Encouraging results from Phase 1 malaria vaccine trial

An experimental malaria vaccine protected a small number of healthy, malaria-naïve adults in the United States from infection for more than one year after immunization, according to results from a Phase 1 trial described in the May 9 issue of Nature Medicine. The vaccine, known as the PfSPZ Vaccine, was developed and produced by Sanaria Inc., of Rockville, Maryland, with support from several Small Business Innovation Research (SBIR) awards from the US National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health. NIAID researchers and collaborators at the University of Maryland School of Medicine in Baltimore, conducted the clinical evaluation of the vaccine, which involved immunization and exposing willing healthy adults to the malariacausing parasite Plasmodium falciparum (P. falciparum) in a controlled setting.

The parasites that cause malaria are transmitted to humans through the bite of an infected mosquito. The PfSPZ Vaccine is composed of live, but weakened P. falciparum sporozoites – the early developmental form of the parasite. Previous research showed the PfSPZ Vaccine to be highly protective three weeks after immunization. In this trial, researchers assessed if protection could last for five months to a year.

“Malaria remains one of the most devastating diseases in the world, especially among young children in Africa,” said NIAID director Anthony S. Fauci, M.D. “A malaria vaccine that provides long-term protection is urgently needed to reduce mortality and eliminate transmission. This study is an encouraging step forward in our goal to control and ultimately eradicate malaria.”

The Phase 1 trial took place at the NIH Clinical Center in Bethesda, Maryland, and at the University of Maryland Medical Center and enrolled 101 healthy adults aged 18 to 45 years who had never had malaria. Of these volunteers, 59 received the PfSPZ Vaccine; 32 participants served as controls and were not vaccinated. Vaccine recipients were divided into several groups to assess the roles of the route of administration, dose, and number of immunizations in conferring short- and long-term protection against malaria.

To determine if the number of immunizations influenced protection, vaccinated participants received either three (nine participants) or four (28 participants) intravenous (IV) immunizations of the Pf- SPZ Vaccine at a higher dose than tested in previous human studies. To compare the protective efficacy of different routes of administration, eight participants received four immunizations via intramuscular injection (IM) at a dose approximately 10-fold higher than the dose administered intravenously. This was done to help the research team assess if IV administration was necessary and more efficient based on the dose required.

To evaluate how well the PfSPZ Vaccine prevented malaria infection, all participants – including the control participants who were not vaccinated – were exposed at varying times to the bites of mosquitoes carrying the same P. falciparum strain from which the PfSPZ Vaccine was derived. The Walter Reed Army Institute of Research in Silver Spring, Maryland, carried out this controlled human malaria infection procedure – a standard process in early phase malaria vaccine trials.

To assess short-term protection, participants were exposed to the bites of parasiteinfected mosquitoes three weeks after receiving their final vaccination. Scientists then took blood samples from each participant to measure parasite levels for evidence of protection. For nine participants who received three IV doses, three were protected, or had no detectable parasites in their blood. For the nine participants who received four IV doses, seven were protected. Only three of the eight participants who received four IM doses were protected, indicating that IV administration afforded higher levels of protection at a lower dose.

To assess long-term protection, an additional group of 11 participants received four IV doses of the investigational vaccine and were exposed to the bites of malaria parasite-infected mosquitoes 21 weeks after their final vaccination. Scientists found that six of 11 participants (55%) had no detectable parasites in their blood after this exposure. Four of these six participants, plus one of the participants who received the same four doses via IV and had no parasites in the blood after exposures at three weeks and 21 weeks, were exposed to mosquito bites again at 59 weeks after their final vaccination. All five participants exposed at 59 weeks did not develop parasites in their blood, while all six unvaccinated control participants became infected with malaria parasites.

Collectively, the data showed that the PfSPZ Vaccine provided malaria protection for more than one year in 55% of people without prior malaria infection. In those individuals, the PfSPZ Vaccine appeared to confer sterile protection, meaning the individuals would be protected against disease and could not further transmit malaria. The vaccinations were also well-tolerated among participants, and there were no serious adverse events attributed to vaccination.

“It is now clear that administering the PfSPZ Vaccine intravenously confers long-term, sterile protection in a small number of participants, which has not been achieved with other current vaccine approaches,” said Robert A. Seder, M.D., chief of the Cellular Immunology Section of NIAID’s Vaccine Research Center and principal investigator of the trial. “Based on the favourable safety profile, we’re testing higher doses in larger trials to see ifeven greater protection can be achieved long-term against other P. falciparum strains different than the vaccine strain.”


High-risk treatment for MS shown to fully halt clinical relapses over long term

A new use of chemotherapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has fully halted clinical relapses and development of new brain lesions in 23 of 24 patients with multiple sclerosis (MS) for a prolonged period without the need for ongoing medication, according to a new phase 2 clinical trial, published in The Lancet. Eight of the 23 patients had a sustained improvement in their disability 7.5 years after treatment. This is the first treatment to produce this level of disease control or neurological recovery from MS, but treatmentrelated risks limit its widespread use.

