Tag Archives: antibody

The fascinating science behind the first human HIV mRNA vaccine trial – what exactly does it entail?

In a moment described as a “potential first step forward” in protecting people against one of the world’s most devastating pandemics, Moderna, International AIDS Vaccine Initiative (IAVI), and the Bill and Melinda Gates Foundation have joined forces to begin a landmark trial — the first human trials of an HIV vaccine based on messenger ribonucleic acid (mRNA) technology. The collaboration between these organizations, a mixture of non-profits and a company, will bring plenty of experience and technology to the table, which is absolutely necessary when taking on this type of mammoth challenge.

The goal is more than worth it: helping the estimated 37.7 million people currently living with HIV (including 1.7 million children) and protecting those who will be exposed to the virus in the future. Sadly, around 16% of the infected population (6.1 million people) are unaware they are carriers.

Despite progress, HIV remains lethal. Disturbingly, in 2020, 680,000 people died of AIDS-related illnesses, despite inroads made in therapies to dampen the disease’s effects on the immune system. One of these, antiretroviral therapy (ART), has proven to be highly effective in preventing HIV transmission, clinical progression, and death. Still, even with the success of this lifelong therapy, the number of HIV-infected individuals continues to grow.

There is no cure for this disease. Therefore, the development of vaccines to either treat HIV or prevent the acquisition of the disease would be crucial in turning the tables on the virus.

However, it’s not so easy to make an HIV vaccine because the virus mutates very quickly, creating multiple variants within the body, which produce too many targets for one therapy to treat. Plus, this highly conserved retrovirus becomes part of the human genome a mere 72 hours after transmission, meaning that high levels of neutralizing antibodies must be present at the time of transmission to prevent infection.

Because the virus is so tricky, researchers generally consider that a therapeutic vaccine (administered after infection) is unfeasible. Instead, researchers are concentrating on a preventative or ‘prophylactic’ mRNA vaccine similar to those used by Pfizer/BioNTech and Moderna to fight COVID-19.

What is the science behind the vaccine?

The groundwork research was made possible by the discovery of broadly neutralizing HIV-1 antibodies (bnAbs) in 1990. They are the most potent human antibodies ever identified and are extremely rare, only developing in some patients with chronic HIV after years of infection.

Significantly, bnAbs can neutralize the particular viral strain infecting that patient and other variants of HIV–hence, the term ‘broad’ in broadly neutralizing antibodies. They achieve this by using unusual extensions not seen in other immune cells to penetrate the HIV envelope glycoprotein (Env). The Env is the virus’s outer shell, formed from the cell membrane of the host cell it has invaded, making it extremely difficult to destroy; still, bnAbs can target vulnerable sites on this shell to neutralize and eliminate infected cells.

Unfortunately, the antibodies do little to help chronic patients because there’s already too much virus in their systems; however, researchers theorize if an HIV-free person could produce bnABS, it might help protect them from infection.

Last year, the same organizations tested a vaccine based on this idea in extensive animal tests and a small human trial that didn’t employ mRNA technology. It showed that specific immunogens—substances that can provoke an immune response—triggered the desired antibodies in dozens of people participating in the research. “This study demonstrates proof of principle for a new vaccine concept for HIV,” said Professor William Schief, Department of Immunology and Microbiology at Scripps Research, who worked on the previous trial.

BnABS are the desired endgame with the potential HIV mRNA vaccine and the fundamental basis of its action. “The induction of bnAbs is widely considered to be a goal of HIV vaccination, and this is the first step in that process,” Moderna and the IAVI (International AIDS Vaccine Initiative) said in a statement.

So how exactly does the mRNA vaccine work?

The experimental HIV vaccine delivers coded mRNA instructions for two HIV proteins into the host’s cells: the immunogens are Env and Gag, which make up roughly 50% of the total virus particle. As a result, this triggers an immune response allowing the body to create the necessary defenses—antibodies and numerous white blood cells such as B cells and T cells—which then protect against the actual infection.

Later, the participants will also receive a booster immunogen containing Gag and Env mRNA from two other HIV strains to broaden the immune response, hopefully inducing bnABS.

Karie Youngdahl, a spokesperson for IAVI, clarified that the main aim of the vaccines is to stimulate “B cells that have the potential to produce bnAbs.” These then target the virus’s envelope—its outermost layer that protects its genetic material—to keep it from entering cells and infecting them.  

Pulling back, the team is adamant that the trial is still in the very early stages, with the volunteers possibly needing an unknown number of boosters.

“Further immunogens will be needed to guide the immune system on this path, but this prime-boost combination could be the first key element of an eventual HIV immunization regimen,” said Professor David Diemert, clinical director at George Washington University and a lead investigator in the trials.

What will happen in the Moderna HIV vaccine trial?

