Research News

COVAXIN vaccine shows remarkable immunogenicity and protective efficacy against SARS-CoV-2 (new coronavirus). It’s research name is BBV152 which an inactivated SARS-CoV-2 vaccine.

Two doses vaccination regimen of inactivated SARS-CoV-2 vaccine candidates was administered in 20 rhesus macaques (divided into four groups equally). One group was administered with placebo, while three groups were immunized with 3 different vaccine candidates at 0 and 14 days. All the macaques were exposed to viral challenge 14 days after the 2nd dose. The results showed protective efficacy, increasing SARS-CoV-2 specific IgG and neutralizing antibodies, reducing replication of the virus in the nasal cavity, throat, and lung tissues of monkey.

No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group. Adverse events were not seen in animals immunized with a two-dose vaccination regimen.

Genomic RNA (gRNA) was detected from nasal swab (NS) specimens of all animals in the placebo group from 1 to 7 DPI (Days Post-Infection). Viral clearance was observed in NS specimens of all the animals from the vaccinated group on 7 DPI. Subgenomic RNA (sgRNA) was detected in two of five animals at 3 DPI and one of five animals at 7 DPI of the placebo group.  sgRNA was detected in the NS sample of only one animal of the vaccinated group IV on 5 DPI.

Neutralizing antibodies and IgG responses were observed from 3rd-week post-immunization in vaccinated groups. IgG titer rose in an increasing pattern with the highest response in group III. The presence of gRNA in NS was observed in the placebo group until 7 DPI. Vaccinated groups had no detectable gRNA in NS on 7 DPI indicating the ability of vaccine candidates to limit upper respiratory tract viral replication, which is a key factor determining the virus transmission.

gRNA and sgRNA were not detected in the Bronchoalveolar lavage fluid from 5 DPI suggesting that vaccination hindered virus replication and enabled faster clearance from lower airway protecting the animals. gRNA was detected in multiple organs at necropsy in the placebo group, whereas it was found to be cleared in the vaccinated groups.

Altogether this study demonstrates that a two-dose vaccination regimen using 3µg dose of the vaccine candidate with adjuvant induce a significant immune response and provide effective protection in animals challenged with SARS-CoV-2.

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The world was already struggling with some highly infectious diseases like tuberculosis, influenza, when COVID-19 struck. It is a highly transmissible disease and spreads within fraction of a second. Infected patient’s respiratory secretions are highly contagious and there are very high chances of spread of disease through this.

In a development that could bring huge relief for healthcare professionals, Sree Chitra Institute of Medical Sciences in Thiruvananthapuram has developed canister bags, lined with super-absorbent material containing an effective disinfectant. The bag has been named AcryloSorb. The method is meant for safe handling and disposal of respiratory secretions of patients in Intensive Care Units as well as of those admitted in wards with copious respiratory secretions.

“Disposal of respiratory secretions of patients suffering from highly contagious diseases such as COVID-19, tuberculosis (TB) and influenza, poses a high risk of infection among healthcare workers. In the canister bags, secretions are sucked into bottles or canisters using vacuum line and discarded through the waste fluid disposal system after subjecting to decontamination process. There is a high risk of contamination during the handling that poses a high risk to health workers. The disposal needs well-equipped sluice rooms with disinfection facilities. The canister bags can absorb 500 ml of secretions and solidify them immediately. And the presence of the disinfectant makes the whole system decontaminated within no time,” says a press statement issued by the institute.

“ Disposal of respiratory secretions of patients suffering from highly contagious diseases such as COVID-19, tuberculosis (TB) and influenza, poses a high risk of infection among healthcare workers.

The product has been tested as per international standards and the linear structure has a patented design, the institute states. Field trials of the in-house designed suction canister liner bags are being conducted at the institute. It’s expected to bring the bag to the market at a cost of Rs 100 per bag.

Sree Chitra Institute claims the canister bag allows easy, spill-proof disposal of the biomedical waste. The press release reads, “Solidification and disinfection inside the bags eliminate the risk of secondary infections by avoiding spilling, and aerosol formation. Canister bags are enclosed in a customizable sealer bag which can pack it as spill-proof decontaminated biomedical waste disposable through incineration.”

The team that developed the technology include Dr Manju, S, Dr Manoj Komath, Dr Asha Kishore (who is also the Institute Director) and Dr Ajay Prasad Hrishi who are biomaterial scientists and clinicians - The institute has transferred the know-how of the bags to Romsons Scientific and Surgical Private Limited in Uttar Pradesh that produces medical devices.

