WASHINGTON: Scientists have discovered how the immune system makes a powerful antibody that blocks HIV infection of cells by targeting a key site, paving way for an effective vaccine for the deadly virus.
Researchers believe that if a vaccine could elicit potent antibodies to a specific conserved site in the V1V2 region of the virus, one of a handful of sites that remains constant on the fast-mutating virus, then the vaccine could protect people from HIV infection.
Analyses of the results of a clinical trial of the only experimental HIV vaccine to date to have modest success in people suggest that antibodies to sites within V1V2 were protective.
The new findings point the way towards a potentially more effective vaccine that would generate V1V2-directed HIV neutralising antibodies, researchers said.
The study led by the National Institute of Allergy and Infectious Diseases ( NIAID) scientists began by identifying an HIV-infected volunteer who naturally developed V1V2-directed HIV neutralising antibodies, named CAP256-VRC26, after several months of infection.
Using techniques similar to those employed in an earlier study of HIV-antibody co-evolution, the researchers analysed blood samples donated by the volunteer between 15 weeks and 4 years after becoming infected.
This enabled the scientists to determine the genetic make-up of the original form of the antibody; to identify and define the structures of a number of the intermediate forms taken as the antibody mutated towards its fullest breadth and potency.
It also allowed them to describe the interplay between virus and antibody that fostered the maturation of CAP256-VRC26 to its final, most powerful HIV-fighting form.
The study showed that after relatively few mutations, even the early intermediates of CAP256-VRC26 can neutralise a significant proportion of known HIV strains.
This improves the chances that a V1V2-directed HIV vaccine developed based on the new findings would be effective, according to scientists, who have begun work on a set of vaccine components designed to elicit V1V2 neutralising antibodies and guide their maturation.
Scientists have discovered a mechanism that helps HIV evade antibodies and stabilise key proteins, a finding that could pave way for more effective vaccine for the deadly virus.
National Institutes of Health (NIH) scientists found the mechanism involved in stabilising key HIV proteins and thereby concealing sites where some of the most powerful HIV neutralising antibodies bind.
Numerous spikes jut out of the surface of HIV, each containing a set of three identical, bulb-shaped proteins called gp120 that can be closed together or spread apart like the petals of a flower, researchers said.
Some of the most important sites targeted by HIV neutralising antibodies are hidden when the three gp120s, or the trimer, are closed, and the gp120 trimer remains closed until the virus binds to a cell, they said.
The researchers discovered that certain amino acids located on the gp120 protein undergo a process that stabilises the trimer in its closed position.
In this process, called sulfation, the amino acids acquire a sulfur atom surrounded by four oxygen atoms.
By either blocking or increasing sulfation of these amino acids, the researchers changed the sensitivity of the virus to different neutralising antibodies, indicating that the trimer was being either opened or closed.
The scientists suggest that if the synthesised gp120 widely used in HIV research were fully sulfated during manufacture, the resulting product would adopt a more true-to-life structure and more closely mirror the way the immune system sees unbound HIV.
This might help generate a more effective HIV vaccine, NIH researchers said.
They added that full sulfation of gp120 may enable scientists to crystallise the molecule more readily, which also could advance HIV vaccine design.
Research published in the journal Nature has shown that vaccinated monkeys can clear Simian Immunodeficiency Virus (SIV) infection from their bodies.
It was effective in nine of the 16 monkeys that were inoculated.
The US scientists say they now want to use a similar approach to test a vaccine for HIV in humans.
Prof Louis Picker, from the Vaccine and Gene Therapy Institute at Oregon Health and Science University, said: “It’s always tough to claim eradication – there could always be a cell which we didn’t analyse that has the virus in it. But for the most part, with very stringent criteria… there was no virus left in the body of these monkeys.”
Search and destroy
The research team looked at an aggressive form of virus called SIVmac239, which is up to 100 times more deadly than HIV.
Infected monkeys usually die within two years, but in some inoculated primates the virus did not take hold.
