Long-term Immunity Research Articles

Babesia microti alleviates disease manifestations caused by Plasmodium berghei ANKA in murine co-infection model of complicated malaria.

Malaria remains one of the most significant health issues worldwide, accounting for 2.6% of the total global disease burden, and efforts to eliminate this threat continue. The key focus is to develop an efficient and long-term immunity to this disease via vaccination or therapeutic approach, and innovative strategies would enable us to achieve this target. Previously, using a mouse co-infection disease model, cross-protection was illustrated between Babesia microti and Plasmodium chabaudi. Hence, this study was planned to elucidate the impact of acute B. microti Peabody mjr and Plasmodium berghei ANKA co-infection on the consequence of complicated malaria in the C57BL/6J mouse model of malaria. Furthermore, immune response and pathological features were analyzed, and the course of the disease was compared among experimental groups. Our study established that acute B. microti infection activated immunity which was otherwise suppressed by P. berghei. The immunosuppressive tissue microenvironment was counteracted as evidenced by the enhanced immune cell population in co-infected mice, in contrast to P. berghei-infected control mice. Parasite sequestration in the brain, liver, lung, and spleen of co-infected mice was significantly decreased and tissue injury was ameliorated. Meanwhile, the serum levels of IFN-γ, TNF-α, and IL-12p70 were reduced while the secretion of IL-10 was promoted in co-infected mice. Eventually, co-infected mice showed an extended rate of survival. Hereby, the principal cytokines associated with the severity of malaria by P. berghei infection were TNF-α, IFN-γ, and IL-12p70. Moreover, it was evident from our flow cytometry results that innate immunity is crucial and macrophages are at the frontline of immunity against P. berghei infection. Our study recommended further investigations to shed light on the effects of babesiosis in suppressing malaria with the goal of developing Babesia-based therapy against malaria.

Combination of cancer vaccine with CD122-biased IL-2/anti-IL-2 Ab complex shapes the stem-like effector NK and CD8+ T cells against tumor

BackgroundA key to success of cancer immunotherapy is the amplification and sustenance of various effector cells. The hallmark of prominent antitumor T cells is their long-term effector function. Although interleukin...

Effects of an aged tissue niche on the immune potency of dendritic cells using simulated microgravity

Microgravity accelerates the aging of various physiological systems, and it is well acknowledged that aged individuals and astronauts both have increased susceptibility to infections and poor response to vaccination. Immunologically, dendritic cells (DCs) are the key players in linking innate and adaptive immune responses. Their distinct and optimized differentiation and maturation phases play a critical role in presenting antigens and mounting effective lymphocyte responses for long-term immunity. Despite their importance, no studies to date have effectively investigated the effects of microgravity on DCs in their native microenvironment, which is primarily located within tissues. Here, we address a significantly outstanding research gap by examining the effects of simulated microgravity via a random positioning machine on both immature and mature DCs cultured in biomimetic collagen hydrogels, a surrogate for tissue matrices. Furthermore, we explored the effects of loose and dense tissues via differences in collagen concentration. Under these various environmental conditions, the DC phenotype was characterized using surface markers, cytokines, function, and transcriptomic profiles. Our data indicate that aged or loose tissue and exposure to RPM-induced simulated microgravity both independently alter the immunogenicity of immature and mature DCs. Interestingly, cells cultured in denser matrices experience fewer effects of simulated microgravity at the transcriptome level. Our findings are a step forward to better facilitate healthier future space travel and enhance our understanding of the aging immune system on Earth.

Immunological imprinting of humoral immunity to SARS-CoV-2 in children

Omicron variants of SARS-CoV-2 are globally dominant and infection rates are very high in children. We measure immune responses following Omicron BA.1/2 infection in children aged 6-14 years and relate this to prior and subsequent SARS-CoV-2 infection or vaccination. Primary Omicron infection elicits a weak antibody response with poor functional neutralizing antibodies. Subsequent Omicron reinfection or COVID-19 vaccination elicits increased antibody titres with broad neutralisation of Omicron subvariants. Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primes for robust antibody responses following Omicron infection but these remain primarily focussed against ancestral variants. Primary Omicron infection thus elicits a weak antibody response in children which is boosted after reinfection or vaccination. Cellular responses are robust and broadly equivalent in all groups, providing protection against severe disease irrespective of SARS-CoV-2 variant. Immunological imprinting is likely to act as an important determinant of long-term humoral immunity, the future clinical importance of which is unknown.

