Consumption of cranberry beverage improved endogenous antioxidant status and protected against bacteria adhesion in healthy humans: a randomized controlled trial

Consumption of polyphenol-rich foods is associated with lower risk from many chronic diseases. We hypothesized that a single dose of cranberry beverage would improve indices of oxidative stress, inflammation, and urinary antibacterial adhesion activity in healthy humans. Six males and 6 females (18-35 years; body mass index, 19-25 kg/m²) consumed placebo, cranberry leaf extract beverage, or low-calorie cranberry juice cocktail (LCJC) once in a randomized, double-blind, placebo-controlled cross-over experimental design trial. The washout period between beverages was 1 week. Blood was collected 0, 2, 4, 8, and 24 hours after beverage consumption for measuring oxidative and inflammatory biomarkers. Urine was collected at 0, 0 to 3, 3 to 6, 6 to 9, 9 to 12, and 24 hours postintervention to assess antibacterial adhesion activity. Consumption of cranberry leaf extract beverage elevated (P < .05) blood glutathione peroxidase activity, whereas LCJC consumption increased (P < .05) glutathione concentrations and superoxide dismutase activity compared with placebo. Cranberry leaf extract beverage and LCJC consumption had no effect on the inflammatory biomarkers measured as compared with placebo. At 0 to 3 hours postconsumption, urine from participants who consumed cranberry beverages had higher (P < .05) ex vivo antiadhesion activity against P-fimbriated Escherichia coli compared with placebo. An acute dose of cranberry beverages improved biomarkers of antioxidant status and inhibition of bacterial adhesion in urine.     

Lemierre's Syndrome Caused by Klebsiella pneumoniae in a Diabetic Patient: A Case Report and Review of the Literature

Lemierre''s syndrome is characterized by an oropharyngeal infection with internal jugular vein thrombosis followed by metastatic infections in other organs. This infection is usually caused by Fusobacterium spp. In this report, we present a rare case of Klebsiella pneumoniae-associated Lemierre''s syndrome in a patient with poorly-controlled diabetes mellitus. The infection was complicated by septic emboli in many organs, which led to the patient''s death, despite combined antibiotics, anticoagulant therapy, and surgical intervention. Therein, a literature review was performed for reported cases of Lemierre''s syndrome caused by Klebsiella pneumoniae and the results are summarized here.     

A randomized, double-blind, placebo-controlled, phase 1/2a study of the safety and immunogenicity of a live, attenuated human parainfluenza virus type 3 vaccine in healthy infants

Objective

To evaluate the safety, tolerability, immunogenicity, and viral shedding profiles of a recombinant, live, attenuated human parainfluenza virus type 3 (HPIV3) vaccine, rHPIV3cp45, in healthy HPIV3-seronegative infants 6 to <12 months of age.

Methods

In this double-blind, multicenter study, subjects were randomized 2:1 to receive a 10⁵ TCID₅₀ dose of rHPIV3cp45 (n = 20) or placebo (n = 10) at enrollment and at 2 and 4 months after the first dose. Blood for evaluation of antibody to HPIV3 was collected at baseline and approximately 1 month after each dose. Solicited adverse events (SEs) and unsolicited adverse events (AEs) were collected on days 0-28 after each dose. Nasal wash samples for vaccine virus shedding were collected 3 times after each dose (7-10, 12-18, and 28-34 days post dose) and at unscheduled illness visits. Subjects were followed for 180 days after the last dose.

Results

Vaccine virus was shed by 85% of vaccine recipients after dose 1, by 1 subject after dose 2, and was not shed by any subject after dose 3. The highest titer of shed virus was detected on day 7 after dose 1. The attenuation phenotype and the genotype of the vaccine virus were stable in shed virus. Seroresponse (≥4-fold rise in HPIV3 antibody from baseline) occurred in 61% of subjects after dose 1 and in 77% after dose 3. Either seroresponse or shedding occurred in 95% of vaccine subjects. Adverse events were similar in vaccine and placebo recipients.

Conclusion

The safety, shedding, and immunogenicity profiles of rHPIV3cp45 in HPIV3-seronegative infants 6 to <12 months of age support further development of this vaccine.ClinicalTrials.gov Identifier: NCT00508651.     

