Using the Vaccine Adverse Event Reporting System, the number and demographic characteristics of cases of thrombosis with thrombocytopenia syndrome occurring after receipt of COVID-19 vaccines in th... Visual Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination. Using the Vaccine Adverse Event Reporting System, the number and demographic characteristics of cases of thromb... Background: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneou...

Shigellosis is a major cause of moderate to severe diarrhoea and dysentery in children under 5 years of age in low and middle-income countries. The Flexyn2a vaccine conjugates the O-polysaccharide of Shigella flexneri 2a to Pseudomonas aeruginosa exotoxin A. We describe a Phase 2b proof-of-concept challenge study that evaluated safety, immunogenicity, and efficacy of the Flexyn2a vaccine to protect against shigellosis. In this randomized, double blind, placebo-controlled trial, healthy adults were randomized 1:1 to receive Flexyn2a (10 µg) or placebo intramuscularly, twice, 4 weeks apart, followed by challenge 4 weeks later with 1500 colony forming units (CFUs) of S. flexneri 2a strain 2457T. The primary outcome was vaccine-induced protection. S. flexneri 2a lipopolysaccharide (LPS)-specific immune responses were assessed. Sixty-seven subjects were enrolled, 34 received vaccine and 33 placebo. The vaccine was well tolerated; the majority of adverse events were mild in nature. Thirty vaccinees and 29 placebo recipients received the S. flexneri 2a challenge. Vaccination resulted in a 30.2% reduction in shigellosis compared with placebo (13/30 vs. 18/29; p = 0.11; 95% CI -15 to 62.6). Vaccine efficacy was more robust against severe disease, reaching 51.7% (p = 0.015, 95% CI 5.3 to 77.9) against moderate/severe diarrhoea or dysentery concurrent with fever or severe enteric symptoms and 72.4% (p = 0.07) against more severe diarrhoea (≥10 lose stools or ≥1000 g loose stools/24 h). Vaccinated subjects were less likely to need early antibiotic intervention following challenge (protective efficacy 51.7%, p = 0.01; 95% CI 9 to 76.8). In those who developed shigellosis, vaccinated subjects had a lower disease severity score (p = 0.002) than placebo-recipients. Additionally, LPS-specific serum IgG responses in Flexyn2a recipients were associated with protection against disease (p = 0.0016) and with a decreased shigellosis disease score (p = 0.002). The Flexyn2a bioconjugate vaccine was immunogenic, well tolerated and protected against severe illness after Shigella challenge and is a promising Shigella vaccine construct. We identified a strong association between anti-S. flexneri 2a serum IgG and a reduction in disease outcomes. (Clinicaltrials.gov, NCT02646371.) FUNDING: Funding for this study was through a grant from the Wellcome Trust.

Background: The timing of host cytokine responses to influenza vaccination is poorly understood.Objectives: We examined serum cytokine kinetics following inactivated trivalent influenza vaccine (TIV) to better understand potential relationships between markers of inflammation and TIV‐related side effects.Patients/Methods: Twenty healthy adult subjects received TIV. Cytokines/chemokines were assessed in intervals from 3 hours to 14 days. Antibody titers were measured at baseline and Day 14.Results: Serum cytokine responses to TIV were evident as early as 3 hours post‐immunization. Compared to baseline, IFN‐γ and IP‐10 were significantly elevated 7 hours after TIV administration. Both remained elevated and peaked between 16 and 24 hours before returning to baseline by 44 hours post‐vaccination. Although IL‐8 levels were variable between subjects during the first 24 hours after TIV, by 44 hours, IL‐8 was significantly lower compared to baseline. Interestingly, IL‐8 levels remained significantly lower for up to 2 weeks after receiving TIV. Fifteen of 20 subjects reported mild adverse events. The one subject who reported moderate myalgias and injection site pain after vaccination displayed a distinctive, early cytokine response profile which included IL‐6, IL‐2, IL‐8, IP‐10, MCP‐1, TNF‐α, TARC, and MCP‐4.Conclusions: Serum cytokines changed rapidly following TIV and generally peaked at 24 hours. Trivalent influenza vaccine‐induced reductions in IL‐8 occurred later (44 hours) and were sustained for 2 weeks. An outlier response coincided with the only moderate side effects to the vaccine. These data suggest that early cytokine/chemokine responses may provide additional insight into the pathogenesis of adverse events and immune reactivity to vaccination.

