Factors influencing adverse events following COVID-19 vaccination.

Various novel platform technologies have been used for the development of COVID-19 vaccines. In this nested cohort study among healthcare workers in Australia and Brazil who received three different COVID-19-specific vaccines, we (a) evaluated the incidence of adverse events following immunization (AEFI); (b) compared AEFI by vaccine type, dose and country; (c) identified factors influencing the incidence of AEFI; and (d) assessed the association between reactogenicity and vaccine anti-spike IgG antibody responses. Of 1302 participants who received homologous 2-dose regimens of ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac), 1219 (94%) completed vaccine reaction questionnaires. Following the first vaccine dose, the incidence of any systemic reaction was higher in ChAdOx1-S recipients (374/806, 46%) compared with BNT162b2 (55/151, 36%; p = 0.02) or CoronaVac (26/262, 10%; p < 0.001) recipients. After the second vaccine dose, the incidence of any systemic reaction was higher in BNT162b2 recipients (66/151, 44%) compared with ChAdOx1-S (164/806, 20%; p < 0.001) or CoronaVac (23/262, 9%; p < 0.001) recipients. AEFI risk was higher in younger participants, females, participants in Australia, and varied by vaccine type and dose. Prior COVID-19 did not impact the risk of AEFI. Participants in Australia compared with Brazil reported a higher incidence of any local reaction (170/231, 74% vs 222/726, 31%, p < 0.001) and any systemic reaction (171/231, 74% vs 328/726, 45%, p < 0.001), regardless of vaccine type. Following a primary course of ChAdOx1-S or CoronaVac vaccination, participants who did not report AEFI seroconverted at a similar rate to those who reported local or systemic reactions. In conclusion, we found that the incidence of AEFI was influenced by participant age and COVID-19 vaccine type, and differed between participants in Australia and Brazil.

Direct and indirect impacts of ocean acidification and warming on algae-herbivore interactions in intertidal habitats.

Anthropogenically induced global climate change has caused profound impacts in the world ocean. Climate change related stressors, like ocean acidification (OA) and warming (OW) can affect physiological performance of marine species. However, studies evaluating the impacts of these stressors on algae-herbivore interactions have been much more scarce. We approached this issue by assessing the combined impacts of OA and OW on the physiological energetics of the herbivorous snail Tegula atra, and whether this snail is affected indirectly by changes in biochemical composition of the kelp Lessonia spicata, in response to OA and OW. Our results show that OA and OW induce changes in kelp biochemical composition and palatability (organic matter, phenolic content), which in turn affect snails' feeding behaviour and energy balance. Nutritional quality of food plays a key role on grazers' physiological energetics and can define the stability of trophic interactions in rapidly changing environments such as intertidal communities.

Safety of BCG vaccination and revaccination in healthcare workers.

BCG vaccination and revaccination are increasingly being considered for the protection of adolescents and adults against tuberculosis and, more broadly, for the off-target protective immunological effects against other infectious and noninfectious diseases. Within an international randomized controlled trial of BCG vaccination in healthcare workers (the BRACE trial), we evaluated the incidence of local and serious adverse events, as well as the impact of previous BCG vaccination on local injection site reactions (BCG revaccination). Prospectively collected data from 99% (5351/5393) of participants in Australia, Brazil, Spain, The Netherlands and the UK was available for analysis. Most BCG recipients experienced the expected self-limiting local injection site reactions (pain, tenderness, erythema, swelling). BCG injection site itch was an additional common initial local symptom reported in 49% of BCG recipients. Compared to BCG vaccination in BCG-naïve individuals, BCG revaccination was associated with increased frequency of mild injection site reactions, as well as earlier onset and shorter duration of erythema and swelling, which were generally self-limiting. Injection site abscess and regional lymphadenopathy were the most common adverse events and had a benign course. Self-resolution occurred within a month in 80% of abscess cases and 100% of lymphadenopathy cases. At a time when BCG is being increasingly considered for its off-target effects, our findings indicate that BCG vaccination and revaccination have an acceptable safety profile in adults.

Erratum: Factors influencing scar formation following Bacille Calmette-Guérin (BCG) vaccination.

