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Bivalent COVID-19 vaccines comprising ancestral Wuhan-Hu-1 (WH1) and the Omicron BA.1 or BA.5 subvariant elicit enhanced serum antibody responses to emerging Omicron subvariants. Here, we characterized the RBD-specific memory B cell (Bmem) response following a fourth dose with a BA.1 or BA.5 bivalent vaccine, in direct comparison with a WH1 monovalent fourth dose. Healthcare workers previously immunized with mRNA or adenoviral vector monovalent vaccines were sampled before and one month after a fourth dose with a monovalent or a BA.1 or BA.5 bivalent vaccine. Serum neutralizing antibodies (NAb) were quantified, as well as RBD-specific Bmem with an in-depth spectral flow cytometry panel including recombinant RBD proteins of the WH1, BA.1, BA.5, BQ.1.1, and XBB.1.5 variants. Both bivalent vaccines elicited higher NAb titers against Omicron subvariants compared to the monovalent vaccine. Following either vaccine type, recipients had slightly increased WH1 RBD-specific Bmem numbers. Both bivalent vaccines significantly increased WH1 RBD-specific Bmem binding of all Omicron subvariants tested by flow cytometry, while recognition of Omicron subvariants was not enhanced following monovalent vaccination. IgG1+ Bmem dominated the response, with substantial IgG4+ Bmem only detected in recipients of an mRNA vaccine for their primary dose. Thus, Omicron-based bivalent vaccines can significantly boost NAb and Bmem specific for ancestral WH1 and Omicron variants and improve recognition of descendent subvariants by pre-existing, WH1-specific Bmem beyond that of a monovalent vaccine. This provides new insights into the capacity of variant-based mRNA booster vaccines to improve immune memory against emerging SARS-CoV-2 variants and potentially protect against severe disease. Omicron BA.1 and BA.5 bivalent COVID-19 boosters, used as a fourth dose, increase RBD-specific Bmem cross-recognition of Omicron subvariants, both those encoded by the vaccines and antigenically distinct subvariants, further than a monovalent booster. [ABSTRACT FROM AUTHOR]

Travellers visiting rabies-endemic countries are at risk of rabies infection. Assessing travellers' knowledge and risk perception of rabies and risk behaviour during travel can help identify knowledge gaps and improve pre-travel risk education. Cohort study in Dutch adult travellers, using two surveys: one before travel to assess knowledge and perception of rabies, and one after return to identify risk behaviour during travel. The pre-travel and post-travel survey were completed by 301 and 276 participants, respectively. 222 participants had travelled to a high-risk rabies-endemic country. 21.6 % of the participants scored their rabies knowledge as poor. Some participants were unaware cats or bats can transmit rabies (26.6 % and 13.6 %, respectively), or that post-exposure prophylaxis (PEP) is required for certain exposures such as skin abrasions without bleeding or licks on damaged skin (35.5 % and 18.9 %, respectively), while 27.9 % of participants did not know PEP needs to be administered within one day. 115 participants (51.8 %) reported any form of contact with any animal during travel. Two participants reported animal exposure, of which one took adequate PEP measures. Risk factors for animal contact abroad were regularly touching cats or dogs at home or abroad, longer travel duration, having pets during childhood and being an animal lover. Pre-travel rabies risk education currently does not meet travellers' needs, which is reflected in knowledge gaps and engagement in risk behaviour during travel. During pre-travel health advice, avoiding animal contact abroad should be emphasized, and additional education is required about indications for PEP. [ABSTRACT FROM AUTHOR]

Travelers can experience health problems while abroad. This descriptive study aimed to quantify the disease burden leading to hospital-based care, repatriation or death in Dutch travelers during a stay in a foreign country, including Europe. Retrospective study of demographic and clinical data from three medical assistance centers (MACs) and the Dutch Ministry of Foreign Affairs on Dutch travelers receiving hospital-based care or who died abroad in the years 2010–2014. Diagnoses were coded according to the International Classification of Diseases (ICD) and classified using the Global Burden of Disease tool. Data was available for 77,741 travelers' incidents: 75,385 medical consultations and 2,356 deaths. Four in five travelers received inpatient care, of which 36% concerned older travelers (65+) who had significantly longer hospital stays. Overall the top three diagnoses were: injuries (29%), infectious diseases (17%), and cardiovascular diseases (17%). Mental illness was reported in nearly 1.5% of the travelers. Incidence proportions were highest in South-Eastern Asia, with enteric infections as most common diagnosis. Injuries and communicable diseases occurred most often in South-Eastern Asia, while non-communicable diseases were mostly reported in South America. One in five travelers who consulted a physician was repatriated back home, mostly on a scheduled flight with or without medical escort. Cardiovascular diseases and injuries were the leading causes of death. Not only communicable diseases, but also injuries and chronic diseases (in particular cardiovascular diseases) frequently affected travelers' health while staying abroad and frequently necessitated hospital-based care. This should be addressed during the pre-travel counseling. [ABSTRACT FROM AUTHOR]

