Tag Archives: Antibodies

Antibodies against the first coronavirus strain aren’t very effective against emerging forms of the virus

Antibodies from the original strain of the virus that causes COVID-19, the one which started this pandemic, likely do not bind well to newer strains. The findings raise new concerns regarding emerging variants of the virus.

Image credits Katja Fuhlert.

Research from the University of Illinois Urbana-Champaign reports that antibodies against the original coronavirus strain aren’t that effective against some of the strains which developed later. The metastudy analyzed published studies to obtain patient data related to the sequence of antibodies they produced in response to the virus. These antibodies work by binding to, and thus neutralizing, the molecule that allows this virus to infect our cells — a particular spike protein on its surface.

While the antibodies recorded so far in patients who fought off the infection worked well against the original coronavirus strain, they’re not that effective in binding to emerging strains, the team explains. Understanding what kind of antibodies we naturally produce against a particular infection is a key step in the development of a vaccine, they add, so the results of this study could go a long way towards nipping a new pandemic in the bud.

Old dog, new tricks

“Antibody response is quite relevant to everything from understanding natural infection and how we recover from infection to vaccine design. The body has the capability to produce diverse antibody responses—it’s estimated we could make a trillion different antibodies. So when you see people are making quite similar antibodies to a particular virus, we call it convergent antibody response,” says Nicholas Wu, a professor of biochemistry at the University of Illinois, and lead author of the paper.

“That means we can design vaccines trying to elicit this kind of antibody response, and that is probably going to improve the responsiveness of more individuals to the vaccine.”

The team reports that the antibody response to the original virus was consistent among patients. Two main groups of antibodies were identified from published literature on this topic, and both bound well to the virus’ spike protein. Both were, also, quite effective in neutralizing the virus by targeting this protein. As such, our vaccines were also tailored to teach our bodies how to identify and attack the spike protein.

But the data gathered by the authors show that neither of these two groups of antibodies worked particularly well against newer variants of the virus. This has some pretty unpleasant implications for our current vaccines. As they are designed to coax our bodies into producing antibodies that attack the spike protein present on the original coronavirus, and these antibodies don’t bind very well to new strains, we have cause to question how effective current vaccines are at stopping new strains. At the same time, the results point to a particular weakness in our defense, one we could, potentially, fix through the use of vaccine boosters or a similar approach. In epidemiology, “what I don’t know can’t hurt me” is an approach that will get you killed.

“We really focused on characterizing the antibodies created in those infected with the original strain of the virus,” says graduate student Timothy Tan, the first author of the study. “Before we started the study, variants weren’t much of a problem. As they emerged, we wanted to see whether the common antibodies we identified were able to bind to newer variants.”

“Even though this antibody response is very common with the original strain, it doesn’t really interact with variants,” Wu said. “That, of course, raises the concern of the virus evolving to escape the body’s main antibody response. Some antibodies should still be effective—the body makes antibodies to many parts of the virus, not only the spike protein—but the particular groups of antibodies that we saw in this study will not be as effective.”

The team plans to extend their research to the antibody responses to the delta variant and other strains of the coronavirus. Their main objective is to see whether these strains also produce a convergent response in patients, and how the antibodies for these differ from the original strain

“We want to design vaccines and boosters, if needed, that can protect a majority of the population,” Tan said. “We expect that the antibody response to those variants would be quite different. When we have more data about the antibodies of patients who have been infected with variants, understanding the difference in the immune response is one of the directions that we would like to pursue.”

The paper “Sequence signatures of two public antibody clonotypes that bind SARS-CoV-2 receptor binding domain” has been published in the journal Nature Communications.

We finally have a vaccine that works against HIV (in early tests)

Hope against HIV, the human immunodeficiency virus, is closer than any time before. A new vaccine against this virus has shown promise in Phase 1 trials, leading to the production of efficient antibodies in 97% of participants.

Image credits Asian Development Bank / Flickr.

HIV and AIDS, the condition it causes, are undoubtedly some of the most terrifying medical diagnoses one can hear today. Not only the horrendous symptoms, but also the fact that they’re incurable, make them so. But perhaps not incurable for much longer, as new research shows a promising way forward against this deadly disease and the pathogen that causes it.

Immunity at last

“We and others postulated many years ago that in order to induce broadly neutralizing antibodies (bnAbs), you must start the process by triggering the right B cells – cells that have special properties giving them potential to develop into bnAb-secreting cells,” explained Dr William Schief, a professor and immunologist at Scripps Research and executive director of vaccine design at IAVI’s Neutralizing Antibody Center, where the vaccine was developed.