MS is among the most common chronic inflammatory diseases of the central nervous system, with around 2 million people affected worldwide. It is caused when the immune system attacks the body, known as autoimmunity. Some specialist centres offer aHSCT for MS, which involves harvesting bone marrow stem cells from the patient, using chemotherapy to suppress the patient’s immune system, and reintroducing the stem cells into the blood stream to “reset” the immune system to stop it attacking the body. However, many patients relapse after these treatments, so more reliable and effective methods are needed.

Dr Harold L Atkins and Dr Mark S Freedman from The Ottawa Hospital and the University of Ottawa, Ottawa, Canada, and colleagues tested whether complete destruction, rather than suppression, of the immune system during aHSCT would reduce the relapse rate in patients and increase long-term disease remission. They enrolled 24 patients aged 18-50 from three Canadian hospitals who had all previously undergone standard immunosuppressive therapy which did not control the MS. All patients had poor prognosis and their disability ranged from moderate to requiring a walking aid to walk 100m, according to their Expanded Disability Status Scale (EDSS) scores [The Expanded Disability Status Scale is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time].

The researchers used a similar method of aHSCT as is currently used, but instead of only suppressing the immune system before transplantation, they destroyed it completely using a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin. Dr Atkins explains that this treatment is “similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system.”

The primary outcome of the study was multiple sclerosis activity-free survival at 3 years (as measured by relapses of MS symptoms, new brain lesions, and sustained progression of EDSS scores) which occurred in 69.6% of patients after transplantation.

Out of the 24 patients, one (4%) died from hepatic necrosis and sepsis caused by the chemotherapy. Prior to the treatment, patients experienced 1.2 relapses per year on average. After treatment, no relapses occurred during the follow up period (between 4 and 13 years) in the surviving 23 patients. These clinical outcomes were mirrored by freedom from detectable new disease activity on MRI images taken after the treatment. The initial 24 MRI scans revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion.

Furthermore, progressive brain deterioration typical of MS slowed to a rate associated with normal aging in 9 patients with the longest follow-up, and 8 (35%) of 23 patients had a sustained improvement in their EDSS score at 7.5 years after treatment. At 3 years, 6 patients (37%) were able to reduce or stop receiving disability insurance and return to work or school. Eight (33%) of the 24 patients had a moderate toxic effect and 14 (58%) patients had only a mild toxic effect related to transplantation.

Dr Freedman highlights the need to interpret the results withcaution: “The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results. Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with aHSCT, and this treatment should only be offered in specialist centres experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial. Future research will be directed at reducing the risks of this treatment as well as understanding which patients would best benefit from the treatment.”

Writing in a linked Comment, Dr Jan Dörr, from the NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany, says: “These results are impressive and seem to outbalance any other available treatment for multiple sclerosis. This trial is the first to show complete suppression of any inflammatory disease activity in every patient for a long period…However, aHSCT has a poor safety profile, especially with regards to treatment-related mortality.”

He adds: “So, will this study change our approach to treatment of multiple sclerosis? Probably not in the short term, mainly because the mortality rate will still be considered unacceptably high. Over the longer term (and) in view of the increasing popularity of using early aggressive treatment, there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonised and optimised, the tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified.”

  • doi: 10.1016/S0140-6736(16)30169-6

Bariatric surgery significantly improves lipid profile in obese patients

Fifty years after the first reported partialileal bypass, metabolic surgery has an established role in achieving weight loss and reducing cardiovascular death in obese patients. Scientists have now demonstrated that it can significantly benefit the lipid profiles of these patients a year and more after surgery, according to a new report published in The American Journal of Medicine.

Bariatric surgery has evolved into four dominant procedures ranging from largely malabsorptive to completely restrictive: Bilio-pancreatic Diversion (BPD), Rouxen- Y Gastric Bypass (RYGBP), Adjustable Gastric Banding, and Sleeve Gastrectomy. These are regarded as the most effective therapies for treating obesity.

Investigators undertook a meta-analysis of studies on contemporary bariatric surgery outcomes to describe the effects of these procedures on serum lipids of obese patients at one year and more after surgery.

“These procedures have shown significant benefits beyond weight reduction, including improvements in serum lipids. However, changes in serum lipids beyond the period of early, rapid weight loss are not well characterized,” explained lead investigator Sean Heffron, MD, of the Division of Cardiology at NYU Langone Medical Center.

Investigators identified 178 studies that fit the criteria for inclusion in this analysis. Each study needed to involve 20 or more obese adults undergoing RYGBP, Adjustable Gastric Banding, Sleeve Gastrectomy, or BPD, report lipid profile at baseline, and provide follow-up data for at least one year. More than 25,000 patients were included. At the time of surgery, patients were generally between 35 and 45 years old with body mass index (BMI) of between 40 and 50. The mean follow-up across all studies was 27.9 months.

In patients undergoing any form of bariatric surgery, compared to baseline, there were significant reductions in total cholesterol, low density lipoprotein cholesterol, and triglycerides, and a significant increase in high density lipoprotein cholesterol. The magnitude of this change was significantly greater than that observed in nonsurgical control patients.