Patients under immunosuppressive therapy with tumor necrosis factor alpha (TNF-α) antagonists are vulnerable to various opportunistic infections including leishmaniasis. We present a case series of 8 travellers developing cutaneous leishmaniasis whilst on TNF-α antagonist treatment and review the literature on aspects of cutaneous leishmaniasis developing in patients treated with TNF-α antagonists. We make interim recommendations regarding the drug therapy used to maintain remission in travellers with rheumatoid disease travelling to leishmania prone areas. Despite having a medical condition requiring continued rheumatological review the interval to diagnosis appears not to be reduced compared to that described in non-rheumatoid patients. Rheumatologists and family doctors should be aware of the need for post-travel surveillance for leishmaniasis in rheumatoid patients on TNF-alpha antagonist treatment. [ABSTRACT FROM AUTHOR]

Abstract: Unpreserved faecal samples, suspected to contain Entamoeba histolytica/Entamoeba dispar cysts or trophozoites on the basis of microscopic examination, and serum samples from 416 patients were collected in a prospective study to determine whether stool antigen assays and detection of antibodies in serum are reliable methods to distinguish between carriers of E. histolytica and E. dispar in comparison to the reference test: real-time PCR. In 283 patients (68%) DNA of E. histolytica or E. dispar was amplified by real-time PCR: 6 patients with amoebic colitis (2%), 19 carriers of E. histolytica (6.7%), and 258 carriers of E. dispar (91.2%). In 133 patients (31%) no DNA of E. histolytica or E. dispar could be amplified in the stool samples. This patient group was used as control for the evaluation of diagnostic tests. Using real-time PCR as a reference test, the sensitivity and specificity of (1) the Entamoeba test™ for the diagnosis of E. histolytica/E. dispar carrier were 59% and 98%, (2) E. histolytica II™ for the diagnosis of E. histolytica carrier was 71% and 100%, and (3) serology for the diagnosis of E. histolytica infection was 83.3% and 95.2%, respectively. Applied to carriers that did not originate from an endemic country the sensitivity of serology for E. histolytica infection was 90% and specificity was 98.8%. In comparison to real-time PCR the performances of Entamoeba test™ and E. histolytica II™ lacked sensitivity for a reliable diagnosis of E. histolytica/E. dispar infection in a non-endemic setting. In carriers of E. histolytica/E. dispar from non-endemic countries the high specificity of serology can be used to establish the diagnosis of E. histolytica infection if antibodies are present. [Copyright &y& Elsevier]

Background: High basal plasma levels of inflammatory molecules are associated with a higher risk of cardiovascular events. It has been suggested that also the dynamic response to an inflammatory trigger is important in determining cardiovascular risk. The aim of the present study was to evaluate the use of vaccination against yellow fever as an in vivo model to study the interindividual variation in the response to inflammatory triggers. Methods: Ten healthy volunteers were vaccinated with 17D yellow fever vaccine. Blood samples were drawn each day, until Day 8 after vaccination. Automated blood cell counting was performed, and the plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen were determined. Results: In most individuals, CRP levels peaked slightly (45% increase from basal values) around Day 7 after vaccination, preceded by an IL-6 (30%) peak around Day 5. Fibrinogen levels showed a significant increase (10%) from Day 2 after vaccination, with a further rise (17%) around Day 5. The monocyte fraction showed a significant 2-fold increase on Day 7 after vaccination. The lymphocyte fraction increased slightly towards Day 7 (not significant). Conclusion: Our findings show that yellow fever vaccination can be used as a model to study the response to mild stimulation of the inflammatory system. [Copyright &y& Elsevier]

