Strategic silences,eroded trust: The impact of divergent COVID-19 vaccine sentiments on healthcare workers' relations with peers and patients

BackgroundPolarized debates about Covid-19 vaccination and vaccine mandates for healthcare workers (HCWs) challenge Belgian HCWs ability to discuss Covid-19 vaccine sentiments with peers and patients. Although studies have identified drivers of HCWs vaccine hesitancy, they do not include effects of workplace interactions and have not addressed consequences beyond vaccine coverage.MethodsInterviews and focus group discussions with 74 HCWs practicing in Belgium addressed Covid-19 vaccine sentiments and experiences of discussing vaccination with peers and patients.ResultsMost participating HCWs reported difficulties discussing Covid-19 vaccination with peers and patients. Unvaccinated HCWs often feared that expressing their vaccine sentiments might upset patients or peers and that they would be suspended. Consequently, they used social cues to evaluate others’ openness to vaccine-skeptical discourses and avoided discussing vaccines. Surprisingly, some vaccine-confident HCWs hid their vaccine sentiments to avoid peer and patient conflicts. Both vaccinated and unvaccinated HCWs observed that unvaccinated patients occasionally received suboptimal care. Suboptimal care was central in unvaccinated HCW unwillingness to express their vaccine sentiments to peers. Both vaccinated and unvaccinated HCWs described loss of trust and ruptured social relations with peers and patients holding divergent vaccine sentiments.DiscussionBelgian HCW perceived Covid-19 vaccines as a risky discussion topic and engaged in “strategic silences” around vaccination to maintain functional work relationships and employment in health institutions. Loss of trust between HCW and peers or patients, along with suboptimal patient care based on vaccination status, threaten to weaken Belgium’s, and by implication, other health systems, and to catalyze preventable disease outbreaks.     

Estimation of baseline IgG antibody levels to 23 pneumococcal vaccine-type capsular polysaccharides in healthy vaccine naïve Indian adults

Since immunological responses to pneumococcal vaccines are assessed by a fold-increase in antibody levels relative to pre-immunization levels, it is therefore critical to determine baseline antibody levels to establish putative threshold as a measure of normal response. Herein, for the first time, we measured baseline IgG antibody levels in 108 healthy unvaccinated Indian adults using WHO-recommended ELISA. Median baseline IgG concentration ranged between 0.54 µg/mL to 12.35 µg/mL. Highest levels of baseline capsule polysaccharide (cPS)-specific IgG were found against types 14, 19A, and 33F. Whereas, lowest baseline IgG levels were observed against types 3, 4, and 5. Overall, ∼79% of study population had median baseline IgG levels ≥1.3 µg/mL against 74% of cPS’s. Substantial baseline antibody levels in unvaccinated adults were observed. The study would be critical in bridging gaps in baseline immunogenicity data and may offer a valuable foundation for evaluating immune response of Indian adults to pneumococcal vaccination.     

Association between vaccination status,symptom identification and healthcare use: Implications for test negative design observational studies

AimTo test the internal validity of the test-negative design (TND) by investigating associations between maternal influenza vaccination, and new virus detection episodes (VDEs), acute respiratory illness, and healthcare visits in their children.MethodsEighty-five children from a birth cohort provided daily symptoms, weekly nasal swabs, and healthcare use data until age 2-years. Effect estimates are summarised as incidence rate ratios (IRR).ResultsThere was no association between maternal vaccination and VDEs in children (IRR = 1.1; 95 %CI = 0.9–1.2). Influenza-vaccinated mothers were more likely than unvaccinated mothers to both report, and seek healthcare for, acute lower respiratory illness in their children, IRR = 2.4; 95 %CI = 1.2–4.8 and IRR = 2.2; 95 %CI = 1.1–4.3, respectively.ConclusionA key assumption of the TND, that healthcare seeking behaviour for conditions of the same severity is not associated with vaccine receipt, did not hold. Further studies of the performance of the TND in different populations are required to confirm its validity.     