When assessed separately, the magnitude of changes varied greatly by surgical type. Only RYGBP showed improvements in each lipid parameter relative to controls at both one year and last follow-up beyond one year. In the cases of Adjustable Gastric Banding and Sleeve Gastrectomy the response at one year following surgery was not significantly different from non-surgical control patients.

“Differences in triglyceride reduction among procedures were most evident at more than one year after surgery, when reductions in subjects undergoing RYGBP and BPD were nearly 50% greater than in Adjustable Gastric Banding and Sleeve Gastrectomy, despite similar baseline BMI in RYGBP and Adjustable Gastric Banding cohorts,” observed Dr Heffron. “Part of this difference may be secondary to greater weight loss and improvements in insulin sensitivity achieved following RYGBP and BPD versus restrictive procedures. However, the anatomic alterations of RYGBP and BPD may also play important roles. These differences may be relevant in deciding the most appropriate technique for a given patient.”

  • doi: 10.1016/j.amjmed.2016.02.004

Anti-epileptic drug may be linked to birth defects when taken with other drugs

In an analysis of pregnancies in Australia from 1999 to 2014 in which women were taking anti-epileptic drugs, foetal malformation rates fell over time in pregnancies where only one drug was taken, but rates increased in pregnancies where multiple drugs were taken.

The rise in such “polytherapy” malformation rates began around 2005 when levetiracetam and topiramate use began to increase.

Malformation rates were similar in polytherapy pregnancies whether or not levetiracetam was included (7.14% versus 8.38%), but were higher in polytherapy pregnancies involving topiramate (14.94% versus 6.55%).

The findings suggest that use of topiramate in conjunction with other anti-epileptic drugs may enhance its propensity to cause foetal malformations. The mechanisms involved are currently unclear.

“Although the results are based on small numbers of patients in pregnancy, we suggest that the use of topiramate, atleast in combination with other anti-epileptic medications, ought to be used with caution in women who plan to become pregnant,” said Dr Frank Vajda, lead author of the Epilepsia analysis.

  • doi: 10.1111/epi.13415

 


Study shows how changes in gut microbes cause obesity



Obesity is linked to changes in our gut microbes – the trillions of tiny organisms that inhabit our intestines. But the mechanism has not been clear. In a new study published in Nature (9 June 2016), a Yale-led team of researchers has identified how an altered gut microbiota causes obesity.

In an earlier study, Dr Gerald I. Shulman, the George R. Cowgill Professor of Medicine, observed that acetate, a shortchain fatty acid, stimulated the secretion of insulin in rodents. To learn more about acetate’s role, Shulman, who is also an investigator of the Howard Hughes Medical Institute, and a team of Yale researchers conducted a series of experiments in rodent models of obesity.

The research team compared acetate to other short-chain fatty acids and found higher levels of acetate in animals that consumed a high-fat diet. They also observed that infusions of acetate stimulated insulin secretion by beta cells in the pancreas, but it was unclear how.

Next, the researchers determined that when acetate was injected directly into the brain, it triggered increased insulin by activating the parasympathetic nervous system. “Acetate stimulates beta cells to secrete more insulin in response to glucose through a centrally mediated mechanism,” said Shulman. “It also stimulates secretion of the hormones gastrin and ghrelin, which lead to increased food intake.”

Finally, the research team sought to establish a causal relationship between the gut microbiota and increased insulin. After transferring faecal matter from one group of rodents to another, they observed similar changes in the gut microbiota, acetate levels, and insulin.

“Taken together these experiments demonstrate a causal link between alterations in the gut microbiota in response to changes in the diet and increased acetate production,” said Shulman. The increased acetate in turn leads to increased food intake, setting off a positive feedback loop that drives obesity and insulin resistance, he explained.

The study authors suggest that this positive feedback loop may have served an important role in evolution, by prompting animals to fatten up when they stumbled across calorically dense food in times of food scarcity.

“Alterations in the gut microbiota are associated with obesity and the metabolic syndrome in both humans and rodents,” Shulman noted. “In this study we provide a novel mechanism to explain this biological phenomenon in rodents, and we are now examining whether this mechanism translates to humans.”

  • doi: 10.1038/nature18309

Stem cells from umbilical cord blood may help treat eczema

A new study suggests that treatment with stem cells from umbilical cord blood might be an effective therapy for patients with moderateto- severe eczema, or atopic dermatitis.

For the clinical trial, 34 patients were randomly assigned to receive a low dose or high dose of the cells subcutaneously. Fifty-five percent of patients who received the high dose showed a 50% reduction in what’s known as the Eczema Area and Severity Index score at week 12. Immune-related markers of atopic dermatitis also decreased significantly.

“This study is a first-in-class study demonstrating that adults with moderate-to-severe atopic dermatitis responded to a treatment of stem cells derived from umbilical cord blood,” said Dr Tae-Yoon Kim, senior author of the Stem Cells study. “The single treatment of stem cells in patients resulted in the significant and persistent improvement in disease symptoms throughout the follow-up period of 12 weeks.”

The study was conducted at Seoul St. Mary’s Hospital in collaboration with Seoul National University.

  • doi: 10.1002/stem.2401

 

 

Date of upload: 15th May 2016

                                  
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