AIDS Attack: Priming an Immune Response to Conquer HIV

By Esther Cooke, PhD

Infection with HIV remains a prominent pandemic. Last year, an estimated 36.7 million people worldwide were living with HIV, two million of which were newly infected. The HIV pandemic most stringently affects low- and middle-income countries, yet doctors in Saskatchewan, Canada are calling, in September 2016, for a state of emergency over rising HIV rates.

Since the mid-20th century, we have seen vaccination regimes harness the spread of gnarly diseases such as measles, polio, tetanus, and small pox, to name but a few. But why is there still no HIV vaccine?

When a pathogen invades a host, the immune system responds by producing antibodies that recognise and bind to a unique set of proteins on the pathogen’s surface, or “envelope”. In this way, the pathogen loses its function and is engulfed by defence cells known as macrophages. Memory B cells, a type of white blood cell, play a pivotal role in mounting a rapid attack upon re-exposure to the infectious agent. The entire process is known as adaptive immunity – a phenomenon which is exploited for vaccine development.

The cornerstone of adaptive immunity is specificity, which can also become its downfall in the face of individualistic intruders, such as HIV. HIV is an evasive target owing to its mutability and highly variable envelope patterns. Memory B cells fail to remember the distinctive, yet equally smug, faces of the HIV particles. This lack of recognition hampers a targeted attack, allowing HIV to nonchalantly dodge bullet after bullet, and maliciously nestle into its host.

For HIV and other diverse viruses, such as influenza, a successful vaccination strategy must elicit a broad immune response. This is no mean feat, but researchers at The Scripps Research Institute (TSRI), La Jolla and their collaborators are getting close.

The team have dubbed their approach to HIV vaccine design a “reductionist” strategy. Central to this strategy are broadly neutralizing antibodies (bnAb), which feature extensive mutations and can combat a wide range of virus strains and subtypes. These antibodies slowly emerge in a small proportion of HIV-infected individuals. The goal is to steer the immune system in a logical fashion, using sequential “booster” vaccinations to build a repertoire of effective bnAbs.

Having already mapped the best antibody mutations for binding to HIV, Professor Dennis Burton and colleagues at TSRI, as well as collaborators at the International AIDS Vaccine Initiative, set out to prime precursor B cells to produce the desired bnAbs. They did this using an immunogen – a foreign entity capable of inducing an immune response – that targets human germline B cells. The results were published September 8, 2016 in the journal Science.

“To evaluate complex immunogens and immunization strategies, we need iteration – that is, a good deal of trial and error. This is not possible in humans, it would take too long,” says Burton. “One answer is to use mice with human antibody systems.”

The immunogen, donated by Professor William Schief of TSRI, was previously tested in transgenic mice with an elevated frequency of bnAb precursor cells. Germline-targeting was easier than would be the case in humans. In their most recent study, the Burton lab experimented in mice with a genetically humanised immune system, developed by Kymab of Cambridge, UK. This proved hugely advantageous, enabling them to study the activation of human B cells in a more robust mouse model. Burton speaks of their success:

“It worked! We could show that the so-called germline-activating immunogen triggered the right sort of antibody response, even though the cells making that kind of response were rare in the mice.”

The precursor B cells represented less than one in 60 million of total B cells in the Kymab mice, yet almost one third of mice exposed to the immunogen produced the desired activation response. This indicates a remarkably high targeting efficiency, and provides incentive to evaluate the technique in humans. Importantly, even better immunisation outcomes are anticipated in humans due to a higher precursor cell frequency. Burton adds that clinical trials of precursor activation will most likely begin late next year. If successful, development of the so-called reductionist vaccination strategy could one day spell serious trouble for HIV, and other tricky targets alike.

The Danger of Absolutes in Science Communication

 

By Rebecca Delker, PhD

Complementarity, born out of quantum theory, is the idea that two different ways of looking at reality can both be true, although not at the same time. In other words, the opposite of a truth is not necessarily a falsehood. The most well known example of this in the physical world is light, which can be both a particle and a wave depending on how we measure it. Fundamentally, this principle allows for, and even encourages, the presence of multiple perspectives to gain knowledge.

 

This is something I found myself thinking about as I witnessed the twitter feud-turned blog post-turned actual news story (and here) centered around the factuality of physician-scientist Siddhartha Mukherjee’s essay, “Same but Different,” published recently in The New Yorker. Weaving personal stories of his mother and her identical twin sister with experimental evidence, Mukherjee presents the influence of the epigenome – the modifications overlaying the genome – in regulating gene expression. From this perspective, the genome encodes the set of all possible phenotypes, while the epigenome shrinks this set down to one. At the cellular level – where much of the evidence for the influence of epigenetic marks resides – this is demonstrated by the phenomenon that a single genome encodes for the vastly different phenotypes of cells in a multicellular organism. A neuron is different from a lymphocyte, which is different from a skin cell not because their genomes differ but because their transcriptomes (the complete set of genes expressed at any given time) differ. Epigenetic marks play a role here.