This case report describes a patient diagnosed with ongoing portal venous gas, initiated by a rather common Campylobacter enterocolitis and maintained by septic thrombophlebitis and possibly by chronic cholecystitis. Cholecystectomy attenuated the patient''s septic condition. The etiology of portal venous gas determines both the patient''s prognosis and the choice for either conservative or surgical treatment. This report describes persistence of portal venous gas for a long period and a possible role for chronic cholecystitis as a cause. [Copyright &y& Elsevier]

The absence of a consensus-based reference standard for urinary tract infection (UTI) research adversely affects the internal and external validity of diagnostic and therapeutic studies. This omission hinders the accumulation of evidence for a disease that imposes a substantial burden on patients and society, particularly in an era of increasing antimicrobial resistance. We did a three-round Delphi study involving an international, multidisciplinary panel of UTI experts (n=46) and achieved a high degree of consensus (94%) on the final reference standard. New-onset dysuria, urinary frequency, and urinary urgency were considered major symptoms, and non-specific symptoms in older patients were not deemed indicative of UTI. The reference standard distinguishes between UTI with and without systemic involvement, abandoning the term complicated UTI. Moreover, different levels of pyuria were incorporated in the reference standard, encouraging quantification of pyuria in studies done in all health-care settings. The traditional bacteriuria threshold (105 colony-forming units per mL) was lowered to 104 colony-forming units per mL. This new reference standard can be used for UTI research across many patient populations and has the potential to increase homogeneity between studies. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the safety and immunogenicity of a dose-sparing fractional intradermal (ID) booster strategy with the mRNA-1273 COVID-19 vaccine. COVID-19 naive adults aged 18–30 years were recruited from a previous study on primary vaccination regimens that compared 20 μg ID vaccinations with 100 μg intramuscular (IM) vaccinations with mRNA-1273 as the primary vaccination series. Participants previously immunized with ID regimens were randomly assigned (1:1) to receive a fractional ID booster dose (20 μg) or the standard-of-care intramuscular (IM) booster dose (50 μg) of the mRNA-1273 vaccine, 6 months after completing their primary series (ID-ID and ID-IM group, respectively). Participants that had received a full dose IM regimen as the primary series, received the IM standard-of-care booster dose (IM-IM group). In addition, COVID-19 naive individuals aged 18–40 years who had received an IM mRNA vaccine as the primary series were recruited from the general population to receive a fractional ID booster dose (IM-ID group). Immunogenicity was assessed using IgG anti-spike antibody responses and neutralizing capacity against SARS-CoV-2. Cellular immune responses were measured in a sub-group. Safety and tolerability were monitored. In January 2022, 129 participants were included in the study. Fractional ID boosting was safe and well tolerated, with fewer systemic adverse events compared with IM boosting. At day 28 post-booster, anti-spike S1 IgG geometric mean concentrations were 9106 (95% CI, 7150–11 597) binding antibody units (BAU)/mL in the IM-IM group and 4357 (3003–6322) BAU/mL; 6629 (4913–8946) BAU/mL; and 5264 (4032–6873) BAU/mL in the ID-IM, ID-ID, and IM-ID groups, respectively. Intradermal boosting provides robust immune responses and is a viable dose-sparing strategy for mRNA COVID-19 vaccines. The favourable side-effect profile supports its potential to reduce vaccine hesitancy. Fractional dosing strategies should be considered early in the clinical development of future mRNA vaccines to enhance vaccine availability and pandemic preparedness. [ABSTRACT FROM AUTHOR]