MRNA-based SARS-CoV-2 Comirnaty vaccine elicits weak and short specific memory B cell response in individuals with no previous infection.

The dynamics of the memory B cell (MBC) repertoire after SARS-CoV-2 vaccination is crucial for assessing long-term immunity. We compare spike-specific MBC responses between SARS-CoV-2 unexposed and recovered individuals, and their impact on breakthrough infections during follow-up. Spike-specific MBC and T cells were quantified at inclusion and after two doses of mRNA vaccine in a longitudinal cohort of 85 naïve and 64 recovered participants (47 with positive serology and 17 with negative serology after infection). At inclusion, there was minimal spike-specific MBC in naïve SARS-CoV-2 individuals. After the second vaccine dose, MBCs were significantly boosted in naïve individuals, but reached a significantly lower level than that observed even in unvaccinated SARS-CoV-2 convalescents (p<0.001). Furthermore, while the secondary memory B cell (MBC) population consisted of 100%, 33%, and 76% IgG+, IgM+, and IgA+ expressing cells, respectively, in the unexposed group, the MBC response showed a significant decrease across all isotypes. Similarly, although secondary specific IgG+, IgM+, and IgA+-MBC isotypes were found in 100%, 39%, and 76% of the unexposed participants, respectively, the magnitude of the MBC levels was significantly lower for all the isotypes compared to convalescents. Interestingly, convalescents without an initial serological response had a lower MBC response, like what found in unexposed subjects. There was an inverse correlation between specific MBCs (r=-0.307; p=0.027), especially for isotype IgA+ (r=-0.279, p=0.045), and the time since the second vaccination dose. Furthermore, during a median follow-up of 434 days (IQR, 339-495), 49 out of 149 individuals (33%) became infected, 29 in naïve and 20 in convalescent individuals, showing a significant correlation between spike-specific MBC magnitude after vaccination and the time for SARS-CoV-2 infection, especially for IgA+/IgG+ MBC isotypes. MBCs were primed by mRNA-based vaccination in most cases, but SARS-CoV-2 naïve individuals had a blunted specific MBC response, and this was associated with a shorter time to breakthrough SARS-CoV-2 infection.

Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix.

The efficacy of adoptive T-cell therapies largely depends on the generation of T-cell populations that provide rapid effector function and long-term protective immunity. Yet it is becoming clearer that the phenotypes and functions of T cells are inherently linked to their localization in tissues. Here we show that functionally distinct T-cell populations can be generated from T cells that received the same stimulation by altering the viscoelasticity of their surrounding extracellular matrix (ECM). By using a model ECM based on a norbornene-modified collagen type I whose viscoelasticity can be adjusted independently from its bulk stiffness by varying the degree of covalent crosslinking via a bioorthogonal click reaction with tetrazine moieties, we show that ECM viscoelasticity regulates T-cell phenotype and function via the activator-protein-1 signalling pathway, a critical regulator of T-cell activation and fate. Our observations are consistent with the tissue-dependent gene-expression profiles of T cells isolated from mechanically distinct tissues from patients with cancer or fibrosis, and suggest that matrix viscoelasticity could be leveraged when generating T-cell products for therapeutic applications.