 

While many have problems with the buzzword status of epigenetics and the use of the phrase to explain away the many unknowns in biology (here, here), the central critique of Mukherjee’s essay was the extent to which he emphasized the role of epigenetic mechanisms in gene regulation over other well-characterized players, namely transcription factors – DNA binding proteins that are undeniably critical for gene expression. However, debating whether the well-studied transcription factors or the less well-established epigenetic marks are more important is no different than the classic chicken or egg scenario: impossible to assign order in a hierarchy, let alone separate from one another.

 

But whether we embrace epigenetics in all of its glory or we couch the term in quotation marks – “epigenetics” – in an attempt to dilute its impact, it is still worth pausing to dissect why a public exchange brimming with such negativity occurred in the first place.
“Humans are a strange lot,” remarked primatologist Frans de Waal. “We have the power to analyze and explore the world around us, yet panic as soon as evidence threatens to violate our expectations” (de Waal, 2016, p.113). This inclination is evident in the above debate, but it also hints at a more ubiquitous theme of the presence of bias stemming from one’s group identity. Though de Waal deals with expectations that cross species lines, even within our own species, group identity plays a powerful role in dictating relationships and guiding one’s perspective on controversial issues. Studies have shown that political identities, for example, can supplant information during decision-making. Pew Surveys reveal that views on the issue of climate change divide sharply along partisan lines. When asked whether humans are at fault for changing climate patterns, a much larger percentage of democrats (66%) than republicans (24%) answered yes; however, when asked what the main contributor of climate change is (CO2), these two groups converged (democrats: 56%, republicans: 58%; taken from Field Notes From a Catastrophe, p. 199-200). This illustrates the potential for a divide between one’s objective understanding of an issue and one’s subjective position on that issue – the latter greatly influenced by the prevailing opinion of their allied group.

 

Along with group identity is the tendency to eschew uncertainty and nuance, choosing solid footing no matter how shaky the turf, effectively demolishing the middle ground. This tendency has grown stronger in recent years, it seems, likely in response to an increase in the sheer amount of information available. This increased complexity, while important in allowing access to numerous perspectives on an issue, also triggers our innate response to minimize cost during decision-making by taking “cognitive shortcuts” and receiving cues from trusted authorities, including news outlets. This is exacerbated by the rise in the use of social media and shrinking attention spans, which quench our taste for nuance in favor of extremes. The constant awareness of one’s (online) identity in relation to that of a larger group encourages consolidation around these extremes. The result is the transformation of ideas into ideologies and the polarization of the people involved.

 

These phenomena are evident in the response to Mukherjee’s New Yorker article, but they can be spotted in many other areas of scientific discourse. This, unfortunately, is due in large part to a culture that rewards results, promotes an I-know-the-answer mentality, and encourages its members to adopt a binary vision of the world where there is a right and a wrong answer. Those who critiqued Mukherjee for placing too great an emphasis on the role of epigenetic mechanisms responded by placing the emphasis on transcription factors, trivializing the role of epigenetics. What got lost in this battle of extremes was a discussion of the complementary nature of both sets of discoveries – a discussion that would bridge, rather than divide, generations and perspectives.

 

While intra-academic squabbles are unproductive, the real danger of arguments fought in absolutes and along group identity lines lays at the interface of science and society. The world we live in is fraught with complex problems, and Science, humanity’s vessel of ingenuity, is called upon to provide clean, definitive solutions. This is an impossible task in many instances as important global challenges are not purely scientific in nature. They each contain a very deep human element. Political, historical, religious, and cultural views act as filters through which information is perceived and function to guide one’s stance on complex issues. When these issues include a scientific angle, confidence in the institution of science as an (trustworthy) authority plays a huge role.

 

One of the most divisive of such issues is that of genetically modified crops (GMOs). GMOs are crops produced by the introduction or modification of DNA sequence to incorporate a new trait or alter an existing trait. While the debate spans concerns about the safety of GMOs for human health and environmental health to economic concerns over the potential disparate benefits to large agribusiness and small farmers, these details are lost in the conversation. Instead, the debate is reduced to a binary: pro-GMO equals pro-science, anti-GMO equals anti-science. Again, the group to which one identifies, scientists included, plays a tremendous role in determining one’s stance on the issue. Polling public opinion reveals a similar pattern to that of climate change. Even though awareness of genetic engineering in crops has remained constantly low over the years, beliefs that GMOs pose a serious health hazard have increased. What’s worse, these debates treat all GMO crops the same simply because they are produced with the same methodology. While the opposition maintains a blanket disapproval of all engineered crops, the proponents don’t fare better, responding with indiscriminate approval.

