Reduced Vaccine Responses Research Articles

Pathology of Diabetes-Induced Immune Dysfunction.

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

Adjuvant AS01 activates human monocytes for costimulation and systemic inflammation

BackgroundThe adjuvanted recombinant zoster vaccine (RZV) is highly effective even in adults over 80 years old. The high efficacy of RZV is attributed to its highly reactogenic adjuvant, AS01, but limited studies have been done on AS01’s activation of human immune cells. MethodsWe stimulated peripheral blood mononuclear cells (PBMC) with AS01 and used flow cytometry and RNA Sequencing (RNAseq) to analyze the impacts on human primary cells. ResultsWe found that incubation of PBMC with AS01 activated monocytes to a greater extent than any other cell population, including dendritic cells. Both classical and non-classical monocytes demonstrated this activation. RNASeq showed that TNF-ɑ and IL1R pathways were highly upregulated in response to AS01 exposure, even in older adults. ConclusionsIn a PBMC co-culture, AS01 strongly activates human monocytes to upregulate costimulation markers and induce cytokines that mediate systemic inflammation. Understanding AS01’s impacts on human cells opens possibilities to further address the reduced vaccine response associated with aging.

Cellular and humoral immune response in kidney transplant recipients with covid-19 vaccination: a systematic review and meta-analysis

A comprehensive search was carried out in mainstream bibliographic databases or Medical Subject Headings, including ScienDirect, PubMed, Scopus, and ISI Web of Science. The search was applied to the articles that were published between 2021 and mid-2023. With strict literature search and screening processes, it yielded 8 articles from 349 articles of initial literature database. A number of previous studies demonstrated that KTRs or non-KTRs with renal failure markedly reduced vaccine response, whereas adaptive protocols of mRNA COVID-19 vaccination or alternative adjuvant vaccines is now not known yet. A recent study revealed that acute kidney injury and mortality could be caused by SARS-CoV-2 (COVID-19) around 50 % and 23 % of the infected KTRs. No different post-V4-T-cell response and anti-S antibody levels were detected by vaccine type combination (ChAdOx1 plus BNT162b2) among participants, whereas post-V3 seropositivity demonstrated more anti-S antibody levels if administered with BNT162b2, in comparison with ChAdOx1. In conclusion, among the immunocompromised population, including KTRs, DPs, PDs, at least three doses of mRNA-COVID-19 vaccination was recommended to be the preparation of choice. Withdrawal of the immunosuppressants in KTRs and immunocompromised individual’s prior COVID-19 vaccination and at least third dose of mRNA-COVID-19 vaccination should be performed.

Humoral and Cellular Immunological Response in Patients with Kidney Transplantation After messenger-RNA-COVID-19 Vaccination: A Systematic Review and Meta-Analysis

A comprehensive search was carried out in mainstream bibliographic databases or Medical Subject Headings, including ScienDirect, PubMed, Scopus, and ISI Web of Science, following the PRISMA 2020 Guideline. The search was applied to the articles that were published between 2021 and mid-2023. With strict literature search and screening processes, it yielded 7 articles from 349 articles of initial literature database. A number of previous studies demonstrated that KTRs or non-KTRs with renal failure markedly reduced vaccine response, whereas adaptive protocols of mRNA COVID-19 vaccination or alternative adjuvant vaccines is now not known yet. A recent study revealed that acute kidney injury and mortality could be caused by SARS-CoV-2 (COVID-19) around 50 % and 23 % of the infected KTRs. In conclusion, among the immunocompromised population, including KTRs, DPs, PDs, at least three doses of mRNA-COVID-19 vaccination was recommended to be the preparation of choice. Withdrawal of the immunosuppressants in KTRs and immunocompromised individual’s prior COVID-19 vaccination and at least third dose of mRNA-COVID-19 vaccination should be performed.

Robust Vaccine-Induced as Well as Hybrid B- and T-Cell Immunity across SARS-CoV-2 Vaccine Platforms in People with HIV.