Artesunate and sulfadoxine-pyrimethamine combinations for the treatment of uncomplicated Plasmodium falciparum malaria in Uganda: a randomized, double-blind, placebo-controlled trial

Drug-resistant malaria is spreading in Africa. The few available drugs might be safeguarded if combined with an artemisinin derivative. We investigated the efficacy, safety, and tolerability of 2 combinations of artesunate with sulfadoxine-pyrimethamine (SP) in a mesoendemic region in Uganda with SP resistance, from September 1999 to June 2000. In a randomized, double-blind, placebo-controlled trial, 420 children aged 6-59 months with uncomplicated Plasmodium falciparum malaria were assigned SP alone (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine) or combined with artesunate (AS; 4 mg/kg/d) for either 1 d (SPAS1) or 3 d (SPAS3). Children were followed-up for 28 d. Day 14 cure rates were 84.6% (99/117) with SPAS3 and 61.9% (73/118) with SPAS1 compared with 55.8% (86/154) with SP. Corresponding day 28 results were 74.4% (87/117) and 45.2% (52/115) compared with 40.5% (62/153). A significant improvement was obtained with the addition of 3 d, but not 1 d, of artesunate (risk ratio [RR] = 1.5, 95% CI 1.3-1.8 at 14 d and RR = 1.8, 95% CI 1.5-2.3 at 28 d). Both AS regimens achieved significantly faster parasite clearance and lower gametocyte carriage. All drug regimens were well tolerated, but SP alone was ineffective. Treatment efficacy improved with SPAS3 but the cure rate at day 28 was modest. The combinations were well tolerated and safe. In areas where SP resistance is prevalent other combinations should be considered.     

Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.     

Daily flaxseed consumption improves glycemic control in obese men and women with pre-diabetes: a randomized study

The study hypothesis was that fasting glucose, insulin, fructosamine, C-reactive protein, and interleukin-6 decrease and adiponectin increases with daily flaxseed consumption in overweight or obese individuals with pre-diabetes. In this randomized, cross-over study overweight or obese men and postmenopausal women (n = 25) with pre-diabetes consumed 0, 13, or 26 g ground flaxseed for 12 weeks. Glucose, insulin, homeostatic model assessment (HOMA-IR), and normalized percent of α-linolenic fatty acid (ALA) were significantly different by treatment (multiple analysis of variance, P = .036, P = .013, P = .008, P = .024 respectively). Paired t tests showed glucose decreased on the 13 g intervention compared to the 0 g period [13g = −2.10 ± 1.66 mg/L (mean ± SEM), 0 g = 9.22 ± 4.44 mg/L, P = .036]. Insulin decreased on the 13 g intervention but not the 26 g (P = .021) and 0 g (P = .013) periods (13 g = −2.12 ± 1.00 mU/L, 26 g = 0.67 ± 0.84 mU/L, 0g = 1.20 ± 1.16 mU/L). HOMA-IR decreased on the 13 g period but not on the 26 g (P = .012) and 0 g (P = .008) periods (13g = −0.71 ± 0.31, 26g = 0.27 ± 0.24, 0g = 0.51 ± 0.35). The α-linolenic fatty acid decrease for the 0 g period was different than the 13 g (P = .024) and 26 g (P = .000) periods (13 g = 0.20 ± 0.04, 26g = 0.35 ± 0.07, 0g = −0.01 ± 0.07). Fructosamine, high sensitivity C-reactive protein, adiponectin, and high-sensitivity interleukin-6 had no significant differences. Flaxseed intake decreased glucose and insulin and improved insulin sensitivity as part of a habitual diet in overweight or obese individuals with pre-diabetes.     

Immunogenicity and safety of the candidate RTS,S/AS01 vaccine in young Nigerian children: A randomized,double-blind,lot-to-lot consistency trial

Background

For regulatory approval, consistency in manufacturing of vaccine lots is expected to be demonstrated in confirmatory immunogenicity studies using two-sided equivalence trials. This randomized, double-blind study (NCT01323972) assessed consistency of three RTS,S/AS01 malaria vaccine batches formulated from commercial-scale purified antigen bulk lots in terms of anti-CS-responses induced.

Methods

Healthy children aged 5–17 months were randomized (1:1:1:1) to receive RTS,S/AS01 at 0-1-2 months from one of three commercial-scale purified antigen bulk lots (1600 litres-fermentation scale; commercial-scale lots), or a comparator vaccine batch made from pilot-scale purified antigen bulk lot (20 litres-fermentation scale; pilot-scale lot). The co-primary objectives were to first demonstrate consistency of antibody responses against circumsporozoite (CS) protein at one month post-dose 3 for the three commercial-scale lots and second demonstrate non-inferiority of anti-CS antibody responses at one month post-dose 3 for the commercial-scale lots compared to the pilot-scale lot. Safety and reactogenicity were evaluated as secondary endpoints.