“In this trial, the targeted cells were only about one in a million of all naïve B cells. To get the right antibody response, we first need to prime the right B cells. The data from this trial affirms the ability of the vaccine immunogen to do this.”

This vaccine, the product of a collaboration between the Scripps Research institute and non-profit IAVI draws on a novel vaccination approach to help patients develop antibodies against HIV. This approach involves triggering “naive B cells” in our bodies to produce broadly neutralizing antibodies that, in turn, fight the pathogen. It is hoped that these ‘bnAbs’ can attach to proteins called spikes alongside the surface of the HIV virus. These spikes stay very similar in structure and function across different strains of the pathogen, meaning the vaccine could be broadly efficient against it.

This ability to function across strains is a major selling point of this vaccine. HIV affects over 38 million people worldwide but a cure has not yet been forthcoming because the virus has a very fast mutation rate, meaning it can adapt to our immune system and traditional treatment approaches.

The vaccine is meant to be the first in a multi-step vaccination program that aims to coax our bodies into producing a wide range of bnAbs’s, potentially helping against other viruses that have been eluding us so far, according to Europeanpharmaceuticalreview.

The Phase 1 trial included 48 healthy adults who received either a placebo or two doses of the vaccine compound along with an adjuvant developed by GlaxoSmithKline. By the end of the trial, 97% of the participants in experimental groups (i.e. that didn’t receive a placebo) had the desired type of antibody in their bloodstream.

This is the first time we’ve been successful in inducing secretion of broadly-neutralizing antibodies against HIV, the team explains, with lead investigator Dr. Julie McElrath, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division calling it “a landmark study in the HIV vaccine field”.

“This study demonstrates proof of principle for a new vaccine concept for HIV, a concept that could be applied to other pathogens as well,” says Dr Schief.

“With our many collaborators on the study team, we showed that vaccines can be designed to stimulate rare immune cells with specific properties and this targeted stimulation can be very efficient in humans. We believe this approach will be key to making an HIV vaccine and possibly important for making vaccines against other pathogens.”

Needless to say, since this was only a Phase 1 trial, we’re still a considerable way away from seeing this vaccine in a shot. However, the results do pave the way towards a Phase 2, and (hopefully) a Phase 3 for the drug. For the next step, the team is going to collaborate with biotechnology company Moderna to develop and test an mRNA-based vaccine for the same task as their current compound — if successful, this would considerably speed up the process.

Still, for now, the compound works as a proof of concept. It shows that our immune systems can be primed and prepared to face even terrifying pathogens. “This clinical trial has shown that we can drive immune responses in predictable ways to make new and better vaccines, and not just for HIV. We believe this type of vaccine engineering can be applied more broadly, bringing about a new day in vaccinology,” concludes said Dr. Dennis Burton, professor and chair of the Department of Immunology and Microbiology at Scripps Research, scientific director of the IAVI Neutralizing Antibody Center and director of the NIH Consortium for HIV/AIDS Vaccine Development.

The same approach can also be used to try and create new vaccines for other stubborn diseases like influenza, dengue, Zika, hepatitis C, and malaria, the team adds.

COVID-19 antibodies last as long as 8 months

Illustration of antibodies (red and blue) responding to an infection with the new coronavirus SARS-CoV-2 (purple). The virus emerged in Wuhan, China, in December 2019, and causes a mild respiratory illness (COVID-19) that can develop into pneumonia and be fatal in some cases.

Our current understanding of SARS-CoV-2 immunity is mainly based on previous experiences with SARS-CoV (2003) and recent studies in patients infected with and recovered from SARS-CoV-2 (2020). 

Similar to the SARS-CoV infection, the main antibody targets in SARS-CoV-2 are the spike and nucleocapsid proteins (NCP) — and this is where the vaccines also strike. However, it’s not clear if lasting immunity against the novel coronavirus can be achieved because serum antibodies seem to decline. Since this pandemic is still relatively new, we haven’t had much time to explore just how long antibodies and immunity lasts — but new results are coming in.

Two new studies published recently demonstrate that COVID-19 antibodies last as long as 8 months, or potentially even more, giving some good news for a mass vaccination campaign.

