Effects of Salts and Surface Charge on the Biophysical Stability of a Low pI Monoclonal Antibody

The impact of five representative Hofmeister salts (NaCl, KCl, MgCl₂, Na₂SO₄, and NaSCN) on the thermal stability and aggregation kinetics of a slightly acidic monoclonal antibody (mAb) were investigated under different pH conditions. The thermal stability of the mAb was assessed by measuring the lowest unfolding transition temperature, T_m, with differential scanning fluorimetry. MgCl₂ and NaSCN significantly decreased T_m at all three charged states of the mAb, but to the greatest extent when the mAb surface charge was net positive. Non-native aggregation kinetics was monitored by measuring Rayleigh light scattering. When the mAb surface charge was net positive or net neutral, the nucleation rate increased non-monotonically with MgCl₂ and NaSCN but decreased monotonically with NaCl, KCl, and Na₂SO₄. By contrast, when the mAb surface was negatively charged, there were only minor changes in the nucleation rate with all salts tested. Furthermore, there was less structural perturbation and slower aggregation rates when the mAb was net negatively charged than when it was net neutrally or positively charged. The observed salt effects on thermal unfolding are consistent with ion-specific mechanisms dominated by short-range amide backbone binding. On the other hand, the salt effects on nucleation rates appear to be influenced by both amide backbone binding and long-range electrostatic binding of ions to charged amino acid side chains.     

Recombinant zoster vaccine coverage in the United States: An analysis of claims-based data

Recombinant zoster vaccine (RZV) is recommended for individuals ≥ 50 years of age for protection against herpes zoster (HZ). This study quantifies RZV coverage and assesses predictors for RZV vaccination using a U.S. claims database. Univariate linear regression provided annual prevalence of RZV vaccination and multivariable logistic regression provided ORs and 95% CIs for associations between predictors and RZV vaccination. A total of 4,124,315 individuals (19,080,914 person-years) were included in this study. Since receiving FDA approval for the prevention of HZ, RZV coverage (of at least one dose) has reached approximately 17% within the eligible U.S. population by January 2021, although significant disparities between demographic groups were noted. Our findings suggest that HZ vaccine coverage may be reduced below goal in the U.S. and highlights the importance of continuing to monitor RZV vaccination. Additionally, as our study found disparities in vaccine coverage, attention towards marginalized and medically underserved populations is needed.     

Censoring Time Trade-off Values at 0 Versus at −1: How Does the Assumption for Worse-Than-Dead Time Trade-off Values Affect the Modeling of EQ-5D-5L Valuation Data?

ObjectivesA recent study found that negative utility values elicited using composite time trade-off (TTO) were barely associated with the severity of EQ-5D-5L health states, suggesting poor discriminative ability. Assuming negative values provide limited information, this study aimed to explore the usefulness of censoring negative TTO values at 0 in modeling EQ-5D-5L valuation data.MethodsWe analyzed EQ-5D-5L valuation data from China, The Netherlands, Canada, Singapore, and Thailand. For each data set, we estimated value sets using 2 Tobit models, one left-censored at −1 (current practice) and one left-censored at 0 (our proposed method), and compared the model performances. We hypothesized that censoring at 0 and censoring at −1 would produce similar values, though on slightly different scales.ResultsWhen censoring at 0, logical inconsistencies and statistical significance were improved but the value range was compressed. In the cross-attribute level effects model, the 3-level parameters were similar between the models censored at 0 and −1, but the rank order of some dimension parameters was altered. Health state values predicted by the 2 censoring models approximated a perfect agreement after rescaling.ConclusionsCensoring TTO values at 0 improved model estimation and fit but produced higher utility values than models censoring at −1. Investigators of future EQ-5D value set studies using the composite TTO method are advised to examine the validity of negative TTO values before choosing modeling strategies.     

Epidemiology of varicella in Haidian district,Beijing, China—2007–2015

Background1-Dose varicella vaccination was recommended for children in Beijing before November 2012. To further control school-based outbreaks and decrease incidence, a 2-dose vaccination was implemented in 2013. We described the varicella epidemiology and assessed impact of the 2-dose vaccination in Haidian district, Beijing, 2007–2015.MethodsWe examined the estimated incidence and disease characteristics of varicella during 2007–2015 and obtained the 1-dose vaccination coverage for children born during 2005–2013. Number of vaccine doses given was used to indirectly reflect the second-dose vaccination coverage. Overall and age-specific estimated incidences were compared between 2007–2012 and 2013–2015.ResultsA total of 23,497 cases were reported during 2007–2015. Of the 23,497 cases, 13,440 (57.20%) were male, and 68.40% were <20 years of age and 70.02% were students and children in kindergarten. The estimated incidence increased from 82 cases per 100,000 population in 2007 to 104 in 2011, before substantially decreasing from 86 in 2012 to 56 in 2015. The median age increased from 14 years in 2007 to 18 years in 2015. The 1-dose varicella coverage for children at ≥2 years of age gradually increased from 74.21% in 2007 to 90.06% in 2015. Compared with 2007–2012, two-fold average vaccine doses were given during 2013–2015, and the overall estimated incidence declined by 34.4%, particularly in children aged 5–9 years, with a significantly declined trend in children aged 1–9 years and older adolescents aged 15–19 years and non-significantly declined trend in adults aged ≥20 years, but a significant increasing trend in infants.ConclusionsThe overall incidence of varicella has decreased substantially in Haidian district since 2013, with largest decline in children aged 5–9 years. The 2-dose varicella vaccination might not lead to increase in incidence in adults. Long-term surveillance is needed to fully evaluate the long-term impact of the 2-dose varicella vaccination.     