The Phase 1 trial consists of 56 healthy adults who are HIV negative to evaluate the safety and efficacy of vaccine candidates mRNA-1644 and mRNA-1644v2-Core. Moderna will explore how to deliver their proprietary EOD-GT8 60mer immunogen with mRNA technology and investigate how to use it to direct B cells to make proteins that elicit bnABS with the expert aid of non-profit organizations. But readers should note that only one in every 300,000 B cells in the human body produces them to give an idea of the fragility of the probability involved here.

Sensibly, the trial isn’t ‘blind,’ which means everyone who receives the vaccine will know what they’re getting at this early stage. That’s because the scientists aren’t trying to work out how well the vaccine works in this first phase lasting approximately ten months – they want to make sure it’s safe and capable of mounting the desired immune response.

And even though there is much hype around this trial, experts caution that “Moderna are testing a complicated concept which starts the immune response against HIV,” says Robin Shattock, an immunologist at Imperial College London, to the Independent. “It gets you to first base, but it’s not a home run. Essentially, we recognize that you need a series of vaccines to induce a response that gives you the breadth needed to neutralize HIV. The mRNA technology may be key to solving the HIV vaccine issue, but it’s going to be a multi-year process.”

And after this long period, if the vaccine is found to be safe and shows signs of producing an immune response, it will progress to more extensive real-world studies and a possible solution to a virus that is still decimating whole communities.

Still, this hybrid collaboration offers future hope regarding the prioritization of humans over financial gain in clinical trials – the proof is that most HIV patients are citizens of the third world.

As IAVI president Mark Feinberg wrote in June at the 40th anniversary of the HIV epidemic: “The only real hope we have of ending the HIV/AIDS pandemic is through the deployment of an effective HIV vaccine, one that is achieved through the work of partners, advocates, and community members joining hands to do together what no one individual or group can do on its own.”

Whatever the outcome, money is no longer a prerogative here, and with luck, we may see more trials based on this premise very soon.

Masks made of ostrich cells make COVID-19 glow in the dark

In the two years that SARS‑CoV‑2 has ravaged across the globe, it has caused immeasurable human loss. But we as a species have been able to create monumental solutions amidst great adversity. The latest achievement involves a standard face mask that can detect COVID-19 in your breath, essentially making the pathogen visible.

A COVID-19 sample becomes apparent on a mask filter under ultraviolet light. Image credits: Kyoto Prefectural University.

Japanese researchers at Kyoto Prefectural University have created a mask that glows in the dark if COVID-19 is detected in a person’s breath or spit. They did this by coating masks with a mixture containing ostrich antibodies that react when they contact the SARS‑CoV‑2 virus. The filters are then removed from the masks and sprayed with a chemical that makes COVID-19 (if present) viewable using a smartphone or a dark light. The experts hope that their discovery could provide a low-cost home test to detect the virus.

Yasuhiro Tsukamoto, veterinary professor and president of Kyoto Prefectural University, explains the benefits of such a technology: “It’s a much faster and direct form of initial testing than getting a PCR test.”

Tsukamoto notes that it could help those infected with the virus but who show no symptoms and are unlikely to get tested — and with a patent application and plans to commercialize inspection kits and sell them in Japan and overseas within the next year, the test appears to have a bright future. However, this all hinges on large-scale testing of the mask filters and government approval for mass production. 

Remarkably, this all came with a little help from ostriches.

The ostrich immune system is one of the most potent on Earth

To make each mask, the scientists injected inactive SARS‑CoV‑2 into female ostriches, in effect vaccinating them. Scientists then extracted antibodies from the eggs the ostriches produced, as the yolk transfers immunity to the offspring – the same way a vaccinated mother conveys disease resistance to her infant through the placenta. 

An ostrich egg yolk is perfect for this job as it is nearly 24 times bigger than a chicken’s, allowing a more significant number of antibodies to form. Additionally, immune cells are also produced far more quickly in these birds—taking a mere six weeks, as opposed to chickens, where it takes twelve.

Because ostriches have an extremely efficient immune system, thought to be the strongest of any animal on the planet, they can rapidly produce antibodies to fight an enormous range of bacteria and viruses, with a 2012 study in the Brazilian Journal of Microbiology showing they could stop Staphylococcus aureus and E. coli in their tracks – experts also predict that this bird will be instrumental in fending off epidemics in the future.

Tsukamoto himself has published numerous studies using ostrich immune cells harvested from eggs to help treat a host of health conditions, from swine flu to hair loss.

Your smartphone can image COVID-19 with this simple test

The researchers started by creating a mask filter coated with a solution of the antibodies extracted from ostriches’ eggs that react with the COVID-19 spike protein. After they had a working material, a small consort of 32 volunteers wore the masks for eight hours before the team removed the filters and sprayed them with a chemical that caused COVID-19 to glow in the dark. Scientists repeated this for ten days. Masks worn by participants infected with the virus glowed around the nose and mouth when scientists shone a dark light on them.

In a promising turn, the researchers found they could also use a smartphone LED light to detect the virus, which would considerably widen the scope of testing across the globe due to its ease of use. Essentially, it means that the material could be used to the fullest in a day-to-day setting without any additional equipment.

