Importance and value of adjuvanted influenza vaccine in the care of older adults from a European perspective - A systematic review of recently published literature on real-world data.

BACKGROUND: There is an urgent need for improved influenza vaccines especially for older adults due to the presence of immunosenescence. It is therefore highly relevant to compare enhanced influenza vaccines with traditional influenza vaccines with respect to their effectiveness. OBJECTIVE: To compare vaccine efficacy and effectiveness of adjuvanted influenza vaccines (aTIV/aQIV) vs. non-adjuvanted standard-dose (TIV/QIV) and high-dose (TIV-HD/QIV-HD) influenza vaccines regarding influenza-related outcomes in older adults, complementing findings from the European Centre for Disease Prevention and Control (ECDC)'s systematic review of enhanced seasonal influenza vaccines from February 2020. METHODS: A systematic literature search was conducted in Embase and MEDLINE to identify randomised controlled trials, observational studies and systematic reviews, published since ECDC's systematic review (between 7 February 2020 and 6 September 2021). Included studies were appraised with either the Cochrane Risk of Bias tool, ROBINS-I or AMSTAR 2. RESULTS: Eleven analyses from nine real-world evidence (RWE) studies comprising ∼53 million participants and assessing the relative vaccine effectiveness (rVE) of aTIV vs. TIV, QIV and/or TIV-HD in adults aged ≥65 years over the 2006/07-2008/09 and 2011/12-2019/20 influenza seasons were identified. Nine analyses found that aTIV was significantly more effective than TIV and QIV in reducing influenza-related outcomes by clinical setting and suspected influenza outbreaks (rVE ranging from 7.5% to 25.6% for aTIV vs. TIV and 7.1% to 36.3% for aTIV vs. QIV). Seven analyses found similar effectiveness of aTIV vs. TIV-HD in reducing influenza-related medical encounters, inpatient stays and hospitalisations/emergency room visits. In three analyses, aTIV was significantly more effective than TIV-HD in reducing influenza-related medical encounters and office visits (rVE ranging from 6.6% to 16.6%). Risk of bias of identified studies was moderate to high. CONCLUSIONS: Our study suggests that both adjuvanted and high-dose vaccines are effective alternatives for vaccination programmes in older adults and preferable over conventional standard-dose vaccines.

[Segmental necrotizing colitis in a patient with E. coli O104:H4 infection]. / Segmentale nekrotisierende Kolitis bei einem Patienten mit EHEC-Infektion vom Typ O104:H4.

A 29-year-old man presented with abdominal cramps and bloody diarrhoea. Blood tests revealed elevated C-reactive protein (21.3 mg/dL; normal range 0.01 - 0. 82 mg/dL) and white blood cells (28200/µL, normal range 4000 - 10000/µL). Stool tests were negative for enteropathogenic bacteria and Clostridium difficile toxins A/B. Ultrasound and computed tomography showed massive swelling of the transverse colon and right colonic flexure. At endoscopy, circular necrosis of the mucosa was encountered in the proximal segments of the colon whereas distal parts of the organ showed patchy inflammation of minor severity. Extended stool testing identified Escherichia coli type O104:H4 as the causative microorganism. There was no evidence for haemolytic uraemic syndrome. Under conservative treatment the patient recovered clinically, serologically and endoscopically. At follow-up endoscopy, longitudinal ulcers and vital mucosa were present. In this case report the segmental pattern of mucosal necrosis in a patient with EHEC infection is noteworthy.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged ≥65 years.

This randomized, double-blind study evaluated concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (TIV) in adults aged ≥65 years who were naïve to 23-valent pneumococcal polysaccharide vaccine. Patients (N=1160) were randomized 1:1 to receive PCV13+TIV followed by placebo, or Placebo+TIV followed by PCV13 at 0 and 1 months, with blood draws at 0, 1, and 2 months. Slightly lower pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G geometric mean concentrations were observed with PCV13+TIV relative to PCV13. Concomitant PCV13+TIV demonstrates acceptable immunogenicity and safety compared with either agent given alone.

[Diseases caused by human papilloma viruses]. / Erkrankungen durch humane Papillomviren.