A study published in Science Immunology followed a small cohort of Australians from day 4 to day 242 after infection. All patients demonstrated the presence of memory B cells — immune cells that “remember” viral proteins and can trigger rapid production of antibodies when re-exposed to the virus — as long as 8 months after the initial infection.

Researchers took blood samples from 25 confirmed COVID-19 patients with a range of disease severities and 36 healthy control patients from March to September, evaluating each patient’s antibody status and levels of virus-specific immune cells. The study showed that by day 6 post-infection, all patients showed immunoglobulin G (IgG) antibodies for the viral receptor-binding domain (a protein on the viral surface that binds to cell receptors, allowing entry and infection) and the nucleocapsid protein. The immunoglobulin G levels began declining 20 days after symptom onset. However, memory B cell levels continued to rise up to 150 days post-infection and remained detectable 240 days post-symptom onset, suggesting that patient immune systems were primed to respond to reinfection.

According to the authors, cellular immunity could explain why there are few documented cases of reinfection with SARS-CoV-2 and why immunity can last longer than the antibody levels would suggest it.

Another study investigated antibody responses in 58 confirmed COVID-19 patients in South Korea 8 months after asymptomatic or mild SARS-CoV-2 infection.

The team used 4 commercially-available immunoassays:

Except for the anti-N IgG ELISA, all of these immunoassays have been granted Emergency Use Authorization by the US Food and Drug Administration.

For 3 of 4 immunoassays used, seropositivity rates were high (69% to 91.4%; < 0.01). These results, published in Emerging Infectious Diseases, are contradictory to both the first study’s antibody data and previous research that showed antibodies waning after 20 days, but the authors suggest that variations in immunoassay test characteristics and manufacturing may be responsible for the difference.

Increasingly, the scientific evidence seems to suggest

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.

How close are we to reaching herd immunity for the coronavirus?

There are only two ways to innoculate a population against the threat of a novel pathogen: vaccination or herd immunity. Vaccination is simply not an option for the coronavirus at the moment (nor for the next 12-18 months), so that leaves us with herd immunity — the notion that a viral infection stops spreading in a community after a sufficient proportion develops antibodies after recovering from the illness.

Credit: Pixabay.

Although no country has officially declared herd immunity an objective they’re actively pursuing as part of their COVID-19 mitigations strategies, some have flirted with this idea. For instance, Sweden has taken a much more relaxed approach compared to its Scandinavian neighbors, or the world at large for that matter. In the scientific community, this approach (along with the UK’s initial approach) has been seen been by outsiders as a sort of massive (and very dangerous) medical experiment.

While residents in most countries stayed cooped up inside under strict orders not to leave their homes unless necessary, Swedes were told to behave responsibly and far fewer restrictions were truly imposed.

Schools and cafes were allowed to stay open and gatherings of up to 50 people are still fair game. Apart from minor restrictions, the life of the average Swede hasn’t changed all that drastically — at least not in terms of restricted movement.

Unsurprisingly, infection rates skyrocketed compared to neighboring lockdown-loving countries, such as Denmark or Norway.

As of June 1, Sweden had 37,532 cases and 4,395 deaths due to COVID-19, whereas Denmark had 11,699 cases and 576 deaths, and Norway 8,446 cases and 236 deaths. Sweden has a population roughly twice that of Denmark or Norway but its number of cases per million citizens is much higher.

This approach has caused Swedish authorities to come under a lot of fire, but is the country at least close to herd immunity? Not even close, according to recent assessments.

Herd immunity is a distant dream and quite possibly a disastrous strategy to follow

When our body’s immune system is attacked by a virus, white blood cells create antibodies to fight off the invading infection. When the virus comes in contact with us a second time, this time the immune system is primed against it, eliminating the infection before we start to feel sick.

Researchers conducted seroprevalence surveys, in which they took blood samples and analyzed them for antibodies against SARS-CoV2. The samples were taken randomly across a representative sample of the population.

In Stockholm, the most densely populated region of the country, just 7.3% of the population is estimated to have antibodies to the coronavirus. Elsewhere in the country, it’s likely that a much lower proportion of the population has the antibodies.

Elsewhere, in Spain, a similar survey reported a national average of 5% with antibodies for COVID-19, with 11% for Madrid and 7% for Barcelona. In the UK, the national average for COVID-19 antibodies is 5%, although London has 17%.

Worldwide, the WHO estimates that just 3% of the population has antibodies to COVID-19, almost half a year since the outbreak first started in Wuhan, China.