 

Last month The National Academy of Sciences released a comprehensive, 420-page report addressing concerns about GMOs and presenting an analysis of two-decades of research on the subject. While the conclusions drawn largely support the idea that GMOs pose no significant danger for human and environmental health, the authors make certain to address the caveats associated with these conclusions. Though prompted by many to provide the public with “a simple, general, authoritative answer about GE (GMO) crops,” the committee refused to participate in “popular binary arguments.” As important as the scientific analysis is this element of the report, which serves to push the scientific community away from a culture of absolutes. While the evidence at hand shows no cause-and-effect relationship between GMOs and human health problems, for example, our ability to assess this is limited to short-term effects, as well as by our current ability to know what to look for and to develop assays to do so. The presence of these unknowns is a reality in all scientific research and to ignore them, especially with regard to complex societal issues, only serves to strengthen the growing mistrust of science in our community and broaden the divide between people with differing opinions. As one review of the report states, “trust is not built on sweeping decrees.”

 

GMO crops, though, is only one of many issues of this sort; climate change and vaccine safety, for example, have been similarly fraught. And, unfortunately, our world is promising to get a whole lot more complicated. With the reduced cost of high-throughput DNA sequencing and the relative ease of genome editing, it is becoming possible to modify not just crops, but farmed animals, as well as the wild flora and fauna that we share this planet with. Like the other issues discussed, these are not purely scientific problems. In fact, the rapid rate at which technology is developing creates a scenario in which the science is the easy part; understanding the consequences and the ethics of our actions yields the complications. This is exemplified by the potential use of CRISPR-driven gene drives to eradicate mosquito species that serve as vectors for devastating diseases (malaria, dengue, zika, for example). In 2015, 214 million people were affected by malaria and, of those, approximately half a million died. It is a moral imperative to address this problem, and gene drives (or other genome modification techniques) may be the best solution at this time. But, the situation is much more complex than here-today, gone-tomorrow. For starters, the rise in the prevalence of mosquito-borne diseases has its own complex portfolio, likely involving climate change and human-caused habitat destruction and deforestation. With limited understanding of the interconnectedness of ecosystems, it is challenging to predict the effects of mosquito specicide on the environment or on the rise of new vectors of human disease. And, finally, this issue raises questions of the role of humans on this planet and the ethics of modifying the world around us. The fact is that we are operating within a space replete with unknowns and the path forward is not to ignore these nuances or to approach these problems with an absolutist’s mindset. This only encourages an equal and opposite reaction in others and obliterates all hope of collective insight.

 

It is becoming ever more common for us to run away from uncertainty and nuance in search of simple truths. It is within the shelter of each of our groups and within the language of absolutes that we convince ourselves these truths can be found; but this is a misconception. Just as embracing complementarity in our understanding of the physical world can lead to greater insight, an awareness that no single approach can necessarily answer our world’s most pressing problems can actually push science and progress forward. When thinking about the relationship of science with society, gaining trust is certainly important but not the only consideration. It is also about cultivating an understanding that in the complex world in which we live there can exist multiple, mutually incompatible truths. It is our job as scientists and as citizens of the world to navigate toward, rather than away from, this terrain to gain a richer understanding of problems and thus best be able to provide a solution. Borrowing the words of physicist Frank Wilczek, “Complementarity is both a feature of physical reality and a lesson in wisdom.”

 

Extra Protection: New HPV Vaccine Extends Protection to Nine Strains of The Virus

 

By Asu Erden

The human papillomavirus (HPV) is responsible for 5% of all cancers. Until, 2006 there were no commercially available vaccines against the virus. That year, the Food and Drug Administration (FDA) approved the first preventive HPV vaccine, Gardasil (qHPV). This vaccine conveys protection against strains 6, 11, 16, and 18 of the virus and demonstrates remarkable efficacy. The Centers for Disease Control (CDC) estimates that this quadrivalent vaccine prevents 100% of genital pre-cancers and warts in previously unexposed women and 90% of genital warts and 75% of anal cancers in men. While this qHPV protects against 70% of HPV strains, there remains a number of high-risk strains such as HPV 31, 35, 39, 45, 51, 52, 58 for which we do not yet have prophylactic vaccines.

