Perspectives of European Patient Advocacy Groups on Volunteer Registries and Vaccine Trials: VACCELERATE Survey Study.

BACKGROUND: The VACCELERATE Pan-European Scientific network aims to strengthen the foundation of vaccine trial research across Europe by following the principles of equity, inclusion, and diversity. The VACCELERATE Volunteer Registry network provides access to vaccine trial sites across the European region and supports a sustainable volunteer platform for identifying potential participants for forthcoming vaccine clinical research. OBJECTIVE: The aim of this study was to approach members of patient advocacy groups (PAGs) across Europe to assess their willingness to register for the VACCELERATE Volunteer Registry and their perspectives related to participating in vaccine trials. METHODS: In an effort to understand how to increase recruitment for the VACCELERATE Volunteer Registry, a standardized survey was developed in English and translated into 8 different languages (Dutch, English, French, German, Greek, Italian, Spanish, and Swedish) by the respective National Coordinator team. The online, anonymous survey was circulated, from March 2022 to May 2022, to PAGs across 10 European countries (Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Spain, and Sweden) to share with their members. The questionnaire constituted of multiple choice and open-ended questions evaluating information regarding participants' perceptions on participating in vaccine trials and their willingness to become involved in the VACCELERATE Volunteer Registry. RESULTS: In total, 520 responses were collected and analyzed. The PAG members reported that the principal criteria influencing their decision to participate in clinical trials overall are (1) the risks involved, (2) the benefits that will be gained from their potential participation, and (3) the quality and quantity of information provided regarding the trial. The survey revealed that, out of the 520 respondents, 133 individuals across all age groups were "positive" toward registering in the VACCELERATE Volunteer Registry, with an additional 47 individuals reporting being "very positive." Respondents from Northern European countries were 1.725 (95% CI 1.206-2.468) times more likely to be willing to participate in the VACCELERATE Volunteer Registry than respondents from Southern European countries. CONCLUSIONS: Factors discouraging participants from joining vaccine trial registries or clinical trials primarily include concerns of the safety of novel vaccines and a lack of trust in those involved in vaccine development. These outcomes aid in identifying issues and setbacks in present registries, providing the VACCELERATE network with feedback on how to potentially increase participation and enrollment in trials across Europe. Development of European health communication strategies among diverse public communities, especially via PAGs, is the key for increasing patients' willingness to participate in clinical studies.

The Challenges of Vaccine Trial Participation among Underserved and Hard-to-Reach Communities: An Internal Expert Consultation of the VACCELERATE Consortium.

Underserved and hard-to-reach population groups are under-represented in vaccine trials. Thus, we aimed to identify the challenges of vaccine trial participation of these groups in member countries of the VACCELERATE network. Seventeen National Coordinators (NC), each representing their respective country (15 European countries, Israel, and Turkey), completed an online survey. From 15 eligible groups, those that were more frequently declared underserved/hard-to-reach in vaccine research were ethnic minorities (76.5%), persons experiencing homelessness (70.6%), illegal workers and refugees (64.7%, each). When prioritization for education on vaccine trials was considered, ethnic groups, migrants, and immigrants (5/17, 29.4%) were the groups most frequently identified by the NC as top targets. The most prominent barriers in vaccine trial participation affecting all groups were low levels of health literacy, reluctance to participate in trials due to engagement level, and low levels of trust in vaccines/vaccinations. This study highlighted population groups considered underserved/hard-to-reach in countries contained within the European region, and the respective barriers these groups face when participating in clinical studies. Our findings aid with the design of tailored interventions (within-and across-countries of the European region) and with the development of strategies to overcome major barriers in phase 2 and phase 3 vaccine trial participation.

Sociodemographic disparities affect COVID-19 vaccine uptake in non-elderly adults with increased risk of severe COVID-19.

