A randomized double-blinded trial to assess recurrence of systemic allergic reactions following COVID-19 mRNA vaccination

BACKGROUND: Systemic allergic reactions (sARs) following coronavirus disease 2019 (COVID-19) mRNA vaccines were initially reported at a higher rate than after traditional vaccines. OBJECTIVE: We aimed to evaluate the safety of revaccination in these individuals and to interrogate mechanisms underlying these reactions. METHODS: In this randomized, double-blinded, phase 2 trial, participants aged 16 to 69 years who previously reported a convincing sAR to their first dose of COVID-19 mRNA vaccine were randomly assigned to receive a second dose of BNT162b2 (Comirnaty) vaccine and placebo on consecutive days in a blinded, 1:1 crossover fashion at the National Institutes of Health. An open-label BNT162b2 booster was offered 5 months later if the second dose did not result in severe sAR. None of the participants received the mRNA-1273 (Spikevax) vaccine during the study. The primary end point was recurrence of sAR following second dose and booster vaccination; exploratory end points included biomarker measurements. RESULTS: Of 111 screened participants, 18 were randomly assigned to receive study interventions. Eight received BNT162b2 second dose followed by placebo; 8 received placebo followed by BNT162b2 second dose; 2 withdrew before receiving any study intervention. All 16 participants received the booster dose. Following second dose and booster vaccination, sARs recurred in 2 participants (12.5%; 95% CI, 1.6 to 38.3). No sAR occurred after placebo. An anaphylaxis mimic, immunization stress-related response (ISRR), occurred more commonly than sARs following both vaccine and placebo and was associated with higher predose anxiety scores, paresthesias, and distinct vital sign and biomarker changes. CONCLUSIONS: Our findings support revaccination of individuals who report sARs to COVID-19 mRNA vaccines. Distinct clinical and laboratory features may distinguish sARs from ISRRs

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The roles of stem cell factor and interleukin-7 in development of TCRgammadelta cells

Interleukin 7 (IL-7) is absolutely required for development of TCRγδ cells. IL-7 deficient (IL-7–/–) mice have reduced numbers of B and TCRαδ cells, but completely lack mature TCRγδ cells. To date, the precise role of IL-7 in TCRγδ development has not been pinpointed. We have used neonatal thymectomy (nTx) and thymus grafting, tissue-specific iFABP-IL7 transgenic IL-7–/– mice, or G8 TCRγδ-transgenic IL-7–/– mice to identify IL-7 dependent stages of TCRγδ cell development. The data presented show that IL-7 first acted on T cell precursors to stimulate TCRγ gene rearrangement. Expression of a fully rearranged TCRγδ transgene restored TCRγδ cells to IL-7 –/– mice, and endogenous TCRγ chains were expressed by TCRγδ cells in G8 IL-7+/– mice, but not G8 IL-7–/– mice. IL-7 directed TCRγ gene rearrangement in two different anatomic locations: in the thymus for thymus-derived TCRγδ cells, or in the intestinal epithelium for extrathymic TCRγδ intraepithelial lymphocytes (IEL). TCRγδ cells developed in IL-7 + thymi that had been grafted to nTx IL-7–/– mice. TCRγδ IEL also developed in IL-7–/– mice in which IL-7 expression was restored specifically to the intestinal epithelium. TCRγδ+ thymocytes derived from early fetal liver precursors did not require additional IL-7. In contrast, the survival of TCRγδ+ thymocytes derived from late fetal liver or adult bone marrow was IL-7 dependent. Neither fetal liver- nor bone marrow-derived mature TCRγδ cells required extrathymic IL-7 in order to survive. Instead, the maintenance and proliferation of TCRγδ IEL was dependent upon another cytokine, stem cell factor (SCF). Mice with a reduced function mutation in the SCF receptor c-Kit (W/ WV), had reduced numbers of TCRγδ IEL, because in the absence of optimal SCF/c-Kit interactions TCRγδ cells proliferated less. With regard to the role of IL-7 in the development of TCRγδ cells, these data illustrated that IL-7 influenced immature TCRγδ cells at multiple stages, and that the developmental requirements of TCRγδ cells arising at different times during ontogeny differed in their dependence upon IL-7. These data also provided the first unequivocal evidence that extrathymic TCRγδ IEL development occurred in situ, within the intestinal epithelium.