Human papilloma viruses are responsible for a large number of benign and malignant lesions of the skin. HPV 6 and 11 cause up to 90 % of condylomata. Almost each cervical cancer is associated with HPV. HPV 16 und 18 induce up to 70 % of cervical neoplasias. The vaccination against HPV is internationally implemented and should be applied to young girls aged 12 to 17 according to STIKO criteria. The vaccination may reduce the rate of cervical cancer by 70 % and the rate of cervical intraepithelial neoplasia by 50 %. Many studies demonstrated the efficacy and safetyness of both vaccines. Gardasil (®) offers protection against HPV 6, 11, 16 and 18, Cervarix (®) against HPV 16 and 18. Protection against condylomata is offered by the quadrivalent vaccine in 90 %. The bivalent vaccine has demonstrated type-specific protection against the five most frequent cancer inducing types (16, 18, 31, 33, 45). The production of VLPs is an innovative technology. A comparison of both vaccines, Cervarix (®) and Gardasil (®), showed a higher immunogenicity for Cervarix (®). In Germany the immunization rates are still low comparing to other countries. As a method for secondary prevention of cervical cancer the PAP smear is still an effective method.

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.

Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria.

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years. Most patients (188/217; 86.6%) had severe to moderately severe haemophilia A, of whom 153 completed sufficient diary information for the main efficacy analysis. These 153 patients experienced a median of 6.6 (interquartile range 1.4-18.6) bleeding episodes per year. Patients treated with prophylaxis experienced a median of 4.4 (1.1-9.3) bleeds per year, while patients treated on-demand experienced a median of 22.8 (11.3-29.0) bleeds per year. Overall, most physicians (41/43 [95.3%]) were 'very satisfied' or 'satisfied' with the efficacy of REFACTO in the treatment of bleeding episodes. A total of 137 non-serious adverse events have been reported in 52/217 patients (24.0%) to date. In addition, 129 serious adverse events in 87 patients (40%) were reported, including 41 cases of 'less than expected therapeutic effect' (LETE). Of these, 39 LETE cases were reported in one centre; however, patients in this centre experienced considerably fewer bleeding episodes per year than patients outside this centre. Overall, six patients (2.8%) have developed de novo inhibitors, three of which were considered high titre. Four of these patients were at high risk (0-50 exposure days [ED]) of inhibitor formation, one was at intermediate risk (51-100 ED) and one was at low risk (>100 ED). These results emphasize the benefit of postmarketing surveillance and, overall, this study confirms the efficacy, safety and tolerability of REFACTO in the treatment of patients with haemophilia A.

Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein.

Prion diseases are fatal neurodegenerative disorders in man and animal associated with conformational conversion of a cellular prion protein (PrPc) into the pathologic isoform (PrPSc). The function of PrPcand the tertiary structure of PrPScare unclear. Various data indicate which parts of PrP might control the species barrier in prion diseases and the binding of putative factors to PrP. To elucidate these features, we analyzed the evolutionary conservation of the prion protein. Here, we add the primary PrP structures of 20 ungulates, three rodents, three carnivores, one maritime mammal, and nine birds. Within mammals and birds we found a high level of amino acid sequence identity, whereas between birds and mammals the overall homology was low. Various structural elements were conserved between mammals and birds. Using the CONRAD space-scale alignment, which predicts conserved and variable blocks, we observed similar patterns in avian and mammalian PrPs, although 130 million years of separate evolution lie in between. Our data support the suggestion that the repeat elements might have expanded differently within the various classes of vertebrates. Of note is the N-terminal part of PrP (amino acid residues 23-90), which harbors insertions and deletions, whereas in the C-terminal portion (91-231) mainly point mutations are found. Strikingly, we found a high level of conservation of sequences that are not part of the structured segment 121-231 of PrPcand of the structural elements therein, e.g. the N-terminal region from amino acid residue 23-90 and the regions located upstream of alpha-helices 1 and 3.

Seroprevalence of dengue, chikungunya and Sindbis virus infections in German aid workers.

