ScienceDaily (Mar. 16, 2010) - A booster shot appears to improve tuberculosis (TB) resistance in previously vaccinated adults, according to new research in South Africa.

The study has been published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

“The world urgently needs new, better vaccines against TB,” said Willem Hanekom M.B. Ch.B., associate professor and co-director, South African Tuberculosis Vaccine Initiative (SATVI). “It is important to test the safety of these vaccines in settings where TB is very common, such as South Africa.”

Every year 1.7 million people die from TB, according to the World Health Organization. This study is the first to report results from testing an adenovirus-35-based vaccine in humans. Adenovirus-35 is attractive to vaccine developers because fewer humans have been exposed to this strain of the virus, compared with many other adenoviruses, and the immunity from exposure is therefore less likely to interfere with the vaccine’s action.

The Aeras-402 vaccine, developed by Aeras Global Tuberculosis Foundation and Crucell, was made by weakening the virus in the lab, so that it can no longer replicate and cause disease. Parts of the TB bacterium that are important to stimulate the immune system (antigens) were then inserted into the virus.

“We showed that the vaccine was safe in healthy adults who have previously been vaccinated with the current TB vaccine, BCG,” said Dr. Hanekom. “Aeras-402 was able to stimulate the immune system in a manner thought to be important for protection against TB. This included activation of both CD4 and CD8 T cells. Potent activation of CD8 T cells by a new TB vaccine has not been demonstrated to date.”

Animal testing of AERAS-402 had showed promise, and the researchers had expected to see stimulation of CD4 cells, but were “pleasantly surprised” at how well CD8 T cells were also stimulated.

“We are completing a trial of Aeras-402 in babies, to make sure that the vaccine is safe and immunogenic in this population,” said Dr. Hanekom. “If all the studies go well, we will proceed with a Phase IIb study of Aeras-402 in up to 4,000 BCG-vaccinated babies, who will receive either the vaccine or a placebo in their first year of life. The results should indicate whether the vaccine may prevent TB disease. An effective booster vaccine would ultimately reduce the incidence of TB disease and, consequently, the spread of the TB pandemic.”

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Adapted from materials provided by American Thoracic Society, via EurekAlert!, a service of AAAS.

ScienceDaily (Feb. 16, 2010) - An international team of researchers has found that adding a humanized monoclonal antibody called daclizumab to standard treatment reduces the number of new or enlarged brain lesions in patients with relapsing multiple sclerosis. This new study was published online Feb. 16, 2010, and in the March edition of the Lancet Neurology.

Multiple sclerosis (MS) is a debilitating disease in which the body’s immune system attacks the fatty substance that surrounds and protects the nerve fibers in the brain and spinal cord. The resulting damage interferes with the transmission of nerve signals between the brain and spinal cord and other parts of the body, producing a variety of symptoms including problems with balance, coordination, vision, and even mental function. Approximately 85 percent of multiple sclerosis patients are initially diagnosed with relapsing MS, in which clearly-defined attacks of worsening neurologic function are followed by partial or complete recovery periods during which no disease progression occurs.

“Previous research has shown that treatment with daclizumab reduced multiple sclerosis disease activity,” says John W. Rose, M.D., professor of neurology at the University of Utah School of Medicine, Neurovirology Research Laboratory, Veterans Affairs Salt Lake City Health Care System and the University of Utah, an author on the study. “Our work in the CHOICE trial shows that daclizumab significantly reduces MS lesion formation in people with active relapsing disease.”

Monoclonal antibodies are immune system proteins that preferentially bind to specific target cells, triggering the immune system to attack those cells. Daclizumab is a monoclonal antibody specific for CD25, a protein that is expressed on activated T cells, and binding of daclizumab to CD25 results in selective inhibition of these activated T cells. Daclizumab treatment has been studied in patients with human autoimmune conditions, such as MS, that are characterized by abnormal T-cell responses.

Rose and his colleagues performed a randomized, double-blind, placebo-controlled study at 51 centers in the U.S., Canada, Germany, Italy, and Spain. They recruited 230 patients with relapsing MS who were taking interferon beta and randomly assigned them to receive add-on treatment with high-dose daclizumab, low-dose daclizumab, or placebo. The primary objective of the study was to assess whether daclizumab affected MS disease activity by measuring the total number of new or enlarged lesions in the brain during 24 weeks of treatment.

In addition to finding that add-on treatment with high-dose daclizumab resulted in a significantly lower number of new or enlarged MS lesions, the researchers found that patients treated with either high- or low-dose daclizumab had a seven to eight times higher number of immune cells called CD56bright natural killer cells (NK Cells). Previous research has shown that untreated MS patients have lower numbers of these NK cells than healthy individuals.

“Several lines of evidence point to a potential function for CD56bright natural killer cells in regulating the immune system,” explains Rose. “This study provides confirmatory data that daclizumab treatment causes an expansion of CD56bright natural killer cells and adds support to the theory that this expansion might mediate some of the effects of daclizumab on reducing multiple sclerosis lesion activity.” Further research is needed to clarify whether the risk-benefit of daclizumab is better when the drug is used alone or in combination with interferon beta, as well as to determine the optimum dose and length of treatment needed to see the full therapeutic effects of the drug.