Few studies have comprehensively compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced and hybrid B- and T-cell responses in people with HIV (PWH) to those in comparable controls without HIV. We included 195 PWH and 246 comparable controls from the AGEhIV COVID-19 substudy. A positive nucleocapsid antibody (INgezim IgA/IgM/IgG) or self-reported PCR test defined prior SARS-CoV-2 infection. SARS-CoV-2 anti-spike (anti-S) IgG titers and anti-S IgG production by memory B cells were assessed. Neutralizing antibody titers were determined in a subset of participants. T-cell responses were assessed by gamma interferon (IFN-γ) release and activation-induced marker assay. We estimated mean differences in postvaccination immune responses (β) between levels of determinants. Anti-S IgG titers and anti-S IgG production by memory B cells were not different between PWH and controls. Prior SARS-CoV-2 infection (β = 0.77), receiving mRNA vaccine (β = 0.56), female sex (β = 0.24), fewer days between last vaccination and sampling (β = 0.07), and a CD4/CD8 ratio of <1.0 (β = -0.39) were independently associated with anti-S IgG titers, but HIV status was not. Neutralization titers against the ancestral and Delta and Omicron SARS-CoV-2 variants were not different between PWH and controls. IFN-γ release was higher in PWH. Prior SARS-CoV-2 infection (β = 2.39), HIV-positive status (β = 1.61), and fewer days between last vaccination and sampling (β = 0.23) were independently associated with higher IFN-γ release. The percentages of SARS-CoV-2-reactive CD4+ and CD8+ T cells, however, were not different between PWH and controls. Individuals with well-controlled HIV generally mount robust vaccine-induced as well as hybrid B- and T-cell immunity across SARS-CoV-2 vaccine platforms similar to controls. Determinants of a reduced vaccine response were likewise largely similar in both groups and included a lower CD4/CD8 ratio. IMPORTANCE Some studies have suggested that people with HIV may respond less well to vaccines against SARS-CoV-2. We comprehensively compared B- and T-cell responses to different COVID-19 vaccines in middle-aged persons with well-treated HIV and individuals of the same age without HIV, who were also highly comparable in terms of demographics and lifestyle, including those with prior SARS-CoV-2 infection. Individuals with HIV generally mounted equally robust immunity to the different vaccines. Even stronger immunity was observed in both groups after prior SARS-CoV-2 infection. These findings are reassuring with respect to the efficacy of SARS-Cov-2 vaccines for the sizable and increasing global population of people with HIV with access and a good response to HIV treatment.

Obesity in adolescents does not influence early immune responses to influenza vaccination

Background Obesity has been linked to reduced vaccine responses against tetanus, hepatitis B and influenza. Data on the influence of paediatric obesity on influenza vaccine response is still lacking and this study aims to fill the gap. Methods A total of 30 children with obesity and 30 children with normal weight, aged 12–18 years, were recruited. Participants were vaccinated with a tetravalent influenza vaccine. Blood was collected prior to the vaccination and again four weeks later. The humoral response was assessed with haemagglutinin inhibition assay. The cellular response was assessed with T-cell stimulation assays measuring TNF-α, IFN-γ, IL-2 and IL-13. Results Of the 29/30 from the study group and 30/30 from the control group finished both visits. Seroconversion occurred for > 90% of participants in both groups for the A/H1N1, A/H3N2 and B/Victoria strains, but the B/Yamagata strain had lower seroconversion rates (93% in the study group and 80% in the control group). 97-100% of participants from both groups had adequate serological responses following vaccination. Cellular responses were similar between the two groups post-vaccination. Conclusions Early humoral and cellular immune responses to influenza vaccinations are similar among adolescents with obesity and normal weight.

Clinical outcome of SARS-CoV-2 infections occurring in multiple myeloma patients after vaccination and prophylaxis with tixagevimab/cilgavimab.