[This corrects the article DOI: 10.1016/j.heliyon.2023.e15241.].

Factors influencing scar formation following Bacille Calmette-Guérin (BCG) vaccination.

The prevalence of scar formation following Bacille Calmette-Guérin (BCG) vaccination varies globally. The beneficial off-target effects of BCG are proposed to be stronger amongst children who develop a BCG scar. Within an international randomised trial ('BCG vaccination to reduce the impact of coronavirus disease 2019 (COVID-19) in healthcare workers'; BRACE Trial), this nested prospective cohort study assessed the prevalence of and factors influencing scar formation, as well as participant perception of BCG scarring 12 months following vaccination . Amongst 3071 BCG-recipients, 2341 (76%) developed a BCG scar. Scar prevalence was lowest in Spain and highest in UK. Absence of post-injection wheal (OR 0.4, 95%CI 0.2-0.9), BCG revaccination (OR 1.7, 95%CI 1.3-2.0), female sex (OR 2.0, 95%CI 1.7-2.4), older age (OR 0.4, 95%CI 0.4-0.5) and study country (Brazil OR 1.6, 95%CI 1.3-2.0) influenced BCG scar prevalence. Of the 2341 participants with a BCG scar, 1806 (77%) did not mind having the scar. Participants more likely to not mind were those in Brazil, males and those with a prior BCG vaccination history. The majority (96%) did not regret having the vaccine. Both vaccination-related (amenable to optimisation) and individual-related factors affected BCG scar prevalence 12 months following BCG vaccination of adults, with implications for maximising the effectiveness of BCG vaccination.

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

The safety of co-administration of Bacille Calmette-Guérin (BCG) and influenza vaccines.

BACKGROUND: With the emergence of novel vaccines and new applications for older vaccines, co-administration is increasingly likely. The immunomodulatory effects of BCG could theoretically alter the reactogenicity of co-administered vaccines. Using active surveillance in a randomised controlled trial, we aimed to determine whether co-administration of BCG vaccination changes the safety profile of influenza vaccination. METHODS: Participants who received influenza vaccine alone (Influenza group) were compared with those who also received BCG-Denmark vaccine in the contralateral arm (Influenza+BCG group). Data on the influenza vaccination site were collected using serial questionnaires and active follow-up for 3 months post vaccination. RESULTS: Of 1351 participants in the Influenza+BCG group and 1418 participants in the Influenza group, 2615 (94%) provided influenza vaccine safety data. There was no significant difference in the proportion of participants with any local adverse reaction between the Influenza+BCG group and the Influenza group (918/1293 [71.0%] versus (906/1322 [68.5%], p = 0.17). The proportion of participants reporting any pain, erythema and tenderness at the influenza vaccination site were similar in both groups. Swelling was less frequent (81/1293 [6.3%] versus 119/1322 (9.0%), p = 0.01) and the maximal diameter of erythema was smaller (mean 1.8 cm [SD 2.0] versus 3.0 cm [SD 2.5], p<0.001) in the Influenza+BCG group. Sixteen participants reported serious adverse events: 9 participants in the Influenza+BCG group and 7 in the Influenza group. CONCLUSIONS: Adverse events following influenza vaccination are not increased when BCG is co-administered.

Comparison of Antimicrobial Stewardship and Infection Prevention and Control Activities and Resources Between Low-/Middle- and High-income Countries.