After rabies pre-exposure prophylaxis (PrEP) vaccination, scarcely available rabies immunoglobulins are not required for post-exposure prophylaxis (PEP). However, PrEP is not sufficiently accessible as it is cost-intensive and time-intensive. This study investigates whether rabies PrEP schedules can be shortened to one visit, removing some of these barriers. In a block-randomised (2:2:2:1) controlled, multicentre non-inferiority trial, healthy adult travellers (aged 18–50 years and >50 years) were randomly assigned to (A) single-visit intramuscular (1·0 mL); (B) single-visit intradermal (0·2 mL); (C) standard two-visit intramuscular (1·0 mL; day 0 and 7) PrEP; or (D) no rabies vaccination. 6 months later, participants received simulated intramuscular rabies PEP (1·0 mL; day 0 and 3). Rabies virus neutralising antibody (RVNA) concentrations were measured repeatedly. The primary outcome was the fold increase in geometric mean RVNA concentrations between day 0 and 7 after simulated PEP for all participants. The two main comparisons of this primary outcome are between the standard two-visit schedule and the one-visit intramuscular schedule, and between the standard two-visit schedule and the one-visit intradermal schedule. The non-inferiority margin was 0·67. This study is registered with EudraCT, 2017-000089-31. Between May 16, 2018, and March 26, 2020, 288 healthy adult travellers were randomly assigned and 214 participants were evaluated for the primary outcome. Single-visit intramuscular rabies PrEP induced an anamnestic antibody response non-inferior compared with the two-visit intramuscular schedule; single-visit intradermal PrEP did not. The fold increases in the single-visit intramuscular and the single-visit intradermal schedule were 2·32 (95% CI [1·43–3·77]) and 1·11 (0·66–1·87) times as high as the fold increase in the standard schedule, respectively. No vaccine-related serious adverse events were observed. Adverse events related to vaccination were mostly mild. Single intramuscular rabies vaccination can effectively prime travellers (aged 18–50 years), and potentially other populations, and could replace current standard two-visit rabies vaccination as PrEP. ZonMW. For the Dutch translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

Urinary tract infection (UTI) is common among older women. However, diagnosis is challenging because of frequent chronic lower urinary tract symptoms, cognitive impairment, and a high prevalence of asymptomatic bacteriuria (ASB). Current urine diagnostics lack specificity, leading to unnecessary treatment and antimicrobial resistance. This study aimed to evaluate the diagnostic accuracy of 12 urine biomarkers for diagnosing UTI in older women. In this case-control study, cases were women ≥65 years with ≥2 new-onset lower urinary tract symptoms, pyuria, and one uropathogen ≥104 CFU/mL. Controls were asymptomatic and classified as ASB (one uropathogen ≥105 CFU/mL), negative culture, or mixed flora. Urine biomarker concentrations were measured through liquid chromatography-mass spectrometry and ELISA. Diagnostic accuracy parameters of individual biomarkers and a biomarker model were derived from receiver operating characteristic curves. We included 162 community-dwelling and institutionalized older women. Five urine inflammatory biomarkers demonstrated high discriminative ability (area under the curve ≥0.80): interleukin 6, azurocidin, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinases 2, and C-X-C motif chemokine 9. Azurocidin exhibited the highest diagnostic accuracy (sensitivity 86% [95% CI 75%–93%] and specificity 89% [95% CI 82%–94%] at 16.7 ng/mmol creatinine). A combined biomarker and pyuria model showed improved diagnostic accuracy in patients with UTI and ASB, compared with pyuria alone. We identified several urine biomarkers that accurately differentiated older women with UTI from asymptomatic women, including ASB. These findings represent a potential advancement towards improved diagnostics for UTI in older women and warrant validation in a diverse population. [ABSTRACT FROM AUTHOR]

The association of biological female sex with outcome in patients with Staphylococcus aureus bacteraemia remains unresolved. The aim of this study was to determine the independent association of female sex with management and mortality in patients with S. aureus bacteraemia. This is a post hoc analysis of prospectively collected data from the S. aureus Bacteraemia Group Prospective Cohort Study. Adult patients with monomicrobial S. aureus bacteraemia at Duke University Medical Center were enrolled from 1994 to 2020. Univariable and multivariable Cox regression analyses were performed to assess differences in management and mortality between females and males. Among 3384 patients with S. aureus bacteraemia, 1431 (42%) were women. Women were, as compared with men, more often Black (581/1431 [41%] vs. 620/1953 [32%], p < 0.001), haemodialysis dependent (309/1424 [22%] vs. 334/1940 [17%], p 0.001) and more likely to be infected with methicillin-resistant S. aureus (MRSA) (697/1410 [49%] MRSA in women vs. 840/1925 [44%] MRSA in men, p 0.001). Women received shorter durations of antimicrobial treatment (median 24 [interquartile range 14–42] vs. 28 [interquartile range 14–45] days, p 0.005), and were less likely to undergo transesophageal echocardiography as compared with men (495/1430 [35%] vs. 802/1952 [41%], p < 0.001). Despite these differences, female sex was not associated with 90-day mortality in either univariable (388/1431 [27%] in women vs. 491/1953 [25%] in men, p 0.204) or multivariable analysis (adjusted hazard ratio for women 0.98 [95% CI, 0.85–1.13]). Despite significant differences in patient characteristics, disease characteristics, and management, women and men with S. aureus bacteraemia have a similar mortality risk. [ABSTRACT FROM AUTHOR]

