The Dutch Citizen's Understanding and Perception of the Actors Involved in the Netherlands' COVID-19 Pandemic Response: A Focus Group Study During the First Pandemic Wave.

INTRODUCTION: The COVID-19 pandemic was a public health emergency (PHE) of unprecedented magnitude and impact. It provided the possibility to investigate the Dutch citizens' understanding and perception of the actors involved in the Dutch pandemic response as a PHE unfolded. METHODS: Three focus groups (FGs) were held with 16 Dutch citizens in June 2020. Citizens were recruited using the Dutch Health Care Consumer Panel. During the FGs, participants were asked to fill in a table with actors they thought were involved in the management of the COVID-19 pandemic. They also received information on actors involved in Dutch outbreak responses. Then, the actors named and omitted by the participants were discussed. RESULTS: An analysis of the FGs suggests that the Dutch citizens participating in the study were not fully aware of the scope of actors involved in the Dutch COVID-19 pandemic response. Some participants would have appreciated more information on the actors involved. This would help them have an informed opinion of the actors involved in the decision-making process, and accept non-pharmaceutical interventions implemented. Lastly, most participants recognised that they played a role in limiting the spread of the COVID-19 pandemic. Yet, very few spontaneously mentioned themselves as actors within the COVID-19 pandemic response. CONCLUSION: This study suggests that early in the COVID-19 pandemic, the Dutch citizens participating in this study's FG did not have a complete understanding of the scope of actors involved in the Dutch COVID-19 pandemic response, or the potential role of the citizen. Future research can build on these results to explore the citizen's perception of their role during PHEs of another origin, as well as other geographical and historical contexts. PATIENT OR PUBLIC CONTRIBUTION: The public participated in the focus groups and received a non-expert report summarising the outcomes of the focus groups.

Identifying the sectors involved in the European public health emergency preparedness and response: a systematic review.

OBJECTIVES: A systematic review was conducted with the aims of identifying sectors mentioned in the public health emergency preparedness and response (PHEPR) literature and mapping the involvement of those sectors in the seven PHEPR cycle domains. SETTING: A detailed search strategy was conducted in Embase and Scopus, covering the period between 1 January 2005 and 1 January 2020. METHODS: Published articles focusing on preparedness for and/or response to public health emergencies of multiple origins on the European continent were included. The frequency with which predetermined sectors were mentioned when describing collaboration during the preparedness and response cycle was determined. RESULTS: The results show that description of the involvement of sectors in PHEPR in general and collaboration during PHEPR is predominantly confined to a limited number of sectors, namely 'Governmental institutions', 'Human health industry', 'Experts' and 'Civil Society'. Description is also limited to only three domains of the PHEPR cycle, namely 'Risk and crisis management', 'Pre-event preparations and governance' and 'Surveillance'. CONCLUSIONS: Optimal preparedness and response require predefined collaboration with a broader scope of partners than currently seems to be the case based on this literature review. We recommend considering these outcomes when planning multisectoral collaboration during preparedness and response, as well as the need to further operationalise the term 'multisectoral collaboration' during PHEPRs. PROSPERO REGISTRATION NUMBER: PROSPERO with registration number 176 331.

Evaluation of serological trials submitted for annual re-licensure of influenza vaccines to regulatory authorities between 1992 and 2002.

BACKGROUND: As part of the regulatory requirements, serological evaluation of trivalent inactivated influenza vaccines must be performed before annual re-licensure in the European Union. These studies are typically set up as uncontrolled, open label trials including 2 groups of at least 50 healthy adults and healthy elderly. METHODS: The serological data submitted to the Dutch Medicines Evaluation Board (MEB) for annual re-licensure purposes between 1992 and 2002, were analysed with respect to their ability to assess the immunogenic properties of the vaccines. The trials in this meta-analysis were selected by strictly applying the inclusion and exclusion criteria described in the Committee of Human Medicinal Products (CHMP) Note for Guidance on harmonisation of requirements for influenza vaccines. To select the final dataset additional exclusion criteria were defined: age outside the inclusion criterion of the trial, incomplete demographics, co-morbid conditions, antibody determination by SRH assay, incomplete dataset and sample size smaller than 50 subjects. RESULTS: Out of 51 trials retrieved from the archives, 48 age-defined trials including 2510 adults and 2008 elderly fulfilled all the in- and exclusion criteria. A large proportion of vaccinees already met the threshold for seroprotection at baseline. Post-vaccination, the serological response was shown to be age dependent. Previous influenza vaccinations significantly affected pre-vaccination but not post-vaccination titres. CONCLUSIONS: The annual update trials performed for regulatory purposes have serious methodological limitations, which affect their ability to identify influenza vaccines with low immunogenicity. To establish clinical (protective) efficacy different trials and different assessment criteria are needed.