BACKGROUND: There is limited information about sociodemographic disparities in COVID-19 vaccine uptake among non-elderly adults with an increased risk of severe COVID-19. We investigated the COVID-19 vaccine uptake in individuals aged 18-64 years with an increased risk of severe COVID-19 (non-elderly risk group) in Stockholm County, Sweden. METHOD: We used population-based health and sociodemographic registries with high coverage to perform a cohort study of COVID-19 vaccine uptake of one to four doses up until 21 November 2022. The vaccine uptake in the non-elderly risk group was compared with non-risk groups aged 18-64 years (non-elderly non-risk group) and individuals aged ≥65 years (elderly). RESULTS: The uptake of ≥3 vaccine doses was 55%, 64% and 87% in the non-elderly non-risk group (n = 1,005,182), non-elderly risk group (n = 308,904) and elderly (n = 422,604), respectively. Among non-elderly risk group conditions, Down syndrome showed the strongest positive association with receiving three doses (adjusted risk ratio [aRR] 1.62, 95% confidence interval [CI] 1.54-1.71), whereas chronic liver disease showed the strongest negative association (aRR 0.90, 95% CI 0.88-0.92). Higher vaccine uptake among the non-elderly risk group was associated with increasing age, being born in Sweden, higher education, higher income and living in a household where other adults had been vaccinated. Similar trends were observed for the first, second, third and fourth doses. CONCLUSION: These results call for measures to tackle sociodemographic disparities in vaccination programmes during and beyond the COVID-19 pandemic.

Qdenga® - A promising dengue fever vaccine; can it be recommended to non-immune travelers?

Qdenga® has been approved by the European Medicines Agency (EMA) for individuals > 4 years of age and for use according to national recommendations. The vaccine shows high efficacy against virologically confirmed dengue and severe dengue in clinical studies on 4-16-year old's living in endemic areas. For individuals 16-60 years old only serological data exists and there is no data for individuals > 60 years. Its use as a travel vaccine is still unclear. We present the studies behind the approval and the recommendations for travelers as issued by the Swedish Society for Infectious Diseases Physicians.

VACCELERATE Site Network: Real-time definition of clinical study capacity in Europe.

BACKGROUND: The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. METHODS: Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. RESULTS: As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus. CONCLUSIONS: The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe.

VACCELERATE Volunteer Registry: A European study participant database to facilitate clinical trial enrolment.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has evidenced the key role of vaccine design, obtention, production and administration to successfully fight against infectious diseases and to provide efficient remedies for the citizens. Although clinical trials were rapidly established during this pandemic, identifying suitable study subjects can be challenging. For this reason, the University Hospital Cologne established a volunteer registry for participation in clinical trials first in Germany, which has now been incorporated into the European VACCELERATE clinical trials network and grew to a European Volunteer Registry. As such, VACCELERATE's Volunteer Registry aims to become a common entry point for potential volunteers in future clinical trials in Europe. METHODS: Interested volunteers who would like to register for clinical trials in the VACCELERATE Volunteer Registry can access the registration questionnaire via http://www.vaccelerate.eu/volunteer-registry. Potential volunteers are requested to provide their current country and area of residence, contact information, including first and last name and e-mail address, age, gender, comorbidities, previous SARS-CoV-2 infection and vaccination status, and maximum distance willing to travel to a clinical trial site. The registry is open to both adults and children, complying with national legal consent requirements. RESULTS: As of May 2022, the questionnaire is available in 12 countries and 14 languages. Up to date, more than 36,000 volunteers have registered, mainly from Germany. Within the first year since its establishment, the VACCELERATE Volunteer Registry has matched more than 15,000 volunteers to clinical trials. The VACCELERATE Volunteer Registry will be launched in further European countries in the coming months. CONCLUSIONS: The VACCELERATE Volunteer Registry is an active single-entry point for European residents interested in COVID-19 clinical trials participation in 12 countries (i.e., Austria, Cyprus, Germany, Greece, Ireland, Lithuania, Norway, Portugal, Spain, Sweden and Turkey). To date, more than 15,000 registered individuals have been connected to clinical trials in Germany alone. The registry is currently in the implementation phase in 5 additional countries (i.e., Belgium, Czech Republic, Hungary, Israel and the Netherlands).