Patients with multiple myeloma (MM) frequently reported immune impairment with an increased risk for infection-related mortality. We aimed to evaluate the immune response in MM patients vaccinated for SARS-CoV-2 during active treatment. We enrolled 158 patients affected by active MM or smoldering MM (SMM) and 40 healthy subjects. All subjects received 2 or 3 doses of the BNT162b2 (Pfizer/BioNTech) vaccine, and the anti-spike IgG values were evaluated after every dose. We applied the Propensity Score Matching (PSM) as a consequence of the limited sample size and its heterogeneity to adjust for differences in baseline clinical variables between MM patients who achieved or not a vaccine response after 2 or 3 doses. At 30 days from the second dose, the median antibodies level in MM was 25.2 AU/mL, lower than in SMM and in the control group. The same results were confirmed after the third dose, with lower median anti-spike IgG levels in MM, compared to SMM and control group. Following PSM, lack of response to SARS-CoV-2 complete vaccination plus boost was associated with age more than 70 years old and use of high-dose of steroids. We failed to identify an association between specific treatment types and reduced vaccine response. The use of prophylaxis with tixagevimab/cilgavimab for 40 non-responder patients after 3 doses of vaccine has proven to be an effective and safe approach in reducing the risk of serious illness in the event of a breakthrough SARS-CoV-2 infection, faced with a mild symptomatic course, and in providing protection instead of long-term humoral immune vaccine responses. Following PSM, only the high-risk cytogenetic abnormalities were associated with an increased risk of developing a breakthrough SARS-CoV-2 infection. Monitoring the immune response is fundamental in MM patients that remain highly vulnerable to SARS-CoV-2 despite the vaccine. The use of prophylaxis with tixagevimab/cilgavimab can guarantee better protection from the severe form of the disease.

A meta-analysis of the associations between insufficient sleep duration and antibody response to vaccination

Vaccination is a major strategy to control a viral pandemic. Simple behavioral interventions that might boost vaccine responses have yet to be identified. We conducted meta-analyses to summarize the evidence linking the amount of sleep obtained in the days surrounding vaccination to antibody response in healthy adults. Authors of the included studies provided the information needed to accurately estimate the pooled effect size (ES) and 95% confidence intervals (95% CI) and to examine sex differences.1,2,3,4,5,6,7 The association between self-reported short sleep (<6 h/night) and reduced vaccine response did not reach our pre-defined statistical significant criteria (total n= 504, ages 18-85; overall ES [95% CI]= 0.29 [-0.04, 0.63]). Objectively assessed short sleep was associated with a robust decrease in antibody response (total n= 304, ages 18-60; overall ES [95% CI]= 0.79 [0.40, 1.18]). In men, the pooled ES was large (overall ES [95% CI]= 0.93 [0.54, 1.33]), whereas it did not reach significance in women (overall ES [95% CI]= 0.42 [-0.49, 1.32]). These results provide evidence that insufficient sleep duration substantially decreases the response to anti-viral vaccination and suggests that achieving adequate amount of sleep during the days surrounding vaccination may enhance and prolong the humoral response. Large-scale well-controlled studies are urgently needed to define (1) the window of time around inoculation when optimizing sleep duration is most beneficial, (2) the causes of the sex disparity in the impact of sleep on the response, and (3) the amount of sleep needed to protect the response.

Humoral and Cellular Immune Response among Kidney Transplant Recipients after COVID-19 Vaccination: A Systematic Review and Meta-Analysis

A comprehensive search was carried out in mainstream bibliographic databases or Medical Subject Headings, including ScienDirect, PubMed, Scopus, and ISI Web of Science. The search was applied to the articles that were published between 2021 and mid-2023. With strict literature search and screening processes, it yielded 7 articles from 349 articles of initial literature database. A number of previous studies demonstrated that KTRs or non-KTRs with renal failure markedly reduced vaccine response, whereas adaptive protocols of mRNA COVID-19 vaccination or alternative adjuvant vaccines is now not known yet. A recent study revealed that acute kidney injury and mortality could be caused by SARS-CoV-2 (COVID-19) around 50 % and 23 % of the infected KTRs. In conclusion, among the immunocompromised population, including KTRs, DPs, PDs, at least three doses of mRNA-COVID-19 vaccination was recommended to be the preparation of choice. Withdrawal of the immunosuppressants in KTRs and immunocompromised individuals prior COVID-19 vaccination and at least third dose of mRNA-COVID-19 vaccination should be performed.