“We also succeeded in visualizing the virus antigen on the ostrich antibody-carrying filter when using the LED ultraviolet black light and the LED light of the smartphone as the light source. This makes it easy to use on the mask even at home.”

To further illustrate the practicability of the test, Tsukamoto told the Kyodo news agency he discovered he was infected with the virus after he wore one of the diagnostic masks. The diagnosis was also confirmed using a laboratory test, after which authorities quarantined him at a hotel.

Next, the team aims to expand the trial to 150 participants and develop the masks to glow automatically without special lighting. Dr. Tsukamoto concludes: “We can mass-produce antibodies from ostriches at a low cost. In the future, I want to make this into an easy testing kit that anyone can use.”

Inflammatory bowel disease treatment linked to reduced COVID-19 antibody response

New evidence shows that the commonly-prescribed inflammatory bowel disease (IBD) drug infliximab weakens the immune system to COVID-19 infection, potentially increasing the risk of reinfection.

The findings arose from the CLARITY (ImpaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY) study, which recruited 6,935 patients with Crohn’s disease and ulcerative colitis from 92 UK hospitals between September and December 2020. Researchers plan to follow them up to 40 weeks thereafter.

Two thirds of the cohort (67.6%) took infliximab, while the remainder took vedolizumab. Patients’ median age was 39 years.

The study found that people with COVID-19 infections who also used the inflammatory bowel disease (IBD) drug infliximab had significantly fewer detectable antibodies than those who used vedolizumab, which treats IBD without the immune suppression, according to a study published in the journal Gut.

Lower antibody presence was seen in those who took infliximab, raising the researchers’ concerns about reinfection risk. Researchers note that 3.4% of the infliximab-treated group had SARS-CoV-2 seroprevalence, compared to 6.0% of the vedolizumab-treated group did. Those who were on additional immunomodulators such as thiopurines and methotrexate also had a reduced likelihood of being seropositive.

Of people with confirmed COVID-19 infections, only 48.0% of the 81 treated with infliximab demonstrated seroconversion, compared with 83.3% of the 36 on vedolizumab.

An impaired immune response may boost susceptibility to recurrent COVID-19 and may drive the evolution of new variants of SARS-CoV-2, warn the researchers. However, they are encouraging people to continue to take their medication as the overall COVID-19 risk remains low. Careful monitoring of patients with IBD treated with infliximab, who have been vaccinated against COVD-19, will be needed to ensure they mount a strong enough antibody response to ward off the infection, they advise.

CLARITY study lead, Professor Tariq Ahmad, of the University of Exeter Medical School, said:

“The poor antibody responses observed in patients treated with infliximab raise the possibility that some patients may not develop protective immunity after COVID-19 infection, and might be at increased risk of reinfection. What we don’t yet know is how the use of anti-TNF drugs will impact antibody responses to vaccination.”

DOI:https://doi.org/10.1053/j.gastro.2011.01.055

The burden of inflammatory bowel disease is rising globally. The incidence of IBD is approximately 0.5-24.5 cases per 100,000 person-years for ulcerative colitis and 0.1-16 cases per 100,000 person-years for Crohn disease. Overall, the prevalence for IBD is 396 cases per 100,000 persons annually.

Around two million people worldwide are prescribed anti-tumour necrosis factor (anti-TNF) drugs, which include infliximab. Anti-TNF drugs are effective treatments for immune-mediated inflammatory diseases, but by suppressing the immune system, they can reduce vaccine effectiveness and increase the risk of serious infection.

FDA approves first Ebola treatment

Illustration of the Ebola virus.

Over 2 years since the Kivu Ebola epidemic began in August 2018, the US Food and Drug Administration (FDA) approved the first antibody cocktail for the treatment for Zaire ebolavirus (Ebola virus) infection in adult and pediatric patients.

The drug, called Inmazeb, was developed by Regeneron — a biotech company also testing an antibody treatment for COVID-19. In clinical trials, patients who took Inmazeb were far less likely to die from Ebola virus disease.

In the clinical trial conducted during the outbreak in the North Kivu region, those treated with Inzameb experienced 33.5% mortality after 28 days. The World Health Organization (WHO) reports the virus’ mortality rate can be as high as 90%, depending on the outbreak.

The PALM trial, Pamoja Tulinde Maisha (meaning “together save lives”), is a randomized, controlled trial of four investigational agents (ZMapp, remdesivir, mAb114, and REGN-EB3, now called Inmazeb) for the treatment of patients with Ebola virus disease.

To help control the Ebola virus outbreak, Inmazeb is being administered for free in the DRC with the support of the Biomedical Advanced Research and Development Authority (BARDA), and Regeneron has stated that it is working with non-governmental organizations and public health agencies to make sure the treatment is accessible to low- and middle-income countries.