It used the infectious power of CMV to sweep throughout the body. But instead of causing disease, it has been modified to spur the immune system into action to fight off the SIV molecules.
“It maintains an armed force, that patrols all the tissues of the body, all the time, indefinitely,” explained Prof Picker.
The researchers gave rhesus macaque monkeys the vaccine, and then exposed them to SIV.
They found that at first the infection began to establish and spread. But then the monkeys’ bodies started to respond, searching out and destroying all signs of the virus.
Of the monkeys that successfully responded to the vaccine, they were still clear of infection between one-and-a-half and three years later.
Prof Picker said his team was still trying to work out why the vaccination worked in only about half of the monkeys.
“It could be the fact that SIV is so pathogenic that this is the best you are ever going to get.
“There is a battle going on, and half the time the vaccine wins and half the time it doesn’t,” he said.
The researchers are now testing the vaccine to see if it can be used after SIV exposure to treat and potentially cure infected monkeys.
They also want to see if the technique could work in humans.
Prof Picker said: “In order to make a human version we have to make sure it is absolutely safe.
“We have now engineered a CMV virus which generates the same immune response but has been attenuated [modified to lose its virulence] to the point where we think it is unequivocally safe.”
This would first have to pass through the regulatory authorities, but if it does, he said he hoped to start the first clinical trials in humans in the next two years.
Commenting on the research, Dr Andrew Freedman, from Cardiff University School of Medicine, said: “This suggests that prophylactic vaccines – vaccines designed to prevent infection – using CMV vectors may be a promising approach for HIV.
“While they may not prevent the initial infection, they might lead to subsequent clearance, rather than the establishment of chronic infection.”
A new malaria vaccine, which is being developed in the US, has shown promising results in early stage clinical trials, scientists say. Researchers found that high doses of the vaccine protected 12 out of 15 patients from the disease. The vaccine involves injecting live but weakened malaria-causing parasites directly into patients to trigger immunity.
“We were excited and thrilled by the result, but it is important that we repeat it, extend it and do it in larger numbers,” said lead author Dr Robert Seder, from the Vaccine Research Center at the National Institutes of Health, in Maryland. Previous research has found that exposure to mosquitoes treated with radiation can protect against malaria. But studies have shown that it takes more than 1,000 bites from the insects over time to build up a high level of immunity.
A US biotech company called Sanaria took lab-grown mosquitoes, irradiated them and then extracted the malaria-causing parasite (Plasmodium falciparum), all under the sterile conditions. These living but weakened parasites are then counted and placed in vials, where they can then be injected directly into a patient’s bloodstream. This vaccine candidate is called PfSPZ.
To carry out the Phase-1 clinical trial, the researchers looked at a group of 57 volunteers, none of whom had had malaria before. Of these, 40 received different doses of the vaccine, while 17 did not. They were then all exposed to the malaria-carrying mosquitoes, ‘BBC News’ reported. The researchers found that for the participants not given any vaccine, and those given low doses, almost all became infected with malaria.
However, for the small group given the highest dosage, only three of the 15 patients became infected after exposure to malaria. “Based on the history, we knew dose was important because you needed 1,000 mosquito bites to get protection – this validates that,” Seder said. “It allows us in future studies to increase the dose and alter the schedule of the vaccine to further optimise it. The next critical questions will be whether the vaccine is durable over a long period of time and can the vaccine protect against other strains of malaria,” he said. The results were published in the journal Science.
PUNE: The US patent office has granted patent to an innovative industry-academia research project that has led to a new vaccine adjuvant extracted from ‘ Ashwagandha’, also known as Indian Ginseng, a medicinal plant used in Ayurveda as an immunity enhancer. The grant of patent will further the cause of development of far more effective vaccines meant for improvement of human immune system to counter various ailments.
The Union government’s department of science and technology (DST) had sponsored the research project which was jointly executed by Pune-based Serum Institute of India (SII) and University of Pune’s Inter-disciplinary School of Health Sciences (ISHS).