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There was a tragic event that shook the world in the 1960’s, when a large number of babies were born with severe deformities whose mothers had been prescribed a drug called ‘thalidomide’ for morning-sickness. “The problem was a result of the consumption of two enantiomers without separation. One of the isomer was toxic, while the other was the drug”, says Prof. A. S. Achalkumar, Department of Chemistry, IIT Guwahati. Prof Achalkumar and Prof. Yasuhiro Ishida from RIKEN, Wako-shi campus, Japan, have developed a simple and novel method to separate chiral enantiomers.

Chiral enantiomers are chemicals that have the same molecular formula but different three-dimensional arrangement of the constituent molecular segments. The separation of enantiomers is significant in bio-medical field because many biochemically active chemicals are found as mixtures of two enantiomers, one of which may be beneficial and the other, toxic.

The chemical properties of enantiomers are similar, which makes it very difficult to separate them, or to synthesize specifically one without being contaminated from the other enantiomer. “Nature is master in the exclusive production of enantiomerically pure amino acids and sugars, but man is still trying to master the art of enantioselective synthesis”, observes Prof Achalkumar. The current method to separate enantiomers is by chromatography, which is slow, energy intensive, and requires environmentally harmful solvents.

“Nature is master in the exclusive production of enantiomerically pure amino acids and sugars, but man is still trying to master the art of enantioselective synthesis”

The researchers have separated enantiomers with the use of helical supramolecular polymers. The helical polymers are formed by the salt formation of aromatic carboxylic acid and chiral amino alcohols. In this simple one-pot process they could resolve racemic mixtures into materials rich in one isomer. The interaction sites in supramolecular polymer not only help in the connection of the monomers but also in the recognition of chiral guests. When two salts with the same chirality are mixed, they undergo copolymerization and became soluble, while those with opposite chirality do not form copolymer and hence precipitate. The precipitated compound can be separated easily. The present system can be used for the enantioseparation of the abundant class of chiral amino alcohols, which has huge commercial potential.”

Prof. Ishida adds that although many supramolecular polymers are known, their enantio-separation ability has never been investigated so far. “Development of such process may help in reducing the price of chiral active pharmaceutical ingredients (APIs) and finally that of the medical treatment, itself. In addition, such process can be extended to other classes of chiral molecules”, he says.

The group of researchers is led by Prof. A. S. Achalkumar, and Prof. Yasuhiro Ishida from RIKEN, Wako-shi campus, Japan. Their path-breaking work has recently been published in the prestigious journal, Nature Communications. The paper has been co-authored by Prof. Achalkumar, Prof. Ishida, Dr. Vakayil Praveen, Senior Scientist, CSIR-National Institute for Interdisciplinary Science and Technology, and research scholars Dr. Krishnachary Salikolimi, Ms. Kuniyo Yamada, and Dr. Noriko Horimoto. The research findings have been published in the journal, Nature Communications.

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Caption : A) Arsenic Trioxide (ATO) reduces the clonogenic capacity of medulloblastoma (MB) cell lines of the SHH subgroup (DAOY: TP53 c.725G>T; UW402: TP53 c.464C>A and ONS-76: TP53 wild type). B) Clonogenic assay images for UW402 MB cell line (from the left to the right: control, ATO at 0,5 and 1 μM) after 48hs of treatment. Credit : Paulo Henrique dos Santos Klinger

Researchers affiliated with the University of Sao Paulo’s Ribeirao Preto Medical School (FMRP-USP) in Brazil have demonstrated the potential of a leukemia drug, arsenic trioxide, to treat medulloblastoma, a type of brain cancer most common in children. When they tested arsenic trioxide on cells taken from one of the most aggressive subgroups of this type of tumor, they obtained promising results in terms of tumor cell death. The drug also made the tumor cells more sensitive to radiation therapy.

“Twelve medulloblastoma subgroups are currently recognized according to their molecular characteristics, which also indicate the prognosis. One of the subgroups with the worst prognosis is known as SHH. This tumor has a somatic mutation in gene TP53, and it’s treated with chemical and radiation therapy,” said Paulo Henrique dos Santos Klinger, first author of the article, written as part of his master’s research at FMRP-USP, and supported with a scholarship from the National Council for Scientific and Technological Development (CNPq).

The study was part of the project “Interactions between emerging therapeutic targets and developmental pathways associated with tumorigenesis: emphasis on pediatric malignancies”, which is led by Luiz Gonzaga Tone, a professor at FMRP-USP.