This trial and other studies done during Ebola outbreaks over the past decade showed that it was possible and operationally feasible to conduct scientific research during an epidemic. Researchers are now applying those lessons during the COVID-19 pandemic. One of the US-based trials for the antiviral remdesivir, which the FDA authorized for emergency use, was modeled after the PALM trial.

“Today’s approval highlights the importance of international collaboration in the fight against Ebola virus,” said John Farley, MD, MPH, director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, in a press release.

National Geographic | Should be updated to say Ebola is now treatable & vaccine-preventable

Zaire ebolavirus, commonly known as Ebola virus, is one of four Ebolavirus species that can cause a potentially fatal human disease. Ebola virus is transmitted through direct contact with blood, body fluids and tissues of infected people or wild animals, as well as with surfaces and materials, such as bedding and clothing, contaminated with these fluids. Individuals who provide care for people with Ebola virus, including health care workers who do not use correct infection control precautions, are at the highest risk for infection. Ervebo, the first vaccine for the prevention of Ebola was approved by the European Medicines Agency in October 2019 and the US FDA in December 2019.

Human SARS antibody could pave the way towards a COVID-19 cure

An antibody isolated from a SARS (Severe Acute Respiratory Syndrome) survivor after the 2003 epidemic could pave the way towards a treatment for COVID-19.

Stock image.
Image credits Michal Jarmoluk.

The antibody, named S309, is currently “on a fast-track development and testing path” with California-based Vir Biotechnology. according to a press release. Preliminary findings, published in a study in the journal Nature, suggest that the antibody should be effective against several members of the coronavirus family, including the strain responsible for the current pandemic.

New virus, old tricks

“Right now there are no approved tools or licensed therapeutics proven to fight against the coronavirus that causes COVID-19,” says David Veesler, assistant professor of biochemistry at the University of Washington School of Medicine and lead author of the study. He adds that “we still need to show that this antibody is protective in living systems, which has not yet been done.”

The antibody works against the SARS virus by chemically binding to its spike proteins (the structures that look like ‘spikes’ on the virus’ surface). These are crucial for the mechanisms the virus uses to perceive, access, and infect human cells. By blocking them, the antibody effectively destroys its ability to cause illness.

However, one finding of the study points the way to an exciting possibility: that S309 can also neutralize SARS-CoV-2, the coronavirus responsible for the current outbreak, as well as other strains in its extended family.

First, the team isolated several monoclonal antibodies from the B-type lymphocytes (white blood cells) of a person who got infected and then recovered during the SARS epidemic of 2003. Although these antibodies were tailored to fight another virus, it was for one closely related to the coronavirus, making it likely that they would also interact with it.

Type B lymphocytes form some of the immune system’s ‘memory cells’. Memory cell surfaces are littered with protein receptors that bind to antigens (molecules that give away the presence of an infection) of pathogens the body has fought off in the past. Once this reaction takes place, they direct the body to start producing appropriate antibodies.

Through the use of cryo-electron microscopy studies and binding assays, the team found that the S309 antibody binds to a spike protein that is identical across many lineages of the coronavirus family. This protein is also a critical part of its ability to infect cells, so it’s very unlikely that it would suffer mutations over time. Even better, it’s identical across many coronaviruses the team investigated — meaning it could fight all of those strains.

While the S309 antibody was particularly good at this task, it wasn’t the only useful one. Other antibodies isolated from the patient could also bind to the spike protein, although not as strongly. The authors say a mix of all these antibodies would form the basis of the new treatment. This way, they can support each other’s activity and ensure the highest level of protection possible across multiple strains and in the face of any mutation of the spike proteins, however unlikely.

The treatment could be used to prevent infection in people at high risk of exposure, but it doesn’t work as a vaccine — it would offer protection only for a limited time. Alternatively, it can be applied as therapy for severe cases of COVID-19 in patients who are already infected.

The paper “Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody” has been published in the journal Nature.

James Harrison.

Australia’s ‘Man with the Golden Arm’ retires after saving 2.4 million babies — urges people to “break his record”

One Australian is taking a well-deserved retirement — after saving 2.4 million babies.

James Harrison.

James Harrison.
Image credits Australian Red Cross Blood Service / Facebook.

James Harrison, an 81-year-old Australian man whose blood contains a rare and priceless antibody has donated his last bag of plasma. Despite being a few months over the legal age limit for donors, Harrison has been allowed one final transfusion on Friday, both in recognition of his merits, and, likely, in a testament to just how valuable his blood is — Harrison’s transfusions helped save the lives of some 2.4 million babies, according to the Australian Red Cross Blood Service.

Lifeblood

The Sydney Morning Herald reports that Harrison has donated regularly for more than six decades, between the age of 18 to 81. Over the years, he donated 1,173 times, 1,163 from his right arm, and 10 from his left one.

His drive to donate has its roots in Harrison’s own medical history. At the age of 14, he had one lung removed, and required multiple transfusions. After receiving 2 gallons (7.5 liters) of blood, roughly 13 transfusion units, Harrison became aware of just how important donating is — and decided he would pitch in.