Estimating the full public health value of vaccination

There is an enhanced focus on considering the full public health value (FPHV) of vaccination when setting priorities, making regulatory decisions and establishing implementation policy for public health activities. Historically, a therapeutic paradigm has been applied to the evaluation of prophylactic vaccines and focuses on an individual benefit-risk assessment in prospective and individually-randomized phase III trials to assess safety and efficacy against etiologically-confirmed clinical outcomes. By contrast, a public health paradigm considers the population impact and encompasses measures of community benefits against a range of outcomes. For example, measurement of the FPHV of vaccination may incorporate health inequity, social and political disruption, disruption of household integrity, school absenteeism and work loss, health care utilization, long-term/on-going disability, the development of antibiotic resistance, and a range of non-etiologically and etiologically defined clinical outcomes.Following an initial conference at the Fondation Mérieux in mid-2015, a second conference (December 2016) was held to further describe the efficacy of using the FPHV of vaccination on a variety of prophylactic vaccines. The wider scope of vaccine benefits, improvement in risk assessment, and the need for partnership and coalition building across interventions has also been discussed during the 2014 and 2016 Global Vaccine and Immunization Research Forums and the 2016 Geneva Health Forum, as well as in numerous publications including a special issue of Health Affairs in February 2016.The December 2016 expert panel concluded that while progress has been made, additional efforts will be necessary to have a more fully formulated assessment of the FPHV of vaccines included into the evidence-base for the value proposition and analysis of unmet medical need to prioritize vaccine development, vaccine licensure, implementation policies and financing decisions. The desired outcomes of these efforts to establish an alternative framework for vaccine evaluation are a more robust vaccine pipeline, improved appreciation of vaccine value and hence of its relative affordability, and greater public access and acceptance of vaccines.     

A method for evaluating and comparing immunisation schedules that cover multiple diseases: Illustrative application to the UK routine childhood vaccine schedule

BackgroundIn the UK, the childhood immunisation programme is given in the first 5 years of life and protects against 12 vaccine-preventable diseases. Recently, this programme has undergone changes with addition of vaccination against Meningitis B from September 2015 and the removal of the primary dose of protection against Meningitis C from July 2016. These hanges have direct impact on the associated diseases but in addition may induce indirect effects on the vaccines that are given simultaneously or later in the programme. In this work, we developed a novel formal method to evaluate the impact of vaccination changes to one aspect of the programme across an entire vaccine programme.MethodsFirstly, we combined transmission modelling (for four diseases) and historic data synthesis (for eight diseases) to project, for each disease, the disease burden at different levels of effective coverage against the associated disease. Secondly, we used a simulation model to determine the vector of effective coverage against each disease under three variations of the current childhood schedule. Combining these, we calculated the vector of disease burden across the programme under different scenarios, and assessed the direct and indirect effects of the schedule changes.ResultsThrough illustrative application of our novel framework to three scenarios of the current childhood immunisation programme in the UK, we demonstrated the feasibility of this unifying approach. For each disease in the programme, we successfully quantified the residual disease burden due to the change. For some diseases, the change was indirectly beneficial and reduced the burden, whereas for others the effect was adverse and the change increased the disease burden.ConclusionsOur results demonstrate the potential benefit of considering the programme-wide impact of changes to an immunisation schedule, and our framework is an important step in the development of a means for systematically doing so.     

CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope display high naive precursor frequency and TCR promiscuity

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Serologic correlates of protection for evaluating the response to meningococcal vaccines

Meningococci cause serious disease worldwide and the organism remains the most common cause of bacterial meningitis in children and young adults. The only effective means of controlling disease is through vaccination. Although polysaccharide vaccines have been available for serogroup A, C, Y and W135 for many years, serogroup C polysaccharide-protein conjugate vaccines have only recently been licensed in many countries. Conjugate vaccines for combinations of serogroup A, C, Y and W135 are progressing through clinical trials and major efforts are being made to develop a safe and efficacious vaccine against serogroup B. To assess the quality of the immune response after vaccination, laboratory correlates of protection are needed. For serogroups A and C, serum bactericidal antibody is a well established predictor for protection but for serogroup B, other mechanisms besides serum bactericidal antibody may also be involved in conferring protection against disease. The serologic correlates of protection for evaluating the response to meningococcal vaccines are described in this review.