Trial confirms Ebola vaccine candidate safe, equally immunogenic in Africa

"This is the first study to show comparable safety and immune response of an experimental Ebola vaccine in an African population," says lead author Dr Julie Ledgerwood. "This is particularly encouraging because those at greatest risk of Ebola live primarily in Africa, and diminished vaccine protection in African populations has been seen for other diseases." Credit: © nito / Fotolia

Two experimental DNA vaccines to prevent Ebola virus and the closely related Marburg virus are safe, and generated a similar immune response in healthy Ugandan adults as reported in healthy US adults earlier this year. The findings, from the first trial of filovirus vaccines in Africa, are published in The Lancet.

"This is the first study to show comparable safety and immune response of an experimental Ebola vaccine in an African population," says lead author Dr Julie Ledgerwood from the National Institutes of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, USA. "This is particularly encouraging because those at greatest risk of Ebola live primarily in Africa, and diminished vaccine protection in African populations has been seen for other diseases."

Scientists from the NIAID developed the DNA vaccines that code for Ebola virus proteins from the Zaire and Sudan strains and the Marburg virus protein. The vaccines contain the construction plans for the proteins on the outer surface of the virus. Immune responses against these proteins have shown to be highly protective in non-human primate models.

In this phase 1 trial, the Makerere University Walter Reed Program enrolled 108 healthy adults aged between 18 and 50 from Kampala, Uganda between November, 2009 and April, 2010. Each volunteer was randomly assigned to receive an intramuscular injection of either the Ebola vaccine (30 volunteers), Marburg vaccine (30), both vaccines (30), or placebo (18) at the start of the study, and again 4 weeks and 8 weeks later.

The vaccines given separately and together were safe and stimulated an immune response in the form of neutralising antibodies and T-cells against the virus proteins. Four weeks after the third injection, just over half of the volunteers (57%; 17 of 30) had an antibody response to the Ebola Zaire protein as did 14 of 30 participants who received both the Ebola and Marburg vaccines. 

However, the antibodies were not long-lasting and returned to undetectable levels within 11 months of vaccination.

Both DNA vaccines were well tolerated in Ugandan adults with similar numbers of local and systemic reactions reported in all groups. Only one serious adverse event (neutropenia; low white blood cell count) was reported in a Marburg vaccine only recipient, but was not thought to be vaccine related.

According to Dr Ledgerwood, "These findings have already formed the basis of a more potent vaccine, delivered using a harmless chimpanzee cold virus, which is undergoing trials in the USA, UK, Mali, and Uganda in response to the ongoing Ebola virus outbreak."

Writing in a linked Comment, Dr Saranya Sridhar from the Jenner Institute at the University of Oxford in the UK says, "[This] study deserves to be the focal point around which the broader question of vaccine development, particularly for Africa, must be addressed. With the uncharitable benefit of hindsight in view of the evolving 2014 Ebola outbreak, we must ask ourselves whether a filovirus vaccine should have been in more advanced clinical development. The international response to the present Ebola outbreak is an exemplar of the speed and purpose with which clinical vaccine development can progress and has set the benchmark against which future vaccine development must be judged. This study is the first step on the aspirational road towards the deployment of filovirus vaccines in Africa and must serve to shake the metaphorical cobwebs that can stall our advance towards this destination."

Source: The Lancet

How llamas' unusual antibodies might help in the fight against HIV/AIDS

Llamas contribute to the fight against AIDS. Credit: Nika Stropakke, CC-BY

Most vaccines work by inducing an immune response characterized by neutralizing antibodies against the respective pathogen. An effective HIV vaccine has remained elusive so far, but researchers have continued to make progress, often employing innovative methods. A study published on December 18th in PLOS Pathogens reports that a combination of antibodies from llamas can neutralize (destroy) a wide range of circulating HIV viruses.

After initial disappointment that HIV vaccine candidates were unable to elicit neutralizing antibodies, researchers found that some HIV-infected individuals did produce such antibodies. The current challenge is therefore to find safe and effective vaccine formulations (as opposed to HIV infection) that trigger the development of neutralizing antibodies that can recognize and prevent infection with all or most circulating HIV subtypes.

Many known neutralizing antibodies are directed against a specific part of the virus that binds to the CD4 receptor on the human target cells, and structural biology studies indicated that the site is a narrow groove. Antibodies in most mammals are relatively large proteins made up of two copies of two different individual parts (or chains), and bulkiness might be one reason why neutralizing antibodies are rare. Llamas are a notable exception: besides the common four-chain antibodies they also produce smaller ones made up of only two of the four chains. Robin Weiss, an HIV expert, and Theo Verrips, a llama antibody expert, therefore started working with this unconventional research animal.

Laura McCoy (working with Weiss at University College London, UK) led an international group of researchers to test immunization protocols and the resulting immune response in llamas. Having previously identified one particular HIV neutralizing llama antibody, for this study the researchers immunized two additional llamas and identified a total of three new neutralizing antibodies. The four HIV neutralizing llama antibodies target different parts of the CD4-binding site of the virus, and the researchers could show that when used in combination, rather than interfering with each other, they are more potent and can neutralize all of the 60 different HIV strains tested.