“I was in the hospital for three months and I had 100 stitches,” he recalls. “I was always looking forward to donating, right from the operation, because I don’t know how many people it took to save my life. I never met them, didn’t know them.”

After he started donating blood at the age of 18, doctors discovered that his plasma had a rare component that could save infant lives. That component is an antibody known as Rho(D) immune globulin, which is essentially priceless for doctors. Here’s why.

When a woman with Rh-negative blood is pregnant with an Rh-positive fetus, both are at risk from ‘Rh incompatibility’ — the mother’s body can have an immune reaction to and attack the infant’s blood cells, putting it at risk. The disease causes multiple miscarriages, stillbirths, and brain damage or fatal anemia in newborns.

The antibodies persist between pregnancies and can jeopardize future pregnancies as well. The first treatment for Rh incompatibility was developed in the 1960s, and it’s based entirely on this Rho(D) immune globulin. Harrison just happened to be one person who naturally produced this antibody — and his body produced a lot of it.

“Very few people have the these antibodies in such strong concentrations,” Jemma Falkenmire, of the Australian Red Cross Blood Donor Service, told the Herald. “His body produces a lot of them, and when he donates his body produces more.”

Harrison switched to donating plasma as often as the Blood Service would allow him. His donations allowed millions of Australian women to undergo the treatment they needed to keep their pregnancies healthy.

Despite significant efforts to synthesize the antibody in a lab setting, donors remain our only source of Rho(D) remains. The antibodies are most often seen in some women with Rh-incompatible pregnancies — but the more wide-spread treatment against the condition becomes, the fewer mothers get a chance to develop Rho(D). Some Rh-negative men agree to be exposed to Rh-positive blood in a bid to become donors and fill the supply gap. Finally, a small number of people develop the antibodies after accidentally receiving a transfusion of the wrong kind of blood. Harrison, one of only 200 Rho(D) donors in Australia, is likely one of the latter cases.

His dedication to donating blood, and all the lives his plasma helped save, have earned him the moniker of “Man with the Golden Arm” and a place in the Guinness Book of Records. He’s now too old to be allowed to donate further — and says it’s time for other people to step up.

“Some people say, ‘Oh, you’re a hero,’ ” he told NPR. “But I’m in a safe room, donating blood. They give me a cup of coffee and something to nibble on. And then I just go on my way. No problem, no hardship.”

“I hope it’s a record that somebody breaks,” Harrison told the Blood Service, referring to the impressive number of donations under his belt.

Rat Hippocampus.

Dormant, berserk antibodies could hold the key for HIV vaccine

A class of antibodies known to attack the body itself could prove to be the last line of defense against threats that the immune system can’t engage.

Rat Hippocampus.

Rat hippocampus stained with NeuN antibodies (unrelated to this study, green), myelin basic protein (red), and DNA (blue).
Image credits EnCor Biotechnology Inc. via GerryShaw / Wikimedia.

In a world first, researchers from Sydney’s Garvan Institute of Medical Research report that a population of ‘bad’ antibodies — which are usually inactivated, because they tend to attack the body’s tissues and cells — form a vital last line of defense against invading microbes.

Mr. Hyde

The group of antibodies is usually seen in an inactive form in the body — which prompted most researchers to consider them a relic of our immune systems, discarded and permanently decommissioned by our bodies when they outlived their usefulness. And, at least on first glance, there seems to be a very valid reason for this: the antibodies, when active, attack the body’s own tissues and can lead to autoimmune diseases.

New research shows that the antibodies’ unbridled aggression may actually be by design. The study shows that they become active when a disease overcomes the immune system’s other defenses, or when pathogens try to imitate the body’s cells to stay safe. The antibodies also go through a rapid genetic modification process upon activation, following which they no longer threaten the body. However, they do remain very good at killing pathogens that disguise themselves to look like normal body tissue.

“We once thought that harmful antibodies were discarded by the body — like a few bad apples in the barrel — and no one had any idea that you could start with a ‘bad’ antibody and make it good,” says Professor Chris Goodnow, who lead researcher.

“From these new findings, we now know that every antibody is precious when it comes to fighting invading microbes — and this new understanding means that ‘bad’ antibodies are a valuable resource for the development of vaccines for HIV, and for other diseases that go undercover in the body.”

Certain pathogens, such as Campylobacter or HIV, have evolved to appear almost identical to the body’s cell and can thus fly under the immune system’s radar. Even if detected, these adaptations ensure the viruses are protected, because our bodies systematically avoid using antibodies that are capable of binding (i.e. attacking) its own structures.

Goodnow’s previous research aimed at understanding how our immune systems recognize these threats — some 30 years ago, his search led to a group of mysterious antibodies hidden inside silenced ‘B cells’. These are the immune cells that don’t engage pathogens directly; rather, they’re more like advanced weapon factories, producing biochemical defenses and releasing them into the bloodstream. Unlike your more run of the mill B cells, however, the group his team identified produces antibodies that can pose a danger to the body — so they’re kept on standby, in a silenced state known as ‘anergy’.