Alterations of Immune Cells By Large B Cell Lymphoma Persist Years after Achieving Complete Remission and Correlate with Impaired Adaptive Immunity

Background: The tumor microenvironment (TME) has recently emerged as one of the key players in the understanding of cancer biology and treatment resistance. Cells central to immune inhibition in the TME are myeloid derived suppressor cells (MDSCs). They represent a heterogenous immature myeloid subset which physiologically mediates the termination of inflammatory processes. However, in diffuse large B cell lymphoma (DLBCL), MDSCs are believed to be recruited by the malignant cells which installs a tumor-associated immunosuppression possibly further supporting disease progression. Number and rate of MDSCs correlate with disease stage and represent an independent prognostic factor for poor outcome. Whereas the treatment of DLBCL patients has evolved profoundly the functional consequences of changes in the TME during treatment and, even more so, once patients are cured remain unclear. Hypothesis: With the objective of understanding functional relevance towards adaptive immunity, we aimed to characterize the immune phenotype of patients at different time points during their disease. Method: We established a flow cytometry-based-TruCount analysis of whole blood samples to compare the immune phenotype of newly diagnosed DLBCL patients, of cured patients and of healthy donors. To functionally examine the immune status within the cured cohort after SARS-CoV2-vaccination, T cell vaccine response following in vitro stimulation, anti-spike antibody titers in the serum and serum levels of lineage specific cytokines were measured. To prove the inhibitory properties of MDSCs, we performed T cell suppression assays in co-culture. Results: Patients with active disease at first diagnosis which were treatment naïve displayed increased numbers of monocytic MDSCs (CD14(+) CD15(-) CD11b(+) CD33(+) HLA-DR(-) Lin(-)) compared with healthy donors. In patients at relapse before salvage treatment, average rate and numbers of MDSCs was higher than at first diagnosis. In patients cured from DLBCL the high rate of MDSCs persisted compared to healthy donors or patients with active disease. The increased rate of MDSCs was independent of number of undergone therapy lines, initial Ann Arbor stage or revised international prognostic index (R-IPI). For patients that were SARS-CoV2-vaccinated after the cure from DLBCL, the amount of MDSCs correlated negatively with serum levels of Anti-Spike IgG (p=0.01). With today only 16 samples measured, there was a trend towards a negative correlation between rate of MDSCs and SARS-CoV2-specific activation of T cells as measured by IFN-γ secretion. The correlation between sCD14 and T cell responses, however, reached significance (p=0.0005). Just as MDSCs from patients with active disease, MDSCs derived from cured patients were able to suppress the proliferation of unspecifically stimulated T cells. Furthermore, T cells in the peripheral blood of patients in complete remission after DLBCL showed significant activation and a substantially higher rate of senescence suggesting patterns of chronic inflammation. In line, the possibly cured people showed higher rates of Teffector cells compared with healthy controls. Conclusions: Our results indicate that cured DLBCL patients continue to be in an immunocompromised state even beyond two years after achieving complete remission. The presence of inhibitory myeloid cells with proven ability to suppress immune reactions together with hyperactivated and senescent T cells and an increase of effector T cells supports the conclusion of a systemic immune dysfunction long after the treatment finished. Functionally impaired immune responses compared with healthy people towards SARS-CoV2 indicates that patients cured from DLBCL are a vulnerable group to infection due to reduced vaccine response or virus reactivation. In summary, we show for the first time that patients cured from DLBCL show persisting alterations of immune cells which functionally impair adaptive immunity.

314.4: How Did the Omicron Wave Impact Kidney Transplant Recipients? A Comparative Analysis From a Prospective Cohort Single-Center Study