In order for herd immunity to offer protection from infection to a population, at least 60% of the community would have to have the required antibodies.

Herd immunity: not a viable strategy in light of insufficient information about the coronavirus

Herd immunity hinges on two important factors: the proportion of the population that is infected and the duration of immunity.

In the case of SARS-CoV-2, the question of how long immunity lasts after recovery is still open. In April, the WHO issued a statement claiming there is “no evidence that people who have recovered from Covid-19 and have antibodies are protected from a second infection.”

But since then, research has surfaced suggesting that people do indeed form antibodies and that SARS-CoV-2 isn’t necessarily some superbug on course to rewrite immunology textbooks. One recent study on 285 people who tested positive for Covid-19 found that all of them developed antibodies within 19 days of symptom onset.

As for the question of how long immunity lasts, that’s impossible to tell at this point because the virus is still so new. We’ll have to wait at least a year for definite answers. If immunity only lasts for a few months (which is the case with influenza, for instance), that means that even the people that are immunized now might not be immunized next year, so this makes the herd immunity strategy even more far-fetched.

However, SARS-CoV-2 isn’t the only coronavirus that we know of. Exposure to MERS-CoV, which caused the Middle East respiratory syndrome (MERS) outbreak in 2002-2003, produced antibodies that were present 2-3 years post-illness, according to one study. Another 2016 study found that SARS-recovering patients had T-cells capable of fighting the virus even 11 ears post-infection.

The bad news is that coronaviruses that cause the common cold frequently reinfected previous hosts more than once over the span of a year, indicating that immunity is very short-lived. If immunity to SARS-CoV-2 is anything like that for the cold, then herd immunity won’t work. As such, any national strategy hinging on herd immunity should first wait for peer-reviewed studies that establish how long antibodies for COVID-19 stay in a person’s blood.

But even if immunity would be somewhat long-lasting, more than 57% of the global population would have to be infected, potentially resulting in millions of deaths. While we wait for a vaccine, it seems like the only viable option at this point is suppression/mitigation through constant testing, fast contact tracing as soon as new clusters are identified, and social distancing for many months to come.

A potential treatment against COVID-19 developed from llama antibodies against SARS

A llama named Winter might have given us a treatment against the coronavirus.

Stock Image via Pixabay.

A team of researchers from The University of Texas at Austin, and the National Institutes of Health and Ghent University, Belgium, report developing a potential treatment for COVID-19 by combining two antibody molecules produced by llamas. Because of the small structure of this molecule, it’s probable that it can be administered via an inhaler, allowing it to be administered directly at the site of infection.

Initial testing showed that the compound is effective at blocking the virus’ ability to infect cells in culture. Despite the encouraging results, the treatment still needs to undergo pre-clinical and clinical trials. The study is currently in a preprint format and will be published in the journal Cell on May 5th here.

No-outbreak llama

“This is one of the first antibodies known to neutralize SARS-CoV-2,” said Jason McLellan, Associate Professor of Molecular Biosciences at UT Austin and co-senior author, referring to the virus that causes COVID-19.

The research draws its roots in previous work performed by the team after the SARS and MERS outbreaks in 2016. They were investigating whether a potential vaccine could be designed against these pathogens in llamas, which they injected with stabilized spike proteins recovered from the viruses. These proteins are the biochemical mechanisms that allow the virus to infect human cells.

Llamas, and the camelid family they belong to, produce two kinds of antibodies — one that’s similar to human antibodies, and one that’s about a quarter of the size of ours. The antibodies used in this study were isolated from a llama named Winter, which was about 9 months old at the time.

The smaller antibody molecule that was effective against the SARS virus was able to bind to the SARS-CoV-2 virus, the one responsible for the COVID-19 outbreak, but only “weakly”. However, by merging two of these together, the team created the current treatment. In cell cultures, it showed great effectiveness in blocking the virus’ ability to infect cells. In essence, it chemically ties to the proteins the coronavirus uses to pass through cell membranes and doesn’t let go — so the virus can’t use those proteins any longer.

The team is now preparing for preclinical studies; if everything goes well, the treatment will enter clinical testing (on humans). Just like every other drug, it won’t be approved for use until it passes both of these steps and is deemed safe.

Vaccines against the disease understandably get a lot of attention these days, but this isn’t a vaccine — it’s a treatment. Vaccines are administered in order to train our immune systems against different viruses and start conferring natural protection one or two months after use. Treatment can be used to directly address (or prevent) infection instantly, so, if approved for use, it could be employed to treat patients who are already showing symptoms.