Dr. Jekyl

“The big question about these cells has been why they are there at all, and in such large numbers,” Prof Goodnow says. “Why does the body keep these cells, whose antibodies pose a genuine risk to health, instead of destroying them completely, as we once thought?”

Goodnow’s new paper reports that these cells can, in fact, be re-activated to fight off threats other B cells can’t — but only after they’ve been genetically ‘re-tooled’ for the task.

Working with a preclinical mouse model, the team showed that this group of cells starts producing antibodies when they run into pathogens that appear highly similar to the body’s own cells. Before they engage, however, they go through tiny alterations in their DNA sequence — which, in turn, alter the antibodies’ behavior. This step is crucial: the new model of antibodies no longer attacks the body, but become up to 5000 times more effective in murdering the invaders, the team reports.

In the model they tested, this antibody retooling only involved three DNA changes in the genomes of the B cells. The first change prevented the compounds from binding to the body’s own cells, while the other two were solely aimed at increasing their ability to bind to the invader.

Antibody.

Schematic of an antibody’s structure.
Image credits Mamahdi14 / Wikimedia.

In experiments carried out at the Australian Synchrotron, the team showed how these three DNA changes rearrange the structure of the antibodies (which use tip-like structures to bind to other cells or pathogens) to make them better stick to invaders. One change of note they report on is that the altered antibodies’ tips fit neatly on a nanoscale ‘dimple’ that’s present on the pathogens but not the body’s cells. Another important find is that these antibodies are actually super effective: the results, Goodnow noted, show that they “can be even better than those developed through established pathways”.

It’s important to note that, being drawn from observations on mouse models, the results may not be directly translateable to human biochemistry — although it likely is, further research will be needed before we can say for sure. Regardless, the team hopes their work will pave the way to new and improved vaccines based on these B cells — particularly against pathogens such as HIV, which the rest of the immune system can’t engage.

The paper “Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination” has been published in the journal Science.

Malaria sporozoites.

Human-secreted malaria antibody could usher in an effective, long-term treatment

The discovery of a human antibody that kept the deadliest strain of malaria at bay in mice studies provides new hope that we may finally defeat the parasite.

Malaria sporozoites.

Malaria sporozoites, the infectious form of the malaria parasite.
Image credits NIAID.

Malaria ticks all the right boxes for a horrible disease. First and foremost, it’s deadly. In cases when it’s not, malaria will nonetheless inflict some pretty terrible symptoms on you — ranging from headaches to paroxysm, quite severe brain damage and even coma. It will usually spring up again weeks or months after the initial infection, and tends to keep doing that until it finally gets you. It’s also infuriating to deal with, unless you like staying on the lookout for mosquitos 24/7.

Finally, it’s just kind of gross: malaria isn’t caused by a virus or a bacterium, but by parasitic protozoans — unicellular organisms capable of animal-like behavior such as complex movement or predation. They all belong to the Plasmodium genus, and the most dangerous among them is Plasmodium falciparum.

Despite considerable efforts, there is still no 100% effective, long-term vaccine against malaria — and because of that, the disease can still reap some 430,000 lives each year, primarily youngsters in sub-Saharan Africa.

The means to an end

New research carried out by a massive collaborative effort — bringing together researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, the Fred Hutchinson Cancer Research Center in Seattle, the Johns Hopkins Bloomberg School of Public Health in Baltimore, the Seattle Biomedical Research Institute, and Sanaria Inc., Rockville, Maryland — could finally give us the tools to reliably protect ourselves even from P. falciparum.

The story begins with the blood of a volunteer that had received an experimental vaccine made from whole, but weakened, malaria parasites (called PfSPZ Vaccine-Sanaria). In what biologists probably call a Darwinsend, this volunteer’s body actually produced an antibody to clear off the impaired parasites. The patient was later exposed to infectious, malaria-carrying mosquitos (this was performed under tightly controlled lab conditions, don’t try this at home) and did not become infected — the antibodies actually worked.

Called CIS43, these antibodies were isolated from the volunteer’s blood for further mouse trials. During these trials, CIS43 proved to be highly effective in preventing malaria infection. If additional human clinical trials confirm its anti-malaria effect, the team is confident that CIS43 could form the launching pad for a new prophylactic (i.e. preventive) treatment against malaria, one that should confer resistance for several months after administration.

Malaria plasmodium.

False-colored electron micrograph showing a sporozoite of Plasmodium bergei.
Image credits Ute Frevert, Margaret Shear / Wikimedia.

Such a treatment could be a boon for tourists, health care workers, or military personnel who travel to areas where malaria is common. Should the CIS43-based compound remain effective for up to six months at a time, it could be used to virtually eliminate the disease in malaria-endemic regions as part of a larger treatment plan, alongside antimalarial drugs.