Bivalent mRNA-based COVID-19 vaccines encoding the ancestral and omicron spike (S) protein were developed as a countermeasure against antigenically distinct SARS-CoV-2 variants. We aimed to assess the (variant-specific) immunogenicity and reactogenicity of mRNA-based bivalent omicron (BA.1) vaccines in individuals who were primed with adenovirus-based or mRNA-based vaccines encoding the ancestral spike protein. We analysed results of the direct boost group of the SWITCH ON study, an open-label, multicentre, randomised controlled trial. Health-care workers from four academic hospitals in the Netherlands aged 18–65 years who had completed a primary COVID-19 vaccination regimen and received one booster of an mRNA-based vaccine, given no later than 3 months previously, were eligible. Participants were randomly assigned (1:1) using computer software in block sizes of 16 and 24 to receive an omicron BA.1 bivalent booster straight away (direct boost group) or a bivalent omicron BA.5 booster, postponed for 90 days (postponed boost group), stratified by priming regimen. The BNT162b2 OMI BA.1 boost was given to participants younger than 45 years, and the mRNA-1273.214 boost was given to participants 45 years or older, as per Dutch guidelines. The direct boost group, whose results are presented here, were divided into four subgroups for analysis: (1) Ad26.COV2.S (Johnson & Johnson) prime and BNT162b2 OMI BA.1 (BioNTech–Pfizer) boost (Ad/P), (2) mRNA-based prime and BNT162b2 OMI BA.1 boost (mRNA/P), (3) Ad26.COV2.S prime and mRNA-1273.214 (Moderna) boost (Ad/M), and (4) mRNA-based prime and mRNA-1273.214 boost (mRNA/M). The primary outcome was fold change in S protein S1 subunit-specific IgG antibodies before and 28 days after booster vaccination. The primary outcome and safety were assessed in all participants except those who withdrew, had a SARS-CoV-2 breakthrough infection, or had a missing blood sample at day 0 or day 28. This trial is registered with ClinicalTrials.gov , NCT05471440. Between Sept 2 and Oct 4, 2022, 219 (50%) of 434 eligible participants were randomly assigned to the direct boost group; 187 participants were included in the primary analyses; exclusions were mainly due to SARS-CoV-2 infection between days 0 and 28. From the 187 included participants, 138 (74%) were female and 49 (26%) were male. 42 (22%) of 187 participants received Ad/P and 44 (24%) mRNA/P (those aged <45 years), and 45 (24%) had received Ad/M and 56 (30%) mRNA/M (those aged ≥45 years). S1-specific binding antibody concentrations increased 7 days after bivalent booster vaccination and remained stable over 28 days in all four subgroups (geometric mean ratio [GMR] between day 0 and day 28 was 1·15 [95% CI 1·12–1·19] for the Ad/P group, 1·17 [1·14–1·20] for the mRNA/P group, 1·20 [1·17–1·23] for the Ad/M group, and 1·16 [1·13–1·19] for the mRNA/M group). We observed no significant difference in the GMR between the Ad/P and mRNA/P groups (p=0·51). The GMR appeared to be higher in the Ad/M group than in the mRNA/M group, but was not significant (p=0·073). Most side-effects were mild to moderate in severity and resolved within 48 h in most individuals. Booster vaccination with mRNA-1273.214 or BNT162b2 OMI BA.1 in adult healthcare workers resulted in a rapid recall of humoral and cellular immune responses independent of the priming regimen. Monitoring of SARS-CoV-2 immunity at the population level, and simultaneously antigenic drift at the virus level, remains crucial to assess the necessity and timing of COVID-19 variant-specific booster vaccinations. The Netherlands Organization for Health Research and Development (ZonMw). [ABSTRACT FROM AUTHOR]

Systemic immunosuppressive therapy (IS) renders patients with inflammatory bowel disease (IBD) vulnerable to fulminant hepatitis B virus (HBV) infection. Seroprotection against HBV through a full vaccination scheme is preferably obtained before IS is initiated, but often conflicts with the clinical need to initiate therapy rapidly. Consequently, the vast majority of patients will use IS during booster vaccinations. In this retrospective cohort study, we examined the serological response after a modified vaccination schedule which includes an initial double dose of Fendrix in patients with IBD and compared the results with the serological responses of patients with IBD who received the standard schedule. Seroprotection rates were 86.2 % and 88.9 % in the modified and standard schedule groups respectively. One-third of patients obtained seroprotection after only one double dose vaccine. A double dose may be considered in patients with IBD at high short-term risk of HBV infection when a rapid protective response is warranted. [ABSTRACT FROM AUTHOR]