 

In February of this year, a study by an international team spanning five continents changed this state of affairs. The team led by Dr. Elmar A. Joura, Associate Professor of Gynecology and Obstetrics at the Medical University, published its study in the New England Journal of Medicine. It details a phase 2b-3 clinical study of a novel nine-valent HPV (9vHPV) vaccine that targets the four HPV strains included in Gardasil as well as strains 31, 33, 45, 52, and 58. The 9vHPV vaccine was tested side-by-side with the qHPV vaccine in an international cohort of 14, 215 women. Each participant received three doses of either vaccine, the first on day one, the second dose two months later, and the final dose six months after the first dose. Neither groups differed in their basal health or sexual behavior. This is the immunization regimen currently implemented for the Gardasil vaccine.

 

Blood samples as well as local tissue swabs were collected for analysis of antibody responses and HPV infection, respectively. They revealed the same low percentage of high-grade cervical, vulvar, or vaginal. Antibody responses against the four HPV strains included in the Gardasil vaccine were similar in both treatment groups. Of note is that participants in the 9vHPV vaccine group experienced more mild to moderate adverse events at the site of injection. Dr. Elmar A. Joura explained that these effects are due to the fact that the “[new] vaccine contains more antigen, hence more local reactions are expected. The amount of aluminium [editor’s note: the adjuvant used in the vaccine] was adapted to fit with the amount of antigen. It is the same amount of aluminium as used in the Hepatitis B vaccine.”

 

These results confirm that the novel 9vHPV vaccine raises antibody responses against HPV strains 6, 11, 16, 18 that are as efficacious as the original Gardasil vaccine. In addition, the novel vaccine also raises protection against HPV strains 31, 33, 45, 52, and 58. Importantly, the immune responses triggered by the 9vHPV vaccine are as protective against HPV disease as those raised by the qHPV vaccine.

 

Yet we are all too familiar with the contention surrounding the original qHPV vaccine. And no doubt, this new 9vHPV vaccine will reignite the debate. Those who specifically oppose the HPV vaccine question its safety and usefulness. In terms of its safety, the HPV vaccine has been tested for over a decade prior to becoming commercially available and has been proven completely safe since its introduction a decade ago. Adverse effects include muscle soreness at the site of injection, which is expected for a vaccine delivered into the muscle…

 

As for its usefulness, don’t make me drag the Surgeon General and Elmo onto the stage. The qHPV vaccine has been shown to be safe and to significantly impact HPV-related genital warts, HPV infection, and cervical complications, “as early as three years after the introduction of [the vaccine]” in terms of curtailing the transmission and public health costs of HPV infections and related cancers.   “HPV related disease and cancer is common. It pays off to get vaccinated and even more importantly to protect the children,” noted Dr Elmar A. Joura.

 

Other opponents to the HPV vaccines raise concerns regarding the use of aluminium as the adjuvant in the formulation of the vaccine. This inorganic compound is necessary to increase the immunogenicity of the vaccine and for the appropriate immune response to be raised against HPV. Common vaccines that include this adjuvant include the hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTP), Haemophilus influenzae type b, as well as pneumococcal vaccines.

 

The only question we face is that given the availability of Gardasil, why do we need a nine-valent vaccine? In order to achieve even greater levels of protection in the population at large, extending coverage to additional high-risk HPV strains is of central importance for public health. The team of international scientists that contributed to the study underlined that the 9vHPV vaccine “offers the potential to increase overall prevention of cervical cancer from approximately 70% to approximately 90%.” Thus the novel 9vHPV vaccine offers hope in bringing us even closer to achieving this epidemiological goal. “With this vaccine cervical and other HPV-related cancers could potentially get eliminated, if a good coverage could be achieved. This has not only an impact on treatment costs but also on cervical screening algorithms and long-term costs,” highlighted Dr. Elmar A Joura.

The Hunt for the Holy Grail: A Potential Vaccine against MRSA

 

By Elizabeth Ohneck, PhD

Vaccines represent the “holy grail” in prevention and treatment of infectious diseases. Effective vaccines have allowed the eradication of small pox and contributed to drastic declines in cases of diseases such as polio, measles, and pertussis (whooping cough). As bacterial pathogens become more resistant to a broader spectrum of antibiotics, the desire to develop vaccines against these offenders to prevent disease altogether heightens.

 

Staphylococcus aureus is a common cause of skin and skin structure infections (SSSIs), as well as post-surgical and wound infections. SSSIs, which frequently present as abscesses in the upper layers of skin tissue, can serve as sources of more serious infections with high mortality rates, such as pneumonia, endocarditis, and bloodstream infections, when the bacteria break through the upper layer of tissue and invade other sites of the body. With the high prevalence of methicillin-resistant S. aureus (MRSA) depleting our antibiotic arsenal, S. aureus infections have become difficult to treat, spurring intense investigation into vaccine development.