Induction of humoral and cell-mediated immunity in mice by chitosan-curdlan composite nanoparticles administered intranasally and subcutaneously

Infectious diseases seriously threaten human life. The need for novel delivery systems and adjuvants suitable to be used in clinic for antigens remains a challenge. Among various attempts that have been made to provide optimum immune responses for protein antigens with poor immunogenicity, polymeric nanoparticles offer great opportunities. In this study, carboxymethyl curdlan (CMC) as a polyanionic polymer and chitosan chloride (CC) and N-trimethyl chitosan (TMC) as polycationic polymers were synthesised in-house and composite nanoparticles (CC-CMC-BSA and TMC-CMC-BSA) loaded with bovine serum albumin (BSA) as a model antigen were prepared via polyelectrolyte complexation and reported here for the first time. Nanoparticles with an average size ranging from 153 nm to 615 nm, positive surface charge (from +24 mV to +55 mV) and encapsulation efficiency as high as 90% were obtained depending on the concentration of polymers in the formulation. The nanoparticles showed good physical stability for three months and low toxicity in Calu-3 and A549 cells. Furthermore, SDS integrity of antigen was maintained. In vivo studies in mice indicated that nasal and subcutaneous administration of composite nanoparticles could provide long-term humoral and cellular immunity as determined by serum antibody titres (IgG, IgG1, IgG2a) and cytokine (IL-2, IL-4, IL-6, IL-10 and IFN-γ) levels. Elevated sIgA levels after nasal administration of the nanoparticles showed that mucosal immunity was successfully stimulated. These findings suggest that chitosan-curdlan composite nanoparticles show optimum properties to be used as nanovaccine for nasal immunisation of protein antigens.

Nanoparticle-enhanced proton beam immunoradiotherapy drives immune activation and durable tumor rejection.

The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of lung cancer in mice, we show that PBT in tandem with an anti-PD1 antibody substantially reduced growth in both irradiated and unirradiated tumors. This was accompanied by robust activation of the immune response, as evidenced by whole-tumor and single-cell RNA sequencing showing upregulation of a multitude of immune-related transcripts. This response was further significantly enhanced by the injection of the tumor to be irradiated with NBTXR3 nanoparticles. Tumors of mice treated with the triple combination exhibited increased infiltration and activation of cytotoxic immune cells. This triple combination eradicated both tumors in 37.5% of the treated mice and showed robust long-term immunity to cancer.

Immunogenicity and efficacy of a novel multi-patch SARS-CoV-2/COVID-19 vaccine candidate.

While there has been considerable progress in the development of vaccines against SARS-CoV-2, largely based on the S (spike) protein of the virus, less progress has been made with vaccines delivering different viral antigens with cross-reactive potential. In an effort to develop an immunogen with the capacity to induce broad antigen presentation, we have designed a multi-patch synthetic candidate containing dominant and persistent B cell epitopes from conserved regions of SARS-CoV-2 structural proteins associated with long-term immunity, termed CoV2-BMEP. Here we describe the characterization, immunogenicity and efficacy of CoV2-BMEP using two delivery platforms: nucleic acid DNA and attenuated modified vaccinia virus Ankara (MVA). In cultured cells, both vectors produced a main protein of about 37 kDa as well as heterogeneous proteins with size ranging between 25-37 kDa. In C57BL/6 mice, both homologous and heterologous prime/boost combination of vectors induced the activation of SARS-CoV-2-specific CD4 and CD8 T cell responses, with a more balanced CD8+ T cell response detected in lungs. The homologous MVA/MVA immunization regimen elicited the highest specific CD8+ T cell responses in spleen and detectable binding antibodies (bAbs) to S and N antigens of SARS-CoV-2. In SARS-CoV-2 susceptible k18-hACE2 Tg mice, two doses of MVA-CoV2-BMEP elicited S- and N-specific bAbs as well as cross-neutralizing antibodies against different variants of concern (VoC). After SARS-CoV-2 challenge, all animals in the control unvaccinated group succumbed to the infection while vaccinated animals with high titers of neutralizing antibodies were fully protected against mortality, correlating with a reduction of virus infection in the lungs and inhibition of the cytokine storm. These findings revealed a novel immunogen with the capacity to control SARS-CoV-2 infection, using a broader antigen presentation mechanism than the approved vaccines based solely on the S antigen.