BACKGROUND: The growth of antimicrobial resistance worldwide has led to increased focus on antimicrobial stewardship (AMS) and infection prevention and control (IPC) measures, although primarily in high-income countries (HIC). We aimed to compare pediatric AMS and IPC resources/activities between low- and middle-income countries (LMIC) and HIC and to determine the barriers and priorities for AMS and IPC in LMIC as assessed by clinicians in those settings. METHODS: An online questionnaire was distributed to clinicians working in HIC and LMIC healthcare facilities in 2020. RESULTS: Participants were from 135 healthcare settings in 39 LMIC and 27 HIC. Formal AMS and IPC programs were less frequent in LMIC than HIC settings (AMS 42% versus 76% and IPC 58% versus 89%). Only 47% of LMIC facilities conducted audits of antibiotic use for pediatric patients, with less reliable availability of World Health Organization Access list antibiotics (29% of LMIC facilities). Hand hygiene promotion was the most common IPC intervention in both LMIC and HIC settings (82% versus 91%), although LMIC hospitals had more limited access to reliable water supply for handwashing and antiseptic hand rub. The greatest perceived barrier to pediatric AMS and IPC in both LMIC and HIC was lack of education: only 17% of LMIC settings had regular/required education on antimicrobial prescribing and only 25% on IPC. CONCLUSIONS: Marked differences exist in availability of AMS and IPC resources in LMIC as compared with HIC. A collaborative international approach is urgently needed to combat antimicrobial resistance, using targeted strategies that address the imbalance in global AMS and IPC resource availability and activities.

Revaccination with Bacille Calmette-Guérin (BCG) is associated with an increased risk of abscess and lymphadenopathy.

The reported frequency and types of adverse events following initial vaccination and revaccination with Bacille Calmette-Guérin (BCG) varies worldwide. Using active surveillance in a randomised controlled trial of BCG vaccination (the BRACE trial), we determined the incidence and risk factors for the development of BCG injection site abscess and regional lymphadenopathy. Injection site abscess occurred in 3% of 1387 BCG-vaccinated participants; the majority (34/41, 83%) resolved without treatment. The rate was higher in BCG-revaccinated participants (OR 3.6, 95% CI 1.7-7.5), in whom abscess onset was also earlier (median 16 vs. 27 days, p = 0.008). No participant with an abscess had a positive interferon-gamma release assay. Regional lymphadenopathy occurred in 48/1387 (3%) of BCG-vaccinated participants, with a higher rate in revaccinated participants (OR 2.1, 95% CI 1.1-3.9). BCG-associated lymphadenopathy, but not injection site abscess, was influenced by age and sex. A previous positive tuberculin skin test was not associated with local reactions. The increased risk of injection site abscess or lymphadenopathy following BCG revaccination is relevant to BCG vaccination policy in an era when BCG is increasingly being considered for novel applications.

Management of Bacille Calmette-Guérin Lymphadenitis and Abscess in Immunocompetent Children: A Systematic Review.

BACKGROUND: There is no consensus on managing common adverse reactions to Bacille Calmette-Guérin (BCG) vaccination. We systematically reviewed the management of BCG-associated regional lymphadenitis and injection site abscess in immunocompetent individuals. METHODS: Searches of Medline, Embase and PubMed were done until November 2020. Randomized controlled trials (RCTs) and cohort studies that compared management strategies for complications of intradermal BCG vaccination were included. RESULTS: Of 1338 individual articles, 15 met inclusion criteria. Six RCTs, 4 prospective and 4 retrospective cohort studies compared management in 1022 children with BCG-associated lymphadenitis. For nonsuppurative lymphadenitis, no antimicrobial was found to significantly impact on time to resolution or prevention of suppuration. For suppurative lymphadenitis, there was some evidence that needle aspiration shortens time to resolution and prevents sinus tract formation. Surgical excision (mainly offered for persistent suppurative lymphadenitis) generally had favorable outcome. Two cohort studies (including 1 aforementioned) compared management strategies in up to 36 children with BCG injection site abscess; one showed no difference in outcome in children treated with antibiotics and the other reported complete resolution without treatment. CONCLUSIONS: Evidence does not support a role for antimicrobial therapy in the management of localized reactions to BCG vaccination in immunocompetent children. Needle aspiration may shorten the recovery period for BCG-associated suppurative lymphadenitis. BCG injection site abscess usually heals without treatment. However, studies are limited and cases are not well defined. Growing research into novel BCG applications provides opportunities to investigate optimal management strategies for adverse reactions in a prospective manner using active safety surveillance.

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial).

INTRODUCTION: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19. METHODS AND ANALYSIS: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections. ETHICS AND DISSEMINATION: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

The X-ray fluorescence screening of multiple elements in herbarium specimens from the Neotropical region reveals new records of metal accumulation in plants.