Introduction: The first two years of the SARS-CoV-2 pandemic were marked by an unprecedented impact on the survival of the kidney transplant patient worldwide, a population that accumulates risk factors for worse outcomes and has reduced vaccine response. However, from the end of 2021, the pandemic acquired new nuances, with the broad availability of booster doses of the vaccine – in Brazil, since 08/26/2021 – and the emergence of the Omicron variant, more infectious but possibly less lethal. The aim of our study was to describe how the new era of the pandemic differed from the previous one in a large cohort of renal transplant patients being followed up at a single center. Methods: This single-center prospective cohort study included kidney transplant recipients with confirmed COVID-19 between 03/20/2020 and 02/15/2022. The outcomes of interest were incidence of confirmed SARS-CoV-2 infection, need for hospitalization, mechanical ventilation, dialysis and COVID-19 associated death within 28 days from the onset of symptoms. For the present analysis, we arbitrarily separated the patients into two eras, named “Era 1” (03/20/2020 to 12/02/2021) and “Era 2” (12/17/2021 to 02/15/2022), considering the emergence of the Omicron variant in Brazil at the end of the year 2021 and that there were no cases registered between 12/02/2021 and 12/17/2021. Genetic sequencing to identify the variants was not available in the center. Results: Among the 10,497 kidney transplant recipients in follow up, there were 3,327 cases of confirmed COVID-19 in the entire observation period. There was an increase in the incidence rate from 0.3 cases/1000patients-day in Era 1 to 1.72 cases/1000patients-day in Era 2, and the sharp increase in the number of cases in the last Era is demonstrated in Figure 1. There was no difference in the median age (51 [IQR 42-60] years versus 50 [IQR 40-61] years, p=0.447) or in the proportion of male patients (60.4% versus 58.5%, p=0.294) between the two Eras. There was a significant decrease in the rate of hospitalization (57.5%% versus 29.2%, p<0.0001), need for mechanical ventilation (29.9% versus 16.3%, p<0.0001), dialysis (25.6%% versus 9.1%, p<0.0001) and COVID-19 related death (26.9% versus 10%, p<0.0001, as demonstrated in Figure 1). Conclusion: There was a clear change in the dynamics of the pandemic from December 2021 among renal transplant patients, with higher incidence and lower severity of COVID-19, possibly due, but not limited to, booster vaccination and lower pathogenicity of the Omicron variant.

Old mice and elderly humans make increased autoimmune antibodies, inflammation and SASP from aged-increased B cells (ABCs in mice and DN in humans) which are hypermetabolic

Abstract Immune mechanisms of human and murine diseases of aging include generation of chronic inflammation and autoimmunity. We and others have associated aging in mice and humans with increased chronic inflammation, reduced vaccine response and an increase in a B lymphocyte subset referred to as Age-associated B cells (ABCs) in mice and DN (double negative) in humans. Immune cell function is dependent on metabolic pathways and to date understudied. A. In this work we sorted splenic ABCs (CD19+AA4.1-CD21-CD23−) from young (3–4 months) and old (18–22 months) C57BL/6 mice showing an increased percentage in old and increased RNA expression of SASP (senescence-associated secretory phenotype) pro-inflammatory cytokines (TNFa, IL-6), proinflammatory micro-RNAs (miRs 155 and 16) and cell cycle regulators p16INK4 and p21Waf1 in old ABCs. We also show here old B cells produce more autoimmune IgG antibodies (to MDA, malondialdehyde and ADA, adipocyte-derived antigens), ABCs more than FO (follicular), and ABCs from old more than those from young. Total B cells and ABCs from old mice also have a higher metabolic profile compared with those of young mice. B. The frequency of DN cells is increased in human elderly as well as those younger with obesity. Plasma of obese had more autoantibodies to dsDNA, MDA, and ADA and the DN B cells showed higher levels of IA (Immune activation) markers and transcription factors, e.g. tbx21 (TBET) associated with autoimmunity. We have recently found that elderly human B cells are, like murine, hypermetabolic and are discovering possible mechanisms, such as fatty acids. Supported by grants from NIH (AG32576, AG059719, and AG023717)

Immunogenicity and safety of the CoronaVac vaccine in patients undergoing treatment for breast and lung cancer.

