Timing and sequence of vaccination against COVID-19 and influenza (TACTIC):a single-blind, placebo-controlled randomized clinical trial

Background: Novel mRNA-based vaccines have been used to protect against SARS-CoV-2, especially in vulnerable populations who also receive an annual influenza vaccination. The TACTIC study investigated potential immune interference between the mRNA COVID-19 booster vaccine and the quadrivalent influenza vaccine, and determined if concurrent administration would have effects on safety or immunogenicity. Methods: TACTIC was a single-blind, placebo-controlled randomized clinical trial conducted at the Radboud University Medical Centre, the Netherlands. Individuals ≥60 years, fully vaccinated against COVID-19 were eligible for participation and randomized into one of four study groups: 1) 0.5 ml influenza vaccination Vaxigrip Tetra followed by 0.3 ml BNT162b2 COVID-19 booster vaccination 21 days later, (2) COVID-19 booster vaccination followed by influenza vaccination, (3) influenza vaccination concurrent with the COVID-19 booster vaccination, and (4) COVID-19 booster vaccination only (reference group). Primary outcome was the geometric mean concentration (GMC) of IgG against the spike (S)-protein of the SARS-CoV-2 virus, 21 days after booster vaccination. We performed a non-inferiority analysis of concurrent administration compared to booster vaccines alone with a predefined non-inferiority margin of −0.3 on the log10-scale. Findings: 154 individuals participated from October, 4, 2021, until November, 5, 2021. Anti-S IgG GMCs for the co-administration and reference group were 1684 BAU/ml and 2435 BAU/ml, respectively. Concurrent vaccination did not meet the criteria for non-inferiority (estimate −0.1791, 95% CI −0.3680 to −0.009831) and antibodies showed significantly lower neutralization capacity compared to the reference group. Reported side-effects were mild and did not differ between study groups. Interpretation: Concurrent administration of both vaccines is safe, but the quantitative and functional antibody responses were marginally lower compared to booster vaccination alone. Lower protection against COVID-19 with concurrent administration of COVID-19 and influenza vaccination cannot be excluded, although additional larger studies would be required to confirm this. Trial registration number: EudraCT: 2021-002186-17 Funding: The study was supported by the ZonMw COVID-19 Programme.</p

The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution

Recurrent submicroscopic deletions in genes affecting key cellular pathways are a hallmark of pediatric acute lymphoblastic leukemia (ALL). To gain more insight into the mechanism underlying these deletions, we have studied the occurrence and nature of abnormalities in one of these genes, the B-cell translocation gene 1 (BTG1), in a large cohort of pediatric ALL cases. BTG1 was found to be exclusively affected by genomic deletions, which were detected in 65 out of 722 B-cell precursor ALL (BCP-ALL) patient samples (9%), but not in 109 T-ALL cases. Eight different deletion sizes were identified, which all clustered at the telomeric site in a hotspot region within the second (and last) exon of the BTG1 gene, resulting in the expression of truncated BTG1 read-through transcripts. The presence of V(D)J recombination signal sequences at both sites of virtually all deletions strongly suggests illegitimate RAG1/RAG2-mediated recombination as the responsible mechanism. Moreover, high levels of histone H3 lysine 4 trimethylation (H3K4me3), which is known to tether the RAG enzyme complex to DNA, were found within the BTG1 gene body in BCP-ALL cells, but not T-ALL cells. BTG1 deletions were rarely found in hyperdiploid BCP-ALLs, but were predominant in other cytogenetic subgroups, including the ETV6-RUNX1 and BCR-ABL1 positive BCP-ALL subgroups. Through sensitive PCR-based screening, we identified multiple additional BTG1 deletions at the subclonal level in BCP-ALL, with equal cytogenetic distribution which, in some cases, grew out into the major clone at relapse. Taken together, our results indicate that BTG1 deletions may act as “drivers” of leukemogenesis in specific BCP-ALL subgroups, in which they can arise independently in multiple subclones at sites that are prone to aberrant RAG1/RAG2-mediated recombination events. These findings provide further evidence for a complex and multiclonal evolution of ALL

Tumor Suppressors BTG1 and BTG2 Fulfill Both Unique and Overlapping Functions During Normal B Lymphocyte Development

International audienc

Long-Lasting Enhanced Cytokine Responses Following SARS-CoV-2 BNT162b2 mRNA Vaccination