 

A group from UCLA recently developed a potential vaccine, NDV-3. This vaccine is actually based on a protein from the fungal pathogen Candida albicans, which causes diseases such as thrush and yeast infections. The C. albicans protein is similar in structure to S. aureus adhesins, proteins on the bacterial surface that allow the bacterial cell to stick to host cells. In preliminary studies, the NDV-3 vaccine was shown to be protective against both C. albicans and S. aureus. In a recent paper in PNAS, Yeaman et al. examine in detail the efficacy of this vaccine in MRSA SSSI and invasive infection.

 

To determine the efficacy of the NDV-3 vaccine in prevention of S. aureus SSSIs, the researchers vaccinated mice with NDV-3, and administered a “booster shot” 21 days later. Two weeks after the booster, the mice were infected with S. aureus by subcutaneous injection, or injection just under the skin, to induce abscess formation. Abscess progression and disease outcomes were then monitored for 2 weeks.

 

Abscess formation was slower and the final size and volume of abscesses were smaller in vaccinated mice compared to control mice. In addition, mice vaccinated with NDV-3 were able to clear S. aureus abscesses by 14 days after infection, whereas abscesses in control mice were not resolved. Using a S. aureus strain expressing luciferase, a protein that emits light, the researchers were able to watch proliferation of the bacteria within the abscesses by measuring the strength of the luciferase signal. Vaccination with NDV-3 resulted in a significantly weaker luciferase signal than in unvaccinated mice, indicating NDV-3 vaccination prevents growth of the bacterial population. This finding was supported by a decrease in the number of CFUs (colony-forming units), an estimate of the number of viable bacteria, isolated from abscesses of vaccinated versus unvaccinated mice. Importantly, the researchers conducted these experiments with 3 distinct MRSA strains and observed similar results for each. Together, these findings demonstrate that while the NDV-3 vaccine does not completely prevent SSSIs under these conditions, vaccination can significantly reduce severity.

 

As skin infections can often serve as a source for more serious disseminated infections, the researchers also examined the effect of NDV-3 on the spread of S. aureus from the original site of infection. While control mice developed small abscesses in deeper tissue layers, vaccinated mice showed little to no invasion of infection. Additionally, significantly fewer bacteria were found in the kidneys of vaccinated mice compared to control mice, indicating NDV-3 can prevent the spread of S. aureus from skin infection to more invasive sites.

 

To examine how NDV-3 was stimulating a protective effect against MRSA, the researchers measured the amount of molecules and cells important for immune response to MRSA in vaccinated and unvaccinated mice. Abscesses of vaccinated mice showed a higher density of CD3+ T-cells and neutrophils, as well increased amounts of the cytokines, or immune cell signaling molecules, IL-17A and IL-22. Vaccinated mice also showed higher amounts of antibodies against NDV-3, as well as increased production of antimicrobial peptides, small proteins with antibiotic activity produced by host cells. Thus, the NDV-3 vaccine helps encourage a strong immune response against MRSA.

 

The NDV-3 vaccine was recently tested in a phase I clinical trial and found to be safe and immunogenic (i.e., stimulates an immune response) in healthy human volunteers. While the vaccine in it’s current form doesn’t prevent S. aureus infections altogether, it could help make infections easier to treat by slowing bacterial growth, preventing spread to other tissues, and boosting the host immune defenses. Further research on this vaccine may also lead to a form that is more protective and can better prevent infections.

 

If Only Santa Would be Real…When Are We Going to Have a Universal Flu Vaccine?

 

By Jesica Levingston Mac leod, PhD

Wouldn’t it be great if the answer to that question was “next year” (yep, only a 1 month wait). Sadly, besides all the astonishing efforts of various researchers groups we are just entering the clinical studies that might lead towards a safe and effective vaccine.

Probably you already heard about the antigenic mismatch with the current vaccine (for the strain H3N2): this means that the strains used in the vaccine could potentially not completely cover one or more of the seasonal influenza virus varieties. Therefore, if you got the flu shot, you might get sick anyways.

The concept behind the universal vaccine is to bypass the antigenic mismatch problem and other issues related with the way in which the vaccines are formulated nowadays. As Drs. Natali Pica and Peter Palese explained last year (Pica et al. 2013), the vaccines are prepared year by year with the aim to protect against the virus strains that are predicted to circulate in the next period. But, and there is always a “but” in predictions, an unexpected mutation in the virus not contemplated in the vaccine production, could conclude in a pandemic.

The clue came from thinking outside of the box, and breaking with the traditional dogmas in flu vaccine production. When you get infected with the influenza virus, your immune system targets the head domain of the HA (Hemagglutinin) protein, so the current vaccine production approach was to aim for this antigen. The bad news is that this domain changes every year. The flu vaccines are based on inactivated viruses , when you receive this vaccine, you will generate antibodies to fight these specific HA proteins. In Dr. Palese’s lab they are focus on regions of influenza HA protein that are highly conserved across virus subtypes, like the stalk domain of the HA protein. Also, he is engineering different HA chimeras. This strategy has been really successful, showing protection in animal models (mice and ferrets), and the vaccines were approved to go to clinical trial next year. This universal vaccine offered good protection for pandemics H5N1 and H7N9 influenza viruses.