Those questions, however, will need to be answered with future research. What we know so far is that CIS43 works by binding to a specific region of a key surface protein in the parasites. This region — called an epitope — only occurs once across the whole length of the protein, and is shared across 99.8% of all known P. falciparum strains. In other words, this is a chink in the parasite’s armor. Almost all the strains have it, which means they all need to have it for some task — and if we block that spot, we prevent the protein completely from performing that function.

Researchers at the NIAID Vaccine Research Center are now planning to assess how efficient and safe the use of CIS43 is in controlled, human malaria infection trials sometime next year.

The paper “A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite” has been published in the journal Nature Medicine.

HIV budding.

Scientists tie antibody escorts on white blood cells’ access points to stop HIV dead in its tracks

Researchers have developed a new technique that could provide long-term defense, possibly even a cure, for HIV patients. The method calls for HIV-antibodies to be anchored to immune cells, creating a population of resistant cells which can then take the fight to the virus.

HIV budding.

HIV budding (spherical growth on the left) in a cultured white blood cell.
Image credits C. Goldsmith / CDC.

Scientists at the Scripps Research Institute (TSRI) may have found a way to hit HIV where it hurts it the most — by taking away the virus’ ability to infect white blood cells. The work is remarkable for its shift in the way antibodies are deployed against HIV. Instead of launching a full-body (but low density) flood of antibodies which float freely in the bloodstream, TSRI researchers led by study senior author Richard Lerner, M.D., Lita Annenberg Hazen Professor of Immunochemistry at the institute, have developed a way in which antibodies can be piggybacked directly on white cells. These active compounds will be tied to the same receptors HIV uses to enter the cells, making out immune system finally immune from the dreaded virus.

“This protection would be long term,” said Jia Xie, senior staff scientist at TSRI and first author of the study.

It comes down to something Xie calls the “neighbor effect.” As the old adage goes, one antibody in hand is worth a hundred five capillaries away. Ok, I may have taken some liberty with that but the underlying idea is that concentrating antibodies to first and foremost defend white cells allows our bodies to join in on the fight — regular treatments can’t do that, and they’re left with a lonely uphill battle against HIV. Even worse, in case HIV is flushed out of the system but the patient gets infected again, his or her immune system will be just as abysmal at fighting off the virus.

Safety first, advances second

Before tailoring the technique against HIV, the team worked with rhinovirus (the bug responsible for most common colds) as a test subject. A lentivirus was used as a vector to deliver a set of genes to a culture of human cells, instructing them to manufacture antibodies and bind these to the receptor rhinovirus ties to (ICAM-1). The rhinovirus was then unleashed upon the culture, but with no access point inside the cells it shouldn’t infect most of them, the theory goes.

That ‘most’ is exactly why they didn’t start testing off the bat with HIV. Gene delivery systems are basically dumbed down viruses with edited genomes, which have to infect cells and paste their genetic data inside the host’s genome. But no system can reach all cells, so the culture became a mix of edited (immune) and non-edited (vulnerable) cells. The point of the experiment was to see how the colony as a whole would fare.

It actually went pretty good. There was an initial shock of about two days when the majority of cells died off. Control cultures, which held only unedited cells, never recovered after the infection. Mixed cultures, however, got back to about the same numbers as prior to infection after about 125 hours — only this time, they were all descendants of the most resistant cells. In essence, the team forced the cultures to go through an evolutionary crash course in the lab dish. All the vulnerable cells were consumed in the infection and the resistant cells multiplied and passed off their anti-rhinovirus genes along.

“This is really a form of cellular vaccination,” said Lerner.

HI virion structure.

The best thing about this study is that HIV is technically a lentivirus. Nothing beats a dash of irony to go with your scientific win.
Image credits Thomas Splettstoesser.

Next, they used the same system against HIV. The team tested a number of antibodies to find one which could protect the CD4 receptor (the one HIV uses) on immune cells, copied the corresponding genes in the lentivirus, then let them loose upon the culture. And again, it worked. They further showed that these tethered antibodies worked more efficiently at blocking HIV than free-floating antibodies in another experiment led by study co-authors Devin Sok of the International AIDS Vaccine Initiative (IAVI) and TSRI Professor Dennis Burton.

TSRI now plans to collaborate with researchers at City of Hope’s Center for Gene Therapy to get early efficiency and safety testing done prior to human trials, as per federal regulations.

“We at TSRI are honored to be able to collaborate with physicians and scientists at City of Hope, whose expertise in transplantation in HIV patients should hopefully allow this therapy to be used in people,” Lerner added.

The paper “Immunochemical engineering of cell surfaces to generate virus resistance” has been published in the journal Proceedings of the National Academy of Sciences.

NIH isolates new antibody which neutralizes 98% of HIV strains in lab trials

An antibody produced by an HIV-positive patient has been found to neutralize 98 percent of all HIV strains it was pitted against, including most of those resistant to other antibodies of the same class.

Orange glass antibody. Image credits Upupa4me / Flickr.