Plants have developed a diversity of strategies to take up and store essential metals in order to colonize various types of soils including mineralized soils. Yet, our knowledge of the capacity of plant species to accumulate metals is still fragmentary across the plant kingdom. In this study, we have used the X-ray fluorescence technology to analyze metal concentration in a wide diversity of species of the Neotropical flora that was not extensively investigated so far. In total, we screened more than 11 000 specimens representing about 5000 species from herbaria in Paris and Cuba. Our study provides a large overview of the accumulation of metals such as manganese, zinc, and nickel in the Neotropical flora. We report 30 new nickel hyperaccumulating species from Cuba, including the first records in the families Connaraceae, Melastomataceae, Polygonaceae, Santalaceae, and Urticaceae. We also identified the first species from this region of the world that can be considered as manganese hyperaccumulators in the genera Lomatia (Proteaceae), Calycogonium (Melastomataceae), Ilex (Aquifoliaceae), Morella (Myricaceae), and Pimenta (Myrtaceae). Finally, we report the first zinc hyperaccumulator, Rinorea multivenosa (Violaceae), from the Amazonas region. The identification of species able to accumulate high amounts of metals will become instrumental to support the development of phytotechnologies in order to limit the impact of soil metal pollution in this region of the world.

The safety of BCG revaccination: A systematic review.

INTRODUCTION: Revaccination with Bacillus Calmette-Guérin (BCG) vaccine is not generally recommended due to a lack of proven efficacy of repeat doses for protection against tuberculosis. However, there is a growing interest in the use of BCG vaccine for its 'off-target' effects which might involve revaccination. We did a systematic review of the safety of BCG revaccination. METHODS: MEDLINE (1946 to March 2020) and the BCG World Atlas (updated 2017) were searched, limiting to studies of BCG administration by the intradermal or percutaneous route. Adverse events as well as patient and vaccine characteristics were reviewed. RESULTS: The search identified 388 articles, of which 24 met the inclusion criteria. These reported 22 studies comprising eight randomised trials, four case-control studies, four observational studies and six case series or reports. Overall, there was evidence for a small increase in the rate of mild local and systemic reactions. No serious adverse events were reported in immunocompetent individuals. CONCLUSIONS: Evidence to date suggests that revaccination with BCG vaccine carries minimal risk. Future studies of BCG vaccine for novel applications should report adverse event data stratified by prior BCG vaccination status.

Impact of an antimicrobial stewardship intervention in neonatal intensive care: Recommendations and implementation.

AIM: To (i) determine the appropriateness of antimicrobial prescribing in the neonatal intensive care unit (NICU) and (ii) assess the impact of a collaborative antimicrobial stewardship (AMS) intervention on prescribing practices. METHODS: The intervention was a weekly AMS audit-feedback joint ward round (6-month period) of Neonatology and Infectious Diseases clinicians in a tertiary neonatal intensive care unit in Melbourne, Australia. Antibiotic prescriptions were audited and recommendations delivered in real time. The proportion of recommendations implemented was used to assess acceptability of the intervention. RESULTS: During the study period, there were 23 AMS rounds, during which 249 patients were reviewed at 627 separate episodes. Of these, 233 (37%) episodes were for patients receiving antimicrobials. Of these, 147 (63%) received empirical antimicrobial treatment, 43 (18%) targeted antimicrobial treatment and 43 (18%) antimicrobial prophylaxis. There were 58 (25%) of 233 episodes of inappropriate antibiotic use, and 62 recommendations for improvement. Most common recommendations were to narrow (33/62, 53%) or stop (12/62, 19%) antimicrobials. The majority (45, 73%) of recommendations were accepted, resulting in significant improvement in the proportion of the 233 episodes that had completely appropriate antibiotic prescribing: 175 (75%) to 217 (93%) (relative risk 1.2, 95% confidence intervals 1.1-1.3, P < 0.001). CONCLUSIONS: A collaborative audit-feedback AMS intervention was effective in identifying inappropriate antimicrobial prescriptions and impacted positively on treatment plans. Ancillary benefits were improved communication between departments and the revision of antimicrobial prescribing guidelines.