“The project focuses on an in-depth investigation of dysregulation of the signaling pathways that control normal embryonic development and its link to the onset and progression of pediatric cancer,” Tone said.

Radiotherapy can have severe adverse effects on a child’s brain, causing cognitive, endocrine and motor problems. Hence, the importance of developing therapeutic strategies that reduce or eliminate the need for radiation is important.

In the study, the researchers selected different SHH tumor cell lines and tested different doses of arsenic trioxide, a medication used to treat acute myeloid leukemia. They also tested different doses of radiation in conjunction with the administration of the drug.

On its own, arsenic trioxide proved capable of killing tumor cells and preventing the formation of new tumor cell colonies. The effects were enhanced when the drug was combined with radiation therapy. The drug was not found to be significantly toxic when applied to healthy cells.

Moreover, arsenic trioxide alone could be used to treat pediatric medulloblastoma patients as old as three years, possibly in conjunction with the chemotherapy drugs typically used to treat this type of cancer. Children in this age group with brain cancer cannot be treated with radiation therapy since it may cause irreversible damage to the central nervous system.

Mutation
The drug was chosen because it is a well-known blocker of the SHH signaling pathway in leukemia. The SHH pathway is essential to human embryonic development and is deactivated when embryogenesis is complete. If the pathway is reactivated for some reason, which are currently unknown, then cancer can develop, including some types of skin cancer and various types of leukemia and medulloblastoma.

“Another advantage of arsenic trioxide is its capacity to cross the blood-brain barrier, which protects the central nervous system from circulating toxins or pathogens. Previous studies showed this penetration to be reasonable in medulloblastoma,” said Elvis Terci Valera, last author of the published paper. Valera is an attending physician at the teaching hospital (Hospital das Clínicas) operated by FMRP-USP and a professor at the institution’s child health program.

The prognosis for SHH-type medulloblastomas is typically intermediate, with 50% of patients responding well to treatment. However, the prognosis is worse when a somatic mutation occurs in TP53 because this gene plays a key role in cell division control via the SHH pathway and can counteract alterations that can lead to cancer.

“The germline mutation of this gene points to Li-Fraumeni syndrome, characterized by several clinical factors but generally involving the loss of function of TP53 and increasing the likelihood of various types of tumors,” Klinger said.

Li-Fraumeni syndrome (LFS) confers an inherited familial predisposition to a range of cancers. In children, it entails an augmented risk of the occurrence of medulloblastomas, especially those of the SHH subgroup.

The researchers now plan to test the drug in animal models to determine whether the results are the same as those of the cell experiments. If they are the same, then the treatment may subsequently tested in humans.

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Indian institute of Technology (IIT) Madras researchers have shown that the active principle from turmeric that is curcumin can enhance cancer cell death caused by a protein called ‘TRAIL.’ They performed studies using isolated leukaemia cells from cancer patients and found that non-toxic concentrations of curcumin can significantly increase the efficiency of TRAIL-induced cell death.

There have been considerable efforts in developing therapeutic agents that trigger self-death of cells that malfunction. Apoptotic death or programmed death such destruction of cancer cells could prevent the spread of the disease. One such agent that can trigger self-destruction that has been found promising is a protein called ‘TNF-Related Apoptosis-Inducing Ligand’ (TRAIL). Its ability to selectively kill cancer cells by ‘apoptosis’ has resulted in a number of preclinical studies being carried out all over the world.

In cancer treatment, it is important to induce death of the cancer cells preferentially without extensive damage to healthy cells in the body. Apoptosis is generally preferred over the more aggressive and premature ‘necrosis’ for killing cancer cells because it releases fewer cellular components that trigger inflammation than the latter.

Elaborating on this research and its impact, Prof. Rama Shanker Verma, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, IIT Madras, said, “Despite strong anti-tumor activity of TRAIL in pre-clinical studies, clinical trials results have hitherto been unsatisfactory because cancer cells seem to acquire resistance against TRAIL upon long-term exposure. Thus, the next round of research has been to find chemicals that can reverse resistance and increase sensitivity of cancer cells to TRAIL.”

Several studies have focused on natural compounds that could significantly enhance TRAIL-mediated apoptosis at non-toxic concentrations. The IIT Madras team chose curcumin, the yellow part of the common turmeric that is used in daily cooking, as a sensitizer of TRAIL-resistant cancer cells to apoptosis.