[Vaccines against human papillomavirus (HPV); between registration and implementation]. / Vaccins tegen Humaan papillomavirus (HPV); tussen registratie en implementatie.

--Each year, 600-700 women in the Netherlands are diagnosed with cervical cancer. Over the last 10 years, an average of 250 women have died annually due to cervical cancer. --Gardasil, the first vaccine for Human papillomavirus (HPV), was recently approved in Europe for the prevention of cervical cancer. --The availability of a vaccine for HPV prompts the question whether it should be included in the Dutch National Immunisation Programme. --At the end of 2006, the Medicines Evaluation Board, the Health Council of the Netherlands and the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment organised a workshop for experts in the field to answer that question. --The HPV vaccine provides protection against HPV-16 and HPV-18, which cause approximately 70% of cervical cancers. --Because the efficacy of vaccination is only evident after many years, preserving good participation in the screening programme is essential. --The current screening could be improved by introducing an HPV test combined with self-sampling for women who do not participate in screening. --Vaccination is unarguably an important development. However, there are still several unanswered questions regarding vaccination and its actual protection, duration of protection, long-term safety and cost-effectiveness. --April 1st, 2008, the Health Council of the Netherlands had recommended including HPV vaccination in the National Immunisation Programme.

Annual revaccination against influenza and mortality risk in community-dwelling elderly persons.

CONTEXT: Although large-scale observational studies have demonstrated the effectiveness of influenza vaccination, no large studies have systematically addressed the clinical benefit of annual revaccinations. OBJECTIVE: To investigate the effect of annual influenza revaccination on mortality in community-dwelling elderly persons. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study using the computerized Integrated Primary Care Information (IPCI) database in the Netherlands including community-dwelling individuals aged 65 years or older from 1996 through 2002. For each year, we computed the individual cumulative exposure to influenza vaccination since study start. MAIN OUTCOME MEASURE: Association between the number of consecutive influenza vaccinations and all-cause mortality vs no vaccination after adjusting for age, sex, chronic respiratory and cardiovascular disease, hypertension, diabetes mellitus, renal failure, and cancer. RESULTS: The study population included 26,071 individuals, of whom 3485 died during follow-up. Overall, a first vaccination was associated with a nonsignificant annual reduction of mortality risk of 10% (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78-1.03) while revaccination was associated with a reduced mortality risk of 24% (HR, 0.76; 95% CI, 0.70-0.83). Compared with a first vaccination, revaccination was associated with a reduced annual mortality risk of 15% (HR, 0.85; 95% CI, 0.75-0.96). During the epidemic periods this reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). Similar estimates were obtained for persons with and without chronic comorbidity and those aged 70 years or older at baseline. Overall, influenza vaccination is estimated to prevent 1 death for every 302 vaccinees at a vaccination coverage that varied between 64% and 74%. CONCLUSION: Annual influenza vaccination is associated with a reduction in all-cause mortality risk in a population of community-dwelling elderly persons, particularly in older individuals.

[Critical review of anti-influenza drugs]. / Griepremmers in kritisch perspectief.

Neuraminidase inhibitors such as zanamivir and oseltamivir belong to a new class of antiviral drugs for the treatment and prevention of influenza. As yet however, the therapeutic efficacy of these drugs (shortening of recovery time by approximately one day) has only been demonstrated in healthy adults affected by influenza A, but not in risk groups and in influenza B disease, whereas studies of prophylactic efficacy are still going on. Neither do these drugs impact on viral spread, a public health risk against which the economic advantages of early work resumption have to be weighed. Since flu symptoms can be caused by other germs than the influenza A or B virus, caution in prescribing these drugs seems warranted, also to prevent the development of drug resistance. In addition, when designing therapeutic efficacy trials in risk groups, selecting the rate of secondary complications and death may be more adequate as clinical endpoint than (economically important) duration of illness.

Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins.

The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to cancer cells by active extrusion of a wide range of drugs from the cell. To study their physiological roles, we have generated mice genetically deficient in the mdr1b gene [mdr1b (-/-) mice] and in both the mdr1a and mdr1b genes [mdr1a/1b (-/-) mice]. In spite of the host of functions speculatively attributed to the mdrl-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum-chemical, and immunological parameters were not abnormal in mdr1a/1b (-/-) mice. The high level of mdrlb P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, although the protein did reduce drug accumulation in the adrenal gland and ovaries. Pharmacologically, mdr1a/1b (-/-) mice behaved similarly to the previously analyzed mdr1a (-/-) mice, displaying, for instance, increased brain penetration and reduced elimination of digoxin. However, both mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine from hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytotoxic anticancer drugs. This, and the normal viability of mdr1a/1b (-/-) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.