The mRNA vaccine against COVID-19 protects against severe disease by the induction of robust humoral and cellular responses. Recent studies have shown the capacity of some vaccines to induce enduring non-specific innate immune responses by the induction of trained immunity, augmenting protection against unrelated pathogens. This study aimed to assess whether the mRNA vaccine BNT162b2 can induce lasting non-specific immune responses in myeloid cells following a three-dose vaccination scheme. In a sample size consisting of 20 healthy individuals from Romania, we assessed inflammatory proteins using the Olink® Target 96 Inflammation panel, as well as ex vivo cytokine responses following stimulations with unrelated PRR ligands. We assessed the vaccine-induced non-specific systemic inflammation and functional adaptations of myeloid cells. Our results revealed the induction of a stimulus- and cytokine-dependent innate immune memory phenotype that became apparent after the booster dose and was maintained eight months later in the absence of systemic inflammation

Peripheral blood mononuclear cell hyperresponsiveness in patients with premature myocardial infarction without traditional risk factors

Summary: An increasing number of patients develop an atherothrombotic myocardial infarction (MI) in the absence of standard modifiable risk factors (SMuRFs). Monocytes and macrophages regulate the development of atherosclerosis, and monocytes can adopt a long-term hyperinflammatory phenotype by epigenetic reprogramming, which can contribute to atherogenesis (called “trained immunity”). We assessed circulating monocyte phenotype and function and specific histone marks associated with trained immunity in SMuRFless patients with MI and matched healthy controls. Even in the absence of systemic inflammation, monocytes from SMuRFless patients with MI had an increased overall cytokine production capacity, with the strongest difference for LPS-induced interleukin-10 production, which was associated with an enrichment of the permissive histone marker H3K4me3 at the promoter region. Considering the lack of intervenable risk factors in these patients, trained immunity could be a promising target for future therapy

Multiple <i>BTG1</i> deletion-positive clones are present in specific BCP-ALL subtypes.

<p>(A) Recurrence of multiclonal <i>BTG1</i> deletions. A sensitive PCR method was used to screen for eight different deletion breakpoints (deletion I–VIII) in <i>BTG1</i> MLPA deletion positive (+) cases (n = 65), and to screen for the three most frequent deletion breakpoints (deletion III, V and VIII) in <i>BTG1</i> MLPA deletion negative (−) cases (n = 89). (B) <i>BTG1</i> deletion frequency in the two major cytogenetic subgroups of BCP-ALL (Hyperdiploid and <i>ETV6</i>-<i>RUNX1</i>). Presence of a <i>BTG1</i> deletion in the predominant clone was determined by MLPA on the entire cohort of BCP-ALL cases (n = 722), and was compared to deletions detected as a minor clone in MLPA-negative cases (n = 89) by deletion-spanning PCR. Distributions are similar, being depleted from hyperdiploid cases and enriched in <i>ETV6</i>-<i>RUNX1</i>-positive cases as compared to the total group.</p

Authentic RSSs and candidate RSSs flanking breakpoints of <i>BTG1</i> microdeletions.

<p>Mismatches from consensus are underlined;</p>a<p>RSSs flanking V(D)J gene segments;</p>b<p>Sequence shown is in reverse complement orientation;</p>c<p>Functional cryptic RSSs at proto-oncogene breakpoints <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002533#pgen.1002533-Marculescu1" target="_blank">[18]</a>.</p

<i>BTG1</i> microdeletion occurrence within cytogenetic subgroups of ALL.

<p><i>BTG1</i> deletion status was determined using MLPA.</p>a<p>Because of missing values, numbers do not always add up to 722 BCP-ALL cases. Data was available for 637 cases on hyperdiploidy; 513 cases for <i>ETV6-RUNX1</i>; 648 cases for <i>BCR-ABL1;</i> 649 cases for <i>MLL</i>-rearranged.</p>b<p>The ‘other’ subgroup encompasses cases negative for <i>ETV6-RUNX1</i> or <i>BCR-ABL1</i> translocations, <i>MLL</i>-rearrangement and/or hyperdiploidy. This group includes 10 cases with <i>E2A-PBX1</i> translocation, of which none harbor a <i>BTG1</i> deletion.</p>c<p>Subgroup unknown includes all cases in which no data is available in one or more cytogenetic classifications.</p>d<p>Fisher's exact test was used when sample groups were small.</p