Executive director of SII Suresh Jadhav is the lead author while ISHS head Bhushan Patwardhan and SII research manager Manish Gautam formed the team of inventors. Additional research team included Sunil Gairola and Yojana Shinde from the SII, Dada Patil and Sanjay Mishra from the university.
Jadhav told TOI on Friday, “We are already in the process of developing new vaccines and the US patent will enable us the use the newly developed adjuvant right from the development stage of these vaccines. The new vaccine adjuvant has been found to be far more effective compared to traditional adjuvant. It has shown greater success in applications related to ailments like meningitis; diphtheria; and tetanus, among others,” he added.
According to Patwardhan, “The application of this new adjuvant can be envisaged not only with vaccines against meningitis, polio, diphtheria, tetanus and hepatitis but also holds promise against HIV, tuberculosis and malaria.” Patwardhan has described the project as a unique industry-academia partnership success story with a very high potential of applications owing to the involvement of the industry.
He said, “Newer vaccines include synthetic, recombinant or highly purified subunit antigens that are weakly immunogenic. Therefore vaccine formulations often require adjuvants for better immunological efficiency. Immuno-modulators obtained from different sources like synthetic, bacterial, viral have been used for enhancement of immune response to vaccines. Plant based products are being considered as one option for immune adjuvants.”
He said, “The concept of rasayana in Ayurveda is based on modulation of immune response to provide better immunity and resistance to fight against diseases. Many extracts and formulations prepared from rasayana plants have shown immuno-modulatory activity in various models. Researchers in health sciences have been actively engaged in establishing immuno-modulatory activity of medicinal plants including ‘Ashwagandha’,’Shatavari’ and ‘Guduchi.’ Our studies indicate that these botanical materials have potential to be developed as immuno-adjuvants. As such, it was desirable to develop well characterized and highly pure adjuvant as compared to crude extracts which can be formulated with vaccines.”
The DST had provided a total financial outlay of Rs 90 lakh spread over three years for the research project, which had completed in 2007 and actual development work continued thereafter at the SII. Following Indian patents, the US Patent application was made in 2009.
The project was sponsored by the Union government’s department of science and technology
It was jointly executed Serum Institute of India and the University of Pune’s Inter-disciplinary School of Health Sciences
The US patent will enable researchers to use the adjuvant right from the development stage of the vaccine
The new vaccine adjuvant has been found to be far more effective compared to traditional adjuvant
Scientists say the adjuvant can applicable for vaccines against meningitis, polio, diphtheria, tetanus and hepatitis and also holds promise against HIV, tuberculosis and malaria
A nine-month-old boy from Navi Mumbai has been found to be infected by the vaccine derived polio virus (VDPV). This is the second such case in the state and the fourth in the country in 17 months.
The National Polio Surveillance Project (NPSP) has confirmed that the child has tested positive for the virus, the state directorate of health services says it will wait for the Union health ministry’s report on the case before deciding on whether the child’s condition is due to polio.
Dr Satish Pawar, joint director, directorate of health services, Maharashtra, said, “As on Monday, the diagnosis is that the child is suffering from the Guillian-Barre syndrome which is an autoimmune disorder that occurs when the body’s defence (immune) system mistakenly attacks part of the nervous system. This leads to nerve inflammation that causes muscle weakness and other symptoms.”
According to state health department officials, the child was self-medicated by the parents for a couple of days before his condition worsened and he was brought to BJ Wadia hospital, Parel, on July 11. The child is on a ventilator and his condition has been described as stable.
The authorities are keen to check whether any one else in the area may have also got the virus, and for this they will be collecting stool samples of persons from various age groups beginning on Tuesday. These will be tested at the National Institute of Virology, Pune.
NPSP officials advised that people should continue to immunise their children with the oral vaccine to deal with polio, regardless of the origin of the virus.