To compare seroconversion for SARS-CoV-2 receptor-binding domain (RBD) specific IgG positivity against two doses of the CoronaVac vaccine in breast and lung cancer patients receiving systemic therapy, to determine the factors affecting seropositivity, and to observe long-term results up to a secondary booster vaccine. The analysis included 201 cancer patients (99 breasts, 102 lungs; median age: 59 years (range: 28-92), 42.3 % men) and 97 controls (median age: 62 years (range: 24-87), 38.1 % men). The seropositivity rate for RBD IgG after 2 doses of vaccine in the cancer group was 81.6 % (n=164) and 93.8 % (n=91) in the control group (p=0.005). The median IgG titer of cancer patients was significantly lower than in the control group (338 (IQR, 95-933) AU/mL vs 676 (IQR, 389-1270) AU/mL; p<0.001). Multivariate analysis of all the patients determined that having cancer (OR: 0.303, 95%CI: 0.123-0.750, p=0.010) and being over 60 years of age (OR: 0.447, 95%CI: 0.218-0.917, p=0.028) was associated with a reduced vaccine response. A subgroup analysis of cancer patients revealed that seroconversion was lower in men than in women (75.3 % vs 86.2 %, p=0.049) and lower in ≥60 patients than in <60 patients (75.9 % vs 89.4 %, p=0.014). Cancer patients receiving an active systemic therapy with two doses of the CoronaVac vaccine had a lower antibody response than the non-cancer population, and deaths due to COVID-19 may occur in these patients despite the vaccine. Therefore, extensive protective measures should be taken to protect against COVID-19 in cancer patients aged 60 years and older, who have received two doses of the CoronaVac vaccine (Tab. 4, Fig. 4, Ref. 27).

Low Immunization Rate in Kidney Transplant Recipients Also After Dose 2 of the BNT162b2 Vaccine: Continue to Keep Your Guard up!

We read with interest the report from Georgery et al1 addressing the very low immunization rate of 3.8% in kidney transplant recipients (KTRs) 28 d after 1 dose of the BNT162b2 (Pfizer/BioNTech) vaccine. As addressed by the authors, this is markedly lower than what has been reported in other recent publications on mRNA vaccines (BNT162b2, Pfizer/BioNTech; mRNA-1273, Moderna) in this population.2,3 Our findings after 2 doses of BNT162b2 are in line with their observations. We assessed the serological response 25–89 d after the second dose of the BNT162b2 vaccine in 141 KTRs without a known history of COVID-19 infection and negative SARS-CoV-2 anti-nucleocapsid IgG before vaccination. Antibodies to SARS-CoV-2 spike, the receptor-binding domain of spike and nucleocapsid were measured with a multiplexed bead-based flow cytometric assay as previously described.4 The assay was calibrated to the World Health Organization international standard (National Institute for Biological Standards and Control code 20/136) to assess binding antibody units (BAU). Table 1 summarizes the baseline characteristics and findings following the second dose of BNP162b2 vaccine in the 141 KTRs. The median age was 75 (range, 21–91) y, 56% were male individuals. The median time since transplantation was 9.6 y (range, 0.4–47.1), 72% were transplanted >5 y ago. The majority of the recipients were on a combination of calcineurin inhibitor (CNI), mycophenolate (MPA), and prednisolone (n = 105, 74%). On the day of measurement, only 25 patients (18%) had seroconverted with a mean SARS-CoV-2 spike IgG antibody titer of 21 ± 32 BAU/mL (threshold for positive response: 1.0 BAU/mL). Out of these 25 responders, 16 (64%) did not use MPA and only 6 (24%) were treated with triple maintenance immunosuppression with CNI, MPA, and prednisolone. Patients who seroconverted tended to be younger and had been living with a functioning kidney transplant for a longer time (Table 1). The impact of immunosuppression is obvious, but from the present data, it is not possible to differentiate the exact cause of the negative impact on seroconversion. However, treatment with MPA, especially in triple therapy, appears to lower seroconversion rates. TABLE 1. - Baseline characteristics and findings following the second dose of BNP162b2 (Pfizer/BioNTech) vaccine in kidney transplant recipients All (N = 141) POSitive IgG (N = 25) NEGative IgG (N = 116) Missing P (POS vs NEG) Demographics Age (y) 67.4 ± 17.2 59.1 ± 19.7 69.1 ± 16.2 0 0.02 Male sex 79 (56%) 12 (48%) 67 (58%) 0 0.50 Weight (kg) 74.9 ± 15.2 73.3 ± 12.9 75.3 ± 15.7 2 0.50 BMI (kg/m2) 25.2 ± 4.3 25.6 ± 3.8 25.1 ± 4.4 2 0.52 Time since Tx (y) 11.7 ± 9.8 17.1 ± 13.5 10.4 ± 8.4 0 0.01 First Tx 122 (87%) 20 (80%) 102 (88%) 0 0.41 Living donor 55 (39%) 14 (56%) 41 (35%) 0 0.09 Years in RRT 14.1 ± 9.9 21.8 ± 12.5 12.4 ± 8.4 0 0.001 P-creatinine (µmol/L) 136 ± 78 141 ± 120 135 ± 66 1 0.80 Maintenance immunosuppression CNI + MPA + prednisolonea 105 (74%) 6 (24%) 99 (85%) <0.0001 CNI + prednisolone 19 (13%) 12 (48%) 7 (6%) <0.0001 Other combinationsb 17 (12%) 7 (28%) 10 (9%) 0.02 MPA use 115 (82%) 9 (36%) 106 (91%) <0.0001 Data presented as mean ± SD and number (%). Statistical comparison between groups with positive and negative SARS-CoV-2 IgG samples performed with Student’s T test and chi-square tests. Bold values indicate statistical significance.aCNI type; 35 cyclosporine and 70 tacrolimus.bEverolimus + MPA + prednisolone (n = 7), azathioprine + prednisolone (n = 4), cyclosporine + azathioprine + prednisolone (n = 2), belatacept + MPA + prednisolone (n = 2), belatacept + everolimus + prednisolone (n = 1), tacrolimus + MPA (n = 1).BMI, body mass index; CNI, calcineurin inhibitor; IgG, immunoglobulin G; MPA, mycophenolate; RRT, renal replacement therapy; Tx, transplantation. It is well known that KTRs are at increased risk of a severe outcome if infected with SARS-CoV-2, and there is a hope that vaccination will be protective. Short-term safety data on mRNA vaccines in KTRs seems similar to the general population, but the immunogenicity seems to be markedly reduced.5 To date, it has not been proven that low levels of antibodies to spike predict a lack of protection against severe COVID-19. Although KTRs receiving MPA seem to have a reduced vaccine response rate, with the current knowledge, we do not promote reducing or withholding MPA during revaccination. Early results showing an increase in seroconversion after the second vaccine dose have prompted initiatives to administer a third jab. Whether or not this will enhance the immune response remains to be determined. In the meantime, KTRs should be informed to keep their guard up and behave as if they were not vaccinated!