Suspected allergic reactions after mRNA COVID-19 vaccination withheld multiple individuals from getting fully vaccinated during the pandemic. We vaccinated adults who had experienced possible allergic symptoms after their first intramuscular dose of a COVID-19 mRNA vaccine with a 1/5th fractional intradermal test dose of the mRNA-1273 (Moderna) COVID-19 vaccine. No anaphylactic reactions were observed after intradermal vaccination (n = 56). Serum anti-S1 IgG concentrations were measured using a bead-based multiplex assay four weeks after vaccinations. Antibody concentrations were compared with a previously collected nationwide cohort that had received two intramuscular doses of mRNA-1273. Antibody responses in all subjects tested (n = 47) were comparable to standard of care intramuscular dosing. Fractional intradermal dosing of mRNA COVID-19 vaccines may provide a pragmatic solution that is safe, time efficient compared to skin prick testing, dose sparing and immunogenic in individuals with suspected vaccine allergy. [ABSTRACT FROM AUTHOR]

• The baseline anti-HBs titre in non-responders affects the seroconversion rate after revaccination. • Agreement of assays to differentiate between presence or absence of anti-HBs below the titre of 10 IU/L was substantial, except for ADVIA. • The limit of detection is a reliable cutoff to differentiate between a zero- and poor- responder. • The titre-based strategy results in a reduction of revaccinations needed compared to the standard series. The detection of low levels of antibodies against HBsAg (anti-HBs) below 10 IU/L in non-responders after a primary hepatitis B vaccination, is associated with seroconversion after revaccination. We compared the diagnostic performance of four anti-HBs assays in non-responders in their ability to differentiate between absence or presence of low levels of anti-HBs and propose a revaccination strategy guided by anti-HBs titres. Non-responders were revaccinated with Fendrix 20 μg at 0, 1 and 2 months. Anti-HBs titres were determined by Abbott Architect, Diasorin Liaison, Roche Cobas and Siemens ADVIA Centaur. Inter-assay agreement was evaluated with Cohen's Kappa (k) in baseline samples between zero-responders without detectable antibodies and poor-responders with detectable antibodies < 10 IU/L. Seroconversion rates and geometric mean titres were analysed at 0, 1 and 3 months. A titre-based strategy (one revaccination dose and anti-HBs measurement followed by two more revaccination doses if required) was compared with the standard revaccination series of 3 doses. 57 participants were included in the analysis. k was ≥ 0.65 for all assays except ADVIA (k ≤ 0.41). After one revaccination dose all assays detected a mean seroconversion rate in zero-responders of 42.9%, compared to 85.1% in poor-responders. The difference between zero- and poor-responders in seroconversion rate per assay was significant (p < 0.05). After three revaccination doses the mean seroconversion rate was 88.2% in zero-responders and 98.5% in poor-responders (p > 0.286 per assay). A titre-based strategy reduced the amount of revaccinations by 17% compared with the standard. All assays demonstrated a comparable difference in seroconversion rate between zero- and poor-responders after one revaccination dose. The revaccination strategy could be optimised by differentiation between zero- and poor-responders followed by a titre-guided schedule. [ABSTRACT FROM AUTHOR]