Orange glass antibody.
Image credits Upupa4me / Flickr.

Antibodies are chemical compounds produced by the immune system to deal with pathogens such as bacteria or viruses. They function by binding to them to either neutralize or flag them for disposal by white blood cells. One of the biggest hurdles our bodies have to overcome in creating an efficient HIV antibody is the virus’ ability to rapidly adapt and overcome whatever is thrown at it. So these substances usually see a limited timeframe of efficiency against the virus, after which it morphs becoming untouchable again.

But a new antibody isolated by the US National Institutes of Health (NIH) called N6 has shown it can maintain its ability to recognize HIV even as the virus changes and breaks away from it. It is also an estimated 10 times more potent than VRC01, an antibody in the same class, which has passed to phase II clinical trials on human patients after protecting monkeys against the virus for six months.

“The discovery and characterisation of this antibody with exceptional breadth and potency against HIV provides an important new lead for the development of strategies to prevent and treat HIV infection,” said Anthony S. Fauci from the US National Institute of Allergy and Infectious Diseases.

N6 was tested on 181 different strains of HIV and destroyed 98% of the samples, including 16 out of 20 strains immune to other antibodies of its class. For comparison, VRC01 is only effective against 90% of HIV strains. N6 brings not only a wider scope but also much greater potency, the researchers report.

“Of those antibodies being considered for clinical development, there are examples of antibodies that are extremely broad but moderate in potency (e.g. 10E8 or VRC01) or extremely potent and less broad (e.g. PGT121 or PGDM1400).”

“However, the discovery of the N6 antibody demonstrates that this new VRC01-class antibody can mediate both extraordinary breadth and potency even against isolates traditionally resistant to antibodies in this class.”

One size fits all

To see what makes N6 so good at overcoming the shifting defenses of the virus, the team tracked its behavior over time as it interacted with HIV. They found the antibody targets bits of the virus which stay similar throughout different strains, not those which are prone to change — such as the V5 region. By binding to this area, N6 prevents the virus from infecting the host’s immune cells — which makes HIV-positive individuals’ defenses crumble, developing into AIDS, the acquired immune deficiency syndrome.

“N6 evolved such that its binding was relatively insensitive to the absence or loss of individual contacts typically found in the VRC01 class,” the team reports.

While there are some mutations of HIV that are resistant to N6, they rarely developed. This suggests that the virus doesn’t have as much time to react to the antibody as it has with other treatments scientists are exploring.

“The rare occurrence of N6 resistance mutations suggests that such mutations come at a relatively high fitness cost, which might represent a partial barrier to the selection of resistant mutants,” they explain.

So far, N6 has only been tested in lab settings. Until the results can be re-created in vivo on live human trials, the team recommends we remain cautiously optimistic.

Of course, these results have so far only been demonstrated in the lab, so until we see the same levels of success in actual human trials, we need to remain cautiously optimistic. However, given recent breakthroughs by UK researchers, who managed to completely flush HIV out of a patient’s system and those of a German team’s gene-snipping approach, a reliable cure for HIV/AIDS may be just around the corner.

The full paper “Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth” has been published in the journal Immunity.

Study finds that the mothers of children with autism are more than 21 times as likely to have specific Maternal Autoantibody Related antibodies in their systems

Autism is one of the biggest medical mysteries of the 21st century, and researchers are still trying to figure out the causes of this condition. UC Davis MIND Institute researchers have made a significant step forward in that direction, identifying some specific antibodies that target fetal brain proteins in the blood of women with autistic children.

autism

This finding is the first reported one that pinpoints a specific risk factor for a significant subset of autism cases, as well as a significant biomarker that can be used in early detection and diagnosis. So the thing is that researchers don’t know exactly what causes these women to have such high levels of specific antibodies, but there has been an observed correlation between this and autism in their children. There is not a proven causality between these two elements, it is just a “risk detector”, a very good indication in trying to predict whether a child will suffer or not from autism.

“Now we will be able to better determine the role of each protein in brain development,” said Van de Water, professor of internal medicine, lead author of the study. “We hope that, one day, we can tell a mother more precisely what her antibody profile means for her child, then target interventions more effectively.”

There are some indications that this condition has some similarities with autoimmune diseases:

“It is important to note that women have no control over whether or not they develop these autoantibodies, much like any other autoimmune disorder,” Van de Water said. “And, like other autoimmune disorders, we do not know what the initial trigger is that leads to their production.”

There is no “test” for autism, and this doesn’t automatically establish one, but it is the first step in this direction – and a large step at that.

“These findings are incredibly important because they establish a cause for a significant portion of autism cases, thereby opening up new lines of inquiry into possible biological treatments,” said MIND Institute Director Leonard Abbeduto. “In addition, the findings demonstrate that a diagnostic test is within reach. This test would be invaluable for women who are considering becoming pregnant and could lead to earlier and more accurate diagnosis of children with developmental challenges and help get them into behavioral interventions at younger ages.”

Full scientific article