Reframing the Question: Does Mitochondrial Damage Set the Stage for Future Inflammation?

Reframing the Question: Does Mitochondrial Damage Set the Stage for Future Inflammation?

The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.

Recommendations for the use of COVID-19 vaccines in patients with immune-mediated kidney diseases.

Coronavirus Disease 19 (COVID-19) vaccine platforms are becoming available and are the most promising strategy to curb the spread of SARS-CoV-2 infections. However, numerous uncertainties exist regarding the pros and cons of vaccination, especially in patients with (immune-mediated) kidney diseases on immunosuppressive drugs. Here, members of the Immunonephrology Working Group (IWG) of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) discuss thirteen frequently-asked questions regarding safety and efficacy of the most promising vaccine candidates. Post-marketing surveillance should be performed to estimate the rate of vaccine response (humoral and cellular) of different vaccine platforms, and surveillance of disease activity following administration of COVID-19 vaccines. Some of the candidates induce signaling pathways which also promote autoimmune kidney diseases, e.g. type I interferons in systemic lupus erythematosus. Efficacy estimates would thus far favor the use of selected COVID-19 vaccines, such as BNT162b2, mRNA-1273 or Gam-COVID-Vac. Humoral immune response after vaccination should be monitored using appropriate assays. Even in the absence of neutralizing antibodies patients might be protected by a sufficient cellular immune response capable to reduce severity of COVID-19. A reduced vaccine response after the use of CD20-depleting agents is anticipated, and it is particularly important to discuss strategies to improve vaccine response with these patients. Distancing and shielding measures remain important as not all vaccines fully protect from coronavirus infection. In-depth information about the most pressing vaccine questions is essential to reduce vaccine hesitancy of patients.