“Vaccines have to be given a month or two before infection to provide protection,” McLellan said. “With antibody therapies, you’re directly giving somebody the protective antibodies and so, immediately after treatment, they should be protected. The antibodies could also be used to treat somebody who is already sick to lessen the severity of the disease.”

Such a treatment would be useful for at-risk groups, such as the elderly (who also show a relatively modest response to vaccinations) and workers who have a high risk of exposure such as healthcare workers. The ability to administer this treatment via an inhaler also makes it ” potentially really interesting as a drug for a respiratory pathogen because you’re delivering it right to the site of infection,” said Daniel Wrapp, a graduate student in McLellan’s lab and co-first author of the study.

Some epileptic seizures could be triggered by autoantibodies

Epilepsy can have many origins such as a result of a brain injury or a stroke, it can be triggered by a tumor or even passed down along family lines. Now a new study published in the scientific journal Annals of Neurology by researchers at the University of Bonn has found another mechanism that might cause seizures.

Epilepsy is a disorder in which nerve cell activity in the brain is disturbed, causing seizures. (Image: Pixabay)

While it has been known that some forms of epilepsy are accompanied by inflammation of certain brain regions, the link between these inflammations and the seizures themselves hasn’t always been clear.

It is particularly dangerous when inflammatory reactions affect the hippocampus — a brain structure that plays an important role in memory processes as well as the development of emotions. This causes a condition coined limbic encephalitis, but it is still unclear exactly what processes trigger the condition. The scientists at Bonn have now found that autoantibodies are playing an important role.

Unlike normal antibodies, these autoantibodies are not directed against molecules that have entered the organism from outside, but against the body’s own structures (the prefix “auto” can be translated as “self”).

The Bonn study found these autoantibodies in the spinal fluid of epilepsy patients suffering from acute inflammation of the hippocampus. The autoantibody is directed against the protein drebrin. Drebrin ensures that the contact points (synapses) between nerve cells function correctly.

The problem with autoantibodies is that they act somewhat like a trojan horse.

Information processed in the brain is electrical, however, these synapses communicate via chemical messengers — the previously mentioned neurotransmitters. In response to an electrical pulse, the transmitter synapse emits transmitters that then dock to certain receptors of the receiver synapse, where they in turn also generate electrical pulses. The synaptic vesicles (the “packaging” of the neurotransmitters) are once again absorbed and then are recycled.

In experiments with cell cultures, the Bonn group was able to show that shortly after the addition of the autoantibody to the Petri dish, the neurons began to fire machine-gun-like rapid bursts of electrical impulses. In the human brain, this would then most likely result in an epileptic seizure.

“The autoantibody seems to use this route to sneak into the cell, as with a Trojan horse,” explains Becker’s colleague Prof. Dr. Susanne Schoch McGovern. “We know that this form of electrical excitation is contagious, so to speak. With nerve cells, which are interconnected to form a network, all the nerve cells involved suddenly start firing wildly.”

Besides learning about this new method of potential seizures, these results also give hope for new therapeutic approaches for epilepsy. As an example, active substances such as cortisone can suppress the immune system and thereby possibly also prevent the massive production of autoantibodies.

The researchers also elude that it may also be possible to intercept and incapacitate them specifically with certain drugs. However, they also believe there is still a long way to go before treatment becomes available.

Epilepsy affects both males and females of all races, and according to the Centers for Disease Control and Prevention, as of 2015, almost 40 million people globally suffered. According to a 2016 Lancet publication, the year prior resulted in 125,000 deaths from the condition, an increase from 112,000 in 1990. There are over 150,000 new cases every year and one-in-26 people in the U.S. will develop the disease at some point in their lives. Alexander the Great, Theodore Roosevelt, Napoleon Bonaparte, Neil Young, and Prince are some of the most well-known sufferers of epilepsy.

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.


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.

Nanobodies On The Road To Curing Parkinson’s Disease

Image Credits: Pixabay

study published in the journal BMC Biology by researchers from the United Kingdom, China, and Germany revealed the discovery of nanobodies akin to each other that inhibit the fibril formation of alpha-synuclein, the protein responsible for Parkinson’s Disease (PD).

Parkinson’s Disease, the degenerating movement disorder where nerve cells become impaired and die, disrupts most aspects of life for those stricken with it. The NIH describes this affliction as sporadic, progressive, and chronic. It is thought to result from genetic mutation and environmental factors.