Another strategy, published in Nature Medicine (Sridhar et al.) reports that targeting conserved core proteins using virus-specific CD8+ T cells (lymphocytes or white blood cells with a vital role in the immune system) could provide a draft for a universal influenza vaccine. But… even the scientists implicated in the research were not very positive about how long is going to take to translate this technique to the “outside the lab” world.

The third strategy is coming from an Italian group (Vitelli et al. 2013), and this potential universal influenza vaccine is been tested in animal models by the FDA.  This vaccine uses as a vector the virus PanAd3 (it was isolated from a great ape), which carries 2 genes that express proteins conserved among a variety of influenza viruses. The 2 viral proteins, the matrix protein (M1) and the nucleoprotein (NP), could be expressed for the human cells infected with the recombinant PanAd3 virus and immunize the patient against different influenza viruses.

Other entrepreneurial ideas are blooming around the world in order to solver the “influenza virus infection” problem. The influenza virus kills around 500,000 people annually worldwide (WHO), and affects very negatively the life of other hundreds of thousands. In fact, I do not know anybody who did not got the flu at least ones, I encourage to try to find somebody who was never sick with flu symptoms. This points out how universal this problem is and therefore it should get an universal solution soon.

Why Panic Can Accelerate the Therapies Discovery

 

Jesica Levingston Mac leod, PhD

 

In March, the Center of Disease Control (CDC) reported an outbreak of a “more virulent” Ebola virus infection in Guinea and Sierra Leone .Now, the disease has been spread to Liberia and Nigeria, among other West Africa countries. The final count is more than 1600 confirmed cases of Ebola hemorrhagic fever, with almost 900 deaths caused for this syndrome. Some of these cases included health-care workers. Indeed, two medical doctors were taken back to US to be treated with a new cocktail in the Emory University Hospital facilities in Atlanta, GA. Some Americans began to panic, for example Jon Stewart said in his show that “They are importing Ebola”.

Last week, two patients with Ebola like symptoms were all over the news. One of these cases happened in the New York City Mount Sinai Hospital, and the patient was isolated and tested right away. The hospital sent an email to all the employees updating them about the situation, and the press took over it. The bright side of the situation, in addition to the negative test result for Ebola virus, was the fast reply. The dark side was the paranoia and the lack of information and knowledge about this virus from the Manhattan community. It was alarming to read that some neighbors did not want to go to the emergency room in the hospital for fear to get infected. Well, you can’t get infected just for seating next to a sick person, or talk, or shake your hands: it is not an airborne transmitted virus.

The other problem is that the symptoms are pretty similar to other more “common” diseases: Fever, rash, severe abdominal pain, vomiting, and bleeding, both internally and externally. The difference is that the fatality rate is more than 60%. The transmission of the virus mostly occurs by contact with infected blood, secretions or organs of either bats, nonhuman primates or humans. This is why you should not eat bats or monkeys if you visit any of the affected areas, or hang around any cemeteries. Not surprisingly, Ebola was named as the most frightening disease in the world. It was documented for the first time in 1976 in the Republic of Congo; one of the sources came from the Ebola River.

 

In 2012 an outbreak in Uganda found us in a similar medical emptiness: the research of two of the vaccines that were “apparently” going great had been canceled by the department of defense, due to funding constraints. Therefore, so far we do not have any vaccine or effective treatment available.

In 2009, Dr. Feldmann, by then working in Canada (now in Montana, US), developed a vaccine that was used years after in Germany when a researcher accidentally pricked her finger with a syringe containing Ebola The Feldmann’s vaccine consists in a recombinant vesicular stomatitis virus expressing the Ebola glycoprotein which protects macaques from Ebola virus infections; although this method is not licensed for human use and the government founding has been random. A similar vaccine has been produce by Profectus BioSciences in Tarrytown, New York, but they are also short in the monetary founding that will push the research to the human trials.

The famous ZMapp serum, the treatment that the 2 Americans are receiving, is a cocktail of humanized, three-monoclonal- antibodies. This “cure” was the result of the collaboration of 25 laboratories among seven countries. The project, funded by the National Institute of Allergy and Infectious Diseases (NIAID), has a total budget of $28 millions. The scientific leader is the Dr. Erica Ollmann-Shapire, whom claimed that she would take the cocktail without doubts if she would be infected. Also the company Mapp Biopharmaceutical, based in California, is the principal producer of these antibodies. The initial trials in macaques were very successful, but the approval for the use in human trial is pending until 2015.