World Hepatitis day 2021 –screening and vaccination against Hepatitis B virus in Accra, Ghana

BackgroundIn Ghana, Hepatitis B virus (HBV) infection remains a major public health threat as in many parts of the world. Even with an effective vaccine, there are shortfalls with low vaccine coverage among adults. To create awareness and encourage vaccination, community engagement and public-private partnerships are needed in endemic settings to help fund campaigns and offer screening and vaccinations at no cost to under privileged people.ObjectivesAn awareness and screening exercise was scheduled by University of Ghana-based Hepatitis-Malaria (HEPMAL) project team to coincide with the World Hepatitis Day (WHD) 2021. It was to engage the community in creating awareness of the menace and offer diagnostic services to ascertain prevalence levels and provide needed clinical support.MethodsParticipants from the University of Ghana community and its immediate environs were registered, taken through pre-counselling sessions where they were educated on hepatitis transmission and prevention before consenting. Eligible participants were screened for HBV markers (HBsAg, HBeAg, HBsAb, HBcAb,HbcAg) with a rapid test kit. All HBsAb-negative participants were recommended for initial vaccination at the event, whilst the subsequent shots were administered at the University Hospital Public Health Department. Hepatitis B surface Antigen-positive participants were counselled and referred for appropriate care.Results/ Outcomes: A total of 297 people, comprising of 126 (42%) males and 171 (58%) females aged between 17 and 67 years were screened during the exercise. Amongst these, 246 (82.8%) showed no detectable protective antibodies against HBV and all of them agreed to and were given the first dose HBV vaccine. Additionally, 19 (6.4%) individuals tested positive for HBsAg and were counselled and referred to specialists from the University Hospital for further assessment and management. We found that 59 (19.9%) of our participants had previously initiated HBV vaccination and had taken at least one dose of the vaccine more than 6 months prior to this screening, 3 of whom tested positive for HBsAg. For the three-dose HBV vaccines deployed, a little over 20% (50/246) and a further 17% (33/196) did not return for the second and the third doses respectively, resulting in an overall 66% (163/246) of persons who completed all three vaccinations.Conclusions/ Lessons learnt: Our medical campaign exercise established an active case prevalence rate of 6.4% and achieved a full vaccination success rate of 66% which is critical in the induction of long-term immunity in the participants. Aside these achievements, we would like to reiterate the importance of the use of different approaches including educational events and WHD activities to target groups and communities to raise awareness. Additionally, home and school vaccination programmes may be adopted to enhance vaccine uptake and adherence to the vaccination schedule. We plan to extend this screening exercise to deprived and/or rural communities where HBV incidence may be higher than in urban communities.

Insights into the relationship between persistent antibody secretion and metabolic programming – A question for single-cell analysis

Vaccination aims to generate a protective and persisting antibody response. Indeed, humoral vaccine-mediated protection depends on the quality and quantity of the produced antigen-specific antibodies for its initial magnitude and the persistence of the plasma cells for its duration. Therefore, understanding the mechanisms behind the generation, selection and maintenance of long-lived plasma cells secreting protective antibodies is of fundamental importance for understanding long-term immunity, vaccine responses, therapeutical approaches for autoimmune disease and multiple myeloma. Recent studies have observed correlations between the generation, function and lifespan of plasma cells and their metabolism, with metabolism being both a main driver and primary consequence of changes in cellular behavior. This review introduces how metabolic programs influence and drive immune cell functions in general and plasma cell differentiation and longevity more specifically, summarizing the current knowledge on metabolic pathways and their influences on cellular fate. In addition, available technologies to profile metabolism and their limitations are discussed, leading to the unique and open technological challenges for further advancement of this research field.

Development of a novel modified vaccine (TheraVacM) for curative treatment of mouse solid tumors