The telltale sign indicating its presence is easily discernible: the presence of Lewy bodies in neurons. Difficulty walking, tremors, and rigidity are early symptoms. Later stages include severe cognitive decline. Presently, PD has no cure.

How PD works

Alpha-synuclein proteins form Lewy bodies then conjoin into cytotoxic oligomers, and finally, aggregate into fibrils (small fibers).

[accordion style=”info”][accordion_item title=”What are those?”]Oligomers are long chemical strands, made up monomers. Unlike plastics, which are polymers and can theoretically be any length, oligomers only contain a few monomers, i.e. they are shorter. “Cytotoxic” means these substances are toxic to life.[/accordion_item][/accordion]

They kill dopamine-producing neurons near the base of the brain, resulting in a loss of this chemical messenger molecule — among others, it handles signaling between the substantia nigra and the corpus striatum. This loss leads to neurons with abnormal firing patterns and uncoordinated movement. To illustrate the severity of this illness, most people with Parkinson’s have a noticeable absence of dopamine-producing cells in their substantia nigra. PD victims lose 60-80% of these cells.

A neuron. Image Credits: Wikipedia Commons

Scientists seeking a remedy for this immutable aberration tried a new pair of nanobodies on alpha-synuclein.  Derived from the antibodies of camels, they work remarkably in the laboratory. Their names: NBSyn2 and NBSyn87.

They exceed the abilities of previously studied antibodies and nanobodies. Whereas those took a while to cause sufficient changes to oligomer concentrations, these carry out a rapid conformational conversion. This is great news, as passive immunization using antibodies targeting alpha-synuclein has shown promise in several clinical trials.

After studying them, scientists outlined each of their strengths and shared esoteric knowledge on the nanobodies. To allude to them, NBSyn2 is better at reducing cytotoxicity, they explain, while NBSyn87 slows fibril formation to a greater degree. They break it down further, stating NBSyn2 attributes its ability to its lower positive charge and decreased interaction with the cell membrane. NBSyn87 achieves its feat by binding with a higher affinity, closer to the folding region of the alpha-synuclein protein, thereby slowing fibril formation with steric hindrance.

Lewy bodies. Image Credits: Suraj Rajan / Wikipedia Commons

Working in tandem, these nanobodies do three things: First, they prevent alpha-synuclein from aggregating into Lewy bodies; second, they hinder it from propagating in a prion-like manner; third, they destabilize cytotoxic oligomers through conformational conversion, antagonistically altering its final make-up and stopping its maturity.

Nanobodies got their name, unsurprisingly, from being miniature in size. They’re almost 10 times smaller than normal antibodies. And, being comprised of only heavy chains, they can easily cross the blood-brain barrier and bind to a variety of “hard to reach” epitopes.

[accordion style=”info”][accordion_item title=”Epitope”]An epitope is the part of a molecule to which an antibody ties — this bonding is how they ‘cure things’.[/accordion_item][/accordion]

Only 0.3% of brain synapses use dopamine; however, it has an important role to play in movement, pleasure-seeking, avoiding bad situations, and addictive behaviors, among others. Clinically, dopamine is used to dilate the renal artery and increase cardiac output. It’s in the same family of substances as epinephrine, norepinephrine, histamine, and serotonin — a family called catecholamines.

Mostly affecting those 60 years old and older, an estimated 7 to 10 million people worldwide have PD. That’s 0.09% to 0.13% globally, with the current population standing at 7.6 billion people. In 2009, the highest prevalence of this disease was in the Northeastern United States’ Amish community.

Years of research aimed at developing a quick-acting treatment for PD, using full-length antibodies and antibody fragments, targeted against different regions and different species of alpha-synuclein, led to this study. Still afoot, this undertaking is going somewhere. Now, researchers await the animal testing phase of these nanobodies with anticipation. “This find has the potential to form the basis of a new therapeutic strategy to combat PD and related protein misfolding conditions,” state researchers.

In time, other major protein misfolding diseases that these nanobodies might develop into an antidote to treat include Alzheimer’s Disease, Huntington’s disease, Creutzfeldt-Jakob disease, Cystic Fibrosis, and Gaucher’s Disease.

Research moves closer to a universal flu vaccine

Scientists from the Scripps Research Institute (TSRI) and Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen) have discovered a way to give antibodies the ability to fight a wide range of influenza subtypes. Their work has great potential to one day eliminate the need for repeated seasonal flu shots.