Results

One month post-dose-3, anti-CS antibody geometric mean titres (GMT) for the 3 commercial scale lots were 319.6 EU/ml (95% confidence interval (CI): 268.9–379.8), 241.4 EU/ml (207.6–280.7), and 302.3 EU/ml (259.4–352.3). Consistency for the RTS,S/AS01 commercial-scale lots was demonstrated as the two-sided 95% CI of the anti-CS antibody GMT ratio between each pair of lots was within the range of 0.5–2.0. GMT of the pooled commercial-scale lots (285.8 EU/ml (260.7–313.3)) was non-inferior to the pilot-scale lot (271.7 EU/ml (228.5–323.1)). Each RTS,S/AS01 lot had an acceptable tolerability profile, with infrequent reports of grade 3 solicited symptoms. No safety signals were identified and no serious adverse events were considered related to vaccination.

Conclusions

RTS,S/AS01 lots formulated from commercial-scale purified antigen bulk batches induced a consistent anti-CS antibody response, and the anti-CS GMT of pooled commercial-scale lots was non-inferior to that of a lot formulated from a pilot-scale antigen bulk batch.     

Safety of a quadrivalent meningococcal serogroups A,C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: Results of an open-label,randomized, phase 3b controlled study in healthy infants

Background

The highest risk for invasive meningococcal disease (IMD) is in infants aged <1 year. Quadrivalent meningococcal conjugate vaccination has the potential to prevent IMD caused by serogroups A, C, W and Y. This phase 3b, multinational, open-label, randomized, parallel-group, multicenter study evaluated the safety of a 4-dose series of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, concomitantly administered with routine vaccinations to healthy infants.

Methods

Two-month-old infants were randomized 3:1 to receive MenACWY-CRM with routine vaccines or routine vaccines alone at ages 2, 4, 6 and 12 months. Adverse events (AEs) that were medically attended and serious adverse events (SAEs) were collected from all subjects from enrollment through 18 months of age. In a subset, detailed safety data (local and systemic solicited reactions and all AEs) were collected for 7 days post vaccination. The primary objective was a non-inferiority comparison of the percentages of subjects with ≥1 severe systemic reaction during Days 1–7 after any vaccination of MenACWY-CRM plus routine vaccinations versus routine vaccinations alone (criterion: upper limit of 95% confidence interval [CI] of group difference <6%).

Results

A total of 7744 subjects were randomized with 1898 in the detailed safety arm. The percentage of subjects with severe systemic reactions was 16% after MenACWY-CRM plus routine vaccines and 13% after routine vaccines alone (group difference 3.0% (95% CI −0.8, 6.4%). Although the non-inferiority criterion was not met, post hoc analysis controlling for significant center and group-by-center differences revealed that MenACWY-CRM plus routine vaccinations was non-inferior to routine vaccinations alone (group difference −0.1% [95% CI −4.9%, 4.7%]). Rates of solicited AEs, medically attended AEs, and SAEs were similar across groups.

Conclusion

In a large multinational safety study, a 4-dose series of MenACWY-CRM concomitantly administered with routine vaccines was clinically acceptable with a similar safety profile to routine vaccines given alone.     

Safety,reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: A phase I/II randomized clinical study

Background

New vaccines containing highly conserved Streptococcus pneumoniae proteins such as pneumolysin toxoid (dPly) and histidine-triad protein D (PhtD) are being developed to provide broader protection against pneumococcal disease. This study evaluated the safety, reactogenicity and immunogenicity of different pneumococcal protein-containing formulations in adults.

Methods

In a phase I double-blind study (www.clinicaltrials.gov: NCT00707798), healthy adults (18–40 years) were randomized (1:2:2:2:2:2:2) to receive two doses of one of six investigational vaccine formulations 2 months apart, or a single dose of the control 23-valent pneumococcal polysaccharide vaccine (23PPV; Pneumovax23™, Sanofi Pasteur MSD) followed by placebo. The investigational formulations contained dPly alone (10 or 30 μg), or both dPly and PhtD (10 or 30 μg each) alone or combined with the polysaccharide conjugates of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix™, GlaxoSmithKline Vaccines). Two groups primed with a formulation containing dPly and PhtD (10 or 30 μg each) continued to the follow-up phase II study (NCT00896064), in which they received a booster dose at 5–9 months after primary vaccination.