Vector-borne virus infections were studied in 670 German overseas aid workers who had spent an average of 37.7 months in tropical areas of Africa and Asia. Antibodies to dengue viruses (DEN) were detected by indirect immunofluorescence assay in 43/670 (6.4%) aid workers. Of these 43, 41 (95.3%) were also positive for antibodies to dengue by haemagglutination inhibition assay. The highest seroprevalence was in aid workers returning from Thailand (19.4%), Benin (14.8%) and Burkina Faso (9.2%). Antibodies to chikungunya virus (CHIK) were detected in 9/670 (1.3%) aid workers, and the highest seroprevalence to anti-CHIK IgG was in aid workers who had resided in Benin (5.7%) and Thailand (5.5%). Antibodies to Sindbis virus were detected only in 1/670 (0.1%) aid worker who had been to Zambia. Vector-borne virus infections, especially DEN, pose a health risk for aid workers.

A recombinant Toscana virus nucleoprotein in a diagnostic immunoblot test system.

Sandfly fever, a vector-borne disease endemic in the Mediterranean region, is caused by Toscana virus (TOS). The disease is increasingly important as a travel-related infection. Serological diagnosis is currently dependent on viral antigens derived from TOS-infected cell cultures. In this study, we report the cloning and expression of the TOS nucleoprotein (N) in Escherichia coli and evaluation of the recombinant (r) TOS N protein as an antigen for immunoblot assays. The TOS N gene was amplified by reverse-transcriptase polymerase chain reaction and cloned into the bacterial expression vector pTrcHis-A. Sera with known TOS antibody status were used to evaluate the immunoblot assay. The expressed rTOS N protein was purified and used as antigen for immunoblots. By recombinant immunoblot, the TOS antibody status (IgM and/or IgG) of the test panel was correctly identified. No cross-reactivity was detected. The rTOS N protein is useful as an antigen for immunoblot assays, and will enable more laboratories to perform TOS antibody diagnosis.

Molecular investigation of a multisource outbreak of Crimean-Congo hemorrhagic fever in the United Arab Emirates.

During the investigation of an outbreak of Crimean-Congo hemorrhagic fever (CCHF) in the United Arab Emirates (UAE) between 1994 and 1995, blood samples from suspected CCHF cases and ticks collected from livestock were tested for CCHF virus by antigen-capture ELISA and by a reverse transcription-polymerase chain reaction. Phylogenetic analysis of partial small (S) segment nucleotide sequences from four ticks and five human samples showed that with one exception, all the human and tick viruses clustered along with samples from Pakistan and Madagascar in one distinct lineage. Within this lineage, sequences from the UAE patients were identical or closely related to those from three Hyalomma spp. ticks obtained from livestock recently imported from Somalia. Another sequence from a UAE patient was more closely related to a CCHF virus from Nigeria. These data indicate that the 1994-1995 CCHF epidemic in the UAE was a multisource outbreak possibly associated with importation of CCHF virus-infected livestock and ticks.

Comparison of seven commercial tests for the detection of parvovirus B19-specific IgM.

Several enzyme immunoassays (EIA) for the detection of parvovirus B19 IgM (anti-B19 IgM) are now commercially available. In this study, seven commercial EIAs (Biotrin, DAKO, Viramed, Viratech, R-Biopharm, Mast) were compared with an in-house EIA (MvP-EIA) using native viral B19 particles and the reference IgM radioimmunoassay (MACRIA). A total of 88 sera were tested. Results agreed in 39/88 (44.3%) sera, whereas 47/88 (53.4%) were discrepant and 2/88 (2.3%) gave an equivocal result. Assay sensitivity ranged from 70.3 to 100% and specificity, from 75.9 to 100%. The best results were obtained with two EIAs (Biotrin, DAKO) using baculovirus-expressed B19 proteins as antigen. This study has shown that baculovirus-expressed B19 antibody tests are suitable tools for detecting anti-B19 IgM.

[Pappataci fever]. / Pappataci-Fieber.