Treatment of low-grade non-Hodgkin's lymphoma with continuous infusion of low-dose recombinant interleukin-2 in combination with the B-cell-specific monoclonal antibody CLB-CD19.

Seven patients with low-grade non-Hodgkin's lymphoma were treated with a combination of a murine monoclonal antibody directed against the B-cell-specific antigen CD19 (CLB-CD19), given twice weekly, and continuous infusion of low-dose recombinant interleukin-2 (rIL-2). We demonstrated stable serum CLB-CD19 levels throughout the 12 weeks of treatment, and homing of the antibody into the tumour sites. A variable degree of antigenic modulation was noted. Prolonged treatment resulted in a sustained increase in the number of natural killer cells in the circulation with enhanced cytotoxic capacity, including antibody-dependent cellular cytotoxicity. During the first weeks of treatment, T cell activation occurred in the majority of patients. Toxicity was related to the rIL-2 treatment and consisted of transient constitutional symptoms and a flu-like syndrome without organ dysfunction. A partial remission occurred in one patient, and in another patient who was primarily leukaemic a greater than 50% reduction of circulating B cells was noted. An antitumour effect occurred early during treatment and could not be related to rIL-2-induced modulation of natural killer cell or T lymphocyte activation.

A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part II: Immunological aspects.

Previously we described the clinical aspects of a phase I study of prolonged continuous infusion of low-dose recombinant interleukin-2 (rIL-2). In the present paper we report several immunological effects in 13 patients with melanoma and renal cell cancer treated on an out-patient basis with rIL-2 for uninterrupted periods ranging from 5 to 18 weeks. Groups of three patients were treated at following dose levels 0.18, 0.6, 1.8 or 6 x 10(6) IU m-2 24 h-1 and one patient was treated with 3 x 10(6) IU m-2 24 h-1. Prolonged rIL-2 treatment resulted in a dose-dependent and sustained increase in the percentage and absolute number of (CD56+, CD8dim) natural killer cells. Within this population a preferential increase in the CD56bright cells with low expression of CD16 was observed. The CD27 antigen was also upregulated in the CD56bright CD16dim population. This increase of NK cells was accompanied by an enhancement of the cytotoxic capacity of the peripheral lymphocytes. No consistent signs of T cell activation or expansion were noted.

Protection against lethal Sendai virus infection by in vivo priming of virus-specific cytotoxic T lymphocytes with a free synthetic peptide.

The only peptide of Sendai virus that is recognized by cytotoxic T lymphocytes (CTL) in B6 mice was found with (i) the use of recombinant vaccinia virus constructs containing separate genes of Sendai virus and (ii) a set of overlapping peptides completely spanning the identified nucleoprotein (NP) gene product. This immunodominant NP peptide is recognized by Sendai virus-specific CTL that are known to have therapeutic effects in vivo. By subcutaneous immunization, this peptide induced Sendai virus and NP peptide-specific CTL memory responses in vivo. Most importantly, mice that had been immunized with this peptide were protected against a lethal virus dose, indicating that viral peptides can be used as antiviral T-cell vaccines. The induction of T-cell memory by free peptide immunization potentially has wide applicability in biology and medicine, including protection against infectious disease.

Treatment with monoclonal anti-CD3 antibody protects against lethal Sendai virus infection by induction of natural killer cells.

C57BL/6 mice are protected from a lethal pneumonia caused by Sendai virus when treated with low doses of mAb directed to the CD3 Ag. The protective mechanism is not due to an accelerated Sendai virus-specific Th cell, CTL, or antibody response but to a strong NK cell response via the in vivo induction of lymphokines. Antibodies directed against the NK1.1 and asialo GM1 marker totally reversed the protective effect of anti-CD3 treatment. In vivo treatment with rIL-2 also induced NK activity and induced antiviral protection. Treatment with anti-CD3 protects when given in a narrow time window (1 day before until 1 day after Sendai virus inoculation), indicating that NK activity is protective in the early phase of virus infection.

Eradication of adenovirus E1-induced tumors by E1A-specific cytotoxic T lymphocytes.

