 16 vaccines or vaccine components, funding mechanisms for recommended adult vaccines, and the availability of adult vaccination coverage estimates. Results: Thirty-one of 33 (93.9 %) advanced economies responded to the survey. Twelve of 31 (38.7 %) reported having a comprehensive adult immunization schedule. The total number of vaccines or vaccine components recommended for adults ranged from one to 15 with a median of 10. Seasonal influenza (n = 30), tetanus (n = 28), pneumococcal polysaccharide (n = 27), and hepatitis B (n = 27) were the most frequently recommended vaccines or components. Conclusions: Approximately two-thirds of survey respondents do not have a comprehensive adult vaccine schedule, and most do not measure vaccination coverage. We found that a funding mechanism is available for most recommended adult vaccines.
59 BASIC BIOLOGICAL SCIENCES↗