Monotherapy with immune checkpoint blockade (ICB) antibodies (anti-CTLA4 and anti-PD1/PDL-1) is only effective for 20% to 30% of patients with certain cancers. Patients with cancers harboring few effector T cells (Teffs) are insensitive to ICB therapy. The lack of tumor-specific Teffs is predominantly caused by the paralysis of tumor-infiltrating dendritic cells (TiDCs) resulting from immunosuppression in the tumor microenvironment. We have identified a potent combination of high mobility group nucleosome binding domain 1 (HMGN1, N1) and fibroblast stimulating lipopeptide-1 (FSL-1) that can synergistically trigger maturation of both mouse and human DCs. Accordingly, we designed a combinational anti-cancer immunotherapy with two arms: an immune-activating arm consisting of N1 and FSL-1 to stimulate the generation of Teffs by triggering full maturation of TiDCs, and an ICB arm using anti-PDL-1 or anti-CTLA4 to prevent Teffs from being silenced in the tumor tissue. This combinational immunotherapeutic vaccination regimen dubbed modified TheraVac (TheraVacM) has proved particularly effective as it cured 100% of mice bearing established ectopic CT26 colon and RENCA kidney tumors. The resultant tumor-free mice were resistant to subsequent re-challenge with the same tumors, indicating the generation of long-term tumor specific protective immunity. Since the immune-activating arm also induces full maturation of human DCs, and anti-PDL-1 or anti-CTLA4 have been FDA-approved, this combinational immunotherapy has the potential to be an effective clinical therapy for patients with solid tumors.

Evaluation of the Humoral and Cellular Immune Response Post COVID-19 Infection in Kidney Transplant Recipients.

Kidney transplantation is a major risk factor for severe forms of coronavirus disease 2019 (COVID-19). The dynamics and the persistence of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in this immunocompromised population remain largely unknown. This study aimed to evaluate the persistence of humoral and cellular immune response in kidney transplant recipients (KTRs) and to establish whether immunosuppressive therapy influenced long-term immunity in this population. We report here the analysis of anti-SARS-CoV-2 antibodies and T cell-mediated immune responses in 36 KTRs compared to a control group who recovered from mild COVID-19. After a mean time of 5.22 ± 0.96 months post symptom onset for kidney transplant recipients, 97.22% of patients and 100% of the control group displayed anti-S1 immunoglobulin G SARS-CoV-2 antibodies (p > 0.05). No significant difference was reported in the median of neutralizing antibodies between the groups (97.50 [55.25-99] in KTRs vs. 84 [60-98] in control group, p = 0.35). A significant difference in SARS-CoV-2-specific T cell reactivity was found in the KTRs compared to the healthy controls. The levels of IFNγ release after stimulation by Ag1, Ag2 and Ag3 were higher in the control group compared to the kidney transplant group (p = 0.007, p = 0.025 and p = 0.008, respectively). No statistically significant correlation between humoral and cellular immunity was found in the KTRs. Our findings indicated that humoral immunity persisted similarly for up to 4 to 6 months post symptom onset in both the KTRs and the control group; however, T cell response was significantly higher in the healthy population compared to the immunocompromised patients.

Dectin-1 signaling coordinates innate and adaptive immunity for potent host defense against viral infection.

Most commercial foot-and-mouth disease (FMD) vaccines have various disadvantages, such as low antibody titers, short-lived effects, compromised host defense, and questionable safety. To address these shortcomings, we present a novel FMD vaccine containing Dectin-1 agonist, β-D-glucan, as an immunomodulatory adjuvant. The proposed vaccine was developed to effectively coordinate innate and adaptive immunity for potent host defense against viral infection. We demonstrated β-D-glucan mediated innate and adaptive immune responses in mice and pigs in vitro and in vivo. The expressions of pattern recognition receptors, cytokines, transcription factors, and co-stimulatory molecules were promoted via FMD vaccine containing β-D-glucan. β-D-glucan elicited a robust cellular immune response and early, mid-, and long-term immunity. Moreover, it exhibited potent host defense by modulating host's innate and adaptive immunity. Our study provides a promising approach to overcoming the limitations of conventional FMD vaccines. Based on the proposed vaccine's safety and efficacy, it represents a breakthrough among next-generation FMDvaccines.

Long term SARS-CoV-2-specific cellular immunity after COVID-19 in liver transplant recipients.