How do HTA agencies perceive conditional approval of medicines? Evidence from England,Scotland, France and Canada

There is a growing disconnect between regulatory agencies that are promoting expedited approval to medicines based on early phase clinical evidence and health technology assessment (HTA) agencies that require robust clinical evidence to inform coverage decisions. This paper provides an assessment of the evidence gap between regulatory and HTA agencies on medicines receiving conditional marketing authorisation (CMA) and examines how HTA agencies in France, England, Scotland, and Canada interpret and appraise evidence for these medicines. A mixed methods research design was used to identify the types and frequency of parameters raised in the context of HTA decision-making for all conditional approvals in Europe and Canada between 2010 and 2017. Significant heterogeneity was found across the HTA agencies in England, Scotland, France, and Canada in the assessment of medicines receiving CMA, with the highest likelihood of rejection present in Quebec (50%) and Scotland (25%). Rejected medicines were more likely to have unresolved uncertainties related to the magnitude of clinical benefit, study design, and issues in economic modelling. More systematic use of joint early dialogue and conditional reimbursement pathways would help clarify evidence requirements and avoid delays in patient access to innovative medicines.     

Heroin vaccine: Using titer,affinity, and antinociception as metrics when examining sex and strain differences

Anti-drug vaccines have potential as new interventions against substance use disorder (SUD). However, given the challenges seen with inter-individual variability in SUD vaccine trials to date, new interventions should ensure a robust immune response and safety profile among a diverse population. This requires accounting for sex and heritable genetic differences in response to both abused substances as well as the vaccination itself. To test response variability to our heroin-tetanus toxoid (Her-TT) immunoconjugate vaccine, we vaccinated male and female mice from several mouse strains including Swiss Webster (SW), BALB/c, and Jackson diversity mice (J:DO). Previous studies with vaccinated male SW mice demonstrated a rare hypersensitivity resulting in mice rapidly expiring with exposure to a low dose of heroin. Our results indicate that this response is limited to only male SW mice, and not to any other strain or female SW mice. Our data suggest that this hypersensitivity is not the result of an overactive cytokine or IgE response. Vaccination was similarly effective among the sexes for each strain and against repeated heroin challenge. Inbred BALB/c and J:DO mice were found to have the best vaccine response against heroin in antinociception behavioral assay. These results highlight the importance of incorporating both male and female subjects, along with different strains to mimic diverse human populations, as new SUD vaccines are being tested.     

Preclinical evaluation of an investigational 21-valent pneumococcal conjugate vaccine,V116, in adult-rhesus monkey,rabbit, and mouse models

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116, an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV), containing pneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, and a de-O-acetylated 15B (deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 in adult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.     

Maternal influenza vaccination and child mortality: Longitudinal,population-based linked cohort study

Influenza vaccination is recommended to protect mothers and their infants from influenza. Few studies have evaluated the association between maternal influenza vaccination and child mortality. We aimed to evaluate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and mortality among young children. This longitudinal, population-based cohort study included 191,247 maternal-child pairs in Western Australia between April 2012 and December 2017. Maternal vaccine information was obtained from a state-wide antenatal vaccination database. Mortality was defined as a record of a death registration. We used Cox proportional hazard models, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio of child mortality associated with in utero exposure to seasonal IIV. This study found no association between in utero exposure to seasonal IIV and mortality through age five years.     

Immunogenicity and safety of the RTS,S/AS01 malaria vaccine co-administered with measles,rubella and yellow fever vaccines in Ghanaian children: A phase IIIb,multi-center,non-inferiority,randomized, open,controlled trial