Background: Serological non-response can be present after hepatitis B vaccination in healthy adults. We aimed to establish which of three revaccination regimens is most effective at inducing protective immunity METHODS: Healthy adults (aged 18-80 years) from 16 Dutch centres (13 public health services, two university hospitals, and one travel clinic) were included in this multicentre, parallel group, randomised, controlled, superiority trial. The inclusion criterion was vaccine non-response (hepatitis B surface antibody [anti-HBs] titre <10 IU/L) after a primary series with three doses of one type of recombinant vaccine against hepatitis B virus (either HBVaxPro-10 or Engerix-B at months 0, 1, and 6). Participants were individually randomly assigned (1:1:1:1) to a vaccination series of repeated initial vaccination (HBVaxPro 10 μg or Engerix-B 20 μg) as the control, or to Twinrix 20 μg, Fendrix 20 μg, or HBVaxPro 40 μg. We used a web-based randomisation programme, stratified by centre, with a block size of four. Participants and centres were unmasked to assignment after randomisation. Laboratory staff and investigators were masked to vaccine-group assignment. All revaccination schedules were identical, with intramuscular vaccinations at 0, 1, and 2 months. Anti-HBs was measured at 0, 1, 2, and 3 months. The primary outcome was the percentage of responders (anti-HBs titres ≥10 IU/L) at 3 months. Immunogenicity and safety analyses were based on an intention-to-vaccinate analysis, the immunogenicity analysis with last observation carried forward for missing data, and the Bonferroni and the Benjamini-Hochberg method were applied to correct for multiple testing. The trial was registered in the Dutch National Trial Register and inclusion has been stopped (identifier NL3011; EudraCT-number 2011-005627-40).Findings: The participants were recruited between Nov 1, 2012, and Sept 1, 2017. 480 participants were randomly assigned and included in intention-to-vaccinate analyses: 124 (26%) to control, 118 (25%) to Twinrix, 114 (24%) to HBVaxPro-40, and 124 (26%) to Fendrix. At month 3 the percentage of responders was 83 (67%) of 124 (95% CI 57·9-75·1 in the control group, 94 (80%) of the 118 (71·3-86·5) in the Twinrix group, 95 (83%) of 114 (75·2-89·7) in the HBVaxPro-40 group, and 108 (87%) of 124 (79·9-92·4) in the Fendrix group. Compared with the control group, the percentage of responders was superior for the HBVaxPro-40 group (adjusted difference 21·6% [95% CI 10·4-32·7], p=0·0204 [Bonferroni corrected p value]) and the Fendrix group (26·3% [15·4-37·3], p=0·0006), but not the Twinrix group (25·0% [13·0-37·0]; p=0·0846). One serious adverse event occurred (herpes zoster ophthalmicus) in the Fendrix group, which was not attributed to the vaccine.Interpretation: Revaccinating healthy non-responders with Fendrix or HBVaxPro-40 resulted in significantly higher proportions of responders and therefore indication for these vaccines should be expanded to enable revaccination of non-responders.Funding: National Institute for Public Health and the Environment. [ABSTRACT FROM AUTHOR]

Background Vaccination with conjugated meningococcal vaccines is the best way to prevent invasive meningococcal disease. Changes in serogroup epidemiology have led to the inclusion of quadrivalent vaccines in the national immunization programs of several countries, but vaccines are frequently in short supply. Intradermal administration has the potential to increase vaccine availability through dose reduction, without sacrificing efficacy. It has never before been investigated for glycoconjugate meningococcal vaccines. Methods Different fractional doses of two quadrivalent meningococcal conjugate vaccines (MenACWY-CRM 197 (Menveo®) and MenACWY-TT (Nimenrix®)) were administered intradermally to sequential groups of 4 participants, according to an adaptive dose escalation design, starting at 1/10th of the original dose. Booster doses were given after 4–6 months based on interim serology results using a multiplex bead-based assay (MIA). Final analyses were based on serum bactericidal antibody titers (rSBA). Results A total of 12 subjects were enrolled (average 25 years old, range 19–48). MenACWY-CRM 197 became unavailable during the course of the study and was only evaluated for a 1/10th dose. This dose resulted in less than complete seroprotection for serogroup A but complete protection against the other serogroups. MenACWY-TT was evaluated for a 1/10th and 1/5th dose level. Both fractional doses of MenACWY-TT resulted in complete seroprotection against all vaccine serogroups. Geometric mean titers 1 month after vaccination were lower and decayed faster in the MenACWY-CRM 197 group. Adverse events were mild and there were no serious adverse events. Conclusion Fractional intradermal vaccination against meningococcal disease with quadrivalent conjugate vaccine appears to be safe and effective in our small dose finding study. Tetanus toxoid conjugated vaccine (Nimenrix®) shows a trend towards higher antibody levels compared to CRM 197 -conjugated vaccine (Menveo®). The 1/5th fractional dose of MenACWY-TT appears to result in higher antibody levels than does the 1/10th dose. These results can be used for a larger non-inferiority study. This trial was registered in clinicaltrials.gov under NCT01782066. [ABSTRACT FROM AUTHOR]