Magnitude and Functional Profile of the Human CD4+ T Cell Response throughout Primary Immunization with Tick-Borne Encephalitis Virus Vaccine.

Tick-borne encephalitis (TBE) is a viral infection of the CNS caused by TBE virus. With no specific treatment available, the only protection is a formalin-inactivated whole virus vaccine. Primary immunization with European TBE vaccines, as recommended by the manufacturers, consists of three vaccine doses administered within a 1-y period. Protection from vaccination is believed to be mediated by Abs, yet T cells may also have a protective role. We set out to characterize the human CD4+ T cell response throughout primary TBE immunization. The responses were evaluated before vaccination and 1 mo after each vaccine dose. A heterogeneous magnitude of CD4+ T cell-mediated memory responses was observed in regard to lymphoblast expansion and cytokine production (IFN-γ, IL-2, and TNF), with the highest median magnitude detected after the second dose of vaccine. Stimulation with an overlapping peptide library based on structural TBE virus proteins E and C revealed that CD4+ T cells concomitantly producing IL-2 and TNF dominated the responses from vaccinees after each vaccine dose, whereas a control cohort of TBE patients responded mainly with all three cytokines. CD107a expression was not upregulated upon peptide stimulation in the vaccinees. However, CD154 (CD40L) expression on cytokine-positive memory CD4+ T cells significantly increased after the second vaccine dose. Taken together, TBE vaccination induced CD4+ T cell responses dominated by IL-2 and TNF production together with CD154 upregulation and a lower IFN-γ response compared with TBE patients. This response pattern was consistent after all three doses of TBE vaccine.

Tick-borne Encephalitis Vaccine Failures: A 10-year Retrospective Study Supporting the Rationale for Adding an Extra Priming Dose in Individuals Starting at Age 50 Years.

BACKGROUND: Southern Sweden is endemic for tick-borne encephalitis (TBE), with Stockholm County as one of the high-risk areas. Our aim in this study was to describe cases of vaccine failures and to optimize future vaccination recommendations. METHODS: Patients with TBE were identified in the notification database at the Department of Communicable Disease Control and Prevention in Stockholm County during 2006-2015. Vaccine failure was defined as TBE despite adherence to the recommended vaccination schedule with at least 2 doses. Clinical data were extracted from medical records. RESULTS: A total of 1004 TBE cases were identified, 53 (5%) were defined as vaccine failures. In this latter group, the median age was 62 years (6-83). Forty-three (81%) patients were aged >50 years and 2 were children. Approximately half of the patients had comorbidities, with diseases affecting the immune system accounting for 26% of all cases. Vaccine failures following the third or fourth vaccine dose accounted for 36 (68%) of the patients. Severe and moderate TBE disease affected 81% of the cases. CONCLUSIONS: To our knowledge, this is the largest documented cohort of TBE vaccine failures. Vaccine failure after 5 TBE vaccine doses is rare. Our data provide rationale for adding an extra priming dose to those aged ≥50 years.

Safety and immunogenicity of an inactivated Vero cell_derived Japanese encephalitis vaccine (IXIARO®, JESPECT®) in a pediatric population in JE non-endemic countries: An uncontrolled, open-label phase 3 study.