BackgroundTo optimize vaccine implementation visits for young children, it could be efficient to administer the first RTS,S/AS01 malaria vaccine dose during the Expanded Programme on Immunization (EPI) visit at 6 months of age together with Vitamin A supplementation and the third RTS,S/AS01 dose on the same day as yellow fever (YF), measles and rubella vaccines at 9 months of age. We evaluated the safety and immunogenicity of RTS,S/AS01 when co-administered with YF and combined measles-rubella (MR) vaccines.MethodsIn this phase 3b, open-label, controlled study (NCT02699099), 709 Ghanaian children were randomized (1:1:1) to receive RTS,S/AS01 at 6, 7.5 and 9 months of age, and YF and MR vaccines at 9 or 10.5 months of age (RTS,S coad and RTS,S alone groups, respectively). The third group received YF and MR vaccines at 9 months of age and will receive RTS,S/AS01 at 10.5, 11.5 and 12.5 months of age (Control group). All children received Vitamin A at 6 months of age. Non-inferiority of immune responses to the vaccine antigens was evaluated 1 month following co-administration versus RTS,S/AS01 or EPI vaccines (YF and MR vaccines) alone using pre-defined non-inferiority criteria. Safety was assessed until Study month 4.5.ResultsNon-inferiority of antibody responses to the anti-circumsporozoite and anti-hepatitis B virus surface antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus RTS,S/AS01 alone was demonstrated. Non-inferiority of antibody responses to the measles, rubella, and YF antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus YF and MR vaccines alone was demonstrated. The safety profile of all vaccines was clinically acceptable in all groups.ConclusionsRTS,S/AS01 can be co-administered with Vitamin A at 6 months and with YF and MR vaccines at 9 months of age during EPI visits, without immune response impairment to any vaccine antigen or negative safety effect.     

MAS-1, a novel water-in-oil adjuvant/delivery system,with reduced seasonal influenza vaccine hemagglutinin dose may enhance potency,durability and cross-reactivity of antibody responses in the elderly

BackgroundIncreased influenza vaccine efficacy is needed in the elderly at high-risk for morbidity and mortality due to influenza infection. Adjuvants may allow hemagglutinin (HA) dose-sparing with enhanced immunogenicity. MAS-1 is an investigational water-in-oil emulsion-based adjuvant/delivery system comprised of stable nanoglobular aqueous droplets.MethodsA phase 1, randomized, double-blind, safety and immunogenicity, adjuvant dose escalation trial was conducted in persons aged 65 years and older. MAS-1 adjuvant dose volumes at 0.3 mL or 0.5 mL containing 9 µg per HA derived from licensed seasonal trivalent influenza vaccine (IIV, Fluzone HD 60 µg per HA, Sanofi Pasteur) were compared to high dose (HD) IIV (Fluzone HD). Safety was measured by reactogenicity, adverse events, and safety laboratory measures. Immunogenicity was assessed by serum hemagglutination inhibition (HAI) antibody titers.ResultsForty-five subjects, aged 65–83 years, were randomly assigned to receive 9 µg per HA in 0.3 mL MAS-1 (15 subjects) or HD IIV (15 subjects) followed by groups randomly assigned to receive 9 µg per HA in 0.5 mL MAS-1 (10 subjects) or HD IIV (5 subjects). Injection site tenderness, induration, and pain, and headache, myalgia, malaise and fatigue were common, resolving before day 14 post-vaccination. Clinically significant late-onset injection site reactions occurred in four of ten subjects at the 0.5 mL adjuvant dose. Safety laboratory measures were within acceptable limits. MAS-1-adjuvanted IIV enhanced mean antibody titers, mean-fold increases in antibody titer, and seroconversion rates against vaccine strains for at least 168 days post-vaccination and enhanced cross-reactive antibodies against some non-study vaccine influenza viruses.ConclusionMAS-1 adjuvant provided HA dose-sparing without safety concerns at the 0.3 mL dose, but the 0.5 mL dose caused late injection site reactions. MAS-1-adjuvanted IIV induced higher HAI antibody responses with prolonged durability including against historical strains, thereby providing greater potential vaccine efficacy in the elderly throughout an influenza season.Clinical Trial Registry: ClinicalTrials.gov # NCT02500680.     