“The CHOICE trial showed that treatment with daclizumab was associated with both a significant reduction in MS lesion formation and a robust increase in important cells that help to regulate the immune system,” concludes Rose. “Combined with previous research, these two findings strongly support further study of daclizumab as a clinical treatment for multiple sclerosis.”

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Adapted from materials provided by University of Utah Health Sciences.

ScienceDaily (Feb. 15, 2010) ? Oncogenic retroviruses are a particular family of viruses that can cause some types of cancer. Thierry Heidmann and his colleagues in the CNRS-Institut Gustave Roussy-Universit? Paris Sud 11 “R?trovirus endog?nes et ?l?ments r?tro?des des eucaryotes sup?rieurs” Laboratory have studied these viruses. They have identified a “virulence factor” that inhibits the host immune response and allows the virus to spread throughout the body. This factor is a sequence of amino acids that is located in the envelope protein of the virus.

These scientists have also shown that once mutated to lose its immunosuppressive capability, this envelope protein could serve as a basis for the development of vaccines.

These findings have been published online in the Proceedings of the National Academy of Sciences USA.

Retroviruses are viruses whose genome is made up of RNA. These viruses are unique in possessing an enzyme that enables synthesis from this RNA of a DNA molecule capable of integrating into the DNA of a host cell. The retrovirus then utilizes the cell machinery to replicate. HIV is one of the best-known retroviruses. Oncogenic retroviruses (or oncoretroviruses) are cancer-causing viruses. Numerous oncoretroviruses are associated with animal diseases. In humans, two retroviruses, called HTLV and XMRV, have been associated with a type of leukemia and with prostate cancer.

Researchers in the R?trovirus Endog?nes et El?ments R?tro?des des Eucaryotes Sup?rieurs Laboratory (1), headed by Thierry Heidmann, CNRS Senior Researcher at Institut Gustave Roussy, have been working on the ability of retroviruses to propagate and persist in their hosts by escaping the immune system. They have studied the molecular basis of this process, and have shown that it is driven by the envelope protein of these viruses. First of all, this protein has an essential “mechanical” role, as it induces the fusion of viral particles with the target cell membrane, thus allowing them to penetrate into the cell. Using a mouse model of infection with a murine leukemia virus, the researchers showed that this envelope protein also has a second role that is equally essential to viral propagation in the body: it is immunosuppressive, or in other words it inhibits the host immune response in a radical manner, affecting both the “innate” and “adaptive” immune responses.

The researchers succeeded in locating the domain responsible for this property within the amino acid sequence of the envelope protein. This domain, an authentic virulence factor, is a crucial element in the arsenal that enables retroviruses to invade their host and produce their pathogenic effect. It thus becomes a target of choice for the design of novel antiretroviral therapeutic strategies, including vaccines. The results obtained by these scientists mean it will be possible to follow this path.

hey were able to introduce targeted point mutations into the envelope protein that could suppress its ability to inhibit the immune system which, as expected, reacted much more effectively than with the non-mutated protein, producing a high level of antibodies and inducing antiviral cellular immunity. By working on this mutated protein, it should be possible to develop vaccines for the future. Indeed, after the mouse model, the researchers were able to show that the HTLV and XMRV retroviruses associated with human diseases were both endowed with an immunosuppressive domain in their envelope protein.

(1) CNRS/ Universit? Paris-Sud 11/Institut Gustave Roussy)

Adapted from materials provided by CNRS (D?l?gation Paris Michel-Ange).

1. Schlecht-Louf et al. Retroviral infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.0913122107

ScienceDaily (Feb. 11, 2010) ? Current research suggests that pandemic H1N1 influenza of swine origin has distinct means of transmission from the seasonal flu, yet does not result in the pathogenic severity of avian flu viruses.

Pandemic H1N1 influenza of swine origin is a novel influenza strain that causes a generally mild respiratory illness, but results in severe disease or death in vulnerable individuals. The World Health Organization reports that “as of 17 January 2010, worldwide more than 209 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including at least 14142 deaths.” High risk groups include the very young and old, people with compromised immune systems, and pregnant women.

Unlike seasonal flu, which only infects cells located in the nose and the throat, pandemic H1N1 can replicate efficiently in cells deeper in the lung, similar to the more pathogenic H5N1 ‘bird flu’. Researchers led by Drs. Michael C.W. Chan and Joseph S.Malik Peiris at Queen Mary Hospital, Hong Kong SAR, China compared the cell infection pattern and immune responses of pandemic H1N1 to seasonal flu as well as to highly pathogenic avian influenza strains. They found that in contrast to seasonal flu, pandemic H1N1 and highly pathogenic avian flu could infect the conjunctiva, a membrane that lines the eyelids and covers the white part of the eye, suggesting an additional route of transmission as well as differences in receptor binding profile. However, pandemic H1N1 did not differ from seasonal flu either in replication in nose, throat, and lung cells or in induction of an inflammatory immune response, which is dysregulated in high pathogenic avian flu infections. Taken together, these results are consistent with epidemiological data that suggest that while pandemic H1N1 has subtle differences in transmissibility and pathogenesis from seasonal flu, it does not induce as severe disease as bird flu viruses.