Curcumin is already known to be a potent anti-cancer agent because of its ability to inhibit carcinogenesis and induce apoptosis in various cancer cells. Its function as a sensitizer to TRAIL has been shown in cases of prostate cancer, breast cancer, colon cancer and malignant glioma.

Curcumin is already known to be a potent anti-cancer agent because of its ability to inhibit carcinogenesis and induce apoptosis in various cancer cells.

The IIT Madras Research Team showed that treating leukaemia (blood/bone-marrow cancer) cells with curcumin sensitises the cells to TRAIL and results in more efficient cell death.

“Our findings clearly show that even small concentration of curcumin could potentially enhance the sensitiveness of leukemic cells to TRAIL,” said the researchers.

The IIT Madras Researchers are, however, cautious in extrapolating the results. While the reactions have been carried out in vitro, i.e., with isolated cells outside the human body, ‘in a test tube’, it is unclear if the same results can be obtained in vivo, i.e., inside the body. This doubt arises because curcumin is known to be poorly absorbed into the blood from the gut and its bioavailability for therapeutic purposes is generally poor. Bioavailability is basically the proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect.

But the researchers are hopeful that this difficulty will be circumvented soon. There are many studies ongoing around the world to increase the bioavailability of curcumin.

“Compounds such as quercetin found in onions, green tea etc., and piperazine, found in black and green pepper, have been shown by a few researchers to enhance absorption of curcumin by the body,” added Prof Verma.

There are no confirmatory evidences yet, but such research, combined with observations made by the IIT Madras team, can unleash newer effective and safe therapies for cancer.

This research was led by Prof. Rama Shanker Verma, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, IIT Madras. The paper was co-authored by Ms. Sridevi Surapally, Ms. Madhumathi Jayaprakasam and Prof. Verma. The results of this work were recently published in the journal Pharmacological Reports.

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The Centre for Cellular and Molecular Biology (CCMB) has established stable cultures of coronavirus (SARS-CoV-2) from patients’ samples. Virologists at CCMB have isolated infectious viruses from several isolates. The ability to culture the virus in lab enables CCMB to work towards vaccine development and testing of potential drugs to fight COVID-19.

Novel coronavirus enters human cell by binding with the ACE-2 receptor on the cell surface. Not all cells have ACE-2 receptors. Human epithelial cells in the respiratory tract copiously express ACE-2 receptors, causing respiratory disease in the infected patient. However, we cannot grow human epithelial cells in lab. “Currently, primary epithelial cells generated from human origins do not grow for many generations in labs, which is key to culturing viruses continuously. At the same time, the labs that are growing the virus need an ‘immortal’ cell line”, says Dr Krishnan H Harshan, Principal Scientist, CCMB. They use Vero cells (kidney epithelial cell lines from green African monkey), which express ACE-2 proteins and carry a cell division that allows them to proliferate indefinitely.

But why cultivate a dreadful germ? If we culture a large amount of the virus and inactivate them, then it can be used as inactivated virus vaccine. Once we inject the inactivated virus, the human immune system triggers the production of germ-specific antibodies. One can inactivate the virus by heat or chemical means. The inactivated virus can trigger antibody response, but does not infect and make us sick as they cannot reproduce.

“Currently, primary epithelial cells generated from human origins do not grow for many generations in labs, which is key to culturing viruses continuously. At the same time, the labs that are growing the virus need an ‘immortal’ cell line”

For the development of antibodies or antidots, virus cultures are important. Inactivated viruses can trigger antibody response in other mammalian hosts in addition to humans. Various such hosts are currently under test for their efficiency of antibody response. Such antibodies generated in these non-human hosts can be purified, processed and collected. The antibodies can be used as therapeutic intervention for patients suffering from the infection. Such antibodies can trigger antiviral response upon injection into humans and have the potential of limiting the infection. Administering antibodies does not provide immunity like a vaccine does, but can be considered as anti-dotes against the virus.

These cultures may also be helpful in the process of drug screening. Potential drugs can be tested against the virus in a test-tube for their efficacy.

“Using the Vero cell lines to grow the coronavirus, CCMB is now in a position to isolate and maintain viral strains from different regions. We are working towards producing viruses in huge quantities that can be inactivated, and used in vaccine development and antibody production for therapeutic purposes”, says CCMB Director, Dr Rakesh Mishra. CCMB has also started testing potential drugs with other partners such as the Defence Research Development Organisation (DRDO) using this viral culture.

“We hope that such systems are replicated at multiple research institutes and private companies to become a useful resource in the fight against this pandemic as well as for future preparedness”, said Dr Mishra.

- India Science Wire

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