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.

Heterologous vaccine effects.

The heterologous or non-specific effects (NSEs) of vaccines, at times defined as "off-target effects" suggest that they can affect the immune response to organisms other than their pathogen-specific intended purpose. These NSEs have been the subject of clinical, immunological and epidemiological studies and are increasingly recognized as an important biological process by a growing group of immunologists and epidemiologists. Much remain to be learned about the extent and underlying mechanisms for these effects. The conference "Off-target effects of vaccination" held in Annecy-France (June 8-10 2015) intended to take a holistic approach drawing from the fields of immunology, systems biology, epidemiology, bioinformatics, public health and regulatory science to address fundamental questions of immunological mechanisms, as well as translational questions about vaccines NSEs. NSE observations were examined using case-studies on live attenuated vaccines and non-live vaccines followed by discussion of studies of possible biological mechanisms. Some possible pathways forward in the study of vaccines NSE were identified and discussed by the expert group.

Relationships of Feeding and Mother's Own Milk with Fecal Calprotectin Levels in Preterm Infants.

OBJECTIVE: To describe longitudinal effects of feeding volume and type of milk on fecal calprotectin (f-CP) in very low-birth weight (VLBW) infants. STUDY DESIGN: Prospective data were collected across Neonatal Intensive Care Unit (NICU) admission for 6 weeks or until discharge in 75 VLBW neonates. The mean gestational age on entry into the study was 29 weeks. RESULTS: Seventy-four (99%) mothers provided expressed milk in varying amounts. Twenty-three mothers (31%) provided exclusive mother's own milk (MOM) throughout. Preterm infant formula (PIF) and pasteurized donor milk were added to feedings of remaining infants. Pooled MOM was analyzed weekly for levels of a panel of cytokines, chemokines, and growth factors, and secretory Immunoglobulin A (sIgA) so that the exact amount of exposure to the gut of these milk bioactives could be estimated. f-CP levels ranged from 160 to 350 µg/g stool. Total feeding volume was positively associated with f-CP, controlling for infant weight, and f-CP levels rose across time. Exclusive MOM feedings for the entire measurement period were associated with rising levels of f-CP, but mixed feedings (MOM with added PIF or pasteurized donor milk (PDM) did not show this increase over time. CONCLUSION: The presence of f-CP may represent a response to milk volumes and MOM, which represents normal development rather than always implicating pathological inflammation in the VLBW infant.

In vivo and in vitro antimalarial activity of 4-nerolidylcatechol.

4-Nerolidylcatechol (4-NC) isolated from Piper peltatum L. (Piperaceae) was evaluated for in vitro antiplasmodial activity against Plasmodium falciparum (cultures of both standard CQR (K1) and CQS (3D7) strains and two Amazonian field isolates) and for in vivo antimalarial activity using the Plasmodium berghei-murine model. 4-NC exhibits significant in vitro and moderate in vivo antiplasmodial activity. 4-NC administered orally and subcutaneously at doses of 200, 400 and 600 mg/kg/day suppressed the growth of P. berghei by up to 63% after four daily treatments (days 1-4). Also, 4-NC exhibited important in vitro antiplasmodial activity against both standard and field P. falciparum strains in which 50% inhibition of parasite growth (IC(50) ) was produced at concentrations of 0.05-2.11 µg/mL and depended upon the parasite strain. Interestingly, healthy (non-infected) mice that received 4-NC orally presented (denatured) blood plasma which exhibited significant in vitro activity against P. falciparum. This is evidence that mouse metabolism allows 4-NC or active metabolites to enter the blood. Further chemical and pharmacological studies are necessary to confirm the potential of 4-NC as a new antimalarial prototype.

Relationship between climate, pollen concentrations of Ambrosia and medical consultations for allergic rhinitis in Montreal, 1994-2002.