Plastic response of the oyster Ostrea chilensis to temperature and pCO2 within the present natural range of variability.

Estuaries are characterized by high fluctuation of their environmental conditions. Environmental parameters measured show that the seawater properties of the Quempillén estuary (i.e. temperature, salinity, pCO2, pH and ΩCaCO3) were highly fluctuating and related with season and tide. We test the effects of increasing temperature and pCO2 in the seawater on the physiological energetics of the bivalve Ostrea chilensis. Juvenile oysters were exposed to an orthogonal combination of three temperatures (10, 15, and 20°C) and two pCO2 levels (~400 and ~1000 µatm) for a period of 60 days to evaluate the temporal effect (i.e. 10, 20, 30, 60 days) on the physiological rates of the oysters. Results indicated a significant effect of temperature and time of exposure on the clearance rate, while pCO2 and the interaction between pCO2 and the other factors studied did not show significant effects. Significant effects of temperature and time of exposure were also observed on the absorption rate, but not the pCO2 nor its interaction with other factors studied. Oxygen consumption was significantly affected by pCO2, temperature and time. Scope for growth was only significantly affected by time; despite this, the highest values were observed for individuals subject to to 20°C and to ~1000 µatm pCO2. In this study, Ostrea chilensis showed high phenotypic plasticity to respond to the high levels of temperature and pCO2 experienced in its habitat as no negative physiological effects were observed. Thus, the highly variable conditions of this organism's environment could select for individuals that are more resistant to future scenarios of climate change, mainly to warming and acidification.

Accumulation and biotransformation dynamics of the neurotoxic complex, saxitoxin, in different life stages of Ostrea chilensis.

The neurotoxic complex saxitoxin, is a group of marine toxins that historically has significantly impacted human health and the ability to utilize marine resources. A steady increase in the distribution and intensity of Alexandrium catenella blooms in Chile, and around the world, has caused major ecological and socioeconomic impacts, putting this type of dinoflagellate, and its toxicity, in the spotlight. Ostrea chilensis is a commercially and ecologically important resource harvested from wild populations and farmed in centers of southern Chile, where it is exposed to large harmful algal blooms of the type that can cause paralysis in humans. This study contributes to our understanding about the transfer of toxins from A. catenella cells to juvenile and adult Ostrea chilensis by tracking transformations of the neurotoxic complex until it reaches its most stable molecular form in the intracellular environment of O. chilensis tissues. These biotransformations are different in O. chilensis juveniles and adults, indicating a differentiated response for these two life stages of this bivalve species. These studies can be used for similar analyses in other ecologically and commercially important species of filter feeding organisms, providing greater understanding of the specific interactions of bivalves in scenarios of toxic dinoflagellate proliferations (e.g. A. catenella blooms).

Ocean acidification exacerbates the effects of paralytic shellfish toxins on the fitness of the edible mussel Mytilus chilensis.

High latitudes are considered particularly vulnerable to ocean acidification, since they are naturally low in carbonate ions. The edible mussel Mytilus chilensis is a common calcifier inhabiting marine ecosystems of the southern Chile, where culturing of this species is concentrated and where algal blooms produced by the toxic dinoflagellate A. catenella are becoming more frequent. Juvenile Mytilus chilensis were exposed to experimental conditions simulating two environmental phenomena: pCO2 increase and the presence of paralytic shellfish toxins (PST) produced by the dinoflagellate Alexandrium catenella. Individuals were exposed to two levels of pCO2: 380 µatm (control condition) and 1000 µatm (future conditions) over a period of 39 days (acclimation), followed by another period of 40 days exposure to a combination of pCO2 and PST. Both factors significantly affected most of the physiological variables measured (feeding, metabolism and scope for growth). However, these effects greatly varied over time, which can be explained by the high individual variability described for mussels exposed to different environmental conditions. Absorption efficiency was not affected by the independent effect of the toxic diet; however, the diet and pCO2 interaction affected it significantly. The inhibition of the physiological processes related with energy acquisition by diets containing PST, may negatively impact mussel fitness, which could have important consequences for both wild and cultured mussel populations, and thus, for socioeconomic development in southern Chile.