Chan et al conclude that “the pandemic [H1N1 virus] (but not the seasonal virus) infects conjunctival epithelium, suggest[ing] that the eye may be an important route for acquiring infection with [pandemic H1N1] as compared with seasonal influenza viruses. Furthermore, this observation implies important differences in receptor preference and tissue tropism between the pandemic H1N1 and seasonal influenza viruses, which may have relevance in pathogenesis. … [However,] the 2009 pandemic H1N1 influenza virus is comparable with seasonal influenza in inducing host innate responses and does not have the intrinsic properties of cytokine dysregulation possessed by [the highly pathogenic avian influenza] virus or the 1918 pandemic H1N1 influenza virus.” “While generally mild in the majority of cases, the pandemic H1N1 virus is not just another seasonal flu virus and has subtle peculiarities of its own.” Future studies using host-gene expression profiling of virus infected respiratory cells using microarrays are in progress to further investigate the pathogenesis of this virus.

This work was supported by a Research Fund for Control of Infectious Disease grant (Ref: LAB-15, RFCID commissioned study on human swine influenza virus and RFCID grant, reference no: 06060552, 08070842) from the Research Fund for Control of Infectious Disease, Health, Welfare, and Food Bureau, Hong Kong SAR Government, and the General Research Fund (HKU 7612/08M and 7610/09M to M.C.W.C., HKU 7530/06M to L.L.M.P and HKU 7735/07M to J.M.N), Research Grants Council, Hong Kong SAR Government; Small project funding (reference no: 200907176007 to R.W.Y.C), The University of Hong Kong; National Institutes of Health (NIAID contract HHSN266200700005C) and AoE Funding (AoE/M-12/06) from the Area of Excellence Scheme of the University Grants Committee, Hong Kong SAR Government. This work was also supported by the National Institutes of Health Grant AI59429 and by a grant from the Infectious Disease Science Center.

Adapted from materials provided by American Journal of Pathology, via EurekAlert!, a service of AAAS.

1. Chan et al. Tropism and Innate Host Responses of the 2009 Pandemic H1N1 Influenza Virus in ex Vivo and in Vitro Cultures of Human Conjunctiva and Respiratory Tract. American Journal Of Pathology, 2010; DOI: 10.2353/ajpath.2010.091087

ScienceDaily (Feb. 11, 2010) ? Medical College of Georgia researchers are conducting the first FDA-approved clinical trial to determine whether an infusion of stem cells from umbilical cord blood can improve the quality of life for children with cerebral palsy.

The study will include 40 children age 2-12 whose parents have stored cord blood at the Cord Blood Registry in Tucson, Ariz.

Umbilical cord blood is rich in stem cells, which can divide and morph into different types of cells throughout the body, said Dr. James Carroll, professor and chief of pediatric neurology in MCG School of Medicine and principal investigator on the study.

Cerebral palsy, caused by a brain injury or lack of oxygen in the brain before birth or during the first few years of life, can impair movement, learning, hearing, vision and cognitive skills. Two to 3 children in 1,000 are affected by it, according to the Centers for Disease Control.

Animal studies indicate that infused stem cells help injured brain cells recover and replace brain cells that have died, Dr. Carroll said.

“Autologous stem cell transplantation, in which the transplant recipient is also the donor, is the safest form of stem cell transplantation because it carries virtually no threat of immune system rejection,” he said.

While no controlled clinical trials have been conducted to date, previous studies have shown marked improvement in children with cerebral palsy about three months after an initial infusion of cord blood.

“Evidence up to this point has been purely anecdotal,” Dr. Carroll said. “While a variety of cord blood stem cell therapies have been used successfully for more than 20 years, this study is breaking new ground in advancing therapies for brain injury — a condition for which there is currently no cure.”

Children will begin the study with a neurological exam by MCG pediatric neurologists Elizabeth Sekul and Nicole Brockway. Then, half of the study participants will receive an infusion of their own cord blood while the other half receive a placebo. Three months later, the children will be evaluated without physicians knowing which group received the stem cell infusion. Afterward, children who didn’t get the cord blood initially will receive an infusion. Children will return three and six months later for evaluation.

Researchers will periodically assess the children’s motor skills and neurological development.

“For the purposes of this study, we’re not looking at stem cells as a possible cure; rather whether stem cells can help change the course of these types of brain injuries in children,” Dr. Carroll said.

Study participants must have been unable to sit independently by 12 months or unable to walk by 18 months and must be seizure-free or have seizures that are adequately controlled.

To ensure consistency in cord blood stem cell processing, storage and release for infusion, the Cord Blood Registry is the only family stem cell bank participating in the study.

The trial is also receiving support from the Associazione Figli Inabili Banca d’Italia, a private organization in Italy that provides financial assistance to parents who can’t pay for their children’s medical treatments.

Adapted from materials provided by Medical College of Georgia.