Impact of Vitamin D Supplementation on Influenza Vaccine Response and Immune Functions in Deficient Elderly Persons: A Randomized Placebo-Controlled Trial.

Background: Immunosenescence contributes to reduced vaccine response in elderly persons, and is worsened by deficiencies in nutrients such as Vitamin (Vit-D). The immune system is a well-known target of Vit-D, which can both potentiate the innate immune response and inhibit the adaptive system, and so modulate vaccination response.Objective: This randomized placebo-controlled double-blind trial investigated whether Vit-D supplementation in deficient elderly persons could improve influenza seroprotection and immune response.Design: Deficient volunteers (Vit-D serum <30 ng/mL) were assigned (V1) to receive either 100,000 IU/15 days of cholecalciferol (D, n = 19), or a placebo (P, n = 19), over a 3 month period. Influenza vaccination was performed at the end of this period (V2), and the vaccine response was evaluated 28 days later (V3). At each visit, serum cathelicidin, immune response to vaccination, plasma cytokines, lymphocyte phenotyping, and phagocyte ROS production were assessed.Results: Levels of serum 25-(OH)D increased after supplementation (D group, V1 vs. V2: 20.7 ± 5.7 vs. 44.3 ± 8.6 ng/mL, p < 0.001). No difference was observed for serum cathelicidin levels, antibody titers, and ROS production in D vs. P groups at V3. Lower plasma levels of TNFα (p = 0.040) and IL-6 (p = 0.046), and higher ones for TFGβ (p = 0.0028) were observed at V3. The Th1/Th2 ratio was lower in the D group at V2 (D: 0.12 ± 0.05 vs. P: 0.18 ± 0.05, p = 0.039).Conclusions: Vit-D supplementation promotes a higher TGFβ plasma level in response to influenza vaccination without improving antibody production. This supplementation seems to direct the lymphocyte polarization toward a tolerogenic immune response. A deeper characterization of metabolic and molecular pathways of these observations will aid in the understanding of Vit-D's effects on cell-mediated immunity in aging. This clinical trial was registered at clinicaltrials.gov as NCT01893385.

Priming and Maturation of the Human Fetal Mucosal Immunity Occurs Early in Fetal Development

It has been thought that the immune system is immature at birth. A third of neonatal deaths are attributed to infections and newborns have reduced vaccine responses. Yet, most newborns are healthy. There is limited data on human in utero mucosal immunity. Using CyTOF and next-generation sequencing of B/T-cell receptor (B/TCR) repertoires, we demonstrate that intestinal immunity is complex and functional at 16 weeks’ gestation (GA). B/TCR repertoires are diverse in fetal samples, with an increase in CDR3β/H length and distance-from-germline with advancing GA. Innate immunity is dominated by APCs, including CD103+DCs, ILCs and NK cells. Follicular and transitional B-cells are enriched in the fetal and CD69+IgM+B-cell in neonatal tissue. T-cells represent >50% of leukocytes and majority are memory T-cells. Finally, functional tissue resident memory T-cells are abundant. Our data provide the foundation for a second trimester mucosal immune atlas and suggest that development occurs significantly earlier than previously reported.

Lymph node fibrosis: a structural barrier to unleashing effective vaccine immunity.

There is marked variability in vaccine efficacy among global populations. In particular, individuals in low- to middle-income countries have been shown to be less responsive to vaccines than those from developed nations. Several factors, including endemic infections, nutrition, genetics, and gut microbiome composition, have been proposed to underlie discrepancies in vaccine response. In this issue of the JCI, Kityo et al. evaluated response to yellow fever virus vaccine, inflammation, and lymphatic tissue architecture and fibrosis in three cohorts: two from the U.S. and one from Uganda. Compared with the U.S. subjects, the Ugandan cohort exhibited enhanced cytokine responses, increased lymph node fibrosis, reduced CD4+ T cell levels, and reduced vaccine response. Together, these results provide a link among chronic inflammation, damaged lymphoid architecture, and poor vaccine outcome, and set the stage for future studies to identify strategies to overcome these barriers.