A lot of laboratories along the world are working towards the better understanding of the Ebola virus and the possible vaccines and cures. Most of these researches are founded by the US Department of Defense. But, why does the US Department of Defense care about an African virus? The answer is pretty obvious: it can be used as a bio hazard weapon. On the other hand, no leading pharmaceutical is going to invest in a “very expensive and time consuming” vaccine development to be used in countries that can’t afford even a basic level of health care. Some compounds are showing a promising antiviral effect in vitro and/or an inhibition of a variety of viral proteins activities. Sadly, all of them are in an early stage of drug development. On the other hand,the actual need for a therapy and a vaccine to stop this outbreak is speeding the drug development process.

 

Before freaking out, the best prevention method against this scaring virus is knowledge, so check out the updates in the CDC website.

Marvelous Month of Immunology

 

By Stephanie Swift, PhD

 

Balancing modern and ancient anti-viral immunity

The human genome is stuffed full of ancient retrovirus genomes, a heritable legacy of ancestral infections. These pieces of DNA are dynamic elements, and can hop around the human genome and drive its ongoing diversification. Mostly, though, they are kept subdued by epigenetic changes that prevent them doing any damage. While identifying threatening new viral genetic material is an important job for our innate immune system, there is typically no reaction against these ancient endogenous benign retrovirus cDNAs that in modern terms are essentially a part of our own genome. Yet scientists have now implicated this evolutionary trade off between the immune system being able to sense and react against infectious DNA viruses (like retroviruses, adenoviruses, herpesviruses) while staying quiet against non-infectious ancient viral elements in certain autoimmune diseases, like Aicardi–Goutières syndrome (AGS). In AGS, mutations in the Trex1 exonuclease enzyme allow non-infectious ancient retroviral nucleic acids to accumulate and cause heart damage. They speculate that the immune system is almost inappropriately constrained against sensing these dangerous pools of foreign DNA, leading to autoimmune consequences. Happily, though, there is a potential treatment: using reverse-transcriptase inhibitors to prevent the formation of ancient retroviral immunostimulatory cDNAs in the first place. Learn more about anti-viral immunity here.

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Parasite proves proficient at immune scooping

As T cells bumble around our bodies, they are on constant stand-by to recognise pathogenic target proteins. These pieces of protein are presented to T cells for inspection by other immune cells, known as antigen-presenting cells (APCs). The T cells scoop up the pieces of protein being held up for inspection by the APC, along with a tiny bit of the APC membrance in a process known as trogocytosis. This leads to T cell activation and killing of infected target cells. Now, scientists have discovered that trogocytosis is also used by the gastrointestinal parasite, Entamoeba histolytica, to chew away at individual host cells in the gut until they die. Once that happens, the parasite moves on to the next tasty cell snack. It also appears that practise makes perfect: the parasite refines its killing skills and becomes quicker at ingesting target cells as it spreads from cell-to-cell. Now we know that trogocytosis is involved in this nasty, potentially fatal gastrointestinal disease, we can begin to design therapies that block this pathway and stop the parasite in its tracks.

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Childhood obesity linked to poor vaccine protection

Obese adults are at a greater risk of getting infected by – and dying from – influenza viruses like the pandemic H1N1. So, it’s probably very important for obese individuals to get their flu shot each year. Yet interesting research coming out of the lab of Melinda Beck at the University of North Carolina at Chapel Hill is starting to paint a rather startling picture showing that obese people don’t develop good responses to vaccines compared to healthy weight controls. Antibody levels in the blood decline more quickly over time, and T cells don’t get as robustly activated or produce the same quantity of toxic molecules designed to kill invading pathogens. Even more worryingly, these impaired vaccine responses are not just restricted to obese adults, but are seen in obese children as well. In Canada, an estimated 31.5% of children between the ages of 5-17 are overweight or obese. Since a number of serious childhood infections, including measles and whooping cough, are on the rise, obesity could be a modern risk factor contributing towards the development of serious disease, potentially even in vaccinated individuals where primed immune responses just aren’t as good at dealing with infections.