BACKGROUND: Young travelers to South-East Asia may be at risk for Japanese encephalitis (JE). METHODS: IXIARO® (0.25 ml or 0.5 ml, depending on age) were administrated to 100 travelers aged ≥ 2 months to < 18 years. Solicited AEs were collected for 7 days after each injection, unsolicited adverse events (AEs) for a total of 7 months. JE neutralizing antibodies were assessed in 64 subjects. RESULTS: The most common solicited local AEs were redness (3/12 subjects), induration and tenderness (both 1/12) with 0.25 ml IXIARO®, and tenderness (44/88) and pain (22/88) with 0.5 ml IXIARO®. Common solicited systemic AEs were diarrhea (2/12) and loss of appetite (1/12) with 0.25 ml IXIARO® and muscle pain (27/88) and excessive fatigue (10/88) with 0.5 ml IXIARO®. In total, up to day 56, AEs were reported by 10/12 (83.3%) of subjects who received the 0.25 ml dose and 67/88 (76.1%) of those vaccinated with the 0.5 ml dose. All subjects (62/62; 100%) developed protective levels of JE neutralizing antibodies by Day 56 and 31/34 (91.2%) retained protective titers at Month 7. CONCLUSIONS: IXIARO® was generally well tolerated in children, with an overall AE profile similar to adults. IXIARO® was highly immunogenic in both dose groups.

An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis and drug induced immunosuppression - A prospective, open-label, multi-center study.

BACKGROUND: Previous studies have indicated that a pre-travel single dose of hepatitis A vaccine is not sufficient as protection against hepatitis A in immunocompromised travelers. We evaluated if an extra dose of hepatitis A vaccine given shortly prior to traveling ensures seroconversion. METHOD: Patients with rheumatoid arthritis (n = 69, median age = 55 years) treated with Tumor Necrosis Factor inhibitor(TNFi) and/or Methotrexate (MTX) were immunized with two doses of hepatitis A vaccine, either as double dose or four weeks apart, followed by a booster dose at six months. Furthermore, 48 healthy individuals, median age = 60 years were immunized with two doses, six months apart. Anti-hepatitis A antibodies were measured at 0, 1, 2, 6, 7 and 12 months. RESULTS: Two months after the initial vaccination, 88% of the RA patients had protective antibodies, compared to 85% of the healthy individuals. There was no significant difference between the two vaccine schedules. At twelve months, 99% of RA patients and 100% of healthy individuals had seroprotective antibodies. CONCLUSION: An extra priming dos of hepatitis A vaccine prior to traveling offered an acceptable protection in individuals treated with TNFi and/or MTX. This constitutes an attractive pre-travel solution to this vulnerable group of patients.

Investigation of a food-borne outbreak of gastroenteritis in a school canteen revealed a variant of sapovirus genogroup V not detected by standard PCR, Sollentuna, Sweden, 2016.

A food-borne outbreak of gastroenteritis with more than 650 suspected cases occurred in April 2016 in Sollentuna, Sweden. It originated in a school kitchen serving a total of 2,700 meals daily. Initial microbiological testing (for Campylobacter, Salmonella, Shigella, Yersinia, Giardia, Cryptosporidium, Entamoeba histolytica, adeno-, astro-, noro-, rota- and sapovirus) of stool samples from 15 symptomatic cases was negative, despite a clinical presentation suggestive of calicivirus. Analyses of the findings from both the Sollentuna municipality environmental team and a web-based questionnaire suggested that the source of the outbreak was the salad buffet served on 20 April, although no specific food item could be identified. Subsequent electron microscopic examination of stool samples followed by whole genome sequencing revealed a variant of sapovirus genogroup V. The virus was not detected using standard PCR screening. This paper describes the epidemiological outbreak investigation and findings leading to the discovery.

Tick-borne encephalitis (TBE) vaccine to medically immunosuppressed patients with rheumatoid arthritis: A prospective, open-label, multi-centre study.