Results

Of 156 enrolled and vaccinated adults, 146 completed the primary immunization and 43 adults received a booster dose. During primary and booster vaccination, for any formulation, ≤8.9% of doses were followed by grade 3 solicited local or general adverse events. No fever >39.5 °C (oral temperature) was reported. Unsolicited adverse events considered causally related to vaccination were reported following ≤33.3% of investigational vaccine doses. No serious adverse events were reported for adults receiving investigational vaccine formulations. Formulations containing dPly with or without PhtD were immunogenic for these antigens; polysaccharide conjugate-containing formulations were also immunogenic for those 10 polysaccharides.

Conclusion

Investigational vaccine formulations containing dPly and PhtD were well tolerated and immunogenic when administered to healthy adults as standalone protein vaccine or combined with PHiD-CV conjugates.     

A Phase III,multicenter, randomized,double-blind,active comparator-controlled study to evaluate the safety,tolerability, and immunogenicity of V114 compared with PCV13 in healthy infants (PNEU-PED-EU-1)

BackgroundV114 (15-valent pneumococcal conjugate vaccine [PCV]) contains all serotypes in 13-valent PCV (PCV13) and additional serotypes 22F and 33F. This study evaluated safety and immunogenicity of V114 compared with PCV13 in healthy infants, and concomitant administration with DTPa–HBV–IPV/Hib and rotavirus RV1 vaccines.MethodsV114 and PCV13 were administered in a 2+1 schedule at 2, 4, and 11–15 months of age. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series (PPS), immediately prior to a toddler dose, and 30 days post-toddler dose (PTD). Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for the two additional serotypes.Results1184 healthy infants 42–90 days of age were randomized 1:1 to V114 (n = 591) or PCV13 (n = 593). Proportions of participants with solicited AEs and serious AEs were comparable between vaccination groups. V114 met pre-specified non-inferiority criteria for all 13 shared serotypes, based on the difference in proportions of participants with serotype-specific IgG concentrations ≥0.35 μg/mL (response rate; lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5), and pre-specified superiority criteria for serotypes 22F and 33F (lower bound of two-sided 95% CI >10.0 for response rates and >2.0 for GMC ratios). Antibody responses to DTPa–HBV–IPV/Hib and RV1 vaccines met pre-specified non-inferiority criteria, based on antigen-specific response rates to DTPa–HBV–IPV/Hib and anti-rotavirus IgA geometric mean titers.ConclusionsAfter a 2+1 schedule, V114 elicited non-inferior immune responses to 13 shared serotypes and superior responses to the two additional serotypes compared with PCV13, with comparable safety profile. These results support the routine use of V114 in infants.Trial registration: ClinicalTrials.gov: NCT04031846; EudraCT: 2018-003787-31     

Postprandial hyperglycemia on vascular endothelial function: mechanisms and consequences

Vascular endothelial dysfunction precedes atherosclerosis and contributes to cardiovascular disease (CVD), which accounts for one-third of all deaths in the United States. Chronic hyperglycemia, such as that associated with diabetes, is well known to impair vascular function. However, recent evidence demonstrates that acute or postprandial hyperglycemia (PPH) not only exacerbates vascular endothelial dysfunction in individuals with chronic hyperglycemia but also transiently impairs vascular function in healthy individuals. Postprandial hyperglycemia has been shown to better predict future CVD mortality compared with fasting glucose in both diabetic and normoglycemic individuals. Compelling evidence exists suggesting that PPH-mediated insults to the vascular endothelium contribute to CVD, especially in pathophysiologic conditions whereby vascular recovery is compromised. Although the mechanisms by which PPH induces vascular dysfunction is not fully understood, oxidative stress–mediated disruptions in nitric oxide homeostasis are implicated as key events leading to vascular dysfunction associated with PPH. This review aims to highlight the findings of clinical studies using functional indices of vascular function to demonstrate that PPH impairs vascular function. We will also discuss the evidence showing the central involvement of oxidative stress in dysregulating nitric oxide homeostasis and contributing to PPH-mediated vascular endothelial dysfunction. Lastly, this review will identify areas of knowledge that remain limited and will provide recommendations for future investigation to more fully define PPH as an important risk factor for CVD.     