DS-5670a,a novel mRNA-encapsulated lipid nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2: Results from a phase 2 clinical study

BackgroundDS-5670a is a vaccine candidate for coronavirus disease 2019 (COVID-19) harnessing a novel modality composed of messenger ribonucleic acid (mRNA) encoding the receptor-binding domain (RBD) from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encapsulated in lipid nanoparticles. Here, we report the safety, immunogenicity, and pharmacokinetic profile of DS-5670a from a phase 2 clinical trial in healthy adults who were immunologically naïve to SARS-CoV-2.MethodsThe study consisted of an open-label, uncontrolled, dose-escalation part and a double-blind, randomized, uncontrolled, 2-arm, parallel-group part. A total of 80 Japanese participants were assigned to receive intramuscular DS-5670a, containing either 30 or 60 µg of mRNA, as two injections administered 4 weeks apart. Safety was assessed by characterization of treatment-emergent adverse events (TEAEs). Immunogenicity was assessed by neutralization titers against SARS-CoV-2, anti-RBD immunoglobulin (Ig)G levels, and SARS-CoV-2 spike-specific T cell responses. Plasma pharmacokinetic parameters of DS-5670a were also evaluated.ResultsMost solicited TEAEs were mild or moderate with both the 30 and 60 µg mRNA doses. Four participants (10 %) in the 60 µg mRNA group developed severe redness at the injection site, but all cases resolved without treatment. There were no serious TEAEs and no TEAEs leading to discontinuation. Humoral immune responses in both dose groups were greater than those observed in human convalescent serum; the 60 µg mRNA dose produced better responses. Neutralization titers were found to be correlated with anti-RBD IgG levels (specifically IgG1). DS-5670a elicited antigen-specific T helper 1-polarized cellular immune responses.ConclusionsThe novel mRNA-based vaccine candidate DS-5670a provided favorable immune responses against SARS-CoV-2 with a clinically acceptable safety profile. Confirmatory trials are currently ongoing to evaluate the safety and immunogenicity of DS-5670a as the primary vaccine and to assess the immunogenicity when administered as a heterologous or homologous booster.Trial registry: https://jrct.niph.go.jp/latest-detail/jRCT2071210086.     

Novel colloidal associations of soyasaponins and lipid components (DPPC,cholesterol) as potential adjuvants for vaccines

Soyasaponins from soybean (Glycine max) represent promising new potent adjuvants for vaccine research because of their immunostimulating properties and weak hemolytic activity. In the present study, saponin microstructures of soyasaponins (soyasaponin Bb, soyasaponin Ab) with lipid components (cholesterol, DPPC (dipalmitoylphosphatidylcholine)) were designed by the lipid film method. In interaction studies between soyasaponins (soyasaponin Ab/Bb) and Langmuir monolayers (model membranes), composed of cholesterol and DPPC, marked interactions between soyasaponins and a pure cholesterol monolayer were observed. No interaction was detected for soyasaponins with a pure DPPC monolayer. The intercalation of soyasaponins in a mixed DPPC/cholesterol (3:1, w/w) monolayer was only observed for the monodesmosidic soyasaponin Bb whereas the second sugar chain of the bidesmosidic soyasaponin Ab impaired the access to the monolayer. Transmission electron microscopy was used for visualizing particle formation of soyasaponins and lipid components. Pseudo-binary systems (soyasaponin Ab/Bb, cholesterol) formed colloidal associations built up from ring-like subunits in the nanometer size range. In pseudo-ternary systems (soyasaponin, cholesterol, DPPC) soyasaponin Bb attacked the liposomal membrane by forming colloidal associations. Colloidal associations in pseudo-ternary systems with soyasaponin Ab, cholesterol and a phospholipid were only observed in the presence of PE (phosphatidylethanolamine) instead of DPPC. In an MTT assay with a HaCaT cell line (keratinocyte cell line) the cell viability was neither affected by the soyasaponins nor by the corresponding formulations. Both the pure soyasaponin solution and the saponin formulations may be promising adjuvant systems for the intradermal vaccine application. Furthermore, interaction studies between the model antigen ovalbumin and colloidal associations of saponins and cholesterol using MST (Microscale Thermophoresis) gave first indications of an antigen binding to colloidal associations. Ex vivo T-cell proliferation in the presence of soyasaponin Ab was confirmed.     

The gut microbiome,mild cognitive impairment,and probiotics: A randomized clinical trial in middle-aged and older adults

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