Sandfly fever virus is known to cause pappataci fever. The sandfly fever virus belongs to the Genus Phlebovirus (family: Bunyaviridae) and is endemically found in areas of South Europe, Asia and Africa. In Germany, pappataci fever is only described in connection with travelling to endemic areas. We report on a 15 year-old girl suffering from sandfly fever virus infection after vacation in Turkey. The initial symptoms started with fever for about three days, frontal headache, nausea and arthralgia. After a short time of clinical improvement symptoms recurred and our patient entered hospital with signs of severe meningitis. Liquor analysis showed a lymphocytic meningitis. Due to multiple insect bites on her legs sandfly fever was suspected. Blood analysis confirmed an acute infection with sandfly virus Sicilian from which she completely recovered. ELISA and immunoblot analysis revealed an infection with sandfly virus serotype Sicilian, which was not encountered with meningitis so far. Our case report illustrates that due to increased tourism sandfly fever virus infection has to be considered as a cause of aseptic meningitis in travellers.

Clinical features of Crimean-Congo haemorrhagic fever in the United Arab Emirates.

Crimean-Congo haemorrhagic fever (C-CHF) re-emerged recently in the United Arab Emirates. The clinical outcome of 11 cases of viral haemorrhagic fever patients admitted to hospital between June 1994 and January 1995 is described. Four cases were laboratory confirmed retrospectively as C-CHF, the other patients were diagnosed likely to have the same disease on epidemiological and clinical grounds. In 72.7% of the patients, infection was fatal. Symptoms started 3.5 days before hospitalization. On admission, 81.8% of patients had high fever, 45.5% were vomiting, 63.6% had diarrhoea, 45.5% had haemorrhagic signs, and 18.2% had throat pain. Fatalities occurred 6.8 days after admission. Survivors were hospitalized for 9.3 days. Nosocomial transmission was not observed.

Polymerase chain reaction for diagnosis and identification of distinct variants of Crimean-Congo hemorrhagic fever virus in the United Arab Emirates.

Viral hemorrhagic fever has re-emerged in the United Arab Emirates (UAE) since November 1993. Genomic RNA of Crimean-Congo hemorrhagic virus (C-CHFV) was detected by a newly developed, nested reverse transcriptase polymerase chain reaction (RT-PCR) in the sera of four (25.0%) of 16 suspected cases of viral hemorrhagic fever. The RT-PCR was based on oligonucleotide primers deducted from the small RNA segment encoding the nucleoprotein of the virus. By comparison with a nucleotide sequence of a C-CHFV isolate from a Chinese sheep, a divergence of 10.0-11.8% was detected in the C-CHFV variants causing the UAE outbreak. In the four positive sera, three phylogenetically distinct C-CHFV variants were amplified and confirmed by direct sequencing of the PCR fragments. These C-CHFV sequences were obtained directly from sera of infected humans without prior propagation in cell culture. The RT-PCR allows rapid detection of genomic C-CHFV RNA in clinical specimens and study of the molecular epidemiology of this infection.

Immunoblot detection of antibodies to Toscana virus.

Sera from patients with sandfly fever caused by Toscana virus (TOSV) infection were tested by immunoblot for specific antibody response to TOSV derived from infected Vero-E6 cells. The 28 kDa TOSV nucleoprotein (N) was identified as the major immunodominant protein recognized by immunoblot. In sera of patients with acute TOSV infection, specific antibodies of the IgM, IgA, and IgG class were detected. Using sandfly fever virus, serotypes Sicilian (SFSV) and Naples (SFNV), as antigens for immunoblot, TOSV antibody-positive sera cross-reacted with the corresponding N proteins. These sera reacted for IgM and IgG by SFSV immunoblot, and for IgM by SFNV immunoblot. The diagnosis of sandfly fever may be confirmed by TOSV immunoblot.

Imported vector- and rodent-borne virus infections--an introduction.

Travel is a potent force in the emergence of virus infections. Migration of humans and animals has been the pathway for disseminating virus diseases throughout history. In recent years, dengue virus has been identified as the most important travel-related, vector-borne virus disease. Other vector-borne virus infections, such as sandfly fever, Rift Valley fever, chikungunya fever and Japanese encephalitis, have been diagnosed in travelers returning from endemic areas. Crimean-Congo haemorrhagic fever may not only be imported by infected live stock, but also by travelers. Of rodent-borne virus infections, Lassa fever has been diagnosed occasionally in travelers returning from endemic areas. The potential impact of imported filoviruses is currently discussed.