To understand how the llama immunization--which included two sets of four sequential vaccine injections per animal--worked, the researchers sequenced many copies of antibody-coding genes from blood cells collected after the first set of immunizations and after a further four rounds of vaccination. They also looked at the "naïve" antibody repertoire from seven llamas that had not been vaccinated. The results suggest that the neutralizing antibodies were not part of the pre-immunization repertoire, nor were they detectable after the first vaccination round. Rather, they were generated as immune cells repeatedly encountered the vaccine and responded by maturing specific antibodies that can recognize it.

While it is encouraging that broadly neutralizing antibodies were found in all of the immunized llamas, they are present only at low concentrations in the blood, and so fail to meet the goal for a protective HIV vaccine. Nonetheless, the researchers conclude that the llama model has allowed them to examine the generation of four broadly neutralizing antibodies induced by vaccination, which has not been possible in any other species.

Source: PLOS.

Teeth, sex and testosterone reveal secrets of aging in wild mouse lemurs

A brown mouse lemur in the wild. Mouse lemurs, weighing a mere 30 to 80 grams, are the world's smallest primates. Credit: Jukka Jernvall

Mouse lemurs can live at least eight years in the wild -- twice as long as some previous estimates, a long-term longitudinal study finds.

PLOS ONE published the research on brown mouse lemurs (Microcebus rufus) led in Madagascar by biologist Sarah Zohdy, a post-doctoral fellow in Emory's Department of Environmental Sciences and the Rollins School of Public Health. Zohdy conducted the research while she was a doctoral student at the University of Helsinki.

"It's surprising that these tiny, mouse-sized primates, living in a jungle full of predators that probably consider them a bite-sized snack, can live so long," Zohdy says. "And we found individuals up to eight years of age in the wild with no physical symptoms of senescence like some captive mouse lemurs start getting by the age of four."

It is likely that starvation, predation, disease and other environmental stressors reduce the observed rate of senescence in the wild, Zohdy notes, but a growing body of evidence also suggests that captive conditions may affect mental and physical function.

"We focused on wild mouse lemurs because we want to know what happens naturally when a primitive primate is exposed to all of the extrinsic and intrinsic mortality factors that shaped them as a species," Zohdy says. "Comparing longevity data of captive and wild mouse lemurs may help us understand how the physiological and behavioral demands of different environments affect the aging process in other primates, including humans."

The study determined ages of wild mouse lemurs in Madagascar's Ranomafana National Park through a dental mold method that had not previously been used with small mammals. In addition to the high-resolution tooth-wear analysis for aging, fecal samples underwent hormone analysis.

The researchers found no difference between the longevity of male and female mouse lemurs, unlike most vertebrates where males tend to die first.

"And even more interestingly, we found no difference in testosterone levels between males and females," Zohdy says. Mouse lemurs are female dominant, which may explain why their testosterone levels are on a par with males.

"While elevated male testosterone levels have been implicated in shorter lifespans in several species, this is one of the first studies to show equivalent testosterone levels accompanying equivalent lifespans," Zohdy says.

A co-author of the study is primatologist Patricia Wright of the Centre ValBio Research Station in Madagascar and Stony Brook University. Other institutions involved in the study include Colorado State University, Duke University and the University of Arizona, Tucson.
Mouse lemurs, found only on the island of Madagascar, are the world's smallest primates. They are among nearly 100 species of lemurs that arrived in Madagascar some 65 million years ago, perhaps floating over from mainland Africa on mats of vegetation.

Mouse lemurs weigh a mere 30 to 80 grams but in captivity they live six times longer than mammals of similar body size, such as mice or shrews. Captive gray mouse lemurs (Microcebus murinus) can live beyond age 12. By age four, however, they can start exhibiting behavioral and neurologic degeneration. In addition to slowing of motor skills and activity levels, reduced memory capacity and sense of smell, the captive four-year-olds can start developing gray hair and cataracts, Zohdy says.

The wild brown mouse lemurs in the study were trapped, marked and released during the years 2003 to 2010. A total of 420 dental impressions were taken from the lower-right mandibular tooth rows of 189 unique individuals. Over the course of seven years, 270 age estimates were calculated. For 23 individuals captured three or more times during the duration of the study, the regression slopes of wear rates were calculated and the mean slope was used to calculate ages for all individuals.

"We found that wild brown mouse lemurs can live at least eight years," Zohdy says. "In the population that we studied, 16 percent lived beyond four years of age. And we found no physical signs of senescence, such as graying hair or cataracts, in any wild individual."

Limitations of the study include the inability to document gradual physiological symptoms of senescence in the wild. "Our results do not provide information about wild brown mouse lemurs that can be directly compared to senescence in captive gray mouse lemurs," Zohdy says. "Further research, using identical measures of senescence, will help to reveal whether patterns of physiological senescence occur consistently across the genus and in both captive and wild conditions."

Another confounding factor Zohdy cites is "the Sleeping Beauty effect," the fact that wild mouse lemurs hibernate for half the year, possibly boosting their life span.
"We now know that mouse lemurs can live a relatively long time in the wild," she says, "but we don't know the exact mechanisms behind why they live so long."

Source: Emory Health Sciences