Long-term immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunosuppressed patients is not well characterized. We aimed to explore the long-term natural immunity against SARS-CoV-2 in liver transplant (LT) recipients compared to the non-transplanted population (control group). Fifteen LT recipients and 15 controls matched according to variables associated with disease severity were included at 12 months following the coronavirus disease 2019 (COVID-19) onset. Peripheral blood mononuclear cells were stimulated with peptide pools covering spike (S), nucleocapside (N), and membrane (M) proteins. Reactive CD4+ and CD8+ T cells were identified using flow cytometry, and cytokine production was evaluated in the culture supernatants using cytometric bead array. Serum anti-N and anti-S IgG antibodies were detected with chemiluminescence. The percentage of patients with a positive response in both CD4+ and CD8+ T cells against each viral protein and IL2, IL10, TNF-α, and IFN-γ levels was similar between LT recipients and controls. IFN-γ levels were positively correlated with the percentage of reactive CD4+ (p=0.022) and CD8+ (p=0.043) T cells to a mixture of M+N+S peptide pools. The prevalence and levels of anti-N and anti-S IgG antibodies were slightly lower in the LT recipients, but the difference was not statistically significant. LT recipients exhibited a similar T cell response compared to non-transplanted individuals one year after COVID-19 diagnosis.

PCR99 Regular COVID-19 Booster Shot Preference and Willingness to Pay in the Vietnamese Population: A Theory-Driven Discrete Choice Experiment

This study aims to 1) investigate public acceptance for regular COVID-19 boosters, 2) assess willingness to pay for a COVID-19 booster shot, and 3) identify factors associated with vaccine hesitancy. Our results provide crucial insights and implications for policy response as well as the development of a feasible and effective vaccination campaign, during Vietnam's waning vaccine immunity period. A Discrete Choice Experiment study was conducted among 871 Vietnamese online participants distributed using the snowball sampling method in 2022. Among participants, 87.4% had received or were waiting for a COVID-19 booster shot. However, the willingness to pay was low at $US 8, and most participants indicated an unwillingness to pay (25.8%) or willingness to pay for only half of the vaccine costs (25.4%). While information insufficiency and wariness towards vaccines were factors most associated with the unwillingness to pay, long-term side effects, immunity duration, and mortality rate were the attributes most concerned with during the vaccine decision-making period. Participants who had children less than 18 years old in their homes infected with COVID-19 had a lower willingness to pay (OR = 0.54; 95% CI = 0.39; 0.74). The burden of medical expenses (OR = 0.33; 95% CI = 0.25; 0.45) and fear of vaccine (OR = 0.93; 95% CI = 0.86; 1.00) were the negative factors of the level of willingness to pay. Significant inconsistency between high acceptance and low willingness to pay underscores the role of vaccine information and public trust. In addition to raising awareness about the most concerning characteristics of the COVID-19 booster, social media, and social listening should be utilized in collaboration with health professionals to establish a two-way information exchange. Most importantly, all interventions should be conducted with informational transparency to strengthen trust between the public and authorities.

Evaluation of the long-term memory T cell in mice after immunization with a live tularemia vaccine

The vaccine strain F. tularensis 15 NIIEG induces long-lived cell-mediated immunity but exhibits a certain reactogenicity and genetic instability. Progress in development of a vaccine against tularemia has been limited by a lack of information regarding the mechanisms required to protect against this disease. The BALB/c mouse is the most commonly used animal to study tularemia due to its relatively low cost, well-characterized genetics, available immunological tools and mouse infection with virulent F. tularensis recapitulates human disease.CD4+ and CD8+T cells are known to be critical for the formation of protective immunity but the relative roles of memory T cell subpopulations in long lived protection against virulent strains of F. tularensis are not well established. We hypothesized that this immunity depends on central (TCM) and effector memory (TEM) T cells and their functional activity. In this study we have dissected the T cell immune response in BALB/c mice 30, 60 and 90 days after subcutaneous vaccination with 15 NIIEG.Multiparametric flow cytometry were used to characterize in vitro recall responses of splenocytes to F. tularensis antigen. TEM cells were identified as CD3+CD4+CD44+CD62L- and CD3+CD8+CD44+CD62L-, TCM cells as CD3+CD4+CD44+CD62L+ and CD3+CD8+CD44+CD62L+, respectively. The functional activity of memory T cells was assessed by the following parameters: the level of expression of the activation marker CD69 and cytokine-producing activity by staining with the intracellular cytokines IFNg and TNFa.Thus, development of a long-lived vaccine directed against F. tularensis is dependent on identifying not only the correlates of immunity present early after vaccination, but also those that persist in the host after the effector phase has ended. The maintenance of long-term protective immunity initiated by vaccination with F. tularensis strain 15 NIIEG has been shown to require the presence of antigen-specific CD4+ and CD8+ memory T cells producing IFNg and TNFa and expressing the activation marker CD69. A decrease in count and functional activity of CD8+TCM and CD8+TEM was detected in the long term after vaccination. The detected parameters of functional activity of memory T cells can be used as criteria for evaluation of protective immunity against virulent strains of F. tularensis.