Background The 17D-yellow fever (YF) vaccination is considered contraindicated in immune-compromised patients; however, accidental vaccination occurs. In this population, measuring the immune response is useful in clinical practice. Methods In this study we compare two antibody tests (the Immune Fluorescence Assay and the Plaque Reduction Neutralization Test) in a group of Dutch immune-compromised travellers with a median of 33 days (IQR [28–49]) after primary YF vaccination. Results We collected samples of 15 immune-compromised vaccinees vaccinated with the 17D yellow fever vaccine between 2004 and 2012. All samples measured in the plaque reduction neutralization test yielded positive results (>80% virus neutralization with a 1:10 serum dilution). Immune Fluorescence Assay sensitivity was 28% (95% CI [0.12–0.49]). No adverse events were reported. Conclusions All immune-compromised patients mounted an adequate response with protective levels of virus neutralizing antibodies to the 17-D YF vaccine. No adverse effects were reported. Compared to the plaque reduction neutralization test, the sensitivity of the Immune Fluorescence Assay test was low. Further research is needed to ascertain that 17D vaccination in immune-compromised patients is safe. [ABSTRACT FROM AUTHOR]

Highlights: [•] RCT: fractional dose (1/5th) IM and ID IPV booster vaccine with a jet injector. [•] Somewhat weaker antibody response with fractional dose ID than full dose IM IPV. [•] Significantly weaker response after fractional dose IM vaccination. [•] After 1 year no difference between fractional dose ID and full dose IM. [•] ID but not IM delivery of fractional dose IPV may suffice. [Copyright &y& Elsevier]

Summary: A woman developed Marburg haemorrhagic fever in the Netherlands, most likely as a consequence of being exposed to virus-infected bats in the python cave in Maramagambo Forest during a visit to Uganda. The clinical syndrome was dominated by acute liver failure with secondary coagulopathy, followed by a severe systemic inflammatory response, multiorgan failure, and fatal cerebral oedema. A high blood viral load persisted during the course of the disease. The initial systemic inflammatory response coincided with peaks in interferon-γ and tumour necrosis factor-α concentrations in the blood. A terminal rise in interleukin-6, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) seemed to suggest an advanced pathophysiological stage of Marburg haemorrhagic fever associated with vascular endothelial dysfunction and fatal cerebral oedema. The excess of circulating sVEGF-R1 and the high sVEGF-R1:PlGF ratio shortly before death resemble pathophysiological changes thought to play a causative part in pre-eclampsia. Aggressive critical-care treatment with renal replacement therapy and use of the molecular absorbent recirculation system appeared able to stabilise—at least temporarily—the patient''s condition. [Copyright &y& Elsevier]

Abstract: Trial registration: NTR1043 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1043). Background: Five to ten percent of immunocompetent persons fail to develop a protective immune response to hepatitis B vaccination, and are defined non-responders (NR). We investigated the immune response to intradermal hepatitis B vaccination after pre-treatment of the skin with the TLR7 agonist imiquimod. Methods: Twenty-one non-responders (anti-HBs <10IU/l after at least 6 intramuscular hepatitis B vaccinations) were randomly assigned to the control group (N =11) or the experimental group (N =10). Participants in both groups received 3 intradermal (ID) vaccinations with 5μg HBsAg (0.125mL) at 0, 1 and 6 months. In the experimental group, the dermal site of injection was pre-treated with 250mg imiquimod ointment. Anti-HBs antibodies were determined at 0, 1, 2, 6 and 7 months. Results: In both study groups, 70% of the participants developed a protective immune response (anti-HBs ≥10IU/l), after the 3rd intradermal vaccination. Conclusion: The application of imiquimod on the skin prior to intradermal vaccination did not enhance the humoral response to hepatitis B vaccine. However, irrespective of imiquimod application, 70% of the NR who had not responded to 6 previous intramuscular vaccinations, developed a protective immune response with high affinity antibodies after 3 ID hepatitis B vaccinations with 5μg HBsAg. [Copyright &y& Elsevier]

Abstract: The neutralising antibody response after the yellow fever vaccine (YF-17D) skin test was measured in 7 egg allergic persons in whom further vaccination was abandoned because of a strong local urticarial reaction to the YF-17D vaccine test dose. We found that this test dose of 0.1mL of YF-17D vaccine was sufficient to induce a protective antibody response in all 7 subjects. Intradermal injection of 1/5th dose of the yellow fever vaccine appears to be sufficient, in non-allergic as well as allergic persons, and non-inferior to the subcutaneous full dose. [Copyright &y& Elsevier]