Cytotoxic T lymphocyte (CTL) clones against adenovirus type 5 (Ad5) early region 1 (E1)-transformed cells were generated in C57BL/6 (B6) mice. A defined peptide encoded by Ad5 E1A is the target structure for H-2Db-restricted CTLs. Upon intravenous injection into B6 nude mice bearing Ad5 E1-induced tumors, these CTLs, if combined with recombinant IL-2, destroy subcutaneous tumor masses up to 10 cm3. The in vivo action of CTLs is highly specific, and long-term "memory" persists in treated nude mice months after tumor regression. Our data show an important role for CTLs directed against a viral nuclear oncogene product in tumor eradication.

Lack of correlation between levels of MHC class I antigen and susceptibility to lysis of small cellular lung carcinoma (SCLC) by natural killer cells.

Small cellular lung carcinoma (SCLC) cell lines are susceptible to lysis by NK cells. SCLC, normally negative for MHC class I Ag, were rendered positive for HLA-A and -B Ag by two methods: treatment with IFN-gamma or transfection with HLA class I genes. Exposure to IFN-gamma induced high levels of class I Ag and reduced susceptibility to NK-mediated lysis. However, transfection with either HLA-A2, HLA-B27, or HLA-B27 with beta 2m did not result in reduced susceptibility to NK cells. These transfectants expressed amounts of HLA class I Ag comparable to those in IFN-gamma-treated, untransfected cells. Transfection with the beta 2m gene or plasmid alone neither influenced levels of surface class I Ag nor resulted in reduced susceptibility to lysis by NK cells. Thus, the effects of IFN-gamma on NK susceptibility can be dissociated from the induction of class I Ag.

Failure or success in the restoration of virus-specific cytotoxic T lymphocyte response defects by dendritic cells.

C57BL/6 (B6, H-2b) mice are CTL responders to both Sendai virus and Moloney leukemia virus. In the former response the H-2Kb class I MHC molecule is used as CTL restriction element, in the latter response the H-2Db molecule. B6 dendritic cells (DC) are superior in the presentation of Sendai virus Ag to CTL in comparison with B6 normal spleen cells. Con A blasts have even less capacity to present viral Ag than NSC, and LPS blasts show an intermediate capacity to present viral Ag. H-2Kb mutant bm1 mice do not generate a CTL response to Sendai virus, but respond to Moloney leukemia virus, as demonstrated by undetectable CTL precursors to Sendai virus and a normal CTL precursor frequency to Moloney virus. Compared to B6 mice, other H-2Kb mutant mice show decreased Sendai virus-specific CTL precursor frequencies in a hierarchy reflecting the response in bulk culture. The Sendai virus-specific CTL response defect of bm1 mice was not restored by highly potent Sendai virus-infected DC as APC for in vivo priming and/or in vitro restimulation. In mirror image to H-2Kb mutant bm1 mice, H-2Db mutant bm14 mice do not generate a CTL response to Moloney virus, but respond normally to Sendai virus. This specific CTL response defect was restored by syngeneic Moloney virus-infected DC for in vitro restimulation. This response was Kb restricted indicating that the Dbm14 molecule remained largely defective and that a dormant Kb repertoire was aroused after optimal Ag presentation by DC. In conclusion, DC very effectively present viral Ag to CTL. However, their capacity to restore MHC class I determined specific CTL response defects probably requires at least some ability of a particular MHC class I/virus combination to associate and thus form an immunogenic complex.

Thymic immune response gene function in radiation chimeras reconstituted with purified hemopoietic stem cells.

Thymectomized (C57BL/6[B6] X bm1)F1 mice and thymectomized (B6 X bm12)F1 mice were engrafted with neonatal parental thymus of either B6 type [H-2b mouse, Sendai virus cytotoxic T cell (Tc) responder] or bm1 type (H-2Kb mutant, Sendai virus Tc nonresponder) and B6 type (H-Y Tc responder) or bm12 type (H-2 I-Ab mutant, H-Y Tc nonresponder), respectively. All mice were irradiated and reconstituted with highly purified syngeneic pluripotent hemopoietic stem cells. All types of thymus engraftment resulted in a restored T cell immunocompetence. The Tc reaction to Sendai virus in (B6 X bm1)F1 mice engrafted with both responder type B6 and nonresponder, type bm1 neonatal thymus allowed maturation of Sendai-specific, H-2Kb-restricted Tc. For the Tc reaction to H-Y, only responder type B6 thymus restored the Tc response, whereas this was not achieved with nonresponder type bm12 thymuses. We conclude from this study that in this radiation stem cell chimera system the radioresistant component of the thymus dictates major histocompatibility complex (MHC) specificity and immune response phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.