Safety,tolerability, and immunogenicity of V114 pneumococcal vaccine compared with PCV13 in a 2+1 regimen in healthy infants: A phase III study (PNEU-PED-EU-2)

BackgroundThis phase III study evaluated safety, tolerability, and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine) in healthy infants. V114 contains all 13 serotypes in PCV13 and additional serotypes 22F and 33F.MethodsHealthy infants were randomized to two primary doses and one toddler dose (2+1 regimen) of V114 or PCV13 at 3, 5, and 12 months of age; diphtheria, tetanus, pertussis (DTaP), inactivated poliovirus (IPV), Haemophilus influenzae type b (Hib), hepatitis B (HepB) vaccine was administered concomitantly. Adverse events (AEs) were collected on Days 1–14 following each vaccination. Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured 30 days post-primary series, immediately prior to toddler dose, and 30 days post-toddler dose. Primary objectives included non-inferiority of V114 to PCV13 for 13 shared serotypes and superiority of V114 to PCV13 for serotypes 22F and 33F.Results1191 healthy infants were randomized to V114 (n = 595) or PCV13 (n = 596). Proportions of participants with solicited AEs and serious AEs were comparable between groups. V114 met non-inferiority criteria for 13 shared serotypes, based on difference in proportions with serotype-specific IgG ≥0.35 μg/mL (lower bound of two-sided 95% confidence interval [CI] >−10.0) and IgG geometric mean concentration (GMC) ratios (lower bound of two-sided 95% CI >0.5) at 30 days post-toddler dose. V114 met superiority criteria for serotypes 22F and 33F, based on response rates (lower bound of two-sided 95% CI >10.0) and IgG GMC ratios (lower bound of two-sided 95% CI >2.0) at 30 days post-toddler dose.Antibody responses to DTaP-IPV-Hib-HepB met non-inferiority criteria, based on antigen-specific response rates.ConclusionA two-dose primary series plus toddler dose of V114 was well-tolerated in healthy infants. Compared with PCV13, V114 provided non-inferior immune responses to 13 shared serotypes and superior immune responses to additional serotypes 22F and 33F.     

Adjuvant Systems for vaccines: 13 years of post-licensure experience in diverse populations have progressed the way adjuvanted vaccine safety is investigated and understood

Adjuvant Systems (AS) are combinations of immune stimulants that enhance the immune response to vaccine antigens. The first vaccine containing an AS (AS04) was licensed in 2005. As of 2018, several vaccines containing AS04, AS03 or AS01 have been licensed or approved by regulatory authorities in some countries, and included in vaccination programs. These vaccines target diverse viral and parasitic diseases (hepatitis B, human papillomavirus, malaria, herpes zoster, and (pre)pandemic influenza), and were developed for widely different target populations (e.g. individuals with renal impairment, girls and young women, infants and children living in Africa, adults 50 years of age and older, and the general population). Clearly, the safety profile of one vaccine in one target population cannot be extrapolated to another vaccine or to another target population, even for vaccines containing the same adjuvant. Therefore, the assessment of adjuvant safety poses specific challenges. In this review we provide a historical perspective on how AS were developed from the angle of the challenges encountered on safety evaluation during clinical development and after licensure, and illustrate how these challenges have been met to date. Methods to evaluate safety of adjuvants have evolved based on the availability of new technologies allowing a better understanding of their mode of action, and new ways of collecting and assessing safety information. Since 2005, safety experience with AS has accumulated with their use in diverse vaccines and in markedly different populations, in national immunization programs, and in a pandemic setting. Thirteen years of experience using antigens combined with AS attest to their acceptable safety profile. Methods developed to assess the safety of vaccines containing AS have progressed the way we understand and investigate vaccine safety, and have helped set new standards that will guide and support new candidate vaccine development, particularly those using new adjuvants.Focus on the patientWhat is the context? Adjuvants are immunostimulants used to modulate and enhance the immune response induced by vaccination. Since the 1990s, adjuvantation has moved toward combining several immunostimulants in the form of Adjuvant System(s) (AS), rather than relying on a single immunostimulant. AS have enabled the development of new vaccines targeting diseases and/or populations with special challenges that were previously not feasible using classical vaccine technology.What is new? In the last 13 years, several AS-containing vaccines have been studied targeting different diseases and populations. Over this period, overall vaccine safety has been monitored and real-life safety profiles have been assessed following routine use in the general population in many countries. Moreover, new methods for safety assessment, such as a better determination of the mode of action, have been implemented in order to help understand the safety characteristics of AS-containing vaccines.What is the impact? New standards and safety experience accumulated over the last decade can guide and help support the safety assessment of new candidate vaccines during development.