The aim of this study is to evaluate the influence of meteorological factors on Ambrosia pollen concentrations and its impact on medical consultations for allergic rhinitis of residents from various socio-economic levels in Montréal (Québec, Canada) between 1994 and 2002. The study was conducted to recognize the sensitivity of pollen productivity to daily climate variability in order to estimate the consequences on human health vulnerability in the context of global climate change. Information related to medical consultations for allergic rhinitis due to pollen comes from the Quebec Health Insurance Board (Régie de l'assurance-maladie du Québec). Ambrosia pollen concentration was measured by the Aerobiology Research Laboratories (Nepean, Ontario). Daily temperature (maximum, minimum, and mean) and precipitation data were obtained from the Meteorological Service of Canada. Socio-economic data come from the 1996 and 2001 census data of Statistics Canada. Between 1994 and 2002, during the Ambrosia pollen season, 7667 consultations for allergic rhinitis due to pollen were recorded. We found a significant association between the number of medical consultations and pollen levels. Significant associations were detected for over-consultation the day of exposure, 1, 2, 3 and 5 days after exposure to high levels of pollen. The consultation rate is higher from low-income residents (3.10 consultations per 10,000 inhabitants) than for high-income (1.65 consultations per 10,000 inhabitants). Considering the demonstrated impact of pollen levels on health, it has become critical to ensure adequate monitoring of Ambrosia and its meteorological sensivity in the context of the anticipated climate change and its potential consequences on human health.

An automated multistep high-throughput screening assay for the identification of lead inhibitors of the inducible enzyme mPGES-1.

Prostaglandin E2 synthase (mPGES-1), the enzyme which catalyzes the synthesis of PGE2, is induced during the inflammatory response. For this reason, mPGES-1 could be a potential therapeutic target. A high-throughput screening assay was developed to identify potential inhibitors of mPGES-1. The assay consisted of a 30-s mPGES-1 enzymatic reaction followed by the detection of PGE2 by enzyme immunoassay (EIA). The enzymatic reaction was performed in a batch mode because the instability of the substrate (10 min) limited the number of plates assayed within a working day. The detection of the product by EIA was performed on 3 instruments requiring 14 different steps for complete automation. The authors describe here the optimization and implementation of a 2-part assay on a Thermo CRS robotic system. More than 315,000 compounds were tested, and a hit rate of 0.84% was obtained for this assay. Although the entire assay required multiple steps, the assay was successfully miniaturized and automated for a high-throughput screening campaign.

Effect of fish oil on LDL oxidation and plasma homocysteine concentrations in health.

Oxidation of low-density lipoprotein (LDL) and hyperhomocysteinemia are believed to play a role in therogenesis. Whether n-3 polyunsaturated fatty acids increase LDL susceptibility to oxidation or influence homocysteine (Hcy) metabolism has long been a subject of controversy. In this study, we evaluated the effect of 8 weeks of dietary supplementation with 6 g/day of fish oil (FO; 3 g of n-3 fatty acids) on plasma lipoproteins, in vitro LDL peroxidation, antioxidant status, and plasma Hcy concentrations in 16 normolipidemic subjects. FO rapidly and significantly (P < .01) decreased plasma total and very low density lipoprotein triglyceride concentrations and had no effect on LDL or high-density-lipoprotein cholesterol. The mean lag time before onset of Cu(2+)-induced LDL oxidation, as well as plasma and LDL alpha-tocopherol and beta-carotene concentrations, was unchanged. However, changes in plasma aminothiol concentrations occurred during the study. Specifically, a progressive and significant increase in total Hcy plasma concentrations was observed (13.4% and 20% after 4 and 8 weeks, respectively; P < .01). Total glutathione concentrations were significantly higher after 8 weeks (P < .05). The tHcy increase was not associated with changes in plasma folate or vitamin B(12) concentrations. However, concentrations of plasma nitric oxide metabolites (NO(x) = NO(2) + NO(3)) were significantly higher than at baseline after 8 weeks of FO intake (74%; P < .01). Further, the changes in total Hcy and NO(x) plasma concentrations observed after 8 weeks of FO were found to be significantly correlated (r = .78, P < .001). With this study, we report for the first time the apparent interaction of n-3 fatty acids and nitric oxide on Hcy metabolism.