BACKGROUND: Tick-borne Encephalitis (TBE) is endemic in south-eastern Sweden as well as in the Baltic regions, Central Europe and Russia. Ageing and immunosuppressed individuals are more prone to severe disease and neurological complications. We assessed the immunogenicity of TBE-vaccine in rheumatoid arthritis (RA) patients treated with tumor necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX). METHODS: TBE vaccine, FSME-Immune(®) or Encepur(®), was administered to non-immune RA patients as well as age and gender matched healthy controls. Individuals <60 years of age were given three doses at month 0, 1, 12. Individuals ≥ 60 years old were given an additional priming dose at month 3, i.e. a total of four doses. Tick-borne encephalitis neutralizing antibodies were assessed by a rapid fluorescent focus inhibition test. RESULTS: The study population consisted of 66 patients and 56 age and gender matched healthy controls. Median age was 58.5 years. The patients were either treated with TNFi (n=16), TNFi+MTX (n=36) or MTX (n=14). After the last TBE-vaccine dose, given one year after the first, 39% of the patients compared to 79% of the healthy controls had seroprotective levels (p=<0.05). CONCLUSIONS: Standard TBE-vaccine schedule does not confer enough immunogenicity in this group of immunosuppressed patients, who should be carefully informed about a higher risk for vaccination failure and risk of infection when exposed in high-endemic areas.

The medically immunocompromised adult traveler and pre-travel counseling: status quo 2014.

International travel is increasing among a growing number of medically immunosuppressed patients regaining life-activity due to efficient drugs. Adequate pre-travel advice for this group of patients requires not only a travel-medicine expert but a relevant specialist as well, so that a personalized plan can be made concerning vaccinations and other prophylaxis. Inactivated vaccines can generally be prescribed during immunosuppressive therapy; the risk of inducing an exacerbation of the underlying disease is minimal and even though the post-vaccination antibody response will often be impaired, it will possibly benefit the patient by means of inducing a milder course of the disease. Live vaccines are generally contraindicated and if the risk of getting the disease in a particular country is high, the potential risks must be carefully discussed with the patient. It is essential to try to prevent infections in this group of patients who are more vulnerable to serious complications caused by the immunosuppression. The aim of this review was to summarize the available literature on immunosuppressive drug mechanisms and evidence on pre-travel-vaccinations, malaria prophylaxis as well as drugs preventing tourist diarrhea. The immunocompromised conditions/drugs used in these conditions that are covered include solid organ transplantations (SOT), hematopoietic stem cell transplantations, splenectomy, and chronic inflammatory diseases in adults. HIV and pediatric patient populations are not included.

Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: a prospective, open-label, multi-centre study.

BACKGROUND: Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumour necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX). METHODS: Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM + IgG. RESULTS: The final study population consisted of 53 patients treated with TNFi (n = 15), TNFi + MTX (n = 21) or MTX (n = 17). One and six months after the first dose, 10% and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels. CONCLUSIONS: Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients.

Management of imported malaria in Europe.

In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms.Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT) may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily) until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT) or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the absorption of anti-malarials are important considerations in the choice of treatment.Complicated malaria is treated with intravenous artesunate resulting in a much more rapid decrease in parasite density compared to quinine. Patients treated with intravenous artesunate should be closely monitored for haemolysis for four weeks after treatment. There is a concern in some countries about the lack of artesunate produced according to Good Manufacturing Practice (GMP).

Influenza in travellers.

PURPOSE OF REVIEW: The importance of travelling as an important factor for spread of influenza has become even more evident during the recent pandemic year. All the same, the mechanism for seasonal spreading of influenza is not yet fully understood. RECENT FINDINGS: The incidence of influenza in returning febrile travellers from subtropical and tropical regions is between 5 and 15% with no significant differences between those vaccinated and not vaccinated in the reviewed studies. The power of the studies to detect differences are, however, low. In these studies, 12-85% of the travellers or pilgrims were vaccinated against influenza. Air transportation, and especially long-haul flight, is a key factor for the spread of influenza even though travel restrictions seem to be of no use for preventing a pandemic spread. SUMMARY: Influenza should always be considered in a febrile traveller with or without respiratory symptoms. Future studies on incidence of travel-related influenza should consider the short incubation period for a better estimate. Vaccine from the opposite hemisphere should be made available for travellers, and influenza vaccine studies should focus on optimizing the effect of the vaccine in the elderly and immunocompromised.