Shigella causes morbidity and mortality worldwide, primarily affecting young children living in low-resource settings. It is also of great concern due to increasing antibiotic resistance, and is a priority organism for the World Health Organization. A Shigella vaccine would decrease the morbidity and mortality associated with shigellosis, improve child health, and decrease the need for antibiotics. Controlled human infection models (CHIMs) are useful tools in vaccine evaluation for early up- or down-selection of vaccine candidates and potentially useful in support of licensure. Over time, the methods employed in these models have become more uniform across sites performing CHIM trials, although some differences in conduct persist. In November 2017, a Shigella CHIM workshop was convened in Washington, District of Columbia. Investigators met to discuss multiple aspects of these studies, including study procedures, clinical and immunological endpoints, and shared experiences. This article serves as a uniform procedure by which to conduct Shigella CHIM studies.

The Shigella controlled human infection model (CHIM) is valuable for assessing candidate Shigella vaccine efficacy and potentially accelerating regulatory approval. The Shigella CHIM is currently being conducted at 3 sites in the United States using Shigella flexneri 2a strain 2457T and Shigella sonnei strain 53G. Shigellosis can present variably as watery diarrhea alone or with dysentery, and can be accompanied by manifestations including fever, abdominal cramps, tenesmus, and malaise. For comparability, it is important to harmonize the primary clinical endpoint. An expert working group was convened on 2 February 2018 to review clinical data from Shigella CHIM studies performed to date and to develop a consensus primary endpoint. The consensus endpoint enabled “shigellosis” to present as severe diarrhea or moderate diarrhea or dysentery. The latter 2 criteria are met when concurrent with fever of 38.0°C and/or vomiting, and/or a constitutional/enteric symptom graded at least as “moderate” severity. The use of a blinded independent committee to adjudicate the primary endpoint by subject was also regarded as important. As safety of volunteers in challenge studies is of paramount importance and treatment timing can affect primary outcomes, a standard for early antibiotic administration was established as follows: (1) when the primary endpoint is met; (2) if a fever of ≥39.0°C develops; or (3) if the study physician deems it appropriate. Otherwise, antibiotics are given at 120 hours postinfectious challenge. The working group agreed on objective and subjective symptoms to be solicited, and standardized methods for assessing subject-reported severity of symptoms.

Background: The Delta COVID-19 variant caused a resurgence in cases and deaths during the summer of 2021, particularly among the unvaccinated, highlighting the need to increase vaccine coverage. We describe a survey conducted in September 2021, in the midst of the Delta variant surge, after the FDA fully approved Pfizer-BioNTech’s vaccine for ages 16+ and issued an emergency use authorization for ages 12–15. Methods and Findings: US adults were surveyed to measure COVID-19 vaccination status, intentions, attitudes, values, and trust in public health authorities. More than three-quarters (77%) reported receiving at least one dose of COVID-19 vaccination. Of the unvaccinated, 6% intended to vaccinate, 40% were unlikely to ever vaccinate, and 55% remained uncertain. Most of the unvaccinated were <45 years old (62%), without a bachelor’s degree (83%), earning less than $85,000 annually (74%), and Republican/Independent (66%). Concerns among the unvaccinated-yet-still-uncertain included the vaccines’ safety (86%), speed of development (86%), and suspicion of government (79%) and pharmaceutical companies (69%). Most (86%) of the unvaccinated reported they would not vaccinate if mandated by their employer. About one third (34%) of the unvaccinated reported facing at least one barrier to vaccination. Conclusion: More than half of unvaccinated adults remained uncertain about COVID-19 vaccination, indicating an opportunity to support their decision making. Public health must increase easy and equitable access to vaccination and renew efforts to provide unvaccinated populations access to information from trusted sources.