The team from The Scripps Research Institute and Janssen Pharmaceutical Companies designed a molecule that mimicked the shape of a key part of the influenza virus, inducing a powerful and broadly effective immune response in animal models.
Image credits to The Scripps Research Institute

The research was published online ahead of print on August 24 by the journal Science.

We need better flu vaccines

Every fall, millions of people roll up their sleeves for a flu vaccine (there’s no way a vaccine will give you the flu, find out why here), hoping to give their immune system a leg up on influenza. But the flu virus has thousands of strains that mutate and evolve across seasons, and the vaccine can’t guard against all of them.

Seasonal flu typically causes more than 200,000 hospitalizations and 36,000 deaths every year in the United States, according to the U.S. Centers for Disease Control and Prevention. While yearly flu shots provide some protection, when subtypes not covered by the vaccine do emerge, they can cause a lot of damage. This was evident in the 2009 spread of the H1N1 swine flu subtype that killed an estimated 151,700 to 575,400 people worldwide.

The team hopes to change all that by allowing antibodies to attack a wide range of flu strains. Several studies performed in the last decade by TSRI, Janssen and other institutions have shown that some patients are capable of making powerful antibodies that can fight many subtypes of influenza at once by targeting a site on the influenza virus that does not mutate rapidly. Unfortunately, these “broadly neutralizing antibodies,” or bnAbs, are rare.

Researchers searched for and found a specific protein on the surface of the influenza virus, called hemagglutinin (HA). The protein is present on all subtypes of influenza, and it underpins the viral mechanism for cell infestation. More to the point, the longer, “stem” region of the HA protein, that works to connect the virus to the cell it attacks, plays such a crucial role for influenza viruses that mutations at that site are unlikely to be successful and passed on. Janssen and TSRI tried to make a vaccine that elicits broadly neutralizing antibodies to specifically target the HA protein.

“If the body can make an immune response against the HA stem, it’s difficult for the virus to escape,” Wilson explained.

One vaccine to rule them all

The effort represents the first time scientists have been able to cut off the variable head region of HA, designing features able to stabilize the conformation of the original protein, and at the same time faithfully mimicking the key broadly neutralizing site.

In order to create antibodies that can tie to the HA stem, the researchers looked at influenza’s structure, specifically the universal recognition site (the area where the antibody ties to the virus) of the antibody CR9114 in the HA stem.

A section of a virus strain B/Brisbane/60/2008 (Victoria strain) with the CR9114, CR8071, and CR8033 binding regions (epitopes) colored according to conserved regions across all influenza B virus sequences: red is 98% conserved, orange is 75–98%, yellow is 50–75%.
Image via als.lbl.gov

The vaccine candidate was designed, produced and tested by a team of scientists led by Jaap Goudsmit, head of the Janssen Prevention Center, the paper’s first author Antonietta Impagliazzo (responsible for the design) and co-senior author Katarina Radošević. The ultimate goal was to use this synthetic version of the HA stem in a vaccine to teach the body to make powerful antibodies against influenza virus, priming it to fight off a variety of flu strains.

The scientists then studied the response of rodent and nonhuman primate models given one of several candidate immunogens. They found that animals given one especially stable immunogen produced antibodies that could bind with HAs in many influenza subtypes, even neutralizing H5N1 viruses (“bird” flu).

“This was the proof of principle,” said Wilson. “These tests showed that antibodies elicited against one influenza subtype could protect against a different subtype.”

Scientists studied the structure of the immunogen at every point in the process. Using imaging techniques such as electron microscopy (led by TSRI Associate Professor Andrew Ward and postdoctoral fellow Ryan Hoffman) and x-ray crystallography (led by Wilson and TSRI Staff Scientist Xueyong Zhu), the team showed that the most promising candidate immunogen mimicked the HA stem and that antibodies could bind with the immunogen just as they would with a real virus.

With proof that an immunogen can elicit antibodies against the stem region, Wilson said the next step in this research is to see if the immunogen can do the same in humans.

“While there is more work to be done, the ultimate goal, of course, would be to create a life-long vaccine,” Wilson said.

“This study shows that we’re moving in the right direction for a universal flu vaccine,” said Ian Wilson, Hansen Professor of Structural Biology and chair of the Department of Integrative Structural and Computational Biology at TSRI.

For more influenza vaccine articles click here.