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Huge new database finds early transcriptional programs driving vaccine immunity

In recent years, scientists have made huge progress in furthering our understanding of how the immune system works, and applying this knowledge to vaccine design. Yet we are still pretty much in the dark about what makes a “good” vaccine. Are live replicating microorganisms better than dead ones? Is it better to generate an antibody or a T cell response? Are central memory or effector memory T cells better? Big data promises to help us get to the bottom of these questions, and ten thousand others just like them. By analysing huge data sets, we can begin to tease out correlations and signatures that predict if (and how) a vaccine will protect against its designated disease. Scientists at Emory University recently took the big data approach and created a hugely powerful database loaded with the molecular profiles of over 30,000 human blood transcriptomes from ~500 studies. They used this to look for a signature of protection across 5 successful human vaccines (2 against Neisseria meningitidis, 1 against yellow fever virus and 2 against influenza virus). Since their tested vaccines varied in their nature – some were conjugate vaccines made up of two distinct parts, while some were live attenuated vaccines – it was tricky to come up with a universal vaccination signature between all 5 vaccines beyond the basics of “B cell activation” or “leucocyte differentiation”. Happily, though, it was possible to see similar signatures of immunogenicity within a vaccine class. For example, vaccines that had a large carbohydrate component tended to induce stronger T cell responses, while live attenuated vaccines upregulated larger innate immunity and interferon responses. Very interestingly, they also observed that the two-part vaccines generated a dual-profile immune response established by two distinct molecular mechanisms.

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These posts were originally posted on the Stojdl lab blog.

A Marvellous Month of Infectious Science

Stephanie Swift

Cold weather helps to spread flu across the country

Credit: Michael Mistretta (Flcikr)
Credit: Michael Mistretta (Flcikr)

A very cool new study from McMaster University researchers shows how weather patterns impact the spread of influenza A virus across Canada. Using outbreak data gathered over more than 13 years, the virus could be tracked over time and space. Influenza A tended to first emerge in the colder, less humid provinces of Western Canada (British Columbia and Alberta), and then spread across the country to the East. Schools also represented hotbeds of infection – when they were shut during the Summer, there were significantly fewer cases of flu recorded.

Investigating the ‘ouch’ factor during a bacterial infection

When a bacterial infection takes hold, it’s usually a painful experience. During a normal immune response, immune cells infiltrate the infected area, pummel the invading bacteria and in doing so release molecules that cause swelling and pain. Yet new research from Harvard Medical School shows that it’s not only the immune system that is to blame: at least some of the pain comes from the bacteria themselves secreting factors that can interact directly with our nervous system.

 

The immune system’s need for speed

Credit: Éole Wind (Flickr)
Credit: Éole Wind (Flickr)

Our beautiful human bodies have several portals where nasty pathogens, such as bacteria, can enter and wreak havoc. Once inside the human body, bacteria start reproducing straight away, doubling their numbers around once every 20 minutes. Yet our immune T cells constantly patrol such vulnerable open-access areas, sampling their environment to identify threatening material. A reassuring new study has now come out showing that reactive T cells sense such foreign material within a few seconds, and make the decision to respond to malevolent threats within a speedy minute.

 

Edible vaccines, om nom nom!

Rotavirus infection is one of the major nasty causes of childhood diarrhea, but can happily be prevented with an oral vaccine. Vaccinated children in industrialized countries develop 85-98% immune protection, while those in the third world develop a much lower protection level of 50-60%. The reasons behind this startling difference are not well characterized, but third world kiddies would obviously benefit from a boost in their rotavirus immune protection.

 

Credit: Yamanaka Tamaki (Flcikr)
Credit: Yamanaka Tamaki (Flcikr)

One team has come up with a new way of administering such an immune upgrade – by loading rice, a staple food in the third world, with anti-rotavirus immune-boosting antibodies. This tasty dish could conceivably be consumed regularly during childhood to maintain protection levels.

 

 

Where’s Our Malaria Vaccine? (And Even More Bee Business)

Chris Spencer

If you’re anything like me, you might have asked yourself the question “why is it so hard to vaccinate against malaria.” We’ve got vaccines against many viral and bacterial diseases, so why not against Plasmodium? A review from EMBO reports explains why we’re in somewhat of a predicament when it comes to vaccinating people against the world’s most important tropical disease.

The first hurdle is the inherent complexity of the parasite. There are stages of malaria that live inside blood cells, stages that live in liver cells and a few morphological variants that are briefly present in serum. It could be seen as quite difficult to target the parasite when it has such myriad forms. On top of this, the surface antigens of malaria have evolved to be extremely polymorphic. This alone doesn’t account for the failure of our vaccines so far – it seems malaria has some dastardly method of immune evasion. Continue reading “Where’s Our Malaria Vaccine? (And Even More Bee Business)”

Marvelous Microbes Round-Up

Stephanie Swift

An experimental TB vaccine identifies a cool new way to boost immune protection

Researchers from Canada tested out two new inhaled vaccines against adult tuberculosis, based on adenovirus or vesicular stomatitis virus. While both vaccines generated similar levels of adaptive immunity, only the adenovirus vaccine was also able to robustly activate innate immunity. Innate immunity exists in a state of constant readiness to repel pathogenic invaders, while adaptive immunity requires stimulation, activation and expansion before it can be fully engaged. Continue reading “Marvelous Microbes Round-Up”