Dimethyl itaconate induces long-term innate immune responses and confers protection against infection

Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced exvivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context.

Machine Learning Classification of Time since BNT162b2 COVID-19 Vaccination Based on Array-Measured Antibody Activity.

Vaccines trigger an immunological response that includes B and T cells, with B cells producing antibodies. SARS-CoV-2 immunity weakens over time after vaccination. Discovering key changes in antigen-reactive antibodies over time after vaccination could help improve vaccine efficiency. In this study, we collected data on blood antibody levels in a cohort of healthcare workers vaccinated for COVID-19 and obtained 73 antigens in samples from four groups according to the duration after vaccination, including 104 unvaccinated healthcare workers, 534 healthcare workers within 60 days after vaccination, 594 healthcare workers between 60 and 180 days after vaccination, and 141 healthcare workers over 180 days after vaccination. Our work was a reanalysis of the data originally collected at Irvine University. This data was obtained in Orange County, California, USA, with the collection process commencing in December 2020. British variant (B.1.1.7), South African variant (B.1.351), and Brazilian/Japanese variant (P.1) were the most prevalent strains during the sampling period. An efficient machine learning based framework containing four feature selection methods (least absolute shrinkage and selection operator, light gradient boosting machine, Monte Carlo feature selection, and maximum relevance minimum redundancy) and four classification algorithms (decision tree, k-nearest neighbor, random forest, and support vector machine) was designed to select essential antibodies against specific antigens. Several efficient classifiers with a weighted F1 value around 0.75 were constructed. The antigen microarray used for identifying antibody levels in the coronavirus features ten distinct SARS-CoV-2 antigens, comprising various segments of both nucleocapsid protein (NP) and spike protein (S). This study revealed that S1 + S2, S1.mFcTag, S1.HisTag, S1, S2, Spike.RBD.His.Bac, Spike.RBD.rFc, and S1.RBD.mFc were most highly ranked among all features, where S1 and S2 are the subunits of Spike, and the suffixes represent the tagging information of different recombinant proteins. Meanwhile, the classification rules were obtained from the optimal decision tree to explain quantitatively the roles of antigens in the classification. This study identified antibodies associated with decreased clinical immunity based on populations with different time spans after vaccination. These antibodies have important implications for maintaining long-term immunity to SARS-CoV-2.

A state-of-the-art methodology for high-throughput in silico vaccine discovery against protozoan parasites and exemplified with discovered candidates for Toxoplasma gondii

Vaccine discovery against eukaryotic parasites is not trivial as highlighted by the limited number of known vaccines compared to the number of protozoal diseases that need one. Only three of 17 priority diseases have commercial vaccines. Live and attenuated vaccines have proved to be more effective than subunit vaccines but adversely pose more unacceptable risks. One promising approach for subunit vaccines is in silico vaccine discovery, which predicts protein vaccine candidates given thousands of target organism protein sequences. This approach, nonetheless, is an overarching concept with no standardised guidebook on implementation. No known subunit vaccines against protozoan parasites exist as a result of this approach, and consequently none to emulate. The study goal was to combine current in silico discovery knowledge specific to protozoan parasites and develop a workflow representing a state-of-the-art approach. This approach reflectively integrates a parasite’s biology, a host's immune system defences, and importantly, bioinformatics programs needed to predict vaccine candidates. To demonstrate the workflow effectiveness, every Toxoplasma gondii protein was ranked in its capacity to provide long-term protective immunity. Although testing in animal models is required to validate these predictions, most of the top ranked candidates are supported by publications reinforcing our confidence in the approach.